Patent Application
20190389841
The present invention relates to novel methods of treating triple negative breast cancer 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 including a pharmaceutically acceptable excipient.
Cancer is the second most common cause of death in the United States, exceeded only by heart disease. In the United States, cancer accounts for 1 of every 4 deaths. The 5-year relative survival rate for all cancer patients diagnosed in 1996-2003 is 66%, up from 50% in 1975-1977 (Cancer Facts & Figures American Cancer Society: Atlanta, Ga. (2008)). This improvement in survival reflects progress in diagnosing at an earlier stage and improvements in treatment. Discovering highly effective anticancer agents with low toxicity is a primary goal of cancer research.
Microtubules are cytoskeletal filaments consisting of α and β-tubulin heterodimers and are involved in a wide range of cellular functions, including shape maintenance, vesicle transport, cell motility, and division. Tubulin is the major structural component of the microtubules and a well verified target for a variety of highly successful anti-cancer drugs. Compounds that are able to interfere with microtubule-tubulin equilibrium in cells are effective in the treatment of cancers. Anticancer drugs like taxol and vinblastine that are able to interfere with microtubule-tubulin equilibrium in cells are extensively used in cancer chemotherapy. There are three major classes of antimitotic agents. Microtubule-stabilizing agents, which bind to fully formed microtubules and prevent the depolymerization of tubulin subunits, are represented by taxanes and epothilones. The other two classes of agents are microtubule-destabilizing agents, which bind to tubulin dimers and inhibit their polymerization into microtubules. Vina alkaloids such as vinblastine bind to the vinca site and represent one of these classes. Colchicine and colchicine-site binders interact at a distinct site on tubulin and define the third class of antimitotic agents.
Both the taxanes and vinca alkaloids are widely used to treat human cancers, while no colchicine-site binders are currently approved for cancer chemotherapy yet. However, colchicine binding agents like combretastatin A-4 (CA-4) and ABT-751, are now under clinical investigation as potential new chemotherapeutic agents (Luo et al., ABT-751, “A novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature,” Anticancer Drugs 2009, 20(6), 483-92; Mauer et al., “A phase II study of ABT-751 in patients with advanced non-small cell lung cancer,” J. Thorac. Oncol., 2008, 3(6), 631-6; Rustin et al., “A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer,” Br. J. Cancer, 2010, 102(9), 1355-60).
Unfortunately, microtubule-interacting anticancer drugs in clinical use share two major problems, drug resistance development and neurotoxicity. A common mechanism of drug resistance is because of multidrug resistance proteins (MDRs), namely ATP binding cassette (ABC) transporter protein-mediated drug efflux, limits the efficacy of these drugs (Green et al., “Beta-Tubulin mutations in ovarian cancer using single strand conformation analysis-risk of false positive results from paraffin embedded tissues,” Cancer Letters, 2006, 236(1), 148-54; Wang et al., “Paclitaxel resistance in cells with reduced beta-tubulin,” Biochimica et Biophysica Acta, Molecular Cell Research, 2005, 1744(2), 245-255; Leslie et al., “Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense,” Toxicology and Applied Pharmacology, 2005, 204(3), 216-237).
P-glycoproteins (P-gp protein is encoded by the MDR1 gene) are important members of the ABC superfamily. P-gp prevents the intracellular accumulation of many cancer drugs by actively effluxing drug out of cancer cells, as well as contributing to normal hepatic, renal, or intestinal clearance pathways. Attempts to co-administer P-gp modulators or inhibitors to increase cellular availability by blocking the actions of P-gp have met with limited success (Gottesman et al., “The multidrug transporter, a double-edged sword,” J. Biol. Chem., 1988, 263(25), 12163-6; Fisher et al., “Clinical studies with modulators of multidrug resistance,” Hematology/Oncology Clinics of North America, 1995, 9(2), 363-82).
The other major problem with taxanes, as with many biologically active natural products, is its lipophilicity and lack of solubility in aqueous systems. This leads to the use of emulsifiers like Cremophor EL and Tween 80 in clinical preparations. A number of biologic effects related to these drug formulation vehicles have been described, including acute hypersensitivity reactions and peripheral neuropathies (Hennenfent, et al., “Novel formulations of taxanes: a review. Old wine in a new bottle?” Ann. Oncol., 2006, 17(5), 735-49; ten Tije, et al., “Pharmacological effects of formulation vehicles: implications for cancer chemotherapy,” Clin. Pharmacokinet., 2003, 42(7), 665-85).
Compared to compounds binding the paclitaxel- or vinca alkaloid binding site, colchicine-binding agents usually exhibit relatively simple structures. Thus, providing a better opportunity for oral bioavailability via structural optimization to improve solubility and pharmacokinetic (PK) parameters. In addition, many of these drugs appear to circumvent P-gp-mediated drug resistance. Therefore, these novel colchicine binding site targeted compounds hold great promise as therapeutic agents, particularly since they have improved aqueous solubility and overcome P-gp mediated drug resistance.
Triple negative breast cancer is found in 15% of all cases of breast cancer in the United States. Triple negative breast cancer is defined as tumor that lack expression of estrogen receptor (ER), progesterone receptor (PR), and human epithermal growth factor receptor (HER-2). Triple negative breast cancer is characterized by aggressive clinical behavior and poor prognosis due to rapid resistance to many chemotherapeutic drugs and lack of suitable targets. Currently, there are no approved targeting therapies available. Classic microtubule-targeted drugs (MTDs), such as paclitaxel and its semisynthetic derivatives, have achieved considerable success in the clinical management of breast cancer neoplasms. Anthracyclines and taxanes based chemotherapy is a standard care for triple negative breast cancer. However, eventually most triple negative breast cancer patients will develop drug resistance, tumor relapse, and/or metastasis after a transient response to initial rounds of therapies. There is an urgent need to develop innovative and more effective therapeutic approaches that achieve a more durable response to triple negative breast cancer treatment.
Metastatic ovarian cancer is the most lethal gynecological malignancy in women and chemotherapy is one of the standard treatment options. Even though there are several FDA approved anti-tubulin agents, mainly taxanes, that are included in the effective management of ovarian cancer, drug resistance to taxanes often develops with resulting disease progression.
With the rising incidence of triple negative breast cancer and ovarian cancer and the high resistance to current therapeutic agents, developing more effective drugs for treating such cancers that can effectively circumvent MDR will provide significant benefits to cancer patients.
In one embodiment, the invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer in a subject by administering a therapeutically effective amount of a compound of Formula XI to the subject, wherein Formula XI is represented by:
Another embodiment of the invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer in a subject in need thereof by administering a therapeutically effective amount of a compound of Formula VIII to the subject, wherein Formula VIII is represented by the structure:
Yet another embodiment, of the invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer in a subject in need thereof by administering a therapeutically effective amount of a compound of Formula XI(b) to the subject, wherein Formula
XI(b) is represented by the structure:
wherein R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO— alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
One embodiment of the invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer in a subject in need thereof by administering a therapeutically effective amount of a compound of Formula XI(c) to the subject, wherein the compound of Formula XI(c) is represented by the structure:
Another embodiment of the invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer in a subject in need thereof by administering a compound of Formula XI(e), wherein Formula XI(e) is represented by the structure:
Yet another embodiment of the invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer in a subject in need thereof by administering to the 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 (17ya); and (2-(1H-indol-5-ylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (55).
In another embodiment, the compound of this invention is its stereoisomer, pharmaceutically acceptable salt, hydrate, N-oxide, or combinations thereof. The invention includes pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier.
The subject matter 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, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:
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.
The invention encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (I) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (I) has the formula
wherein
A and C are each independently substituted or unsubstituted single-, fused- or multiple-ring aryl or (hetero)cyclic ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocycles; substituted or unsubstituted, saturated or unsaturated S-heterocycles; substituted or unsubstituted, saturated or unsaturated O-heterocycles; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or substituted or unsubstituted, saturated or unsaturated mixed heterocycles;
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
X is a bond, NH, C1 to C5 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)—, SO2, SO or S;
wherein said A and C rings are optionally substituted by 1-5 substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer between 0-5;
l in an integer between 0-2;
wherein
if B is a benzene ring, a thiophene ring, a furan ring or an indole ring then X is not a bond or CH2, and A is not indole;
if B is indole then X is not 0; and
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The triple negative breast cancer may be taxane-resistance TNBC, taxane-sensitive TNBC, and/or metastasis.
In one embodiment, if B of formula I is a thiazole ring then X is not a bond.
In one embodiment, A in compound of Formula I is indolyl. In another embodiment A is 2-indolyl. In another embodiment A is phenyl. In another embodiment A is pyridyl. In another embodiment A is naphthyl. In another embodiment A is isoquinoline. In another embodiment, C in 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 compound of Formula I is thiazole. In another embodiment, B in compound of Formula I is thiazole; Y is CO and X is a bond. Non limiting examples of compound 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 invention also encompasses a method of treating triple negative breast cancer and/or ovarian cancer in a subject in need thereof by administering at least one compound of formula (Ia) in a therapeutically effective amount to the subject and wherein the compound of formula (Ia) has the structure
wherein
A is substituted or unsubstituted single-, fused- or multiple-ring, aryl or (hetero)cyclic ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocycles; substituted or unsubstituted, saturated or unsaturated S-heterocycles; substituted or unsubstituted, saturated or unsaturated O-heterocycles; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or substituted or unsubstituted, saturated or unsaturated mixed heterocycles;
R1, R2 and R3 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
X is a bond, NH, C1 to C5 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)—, SO2, SO or S;
wherein said A ring is optionally substituted by 1-5 substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer between 0-5;
l is an integer between 0-2;
m is an integer between 1-3;
wherein
if B is a benzene ring, a thiophene ring, a furan ring or an indole ring then X is not a bond or CH2 and A is not indole;
if B is indole then X is not 0;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, if B of formula Ia is a thiazole ring then X is not a bond.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (II) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (II) has the formula:
wherein
R1, R2, R3, R4, R5 and R6 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
X is a bond, NH, C1 to C5 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)—, SO2, SO or S;
i is an integer between 0-5;
l is an integer between 0-2;
n is an integer between 1-3; and
m is an integer between 1-3;
wherein
if B is indole then X is not O;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, if B of formula II is a thiazole ring then X is not a bond.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (III) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (III) has the formula compound of formula (III)
wherein
R4, R5 and R6 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2; and
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
X is a bond, NH, C1 to C5 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)—, SO2, SO or S;
i is an integer between 0-5;
l is an integer between 0-2; and
n is an integer between 1-3;
wherein
if B is indole then X is not 0;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, if B of formula III is a thiazole ring then X is not a bond.
The invention encompasses methods of treating triple negative breast cancer by administering at least one compound of formula (IV) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (IV) has the formula
wherein ring A is an indolyl;
R1 and R2 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
X is a bond, NH, C1 to C5 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)—, SO2, SO or S; wherein said A is optionally substituted by O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2; and
i is an integer between 0-5;
l is an integer between 0-2; and
m is an integer between 1-4;
wherein
if B is a benzene ring, a thiophene ring, a furan ring or an indole ring then X is not a bond or CH2;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, if B of formula IV is a thiazole ring then X is not a bond.
In another embodiment, the indolyl of ring A of formula IV is attached to one of its 1-7 positions to X or direct to B if X is a bond (i.e., nothing).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula IV(a) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula
IV(a) has the formula:
R2, R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2; and
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
X is a bond, NH, C1 to C5 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)—, SO2, SO or S;
i is an integer between 0-5;
l is an integer between 0-2;
n is an integer between 1-2; and
m is an integer between 1-4;
wherein
if B is a benzene ring, a thiophene ring, a furan ring or an indole ring then X is not a bond or CH2;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, if B of formula IVa is a thiazole ring then X is not a bond.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (V) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (V) has the formula:
R4, R5 and R6 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer between 1-5;
l is an integer between 0-2; and
n is an integer between 1-3;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In another embodiment, B of formula V is not a thiazole
In another embodiment, B of formula V is not an oxazole. In another embodiment, B of formula V is not an oxazoline. In another embodiment, B of formula V is not an imidazole. In another embodiment, B of formula V is not a thiazole, oxazole, oxazoline or imidazole.
Compounds encompassed by the method of the invention include the following compounds:
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (VI) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (VI) has the formula:
wherein
R4, R5 and R6 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2; 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)—, SO2, SO or S;
n is an integer between 1-3; and
i is an integer from 1-5;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention encompasses methods with the following compounds:
In one embodiment, this invention is directed to compound 3a:
In one embodiment, this invention is directed to compound 3b:
In one embodiment, this invention is directed to a compound of formula (VII)
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)—, SO2, SO or S;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, this invention is directed to the following compounds:
In one embodiment, this invention is directed to a compound of formula (VIII)
wherein
R4, R5 and R6 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer between 0-5; and
n is an integer between 1-3;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, this invention is directed to the following compounds:
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (IX) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (IX):
wherein
R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH2 or NO2;
A′ is halogen; substituted or unsubstituted single-, fused- or multiple-ring, aryl or (hetero)cyclic ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocycles; substituted or unsubstituted, saturated or unsaturated S-heterocycles; substituted or unsubstituted, saturated or unsaturated O-heterocycles; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or substituted or unsubstituted, saturated or unsaturated mixed heterocycles; wherein said A′ ring is optionally substituted by 1-5 substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer between 1-5; and
n is an integer between 1-3;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, a compound of Formula IX is represented by the structures of the following compounds:
In another embodiment A′ of formula IX is a halogen. In one embodiment A′ of formula IX is a phenyl. In another embodiment A′ of formula IX is 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-(OCH3)3. In another embodiment, A′ of formula IX is substituted or unsubstituted 5-indolyl. In another embodiment, A′ of formula IX is substituted or unsubstituted 2-indolyl. In another embodiment, A′ of formula IX is substituted or unsubstituted 3-indolyl.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (IXa) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (IXa):
wherein
R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2,
—(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH2 or NO2;
A′ is halogen; substituted or unsubstituted single-, fused- or multiple-ring, aryl or (hetero)cyclic ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocycles; substituted or unsubstituted, saturated or unsaturated S-heterocycles; substituted or unsubstituted, saturated or unsaturated O-heterocycles; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or substituted or unsubstituted, saturated or unsaturated mixed heterocycles; wherein said A′ ring is optionally substituted by 1-5 substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer between 1-5; and
n is an integer between 1-3;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In another embodiment A′ of formula IXa is a halogen. In one embodiment A′ of formula IXa is a phenyl. In another embodiment A′ of formula IXa is 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-(OCH3)3. In another embodiment, A′ of formula IXa is substituted or unsubstituted 5-indolyl. In another embodiment, A′ of formula IXa is substituted or unsubstituted 2-indolyl. In another embodiment, A′ of formula IXa is substituted or unsubstituted 3-indolyl.
In another embodiment, a compound of formula IXa is 1-chloro-7-(4-fluorophenyl)isoquinoline. In another embodiment, a compound of formula IXa is 7-(4-fluorophenyl)-1-(1H-indol-5-yl)isoquinoline. In another embodiment, a compound of formula IXa is 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)isoquinoline. In another embodiment, a compound of formula IXa is 1,7-bis(4-fluorophenyl)isoquinoline (40). In another embodiment, a compound of formula IXa is 1,7-bis(3,4,5-trimethoxyphenyl)isoquinoline. In another embodiment, a compound of formula IXa is 1-(4-fluorophenyl)-7-(3,4,5-trimethoxyphenyl)isoquinoline. In another embodiment, a compound of formula IXa is 1-(1H-indol-5-yl)-7-(3,4,5-trimethoxyphenyl)isoquinoline. In another embodiment, a compound of formula IXa is 1-chloro-7-(3,4,5-trimethoxyphenyl)isoquinoline.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XI) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XI) is represented by the structure:
wherein
X is a bond, NH or S;
A is substituted or unsubstituted single-, fused- or multiple-ring aryl or (hetero)cyclic ring systems; substituted or unsubstituted, saturated or unsaturated N-heterocycles; substituted or unsubstituted, saturated or unsaturated S-heterocycles; substituted or unsubstituted, saturated or unsaturated O-heterocycles; substituted or unsubstituted, saturated or unsaturated cyclic hydrocarbons; or substituted or unsubstituted, saturated or unsaturated mixed heterocycles; wherein said A ring is optionally substituted by 1-5 1-5 substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2; and
i is an integer from 0-5;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment if Q of Formula XI is S, then X is not a bond.
In one embodiment, A of compound of Formula XI is Ph. In another embodiment, A of 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 compound of Formula XI is S. In another embodiment, X of 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 salt (5Ha), (2-(p-tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone hydrochloride salt (5Hb), (2-(p-fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone hydrochloride salt (5Hc), (2-(4-chlorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone hydrochloride salt (5Hd), (2-(phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone hydrochloride salt (5He).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XI(a) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula XI(a) is represented by the structure:
wherein R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer from 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XI(b) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula XI(b) is represented by the structure:
wherein R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer from 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XI(c) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula
XI(c) is represented by the structure:
wherein R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer from 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XI(d) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula XI(d) is represented by the structure:
wherein R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer from 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XI(e) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula XI(e) is represented by the structure:
wherein R4 and R5 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2;
i is an integer from 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering compound 55 in a therapeutically effective amount to a subject in need thereof, wherein compound 55 is represented by the structure:
The invention also encompasses methods of treating triple negative breast cancer 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 invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of the following structures in a therapeutically effective amount to a subject in need thereof, wherein the compound is selected from the following structures:
It is well understood that in structures presented in this invention wherein the nitrogen atom has less than 3 bonds, H atoms are present to complete the valence of the nitrogen.
In one embodiment the A, A′ and/or C groups of formula I, I(a), IV, IX, IX(a) and XI are independently substituted and unsubstituted furanyl, indolyl, pyridinyl, phenyl, biphenyl, triphenyl, diphenylmethane, adamantane-yl, fluorene-yl, and other heterocyclic analogs such as, e.g., pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, isoquinolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinalolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium, benzofuranyl, benzodioxolyl, thiranyl, thietanyl, tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl, thiophene-yl, thiepinyl, thianaphthenyl, oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl).
In one embodiment, the A, A′ and/or C groups is substituted and unsubstituted phenyl. In another embodiment, the A, A′ and/or C groups is phenyl substituted by Cl, F or methyl. In one embodiment, the A, A′ and/or C groups is substituted and unsubstituted isoquinolinyl. 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.
In one embodiment, the A, A′ and/or C groups of formula I, I(a), IV, IX, IX(a) and XI can be substituted or unsubstituted. Thus, although the exemplary groups recited in the preceding paragraph are unsubstituted, it should be appreciated by those of skill in the art that these groups can be substituted by 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 by 3,4,5-trimethoxyphenyl. In another embodiment the A, A′ and/or C groups are substituted by alkoxy. In another embodiment the A, A′ and/or C groups are substituted by methoxy. In another embodiment the A, A′ and/or C groups are substituted by alkyl. In another embodiment the A, A′ and/or C groups are substituted by methyl. In another embodiment the A, A′ and/or C groups are substituted by halogen. In another embodiment, the A, A′ and/or C groups are substituted by F. In another embodiment, the A, A′ and/or C groups are substituted by Cl. In another embodiment, the A, A′ and/or C rings are substituted by Br.
The substituents of these A, A′ and/or C groups of formula I, I(a), IV, IX, IX(a) and XI are independently selected from the group of hydrogen (e.g., no substitution at a particular position), hydroxyl, an aliphatic straight- or branched-chain C1 to C10 hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo (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, aminoalkyl, alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C5 to C7 cycloalkyl, arylalkyl, and combinations thereof. Single substituents can be present at the ortho, meta, or para positions. When two or more substituents are present, one of them is preferably, though not necessarily, at the para position.
In one embodiment the B group of formula I, I(a), II, III, IV, IVa and V is selected from substituted or unsubstituted-thiazole, thiazolidine, oxazole, oxazoline, oxazolidine, benzene, pyrimidine, imidazole, pyridine, furan, thiophene, isoxazole, piperidine, pyrazole, indole and isoquinoline, wherein said B ring is linked via any two positions of the ring to X and Y or directly to the A and/or C rings.
In one embodiment the B group of formula I, I(a), II, III, IV, IVa and V is unsubstituted. In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is:
In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is substituted. In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is:
wherein R10 and R11 are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2 or NO2.
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In another embodiment the B group is
In one embodiment the B group of formula I, I(a), II, III, IV, IVa and V is substituted by R10 and R11. In another embodiment, R10 and R11 are both hydrogens. In another embodiment, R10 and R11 are independently O-alkyl. In another embodiment, R10 and R11 are independently O-haloalkyl. In another embodiment, R10 and R11 are independently F. In another embodiment, R10 and R11 are independently Cl. In another embodiment, R10 and R11 are independently Br. In another embodiment, R10 and R11 are independently I. In another embodiment, R10 and R11 are independently haloalkyl. In another embodiment, R10 and R11 are independently CF3. In another embodiment, R10 and R11 are independently CN. In another embodiment, R10 and R11 are independently —CH2CN. In another embodiment, R10 and R11 are independently NH2. In another embodiment, R10 and R11 are independently hydroxyl. In another embodiment, R10 and R11 are independently —(CH2)iNHCH3. In another embodiment, R10 and R11 are independently —(CH2)iNH2. In another embodiment, R10 and R11 are independently —(CH2)iN(CH3)2. In another embodiment, R10 and R11 are independently —OC(O)CF3. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched haloalkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkylamino. In another embodiment, R10 and R11 are independently C1-C5 linear or branched aminoalkyl. In another embodiment, R10 and R11 are independently —OCH2Ph. In another embodiment, R10 and R11 are independently —NHCO-alkyl. In another embodiment, R10 and R11 are independently COOH. In another embodiment, R10 and R11 are independently —C(O)Ph. In another embodiment, R10 and R11 are independently C(O)O-alkyl. In another embodiment, R10 and R11 are independently C(O)H. In another embodiment, R10 and R11 are independently —C(O)NH2. In another embodiment, R10 and R11 are independently NO2.
In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is
wherein R10 and R11 are independently H and 1 is 1. In another embodiment, R10 and R11 are independently O-alkyl. In another embodiment, R10 and R11 are independently O-haloalkyl. In another embodiment, R10 and R11 are independently F. In another embodiment, R10 and R11 are independently Cl. In another embodiment, R10 and R11 are independently Br. In another embodiment, R10 and R11 are independently I. In another embodiment, R10 and R11 are independently haloalkyl. In another embodiment, R10 and R11 are independently CF3. In another embodiment, R10 and R11 are independently CN. In another embodiment, R10 and R11 are independently —CH2CN. In another embodiment, R10 and R11 are independently NH2. In another embodiment, R10 and R11 are independently hydroxyl. In another embodiment, R10 and R11 are independently —(CH2)iNHCH3. In another embodiment, R10 and R11 are independently —(CH2)iNH2. In another embodiment, R10 and R11 are independently —(CH2)iN(CH3)2. In another embodiment, R10 and R11 are independently —OC(O)CF3. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched haloalkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkylamino. In another embodiment, R10 and R11 are independently C1-C5 linear or branched aminoalkyl. In another embodiment, R10 and R11 are independently —OCH2Ph. In another embodiment, R10 and R11 are independently —NHCO-alkyl. In another embodiment, R10 and R11 are independently COOH. In another embodiment, R10 and R11 are independently —C(O)Ph. In another embodiment, R10 and R11 are independently C(O)O-alkyl. In another embodiment, R10 and R11 are independently C(O)H. In another embodiment, R10 and R11 are independently —C(O)NH2. In another embodiment, R10 and R11 are independently NO2.
In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is
wherein R10 and R11 are independently H and 1 is 1. In another embodiment, R10 and R11 are independently O-alkyl. In another embodiment, R10 and R11 are independently O-haloalkyl. In another embodiment, R10 and R11 are independently F. In another embodiment, R10 and R11 are independently Cl. In another embodiment, R10 and R11 are independently Br. In another embodiment, R10 and R11 are independently I. In another embodiment, R10 and R11 are independently haloalkyl. In another embodiment, R10 and R11 are independently CF3. In another embodiment, R10 and R11 are independently CN. In another embodiment, R10 and R11 are independently —CH2CN. In another embodiment, R10 and R11 are independently NH2. In another embodiment, R10 and R11 are independently hydroxyl. In another embodiment, R10 and R11 are independently —(CH2)iNHCH3. In another embodiment, R10 and R11 are independently —(CH2)iNH2. In another embodiment, R10 and R11 are independently —(CH2)iN(CH3)2. In another embodiment, R10 and R11 are independently —OC(O)CF3. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched haloalkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkylamino. In another embodiment, R10 and R11 are independently C1-C5 linear or branched aminoalkyl. In another embodiment, R10 and R11 are independently —OCH2Ph. In another embodiment, R10 and R11 are independently —NHCO-alkyl. In another embodiment, R10 and R11 are independently COOH. In another embodiment, R10 and R11 are independently —C(O)Ph. In another embodiment, R10 and R11 are independently C(O)O-alkyl. In another embodiment, R10 and R11 are independently C(O)H. In another embodiment, R10 and R11 are independently —C(O)NH2. In another embodiment, R10 and R11 are independently NO2.
In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is
wherein R10 and R11 are independently H and 1 is 1. In another embodiment, R10 and R11 are independently O-alkyl. In another embodiment, R10 and R11 are independently O-haloalkyl. In another embodiment, R10 and R11 are independently F. In another embodiment, R10 and R11 are independently Cl. In another embodiment, R10 and R11 are independently Br. In another embodiment, R10 and R11 are independently I. In another embodiment, R10 and R11 are independently haloalkyl. In another embodiment, R10 and R11 are independently CF3. In another embodiment, R10 and R11 are independently CN. In another embodiment, R10 and R11 are independently —CH2CN. In another embodiment, R10 and R11 are independently NH2. In another embodiment, R10 and R11 are independently hydroxyl. In another embodiment, R10 and R11 are independently —(CH2)iNHCH3. In another embodiment, R10 and R11 are independently —(CH2)iNH2. In another embodiment, R10 and R11 are independently —(CH2)iN(CH3)2. In another embodiment, R10 and R11 are independently —OC(O)CF3. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched haloalkyl. In another embodiment, R10 and R11 are independently C1-C5 linear or branched alkylamino. In another embodiment, R10 and R11 are independently C1-C5 linear or branched aminoalkyl. In another embodiment, R10 and R11 are independently —OCH2Ph. In another embodiment, R10 and R11 are independently —NHCO-alkyl. In another embodiment, R10 and R11 are independently COOH. In another embodiment, R10 and R11 are independently —C(O)Ph. In another embodiment, R10 and R11 are independently C(O)O-alkyl. In another embodiment, R10 and R11 are independently C(O)H. In another embodiment, R10 and R11 are independently —C(O)NH2. In another embodiment, R10 and R11 are independently NO2.
In one embodiment, the X bridge of formula 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 C1 to C5 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 formula 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(NH2)—. 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(CH3)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 —(CH2)1-5—(C═O). In another embodiment, the Y bridge is —(C═O)—(CH2)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 —(SO2)—NH—. In another embodiment, the Y bridge is —NH—(SO2)—.
In one embodiment, R1, R2, R3, R4, R5 and R6 of formula Ia, II, III, IV, IV(a), V, VI, VIII, IX, IX(a), XI(a), XI(b), XI(c), XI(d) and XI(e) are independently hydrogen. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently O-alkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently O-haloalkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently F. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently Cl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently Br. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently I. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently haloalkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently CF3. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently CN. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —CH2CN. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently NH2. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently hydroxyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —(CH2)iNHCH3 In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —(CH2)iNH2. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —(CH2)iN(CH3)2. In another embodiment, R2, R3, R4, R5 and R6 are independently —OC(O)CF3. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently C1-C5 linear or branched alkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently haloalkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently alkylamino. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently aminoalkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —OCH2Ph. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —NHCO-alkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently COOH. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —C(O)Ph. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently C(O)O-alkyl. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently C(O)H. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently —C(O)NH2. In another embodiment, R1, R2, R3, R4, R5 and R6 are independently NO2.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XII in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula XII is represented by the structure:
wherein,
P and Q are independently H or
wherein at least one of Q or P is not hydrogen;
R1 and R4 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2; C(O)O-alkyl or C(O)H; wherein at least one of R1 and R4 is not hydrogen;
R2 and R5 are independently 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 1-4;
i is an integer between 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula XIII in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula XIII is represented by the structure:
wherein
R1 and R4 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2; COOH, C(O)O-alkyl or C(O)H; wherein at least one of R1 and R4 is not hydrogen;
R2 and R5 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 1-4;
i is an integer between 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XIV) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XIV) is represented by the structure:
wherein R1 and R4 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; wherein at least one of R1 and R4 is not hydrogen;
R2 and R5 are independently 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 1-4;
i is an integer between 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R1 of compound of formula XII, XIII and XIV is OCH3. In another embodiment, R1 of compound of formula XII, XIII and XIV is 4-F. In another embodiment, R1 of compound of formula XII, XIII and XIV is OCH3 and m is 3. In another embodiment, R4 of compound of formula XII, XIII and XIV is 4-F. In another embodiment, R4 of compound of formula XII, XIII and XIV is OCH3. In another embodiment, R4 of compound of formula XIV is CH3. In another embodiment, R4 of compound of formula XII, XIII and XIV is 4-Cl. In another embodiment, R4 of compound of formula XII, XIII and XIV is 4-N(Me)2. In another embodiment, R4 of compound of formula XII, XIII and XIV is OBn. In another embodiment, R4 of compound of formula XII, XIII and XIV is 4-Br. In another embodiment, R4 of compound of formula XII, XIII and XIV is 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), (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)(4-hydroxy-3,5-dimethoxyphenyl)methanone (12fc), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ga); (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 (121a), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XIVa) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XIVa) is represented by the structure:
wherein R1 and R4 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; wherein at least one of R1 and R4 is not hydrogen;
R2 and R5 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;
R9 is 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 substitutions are independently selected from the group of hydrogen (e.g., no substitution at a particular position), hydroxyl, an aliphatic straight- or branched-chain C1 to C10 hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo (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, aminoalkyl, alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C5 to C7 cycloalkyl, arylalkyl, and combinations thereof;
m is an integer between 1-4;
i is an integer between 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R9 of compound of formula XIVa is CH3. In another embodiment, R9 of compound of formula XIVa is CH2Ph. In another embodiment, R9 of compound of formula XIVa is (SO2)Ph. In another embodiment, R9 of compound of formula XIVa is (SO2)-Ph-OCH3. In another embodiment, R9 of compound of formula XIVa is H. In another embodiment, R4 of compound of formula XIVa is H. In another embodiment, R4 of compound of formula XIVa is CH3. In another embodiment, R4 of compound of formula XIVa is OCH3. In another embodiment, R4 of compound of formula XIVa is OH. In another embodiment, R4 of compound of formula XIVa is 4-Cl. In another embodiment, R4 of compound of formula XIVa is 4-N(Me)2. In another embodiment, R4 of compound of formula XIVa is OBn. In another embodiment, R1 of compound of formula XIVa is OCH3; m is 3 and R2 is H. In another embodiment, R1 of compound of formula XIVa is F; m is 1 and R2 is 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)(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)-1H-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-10imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12dab), (4-fluorophenyl)(2-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)methanone (12cba).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XV) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XV) is represented by the structure:
wherein R4 and R5 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 0-5; and
n is an integer between is 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R4 of compound of formula XV is H. In another embodiment, R4 of compound of formula XV is F. In another embodiment, R4 of compound of formula XV is Cl. In another embodiment, R4 of compound of formula XV is Br. In another embodiment, R4 of compound of formula XV is I. In another embodiment, R4 of compound of formula XV is N(Me)2. In another embodiment, R4 of compound of formula XV is OBn. In another embodiment, R4 of compound of formula XV is OCH3. In another embodiment, R4 of compound of formula XV is CH3. In another embodiment, R4 of compound of formula XV is 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 (12la), (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 (12pa).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XVI) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XVI) is represented by the structure:
wherein R4 and R5 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 0-5; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R3 of compound of formula XVI is halogen. In another embodiment, R3 is F. In another embodiment, R3 is Cl. In another embodiment R3 is Br. In another embodiment R3 is I. In another embodiment R4 is H. In another embodiment R4 is OCH3. In another embodiment R4 is OCH3; n is 3 and R5 is H. In another embodiment R4 is CH3. In another embodiment R4 is F. In another embodiment R4 is Cl. In another embodiment R4 is Br. In another embodiment R4 is I. In another embodiment R4 is N(Me)2. In another embodiment R4 is OBn. In another embodiment, R3 is F; R5 is hydrogen; n is 1 and R4 is 4-Cl. In another embodiment, R3 is F; R5 is hydrogen; n is 1 and R4 is 4-OCH3. In another embodiment, R3 is F; R5 is hydrogen; n is 1 and R4 is 4-CH3. In another embodiment, R3 is F; R5 is hydrogen; n is 1 and R4 is 4-N(Me)2. In another embodiment, R3 is F; R5 is hydrogen; n is 1 and R4 is 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-fluorophenyl)methanone (12gb), (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XVII) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XVII) is represented by the structure:
wherein R4 is 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 R1 and R2 are independently 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 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R4 of compound of formula XVII is halogen. In another embodiment, R4 is F. In another embodiment, R4 is Cl. In another embodiment R4 is Br. In another embodiment R4 is I. In another embodiment, R4 is OCH3. In another embodiment, R4 is CH3. In another embodiment, R4 is N(Me)2. In another embodiment, R4 is CF3. In another embodiment, R4 is OH. In another embodiment, R4 is OBn. In another embodiment, R1 of compound of formula XVII is halogen. In another embodiment, R1 of compound of formula XVII is F. In another embodiment, R1 of compound of formula XVII is Cl. In another embodiment, R1 of compound of formula XVII is Br. In another embodiment, R1 of compound of formula XVII is I. In another embodiment, R1 of compound of formula XVII is OCH3. In another embodiment, R1 of compound of formula XVII is OCH3, m is 3 and R2 is H. In another embodiment, R1 of compound of formula XVII is F, m is 1 and R2 is H. In another embodiment, R4 is F; R2 is hydrogen; n is 3 and R1 is OCH3. In another embodiment, R4 is OCH3; R2 is hydrogen; n is 3 and R1 is OCH3. In another embodiment, R4 is CH3; R2 is hydrogen; n is 3 and R1 is OCH3. In another embodiment, R4 is Cl; R2 is hydrogen; n is 3 and R1 is OCH3. In another embodiment, R4 is N(Me)2; R2 is hydrogen; n is 3 and R1 is OCH3. In one embodiment, R4 of compound of formula XVII is halogen, R1 is H and R2 is halogen. In one embodiment, R4 of compound of formula XVII is halogen, R1 is halogen and R2 is H. In one embodiment, R4 of compound of formula XVII is alkoxy, R1 is halogen and R2 is H. In one embodiment, R4 of compound of formula XVII is methoxy, R1 is halogen and R2 is 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-trimethoxyphenyl)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 (121a), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).
In another embodiment a compound of formula XVII is represented by the structure of formula 12fb:
In another embodiment a compound of formula XVII is represented by the structure of formula 12cb:
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XVIII) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XVIII) is represented by the structure:
wherein
R4 and R7 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;
R5 and R5 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 1-4;
i is an integer between 0-5; and
q is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, W of compound of formula XVIII is C═O. In another embodiment, W of compound of formula XVIII is SO2. In another embodiment, R4 of compound of formula XVIII is H. In another embodiment, R4 of compound of formula XVIII is NO2. In another embodiment, R4 of compound of formula XVIII is OBn. In another embodiment, R7 of compound of formula XVIII is H. In another embodiment, R7 of compound of formula XVIII is OCH3. In another embodiment, R7 of compound of formula XVIII is OCH3 and 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 (10j).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XIX) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XIX) is represented by the structure:
wherein
R1, R4 and R7 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;
R2, R5 and R8 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 1-4;
n is an integer between 1-4;
i is an integer between 0-5; and
q is 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R1, R4 and R7 of formula XIX are independently H. In another embodiment, R1, R4 and R7 of formula XIX are independently O-alkyl. In another embodiment, R1, R4 and R7 of formula XIX are independently halogen. In another embodiment, R1, R4 and R7 of formula XIX are independently CN. In another embodiment, R1, R4 and R7 of formula XIX are independently OH. In another embodiment, R1, R4 and R7 of formula XIX are independently alkyl. In another embodiment, R1, R4 and R7 of formula XIX are independently OCH2Ph. In one embodiment R2, R5 and R5 of formula XIX are independently H. In another embodiment, R2, R5 and R5 of formula XIX are independently O-alkyl. In another embodiment, R2, R5 and R5 of formula XIX are independently halogen. In another embodiment, R2, R5 and R5 of formula XIX are independently CN. In another embodiment, R2, R5 and R5 of formula XIX are independently OH. In another embodiment, R2, R5 and R5 of formula XIX are independently alkyl. In another embodiment, R2, R5 and R5 of formula XIX are independently OCH2Ph. In another embodiment, R5, R2 and R5 of formula XIX are H, R4 is 4-N(Me)2, R1 is OCH3, m is 3 and R7 is OCH3. In another embodiment, R5, R2, R7 and R5 of formula XIX are H, R4 is 4-Br, R1 is OCH3, and 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 (11gaa); (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)-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 (12gba).
In another embodiment a compound of formula XIX is represented by the structure of formula 11cb:
In another embodiment a compound of formula XIX is represented by the structure of formula 11fb:
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XX) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XX) is represented by the structure:
wherein
R4 is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 0-5;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R4 of compound of formula XX is H. In another embodiment, R4 of compound of formula XX is halogen. In another embodiment, R4 is F. In another embodiment, R4 is Cl. In another embodiment R4 is Br. In another embodiment R4 is I. In another embodiment, R4 is alkyl. In another embodiment, R4 is 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 (12la), (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 (121a), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).
In another embodiment a compound of formula XX is represented by the structure of formula 12da:
In another embodiment a compound of formula XX is represented by the structure of formula 12fa:
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XXI) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XXI) is represented by the structure:
wherein
A is indolyl;
R1 and R2 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 by substituted or unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, substituted or unsubstituted —SO2-aryl, substituted or unsubstituted C1-C5 linear or branched 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, NO2 or combination thereof;
i is an integer between 0-5; and
m is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer..
In one embodiment, R1 of compound of formula XXI is OCH3; m is 3 and R2 is hydrogen. In another embodiment, R1 is F; m is 1 and R2 is 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, A ring of compound of formula XXI is substituted 5-indolyl. In another embodiment the substitution is —(C═O)-Aryl. In another embodiment, the aryl is 3,4,5-(OCH3)3-Ph.
In another embodiment, A ring of compound of formula XXI is 3-indolyl. In another embodiment, A ring of compound of formula XXI is 5-indolyl. In another embodiment, A ring of 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 (15xaa); (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (16xaa); 2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya); (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (62a); and (2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XXIa) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XXIa) is represented by the structure:
wherein
A is indolyl;
R1 and R2 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, OCH2Ph, OH, CN, NO2, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;
R7 and R5 are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl, —(CH2)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 by substituted or unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, substituted or unsubstituted —SO2-aryl, substituted or unsubstituted C1-C5 linear or branched 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, NO2 or combination thereof;
i is an integer between 0-5; and
m is an integer between 1-4;
q is an integer between 1-4;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, R1 of compound of formula XXIa is OCH3; m is 3 and R2 is hydrogen. In another embodiment, R1 is F; m is 1 and R2 is hydrogen. In another embodiment, A ring of compound of formula XXIa is substituted 5-indolyl. In another embodiment, A ring of compound of formula XXIa is 3-indolyl. Non limiting examples of compounds of formula XXIa are selected from: (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (16xaa); (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa).
The invention also encompasses methods of treating triple negative breast cancer and/or ovarian cancer by administering at least one compound of formula (XXII) in a therapeutically effective amount to a subject in need thereof, wherein the compound of Formula (XXII) is represented by the structure:
wherein
A is indolyl;
wherein said A is optionally substituted by substituted or unsubstituted O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF3, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, substituted or unsubstituted —SO2-aryl, substituted or unsubstituted C1-C5 linear or branched 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, NO2 or combination thereof;
i is an integer between 0-5;
or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.
In one embodiment, A ring of compound of formula XXII is substituted 5-indolyl. In another embodiment the substitution is —(C═O)-Aryl. In another embodiment, the aryl is 3,4,5-(OCH3)3-Ph.
In another embodiment, A ring of 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 (15xaa); (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya),
In another embodiment a compound of formula XXI or XXII is represented by the structure of formula 17ya:
In one embodiment, Q of compound of formula XII is H and P is
In another embodiment, P of compound of formula XII is H and Q is
In another embodiment, P of compound of formula XII is
and Q is SO2-Ph. In one embodiment. Q of compound of formula XII is H and P is
wherein W is C═O. In another embodiment W of compound of formula XII, XVIII, XIX, or XXIa is C═O. In another embodiment, W of compound of formula XII, XVIII, XIX, or XXIa is SO2. In another embodiment, W of compound of formula XII, XVIII, XIX, or XXIa is C═S. In another embodiment, W of compound of formula XII, XVIII, XIX, or XXIa is S═O.
In one embodiment, Z of compound of formula XIII is oxygen. In another embodiment, Z of compound of formula XIII is sulfur.
In one embodiment, R5 of compound of formula XII-XVI, XVIII, or XIX is hydrogen, n is 1 and R4 is in the para position.
In one embodiment, R4 of compound of formula XII—XX is alkyl. In another embodiment, R4 of compound of formula XII—XX is H. In another embodiment, R4 of compound of formula XII—XX is methyl (CH3). In another embodiment, R4 of compound of formula XII—XX is O-alkyl. In another embodiment, R4 of compound of formula XII—XX is OCH3. In another embodiment, R4 of compound of formula XII—XX is I. In another embodiment, R4 of compound of formula XII—XX is Br. In another embodiment, R4 of compound of formula XII—XX is F. In another embodiment, R4 of compound of formula XII—XX is Cl. In another embodiment, R4 of compound of formula XII—XX is N(Me)2. In another embodiment, R4 of compound of formula XII—XX is OBn. In another embodiment, R4 of compound of formula XII—XX is OH. In another embodiment, R4 of compound of formula XII—XX is CF3.
In one embodiment, R2 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; R1 is OCH3 and m is 3. In another embodiment, R2 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R1 is in the para position. In another embodiment, R2 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R1 is I. In another embodiment, R2 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R1 is Br. In another embodiment, R2 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R1 is F. In another embodiment, R2 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R1 is Cl. In another embodiment, R1 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is I. In another embodiment, R1 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is Br. In another embodiment, R1 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is Cl. In another embodiment, R1 of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is F.
In one embodiment Q of compound of formula XII is H and P is
wherein W is C═O. Non-limiting examples of compounds of formula XII—XVII and XX-XXII are selected from (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa); (4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab); (3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac); (3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ad); (3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae); (4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af); (3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag); (2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah); (2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai); (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-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone hydrochloride (12db-HO); (4-hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12dc); (3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone (12ea); (4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone (12eb); (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 (12ga); (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-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12hb); (2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12la); (4-fluorophenyl)(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanone (12lb); (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ja); (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-(hydroxyphenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12kb); (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (121a); (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 (13fa); and 2-(3,4-dihydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone (13ha).
In one embodiment, P of compound of formula XII is
and Q is SO2-Ph. Non-limiting examples of compound of formula XII wherein P of compound of formula XII is
and Q is SO2-Ph are selected from (4-methoxyphenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11ab); (3-methoxyphenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11ac); (2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)(p-tolyl)methanone (11ah); (4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11af); (3-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11ag); (4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11cb); (1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11da); (4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone (11db); (1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (ilea); (4-fluorophenyl)(1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone (11eb); (2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11fb); (2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-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-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11hb); (1-(phenylsulfonyl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11ia); (1-(phenylsulfonyl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11ib); and (2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11jb); (2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11la); (1-(phenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11pa).
In one embodiment, R4 and R5 of compounds of formula XIII-XVI are hydrogens. Non-limiting examples of compounds of formula XIII-XVI wherein R4 and R5 are hydrogens are selected from (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa); (4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab); (3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac); (3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ad); (3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae); (4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af); (3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag); (2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah); and (2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai).
In one embodiment, P of compound of formula XII is H and Q is
In another embodiment W is C═O. In another embodiment, W of compound of formula XVIII is C═O. Non-limiting examples of compound 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 compound of formula XVIII is SO2. Non-limiting examples of compound of formula XVIII wherein W is SO2 are selected from 2-phenyl-1-(phenylsulfonyl)-1H-imidazole (10a); 2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-imidazole (10x) and 2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).
The present invention further 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, for example, a compound of formulas VIII, XI, XI(b), XI(c), XI((e) and compounds 5a, 5b, 5c, 5d, 5e, 17ya, and 55. The present invention further 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 present invention further encompasses methods of treating prostate cancer using a compound as described herein. The present invention further encompasses methods of treating taxane resistant prostate cancer using a compound as described herein. The present invention further encompasses methods of treating lung cancer using a compound as described herein. The present invention further encompasses methods of treating breast cancer using a compound as described herein. The present invention further encompasses methods of treating melanoma using a compound as described herein. The present invention further encompasses methods of treating glioma using a compound as described herein. The present invention further encompasses methods of treating colon cancer using a compound as described herein. The present invention further 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 present invention further encompasses methods of treating uterine cancer using a compound as described herein. The present invention further encompasses methods of treating pancreatic cancer using a compound as described herein. In one embodiment, the compound is a compound of formulas VIII, XI, 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 17ya. In another embodiment, the compound is compound 55.
As used herein, “single-, fused- or multiple-ring, aryl or (hetero)cyclic ring systems” can be any such ring, including but not limited to phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl, cycloalkenyl, cyclodienyl, fluorene, adamantane, etc.
“Saturated or unsaturated N-heterocycles” can be any such N-containing heterocycle, including but not limited to aza- and diaza-cycloalkyls such as aziridinyl, azetidinyl, diazatidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azocanyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinololinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, etc.
“Saturated or unsaturated O-Heterocycles” can be any such O-containing heterocycle including but not limited to oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium, benzofuranyl, benzodioxolyl, etc.
“Saturated or unsaturated S-heterocycles” can be any such S-containing heterocycle, including but not limited to thiranyl, thietanyl, tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl, thiophene-yl, thiepinyl, thianaphthenyl, etc.
“Saturated or unsaturated mixed heterocycles” can be any heterocycle containing two or more S-, N-, or O-heteroatoms, including but not limited to oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, etc.
As used herein, “aliphatic straight- or branched-chain hydrocarbon” refers to both alkylene groups that contain a single carbon and up to a defined upper limit, as well as alkenyl groups and alkynyl groups that contain two carbons up to the upper limit, whether the carbons are present in a single chain or a branched chain. Unless specifically identified, a hydrocarbon can include up to about 30 carbons, or up to about 20 hydrocarbons, or up to about 10 hydrocarbons. Alkenyl and alkynyl groups can be mono-unsaturated or polyunsaturated. In another embodiment, an alkyl includes C1-C6 carbons. In another embodiment, an alkyl includes C1-C8 carbons. In another embodiment, an alkyl includes C1-C10 carbons. In another embodiment, an alkyl is a C1-C12 carbons. In another embodiment, an alkyl is a C1-C5 carbons.
As used herein, the term “alkyl” can be any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified. In another embodiment, an alkyl includes C1-C6 carbons. In another embodiment, an alkyl includes C1-C8 carbons. In another embodiment, an alkyl includes C1-C10 carbons. In another embodiment, an alkyl is a C1-C12 carbons. In another embodiment, an alkyl is a C1-C20 carbons. In another embodiment, cyclic alkyl group has 3-8 carbons. In another embodiment, branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons.
The alkyl group can be a sole substituent or it can be a component of a larger substituent, such as in an alkoxy, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamido, acetamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methyl-urea, ethyl-urea, propyl-urea, etc.
As used herein, the term “aryl” refers to any aromatic ring that is directly bonded to another group. The aryl group can be a sole substituent, or the aryl group can be a component of a larger substituent, such as in an arylalkyl, arylamino, arylamido, etc. Exemplary aryl groups include, without limitation, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiophene-yl, pyrrolyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, etc.
As used herein, the term “aminoalkyl” refers to an amine group substituted by an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine or trialkylamine. Nonlimiting examples of aminoalkyl groups are —N(Me)2, —NHMe, —NH3.
A “haloalkyl” group refers, in another embodiment, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I. Nonlimiting examples of haloalkyl groups are CF3, CF2CF3, CH2CF3.
In one embodiment, this invention provides a compound used in this invention or its isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, or crystal or combinations thereof. In one embodiment, this invention provides an isomer of the compound of this invention. In another embodiment, this invention provides a metabolite of the compound of this invention. In another embodiment, this invention provides a pharmaceutically acceptable salt of the compound of this invention. In another embodiment, this invention provides a pharmaceutical product of the compound of this invention. In another embodiment, this invention provides a tautomer of the compound of this invention. In another embodiment, this invention provides a hydrate of the compound of this invention. In another embodiment, this invention provides an N-oxide of the compound of this invention. In another embodiment, this invention provides a polymorph of the compound of this invention. In another embodiment, this invention provides a crystal of the compound of this invention. In another embodiment, this invention provides composition comprising a compound of this invention, as described herein, or, in another embodiment, a combination of an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, or crystal of the compound of this 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 this invention are the pure (E)-isomers. In another embodiment, the compounds of this invention are the pure (Z)-isomers. In another embodiment, the compounds of this invention are a mixture of the (E) and the (Z) isomers. In one embodiment, the compounds of this invention are the pure (R)-isomers. In another embodiment, the compounds of this invention are the pure (S)-isomers. In another embodiment, the compounds of this invention are a mixture of the (R) and the (S) isomers.
The compounds of the present invention can also be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers. In another embodiment, the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure). By substantially pure, it is intended that a stereoisomer is at least about 95% pure, more preferably at least about 98% pure, most preferably at least about 99% pure.
Compounds of the present invention can also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
Compounds of the present invention may exist in the form of one or more of the possible tautomers and depending on the particular conditions it may be possible to separate some or all of the tautomers into individual and distinct entities. It is to be understood that all of the possible tautomers, including all additional enol and keto tautomers and/or isomers are hereby covered. For example, the following tautomers, but not limited to these, are included.
The invention includes “pharmaceutically acceptable salts” of the compounds of this invention, which may be produced, by reaction of a compound of this invention with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise 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, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present invention.
Suitable pharmaceutically-acceptable salts of amines of compounds the compounds of this invention may be prepared from an inorganic acid or from an organic acid. In one embodiment, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.
In one embodiment, examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates gluconates, glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, N-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilate, subacetates, tartrates, theophyllineacetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates.
In one embodiment, examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.
In another embodiment, examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benethamines (N-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines, N,N′-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.
In one embodiment, the salts 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 the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ion-exchange resin.
The compounds used in the method of the invention are synthesized according to published methods. In particular, the compounds are synthesized according to the methods described in PCT publication Nos. WO 2010/74776, published Jul. 1, 2010; WO 2011/19059, published Sep. 9, 2010; and WO 2012/027481, published Mar. 1, 2012, hereby incorporated by reference.
Another aspect of the present invention relates to a pharmaceutical composition for use in treating triple negative breast cancer and/or ovarian cancer including a pharmaceutically acceptable carrier and at least one compound described above. Typically, the pharmaceutical composition of the present invention will include a compound or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
Typically, the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and/or excipients. While individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.01 to about 100 mg/kg body wt. The preferred dosages comprise about 0.1 to about 100 mg/kg body wt. The most preferred dosages comprise about 1 to about 100 mg/kg body wt. Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any side effects.
The solid unit dosage forms can be of the conventional type. The solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch. The compounds may be tabulated with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.
The tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can 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 instance, tablets can be coated with shellac, sugar, or both. A syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
For oral therapeutic administration, the active compounds can be incorporated 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. The percentage of the compound in these compositions can, of course, be varied and can 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 will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 800 mg of active compound.
The active compounds or formulations thereof may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.
The 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 syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier 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 a surfactant and other pharmaceutically and physiologically acceptable components. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
The active compounds or formulations thereof may 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. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, 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 aerosols, the compounds or formulations thereof in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered 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 antibodies are used for diagnosis, monitoring, or treatment of cancer. In one embodiment, monoclonal antibodies react against specific antigens on cancer cells. In one embodiment, the monoclonal antibody acts as a cancer cell receptor antagonist. In one embodiment, monoclonal antibodies enhance the patient's immune response. In one embodiment, monoclonal antibodies act against cell growth factors, thus blocking cancer cell growth. In one embodiment, anti-cancer monoclonal antibodies are conjugated or linked to anti-cancer drugs, radioisotopes, other biologic response modifiers, other toxins, or a combination thereof. In one embodiment, anti-cancer monoclonal antibodies are conjugated or linked to a compound as described hereinabove.
Yet another aspect of the present invention relates to a method of treating triple negative breast cancer and/or ovarian cancer that includes selecting a subject in need of treatment 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 administering the compounds, they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer cells or precancerous cells are present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells. Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
The invention encompasses compounds and compositions for use in treating triple negative breast cancer and/or ovarian cancer. At least one compound or a composition comprising the same will have utility in inhibiting, suppressing, enhancing or stimulating a desired response in a subject, as will be understood by one skilled in the art. The compositions may further comprise additional active ingredients, whose activity is useful for the particular application for which the compound of this invention is being administered.
Drug resistance is the major cause of cancer chemotherapy failure. One major contributor to multidrug resistance is overexpression of P-glycoprotein (P-gp). This protein is a clinically important transporter protein belonging to the ATP-binding cassette family of cell membrane transporters. It can pump substrates including anticancer drugs out of tumor cells through an ATP-dependent mechanism. The TNBC may be taxane-resistant TNBC, taxane-sensitive TNBC, and/or metastasis.
The method of treating TNBC was illustrated by the in vitro studies of compound 17ya determining the anticancer activity of the compound. Compound 17ya anti-TNBC activity was compared to colchicine and paclitaxel against cell lines MDA-MB-231 and MDA-MB-468. In tests with MDA-MB-231, the IC50 (nM) was determined to be 17.46, 3.05, and 8.23 for colchicine, paclitaxel, and compound 17ya, respectively, and the SE was 0.05, 0.04, and 0.05, respectively. In tests with MDA-MB-468, the IC50 (nM) was determined to be 9.80, 4.61, and 22.96 for colchicine, paclitaxel, and compound 17ya, respectively, and the SE was 0.02, 0.03, and 0.02, respectively.
The cell apoptosis induction of compound 17ya on TNBC cells was also determined as compared against a control were 100 nM compound 17ya was studied at 24 hours, 48 hours, and 72 hours. See
The anti-cancer activity of compound 17ya was compared against paclitaxel. It was determined that compound 17ya inhibited TNBC tumor growth significantly over the control and similarly to paclitaxel treatment.
The anti-metastatic activity of compound 17ya in vivo was also studied. The activity of compound 17ya (10 mg/kg) was compared to a control and paclitaxel (10 mg/kg) in H 7 E sections from lungs.
The efficacy of compound 17ya in vitro was determined using an orthotopic ovarian cancer mouse model. Two weeks after transplantation of SKOV3 cells into the left-side ovaries in NSG female mice, the mice were treated with vehicle or compound 17ya (10 mg/kg) orally for 4 weeks (5 treatments per week). To test the activity of compound 17ya in SKOV3 and OVCAR3 cells, cell survival ability was studied by performing colony formation assay. Cell migration and invasion were examined by using a modified transwell chamber. Precoated matrigel on the transwell inserts were used to test cells invasion ability.
Treatment with compound 17ya significantly inhibited SKOV3 ovarian tumor growth and metastasis to major organs (liver and spleen) in vivo, compared with the vehicle control (Table 1). Upon treatment with compound 17ya for 2 weeks at 10 nM or 30 nM concentration, cell growth in both SKOV3 and OVCAR3 was significantly reduced. Consistent with this finding, abilities of ovarian cancer cell migration and invasion were substantially inhibited with 20 nM of compound 17ya treatment in both SKOV3 and OVCAR3 cells. The results are summarized in the following Table 1:
The test results demonstrated that orally available compound 17ya effectively inhibited tumor growth and metastasis in orthotopic ovarian cancer mouse model without acute toxicity and reduce ovarian cancer cells survival, migration and invasion abilities and concluding that compound 17ya is a tubulin inhibitor for the treatment of ovarian cancer.
In one embodiment, this invention provides methods for treating triple negative breast cancer and/or ovarian cancer comprising administering to the 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 the triple negative breast cancer.
The invention encompasses a method of treating a subject suffering from triple negative breast cancer and/or ovarian cancer comprising administering to the subject at least one compound described above, or its isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystal or any combination thereof in an amount effective to treat triple negative breast cancer in the subject. In another embodiment, the compound is compound 12db. In another embodiment, the compound is compound 11cb. In another embodiment, the compound is compound 11fb. In another embodiment, the compound is compound 12da. In another embodiment, the compound is compound 12fa. In another embodiment, the compound is compound 12fb. In another embodiment, the compound is compound 12cb. In another embodiment, the compound is compound 55. In another embodiment, the compound is compound 6b. In another embodiment, the compound is compound 17ya.
A still further aspect of the present invention relates to a method of treating or preventing a cancerous condition that includes: providing at least one compound described above and then administering an effective amount of the compound to a patient in a manner effective to treat or prevent a cancerous condition.
According to one embodiment, the patient to be treated is characterized by the presence of a precancerous condition, and the administering of the compound is effective to prevent development of the precancerous condition into the cancerous condition. This can occur by destroying the precancerous cell prior to or concurrent with its further development into a cancerous state.
According to another embodiment, the patient to be treated is characterized by the presence of a cancerous condition, and the administering of the compound is effective either to cause regression of the cancerous condition or to inhibit growth of the cancerous condition, i.e., stopping its growth altogether or reducing its rate of growth. This preferably occurs by destroying cancer cells, regardless of their location in the patient body. That is, whether the cancer cells are located at a primary tumor site or whether the cancer cells have metastasized and created secondary tumors within the patient body.
As used herein, subject or patient refers to any mammalian patient, including without limitation, 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, while the methods as described herein may be useful for treating either males or females.
When administering the compounds, they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer cells or precancerous cells are present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells. Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
The method encompasses administering at least one compound in combination with an anti-cancer agent by administering the compounds as herein described, alone or in combination with other agents.
When the compounds or pharmaceutical compositions of the present invention are administered to treat, suppress, reduce the severity, reduce the risk, or inhibit a cancerous condition, the pharmaceutical composition can also contain, or can be administered in conjunction with, other therapeutic agents or treatment regimen presently known or hereafter developed for the treatment of various types of cancer. Examples of other therapeutic agents or treatment regimen include, without limitation, radiation therapy, immunotherapy, chemotherapy, surgical intervention, and combinations thereof.
The following examples are presented to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.
The Examples set forth below are for illustrative purposes only and are not intended to limit, in any way, the scope of the present invention.
Cell culture. 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), 100 U/ml penicillin, and 100 μg/ml streptomycin (Invitrogen; Carlsbad, Calif.). Cells were cultured in 5% carbon dioxide (CO2) and 37° C. incubator.
General.
All reagents were purchased from Sigma-Aldrich Chemical Co., Fisher Scientific (Pittsburgh, Pa.), AK Scientific (Mountain View, Calif.), Oakwood Products (West Columbia, S.C.), etc. and were used without further purification. Moisture-sensitive reactions were carried under an argon atmosphere. ABT-751 was prepared according methods reported by Yoshino et al.26 Routine thin layer chromatography (TLC) was performed on aluminum backed Uniplates (Analtech, Newark, Del.). Melting points were measured with Fisher-Johns melting point apparatus (uncorrected). NMR spectra were obtained on a Bruker AX 300 (Billerica, Mass.) spectrometer or Varian Inova-500 (Vernon Hills, Ill.) spectrometer. Chemical shifts are reported as parts per million (ppm) relative to TMS in CDCl3. Mass spectral data was collected on a Bruker ESQUIRE electrospray/ion trap instrument in positive and negative ion modes. Elemental analyses were performed by Atlantic Microlab Inc.
Cell clonogenic survival assay. 350 SKOV3 or OVCAR3 cells were seeded on 6-well plates and cultured for 3 days with DMEM containing 10% FBS (i.e., growth media). On the third day of culture, the media was replaced with fresh growth media containing varying concentrations of compound 17ya ranging from 0, 1.25, 2.5, 5, 10 and 30 nM. The media was replaced every 3 days with fresh growth media containing compound 17ya until the 13th day 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. The cell migration assay was performed using a modified transwell chamber (BD FALCON, San Jose, Calif.). The chambers were inserted into 24-well cell culture plates. 3×104 SKOV3 or OVCAR3 cells with compound 17ya (20 nM) and vehicle treatment in 300 μl serum-free DMEM were added to the upper chamber. DMEM containing 10% FBS (serving as the chemoattractant) was added into the lower chamber of each well and incubated for 8 h. The medium and nonmigrated cells in the upper chamber were removed, while the migrated cells on the lower side of the membranes were fixed with methanol and stained with crystal violet. Pictures were taken at 10× magnification, and cells from at least three different fields were counted.
Cell invasion assay. SKOV3 or OVCAR3 (5×105) cells with compound 17ya (20 nM) and vehicle treatment were seeded in 300 μl serum-free DMEM onto inserts precoated with Matrigel (BD BIOCOAT using 24-well Tumor Invasion System (BD BioSciences, San Jose, Calif.). DMEM containing 10% FBS was added to the bottom chamber of the invasion system as the chemoattractant and incubated for 24 h. The medium and nonmigrated cells in the upper chamber were removed, while the migrated cells on the lower side of the membranes were fixed with methanol and stained for 5 min with hematoxylin and eosin. Pictures were taken at 10× magnification. Invaded cells were counted in at least three different fields.
Orthotopic ovarian cancer mouse model. 5×105 SKOV3 cells labeled with a lentiviral vector expressing luciferase (pLenti-UBC-Luc2-T2A-mKate) were intrabursally injected into 10 two-month old NOD.Cg-Prkdcscid Il2rgtmlWjl/SzJ severely immunocompromised female mice (NSG). Two weeks after transplantation of SKOV3 cells into the left-side ovaries in NSG female mice, the mice were treated with vehicle or compound 17ya (10 mg/kg) orally for 4 weeks (5 treatments per week). Five mice were used for each group. Tumor initiation and metastasis were monitored once a week using a Xenogen imaging system. All mice were sacrificed at two months; the ovaries and metastasized organs were harvested and imaged using Xenogen imaging system; the tumors were weighed and tissues were processed for H&E staining.
The treatment with compound 17ya inhibited ovarian cancer cell survival. To test the effect of compound 17ya on ovarian cancer cells, cell survival was examined by assaying 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 of: 0, 1.25, 2.5, 5, 10 and 30 nM. On the 13th day, the colonies were stained with crystal violet. Compound 17ya significantly inhibited cell survival in both SKOV3 and OVCAR3 cells as illustrated in
Treatment with compound 17ya inhibited ovarian cancer cells migration and invasion. Using transwell plates, cell migration was tested against compound 17ya and vehicle treatment cells. It was found that cell migration was significantly reduced in both SKOV3 and OVCAR3 cells with compound 17ya as illustrated in
Compound 17ya inhibited ovarian tumor growth and metastasis in vivo. An orthotopic ovarian cancer mouse model was established. 5×105 Wildtype SKOV3-Luc2 cells were intrabursally injected into 2 month old NSG female mice and mice were treated five days a week for 4 weeks. Tumors were collected and imaged using Xenogen system. SKOV3 cells transduced with a lentiviral luciferase vector were injected into the left-side ovaries in two-month NSG mice, the mice were treated with vehicle or compound 17ya (10 mg/kg) for 4 weeks. Treatment with compound 17ya significantly inhibited SKOV3 ovarian tumor growth as illustrated in
Materials and Methods
Chemical compounds and cell lines. Colchicine was purchased from Sigma (St. Louse, Mo.). Paclitaxel was purchased from LC Laboratories (Woburn, Mass.). Compound 17ya was synthesized as described (Chen et al., “Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogues targeting tubulin polymerization as antiproliferative agents.” J. Med. Chem., 2012, 55. 7285-7289.), with purity (>98%) and identity verified by HPLC, HR-MS (Waters, Milford, Mass.) and proton nuclear magnetic resonance (Bruker, Billerica, Mass.). Two human triple negative breast cancer (TNBC) cell lines were used in this study: MDA-MB-231 and MDA-MB-468 purchased from ATCC (Manassas, Va.) and authenticated prior to use for this study. These cells were cultured in DMEM medium (Mediatech, Inc., Manassas, Va.) supplemented with 10% fetal bovine serum (Atlanta Biologicals, Lawrenceville, Ga.) and 1% antibiotic-antimycotic Solution (Sigma-Aldrich, St. Louis, Mo.) at 37° C. in a humidified atmosphere containing 5% CO2.
Cell viability assay. The anti-proliferative effect of compound 17ya was investigated in human melanoma (A375 and M14), human HER2-positive breast (MDA-MB-453 and SKBR3) and TNBC (MDA-MB-231 and MDA-MB-468) cancer cell lines using routine MTS assay as described by Li et al., “A Potent, Metabolically Stable Tubulin Inhibitor Targets Colchicine Binding Site and Overcomes Taxane Resistance,” Cancer Res., 2018, 78, 265-277. IC50 (50% of cell growth inhibition) values were calculated by GraphPad Prism 7 software using nonlinear regression.
Colony formation assay. MDA-MB-231 or MDA-MB-468 cells were seeded into 12-well plates with cell density of 200 cells/well and incubated for 24 h. Cells were then treated with colchicine, paclitaxel and Compound 17ya at different concentrations. The medium of each group was renewed once a week. After culture for 7 days (MDA-MB-231) and 14 days (MDA-MB-468), the cells were washed with PBS, fixed with methanol and stained with 0.5% crystal violet. The morphology of colonies was captured under a microscope and colony area was quantified using ImageJ software (NIH, Bethesda, Md.). The drug treatment was performed in triplicate.
Caspase 3/7 activity assay. Apoptosis induced by compound 17ya was measured using 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 Studies of Novel Surviving Inhibitors with Potent Anti-Proliferative Properties,” PLoS One, 2015, 10, e0129807. 5000 cells were seeded in each well of a 96-well plate and treated with compound 17ya 20 nM for 24 h in triplicate. The caspase 3/7 activity was normalized by total protein content in each sample.
Cell migration and invasion assay. Chemotactic cell migration was carried out using Transwell 96-well plate contained a membrane insert (pore size 8 μm) and a tray (BD Biosciences, CA), and the effect of compound 17ya on cell invasion was performed using matrigel invasion chamber (Corning, N.Y.). In both assays, MDA-MB-231 and MDA-MB-468 cells in serum-free medium were starved for 24 h, followed by suspending the cells in serum-free medium containing 16 nM colchicine and compound 17ya and plating them in the top chamber of the membrane insert or matrigel-coated membrane in triplicate. Medium containing serum was added in the lower chamber as a chemoattractant. After 24 h incubation for MDA-MB-231 cells and 48 h incubation for MDA-MB-468 cells, the cells that did not migrate through the membrane or invade through the matrigel were removed by cotton swabs while the cells that had migrated or invaded to the bottom surface of the chamber were fixed in 4% buffered formalin phosphate solution, stained with 0.5% crystal violet solution and imaged by a microscope. The number of cells migrated or invaded were counted manually using ImageJ software.
Cell migration was also analyzed by the scratch assay. Briefly, MDA-MB-231 cells (105 cells/well) and MDA-MB-468 (2×105 cells/well) cells were seeded in 12-well plates and incubated overnight. The following day, a scratch was made in the cell monolayer by using a sterile 200-μl pipette tip. After washing away the floating cells, the cell culture medium was replaced by medium containing vehicle DMSO, colchicine, paclitaxel or compound 17ya at specific concentration (e.g., 16 nM). After 12 h, 24 h and 48 h, the wound width was determined and imaged with Evos Fl Imaging System (Life Technologies, Carlsbad, Calif.). The extent of wound closure was shown as the percentage of decrease of the original scratch width at each measured time point. Experiments were done in triplicate.
Immunofluorescence staining. 105 MDA-MB-231 cells or 2×105 MDA-MB-468 cells were seeded in 6-well plates on sterile coverslips for 24 h prior to treatment with 32 nM colchicine, paclitaxel and compound 17ya for 18 h. For tubulin visualization, cells were washed three times with PBS, fixed with 4% paraformaldehyde for 15 min and permeabilized with 0.2% Triton X-100 in PBS for 15 min. Then the cells were blocked in 1.5% bovine serum albumin (BSA), 0.1% Tween 20 in PBS for 1 h and incubated anti-α-tubulin antibody (Thermo Fisher Scientific, Waltham Mass.) in 1% bovine serum albumin (BSA), 0.1% Tween 20 in PBS overnight at 4° C. The following day, cells were washed and incubated with Alexa Fluor 647 goat anti-mouse IgG (Molecular Probes, Eugene Oreg.) in dark for 1 h at room temperature, followed by the addition of Prolong Diamond Antifade reagent with DAPI (Invitrogen, Carlsbad, Calif.) and subsequent mounting with slides. Images depicted in figures were obtained with a Keyence BZ-X700 microscope (Keyence, Osaka Japan).
Detection of apoptosis. MDA-MB-231 and MDA-MB-468 Cells were seeded in 6-well plates (2×105/well). After incubating overnight, cells were treated with 100 nM compound 17ya for 24 h, 48 h and 72 h. A dose dependent investigation was carried out by treating cells with increasing doses for 48 h. Cells were then washed twice with PBS and 105 cells were suspended in 200 ul Annexin V-FITC binding buffer (eBioscience, Grand Island, N.Y.). 185 μl cell suspension were added 5 μl Annexin V-FITC and 10 μl propidium iodide cell suspension, after mixture and incubation for 10 min at room temperature, the cells were analyzed by a Bio-Rad ZE5 cell analyzer (Bio-rad, Hercules, Calif.).
Cell Cycle Analysis, Western Blotting, In Vivo Orthotopic Xenograft Model.
All animal studies were carried out in adherence to the NIH Principles of Laboratory Animal Care and protocols approved by the Institutional Animal Care and Use Committee at the University of Tennessee Health Science Center. Female Nod-Scid-γ (NSG) mice at 5-6 weeks of age were housed in a specific pathogen free environment with a 12:12-hour light-dark cycle. Temperature was maintained at 20-26° C. and the relative humidity was maintained at 30-70%. 2.5×105 MDA-MB-231 cells in 10 μl of HBSS were surgically inoculated into the left and right inguinal mammary gland fat pads of NSG mice as described by Pfeffer et al., “Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells,” J. Biol. Chem., 2013, 288, 27480-27493, hereby incorporated by reference. Mice were inspected weekly for tumor appearance until the average tumor size reached 100 mm3. Then the mice were randomly divided into 3 groups (n=5 per group) and drug treatment was started. The control group was administered with vehicle (1:1 ratio of PEG 300:water) orally, drug treatment groups were administered 5 mg/kg compound 17ya or 10 mg/kg compound 17ya orally five times a week, respectively. Primary tumor size was monitored twice a week using a digital caliper and body weight of the mice was recorded during the treatment. The tumor volume was calculated using the formula volume=(width2×length)/2. After 33 days treatment, when the tumor size in the vehicle group reached 1000 mm3, tumors and major organs were imaged and collected in 10% buffered formalin phosphate solution for histological analysis. Another similar orthotopic xenograft model for comparing the efficacy of compound 17ya with paclitaxel was performed as described above. The mice were randomized into 3 groups with 8 mice per group. Identically, the control group was administered with vehicle (1:1 ratio of PEG 300:water) orally, paclitaxel group was administered 12.5 mg/kg paclitaxel via intraperitoneal injection every other day and compound 17ya group was administered 12.5 mg/kg compound 17ya orally five times a week, and tumors and major organs were collected in 10% buffered formalin phosphate solution for histological analysis when the tumor size in the vehicle group reached 1000 mm3.
Experimental lung metastasis model: 7-8-week-old NSG mice were used to investigate the efficacy of compound 17ya to inhibit the metastasis of TNBC. 2×105 MDA-MB-231 cells in 100 μl of HBSS was inoculated into each mouse via tail vein injection. Vehicle, 10 mg/kg compound 17ya and 10 mg/kg paclitaxel treatments with the same dose frequency of the orthotopic xenograft model were started after 24 h. Animal health and body weight were monitored weekly during the treatment. After 23 days, the mice were sacrificed and all major organs were imaged and collected in 10% buffered formalin phosphate solution for subsequent histology and immunohistochemistry analysis.
Histology and immunohistochemistry (IHC) analysis: Fixed tumors and organs were embedded in paraffin and several section slides were cut for further Hematoxylin/eosin (H&E) staining and IHC staining. H&E staining and IHC staining were carried out as previously described. Primary antibodies used in IHC staining included rabbit anti-Ki67 (1:400), rabbit anti-CD31 (1:100), rabbit anti-cleaved Parp (1:50) and rabbit anti-cleaved caspase 3 (1:200) (#9027; #77699; #5625; #9661, Cell Signal Technology, Danvers Mass.), and biotinylated horse anti-rabbit IgG antibody (BA-1100, Vector Laboratories Inc., Burlingame, Calif.) was used as the secondary antibody. Anti-mitochondria IHC staining was performed to visualize the metastasis of MDA-MB-231 cells in experimental lung metastasis model. Images were acquired with a Keyence BZ-X700 microscope.
Compound 17ya extenuates the proliferation of different breast cancer cells. Compound 17ya previously was tested in a panel of melanoma cancer cell lines with an IC50 of 10 nM as described by Li et al., “Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogues targeting tubulin polymerization as antiproliferative agents,” J. Med. Chem., 2012, 55 7285-7289. Compound 17ya was evaluated to determine whether it could also inhibit the growth of breast cancer cells using MTS assay. Table 2 showed that compound 17ya had anti-proliferative effect against breast cancer cell lines, especially in TNBC. The testing incorporated two well-known tubulin inhibitors, colchicine and paclitaxel, to compare the efficacy of compound 17ya against TNBC cell growth. The results of the test are illustrated in
Compound 17ya inhibited TNBC cells migration and invasion. The effect of compound 17ya on the migration and invasion of TNBC cells after 24 or 48 hours of drug treatment was investigated.
Compound 17ya interfered with microtubule assembly and mitotic spindle organization: Compound 17ya was used with immunofluorescence staining to visualize the microtubule network and compared with known microtubule-destabilizing agent colchicine and microtubule-stabilizing agent paclitaxel. TNBC cells in negative control group showed intact microtubule fibers and organization of microtubules.
Compound 17ya induced increased apoptosis in TNBC cells: Since many tubulin inhibitors were reported to have pro-apoptotic effect on cancer cells, compound 17ya was studied to determine the effect on apoptosis induction in TNBC cells. MDA-MB-231 cells were treated with 100 nM Compound 17ya in a time-dependent manner. Compound 17ya induced the cells to apoptosis as illustrated in
Compound 17ya inhibited TNBC tumor growth and metastasis in vivo. To validate in vitro results, the anti-cancer activity of compound 17ya in orthotopic TNBC mouse model was studied to determine if the potent effect of compound 17ya in vitro could be observed in vivo. After 33 days of treatment, treatment with compound 17ya inhibited TNBC tumor growth in a dose dependent manner without interfering with the body weight of mice. The results are illustrated in
In addition to the materials and methods described above, the following examples utilized the following procedures.
Cell cycle analysis. To determine the cell cycle profile in the mitotic phase (especially G2 and M phase), cells were treated with colchicine, paclitaxel, and compound 17ya. The cells were harvested by trypsinization, fixed, permeabilized, stained with anti-phospho-Histone H3-AlexaFluor® 488 antibody on ice for 1 h in the dark and incubated with freshly prepared propidium iodide/Rnase solution for 30 min at room temperature in the dark according to the manufacturer's protocol (#FCCH0225103, EMD Millipore Corp., Burlington Mass.). Stained cells were then analyzed by Bio-Rad ZE5 cell analyzer (Bio-Rad, Hercules, Calif.). Data were processed, and graphs generated using FlowJo (FlowJo, LLC, Ashland, Oreg.).
Western Blotting. Cells were incubated with increasing doses of compound 17ya and 100 nM colchicine and paclitaxel for 24 h, or 100 nM compound 17ya for 24 h, 48 h, and 72 h as time-dependent investigation. Then the cells were harvested, washed with ice-cold PBS, lysed in RIPA buffer (25 nM Tris pH 7.6, 150 nM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) with Halt™ protease and phosphatase inhibitor (Thermo Fischer Scientific) and then centrifuged at 13000 rpm at 4° C. for 10 min. Protein in the supernatant was determined by BCA Protein Assay (Thermo Fischer Scientific). Equal amounts of each denatured protein sample were loaded and separated by SDS-PAGE gradient gels (Bio-Rad, #456-1083). Protein was wet-box transferred to PVDF membranes. The membranes were then blocked in 5% non-fat milk in TBST solution at room temperature for 1 h, incubated with primary antibodies overnight at 4° C. and bound with secondary antibody for 1 h subsequently. The following primary antibodies were used: rabbit anti-Poly (ADP-ribose) polymerase (PARP, 1:1000), rabbit anti-cleaved PARP (1:1000), rabbit anti-cleaved-capase-3 (1:1000) and rabbit anti-GAPDH HRP conjugate (#9532; #5625; #9661; #3683, Cell Signal Technology, Danvers, Mass.). Bound proteins were detected using Clarity™ Western ECL Substrate (Bio-Rad, #1705060) and visualized by ChemiDoc-It2 Imager system (UVP, LCC, Upland, Ca).
In vivo orthotoxic xenograft model. All animal studies were carried out in adherence to the NIH Principles of Laboratory Animal Care and protocols approved by the Institutional Animal Care and Use Committee at the University of Tennessee Health Science Center. Female Nod-Scid-γ (NSG) mice at 5-6 weeks of age were housed in a specific pathogen free environment with a 12:12-hour light-dark cycle. Temperature was maintained at 20-26° C. and the relative humidity was maintained at 30-70%. 2.5×105 MDA-MB-231 cells in 10 μl of HBSS were surgically inoculated into the left and right inguinal mammary gland fat pads of NSG mice as described by Pfeffer et al., “Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells,” J. Biol. Chem., 2013, 288, 27480-27493, hereby incorporated by reference. Mice were inspected weekly for tumor appearance until the average tumor size reached 100 mm3. Then the mice were randomly divided into 5 groups (n=14 in vehicle control group, n=8 in drug treated group) and drug treatment was started. The control group was administered with vehicle (1:1 ratio of PEG 300:water) orally, drug treatment groups were administered 5 mg/kg compound 17ya, 10 mg/kg compound 17ya, 12.5 mg/kg compound 17ya orally five times a week, and 12.5 mg/kg paclitaxel via intraperitoneal injection every other day, respectively. Primary tumor size was monitored twice a week using a digital caliper and body weight of the mice was recorded during the treatment. The tumor volume was calculated using the formula volume=(width2×length)/2. After 18 days treatment, when the tumor size in the vehicle group reached 1000 mm3, tumors and major organs were imaged and collected in 10% buffered formalin phosphate solution for histological analysis.
Compound 17ya extenuated the proliferation of different breast cancer cells and interfered microtubule assembly and mitotic spindle organization. Compound 17ya previously was tested in a panel of melanoma cancer cell lines with an average IC50 of 4 nM, and now was evaluated to determine whether compound 17ya could inhibit the growth of breast cancer cells using MTS assay. The results demonstrated that compound 17ya had an anti-proliferative effect against breast cancer cell lines, with IC50 value of 14 nM in HER2-positive breast cancer cells and 8 nM in TNBC cells. Tubulin-destabilizing colchicine and tubulin-stabilizing agent paclitaxel were incorporated to compare the efficacy of colchicine, paclitaxel, and compound 17ya against TNBC cell growth. (See
Immunofluorescence staining was used to visualize the microtubule network in comparison with colchicine and paclitaxel. TNBC cells in the negative control group showed intact microtubule fibers and organization of microtubules, as illustrated in
Compound 17ya inhibited TNBC cell migration and invasion. The example focused on the effect of compound 17ya on the migration and invasion of TNBC cells after 24 or 48 hours of treatment. Compound 17ya inhibited TNBC cells ability to migrate through a membrane insert in the presence of 16 nM concentration by an average migration rate of 40% in MDA-MB-231 cells and 34% in MDA-MB-468 cells as compared to a control group (migration rate 100%) as illustrated in
Compound 17ya blocks TNBC cells in G2/M phase and induced cell apoptosis. Microtubule dynamics play a significant role in cell division. Its disruption may lead to the mitotic arrest of growing cells in metaphase and ultimately cause cell death. In this example it was determined that compound 17ya can affect cell cycle arrest. A flow cytometry analysis was conducted of cells treated for 24 hours with 100 nM colchicine, 100 nM paclitaxel, and different concentrations of compound 17ya. Different compounds showed divergent effects on the cell cycle progression in different cells lines. Compound 17ya treatment induced the accumulation of MDA-MB-231 cells in the G2 and M phase with a reduction in the population of cells in the G1 and S phase in a dose dependent manner. Colchicine and paclitaxel, employed as positive controls, also arrested MDA-MB-231 cells in G2/M phase as illustrated in
The pro-apoptotic effect on TNBC cells by compound 17ya was studied. The effect of compound 17ya on apoptosis induction in TNBC cells was studied using Annexn V-FITC-PI double staining method. MDA-MB-231 and MDA-MB-468 cells were treated with increasing concentrations of compound 17ya for 24 h. Quantitatively, compound 17ya initiated apoptotic cell death in a dose dependent manner, indicated by the appearance of Annexin-V+/PI− cells, Annexin-V+/PI+ cells and Annexin-V−/PI+ cells shown in the representative histograms of
Caspases and PARP play an important role in the initiation and execution of programmed cell death. We determined the effect of compound 17ya on whether it triggered apoptotic cell death through regulating caspase-3/PARP pathway, expression of cleaved-caspase-3, and cleaved PARP in TNBC cells treated with compound 17ya as analyzed by Western blotting. The results demonstrated that the expression of cleaved-caspase-3 and cleaved-PARP were increased in a dose dependent manner after 24 hours of treatment of compound 17ya, although their expression were lower than those in paclitaxel-treated group both in MDA-MB-231 (
Compound 17ya inhibits TNBC tumor growth in vivo. Compound 17ya affects the in vivo growth of human cancer cell lines, as investigated by the anticancer activity in orthotopic TNBC mouse model. Since paclitaxel is one of the widely used chemotherapeutics for TNBC treatment in the clinic; it was incorporated as a comparison. NSG mice bearing MDA-MB-231 xenografts were treating with vehicle, 5 mg/kg Compound 17ya, 10 mg/kg compound 17ya, 12.5 mg/kg compound 17ya, and 12.5 mg/kg paclitaxel for 18 days. As compared to the vehicle treated group, the percentage increase of tumor size was significantly decreased in 10 mg/kg and 12.5 mg/kg compound 17ya and paclitaxel-treated groups, while the 5 mg/kg oral administration showed relatively weak tumor growth inhibition as illustrated in
Compound 17ya induces tumor necrosis, anti-angiogenesis, and apoptosis in vivo. Tumors were excised stained with H&E and the expression of cell proliferation marker Ki67, prognostic angiogenic marker CD31, apoptotic markers cleaved-PARP, and cleaved-caspase-3 were determined through IHC staining. Natural necrosis happens inside the tumor caused by internal hypoxia, both H&E and IHC were imaged near the margin of the tumor. Both compound 17ya and paclitaxel treatment increased the number of necrotic tumor cells with pyknosis, indicated by nuclear shrinkage. Necrotic cells increased with the dose of compound 17ya from 5 mg/kg to 12.5 mg/kg. An increased percentage of necrotic area of whole tumors was observed with the compound 17ya treated group as compared to the vehicle treated counterpart as illustrated in
Compound 17ya inhibited TNBC spontaneous metastasis and cancer in lung metastasis mouse model. The experiment tested the inhibition of spontaneous lung metastasis of mice in vehicle, compound 17ya at 5 mg/kg, 10 mg/kg, and 12.5 mg/kg, and paclitaxel 12.5 mg/kg. In the vehicle group, the lung metastasis foci were increased in the lung lobe (four mice had large metastasis, 10 mice had more than five lung metastases). Compound 17ya inhibited the spontaneous metastasis of TNBC cells with some few metastasis foci in 5 mg/kg treated group (six mice with few metastases, two mice without metastases), one or two small metastasis foci in 10 mg/kg treated group (four mice with few metastases, four mice without metastases), a metastasis or none observed in the 12.5 mg/kg treated group (one mouse with one lung metastasis, seven with no metastasis), and no metastasis was observed in the 12.5 mg/kg paclitaxel treated group (all eight mice had no metastasis), indicating the significant role of compound to inhibit metastasis of TNBC.
Since compound 17ya decreased the number and size of TNBC metastases in an orthotopic mouse model, an experimental lung metastasis model was used to evaluate the anti-metastasis effect of the compound. Due to the weakness of mice after tail vein inoculation, 10 mg/kg of paclitaxel and 10 mg/kg of compound 17ya were chosen as the dosage for this study. After 22 days of treatment, mice were euthanized and lungs, livers, kidneys, and spleens were harvested, fixed, and examined by anti-mitochondria IHC and H&E staining. The lungs in the vehicle group were full of metastasis (indicated by brown dots), while the lungs in the compound 17ya and paclitaxel treated groups exhibited significantly inhibited lung metastasis of TNBC. Results of the liver and spleen tissues were similar. Fever metastases were detected in the kidneys of vehicle mice, while the kidneys of the compound 17ya and paclitaxel treated groups were clear, that demonstrated that compound 17ya inhibited metastases of TNBC. Body weights and physical activities of mice were normal in the compound 17ya treated group, while body weights and physical activities of mice in the paclitaxel treated group were slightly decreased, demonstrating the toxicity of paclitaxel during long term treatment. H&E staining showed that multiple metastases with varying sized were observed in the lung, liver, kidney, and spleen of vehicle mice, whereas the metastases of compound 17ya and paclitaxel treated mice were sparse and smaller. The lung results indicated that compound 17ya showed comparable efficacy to paclitaxel in suppressing metastasis of TNBC cells without significant toxicity in 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 claims which follow.
This application claims the benefit of U.S. Provisional Application Nos. 62/671,824, filed May 15, 2018; 62/741,494, filed Oct. 4, 2018; and 62/805,826, filed Feb. 14, 2019, hereby incorporated by reference.
The invention described herein was made with government support under Grant No. CA148706, awarded by The National Institutes of Health. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 62671824 | May 2018 | US | |
| 62741494 | Oct 2018 | US | |
| 62805826 | Feb 2019 | US |
