COMPOUNDS FOR TREATMENT OF PANCREATIC CANCER

FIELD OF THE INVENTION

The present invention relates to novel methods of treating pancreatic 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.

BACKGROUND OF THE INVENTION

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 al-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 interfere with microtubule-tubulin equilibrium in cells are effective in the treatment of cancers. Anticancer drugs like taxol and vinblastine 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. Thoroc. 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, resistance and neurotoxicity. A common mechanism of multidrug resistance (MDR), namely ATP binding cassette (ABC) transporter protein-mediated drug efflux, limits their efficacy (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, encoded by the MDR1 gene) are important members of the ABC superfamily. P-gp prevents the intracellular accumulation of many cancer drugs by increasing their efflux out of cancer cells, as well as contributing to 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 MDR. 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 MDR.

Pancreatic cancer is one of the most lethal cancers and ranked as the fourth most common cause of cancer-related deaths among both men and women in the United States. Siegel, et al., “Cancer statistics,” Cancer J. Clin., 2016, 66, 7-30. The management of pancreatic cancer is exceptionally difficult due to poor response to available therapeutic regimens. Ansari et al., “Update on the management of pancreatic cancer: surgery is not enough,” World J Gastroenterol 2015, 21, 3157-3165. Thus, the identification of newer, highly effective therapeutic agents with no or minimal toxicity is highly desirable for the improved management of pancreatic cancer.

With the rapidly rising incidence of pancreatic 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.

SUMMARY OF THE INVENTION

In one embodiment, the invention encompasses methods of treating pancreatic 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:

embedded image

- wherein
- X is a bond, NH or S;
- Q is O, NH or S; and
- A is a ring and is substituted or unsubstituted saturated or unsaturated single-, fused- or multiple-ring, aryl or (hetero)cyclic ring system; N-heterocycle; S-heterocycle; O-heterocycle; cyclic hydrocarbon; or mixed heterocycle;
- wherein the A ring is optionally substituted by 1-5 substituents which are independently 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-C₅linear or branched alkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO— alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;
- i is an integer between 0-5;
- wherein if Q is 5, then X is not a bond and pharmaceutically acceptable salts thereof.

Another embodiment of the invention encompasses methods of treating pancreatic 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:

embedded image

- R₄, R₅and R₆each independently is 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-C₅linear or branched alkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;
- Q is S, O or NH;
- i is an integer between 0-5; and
- n is an integer between 1-3 and pharmaceutically acceptable salts thereof.

Yet another embodiment, of the invention encompasses methods of treating pancreatic 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:

embedded image

- wherein R₄and R₅are 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-C₅linear or branched alkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;
- i is an integer from 0-5; and
- n is an integer between 1-4 and pharmaceutically acceptable salts thereof.

One embodiment of the invention encompasses methods of treating pancreatic 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:

embedded image

wherein R₄and R₅are 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-C₅linear or branched alkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

- i is an integer from 0-5; and
- n is an integer between 1-4 and pharmaceutically acceptable salts thereof.

Another embodiment of the invention encompasses methods of treating pancreatic cancer in a subject in need thereof by administering a compound of Formula XI(e), wherein Formula XI(e) is represented by the structure:

embedded image

- wherein R₄and R₅are 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-C₅linear or branched alkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;
- i is an integer from 0-5; and
- n is an integer between 1-4 and pharmaceutically acceptable salts thereof.

Yet another embodiment of the invention encompasses methods of treating pancreatic 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.

BRIEF DESCRIPTION OF THE DRAWINGS

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:

FIGS. 1A and 1B illustrate two graphs of the anti-cancer activity of Compound 17ya in vitro. FIG. 1A illustrates the IC₅₀of Compound 17ya was 20, 30 and 40 nM in Panc-1, AsPC-1 and HPAF-II, respectively, after 24 hours of treatment. FIG. 1B illustrates the IC₅₀of Compound 17ya was 8.2, 12.5, and 20 nM in Panc-1, AsPC-1 and HPAF-II, respectively, after 48 hours of treatment.

FIGS. 2A and 2B illustrate the growth inhibitory effect of Compound 17ya. FIG. 2A illustrates the growth curve, recorded as the basal cell index value, wherein Compound 17ya significantly reduced the cell index in a dose-dependent manner compared over the control (vehicle) in treating pancreatic cancer cells, Panc-1. FIG. 2B illustrates the growth curve, recorded as the basal cell index value (y axis is Cell Index), wherein Compound 17ya significantly reduced the cell index in a dose-dependent manner compared over the control (vehicle) in treating pancreatic cancer cells, AsPC-1

FIGS. 3A, 3B, and 3C illustrate the effect of Compound 17ya on the growth of pancreatic cancer cells. FIG. 3A illustrates the effect of Compound 17ya at 0, 1.25, 25, and 5 nM on pancreatic cancer cells Panc-1 in the colony formation and clonogenic potential (%) in graphic representation. FIG. 3B illustrates the effect of Compound 17ya at 0, 1.25, 2.5, and 5 nM on pancreatic cancer cells AsPC-1 in the colony formation and clonogenic potential (%) in graphic representation. FIG. 3C illustrates the effect of Compound 17ya at 0, 1.25, 2.5, and 5 nM on pancreatic cancer cells HPAF-II in the colony formation and clonogenic potential (%) in graphic representation.

FIGS. 4A and 4B illustrate the effect of Compound 17ya on the expression of βIII and βIV-tubulins in pancreatic cancer cells. FIG. 4A illustrates in graphical form the dose-dependent manner in which Compound 17ya (from 0 to 20 nM) inhibited mRNA expression of βI-tubulin, βIIa-tubulin, βIIb-tubulin, βIII-tubulin, βIVa-tubulin, βIVb-tubulin, βV-tubulin, and βVI-tubulin using pancreatic cancer cells Panc-1 and AsPC-1, as determined by qRT-PCR. FIG. 4B illustrates in western blot analysis of the dose-dependent manner in which Compound 17ya (from 0 to 20 nM) inhibited mRNA expression of βI-tubulin, βIIa-tubulin, βIIb-tubulin, βIII-tubulin, βIVa-tubulin, βIVb-tubulin, βV-tubulin, and βVI-tubulin using pancreatic cancer cells Panc-1 and AsPC-1.

FIGS. 5A and 5B illustrate the effect of Compound 17ya on pancreatic cancer cells Panc-1 in graphical form and by western blot analysis. FIG. 5A illustrates in graphical form the effect of Compound 17ya (ABI-231), cochicine, vinorelbine, and paclitaxel on βIII-tubulin mRNA (fold change) on pancreatic cancer cells Panc-1 as treated with 5-40 nM. FIG. 5B illustrates in western blot the protein levels after treatment with Compound 17ya, coichicine, vinorelbine, and paclitaxel on βIII-tubulin.

FIGS. 6A, 6B, and 6C illustrate cell inhibition growth of Compound 17ya, coichicine, vinorelbine, and paclitaxel on pancreatic cell lines Panc-1, AsPC-1, and HPAF-II, respectively. FIG. 6A illustrates the cell inhibition growth by Compound 17ya, coichicine, and vinorelbine on pancreatic cells Panc-1, at 0, 5, 10, 20, and 40 nM.

FIG. 6B illustrates the cell inhibition growth by Compound 17ya, coichicine, and vinorelbine on pancreatic cells AsPC-1, at 0, 5, 10, 20, and 40 nM. FIG. 6C illustrates the cell inhibition growth by Compound 17ya, coichicine, and vinorelbine on pancreatic cells HPAF-II, at 0, 5, 10, 20, and 40 nM.

FIGS. 7A, 7B, and 7C illustrate effect of Compound 17ya on the expression of miR-200c in pancreatic cell lines Panc-1 and AsPC-1. FIG. 7A illustrates in graphical form the effect of Compound on 17ya on miR-200C (fold change) on pancreatic cell lines Panc-1, AsPC-1, and HPAF-II at 0, 5, 10, and 20 nM. FIG. 7B illustrates in graphical form the inhibition of miR-200c on the effect of Compound 17ya on expression of βIII-tubulin, which was rescued by transfecting the cells with miR-200c inhibitor. FIG. 7C illustrates the effect on protein of Compound 17ya and miR-200c mimic transfection of Panc-1 cells.

FIGS. 8A and 8B illustrates the effect of Compound 17ya on the migration of pancreatic cancer cells. FIG. 8A illustrates via healing wound graphs the inhibition by Compound 17ya on migration of pancreatic cells Panc-1 at 0, 1.25, and 2.5 nM. FIG. 8B illustrates via healing wound graphs the inhibition by Compound 17ya on migration of pancreatic cells AsPC-1 at 0, 1.25, and 2.5 nM.

FIGS. 9A and 9B illustrate the effect of Compound 17ya on pancreatic cell migration by transwell assay. FIG. 9A illustrates that Compound 17ya showed significant inhibition of Panc-1 and AsPC-1 pancreatic cells in a dose dependent manner (0, 1.25, and 2.5 nM). FIG. 9B illustrates in graphical form the same data on inhibition of cell migration of pancreatic cell lines Panc-1 and AsPC-1.

FIGS. 10A and 10B illustrate the effect of Compound 17ya on the migration and invasion of pancreatic cell lines Panc-1 at sublethal levels. FIG. 10A illustrates that Compound 17ya showed significant inhibition of Panc-1 and AsPC-1 pancreatic cell lines at sub lethal concentrations. FIG. 10B illustrates in graphical form the same data on inhibition of cell migration of pancreatic cell lines Panc-1 and AsPC-1.

FIGS. 11A and 11B illustrate graphs of cell migration and cell invasion as cell index over time (hours). FIG. 11A illustrates the effect of Compound 17ya at 5, 10, and 20 nM as compared to the control on cell migration on pancreatic cells Panc-1. FIG. 11B illustrates the effect of Compound 17ya at 5, 10, and 20 nM as compared to the control on cell invasion on pancreatic cells Panc-1.

FIGS. 12A, 12B, 12C, 12D, and 12E illustrate the effect of Compound 17ya on the cell cycle and its distribution and induced apoptosis in pancreatic cancer cells. FIG. 12A illustrates that Compound 17ya arrested the cell cycle of pancreatic cells Panc-1 at 5 nM, 10 nM, and 20 nM. FIG. 12B illustrates, using Western blot, that Compound 17ya in a dose dependent manner inhibit the protein levels of cyclin B1 and cdc25c in Panc-1 and AsPC-1 cells. FIG. 12C illustrates the effect of Compound 17ya on apoptosis induction in pancreatic cancer cells (Panc-1) by Annexin V-7AAD staining and mitochondrial membrane potential using flow cytometer. FIG. 12D illustrates, using Western blot, that Compound 17ya in a dose dependent manner inhibit the protein levels of cyclin B1 and cdc25c in Panc-1 and AsPC-1 cells. FIG. 12E illustrates a dose-dependent (5-20 nM) decrease of TMRE staining in pancreatic cells Panc-1 and illustrates the data in graphical form.

FIGS. 13A, 13B, 13C, 13D, 13E, 13F, 13G, 13H, and 13I illustrate the effective inhibition of pancreatic tumor growth in a xenograft mouse model. FIG. 13A illustrates the comparison between control and Compound 17ya in the reduction of tumor size. FIG. 13B illustrates the graphical representation in the reduction of tumor size and growth of the control as compared to Compound 17ya (50 nM). FIG. 13C illustrates the graphical representation in the reduction of tumor weight of the control as compared to Compound 17ya (50 nM). FIG. 13D illustrates the IHC results of the effective inhibition of PCNA expression by Compound 17ya as compared to the control as shown by immunohistochemistry. FIG. 13E illustrates the Western blot comparison of Compound 17ya and control with various tubulin. FIG. 13F illustrates the effect of Compound 17ya at the mRNA expression of βIII and βIVb-tubulins in xeonograph tumor tissues. FIG. 13G illustrates the effect Compound 17ya has on tubulin expression as compared to the control. FIG. 13H illustrates in graphical form the effect of Compound 17ya on the miR-200c (fold expression) as compared to the control. FIG. 13I illustrates the in situ hybridization assays on the expression of miE-200c in excised tumors.

FIG. 14A-D illustrate VERU-111 (compound 17ya) inhibited pancreatic cancer. FIG. 14A(i-ii) illustrate the dose dependent effect of VERU-111 (compound 17ya) over cell lines Panc-1, AsPC-1, and HPAF-II as percent of cell viability. FIG. 14B(i-ii) illustrate the time dependent effect of VERU-111 (compound 17ya) at 5 nM, 10 nM, and 20 nM as comparted to a control. FIG. 14C illustrates the effect of VERU-111 (compound 17ya) at 1.25 nM, 2.5 nM, and 5 nM as comparted to a control with Panc-1 (FIG. C(i)), AsPC-1 (FIG. C(ii)), or HPAF-II (FIG. C(iii)) cell lines. FIG. 14D illustrates the effect of VERU-111 (compound 17ya) at 1.25 nM, 2.5 nM, and 5 nM as comparted to a control with Panc-1 (FIG. D(i)), AsPC-1 (FIG. D(ii)), or HPAF-II (FIG. D(iii)) cell lines in bar graph form.

FIG. 15 illustrates VERU-111 (compound 17ya) inhibited pancreatic cancer.

FIG. 16 illustrates VERU-111 (compound 17ya) in preclinical safety (less myelosuppression, less neurotoxicity, maintains body weight), where FIG. 16 illustrates the toxicity tests of liver weight and white blood count (WBC) in mice in the use of VERU-111 (3.3 mpk or 6.7 mpk) and VERU-112 (10 mpk and 30 mpk) as compared to a control and DTX (10 mpk and 20 mpk).

FIG. 17 illustrates VERU-111 (compound 17ya) in preclinical safety (less myelosuppression, less neurotoxicity, maintains body weight), where FIG. 17 illustrates the neurotoxicity tests (hot plate test at 5.-52.5° C. and the time require to lick the paw recorded as latency period for pain threshold) in mice in the use of VERU-111 (3.3 mpk or 6.7 mpk) and VERU-112 (10 mpk and 30 mpk) as compared to a control and DTX (10 mpk and 20 mpk).

FIG. 18 illustrates VERU-111 (compound 17ya) as antiproliferative and maintains body weight as contrasted to the lack of efficacy of docetaxel in PC-3/Txr tumors, VERU-111 (compound 17ya) was dosed orally and had >100% TGI without an effect on body weight.

FIG. 19 illustrates nonclinical results in assessment of blockade of HERG potassium channels stably expressed in HEK293 cells and central nervous system safety study in rats with an IC₂₀of 9.23 nM and the oral administration of VERU-111 (compound 17ya) at doses up to and including 10 mg/kg was not associated with any adverse effects on neurobehavioral function in rats.

FIG. 20 illustrates VERU-111 (compound 17ya) nonclinical results in cardiovascular and respiratory evaluation study in beagle dogs where VERU-111 (compound 17ya) was administered as doses of 2, 4, and 8 mg/kg to dogs and did not produce mortality or effects on blood pressure, heart rate, or the evaluated electrocardiogram or respiratory parameters. Increases in body temperature (50.7° C. maximum change) were observed at all doses of VERU-111 (compound 17ya) from approximately 3.5 to 11 hours post dose. Vomitus was noted between 4 and 24 hours following the 8 mg dose. Oral administration of VERU-111 (compound 17ya) at doses up to and including 8 mg/kg was not associated with any adverse effects on cardiovascular or respiratory function in dogs.

FIG. 21 illustrates VERU-111 (compound 17ya) pharmacokinetics in dogs were mean (±SD) and CV % for VERU-111 (compound 17ya) pharmacokinetic parameters on days 1 and 7 following oral capsule administration of 5 and 10 mg/kg VERU-111 to male gods.

FIG. 22 illustrates VERU-111 (compound 17ya) 28-day oral capsule toxicity study in beagle dogs that found that it did not impact dog survival, no ophthalmoscopic findings; no changes in hematology, coagulation, and urinalysis parameters; no clinical or macroscopic pathologic observations; at 4 and 8 mg/kg mild observations of inappetence, vomiting emesis, and diarrhea; dogs at 8 mg/kg/day had body weight losses; had QTc prolongation that exceeded 10% change; and reduced thymus organ weights and reduction of lymphocytes in thymus; no observed adverse effect level (NOAEL) was 4 mg/kg/day; and following 28 days of dose at 4 mg/kg/day the mean Cmax and AUC_0-12hrvalues were 23.2 ng/ml and 71.7 hr*ng/mL, respectively.

FIGS. 23A and 23B illustrate VERU-111 (compound 17ya) 28-Day oral capsule toxicity study in dogs—weight. FIG. 23A illustrates the mean body weight in male dogs relative to time (weeks) from the start date. FIG. 23B illustrates the mean body weight in dogs relative to time (weeks) from the start date.

FIG. 24 illustrates VERU-111 (compound 17ya) 28-Day oral capsule toxicity study in dogs-QT interval.

FIG. 25 illustrates VERU-111 (compound 17ya) 28-Day oral capsule toxicity study in dogs-Hematology.

FIG. 26 illustrates VERU-111 (compound 17ya) 28-Day oral capsule toxicity study in dogs-Hematology.

FIG. 27 illustrates VERU-111 (compound 17ya) 28-Day oral capsule toxicity study in dogs-Liver function tests.

FIG. 28 illustrates VERU-111 (compound 17ya) 28-Day oral capsule toxicity study in dogs-Liver function tests.

FIG. 29A-B illustrate compound 17ya 28-day oral capsule toxicokinetics study in beagle dogs. FIG. 29A illustrates individual and mean compound 17ya C values on Days 1 and 28 following daily oral capsule administration of 2, 4, and 8 mg/kg compound 17ya to dogs (males and females combined). FIG. 29B illustrates individual and mean compound 17ya AUC_0-12hrvalues on Days 1 and 28 following daily oral capsule administration of 2, 4, and 8 mg/kg compound 17ya to dogs (males and females combined).

It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses methods of treating pancreatic 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

embedded image

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;

B is

embedded image

R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

X is a bond, NH, C₁to C₅hydrocarbon, 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

i is an integer between 0-5;

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 O; and

or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite, tautomer or isomer.

The pancreatic 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 pancreatic 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

embedded image

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;

B is

embedded image

R₁, R₂and R₃are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

X is a bond, NH, C₁to C₅hydrocarbon, 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

i is an integer between 0-5;

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 CH₂and A is not indole;

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 Ia is a thiazole ring then X is not a bond.

The invention also encompasses methods of treating pancreatic 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:

embedded image

wherein

B is

embedded image

R₁, R₂, R₃, R₄, R₅and R₆are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

X is a bond, NH, C₁to C₅hydrocarbon, 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 pancreatic 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

embedded image

wherein

B is

embedded image

R₄, R₅and R₆are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂; and

R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

X is a bond, NH, C₁to C₅hydrocarbon, 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 O;

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 pancreatic 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

embedded image

wherein ring A is an indolyl;

B is

embedded image

R₁and R₂are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

X is a bond, NH, C₁to C₅hydrocarbon, 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or 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 pancreatic 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:

embedded image

B is

embedded image

R₁, R₂, R₄and R₅are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂; and

R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

X is a bond, NH, C₁to C₅hydrocarbon, 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 pancreatic 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:

embedded image

B is

embedded image

In another embodiment, B of formula V is not a thiazole

embedded image

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:

R₄, R₅

Compound
B

and R₆

embedded image

1a 1b

embedded image

H H

1c

embedded image

H

1d

embedded image

H

1e

embedded image

H

1f

embedded image

H

1g

embedded image

H

1h

embedded image

H

1i

embedded image

H

1k

embedded image

H

1l

embedded image

H

35a

embedded image

H

36a

embedded image

The invention also encompasses methods of treating pancreatic 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:

embedded image

wherein

R₄, R₅and R₆are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or 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:

R₄, R₅

Compound
Y
and R₆

embedded image

1h 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k
—C═O —C═C(CH₃)₂ —CH—OH —C═CH—CN (cis and trans) —C═N—NH₂ (cis and trans) —C═N—OH (cis and trans) —C═N—OMe (cis and trans) —(C═O)—NH— —NH—(C═O)— nothing —C═N—CN (cis and trans) C═O
H H H H H H H H H H H R₄= R₆= H R₅= p-F

2l
C═O
R₄= R₆= H

R₅= p-OH

2m
C═O
R₄= R₆= H

R₅= p-CH₃

2n
C═O
R₄= R₆= H

R₅= p-CH₂—CN

2o
C═O
R₄= R₆= H

R₅= p-N(CH₃)₂

2p
C═O
R₄= m-F;

R₅= p-F;

R₆= m-F;

n = 1

2q
C═O
R₄= R₆= H

R₅=

p-CH₂(C═O)NH₂

2r
C═O
R₄= R₆= H

R₅= p-CH₂NH₂

2s
C═O
R₄= R₆= H

R₅= p-CH₂NH—CH₃

2t
C═O
R₄= m-OMe;

R₅= p-OMe;

R₆= m-OMe;

n = 1

2u
C═O
R₄= R₆= H

R₅= p-CH₂NMe₂

In one embodiment, this invention is directed to compound 3a:

embedded image

In one embodiment, this invention is directed to compound 3b:

embedded image

In one embodiment, this invention is directed to a compound of formula (VII)

embedded image

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:

Compound
Y

embedded image

4a 4b 4c 4d
S SO₂ SO —(SO₂)—NH—

In one embodiment, this invention is directed to a compound of formula (VIII)

embedded image

Q is S, O or NH;

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 methods using the following compounds:

Compound
R₄
R₅
R₆
Q

embedded image

5a 5b 5c 5d 5e
H n = 1 H n = 1 H n = 1 H n = 1 H n = 1
H p-CH₃ p-F p-Cl H
H H H H H
S S S S N

The invention also encompasses methods of treating pancreatic 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):

embedded image

wherein

R₄and R₅are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO— alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH₂or NO₂;

A′ is halogen; substituted or unsubstituted 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂;

i is an integer between 1-5; 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:

Compound
A′
R₄, R₅

embedded image

H

6b

embedded image

H

6c

embedded image

H

6d
Cl
H

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. In another embodiment, compounds of formula IX are presented in FIG. 16A.

The invention also encompasses methods of treating pancreatic 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):

embedded image

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 pancreatic 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:

embedded image

wherein

X is a bond, NH or S;

Q is O, NH or S; and

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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or 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 5, 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 pancreatic 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:

embedded image

The invention also encompasses methods of treating pancreatic 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:

embedded image

The invention also encompasses methods of treating pancreatic 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: XI(c)

embedded image

The invention also encompasses methods of treating pancreatic 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: XI(d)

embedded image

The invention also encompasses methods of treating pancreatic 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:

embedded image

The invention also encompasses methods of treating pancreatic cancer by administering compound 55 in a therapeutically effective amount to a subject in need thereof, wherein compound 55 is represented by the structure:

embedded image

The invention also encompasses methods of treating pancreatic cancer by administering compound 17ya in a therapeutically effective amount to a subject in need thereof, wherein compound 17ya is represented by the structure:

embedded image

The invention also encompasses methods of treating pancreatic 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:

compound
structure

8

embedded image

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 C₁to C₁₀hydrocarbon, 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 C₅to C₇cycloalkyl, 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 poro 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:

embedded image

In another embodiment the B group of formula I, I(a), II, III, IV, Ia and V is substituted. In another embodiment the B group of formula I, I(a), II, III, IV, IVa and V is:

embedded image

wherein R₁₀and R₁₁are 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-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂or NO₂.