BACKGROUND

Field of the Invention

The present disclosure relates to isotopologues of niraparib, where one or more hydrogen atoms are substituted with deuterium.

Description of the Related Art

Niraparib, or (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide, is shown below:



Niraparib, and salts, solvates, hydrates, and polymorphs thereof, are known as PARP inhibitors (inhibitors of poly ADP ribose polymerase). Niraparib and pharmaceutical compositions comprising the same have utility in the treatment of a BRCA-mutation positive ovarian cancer and BRCA-positive breast cancer. Definitions and descriptions of these conditions are known to the skilled practitioner and are further delineated in various patents and patent applications and references contained therein. See alsoHarrison's Principles of Internal Medicine16th Edition, Kasper, D. L., et. al. Eds., 2004, McGraw-Hill Professional;Robbins&Cotran Pathologic Basis of Disease, Kumar, V. et. al. Eds., 2004, W. B. Saunders.

Niraparib, previously known as MK-4827, is an inhibitor of poly ADP ribose polymerase (PARP) enzymes, including PARP1, PARP2and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Niraparib is a useful agent for the treatment of cancers in people with hereditary BRCA-1 or BRCA-2 mutations, including various ovarian, breast, and prostate cancers. BRCA-1 or BRCA-2 mutations may cause a genetic predisposition to the development of some forms of cancer and may be resistant to many forms of cancer treatment. However, cancer cells of this type have an increased reliance on PARP to repair the cellular DNA and enable the cancer cells to continue dividing, and thus may be particularly vulnerable to PARP inhibitors. Thus, agents selectively inhibiting PARP may be of benefit for the treatment of such cancers.

Niraparib has shown excellent PARP1and PARP2inhibition activity, with IC50values of 3.8 nM and 2.1 nM, respectively. In a whole cell assay, niraparib inhibits PARP activity, with an EC50value of 4 nM, and inhibits the proliferation of cancer cells with mutant BRCA-1 and BRCA-2, with CC50in the 10-100 nM range.

Niraparib demonstrates efficacy in vivo as a single agent in a mouse xenograft model of BRCA-1 deficient cancer. At 80 mg/kg (qd, oral dosing), a significant inhibition of tumor growth was observed after only one or two weeks of treatment. Continuous daily dosing for three or four weeks was more efficacious and induced tumor shrinkage, with complete and sustained regression observed after four week treatment. Niraparib was also shown to be active in a CAPAN-1 pancreatic cancer cell xenograft model, with ˜60% tumor growth inhibition at 80 mg/kg (qd, oral dosing) for two, three, or four weeks. In addition, it strongly enhances the effect of radiation on a variety of human tumor xenografts, both p53 wild type and p53 mutant. Enhancement of radiation response is observed in clinically relevant radiation-dose fractionation schedules. See Jones, P. et al. “Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors,”J. Med. Chem.2009, 52, 7170-7185; Jones, P. et al. “Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination,”J. Med. Chem.2015, 58, 3302-3314.

In a Phase 3 trial (NOVA) with 500 enrolled patients with recurrent ovarian cancer following platinum-based chemotherapy, niraparib significantly achieved its primary endpoint of progression-free survival (PFS) in the germline BRCA mutant patients, with a hazard ratio of 0.27. The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for the control. This trial also successfully achieved its primary endpoint of PFS in non-gBRCAmut cohort for patients with HRD (homologous recombination deficient)-positive tumors, with a hazard ratio of 0.38. The median PFS for patients with HRD-positive tumors treated with niraparib was 12.9 months, compared to 3.8 months for the control. Niraparib also showed statistical significance in the overall non-germline BRCA mutant cohort, which included patients with both HRD-positive and HRD-negative tumors, with a hazard ratio of 0.45. The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for the control. See Nasdaq GlobeNewswire, “TESARO's Niraparib Significantly Improved Progression-Free Survival for Patients With Ovarian Cancer in Both Cohorts of the Phase 3 NOVA Trial,” Jun. 29, 2016, Waltham, Mass. (available at globenewswire.com/news-release/2016/06/29/852247/0/en/TESARO-s-Niraparib-Significantly-Improved-Progression-Free-Survival-for-Patients-With-Ovarian-Cancer-in-Both-Cohorts-of-the-Phase-3-NOVA-Trial.html).

Currently ongoing studies of niraparib include a Phase 2 trial in patients with ovarian cancer (the QUADRA trial), a Phase 3 trial for the treatment of patients with BRCA-positive breast cancer (the BRAVO trial), and a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial). Several combination studies are also underway, including trials of niraparib in combination with pembrolizumab, bevacizumab, and temozolomide. See Nasdaq GlobeNewswire, “TESARO Provides Pipeline Update at ASCO Investor Briefing,” Jun. 4, 2016 (available at ir.tesarobio.com/news-releases/news-release-details/tesaro-provides-pipeline-update-asco-investor-briefing).

The most common (≥10%) treatment-emergent grade 3/4 adverse events were thrombocytopenia (28.3%), anemia (24.8%), and neutropenia (11.2%). The discontinuation rate was 14.7% for niraparib treated patients and 2.2% for the control. See Nasdaq GlobeNewswire, “TESARO's Niraparib Significantly Improved Progression-Free Survival for Patients With Ovarian Cancer in Both Cohorts of the Phase 3 NOVA Trial,” Jun. 29, 2016, Waltham, Mass. (available at globenewswire.com/news-release/2016/06/29/852247/0/en/TESARO-s-Niraparib-Significantly-Improved-Progression-Free-Survival-for-Patients-With-Ovarian-Cancer-in-Both-Cohorts-of-the-Phase-3-NOVA-Trial.html).

Thus there remains an unmet clinical need for a method of administering higher doses of niraparib to patients in a manner that eliminates or minimizes adverse events, such as thrombocytopenia, anemia, and neutropenia, and other potentially dangerous side effects that may occur with niraparib therapy. A compound displaying the beneficial activities of niraparib with a decreased metabolic liability that further extends its effective pharmacological life by increasing the concentration of the agent in the blood and improving the effective bioavailability will lead to a lower required dosage, thereby reducing the potential toxicity and other side effects.

SUMMARY

A deuterated compound having the structure of Formula I:


or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a salt of a prodrug thereof; or a hydrate or polymorph thereof;

wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y9′, Y10, Y10′, Y11, Y11′, Y12, Y12′, and Y13are selected from the group consisting of hydrogen or deuterium,wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y9′, Y10, Y10′, Y11, Y11′, Y12, Y12′, and Y13is deuterium; and

wherein each carbon is independently optionally replaced with13C is disclosed herein.

The disclosed niraparib isotopologues are PARP inhibitors and possess unique biopharmaceutical and metabolic properties as compared to niraparib. The disclosed compounds may also be used to accurately determine the concentration of niraparib in biological fluids and to determine metabolic patterns of niraparib and its isotopologues. Compositions comprising the disclosed compounds and methods for treating BRCA-mutation positive ovarian cancer and BRCA-positive breast cancer, alone or in combination with additional agents, are also disclosed herein.

Without being bound by any theory of operation, it is believed that niraparib may be primarily metabolized by CYP3A and other drug metabolizing enzymes. The primary metabolic pathways for niraparib may involve oxidation, presumably at the benzylic carbon and/or at the electron rich nitrogen and/or α-carbons of the piperidine ring, including N-oxidation, oxidative N-dealkylation, ring oxidation, and ring opening. A radiolabeled disposition study with [14C]-niraparib dosed IV to bile duct cannulated rats has found numerous metabolites, along with 45% of recovered radioactivity as the parent drug. See Jones, P. et al. “Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination,”J. Med. Chem.2015, 58, 3302-3314.

Limiting the production of these metabolites has the potential to decrease the danger of the administration of niraparib and related drugs and may even allow increased dosage and concomitant increased efficacy. All of these transformations may occur through polymorphically-expressed enzymes, thus exacerbating the interpatient variability. For all of the foregoing reasons, there is a strong likelihood that a drug with a longer half-life will diminish the aforementioned problems and result in greater efficacy and cost savings.

Various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, and/or (f) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for both intentional and unintentional polypharmacy. Deuteration offers a strong potential to slow drug metabolism via various oxidative and other modification mechanisms. In particular, deuteration of drugs produces benefits when using combinations of different medications, which is common for patients suffering from cancer.

The disclosed compounds and compositions are also useful as analytical reagents for determining the concentration of niraparib in solution. As used herein, niraparib refers to the compound wherein all hydrogen atoms and all carbon atoms are present at the approximate percentages of their natural isotopic abundance. While some variation of natural isotopic abundance does occur depending upon the origin of chemical starting materials and reagents, the concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial with respect to the degree of stable isotopic substitution of compounds disclosed herein. See, e.g., Wada, E. et al.Seikagaku,1994 66, 15; Ganes, L. Z. et al.Comp. Biochem. Physiol. A Mol. Integr. Physiol.1998, 119, 725.

The altered properties of the disclosed compounds will not significantly affect their ability to bind to their protein target. This is because such binding is primarily dependent upon non-covalent binding between the protein and the inhibitor, and may be impacted both positively and negatively by isotopic substitution depending on the specific substitution involved, and any negative effects that a heavier atom in the disclosed compounds may have on the highly optimized non-covalent binding between the disclosed compounds and their targeted proteins will be relatively minor. Major factors contributing to the noncovalent recognition of small molecules by proteins and the binding strength between them include Van der Waals forces, hydrogen bonds, ionic bonds, molecular reorganization, desolvation energy of the small molecule, hydrophobic interactions, and, in some situations, displacement energy for pre-existing bound ligands. See, e.g.,Goodman&Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, Hardman, J. G. et al., Eds. 2001, McGraw-Hill;The Organic Chemistry of Drug Design and Drug Action, Silverman, R. B., 2004, Academic Press.

The disclosed compounds possess molecular topologies very similar to niraparib, as the exchange of deuterium for hydrogen does not appreciably alter molecular configuration, and the exchange of13C for12C is conformationally neutral. See Holtzer, M. E. et al.Biophys J.2001, 80, 939. Deuterium replacement does cause a slight decrease in Van der Waals radius, see Wade, D.Chem. Biol. Interact.1999, 117, 191, but such decrease will likely not appreciably reduce the binding affinity between the disclosed compounds and their receptors as compared to niraparib. Further, the slightly smaller size of the disclosed deuterated compounds prevents additional undesirable steric interactions with the binding protein as compared to niraparib.

Neither deuterium nor13C atoms in the disclosed compounds contribute significantly to hydrogen bonding or ionic interactions with the protein receptors. This is because the major hydrogen bond and ionic interactions formed by niraparib with its targeted proteins are mediated by the oxygens, nitrogens, and the amine-bound hydrogens within niraparib. Any deuterium atoms attached to the amine nitrogen will be rapidly exchanged with bulk solvent protons under physiological conditions. Protein reorganization or side chain movement will be identical between the disclosed compounds and niraparib. Desolvation energy of the disclosed compounds will be equivalent to or less than that of niraparib, resulting in neutral or increased binding affinity for the receptor. See Turowski, M. et al.J. Am. Chem. Soc.2003, 125, 13836. The replacement of12C by13C in the disclosed compounds will also cause no significant change in desolvation energy. Thus, the disclosed compounds will advantageously retain substantial PARP inhibitory activity with a reduced rate of metabolite generation.

The disclosed compounds and compositions are also useful as analytical reagents for determining the concentration of niraparib in solution.

