Tosylate salts of the anticancer drug lapatinib.

Two tosylate salts of an anticancer drug lapatinib, viz. a monotosylate [systematic name: ({5-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)quinazolin-6-yl]furan-2-yl}methyl)[2-(methylsulfonyl)ethyl]azanium 4-methylbenzenesulfonate], C29H27ClFN4O4S(+)·C7H7O3S(-), (I), and a ditosylate [systematic name: 4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)-6-]5-({[2-(methylsulfonyl)ethyl]azaniumyl}methyl)furan-2-yl[quinazolin-1-ium bis(4-methylbenzenesulfonate)], C29H28ClFN4O4S(2+)·2C7H7O3S(-), (II), were obtained during crystallization attempts for polymorphism. In both structures, the lapatinib cation is in a distorted U-like conformation and the tosylate anion is clamped between the aniline N atom and methylamine N atom through N-H···O hydrogen bonds, forming an R2(2)(15) ring motif. The 4-anilinoquinazoline ring system is essentially planar in (I), while it is twisted in (II), controlled by an intramolecular C-H···N interaction. In (I), alternating cations and anions are linked by N-H···O hydrogen bonds into C2(2)(6) chains. These chains are linked by cations in a helical manner. The presence of the additional tosylate anion in (II) results in the formation of one-dimensional tapes of fused hydrogen-bonded rings through N-H···O and C-H···O interactions. These studies augment our understanding of the role of nonbonded interactions in the solid state, which is useful for correlation to the physicochemical properties of drug products.

Design, synthesis and preclinical evaluation of NRC-AN-019.

Imatinib mesylate is the first tyrosine kinase inhibitor developed and approved for the treatment of chronic myeloid leukemia (CML). In the past few years development of resistance towards imatinib mesylate has been reported. To overcome this problem a series of phenyl amino pyrimidine derivatives have been designed, prepared and evaluated for anti-proliferative activity against the BCR­ABL­positive leukemia cell line K562. Among these phenyl amino pyrimidine derivatives, NRC­AN­019 has been found to be a promising new lead compound for the therapy of imatinib mesylate-resistant chronic myeloid leukemia. In this communication, we describe the design, preparation and preclinical studies of NRC­AN­019.

Antitumor activity of NRC-AN-019 in a pre-clinical breast cancer model.

Breast cancer is the second most frequently diagnosed tumor in women. Overexpression of human epidermal growth factor receptors (EGFRs) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior and response to systemic therapy. In this study, we describe a novel compound (NRC-AN-019), which has better antitumor activity than Lapatinib. Here, we demonstrate that NRC-AN-019 is more effective in inhibiting angiogenic potential and proliferation of both MDAMB231 and HTB20/BT474 cells. FACS analysis shows that NRC-AN-019 treatment caused the accumulation of MDAMB231 and BT474 cells in the sub G0/1 phase in a dose-dependent manner and was accompanied by increased PARP cleavage, which is indicative of apoptosis. In addition, we observed inhibition of EGFR phosphorylation in both MDAMB231 and BT474 cells. From our animal studies using SCID mice implanted with BT474 cells, we observed dose-dependent inhibition of tumor growth in NRC-AN-019-treated animals compared to controls or Lapatinib-treated mice at comparable concentrations. The dose-dependent inhibition of EGFR phosphorylation was confirmed by immunohistochemical analysis of tumor sections. In vitro results demonstrate that NRC-AN-019 is superior to Lapatinib in EGFR-overexpressing cells and has strong anti-angiogenic, anti-proliferative and pro-apoptotic properties in an EGFR-overexpressing background (BT474). In vivo studies demonstrate that the antitumor activity of NRC-AN-019 is better over Lapatinib. These results suggest that NRC-AN-019 has greater therapeutic potential in the treatment of Her-2-positive breast cancer.

Sorafenib and its tosylate salt: a multikinase inhibitor for treating cancer.

Sorafenib, a drug that targets malignant cancer cells and cuts off the blood supply feeding the tumour, has been crystallized as the free base, 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpyridine-2-carboxamide, C(21)H(16)ClF(3)N(4)O(3), (I), and as a tosylate salt, 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl)pyridinium 4-methylbenzenesulfonate, C(21)H(17)ClF(3)N(4)O(3)(+)·C(7)H(7)O(3)S(-), (II). In both structures, the sorafenib molecule is in an extended conformation. The pyridine-2-carboxamide group exhibits a syn conformation of the N atoms in (I), whereas an almost anti orientation is present in (II). In both crystal structures, the two terminal groups, viz. pyridine-2-carboxamide and the trifluorophenyl ring, are oriented differently to the conformations found in enzyme-bound sorafenib. The sorafenib molecules in (I) are linked into zigzag chains by N-H···O hydrogen bonds, whereas in (II) the presence of the additional tosylate anion results in the formation of chains of fused hydrogen-bonded rings. This study reveals the variations in the solid-state conformation of the sorafenib molecule in different crystalline environments.