Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
  • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• Vinca alkaloids originally isolated from the periwinkle plant [Vinca rosea Linn., now
• Vindesine also acts similarly in inhibiting microtubule assembly and inhibiting cell
• hydrocarbyl ether is referred to as a "hydrocarbyloxy” group rather than a "hydrocarboxy” group as may possibly be more proper when following the usual rules of chemical nomenclature.
• Illustrative hydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclohexenyloxy groups and the like.
• N is nitrogen and one of W, X, Y and Z can also be nitrogen (N) .
• W, X, Y and Z are nitrogen and one of W, X, Y and Z.
• wiredchemist com/chemistry/data/hammett_sigma_constan ts .
• the Hammett sigma value for a para-position amino group according to the Hine text, above, is -0.66.
• a contemplated compound of structural Formula A above can have a fluorine atom (F) at the 10' position or a hydrido group at that position (R b ) .
• F fluorine atom
• R b hydrido group at that position
• the preparation of 10' -F-substituted 20'- hydroxy-vinca derivative compounds is taught in the inventor's U.S. Patent No. 8,940,754, whose teachings are incorporated by reference. Broadly, that patent teaches reaction of 10-fluorocatharanthine (a 10- fluorinated derivative of Compound 2 that was shown previously) is , reacted with vindoline (3) to begin the synthesis of an appropriate vinblastine
• the contemplated compounds are amines.
• Parental vinblastine has reported pKa values of 5.4 and 7.4, whereas vincristine has reported pKa values of 6.04 and 7.67.
• Both compounds are sold commercially as their sulfate salts .
• Vindesine is reported to have pka values of 6.04 and 7.67 [The Merck Index, 12 th ed., Merck and Co., Whitehouse Station, NJ, 1996, page 1704] .
• Vindesine is also commercially available as the sulfate salt.
• Exemplary salts useful for a contemplated compound include but are not limited to the
• ethanesulfonate glucoheptanoate , glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide , hydroiodide, 2-hydroxy- ethanesulfonate, lactate, maleate, methanesulfonate , nicotinate, 2-naphthalenesulfonate, oxalate,
• the salts can also be used as an aid in the isolation, purification or
• capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
• the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or
• Tablets and pills can additionally be prepared with enteric coatings.
• a mammal in need of treatment (a subject) and to which a pharmaceutical composition containing a contemplated compound is administered can be a primate such as a human, an ape such as a chimpanzee or gorilla, a monkey such as a cynomolgus monkey or a macaque, a laboratory animal such as a rat, mouse or rabbit, a companion animal such as a dog, cat, horse, or a food animal such as a cow or steer, sheep, lamb, pig, goat, llama or the like.
• a contemplated 20 ' -hydroxy-vinca derivative compound is administered with one or more other anti-neoplastic compounds.
• Such joint therapy is well known in the art, with other drugs such as cisplatin,
• pyrrolidine urea 8 which exhibited improved cell growth inhibition relative to vinblastine.
• a series of functionalized or substituted pyrrolidines were incorporated into the C20'-urea through reaction of 20 ' -aminovinblastine (6), derived from reduction of the hydroazidation product 5, with either
• Pgp P-glycoprotein
• analogues ( 58 , 60 and 61 ) reported here.
• vinblastine displaced 31% of the BODIPY-vinblastine bound to tubulin (Table 5) .
• 10' -Fluorovinblastine and 28 which are roughly 10- fold more potent than vinblastine, displayed a higher tubulin affinity, displacing 48-49% of the BODIPY- vinblastine.
• the three ultra-potent vinblastines (58, 60 and 61) each 100-fold more potent than vinblastine, displaced 100% of the
• vinepidine and vincristine were the most potent followed by vindesine and vinblastine. However, they also found that vinblastine and vindesine were generally more potent than vincristine and vindesine in in vitro cell proliferation studies. Thus, the correlation shown here does not hold in all study systems .
• the isoindoline group of modeled 9 extends behind the loop peptide into a channel continuing along the tubulin protein-protein interface.
• microtubulin .
• HCT116/VM46 a vinblastine-resistant strain of
• HCT116 HCT116 cells in culture.
• a population of cells (>1 x 10 6 cells/mL as determined with a hemocytometer ) was diluted with an appropriate amount of Dulbecco' s Modified Eagle Medium (DMEM, Gibco) containing 10% fetal bovine serum (FBS, Gibco) to a final DMEM, Gibco
• DMEM Dulbecco' s Modified Eagle Medium
• FBS fetal bovine serum
• phosphatase assay was used to establish the IC 5 o values as follows: the media in each cell was removed and 100 ⁇ L, of phosphatase solution (100 mg phosphatase substrate in 30 mL of 0.1 M NaOAc, pH 5.5, 0.1% Triton X-100 buffer) was added to each well. The plates were incubated at 37 °C for either 5 minutes (L1210) or 15 minutes (HCT116 and
• the BODIPY- vinblastine fluorescence intensity was measured (Ex 480 nm, Em 514 nm, Cutoff 495 nm) at 37 °C.
• Control measurements were performed with BODIPY-VBL (control 1) in the absence of a competitive ligand (maximum FI enhancement due to tubulin binding) and (control 2) in the absence of tubulin (no FI enhancement due to tubulin binding) .
• % BODIPY-VBL displacement was calculated by the formula (Control 2 FI - Experiment FI)/ (Control 2 FI - Control 1 FI) ⁇ 100.
• PEM 80 mM PIPES-K pH 6.8, 2 mM MgS0 4 , 0.5 mM EGTA pH 6.8.
• Butyloxycarbonyl) amino) pyrazine-2- carboxamido) isoindoline-2-carboxylate The product precipitates from the reaction solution as a white solid and was isolated by filtration, rinsing with cold EtOAc. Further

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 2017
  • 2017-05-30 WO PCT/US2017/035027 patent/WO2017210206A1/en not_active Ceased
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