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1. WO2020113130 - TUMOR TARGETING VITAMIN B12 DERIVATIVES FOR X-RAY ACTIVATED CHEMOTHERAPY

Publication Number WO/2020/113130
Publication Date 04.06.2020
International Application No. PCT/US2019/063790
International Filing Date 27.11.2019
IPC
A61K 31/714 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
70Carbohydrates; Sugars; Derivatives thereof
7135Compounds containing heavy metals
714Cobalamins, e.g. cyanocobalamin, vitamin B12
A61K 47/48 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
48the non-active ingredient being chemically bound to the active ingredient, e.g. polymer drug conjugates
A61K 51/04 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
51Preparations containing radioactive substances for use in therapy or testing in vivo
02characterised by the carrier
04Organic compounds
CPC
A61K 45/06
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
45Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 47/50
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
A61K 51/04
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
51Preparations containing radioactive substances for use in therapy or testing in vivo
02characterised by the carrier ; , i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
04Organic compounds
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
Applicants
  • THE TRUSTEES OF DARTMOUTH COLLEGE [US]/[US]
Inventors
  • SHELL, Jennifer
  • POGUE, Brian
Agents
  • VOCK, Curtis
  • BARTON, Steven K.
  • LINK, Douglas
  • COUGHLIN, Sean M.
  • DECONTI, Giulio A.
  • ANIS, Hissan
  • JEFFRIES, James H.
  • LAMBRECHTS, Robert J.
  • POPLIN, Alan J.
  • CHEN, Xiaoyue (Peter)
  • TRINQUE, Brian C.
  • VELEMA, James H.
  • DIZEREGA, Philip
  • DELANEY, Marie J.
  • MORIARTY, Gordon R.
  • LIU, Jiangqiong (Jessica)
  • RUDOLPH, Rebecca
Priority Data
62/773,09729.11.2018US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) TUMOR TARGETING VITAMIN B12 DERIVATIVES FOR X-RAY ACTIVATED CHEMOTHERAPY
(FR) DÉRIVÉS DE VITAMINE B12 CIBLANT UNE TUMEUR POUR UNE CHIMIOTHÉRAPIE ACTIVÉE PAR RAYONS X
Abstract
(EN)
A therapeutic agent has an antineoplastic drug bonded with an X-ray-cleavable bond to cobalt of cobalamin. In embodiments, the drug is doxorubicin, paclitaxel, methotrexate, erlotinib, chlorambucil, dasatinib, SN38, colchicine, or gefitinib; and in embodiments a Cy5 fluorophore bonded to ribose of the cobalamin. The agent is formed by reducing hydroxocobalamin with zinc, reacting with 3-bromopropylamine to form aminopropyl cobalamin; and linking the drug to the aminopropyl cobalamin by conjugation through a hydroxyl group by carbamate formation with 1,1'-Carbonyl-di-(1,2,4-triazole). An optional Cy5 handle is added by coupling a 5' hydroxyl group of a ribose first with ethylene diamine and then with N-hydroxysuccinimide of Cy5. The agent treats cancer by administration in a dose expected to induce apoptosis in cells of the cancer when the light-cleavable bond is cleaved, the cancer absorbs the agent; and the cancer is exposed to X-ray or visible light to cleave the X-ray-light-cleavable bond.
(FR)
Un agent thérapeutique a un médicament antinéoplasique lié avec une liaison clivable par rayons X au cobalt de la cobalamine. Dans des modes de réalisation, le médicament est la doxorubicine, le paclitaxel, le méthotrexate, l'erlotinib, le chlorambucil, le dasatinib, le SN38, la colchicine, ou le géfitinib; et dans des modes de réalisation, un fluorophore Cy5 lié au ribose de la cobalamine. L'agent est formé par réduction d'hydroxocobalamine avec du zinc, réaction avec de la 3-bromopropylamine pour former de la cobalamine d'aminopropyle; et par liaison du médicament à la cobalamine aminopropyle par conjugaison à travers un groupe hydroxyle par formation de carbamate avec 1,1'-carbonyl-di-(1,2,4-triazole). Une poignée de Cy5 facultative est ajoutée par couplage d'un groupe hydroxyle 5' d'un ribose d'abord avec de l'éthylène diamine, puis avec du N-hydroxysuccinimide de Cy5. L'agent traite le cancer par administration dans une dose prévue pour induire l'apoptose dans des cellules du cancer lorsque la liaison clivable par la lumière est clivée, le cancer absorbe l'agent; et le cancer est exposé aux rayons X ou à une lumière visible pour cliver la liaison clivable par rayons X.
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