US 12,280,115 B2
Cytokine-bisphosphonate conjugates
Gerard Karsenty, New York, NY (US); Julian Berger, New York, NY (US); and Han Xiao, Houston, TX (US)
Assigned to The Trustees of Columbia University in the City of New York, New York, NY (US); and William Marsh Rice University, Houston, TX (US)
Filed by The Trustees of Columbia University in the City of New York, New York, NY (US); and William Marsh Rice University, Houston, TX (US)
Filed on Apr. 9, 2024, as Appl. No. 18/630,263.
Application 18/630,263 is a continuation of application No. PCT/US2022/077956, filed on Oct. 12, 2022.
Claims priority of provisional application 63/255,104, filed on Oct. 13, 2021.
Prior Publication US 2024/0269294 A1, Aug. 15, 2024
Int. Cl. A61K 47/54 (2017.01); A61P 21/00 (2006.01)
CPC A61K 47/548 (2017.08) [A61K 47/545 (2017.08); A61P 21/00 (2018.01)] 7 Claims
 
1. A cytokine-bisphosphonate conjugate having the structure:
a)

OG Complex Work Unit Chemistry
wherein
the cytokine comprises an azidophenylalanine residue, wherein the triazole set forth above is composed from an azide group of the azidophenylalanine residue,
and wherein

OG Complex Work Unit Math
R1=H, OH, a halogen, CN, COOH, CONH2, an alkyl ester, an alkyl, an aryl, or a heteroaryl,
and
R2, R3, R4, and R5 are each independently H, alkyl, aryl, or a heteroaryl;
or
b)

OG Complex Work Unit Chemistry
wherein
the cytokine comprises a native lysine residue, and wherein Y comprises a nitrogen of a sidechain of the native lysine residue and wherein Y is an alkylimine, an amide, a urea, thiourea, a sulfamidate, a substituted benzo[d][1,2,3]triazin-4(3H)-one, or a substituted 2-alkyliminoboronic acid,
and wherein
when Y is an alkylimine, the bisphosphonate is attached via an imine carbon atom and the cytokine is attached at a nitrogen atom of the alkylimine, or
when Y is an amide, the bisphosphonate is attached via a carbonyl carbon atom of the amide and the cytokine is attached at a nitrogen atom of the amide, or
when Y is a urea, the bisphosphonate is attached to one of the nitrogen atoms thereof and the cytokine is attached at the other nitrogen atom of the urea, or
when Y is a thiourea, the bisphosphonate is attached to one of the nitrogen atoms thereof and the cytokine is attached at the other nitrogen atom of the thiourea, or
when Y is a sulfamidate, the bisphosphonate is attached at one of the oxygen atoms thereof, and the cytokine is attached at a nitrogen atom of the sulfamidate, or
when Y is a substituted benzo[d][1,2,3]triazin-4(3H)-one, the bisphosphonate is attached at the 5, 6, 7, or 8 position and the cytokine is attached at the nitrogen atom alpha to the carbonyl,
and
wherein l=0 to 12, m=0 to 8, and n=1 to 10;
or a pharmaceutically-acceptable salt thereof,
wherein the cytokine is IL-6, Leptin, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC), or IL-27.