US 11,692,022 B2
Thiosuccinyl-crosslinked hemoglobin analogs and methods of use and preparation thereof
Kwok Chu Butt, Hong Kong (CN); Norman Fung-Man Wai, Vancouver (CA); Hiu Chi Chong, Hong Kong (CN); Wing Fung Wu, Hong Kong (CN); Colin Pak Fai Yeh, Hong Kong (CN); and Benjamin Chi Yin Wai, Vancouver (CA)
Assigned to Billion King International Limited, Hong Kong (CN)
Filed by Billion King International Limited, Hong Kong (CN)
Filed on Aug. 25, 2022, as Appl. No. 17/822,174.
Application 17/822,174 is a division of application No. 16/947,993, filed on Aug. 27, 2020, granted, now 11,479,597.
Claims priority of provisional application 62/893,220, filed on Aug. 29, 2019.
Prior Publication US 2023/0111100 A1, Apr. 13, 2023
Int. Cl. C07K 14/805 (2006.01); C07K 1/107 (2006.01); A61P 1/16 (2006.01); A61P 7/08 (2006.01); A61P 13/12 (2006.01); A61P 25/00 (2006.01); A61P 35/00 (2006.01); A61P 9/10 (2006.01); A61K 38/00 (2006.01)
CPC C07K 14/805 (2013.01) [A61P 1/16 (2018.01); A61P 7/08 (2018.01); A61P 9/10 (2018.01); A61P 13/12 (2018.01); A61P 25/00 (2018.01); A61P 35/00 (2018.01); C07K 1/1077 (2013.01); A61K 38/00 (2013.01)] 1 Claim
 
1. A method of supplying oxygen to the tissues and organs in a subject in need thereof wherein the method comprises transfusing into the system of the subject a therapeutically effective amount of a thiosucciniyl-crosslinked hemoglobin comprising a tetrameric hemoglohin and at least one thiosuccinyl crosslinking moiety of Formula 1:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or zwitterion thereof, wherein
each N* independently represents a nitrogen selected from the group consisting of a nitrogen in a lysine residue side chain in the tetrameric hemoglobin and a nitrogen at a N-terminus in the tetrameric hemoglobin; and
R1 is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or —(CR2)nY, wherein n is an integer selected from 0-10; R for each instance is independently hydrogen, alkyl, aralkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two instances of R taken together form a 3-6 membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and Y is selected from the group consisting of OR4, SR4, N(R4)2, —(C═O)R4, —(C═O)OR4, —O(C═O)R4, —O(C═O)OR4, —(C═O)N(R4)2, —(NR4)(C═O)R4, —(NR4)(C═O)OR4, —O(C═O)N(R4)2, —O(C≡NR4)N(R4)2, —(NR4)(C═O)N(R4)2, —(C≡NR4)N(R4)2, —(NR4)(C≡NR4)N(R4)2, —(S═O)R4, —S(O)2R4, —S(O)2OR4, —S(O)2N(R4)2, —OS(O)2R4, —(NR4)S(O)2R4, —OS(O)2OR4, —OS(O)2N(R4)2, —(NR4)S(O)2N(R4)2, —(NR4)S(O)2OR4, and —(CRR2R3), wherein R2 is hydrogen, alkyl, aralkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR4, SR4, N(R4)2, —(C═O)R4, —(C═O)OR4, —O(C═O)R4, —O(C═O)OR4, —(C═O)N(R4)2, —(NR4)(C═O)R4, —(NR4)(C═O)OR4, —O(C═O)N(R4)2, —O(C≡NR4)N(R4)2, —(NR4)(C═O)N(R4)2, —(C≡NR4)N(R4)2, —(NR4)(C≡NR4)N(R4)2, —(S═O)R4, —S(O)2R4, —S(O)2OR4, —S(O)2N(R4), —OS(O)2R4, —(NR4)S(O)2R4, —OS(O)2OR4, —OS(O)2N(R4)2, —(NR4)S(O)2N(R4)2, or —(NR4)S(O)2OR4; R3 is hydrogen, alkyl, aralkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR4, SR4, N(R4)2, —(C═O)R4, —(C═O)OR4, —O(C═O)R4, —O(C═O)OR4, —(C═O)N(R4)2, —(NR4)(C═O)R4, —(NR4)(C═O)OR4, —O(C═O)N(R4)2, —O(C≡NR4)N(R4)2, —(NR4)(C═O)N(R4)2, —(C≡NR4)N(R4)2, —(NR4)(C≡NR4)N(R4)2, —(S═O)R4, —S(O)2R4, —S(O)2OR4, —S(O)2N(R4)2, —OS(O)2R4, —(NR4)S(O)2R4, —OS(O)2OR4, —OS(O)2N(R4)2, —(NR4)S(O)2N(R4)2, or —(NR4)S(O)2OR4; and R4 for each instance is independently selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or R1 is a moiety selected from the group consisting of:

OG Complex Work Unit Chemistry
N5-(1-((carboxymethyl)amino)-1-oxo-3λ3-propan-2-yl)glutamine or a pharmaceutically acceptable salt thereof wherein m is a whole number selected from 1-1000, and wherein the thiosuccinyl-crosslinked hemoglobin is substantially pure.