US 11,725,064 B2
Chimeric small molecules for the recruitment of antibodies to cancer cells
David Spiegel, New Haven, CT (US); Ryan Murelli, Belleville, NJ (US); and Andrew Zhang, Waltham, MA (US)
Assigned to YALE UNIVERSITY, New Haven, CT (US)
Filed by YALE UNIVERSITY, New Haven, CT (US)
Filed on May 17, 2021, as Appl. No. 17/322,124.
Application 14/480,204 is a division of application No. 13/173,480, filed on Jun. 30, 2011, granted, now 8,852,630, issued on Oct. 7, 2014.
Application 17/322,124 is a continuation of application No. 16/881,111, filed on May 22, 2020, granted, now 11,014,992.
Application 16/881,111 is a continuation of application No. 16/045,855, filed on Jul. 26, 2018, granted, now 10,703,823, issued on Jul. 7, 2020.
Application 16/045,855 is a continuation of application No. 15/083,025, filed on Mar. 28, 2016, granted, now 10,066,026, issued on Sep. 4, 2018.
Application 15/083,025 is a continuation of application No. 14/480,204, filed on Sep. 8, 2014, granted, now 9,296,708, issued on Mar. 29, 2016.
Application 13/173,480 is a continuation in part of application No. 12/991,926, granted, now 8,859,509, issued on Oct. 14, 2014, previously published as PCT/US2009/002957, filed on May 13, 2009.
Claims priority of provisional application 61/127,539, filed on May 13, 2008.
Claims priority of provisional application 61/360,732, filed on Jul. 1, 2010.
Prior Publication US 2022/0023428 A1, Jan. 27, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/54 (2017.01); A61K 47/68 (2017.01); A61K 45/06 (2006.01); C07K 16/44 (2006.01); C07K 16/30 (2006.01); A61K 31/4192 (2006.01); C07D 249/04 (2006.01); A61K 9/00 (2006.01); A61K 47/64 (2017.01); A61K 47/55 (2017.01)
CPC C07K 16/44 (2013.01) [A61K 9/0019 (2013.01); A61K 31/4192 (2013.01); A61K 45/06 (2013.01); A61K 47/54 (2017.08); A61K 47/549 (2017.08); A61K 47/55 (2017.08); A61K 47/646 (2017.08); A61K 47/68 (2017.08); A61K 47/6803 (2017.08); A61K 47/6869 (2017.08); A61K 47/6873 (2017.08); A61K 47/6891 (2017.08); C07D 249/04 (2013.01); C07K 16/3069 (2013.01); C07K 2317/31 (2013.01)] 34 Claims
 
1. A compound according to the chemical structure:

OG Complex Work Unit Chemistry
Wherein n is independently 1 or 2;
A is an antibody binding moiety according to the chemical structure:

OG Complex Work Unit Chemistry
Where Y′ is H or NO2;
X is O, CH2, NR1, S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
R1 is H, a C1-C3 alkyl group, or a —C(O)(C1-C3) group;
Xb is a bond, O, CH2, NR1 or S;
B is a cell binding moiety according to the chemical formula:

OG Complex Work Unit Chemistry
Where X1 and X2 are each independently CH2, O, NH or S;
X3 is O, CH2, NR1, S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
R1 is H, a C1-C3 alkyl group, or a —C(O)(C1-C3) group;
k is an integer from 1 to 10;
L is a linker according to the chemical formula:

OG Complex Work Unit Chemistry
Or L is a polyethylene glycol, polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 20 glycol units;
Where Ra is H, C1-C3 alkyl or alkanol or together with Ra forms a proline side chain with R3;
R3 forms a proline side chain with Ra or R3 is a side chain derived from an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan and valine; and
Each m is independently an integer from 1 to 12; or
L is a linker according to the chemical formula:

OG Complex Work Unit Chemistry
Where Z and Z′ are each independently a bond, —(CH2)i—O, —(CH2)i—S, —(CH2)i—N—R,

OG Complex Work Unit Chemistry
wherein said —(CH2); group, if present in Z or Z′, is bonded to[CON], antibody binding terminus (ABT) or cell binding terminus (CBT);
Each R is independently H, or a C1-C3 alkyl or alkanol group;
Each R2 is independently H or a C1-C3 alkyl group;
Each Y is independently a bond, O, S or N—R;
Each i is independently an integer from 0 to 15;
D is

OG Complex Work Unit Chemistry
or a bond,
with the proviso that Z, Z′ and D are not each simultaneously bonds;
j is an integer from 1 to 100;
m′ is an integer from 1 to 100;
n′ is an integer from 1 to 100; and
X″ is O, S or N—R,
R is as defined above; and
[CON] is a bond or a moiety according to the chemical structure:

OG Complex Work Unit Chemistry
Where X2 is O, S, NR4, S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
X3 is NR4, O or S; and R4 is H, a C1-C3 alkyl or alkanol group, or a —C(O)(C1-C3) group; or
a pharmaceutically acceptable salt thereof.