US 12,083,181 B2
Bi-functional molecules to degrade circulating proteins
David Spiegel, New Haven, CT (US); and David Caianiello, New Haven, CT (US)
Assigned to YALE UNIVERSITY, New Haven, CT (US)
Filed by Yale University, New Haven, CT (US)
Filed on Jan. 30, 2023, as Appl. No. 18/161,633.
Application 18/161,633 is a continuation of application No. 17/695,259, filed on Mar. 15, 2022.
Application 17/695,259 is a continuation in part of application No. 17/046,192, granted, now 11,767,301, previously published as PCT/US2019/026239, filed on Apr. 8, 2019.
Claims priority of provisional application 62/788,052, filed on Jan. 3, 2019.
Claims priority of provisional application 62/655,028, filed on Apr. 9, 2018.
Prior Publication US 2024/0050578 A1, Feb. 15, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/55 (2017.01); A61K 45/06 (2006.01); A61K 47/54 (2017.01)
CPC A61K 47/55 (2017.08) [A61K 45/06 (2013.01); A61K 47/545 (2017.08); A61K 47/549 (2017.08)] 23 Claims
 
1. A compound according to the chemical structure:

OG Complex Work Unit Chemistry
wherein:
[IgGBM] is an IgG binding moiety selected from the group consisting of:
Fc-III

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FcBP-1,
FcBP-2, and
Fc-III-4c

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[ASGPRBM] is an asialoglycoprotein binding moiety according to the structure:

OG Complex Work Unit Chemistry
wherein:
R1 is —CH2OH;
R3 is

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RN, RN1, RN2, and RN3 are each independently H or C1-C3 alkyl which is optionally substituted with up to 3 halogen groups and up to 2 hydroxyl groups;
RN4 is H,

OG Complex Work Unit Chemistry
or C1-C3 alkyl which is optionally substituted with up to 3 halogen groups and up to 2 hydroxy groups;
each occurrence of K is independently 0, 1, 2, 3, or 4;
each —(CH2)K group is independently optionally substituted with up to 4 C1-C3 alkyl groups which are independently optionally substituted with up to 3 fluoro groups and up to 2 hydroxyl groups;

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is a chemical linker that links the [IgGBM] group to the
[ASGPRBM] through one or more optional [CON] groups, or

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is a chemical linker group comprising one or more functional groups that covalently bond the linker group to the [IgGBM] group or an optional [CON] group;
R2 is:
i)

OG Complex Work Unit Chemistry
wherein RAM is H, C1-C4 alkyl optionally substituted with up to 3 halogen groups and up to 2 hydroxyl groups, —(CH2)KCOOH, —(CH2)KC(═O)O—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, —O—C(═O)—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, —C(═O)—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, —(CH2)K—NRN3RN4; or
ii)

OG Complex Work Unit Chemistry
wherein:
RTA is:
a) H, CN, NRN1RN2, —(CH2)KOH, —(CH2)KO(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, C1-C4 alkyl optionally substituted with up to 3 halogen groups, —(CH2)KCOOH, —(CH2)KC(═O)O—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, —O—C(═O)—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, or —C(═O)—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, or RTA is C3-C10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroatoms, each of the aryl or heteroaryl groups being optionally substituted with up to three CN, NRN1RN2, —(CH2)KOH, —(CH2)KO(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, C1-C3 alkyl optionally substituted with up to 3 halogen groups and up to 2 hydroxy groups, —O—(C1-C3-alkyl) optionally substituted from up to 3 halogen groups, —(CH2)KCOOH, —(CH2)KC(═O)O—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, O—C(═O)—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, or —(CH2)KC(═O)—(C1-C4 alkyl) optionally substituted with up to 3 halogen groups, or
b)

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optionally substituted with up to three C1-C3 alkyl groups which are optionally substituted with up to 3 halogen groups, or
c)

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each [CON] is an optional connector chemical moiety which, when present, is independently a group according to the structure:
i) a group according to the structure:

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wherein:
RCON1 and RCON2 are each independently H, methyl, or a bond;
X2 is independently at each occurrence —CH2—, —O—, —S—, NR4—, —C(═O)—, —S(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, or —OS(═O)2O—;
X3 is independently at each occurrence —O—, —S—, or —N(R4)—; and
R4 is independently at each occurrence H, C1-C3 alkyl, C1-C3 alkanol, or —C(═O)(C1-C3 alkyl);
or
ii) a group according to the structure:

OG Complex Work Unit Chemistry
wherein:
R1 is independently H or C1-C3 alkyl; and
n″ is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
or
iii) a group according to the structure:

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wherein
R1CON, R2CON, and R3CON are each independently H, —(CH2)MC1—, —(CH2)MC1aC(═O)XA(NR4)XA—(CH2)MC1a—, —(CH2)MC1a(NR4)XAC(═O)XA—(CH2)MC1a—, or —(CH2)MC1aO—(CH2)MC1—C(═O)NR4—, with the proviso that R1CON, R2CON, and R3CON are not simultaneously H;
each MC1 is independently 1, 2, 3, or 4;
each MC1a is independently 0 1, 2, 3, or 4;
each XA is independently 0 or 1; and
R4 is H, C1-C3 alkyl, C1-C3 alkanol, or —C(═O)(C1-C3 alkyl), with the proviso that MC1a and XA in a moiety are not all simultaneously 0; or
iv) a group according to the structure:

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[LINKER] is:
i) a polyethyleneglycol linker having from 2 to 12 ethylene glycol residues, or
ii) a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing 1 to 100 alkylene glycol units, or
iii) a group according to the structure:

OG Complex Work Unit Chemistry
wherein
Ra is H, C1-C3 alkyl, or C1-C3 alkanol, or Ra taken together with R3 forms a pyrrolidine ring or a hydroxypyrrolidine ring,
m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, and
R3 is an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxyproline (R3 forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl);
or
iv) a group according to the structure:

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wherein:
Ram is H or C1-C3 alkyl optionally substituted with up to two hydroxyl groups;
na is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and
m is an integer from 1 to 100;
or
v) a group according to the chemical formula:

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wherein:
Z and Z′ are each independently a bond, —(CH2)i—O—, —(CH2)i—N(R)—,

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wherein:
the —(CH2)i group, if present in Z or Z′, is bonded to a connector group [CON], [IgGBM], or [ASGPRBM];
each R is H, C1-C3 alkyl, or C1-C3 alkanol;
each R2 is independently H or C1-C3 alkyl;
each Y is independently a bond, —O—,—S—, or —N(R)—;
each i is independently 0 to 100;
D is

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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;
X1 is —O—, —S—, or —N(R)—;
R is H, C1-C3 alkyl, or C1-C3 alkanol; and
or
vi) a group according to the structure:

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wherein
n is an integer from 1 to 25;
n′ is an integer from 1 to 25;
n″ is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
or
vii) a group with the formula: PEG-[CON]-PEG, wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues and [CON] is a triazole group

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each occurrence of IM is independently 1, 2, or 3;
k′ is independently 1, 2, or 3;
j′ is independently 1, 2, or 3;
h is independently 1, 2, or 3;
h′ is independently 1, 2, or 3;
iL is independently 1, 2, or 3;
or a salt, stereoisomer, or solvate thereof.