Rifamycin analogs and antibody-drug conjugates thereof
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsThomas Nittoli, Seungyong Sean Choi, Mrinmoy Saha
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Abstract
The disclosure relates to rifamycin analog compounds, intermediates and precursors thereof, and pharmaceutical compositions capable of inhibiting bacterial growth (e.g., S. aureus growth) and treating bacterial infections (e.g., S. aureus infections). The disclosure further relates to antibody-drug conjugates of rifamycin analog compounds and antibodies, for example, antibodies specific for infectious disease-related targets such as membrane glycoprotein receptor (MSR1), wall teichoic acids (WTA) or Protein A, and methods of use thereof to inhibit bacterial growth and treat bacterial infections.
Claims15
A compound having a structure according to formula (V):
- or a pharmaceutically acceptable salt thereof wherein:
- X is selected from —O— and —NR*—;
- Ra is selected from hydrogen and —OR*;
- R6 is selected from RN, an aliphatic C6-C20 hydrocarbon, an aromatic C5-C20 hydrocarbon, a heteroaromatic C1-C20 hydrocarbon, a cyclic aliphatic C3-C20 hydrocarbon, a heterocyclic C1-C20 hydrocarbon, and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted with one or more of -OH, —OR*, —NH2, —NHR*, —N(R*)2, —N(R*)3+, —N(R*)-(C═O)-R*, —(C═O)-R*, —CHO, —CO2H, —CO2R* and combinations thereof;
- RN is selected from:
- wherein the symbol represents the point of attachment;
- and R′, R″ and R′″ are selected from a hydrogen, a C1-C6 aliphatic hydrocarbon, and a protecting group selected from FMOC and Boc, or wherein R′ and R″ together form an aliphatic monocyclic, an aliphatic bicyclic, or an aliphatic polycyclic structure;
- and
- R* is independently at each occurrence selected from hydrogen, an aliphatic C1-C6 hydrocarbon, an aromatic C6-C7 hydrocarbon, and combinations thereof, which optionally comprise 1-3 heteroatoms selected from O, N and combinations thereof.
A compound having a structure according to formula (V):
- or a pharmaceutically acceptable salt thereof wherein:
- X is selected from —O— and —NR*—;
- Ra is selected from hydrogen and —OR*;
- R6 is selected from RN, an aliphatic C6-C20 hydrocarbon, an aromatic C5-C20 hydrocarbon, a heteroaromatic C1-C20 hydrocarbon, a cyclic aliphatic C3-C20 hydrocarbon, a heterocyclic C1-C20 hydrocarbon, and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted with one or more of -OH, —OR*, -NH2, —NHR*, —N(R*)2, —N(R*)3+, —N(R*)-(C═O)-R*, —(C═O)-R*, —CHO, —CO2H, —CO2R* and combinations thereof;
- RN is selected from:
- wherein R′, R″ and R′″ are independently at each occurrence selected from hydrogen and an aliphatic hydrocarbon, and wherein the symbol represents the point of attachment, and
- R* is independently at each occurrence selected from hydrogen, an aliphatic C1-C20 hydrocarbon, an aromatic C5-C20 hydrocarbon, a heteroaromatic C1-C20 hydrocarbon, a cyclic aliphatic C3-C20 hydrocarbon, a heterocyclic C1-C20 hydrocarbon, and combinations thereof, which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.
A compound having the structure selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.