Prodrugs of glutamine analogs
AssigneesThe Johns Hopkins University, Ustav Organicke Chemie A Biochemie Av Cr, V.V.I.
InventorsBarbara Slusher, Rana Rais, Lukas Tenora, Pavel Majer, Andrej Jancarik
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Abstract
The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R1, R2, R2′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON). The disclosure also provides compounds having formula (I) for use in treating cancer.
Claims25
A compound having formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- X is selected from the group consisting of a bond, —O—, and —(CH2)n—, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
- R1 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, Q cycloalkyl, substituted C3-C10 cycloalkyl, C1-C6 alkenyl, and substituted C2-C6 alkenyl;
- R2 is —C(═O)—O—(CR3R4)m—O—C(═O)—R10;
- R2′ is selected from the group consisting of H, C1-C6 alkyl, and substituted C1-C6 alkyl;
- each R3 and R4 are independently H, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, —(CR3R4)m—NR5R6, or
- m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
- R5 and R6 are independently H or alkyl;
- and
- R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
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7-13. (canceled)
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A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a compound of having formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- X is —(CH2)n—, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
- R1 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, C1-C6 alkenyl, and substituted C2-C6 alkenyl;
- R2 is an amino acid, an N-substituted amino acid, or —C(═O)—O—(CR3R4)m—O—C(═O)—R10;
- R2′ is selected from the group consisting of H, C1-C6 alkyl, and substituted C1-C6 alkyl;
- each R3 and R4 are independently H, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, —(CR3R4)m—NR5R6, or
- m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
- R5 and R6 are independently H or alkyl;
- and
- R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
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Dependencies are inferred from the claim text.