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US 10,882,871 B2Granted
18/19F-labelled compounds which target the prostate specific membrane antigen
AssigneesBritish Columbia Cancer Agency Branch, The University of British Columbia
InventorsFrancois Benard, Kuo-shyan Lin, David Perrin, Zhibo Liu, Hsiou-ting Kuo, Jinhe Pan, Aron Roxin, Mathieu Lepage
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Abstract
This disclosure relates to novel compounds comprising a zwitterionic trifluoroborate prosthetic group which target prostate-specific membrane antigen (PSMA), e.g. in prostate cancer. The compounds have Formula I, wherein each R1 is an anionic group, L is a linker and R2B-F3 is —N(R3)2CH2BF3, a pyridinium group substituted with BF3 or methyl BF3, or an azole group substituted with methyl BF3. Methods and uses of imaging and treating PSMA-expressing cancers are also disclosed.
Claims20
A compound, the compound having Formula I or being a salt or solvate of Formula I
- wherein:
- each R1 is independently CO2H, PO3H2, SO2H, SO3H, SO4H or OPO3H2;
- R2BF3:
- is —N(R3)2CH2BF3 wherein each R3 is independently:
- H, methyl, X2-X15 akyl, X2-X15 heteroalkyl, X3-X15 aryl or X3-X15 heteroaryl;
- wherein the X2-X15 akyl or the X2-X15 heteroalkyl is one or more of:
- branched or linear;
- acyclic, cyclic or multi-cyclic;
- saturated or unsaturated;
- and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate;
- wherein the X3-X15 aryl or the X3-X15 heteroaryl is one or more of:
- cyclic or multi-cyclic;
- aromatic or nonaromatic;
- and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate;
- wherein each X is independently C, N, O, P, S or Se;
- and wherein the N in the —N(R3)2CH2BF3 is linked to the X2-X15 akyl, the X2-X15 heteroalkyl, the X3-X15 aryl or the X3-X15 heteroaryl through at least two C atoms in the X2-X15 akyl, the X2-X15 heteroalkyl, the X3-X15 aryl or the X3-X15 heteroaryl;
- forms a pyridinium group that is C-substituted with —B−F3 or N-substituted with CH2B−F3, and which is optionally substituted with one or more halogens, methyl groups, aryl groups, branched or linear alkyl groups, hydroxyls, esters, thiols, thioethers, amines, ketones, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups;
- or
- forms:
- in which R is alkyl or aryl;
- in which R is alkyl or aryl;
- wherein the azole ring is optionally further substituted with one or more halogens, alkyls, ketones, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups;
- and
- L is ether, ester, thioether, disulfide, thioester, amide, carbamate, ureido, phosphodiester, polyethylene glycol (PEG), peptide, polypeptide or R4R5R6 in which R4, R5 and R6 together form X1-X100 alkyl, X1-X100 heteroalkyl, X3-X100 aryl or X3-X100 heteroaryl, wherein the X1-X100 alkyl or the X1-X100 heteroalkyl of R4R5R6 is one or more of:
- branched or linear;
- acyclic, cyclic or multi-cyclic;
- saturated or unsaturated;
- and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate;
- wherein the X3-X15 aryl or the X3-X15 heteroaryl is one or more of:
- cyclic or multi-cyclic;
- aromatic or nonaromatic;
- and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate;
- and wherein each X is independently C, N, O, P, S or Se.
30 more elements
A compound, which:
- or a salt or solvate thereof.
A compound, the compound having Formula II or a salt or solvate thereof
- wherein:
- each R1 is independently CO2H;
- R2BF3:
- is -N(CH3)2CH2BF3;
- or
- in which R in the pyridine substituted —OR, —SR, —NHR, —NR—or —NR2 is aryl or branched or linear alkyl, and in which the pyridinium ring is optionally further substituted with one or more of halogens, aryls, branched or linear alkyls, carboxaldehydes, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups;
- or
- forms:
- in which R is alkyl or aryl;
- in which R is alkyl or aryl;
- wherein the azole ring is optionally further substituted with one or more halogens, alkyls, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups;
- and
- L is R4R5R6 in which:
- R4 is absent, -CH2-, -CH2CH2- or -CH2CH2CH2-.
- R5 is -S-, -NHC(O)-, -C(O)-, -C(O)O- or -OC(O)-;
- R6 is (phenyl)CH2R7, (pyridyl)CH2R7,
- or wherein R7 is absent or
- wherein R8 is a an aliphatic or aromatic hydrophobic side chain of a natural or artificial amino acid, and wherein R9 is a C1-C30 alkyl or X1-X30 heteroalkyl that is one or more of:
- branched or linear;
- acyclic, cyclic or multi-cyclic;
- saturated or unsaturated;
- and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, -OPO3H2 and —OSO3H;
- and wherein each X is independently C or a heteroatom selected from N, O, P, S or Se.
20 more elements
Dependencies are inferred from the claim text.