Organotrifluoroborate mimics of amino acids and uses thereof
AssigneesThe United States of America, as represented by the Secretary, Department of Health and Human, Human Services
InventorsZhibo Liu, Xiaoyuan Chen
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Abstract
Disclosed are boron mimics of amino acids which are compounds, salts, solvates, or stereoisomers of the Formula (I): wherein A, R1, R2, and R3 are defined herein, and processes for the preparation of the compounds, salts, solvates, or stereoisomers. The compounds, salts, solvates, or stereoisomers of Formula (I) may be used in boron neutron capture therapy. The compounds, salts, solvates, or stereoisomers of Formula (I) with at least one fluorine being, 18F are useful for imaging tumors using positron emission tomography and for evaluating the treatment potential of anti-cancer drugs.
Claims30
A compound of the Formula (I):
- wherein
- A is optionally substituted alkylenyl, wherein the substituents are selected from halo, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido,
- wherein each substituent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally fused with one or more groups selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
- wherein each substituent alkoxyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido,
- wherein substituent guanidino is optionally further substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
- wherein each of R1, R2, and R3 is independently H or alkyl, the alkyl optionally substituted with one or more substituents selected from halo, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido;
- or
- A and R1 together with the nitrogen of the NR1R2R3+ moiety form a heterocycloalkyl or heteroaryl ring, wherein the ring is optionally substituted with one or more substituents selected from halo, alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido;
- or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
-3. (canceled)
-12. (canceled)
(canceled)
-19. (canceled)
A method of imaging tumor uptake in a tissue, the method comprising:
- identifying an amino acid having at least one COO− moiety,
- generating a boramino acid mimic, wherein the boramino acid mimic has the same structure as the amino acid except a COO− moiety of the amino acid is replaced with a BF3− moiety in the boramino acid mimic, wherein at least one fluorine is 18F,
- exposing a tissue with a tumor to the boramino acid mimic, and
- utilizing positron emission tomography to take an image of the tumor within the tissue.
-23. (canceled)
A process for the preparation of a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of the Formula (I):
- the process comprising reacting a compound of Formula (III)
- with fluorine to produce a compound of Formula (I),
- wherein
- Bpin is boronic acid pinacol ester;
- A is optionally substituted alkylenyl, wherein the substituents are selected from halo, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido,
- wherein each substituent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally fused with one or more groups selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
- wherein each substituent alkoxyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido,
- wherein substituent guanidino is optionally further substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
- wherein each of R1, R2, and R3 is independently H or alkyl, the alkyl optionally substituted with one or more substituents selected from halo, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido;
- or
- A and R1 together with the nitrogen of the NR1R2R3+ moiety form a heterocycloalkyl or heteroaryl ring, wherein the ring is optionally substituted with one or more substituents selected from halo, alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, COOR2, NR2R3, CONR2R3, SR2, guanidino, alkynyl, and azido.
(canceled)
A method of imaging tumor uptake, the method comprising
- identifying an amino acid having at least one COO− moiety,
- generating a boramino acid mimic, wherein the boramino acid mimic has the same structure as the amino acid except a COO− moiety of the amino acid is replaced with a BF3− moiety in the boramino acid mimic, wherein at least one fluorine is 18F,
- administering to a subject with a tumor an effective amount of the boramino acid mimic, and
- utilizing positron emission tomography to take an image of the tumor within the subject.
Dependencies are inferred from the claim text.