Compositions and methods for inhibiting dihydroorotate dehydrogenase
AssigneeClear Creek Bio, Inc.
InventorsVikram S. Kumar, David P. Hesson, Ping Huang, Mo Jia, Xianjun You
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Abstract
The invention provides therapeutic compositions that contain an inhibitor of dihydroorotate dehydrogenase (DHODH) and promote sustained elevation of dihydroorotate (DHO) levels in a patient. The compositions are useful for treating disorders associated with unregulated DHODH activity, such as acute myeloid leukemia. The invention also provides methods of determining therapeutically effective doses of compositions that contain a DHODH inhibitor. The invention further provides methods of synthesis of 2-(2′-halo-1-1′-biphenyl-4-yl)-quinoline carboxylic acids, which are useful as DHODH inhibitors.
Claims20
A method of making a 2-(2′-halo-1-1′-biphenyl-4-yl)-quinoline carboxylic acid, the method comprising:
- incubating a compound of formula (I) with a compound of formula (II) in a mixture comprising a base at a temperature of from 60° C. to 70° C.;
- and
- adding an acid, to the mixture, thereby creating a compound of formula (III) according to following reaction:
- wherein:
- R1, R2, R3, and R4 are independently H, F, Cl, Br, I, CH3, CF3, SCH3 or CH2 CH3, at least two of R1, R2, R3, and R4 being H;
- R5 is H, alkoxy of 1-3 carbon atoms, or alkyl of 1-2 carbon atoms;
- R6 and R7 are independently H, F, Cl, Br, alkyl of 1-5 carbon atoms, NO2, OH, CF3 or OCH3;
- X is a halogen.
A method of making a 2-(2′-halo-1-1′-biphenyl-4-yl)-quinoline carboxylic acid, the method comprising:
- incubating a compound of formula (I) with a compound of formula (II) in a mixture comprising a base for from 15 hours to 30 hours;
- and
- adding an acid, to the mixture, thereby creating a compound of formula (III) according to following reaction:
- wherein:
- R1, R2, R3, and R4 are independently H, F, Cl, Br, I, CH3, CF3, SCH3 or CH2 CH3, at least two of R1, R2, R3, and R4 being H;
- R5 is H, alkoxy of 1-3 carbon atoms, or alkyl of 1-2 carbon atoms;
- R6 and R7 are independently H, F, Cl, Br, alkyl of 1-5 carbon atoms, NO2, OH, CF3 or OCH3;
- X is a halogen.
Dependencies are inferred from the claim text.