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.
Claims8
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;
- and
- adding an acid, to the mixture, thereby creating a compound of formula (III) according to following reaction:
- R1, R2, R3, and R4 are independently H, F, Cl, Br, I, CH3, CF3, SCH3 or CH2CH3, 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;
- and
- the incubating step comprises at least one of:
- incubating the mixture at a temperature of from about 60° C. to about 70° C.,
- the mixture comprising a molar ratio of the base to the compound of formula (II) of from about 5:1 to about 8:1, and
- incubating the mixture for from about 15 hours to about 30 hours.
Dependencies are inferred from the claim text.