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.

Provided is a method for industrially advantageously synthesizing a production intermediate of a quinolinecarboxamide derivative or a salt thereof. The present invention provides a method for producing a quinolinecarboxylic acid derivative of formula (4) or a salt thereof, including reacting an aniline of the following formula (1), in the presence of boron trifluoride-tetrahydrofuran complex or boron trifluoride-diethyl ether complex, with an aldehyde of formula (2) and subsequently reacting the resulting compound with an α-keto acid of formula (3), wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, or the like, R.sup.5 represents a hydrogen atom, a lower alkyl group, or the like, and R.sup.6 represents a hydrogen atom, a lower alkyl group, or the like.

##STR00001##

Provided is a method for industrially advantageously synthesizing a production intermediate of a quinolinecarboxamide derivative or a salt thereof. The present invention provides a method for producing a quinolinecarboxylic acid derivative of formula (4) or a salt thereof, including reacting an aniline of the following formula (1), in the presence of boron trifluoride-tetrahydrofuran complex or boron trifluoride-diethyl ether complex, with an aldehyde of formula (2) and subsequently reacting the resulting compound with an α-keto acid of formula (3), wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, or the like, R.sup.5 represents a hydrogen atom, a lower alkyl group, or the like, and R.sup.6 represents a hydrogen atom, a lower alkyl group, or the like.

##STR00001##

Compositions containing a phenylquinoline derivative compound having peroxisome proliferator-activated receptor a (PPARα) agonistic activity, and methods of their use in enhancing PPARα activity in retinal cells, and in treating ocular disorders or conditions, such as but not limited to retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and diabetic macular edema are disclosed.

Disclosed herein are compounds, 3,4,6,8-substituted-2-([1′-biphenyl]-4-yl)quinoline analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. The disclosed compounds can demonstrate flip-flop kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. The disclosed compounds can demonstrate a sustained pharmacokinetic profile instead of an immediate release profile. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Disclosed herein are compounds, 3,4,6,8-substituted-2-([1′-biphenyl]-4-yl)quinoline analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. The disclosed compounds can demonstrate flip-flop kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. The disclosed compounds can demonstrate a sustained pharmacokinetic profile instead of an immediate release profile. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

A compound represented by Formula (1): ##STR00001##
The compound can be used as insecticides.

A compound represented by Formula (1): ##STR00001##
The compound can be used as insecticides.

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.

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.