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US 8,283,370 B2Granted
Imidazolidinedione derivatives as antimalarial agents, preparation thereof, and methods of use
AssigneeThe United States of America as represented by the Secretary of the Army
InventorsAi Jeng Lin, Michael P. Kozar, Michael T. O'Neil, Alan J. Magill, David L. Saunders
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Abstract
Embodiments disclosed herein relate to new imidazolidinedione derivatives, methods of making these compounds, and methods of using the same to prevent, treat, or inhibit malaria in a subject.
Claims20
A compound having the formula I:
- or a tautomer thereof, or their pharmaceutically acceptable salts,
- wherein:
- R1 is aryl or heteroaryl, each optionally substituted with one or more R1a;
- each R1a is independently selected from the group consisting of hydroxyl, carboxyl, halo, aralkyl, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy, optionally substituted with up to 5 fluoro;
- R2 is an optionally substituted substituent selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl(CH2)n—, aryl(CH2)n—, heteroaryl(CH2)n—, alkylaryl, heterocyclyl(CH2)n—, aminoalkyl, R2aR2bN(CH2)n—, or R2 is R5O—;
- n is an integer selected from 0, 1, 2, 3, 4, 5, 6, or 7;
- R2a is selected from the group consisting of hydrogen, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
- R2b is selected from the group consisting of hydrogen, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
- R3 is C1-10 alkyl optionally substituted with up to 5 fluoro;
- and
- R5 is an optionally substituted substituent selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl(CH2)n—, aryl(CH2)n—, heteroaryl(CH2)n—, alkylaryl, heterocyclyl(CH2)n—, aminoalkyl, and R2aR2bN(CH2)n—.
8 more elements
A method for making a compound of formula II:
- or a tautomer thereof, or their pharmaceutically acceptable salts,
- comprising intermixing a compound of formula IIa:
- with a compound of formula A:
- in the presence of a base,
- wherein:
- the base is selected from the group consisting of triethyl amine, diisopropyul ethyl amine, dimethyl amino pyridine (DMAP), DBU, DBN, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, and combinations thereof;
- X is halo or R4C(═O)O—;
- R1 is aryl or heteroaryl, each optionally substituted with one or more R1a;
- each R1a is independently selected from the group consisting of hydroxyl, carboxyl, halo, aralkyl, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy, optionally substituted with up to 5 fluoro;
- R3 is C1-10 alkyl optionally substituted with up to 5 fluoro;
- and
- R4 is selected from the group consisting of aryl, heteroaryl, C3-7 cycloalkyl, and C1-6 alkyl, each optionally substituted with up to 5 fluoro.
9 more elements
A method for making a compound of formula III:
- or a tautomer thereof, or their pharmaceutically acceptable salts,
- comprising intermixing a compound of formula IIIa:
- with a compound of formula B:
- under heating conditions,
- wherein:
- R1 is aryl or heteroaryl, each optionally substituted with one or more R1a;
- each R1a is independently selected from the group consisting of hydroxyl, carboxyl, halo, aralkyl, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy, optionally substituted with up to 5 fluoro;
- R3 is C1-10 alkyl optionally substituted with up to 5 fluoro;
- R6 is selected from the group consisting of C1-6 alkyl, C3-10 cycloalkyl, aryl, heteroaryl, heterocyclyl, C3-10 cycloalkylCH2—, arylCH2—, heteroarylCH2—, heterocyclylCH2—, R6aR6bN(CH2)n—;
- n is an integer selected from 1, 2, 3, 4, 5, or 6;
- R6a is selected from the group consisting of hydrogen, and C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
- and
- R6b is selected from the group consisting of alkoxycarbonyl, and C1-6 alkyl optionally substituted with up to 5 fluoro.
10 more elements
A compound represented by structural formula 5, or 6,
- or a pharmaceutically acceptable equivalent or pharmaceutically acceptable salt of said compound;
- wherein R is an optionally substituent selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heterocyclic rings, and aminoalkyl.
Dependencies are inferred from the claim text.