Substituted 2-alkyl-1-oxo-n-phenyl-3-heteroaryl-1,2,3,4-tetrahydroisoquinoline-4-carboxamides for antimalarial therapies
AssigneesSt. Jude Children's Research Hospital, Rutgers, The State University of New Jersey, Mmv Medicines for Malaria Venture
InventorsRodney Kiplin Guy, Fangyi Zhu, Wendyam Armand Guiguemde, David Floyd, Spencer Knapp, Philip Stein, Steve Castro
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Abstract
In one aspect, the invention relates to novel substituted 2-alkyl-1-oxo-N-phenyl-3-heteroaryl-1,2,3,4-tetrahydroisoquinoline-4-carboxamides; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating and/or preventing malaria. 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 invention.
Claims22
1-24. (canceled)
A method for the prevention or treatment of malaria comprising the step of administering to a primate in need thereof, a therapeutically effective amount of at least one compound having a structure represented by a Formula (I):
- wherein Ar is monocyclic heteroaryl selected from 2-furanyl, 3-furanyl, imidazolyl, 4-isoxazolyl, 4-pyrazolyl, N-methyl-4-pyrazolyl, 5-thiazolyl, 5-isothiazolyl, 4-isothiazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, or 4-pyridazinyl and, valence permitting, is substituted with 0-3 groups selected from fluoro, chloro, bromo, iodo, cyano, methyl, trifluoromethyl, methoxyl, or ethoxyl;
- R1 is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, or cyclobutyl and, valence permitting, is substituted with 0-3 groups selected from fluoro, chloro, bromo, iodo, cyano, methoxyl, or ethoxyl;
- R2 and R3 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, cyano, fluoro, chloro, bromo, or iodo;
- R4 is hydrogen, C1-C4 alkyl, or a hydrolysable residue;
- R5a and R5b are independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxyl, C1-C4 haloalkoxyl, or C1-C4 polyhaloalkoxyl;
- R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxyl, C1-C4 haloalkoxyl, or C1-C4 polyhaloalkoxyl;
- provided that if Ar is unsubstituted thiopheneyl, then R1 is not isopropyl, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, as well as tautomers, geometrical isomers, optically active forms thereof.
A compound having a structure represented by a formula:
- wherein Ar1 is selected from 3-pyridinyl, 4-isoxazolyl, N-methyl-4-pyrazolyl, 4-pyrazolyl, 4-isothiazolyl, 5-thiazolyl, 5-pyrimidinyl, or 4-pyridazinyl;
- R1 is selected from CF3 or (CH3)2CH;
- R2 and R3 are independently selected from H, H, OCH3 or F;
- Ar2 has a structure represented by a formula:
- wherein R4a, R4b and R5 are independently selected from H, CN, F, Cl or OCF3, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, as well as tautomers, geometrical isomers, optically active forms thereof, as well as tautomers, geometrical isomers, optically active forms thereof.
A process for the preparation of a compound of Formula (II) wherein Ar1 is selected from 3-pyridinyl, 4-(1-methylpyrazolyl) or 4-pyrazolyl;
- R1 is selected from CF3, propyl, cyclopropyl or (CH3)2CH;
- R2 and R3 are independently selected from H, OCH3 or F;
- R5a, R5b and R6 are independently selected from H, CN, F, Cl or OCF3, comprising a step of reacting a carboxylic acid of formula 2a wherein Ar1 is selected from 3-pyridinyl, 4-(1-methylpyrazolyl) or 4-pyrazolyl;
- R1 is selected from CF3, propyl, cyclopropyl or (CH3)2CH;
- R2 and R3 are independently selected from H, OCH3 and F with an aryl amine of formula 3a wherein R4a, R4b and R are independently selected from H, CN, F, Cl or OCF3:
An intermediate of Formula 2a
- selected from 3-pyridinyl, 4-(1-methylpyrazolyl) or 4-pyrazolyl;
- R1 is selected from CF3, propyl, cyclopropyl or (CH3)2CH;
- R2 and R3 are independently selected from H, OCH3 or F;
- and R5a, R5b and R6 are independently selected from H, CN, F, Cl or OCF3 selected from:
- 1-oxo-2-isobutyl-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(2,2,2-trifluoroethyl)-3-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(2,2,2-trifluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(2,2,2-trifluoroethyl)-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(cyclopropylmethyl)-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(1-butyl)-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-isobutyl-3-(isothiazol-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-isobutyl-3-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-isobutyl-3-(5-cyanothiophen-2-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(2,2,2-trifluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-cyclopropylmethyl-3-(5-cyanothiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- 1-oxo-2-(1-butyl)-3-(5-cyanothiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
- or
- 2-isobutyl-7-methoxy-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid.
Dependencies are inferred from the claim text.