Truxillic acid monoester-derivatives as selective fabp5 inhibitors and pharmaceutical compositions and uses thereof

A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound having the structure:

• wherein
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when the compound has the stereochemistry of structure I
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl, or
• wherein when the compound has the stereochemistry of structure I and when one of R1 or R2 is —C(═O)OH and R4, R5, R6, R7, R9, R10, R11 and R12 are each H and R3 and R8 are each —OCH3, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is 1-naphthalene or —C(═O)O-alkyl-R14 where the alkyl is a C1 alkyl and the R14 is 9-fluorene;
• wherein when the compound has the stereochemistry of structure II
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when the compound has the stereochemistry of structure III
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• or an enantiomer or racemate thereof;
• or a pharmaceutically acceptable salt thereof.

A method of treating pain in a subject without the side-effects of excessive inhibition of FABP3 comprising administering to the subject an effective amount of a compound having the structure:

• wherein
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when the compound has the stereochemistry of structure I
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when the compound has the stereochemistry of structure II
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when the compound has the stereochemistry of structure III
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• or a method comprising administering to the subject an effective amount of a compound having the structure:
• wherein
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when the compound has the stereochemistry of structure I
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when one of R1 or R2 is —C(═O)OH and R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each H, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is methyl, 2-propyl, pentyl, octyl, —CH2C(O)CH3, 1-naphthalene, 2-naphthalene, 2-indane, 2-methylphenyl, 2-iodophenyl, 2-ethynylphenyl, 2-(1,1′-biphenyl), 3-(1,1′-biphenyl), 4-(1,1′-biphenyl), 2-(2′-hydroxy-1,1′-biphenyl), 2,4,5-trichlorophenyl, 2-phenylcyclohexyl, 1-naphthalene-6-acetamide, 1-naphthalene-5-ethyne, cyclohexyl, 3-[1-(3,6,9-trioxa-dodecanyl)-1,2,3-triazol-4-yl]phenyl, or —C(═O)O-alkyl-R14 where the alkyl is a branched C2 alkyl and the R14 is phenyl or the alkyl is a C1 alkyl and the R14 is phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, or 9-fluorene,
• wherein when one of R1 or R2 is —C(═O)OH and R4, R5, R6, R7, R9, R10, R11 and R12 are each H and R3 and R8 are each —OCH3, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is 1-naphthalene, 2-naphthalene, 2-phenylcyclohexyl, or —C(═O)O-alkyl-R14 where the alkyl is a C1 alkyl and the R14 is 9-fluorene,
• wherein when one of R1 or R2 is —C(═O)OH and R4, R5, R6, R7, R9, R10, R11 and R12 are each H and R3 and R8 are each —Cl or —Br, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is 2-phenylcyclohexyl,
• wherein when one of R1 or R2 is —C(═O)OH and R4, R5, R6, R9, R10, and R11 are each H and R3, R7, Re and R12 are each —Cl, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is 2-phenylcyclohexyl,
• wherein when one of R1 or R2 is —C(═O)OH and R3, R4, R6, R7, R8, R9, R11, and R12 are each H and R5 and R10 are each —OH, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is 1-naphthalene,
• wherein when one of R1 or R2 is —C(═O)OH and R3, R6, R7, R8, R11, and R12 are each H, R4 and R9 are each OCH3, and R5 and R10 are each —OH, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is 1-naphthalene,
• wherein when the compound has the stereochemistry of structure II
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• wherein when one of R1 or R2 is —C(═O)OH and R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each H, then the other of R1 or R2 is other than —C(═O)OR13 where R13 is methyl, 2-propyl, pentyl, octyl, —CH2C(O)CH3, 1-naphthalene, 2-naphthalene or 2-methylphenyl, or —C(═O)O-alkyl-R14 where the alkyl is a branched C2 alkyl and the R14 is phenyl,
• wherein when the compound has the stereochemistry of structure III
• then
• one of R1 or R2 is —C(═O)OH and the other of R1 or R2 is —C(═O)OR13 or —C(═O)O-alkyl-R14,
• wherein
• R13 is cycloalkyl, aryl or heteroaryl, and
• R14 is cycloalkyl, aryl or heteroaryl;
• and
• R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently, H, —OH, —OR15, or halogen
• wherein R15 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl,
• or an enantiomer or racemate thereof;
• or a pharmaceutically acceptable salt thereof.