Multitarget FAAH and COX inhibitors and therapeutical uses thereof
Multitarget inhibitors of the enzymes Fatty Acid Amide Hydrolase (FAAH), Cyclooxygenase-1 (COX-1) and/or Cyclooxygenase-2 (COX-2) having a specific carbamate moiety on the meta or ortho position of the A ring of a substituted biphenyl core and having an halogen in the ortho position of the B ring of the biphenyl core. Also concerns the therapeutical application of the multitarget inhibitors, in particular, in the prevention and treatment of cancer.
1. A compound that simultaneously inhibits the enzymes Fatty Acid Amide Hydrolase (FAAH), Cyclooxygenase-1 (COX-1) and/or Cyclooxygenase-2 (COX-2) having the formula (la)
or pharmaceutically acceptable salts thereof,
wherein
the phenyl ring A is substituted in the meta or ortho position with the carbamoyl group,
R 1 is halogen,
R 2 is a group —CHR 5 —(C═O)—R 6
wherein R 5 is (C 1 -C 6 )_alkyl, and R 6 is —OH, and R 3 and R 4 are independently selected from a group consisting of H, (C 1 -C 10 ) _alkyl, (C 3 -C 9 ) cycloalkyl (C 0 -C 4 ) alkyl, phenyl (C 0 -C 4 ) alkyl, phenyl and (C 3 -C 9 )_cycloalkyl.
2. A compound according to claim 1 , wherein R 1 is F and R 2 is
a group —CHR 5 —(C═O)—R 6 , wherein R 5 is (C 1 -C 6 )_alkyl, and R 6 is —OH.
3. A compound according to claim 1 , wherein R 3 and R 4 are independently selected from a group consisting of (C 1 -C 10 )_alkyl, (C 3 -C 9 ) cycloalkyl_(C 0 -C 4 )_alkyl, and phenyl (C 0 -C 4 )_alkyl.
4. A compound according to claim 1 , wherein
R 3 is H, and
R 4 is (C 1 -C 10 ) alkyl, (C 3 -C 9 ) cycloalkyl (C 0 -C 4 ) alkyl, or phenyl (C 0 -C 4 ) alkyl.
5. A compound according to claim 1 , wherein
R 1 is F; R 2 is —CHR 5 —(C═O)—R 6 wherein R 5 is CH 3 , R 6 is OH,
R 3 is H, and
R 4 is (C 1 -C 10 ) alkyl, (C 3 -C 9 ) cycloalkyl (C 0 -C 4 )_alkyl, or phenyl (C 0 -C 4 )alkyl.
6. A pharmaceutical composition comprising a compound of formula (la) or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutical acceptable carrier and/or excipient.