Patent NZ-512306-A (NZ)
Title: Acetylenic sulfonamide thiol tace inhibitors
Inventor: LEVIN JEREMY IAN
IPC: A61P31/04
Filed: 2000-01-27
Abstract: A compound having the formula B where n'= 1 or 2, or n'= 2 then A is absent, or when n'= 1, then A is H or R14C(=W)-. W is oxygen or sulfur. X is SO2, or-P (O)-R10. Y is aryl or heteroaryl as defined below, with the proviso that X and Z may not be bonded to adjacent atoms of Y. Z is O, NH, CH2 or S. R1 is hydrogen, aryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms. R2 is hydrogen, aryl or heteroaryl as defined below, cycloalkyl of 3-6 carbon atoms,-C5-C8-cycloheteroalkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, or CONR8R9; or R1, and R2, together with the atom to which they are attached, may form a ring wherein R1, and R2 represent a divalent moiety of the formula I. In formula I, Q = a carbon-carbon single or double bond, O, S, SO,-N-R11, or -CONR15; m = 1-3; r = 1 or 2, with the proviso that when Q is a bond, r is equal to 2. Aryl is phenyl or naphthyl optionally substituted by one to two substituents selected from R7, where R7, is as defined below. Heteroaryl is defined as optionally mono-or di- substituted by R7, where K is defined as O, S or-NR15. R3 is hydrogen or alkyl of 1-6 carbon atoms; or R1, and R3, together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R1 and R3 represent divalent moieties of the formulae II and III. In formulae II and III Q and m are as defined above. A is aryl or heteroaryl; s is 0-3; u is 1-4; R4 and R5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms,-CN, -CCH. R6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms or-C5-Cg-cycloheteroalkyl as defined below. R7 is hydrogen, halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -OR8,-CN,-COR8, perfluoroalkyl of 1-4 carbon atoms,-O, perfluoroalkyl of 1-4 carbon atoms, CONR8R9,-S (O) nR8, -OPO (OR8) OR9, -PO (OR8) R9, -OC (O) NR8R9, -C(O)NR8OR9, -COOR8, -S03 H,-NR,, R,,-N [ (Cl-),], NR,,-NRCOR, -NRCOOR, -S02NRR, -NO2, -N(R8)SO2R9, -NR8CONR8R9, -NR8C(=NR9)NR8R9, -tetrazol- 5-yl, -SO2NHCN, -SO2NHCONR8R9, phenyl, heteroaryl as defined above, or-C5-C8-cycloheteroalkyl as defined below; wherein- NR8R9 may form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring; wherein-C5-C8- cycloheteroalkyl is defined as in figure I. In figure I, K is defined as above; R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl or-C5-C8- cycloheteroalkyl; or R8 and R9, together with the nitrogen atom to which they are attached may form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine or azetidine ring. R10 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl as defined above; R11, is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3- 6 carbon atoms, aryl, heteroaryl,-S (O)nR8, -COOR8, - CONR8R9, -SO2NR8R9 or -COR8. R12 and R13 are independently selected from H,-OR8,-NR8R9, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl,-COOR8; -CONR8R9; or R12 and R13 together form a-C3-C6-cycloalkyl of 3-6 carbon atoms or a-C5-C8- cycloheteroalkyl ring; or R12 and R13 together with the carbon to which they are attached, form a carbonyl group; with the proviso that R10 and R12or R11 and R12 may form a cycloheteroalkyl ring, wherein cycloheteroalkyl is as defined above, when they are attached to adjacent atoms; Rl4 is-OR8,-NR8R9, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl; R15 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3- 6 carbon atoms; and n is O-2; or a pharmaceutically acceptable salt. Inhibiting pathological changes mediated by TNF-a converting enzyme (TACE) in mammals treating rheumatoid arthritis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection.