Patent EA-005207-B1 (EA)
Title: Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
Inventor: LINK JAMES
IPC: C07D319/18
Filed: 1999-12-29
Abstract: 1. A compound of formula I wherein R1, R2, R3, R4, and R5 are independently selected from a. hydrogen, b. halogen, c. C1-C10 alkyl, d. haloalkyl, e. C1-C10 alkoxy, f. cyano, g. nitro, h. carboxaldehyde, and with the proviso that at least one of R1 or R3 is a "cis-cinnamide" or a "trans-cinnamide", defined as , wherein R8 and R9 are independently selected from a. hydrogen, and b. C1-C10 alkyl, c. carboxy C1-C10 alkyl, d. C1-C10 alkylaminocarbonyl alkyl, and e. C1-C10 dialkylaminocarbonyl-C1-C10 alkyl, and R10 and R11 are independently selected from a. hydrogen, b. C1-C10 alkyl; c. C3-C12 cycloalkyl, d. C1-C10 alkoxycarbonyl-C1-C10 alkyl, e. hydroxy-C1-C10alkyl, f. heterocyclyl represent a 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring, g. heterocyclyl-C1-C10alkyl, wherein heterocyclyl as defined above; h. heterocyclylamino, i. substituted heterocyclyl, and j. substituted heterocyclylalkyl, or where NR10R11 is heterocyclyl or substituted heterocyclyl, where substituents are independently selected from 1) C1-C10 alkyl, 2) C1-C10 alkoxy, 3) C1-C10 alkoxy-C1-C10alkyl, 4) C3-C12 cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8) heterocyclyl-C1-C10alkylaminocarbonyl, 9) hydroxy, 10) hydroxy-C1-C10alkyl, 11) hydroxy-C1-C10alkoxy-C1-C10alkyl, 12) carboxy, 13) carboxy-C1-C10alkyl, 14) carboxycarbonyl, 15) carboxaldehyde, 16) C1-C10 alkoxycarbonyl, 17) aryl-C1-C10alkoxycarbonyl, 18) amino-C1-C10alkyl, 19) amino-C1-C10alkanoyl, 20) carboxamido, 21) C1-C10alkoxycarbonyl-C1-C10alkyl, 22) carboxamido-C1-C10 alkyl, 23) cyano, 24) tetrazolyl, 25) substituted tetrazolyl, 26) C1-C10 alkanoyl, 27) hydroxy-C1-C10alkanoyl, 28) C1-C10alkanoyloxy, 29) C1-C10alkanoylamino, 30) C1-C10alkanoyloxy-C1-C10alkyl, 31) C1-C10alkanoylamino-C1-C10alkyl, 32) sulfonate, 33) C1-C10alkylsulfonyl, 34) C1-C10alkylsulfonylaminocarbonyl, 35) arylsulfonylaminocarbonyl, and 36) heterocyclylsulfonylaminocarbonyl, and wherein Ar is a substituted aryl or substituted heteroaryl group, where substitutions are independently selected from a. hydrogen, b. halogen, c. C1-C10 alkyl, d. aryl, e. halo C1-C10 alkyl, f. hydroxy, g. C1-C10 alkoxy, h. C1-C10 alkoxy-C1-C10alkyl, i. C1-C10alkoxycarbonyl, j. C1-C10alkoxy-C1-C10alkoxy, k. hydroxy-C1-C10alkyl, l. amino-C1-C10alkyl, m. aminocarbonyl, n. C1-C10alkyl(C1-C10alkoxycarbonylalkyl-C1-C10)amino-C1-C10alkyl, o. heterocyclyl, p. heterocyclyl-C1-C10 alkyl, q. substituted heterocyclyl-C1-C10alkyl, r. carboxaldehyde, s. carboxaldehyde hydrazone, t. carboxamide, u. C1-C10alkoxycarbonyl-C1-C10alkyl, v. carboxy, w. carboxy-C1-C10alkyl, x. hydroxycarbonyl-C1-C10alkyl (carboxy-C1-C10alkyl), y. hydroxy-C1-C10alkylaminocarbonyl, z. cyano, aa. amino, bb. heterocyclyl-C1-C10alkylamino, ee. heterocyclyl-C1-C10alkylaminocarbonyl, and dd. "trans-cinnamide" with the proviso that (i) if Ar is phenyl and R1, R2, R3, R4, and R5 are simultaneously hydrogen, then R3 is not a "cis-cinnamide" or a "trans-cinnamide", in which R8 is methyl, R9 is hydrogen, and R10 and R11 are simultaneously -C2H5 and (ii) if Ar is pyridyl or pyridyl substituted by C1-3 alkyl, and R1, R2, R3, R4, and R5 are simultaneously hydrogen, then R3 is not a "cis-cinnamide" or a "trans-cinnamide", in which R8 is hydrogen, R9 is hydrogen or C1-3 alkyl, and R10 and R11 are independently hydrogen, C1-3 alkyl or C3-6 cycloalkyl, or a pharmaceutically-acceptable salt or prodrug thereof. 2. A compound according to Claim 1 wherein R1 is a "cis-cinnamide" or a "trans-cinnamide", and R3 is hydrogen. 3. A compound according to Claim 1 wherein R3 is a "cis-cinnamide" or a "trans-cinnamide", and R1 is hydrogen. 4. A compound according to Claim 1 wherein R3 is a "cis-cinnamide" or a "trans-cinnamide", and R1, R8, and R9 are hydrogen. 5. A compound according to Claim 4 wherein R3 is a "cis-cinnamide". 6. A compound according to Claim 4 wherein R3 is a "trans-cinnamide". 7. A compound according to Claim 1 wherein R3 is a "cis-cinnamide" or a "trans-cinnamide", R1, R2 and R4 are each independently hydrogen or C1-C10 alkyl; and R5 is selected from halogen, haloalkyl, and nitro. 8. A compound according to Claim 4 wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. 9. A compound according to Claim 4 wherein R1o and R11 are each independently selected from hydrogen, C1-C10 alkyl, C3-12 cycloalkyl, C1-C10 alkoxycarbonyl- C1-C10 alkyl, hydroxy- C1-C10 alkyl and heterocyclyl- C1-C10 alkyl. 10. A compound according to Claim 4 wherein NR10R11 is heterocyclyl or substituted heterocyclyl. 11. A compound according to Claim 8 wherein Ar is selected from substituted phenyl, 1,3-benzimidazol-2-one, 1,4-benzodioxane, 1,3-benzodioxole, 1-benzopyr-2-en-4-one, indole, isatin, 1,3-quinazolin-4-one and quinoline. 12. A compound according to Claim 1 selected from the group consisting of: (2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl) [2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)]2-chloro-4-(E-((4-(2-hydroxyethyl)-piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl) [2-chloro-4(E-((2-hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((4-hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-onyl)propylamino)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide; (2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Ch