Patent IL-129953-A (IL)
Title: Compounds useful in the synthesis of conjugates of methyltrithio anti-tumour agents
IPC: C07H15/20
Filed: 1995-06-01
Abstract: A compound of the formula Z3(CO-Alk1-Sp1-Ar-Sp2-alk2-C(Z1)=Z2) wherein Z3 is halogen, hydroxy, OM wherein M is a metal completing a salt, -N3, Alk1 and Alk2 ar indepdnently a bond or branched or unbranched (C1-C10) alkylene chain; Sp1 is a bond, -S-, -O-, -CONH-, -NHCO-, -NR'-, -N(CH2CH2)2N-, or -X-Ar'-Y-(CH2)n-Z wherein X, Y, and Z are independently a bond, -NR'-, -S- or -O-, with the proviso that when n = 0, then at least one of Y and Z must be a 2272 כ" ה באלול התשס" א - September 13, 2001 bond and Ar' is 1, 2- 1,3-, or 1, 4-phenylene optionally substituted with one, two, or three groups of (C1-C5) alkyl, (C1-C4) alkoxy, (C1-C4) thioalkoxy, halogen, nitro, COOR', -CONHR', O(CH2)nCOOR', S(CH2)aCOOR', O(CH2)nCONHR', or S(CH2)nCONHR', with the proviso that when alk1 is a bond, Sp1 is a bond; n is an integer from 0 to 5; R' is a branched or unbranched (C1-C5) chain optionally substituted by one or two groups of -OH, (C1-C4) alkoxy, (C1-C4) thioalkoxy, halogen, nitro, (C1-C3) dialkylamino, or (C1-C3) trialkylammonium-A- where A- is a pharmaceutically acceptable anion completing a salt; Ar is 1, 2-, 1, 3, or 1, 4-phenylene optionally substituted with one, two, or three groups of (C1-C6) alkyl, (C1-C5) alkoxy, (C1-C4) thioalkoxy, halogen, nitro, or COOR, CONHR', O(CH2)nCOOR', S(CH2)aCOOR', O(CH2)nCONHR', or S(CH2)nCONHR' wherein n and R' are as defined above or a 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6-, or 2,7-naphthylidene or each naphthylidene or phenothiazine optionally substituted with one, two, three, or four groups of (C1-C6) alkyl, (C1-C5) alkoxy, (C1-C4) thioalkoxy, halogen, nitro, COOR', CONHR', O(CH2)nCOOR', S(CH2)n COOR'. O(CH2)NCONHR', or S(CH2)nCONHR' wherein n and R' are as defined above, with the proviso that when Ar is naphthylidene, Z1 is not hydrogen and with the proviso that when Ar is phenothiazine, Sp1 is a bond only connected to nitrogen and Alk1 is not a bond; Sp2 is a bond, -S-, or -O-, with the proviso that when alk2 is a bond, Sp2 is a bond; Z1 is H, (C1-C5) alkyl, or phenyl optionally substituted with one, two, or three groups of (C1-C5) alkyl, (C1-C4) alkoxy, (C1-C4) thioalkoxy, halogen, nitro, COOR', CONHR', O(CH2)nCOOR', S(CH2)nCOOR', O(CH2)nCONHR', or S(CH2)nCONHR' wherein n and R' are as defined above; Z2 is Q-Sp-S-S-W, wherein W is 2273 כ" ה באלול התשס" א - September 13, 2001 R5 is -CH3, -C2H5, or -CH(CH3)2; X is an iodine or bromine atom; R5' is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched (C1-C10) alkyl or (C1-C10) alkylene group, a (C6-C11) aryl group, a (C6-C11) aryl-alkyl (C1-C5) group, or a heteroaryl or heteroaryl-alkyl (C1-C5) group wherein heteroaryl is 2- or 3-furyl, 2-or 3-thienyl, 2-or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl optionally substituted by one or more hydroxy, amino. carboxy, halo, nitro, lower (C1-C3) alkoxy, or lower (C1-C5) thioalkoxy groups; Sp is a straight or branched -chain divalent or trivalent (C1-C18) radical, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent (C3-C18) cycloalkyl or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C1-C18) radical, divalent or trivalent cycloalkyl- or heterocycloalkyl-alkyl (C1-C18) radical or divalent or trivalent (C2-C18) unsaturated alkyl radical, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein when Sp is a trivalent radical, Sp may be additionally substituted by lower (C1-C5) dialkylamino, lower (C1-C5) alkoxy, hydroxy, or lower (C1-C5) alkylthio groups; Q is =NHCO-, =NHNCS-, =NHNCONH-, =NHNCSNH-, or =NO-. 2274 כ" ה באלול התשס" א - September 13