Patent TW-394778-B (TW)
Title: Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
Inventor: HAMANN PHILIP ROSS
IPC: A61K47/48
Filed: 1994-10-12
Granted: 2000-06-21
Abstract: This invention describes carrier-drug conjugates prepared from disulfide analogs of the calicheamicin family of potent antitumor antibiotics and their derivatives, as well as similar analogs from related antitumor antibiotics such as the esperamicins. The carrier can be an antibody, growth factor, or steroid which targets an undesired population of cells, such as those of a tumor. Whole protein carriers as well as their antigen-recognizing fragments and their chemically or genetically manipulated counterparts are useful for the targeting portion of the conjugates. This invention includes compounds required for the synthesis of these conjugates, appropriate pharmaceutical compositions of the carrier-drug conjugates, and their method of use. A cytotoxic drug conjugate of formula Z<3>[CO-Alk<1>-Sp<1>-Ar-Sp<2>-Alk<2>-C(Z<1>)=Z<2>]m, wherein Z3 is a protein selected from mono-and polyclonal antibodies, their antigen-recognizing fragments, and their chemically or genetically manipulated counterparts, wherein a covalent bond to the protein is an amide formed from reaction with lysine side chains; ALK1 is a bond or unbranched (C1-C5 or C10) alkylene chain; ALK2 is a bond or unbranched (C1-C2) alkylene chain; SP1 is a bond, -O-, -NHCO-, -N(CH2CH2)2N- or-O-Ar'-CH2-NH- wherein Ar' is 1,2-phenylene substituted with one methoxy, with the proviso that when ALK1 is a bond, SP1 is a bond; Ar is 1, 2-, 1, 3-, or 1, 4-phenylene optionally substituted with methyl, methoxy, dimethoxy, chloro, fluoro, nitro, COOCH3, 3-bromopropoxycarbony1, 2-dimethylaminoethylaminocarbonyl, 2-imethylaminoethylaminocarbonyl, or OCH2(CO)NHCH2CH2N(CH3)3, or Ar is a 1,2- or 2, 6-aphthylidene 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, or COOR', CONHR', O(CH2)nCOOR', S(CH2)nCOOR', O(CH2)nCONHR', or S(CH2)nCONHR' wherein n and R' are as defined in claim 1, with the proviso that when Ar is naphthylidene, Z<1> is not hydrogen and with the proviso that when Ar in phenothiazine, Sp<1> is a bond only connected to nitrogen; Sp<2> is a bond, -S-, or -O-, with the proviso that when Alk<2> is a bond, Sp<2> is a bond; Z<1> 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 in claim 1; Z<2> is Q-Sp-SS-W, wherein W is (formula); R2 is (formula) or H; R4 is (formula) or H; R6 or R7 is H or 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-methylimidizolyl), 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-methylimidizolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, Sp can be additionally substituted by lower (C1-C5) dialkylamino, lower (C1-C5) alkoxy, hydroxy, or lower (C1-C5) alkylthio groups; and Q is =NHNCO-, =NHNCS-, =NHNCONH-, =NHNCSNH-, or =NHO-; m is an integer from about 0.1 to 15.