Conjugates of methyltrithio antitumor agents and intermediates for their synthesis

A cytotoxic drug conjugate of formula:

• Z.sup.3 (CO--Alk.sup.1 --Sp.sup.1 --Ar--Sp.sup.2 --Alk.sup.2 --C(Z.sup.1).dbd.Z.sup.2)m
• wherein
• Z.sup.3 is a protein selected from mono- and polyclonal antibodies, their antigen-recognizing fragments, and their chemically or genetically manipulated counterparts, and growth factors and their chemically or genetically manipulated counterparts, wherein a covalent bond to the protein is an amide formed from reaction with lysine side chains, or a steroid, wherein the covalent bond to the steroid is an amide or an ester;
• Alk and Alk.sup.2 are independently a bond or branched or unbranched (C.sub.1 -C.sub.10) alkylene chain;
• Sp.sup.1 is a bond, --S--, --O--, --CONH--, --NHCO--, --NR'--, --N(CH.sub.2 CH.sub.2).sub.2 N--, or --X--Ar'--Y--(CH.sub.2).sub.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 bond and Ar' is 1,2-, 1,3-, or 1 ,4-phenylene optionally substituted with one, two, or three groups of (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.4) alkoxy, (C.sub.1 -C.sub.4) thioalkoxy, halogen, nitro, COOR', CONHR', O(CH.sub.2).sub.n COOR', S(CH.sub.2).sub.n COOR', O(CH.sub.2).sub.n CONHR', or S(CH.sub.2).sub.n CONHR', with the proviso that when Alk.sup.1 is a bond, Sp.sup.1 is a bond;
• n is an integer from 0 to 5;
• R' is a branched or unbranched (C.sub.1 -C.sub.5) chain optionally substituted by one or two groups of --OH, (C.sub.1 -C.sub.4) alkoxy, (C.sub.1 -C.sub.4) thioalkoxy, halogen, nitro, (C.sub.1 -C.sub.3) dialkylamino, or (C.sub.1 -C.sub.3) trialkylammonium --A.sup.- where A.sup.- 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 (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.5) alkoxy, (C.sub.1 -C.sub.4) thioalkoxy, halogen, nitro, or COOR', CONHR', O(CH.sub.2).sub.n COOR', S(CH.sub.2).sub.n COOR', O(CH.sub.2).sub.n CONHR', or S(CH.sub.2).sub.n CONHR' 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 ##STR15## each naphthylidene or phenothiazine optionally substituted with one, two, three, or four groups of (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.5) alkoxy, (C.sub.1 -C.sub.4) thioalkoxy, halogen, nitro, or COOR', CONHR', O(CH.sub.2).sub.n COOR', S(CH.sub.2).sub.n COOR', O(CH.sub.2).sub.n CONHR', or S(CH.sub.2).sub.n CONHR' wherein n and R' are as defined above, with the proviso that when Ar is naphthylidene, Z.sup.1 is not hydrogen and with the proviso that when Ar is phenothiazine, Sp.sup.1 is a bond only connected to nitrogen;
• Sp.sup.2 is a bond, --S--, or --O--, with the proviso that when Alk.sup.2 is a bond, Sp.sup.2 is a bond;
• Z.sup.1 is H, (C.sub.1 -C.sub.5) alkyl, or phenyl optionally substituted with one, two, or three groups of (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.4) alkoxy, (C.sub.1 -C.sub.4) thioalkoxy, halogen, nitro, COOR', CONHR', O(CH.sub.2).sub.n COOR', S(CH.sub.2).sub.n COOR', O(CH.sub.2).sub.n CONHR', or S(CH.sub.2),CONHR' wherein n and R' are as defined above;
• Z.sup.2 is Q--Sp--S--S--W, wherein W is ##STR16## R.sub.5 is --CH.sub.3, --C.sub.2 H.sub.5, or --CH(CH.sub.3).sub.2 ;
• X is an iodine or bromine atom;
• R.sub.5' is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched (C.sub.1 -C.sub.10) alkyl or (C.sub.1 -C.sub.10) alkylene group, a (C.sub.6 -C.sub.1 l) aryl group, a (C.sub.6 -C.sub.11) aryl-alkyl (C.sub.1 -C.sub.5) group, or a heteroaryl or heteroaryl- alkyl (C.sub.1 -C.sub.5) 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-heteroaryl optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, lower (C.sub.1 -C.sub.3) alkoxy, or lower (C.sub.1 -C.sub.5) thioalkoxy groups;
• Sp is a straight or branched-chain divalent or trivalent (C.sub.1 -C.sub.18) radical, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent (C.sub.3 -C.sub.18) cycloalkyl or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C.sub.1 -C.sub.18) radical, divalent or trivalent cycloalkyl- or heterocycloalkyl-alkyl (C.sub.1 -C.sub.18) radical or divalent or trivalent (C.sub.2 -C.sub.18) 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 can be additionally substituted by lower (C.sub.1 -C.sub.5) dialkylamino, lower (C.sub.1 -C.sub.5) alkoxy, hydroxy, or lower (C.sub.1 -C.sub.5) alkylthio groups;
• and
• Q is .dbd.NHNCO--, .dbd.NHNCS--, .dbd.NHNCONH--, .dbd.NHNCSNH--, or .dbd.NHO--
• m is from about 0.1 to 15.