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Conjugates of methyltrithio antitumor agents and intermediates for their synthesis

  • US 5,773,001 A
  • Filed: 06/03/1994
  • Issued: 06/30/1998
  • Est. Priority Date: 06/03/1994
  • Status: Expired due to Term
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3
Assignments
First Claim
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1. A cytotoxic drug conjugate of formula: 

  • 

    space="preserve" listing-type="equation">Z.sup.3 (CO--Alk.sup.1 --Sp.sup.1 --Ar--Sp.sup.2 --Alk.sup.2 --C(Z.sup.1)═

    Z.sup.2)mwhereinZ3 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 Alk2 are independently a bond or branched or unbranched (C1 -C10) alkylene chain;

    Sp1 is a bond, --S--, --O--, --CONH--, --NHCO--, --NR'"'"'--, --N(CH2 CH2)2 N--, 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 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)n COOR'"'"', S(CH2)n COOR'"'"', O(CH2)n CONHR'"'"', or S(CH2)n CONHR'"'"', 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)n COOR'"'"', S(CH2)n COOR'"'"', O(CH2)n CONHR'"'"', or S(CH2)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 (C1 -C6) alkyl, (C1 -C5) alkoxy, (C1 -C4) thioalkoxy, halogen, nitro, or COOR'"'"', CONHR'"'"', O(CH2)n COOR'"'"', S(CH2)n COOR'"'"', O(CH2)n CONHR'"'"', or S(CH2)n CONHR'"'"' 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;

    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)n COOR'"'"', S(CH2)n COOR'"'"', O(CH2)n CONHR'"'"', or S(CH2),CONHR'"'"' wherein n and R'"'"' are as defined above;

    Z2 is Q--Sp--S--S--W, wherein W is ##STR16## R5 is --CH3, --C2 H5, 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 -C1 l) 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-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 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 from about 0.1 to 15.

      

    

  

  
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