Patent NZ-328762-A (NZ)
Title: Protein or steroid based cytotoxic drug conjugates as antitumour agents
Inventor: HOLLANDER IRWIN
IPC: A61K47/48
Filed: 1997-09-17
Abstract: A cytotoxic drug conjugate of formula I below can be used to control the growth of cancer cells in a mammalian species. Formula I:      Z3[CO-Alk1-Sp1-Ar-Sp2-Alk2-C(Z1)=Z2]m Wherein; Z3 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 "m" lysine side chains, or a steroid, wherein the covalent bond to the steroid is an amide or an ester; Alk1 and Alk2 are independently a bond or optionally branched (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 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)nCOOR', 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)nCOOR', 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 a phenothiazine, where each naphthylidene or phenothiazine is 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 above with the proviso that when Ar is naphthylidene, Z1 is not hydrogen, and when Ar is phenothiazine, Sp1 is a bond only connected to nitrogen; Sp2 is a bond, -S-, or -O-; 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-SS-W, wherein W is depicted in formula II above; 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-; and m is an integer from 0.1 to 15.