Combinatorial methods to improve the therapeutic benefit of bisantrene and analogs and derivatives thereof

A method to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising the steps of:

• (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the drug therapy;
• and
• (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the drug therapy;
• wherein the drug therapy comprises administration of bisantrene or a derivative or analog thereof;
• and wherein the factor or parameter is use of bisantrene or a derivative or analog thereof in a combinatorial regime;
• wherein, when the use in a combinatorial regime is a use of a derivative or analog of bisantrene, the derivative or analog of bisantrene is selected from the group consisting of:
• (a) the analog of Formula (II)
• (b) the bisantrene analog of Formula (III)
• (c) the bisantrene analog of Formula (IV)
• (d) the bisantrene analog of Formula (V)
• (e) the bisantrene analog of Formula (VI)
• (f) the bisantrene analog of Formula (VII)
• (g) the bisantrene analog of Formula (VIII)
• (h) the bisantrene analog anthracen-9-ylmethylene-[2-methoxyethoxymethylsulfanyl]-5-pyridin-3-yl-[1,2,4]triazol-4-amine;
• (i) the bisantrene analog of Formula (X)
• (j) the bisantrene analog of Formula (XI)
• (k) the bisantrene analog of Formula (XII)
• (l) the bisantrene analog of Formula (XIII)
• (m) bisantrene analogs of Formula (XIV)
• wherein R1 and R3 are the same or different and are hydrogen, C1-C6 alkyl, —C(O)—R5, wherein R5 is hydrogen, C1-C6 alkyl, phenyl, mono-substituted phenyl (wherein the substituent can be ortho, meta, or para and is fluoro, nitro, C1-C6 alkyl, C1-C3 alkoxy, or cyano), pentafluorophenyl, naphthyl, furanyl,
• or
• —SO3H;
• wherein only one of R1 and R3 may be hydrogen or C1-C6 alkyl;
• R2 and R4 are the same or different and are:
• hydrogen, C1-C4 alkyl or —C(O)—R6, where R6 is hydrogen, C1-C6 alkyl, phenyl, mono-substituted phenyl (wherein the substituent may be in the ortho, meta, or para position and is fluoro, nitro, C1-C6 alkyl, C1-C3 alkoxy, or cyano), pentafluorophenyl, naphthyl, furanyl, or —CH2OCH3, and wherein the compounds can have the schematic structure B(Q)n, wherein B is the residue formed by removal of a hydrogen atom from one or more basic nitrogen atoms of an amine, amidine, guanidine, isourea, isothiourea, or biguanide-containing pharmaceutically active compound, and Q is hydrogen or A, wherein A is
• such that R′ and R″ are the same or different and are R (where R is C1-C6 alkyl, aryl, aralkyl, heteroalkyl, NC—CH2CH2—,
• Cl3C—CH2—, or R7OCH2CH2—, where R7 is hydrogen or C1-C6 alkyl, hydrogen, or a pharmaceutically acceptable cation or R′ and R″ are linked to form a —CH2CH2— group or a
• group, and n is an integer representing the number of primary or secondary basic nitrogen atoms in the compound such that at least one Q is A;
• (n) the bisantrene analog 9,10-bis[(2-hydroxyethyl)iminomethyl]anthracene;
• (o) the bisantrene analog 9,10-bis{[2-(-2-hydroxyethylamino)ethyl]iminomethyl anthracene;
• (p) the bisantrene analog 9,10-bis{[2-(-2-hydroxyethylamino)ethyl]iminomethyl anthracene;
• (q) the bisantrene analog 9,10-bis{[2-(morpholin-4-yl)ethyl]iminomethyl anthracene;
• (r) the bisantrene analog 9,10-bis[(2-hydroxyethyl)aminomethyl]anthracene;
• (s) the bisantrene analog 9,10-bis{[2-(2-hydroxyethylamino)ethyl]aminomethyl}anthracene tetrahydrochloride;
• (t) the bisantrene analog 9,10-bis{[2-(piperazin-1-yl)ethyl]aminomethyl}anthracene hexahydrochloride;
• (u) the bisantrene analog 9,10-bis{[2-(morpholin-4-yl)ethyl]aminomethyl}anthracene tetrahydrochloride;
• (v) N,N′-bis[2-(dimethylamino)ethyl]-9,10-anthracene-bis(methylamine);
• (w) N,N′-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis(methylamine);
• and
• (x) salt forms of the compounds of (a)-(w);
• and
• wherein the drug therapy is administered to treat a form of cancer selected from the group consisting of refractory breast cancer, triple-negative breast cancer, acute myelocytic leukemia, and acute leukemias of childhood.