US 2014/0275168 A1Published application

Indirubin derivatives, and uses thereof

AssigneeCity of Hope

InventorsSangkil NAM, Richard JOVE, Leandros SKALTSOUNIS

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Abstract

Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). Indirubin derivatives (IRDs) potently reduce the viabilities of various cancer cells and affect kinase activities. IRDs disclosed herein provide new therapeutics for cancer and conditions regulated by the kinase activities.

Claims22

Dependent claims

An indirubin derivative (IRD) comprising a structure of Structure A:

and the pharmaceutically acceptable solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein:
X is C or N;
RX is selected from the group consisting of nothing, H, halogen, and haloalkyl;
R6 is selected from the group consisting of H, halogen, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkoxy;
R5 is selected from the group consisting of H, halogen, nitro, amino, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkyl;
Y is N or O, wherein:
when Y is N, RY is selected from the group consisting of nothing, H, hydroxy, alkoxy, haloalkoxy, substituted and unsubstituted —O—C(C═O)—N(R′) R″, substituted and unsubstituted —O—C(C═O)—R0, and O—R—R′, and
when Y is O, RY is nothing;
R′5 is selected from the group consisting of H, alkoxy, nitro, —CN, —C(═O)—O—R0, —C(═O)—OH, —C(C═O)H, heteroaryl, —C═N—OH and —R—OH;
R′6 is selected from the group consisting of H, halogen, alkyl and —C(═O)—O—R0;
Z is N or S;
Rz is selected from the group consisting of H, 0, —C(═O)—R0;
each R is independently nothing or substituted or unsubstituted alkylenyl;
each R0 is independently substituted or unsubstituted alkyl;
each R′ and R″ are independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylamino, substituted and unsubstituted haloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl;
and
with the proviso that the IRD is not indirubin, indirubin-3′-oxime, indirubin-3′-acetoxime, indirubin-3′-methoxime, IRD Nos. 2, 58, 59, 61, 64-72, 74, 77-88, 90, 129-132, 142-144, 146, 161, a compound having the structure of Structure A, wherein:
R5 and R′5 are H;
Z is N;
X is C;
RX is H;
wherein:
when Y is O;
RZ is H;
and R6 and R′6 are H or Br;
when Y is O;
RZ is CH3;
R6 is H or Br;
and R′6 is H;
when Y is N;
RY is —OH;
RZ is H;
and R6 and R′6 are H or Br;
when Y is N;
RY is —OH;
RZ is CH3;
R6 is H or Br;
and R′6 is H;
when Y is N;
RY is —OCH3 or —OC(═O)—CH3;
RZ and R′6 are H;
and
R6 is Br;
or
when Y is N;
R6 is Br;
RZ and R′6 are H;
RY is 2-bromoethyl, 2-hydroxyethoxy, 2,3,-dihydroxypropoxy, N,N-diethylcarbamyloxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-(pyrrolidin-1′-yl)ethyl, 2-(morpholin-1′-yl)ethoxy, 2-[N,N-(2-hydroxyethyl)amino]ethoxy, 2-[N-methyl, N-(2′,3′-dihydroxypropyl)amino]ethoxy, 2-(piperazin-1′-yl)ethoxy, 2-(4′-methyl-piperazin-1′-yl)ethoxy, 2-{4′-[2″-(2″-hydroxyethoxy)-ethyl]piperazin-1′-yl}ethoxy, 2-[4′-(2″-hydroxyethyl)-piperazin-1-yl]ethoxy, or 2-[4′-(2″-methoxyethyl)-piperazin-1-yl]ethoxy;
or
a compound having the structure of Structure A, wherein:
R′5 is Br;
Z is N;
X is C;
RX is H;
RZ, R′6, and R6 are H;
R5 is H or Br;
and Y is O;
or
R′5 is H;
Z is N;
X is C;
RX is H;
wherein:
when R5, RZ, R′6, and R6 are H;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
when RZ, R′6, and R6 are H;
R5 is Cl, Br, nitro, or methyl;
and Y is O;
when RZ, R′6, and R6 are H;
R5 is I;
Y is O or N;
and RY is nothing, or OH;
when RZ, and R′6 are H;
R5 is amino;
R6 is H or Br;
Y is O or N;
and RY is nothing, or OH;
when R5, and RZ are H;
R′6 is H or Br;
R6 is Br;
Y is O or N;
and RY is nothing, or OH;
when R5, R′6, and RZ are H;
R6 is Br;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
when R5, and R′6 are H;
RZ is CH3;
R6 is Br or H;
Y is O or N;
and RY is nothing, or OH;
when R5, R′6, and RZ are H;
R6 is I, Br, Cl, F, or —CH2═CH2;
R6 is Cl;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
when R′6, and RZ are H;
R5 is nitro or CH3;
R6 is Br;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
or
when R′6, and RZ are H;
R5 and R6 are Cl;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc.

104 more elements

Dependencies are inferred from the claim text.

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Abstract

An indirubin derivative (IRD) comprising a structure of Structure A:

and the pharmaceutically acceptable solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein:
X is C or N;
RX is selected from the group consisting of nothing, H, halogen, and haloalkyl;
R6 is selected from the group consisting of H, halogen, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkoxy;
R5 is selected from the group consisting of H, halogen, nitro, amino, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkyl;
Y is N or O, wherein:
when Y is N, RY is selected from the group consisting of nothing, H, hydroxy, alkoxy, haloalkoxy, substituted and unsubstituted —O—C(C═O)—N(R′) R″, substituted and unsubstituted —O—C(C═O)—R0, and O—R—R′, and
when Y is O, RY is nothing;
R′5 is selected from the group consisting of H, alkoxy, nitro, —CN, —C(═O)—O—R0, —C(═O)—OH, —C(C═O)H, heteroaryl, —C═N—OH and —R—OH;
R′6 is selected from the group consisting of H, halogen, alkyl and —C(═O)—O—R0;
Z is N or S;
Rz is selected from the group consisting of H, 0, —C(═O)—R0;
each R is independently nothing or substituted or unsubstituted alkylenyl;
each R0 is independently substituted or unsubstituted alkyl;
each R′ and R″ are independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylamino, substituted and unsubstituted haloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl;
and
with the proviso that the IRD is not indirubin, indirubin-3′-oxime, indirubin-3′-acetoxime, indirubin-3′-methoxime, IRD Nos. 2, 58, 59, 61, 64-72, 74, 77-88, 90, 129-132, 142-144, 146, 161, a compound having the structure of Structure A, wherein:
R5 and R′5 are H;
Z is N;
X is C;
RX is H;
wherein:
when Y is O;
RZ is H;
and R6 and R′6 are H or Br;
when Y is O;
RZ is CH3;
R6 is H or Br;
and R′6 is H;
when Y is N;
RY is —OH;
RZ is H;
and R6 and R′6 are H or Br;
when Y is N;
RY is —OH;
RZ is CH3;
R6 is H or Br;
and R′6 is H;
when Y is N;
RY is —OCH3 or —OC(═O)—CH3;
RZ and R′6 are H;
and
R6 is Br;
or
when Y is N;
R6 is Br;
RZ and R′6 are H;
RY is 2-bromoethyl, 2-hydroxyethoxy, 2,3,-dihydroxypropoxy, N,N-diethylcarbamyloxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-(pyrrolidin-1′-yl)ethyl, 2-(morpholin-1′-yl)ethoxy, 2-[N,N-(2-hydroxyethyl)amino]ethoxy, 2-[N-methyl, N-(2′,3′-dihydroxypropyl)amino]ethoxy, 2-(piperazin-1′-yl)ethoxy, 2-(4′-methyl-piperazin-1′-yl)ethoxy, 2-{4′-[2″-(2″-hydroxyethoxy)-ethyl]piperazin-1′-yl}ethoxy, 2-[4′-(2″-hydroxyethyl)-piperazin-1-yl]ethoxy, or 2-[4′-(2″-methoxyethyl)-piperazin-1-yl]ethoxy;
or
a compound having the structure of Structure A, wherein:
R′5 is Br;
Z is N;
X is C;
RX is H;
RZ, R′6, and R6 are H;
R5 is H or Br;
and Y is O;
or
R′5 is H;
Z is N;
X is C;
RX is H;
wherein:
when R5, RZ, R′6, and R6 are H;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
when RZ, R′6, and R6 are H;
R5 is Cl, Br, nitro, or methyl;
and Y is O;
when RZ, R′6, and R6 are H;
R5 is I;
Y is O or N;
and RY is nothing, or OH;
when RZ, and R′6 are H;
R5 is amino;
R6 is H or Br;
Y is O or N;
and RY is nothing, or OH;
when R5, and RZ are H;
R′6 is H or Br;
R6 is Br;
Y is O or N;
and RY is nothing, or OH;
when R5, R′6, and RZ are H;
R6 is Br;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
when R5, and R′6 are H;
RZ is CH3;
R6 is Br or H;
Y is O or N;
and RY is nothing, or OH;
when R5, R′6, and RZ are H;
R6 is I, Br, Cl, F, or —CH2═CH2;
R6 is Cl;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
when R′6, and RZ are H;
R5 is nitro or CH3;
R6 is Br;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc;
or
when R′6, and RZ are H;
R5 and R6 are Cl;
Y is O or N;
and RY is nothing, OH, OCH3 or OAc.

104 more elements