Taccalonolide microtubule stabilizers

Patent metadata

Field	Value
Publication number	US-2016257707-A1
Application number	US-201615153470-A
Country	US
Kind code	A1
Filing date	May 12, 2016
Priority date	Jun 6, 2011
Publication date	Sep 8, 2016
Grant date	—

Abstract

The invention provides epoxytaccalonolide microtubule stabilizers and their use as anti-proliferative microtubule stabilizing agents.

First claim

1 . A compound of the formula:

wherein:
R 1 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 2 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof, or R 2 is taken together with R 3 to form an epoxide at C-2/C-3;
R 3 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , and substituted versions thereof, or R 3 is taken together with R 2 as defined above;
R 5 is absent, hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 6 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof, or oxo if R 6′ is not present, or R 6 is taken together with R 7 to form an epoxide at C-6/C-7;
R 6′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 7 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof, or oxo if R 7′ is not present, or R 7 is taken together with R 6 as defined above;
R 7′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 11 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 12 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 15 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 20 is hydrogen, amino, cyano, azido, halo, hydroxy, hydroperoxy, alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof,
R 21 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof,
R 25 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof,
R 26 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof, or oxo if R 26′ is not present;
R 26′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof;
R 27 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl (C≦12) , alkenyl (C≦12) , alkoxy (C≦12) , acyl (C≦12) , acyloxy (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , amido (C≦12) , alkylthio (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heterocycloalkyl (C≦12) , or substituted versions thereof; and
X is O, NR′ or CR′ 2 , wherein each R′ is independently hydrogen or alkyl (C≦6) ;

or a pharmaceutically acceptable salt thereof,
wherein the —O— bridging C-22 and C-23 is optionally replaced with a double bond between C-22 and C-23;
provided, however, that Formula I does not include the compound wherein R 1 is acetoxy, R 2 taken together with R 3 forms an epoxide at C-2/C-3; R 5 is hydrogen, R 6 is oxo and R 6′ is not present, R 7 is hydroxy and R 7′ is hydrogen, each of R 11 , R 12 and R 15 are acetoxy, one of R 20 or R 21 is methyl and the other is hydrogen, R 25 is OH, R 26 is oxo and R 26′ is not present, R 27 is methyl, and X is O.

2 . The compound of claim 1 , wherein:
R 1 is hydroxy, alkoxy (C≦12) or acyloxy (C≦12) ; R 2 is hydroxy, halogen, alkoxy (C≦12) or acyloxy (C≦12) , or R 2 is taken together with R 3 to form an epoxide at C-2/C-3; R 3 is hydroxy, halogen, alkoxy (C≦12) or acyloxy (C≦12) , or R 2 is taken together with R 3 as defined above; R 5 is hydrogen, hydroxy, amino, alkoxy (C≦9) , alkylamino (C≦6) , or dialkylamino (C≦12) ; R 6 is hydrogen, hydroxy, alkoxy (C≦8) , acyloxy (C≦8) , amide (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , or oxo; R 6′ when present is hydrogen, hydroxy, alkoxy (C≦8) , acyloxy (C≦8) , amide (C≦12) , alkylamino (C≦12) or dialkylamino (C≦12) , R 7 is hydrogen, hydroxy, alkoxy (C≦8) , acyloxy (C≦8) , or oxo if R 7′ is not present; R 7′ when present is hydrogen, hydroxy, alkoxy (C≦8) , or acyloxy (C≦8) ; R 11 is hydrogen, hydroxy, alkoxy (C≦8) , or acyloxy (C≦8) ; R 12 is hydrogen, hydroxy, alkoxy (C≦8) , or acyloxy (C≦8) ; R 15 is hydrogen, hydroxy, alkoxy (C≦8) or acyloxy (C≦8) ; R 20 is hydrogen, methyl, hydroxy, hydroperoxy, alkoxy (C≦8) or acyloxy (C≦8) ; R 21 is hydrogen or methyl; R 25 is hydrogen, hydroxy, alkoxy (C≦8) or acyloxy (C≦8) ; R 26 is hydrogen, hydroxy, alkoxy (C≦8) or oxo if R 26′ is not present; R 26′ when present is hydrogen, hydroxy or alkoxy (C≦8) ; R 27 is hydrogen or alkyl (C≦6) ; and X is O, NR′ or CR′ 2 , wherein each R′ is independently hydrogen or alkyl (C≦6) ;
or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein, R 1 is acyloxy (C≦12) ,

Assignees

• Univ Texas

Inventors

• Mooberry Susan L
• Peng Jiangnan
• Risinger April L
• Li Jing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D493/08

  Bridged systems · CPC title

• A61K31/585

  containing lactone rings, e.g. oxandrolone, bufalin · CPC title

• C07J71/001 Primary

  Oxiranes · CPC title

• C07J71/0005

  Oxygen-containing hetero ring · CPC title