IP Library › Granted Patent US 9,340,572

Granted Patent B2

US 9,340,572 · App. 14/096,876 · Granted May 17, 2016

Taccalonolide microtubule stabilizers

Inventors: Susan L. Mooberry (San Antonio, TX); Jiangnan Peng (San Antonio, TX); April L. Risinger (San Antonio, TX); Jing Li (San Antonio, TX)

Assignee: The Board of Regents of the University of Texas System

C07J71/001 C07D493/08 C07J71/0005

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Quick Facts

Patent No.: US 9,340,572
App. No.: 14/096,876
Granted: May 17, 2016
Kind: B2

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Abstract

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

Claims (512)

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, 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 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, 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 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, 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 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, 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 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;

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) , acetyloxy, isobutyrate, isovalerate, alkoxy, or hydroxy.

4. The compound of claim 1 , wherein one or both of R 2 and/or R 3 are acyloxy (C≦12) , or R 2 and R 3 , taken together, form an epoxide at C-2/C-3.

5. The compound of claim 1 , wherein R 5 is hydrogen, hydroxy, alkoxy, acyloxy, or R 5 is absent.

6. The compound of claim 1 , wherein R 6 is oxo, hydroxy, acyloxy (C≦12) , alkylamino (C≦12) or dialkylamino (C≦12) , or R 6 and R 7 , taken together, form an epoxide at C-6/C-7.

7. The compound of claim 1 , wherein R 7 is acyloxy (C≦12) , acetyloxy, hydroxy, alkoxy or oxo.

8. The compound of claim 1 , wherein R 15 is hydroxy, alkoxy, hydrogen, oxo, acyloxy (C≦12) , or acetyloxy.

9. The compound of claim 1 , wherein X is O or NR′.

10. A compound having the structure:

wherein, unless otherwise indicated in the following table:

R 2 and R 3 taken together form an epoxide,

R 6 is oxo, and R 6′ is not present,

R 12 is —OAc,

R 20 is methyl,

R 21 is hydrogen,

R 25 is hydroxy,

R 26 is oxo, and R 26′ is not present,

R 27 is methyl,

X is O, and

Compound

R 1

R 5

R 7

R 7′

R 11

R 15

Other

Taccalonolide AJ

—OAc

—H

—OH

—H

—OAc

—OH

Epoxytaccalonolide V

—OAc

—OH

—OAc

—H

—OAc

R12 = —OH

Epoxytaccalonolide H

—OAc

—H

═O

Abs.

—OAc

Epoxytaccalonolide AD

—OAc

Abs.

═O

Abs.

—OAc

R 6 = —OH,

5,6 Δ double

bond

Epoxytaccalonolide AE

—OAc

—H

—OH

—OAc

Epoxytaccalonolide H2

—OAc

—H

—OH

Abs.

—OAc

7,8 Δ double

bond

Epoxy-TA-NaBH4-12

—OAc

—H

—OH

—H

—OAc

—OH

R 6 = —OAc,

R 6′ = —H

Epoxy-TA-NaBH4-10

—OAc

—H

—OH

—H

—OAc

—OH

R 6 = —OH,

R 6′ = —H

Epoxy-TB-Ac-16

—OAc

—H

—OAc

—H

—OAc

—OH

R 25 = —OAc

Epoxytaccalonolide D

—OAc

—H

—OAc

—H

—OAc

—OH

Epoxytaccalonolide E

—OAc

—H

—OH

—H

—OAc

Epoxytaccalonolide F

—OAc

—H

—OH

—H

—OH

—OAc

Epoxytaccalonolide L

—OAc

—H

—OH

—H

—OC(O)CH 2 OH

—OAc

Epoxytaccalonolide N

—OAc

—H

—OH

—H

—OH

Epoxytaccalonolide G

—OAc

—OH

—H

Epoxytaccalonolide R

—OAc

—OH

—OAc

—H

—OAc

Epoxytaccalonolide S

isobutyrate

—H

—OH

—H

—OAc

Epoxytaccalonolide T

3-methyl

—OH

—OAc

—H

—OAc

butanoate

Epoxytaccalonolide U

—OH

—OAc

—H

—OAc

Epoxytaccalonolide Z

—OAc

—OH

—H

—OAc

Epoxytaccalonolide AA

—OAc

—OH

—OAc

—H

—OAc

Epoxytaccalonolide AB

—OAc

—OH

—H

—OAc

—OH

Epoxytaccalonolide AG

3-methyl

—OH

—H

—OAc

butanoate

Epoxytaccalonolide AH

3-methyl

—H

—OH

—H

—OAc

butanoate

Epoxytaccalonolide AI

3-methyl

—H

—OH

—H

—OH

butanoate

Epoxytaccalonolide I

—OAc

—H

═O

Abs.

—OAc

—OH

R 6 = α-OH

Epoxytaccalonolide J

—OAc

—H

═O

Abs.

—OAc

R 6 = α-OH

Epoxytaccalonolide K

—OAc

—OH

═O

Abs.

—OAc

—OH

R 6 = α-OH

Epoxytaccalonolide M

—OAc

—OH

═O

Abs.

—H

═O

R 6 = α-OH

Epoxytaccalonolide W

—OAc

—H

—OH

—H

—OAc

—OH

R 20 = OH

R 21 = Me

Epoxytaccalonolide AC

—OAc

—H

—OH

—H

—OAc

R 20 = OOH

R 21 = Me

11. A composition comprising at least 90% by weight of a compound of Formula I, wherein Formula I has the structure:

wherein:

X is O, NR′ or CR′ 2 , wherein each R′ is independently hydrogen or alkyl (C≦6) ;

or a pharmaceutically acceptable salt thereof.

12. A composition comprising a compound of Formula I and a pharmaceutically acceptable carrier therefor, wherein Formula I has the structure:

wherein:

X is O, NR′ or CR′ 2 , wherein each R′ is independently hydrogen or alkyl (C≦6) ;

or a pharmaceutically acceptable salt thereof.

13. The composition of claim 12 , wherein, unless otherwise indicated in the following table, the compound is selected from the group consisting of compounds of Formula I wherein:

R 2 and R 3 taken together form an epoxide,

R 6 is oxo, and R 6′ is not present,

R 12 is —OAc,

R 20 is methyl,

R 21 is hydrogen,

R 25 is hydroxy,

R 26 is oxo, and R 26′ is not present,

R 27 is methyl,

X is O, and

Compound

R 1

R 5

R 7

R 7′

R 11

R 15

Other

Taccalonolide AI

3-methyl butanoate

—H

—OH

—H

—OH

Taccalonolide AA

—OAc

—OH

—OAc

—H

—OAc

Taccalonolide Z

—OAc

—OH

—H

—OAc

Taccalonolide AB

—OAc

—OH

—H

—OAc

—OH

Taccalonolide AC

—OAc

—H

—OH

—H

—OAc

R 20 = OOH

R 21 = Me

Taccalonolide AD

—OAc

Abs.

═O

Abs.

—OAc

R 6 = OH,

5,6 Δ double

Taccalonolide AE

—OAc

—H

—OH

—OAc

Taccalonolide AG

3-methyl butanoate

—OH

—H

—OAc

Taccalonolide AH

3-methyl butanoate

—H

—OH

—H

—OAc

Taccalonolide H2

—OAc

—H

—OH

Abs.

—OAc

7,8 Δ double

bond

TA-NaBH4-12

—OAc

—H

—OH

—H

—OAc

—OH

R 6 = —OAc,

R 6′ = —H

TA-NaBH4-10

—OAc

—H

—OH

—H

—OAc

—OH

R 6 = —OH,

R 6′ = —H

TB-Ac-16

—OAc

—H

—OAc

—H

—OAc

—OH

R 25′ = —OAc

Taccalonolide AL

—OAc

—OH

—H

—OH

Taccalonolide AM

3-methyl butanoate

—OH

—H

—OH

Taccalonolide AN

—OH

—H

—OH

—H

—OH

Taccalonolide AP

—OAc

—OH

—H

—OAc

Taccalonolide AQ

—OH

—H

—OAc

R 2 = —OAc

R 3 = —Cl

14. A composition comprising a compound and a pharmaceutically acceptable carrier therefor, wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. A method of treating a hyperproliferative disorder in a patient, wherein said hyperproliferative disorder is selected from the group consisting of breast cancer, ovarian cancer, lung cancer, cervical cancer and prostate cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 1 .

16. A method of treating a hyperproliferative disorder in a patient, wherein said hyperproliferative disorder is selected from the group consisting of breast cancer, ovarian cancer, lung cancer, cervical cancer and prostate cancer, the method comprising administering to a patient in need thereof an effective amount of a composition of claim 13 .

17. A compound according to claim 1 for the treatment of a hyperproliferative disorder in a patient, wherein said hyperproliferative disorder is selected from the group consisting of breast cancer, ovarian cancer, lung cancer, cervical cancer and prostate cancer.

Assignments (2)

CONFIRMATORY LICENSE Recorded Jun 9, 2016

From: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 038943/0333 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 25, 2016

From: MOOBERRY, SUSAN L.; PENG, JIANGNAN; RISINGER, APRIL L.; LI, JING

To: THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

Reel/Frame 038102/0713 →

Continuity (4)

Continuation PCTUS2012041152 · Jun 6, 2012

Provisional Application 61493653 · Jun 6, 2011

Provisional Application 61535202 · Sep 15, 2011

Related Publication 20140357608A1 · Dec 4, 2014