US2016257707A1PendingUtilityA1
Taccalonolide microtubule stabilizers
Est. expiryJun 6, 2031(~4.9 yrs left)· nominal 20-yr term from priority
A61P 35/00C07D 493/08A61K 31/585C07J 71/001C07J 71/0005A61K 36/894
43
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Claims
Abstract
The invention provides epoxytaccalonolide microtubule stabilizers and their use as anti-proliferative microtubule stabilizing agents.
Claims
exact text as granted — not AI-modified1 . 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) , 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 . The compound of claim 1 , wherein said compound has 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
—OAc
R 12 = —OH
Epoxytaccalonolide H
—OAc
—H
═O
Abs.
—OAc
—OAc
Epoxytaccalonolide
—OAc
Abs.
═O
Abs.
—OAc
—OAc
R 6 = —OH,
AD
5,6 Δ double
bond
Epoxytaccalonolide
—OAc
—H
—OH
—OH
—OAc
—OAc
AE
Epoxytaccalonolide
—OAc
—H
—OH
Abs.
—OAc
—OAc
7,8 Δ double
H2
bond
Epoxy-TA-NaBH4-
—OAc
—H
—OH
—H
—OAc
—OH
R 6 = —OAc,
12
R 6′ = —H
Epoxy-TA-NaBH4-
—OAc
—H
—OH
—H
—OAc
—OH
R 6 = —OH,
10
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
—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
—H
—OH
Epoxytaccalonolide G
—OAc
—OH
—OH
—H
—H
—H
Epoxytaccalonolide R
—OAc
—OH
—OAc
—H
—H
—OAc
Epoxytaccalonolide S
isobutyrate
—H
—OH
—H
—H
—OAc
Epoxytaccalonolide T
3-methyl
—OH
—OAc
—H
—H
—OAc
butanoate
Epoxytaccalonolide U
—OH
—OH
—OAc
—H
—H
—OAc
Epoxytaccalonolide Z
—OAc
—OH
—OH
—H
—OAc
—OAc
Epoxytaccalonolide
—OAc
—OH
—OAc
—H
—OAc
—OAc
AA
Epoxytaccalonolide
—OAc
—OH
—OH
—H
—OAc
—OH
AB
Epoxytaccalonolide
3-methyl
—OH
—OH
—H
—H
—OAc
AG
butanoate
Epoxytaccalonolide
3-methyl
—H
—OH
—H
—H
—OAc
AH
butanoate
Epoxytaccalonolide
3-methyl
—H
—OH
—H
—H
—OH
AI
butanoate
Epoxytaccalonolide I
—OAc
—H
═O
Abs.
—OAc
—OH
R 6 = α-OH
Epoxytaccalonolide J
—OAc
—H
═O
Abs.
—OAc
—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
—OAc
—H
—OH
—H
—OAc
—OAc
R 20 = OOH
AC
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:
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, 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,
wherein the —O— bridging C-22 and C-23 is optionally replaced with a double bond between C-22 and C-23.
12 . A composition comprising a compound of Formula I and a pharmaceutically acceptable carrier therefor, wherein Formula I has the structure:
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, 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, 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.
13 . The composition of claim 12 , wherein, unless otherwise indicated in the following table, the compound is selected from the group consisting of compounds having the structure:
the —O— bridging C-22 and C-23 is optionally replaced with a double bond between C-22 and C-23; 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
—H
—OH
—H
—H
—OH
butanoate
Taccalonolide AA
—OAc
—OH
—OAc
—H
—OAc
—OAc
Taccalonolide Z
—OAc
—OH
—OH
—H
—OAc
—OAc
Taccalonolide AB
—OAc
—OH
—OH
—H
—OAc
—OH
Taccalonolide AC
—OAc
—H
—OH
—H
—OAc
—OAc
R 20 = OOH
R 21 = Me
Taccalonolide AD
—OAc
Abs.
═O
Abs.
—OAc
—OAc
R 6 = OH,
5,6 Δ double bond
Taccalonolide AE
—OAc
—H
—OH
—OH
—OAc
—OAc
Taccalonolide AG
3-methyl
—OH
—OH
—H
—H
—OAc
butanoate
Taccalonolide AH
3-methyl
—H
—OH
—H
—H
—OAc
butanoate
Taccalonolide H2
—OAc
—H
—OH
Abs.
—OAc
—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
—OH
—H
—H
—OH
Taccalonolide AM
3-methyl
—OH
—OH
—H
—H
—OH
butanoate
Taccalonolide AN
—OH
—H
—OH
—H
—H
—OH
Taccalonolide AP
—OAc
—OH
—OH
—H
—H
—OAc
Taccalonolide AQ
—OH
—OH
—OH
—H
—OAc
—OAc
R 2 = —OAc
R 3 = —Cl
14 . The composition of claim 12 , 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, 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, the method comprising administering to a patient in need thereof an effective amount of a composition of claim 13 .
17 . Use of a compound according to claim 1 in the preparation of a medicament for the treatment of a hyperproliferative disorder in a patient.
18 . Use of a composition according to claim 13 in the preparation of a medicament for the treatment of a hyperproliferative disorder in a patient.
19 . A compound according to claim 1 for the treatment of a hyperproliferative disorder in a patient.
20 . A method of producing a mixture of epoxytaccalonolides, said method comprising subjecting a solution of a taccalonolide-containing crude extract of the roots and/or rhizomes of a Tacca species in an organic solvent to epoxidation.Join the waitlist — get patent alerts
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