Epothilone analogs

Details Epothilone analogs Epothilone analogs

1998-06-22

2002-04-30

Coleman, Brenda (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S131000, C548S143000, C548S236000, C548S247000

Reexamination Certificate

active

06380394

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to epothilone analogs having side chain modifications and to methods for producing such compounds using solid phase and solution phase chemistries.
BACKGROUND OF THE INVENTION
The epothilones (1-5,
FIG. 1
) are natural substances which exhibit cytotoxicity against taxol-resistant tumor cells by promoting the polymerization of &agr;- and &bgr;-tubulin sub-units and stabilizing the resulting microtubule assemblies. Epothilones displace Taxol™ from its microtubul binding site and are reported to be about 2000-5000 times more potent than Taxol with respect to the stabilization of microtubules.
What is needed are analogs of epothilone A and B and libraries of analogs of epothilone A and B that exhibit superior pharmacological properties in the area of microtubule stabilizing agents.
Furthermore, what is needed are methods for producing synthetic epothilone A, epothilone B, analogs of epothilone A and B, and libraries of epothilone analogs, including epothilone analogs possessing both optimum levels of microtubule stabilizing effects and cytotoxicity.
BRIEF SUMMARY OF THE INVENTION
One aspect of the invention is directed to an epothilone analog represented by the following structure:
In the above structure, R
2
is absent or oxygen; “a” can be either a single or double bond; “b” can be either absent or a single bond; and “c” can be either absent or a single bond. However, the following provisos apply: if R
2
is oxygen, then “b” and “c” are both a single bonds and “a” is a single bond; if R
2
is absent, then “b” and “c” are absent and “a” is a double bond; and if “a” is a double bond, then R
2
, “b”, and “c” are absent. R
3
is a radical selected from the group consisting of hydrogen, methyl, —CHO, —COOH, —CO
2
Me, —CO
2
(tert-butyl), —CO
2
(iso-propyl), —CO
2
(phenyl), —CO
2
(benzyl), —CONH(furfuryl), —CO
2
(N-benzo-(2R,3S)-3-phenylisoserine), —CONH(methyl)
2
, —CONH(ethyl)
2
, —CONH(benzyl), —CH═CH
2
, —C≡CH, and —CH
2
R
11
, wherein R
11
is a radical selected from the group consisting of —OH, —O-Trityl, —O—(C
1
-C
6
alkyl), —(C
1
-C
6
alkyl), —O-benzyl, —O-allyl, —O—COCH
3
, —O—COCH
2
Cl, —O—COCH
2
CH
3
, —O—COCF
3
, —O—COCH(CH
3
)
2
, —O—COC(CH
3
)
3
, —O—CO(cyclopropane), —OCO(cyclohexane), —O—COCH═CH
2
, —
0
—CO—Phenyl, —O-(2-furoyl), —O-(N-benzo-(2R,3S)-3-phenylisoserine), —O-cinnamoyl, —O-(acetyl-phenyl), —O-(2-thiophenesulfonyl), —S—(C
1
-C
6
alkyl), —SH, —S-Phenyl, —S-Benzyl, —S-furfuryl, —NH
2
, —N
3
, —NHCOCH
3
, —NHCOCH
2
Cl, —NHCOCH
2
CH
3
, —NHCOCF
3
, —NHCOCH(CH
3
)
2
, —NHCOC(CH
3
)
3
, —NHCO(cyclopropane), —NHCO(cyclohexane), —NHCOCH═CH
2
, —NHCO-Phenyl, —NH(2-furoyl), —NH-(N-benzo-(2R,3S)-3-phenylisoserine), —NH-(cinnamoyl), —NH-(acetyl-phenyl), —NH-(2-thiophenesulfonyl), —F, —Cl, I, and —CH
2
CO
2
H. R
4
and R
5
are each independently selected from hydrogen, methyl or a protecting group. R
1
is a radical selected from the following structures:
In a preferred embodiment, R
3
is hydrogen or —CH
2
R
11
, R
11
is a radical selected from the group consisting of —OH and —F, and R
1
is a radical selected from the following structures:
Another aspect of the invention is directed to a process for synthesizing an epothlone analog, or a salt thereof The process includes a coupling step wherein an epothilone intermediate and an aromatic stannane are coupled by means of a Stille coupling reaction for producing the epothilone analog. The epothilone is represented by the following structure:
The epothilone intermediate is represented by the following structure:
In the above structures, R
1
and R
4
are each independently selected from hydrogen, methyl or a protecting group; R
5
is —CH
2
R
x
wherein R
x
is a radical selected from the group consisting of —OH, —O-Trityl, —O—(C
1
-C
6
alkyl), —(C
1
-C
6
alkyl), —O-benzyl, —O-allyl, —O—COCH
3
, —O—COCH
2
Cl, —O—COCH
2
CH
3
, —O—COCF
3
, —O—COCH(CH
3
)
2
, —O—COC(CH
3
)
3
, —O—CO(cyclopropane), —OCO(cyclohexane), —O—COCH═CH
2
, —O—CO-Phenyl, —O-(2-furoyl), —O-(N-benzo-(2R,3S)-3-phenylisoserine), —O-cinnamoyl, —O-(acetyl-phenyl), —O-(2-thiophenesulfonyl), —S—(C
1
-C
6
alkyl), —SH, —S-Phenyl, —S-Benzyl, —S-furfuryl, —NH
2
, —N
3
, —NHCOCH
3
, —NHCOCH
2
Cl, —NHCOCH
2
CH
3
, —NHCOCF
3
, —NHCOCH(CH
3
)
2
, —NHCOC(CH
3
)
3
, —NHCO(cyclopropane), —NHCO(cyclohexane), —NHCOCH═CH
2
, —NHCO-Phenyl, —NH(2-furoyl), —NH-(N-benzo-(2R,3S)-3-phenylisoserine), —NH-(cinnamoyl), —NH-(acetyl-phenyl), —NH-(2-thiophenesulfonyl), —F, —Cl, —I, and —CH
2
CO
2
H and methyl; and the aromatic stannane is a compound represented as (R
y
)
3
Sn—R
10
wherein R
y
is either n-butyl or methyl; R
10
is a radical selected from a group consisting of one of the following structures:
and (in a broader aspect of the invention)
wherein Rx is acyl, especially lower alkanoyl, such as acetyl.


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