Epothilone analogs

Details Epothilone analogs Epothilone analogs

1997-09-04

2002-08-27

Stockton, Laura L. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S204000

Reexamination Certificate

active

06441186

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to epothilone A, epothilone B, epothilone analogs, libraries of epothilone analogs, and methods for producing such compounds using solid phase and solution phase chemistries.
BACKGROUND OF THE INVENTION
Epothilone A (1,
FIG. 1
) and epothilone B (2,
FIG. 1
) are natural substances isolated from myxobacteria Sorangium cellulosum strain 90. These natural substances exhibit cytotoxicity against taxol-resistant tumor cells and may prove to have a clinical utility comparable or superior to Taxol. (For Taxol references see: Horwitz et al. Nature 277, 665-667 (1979); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 33, 15-44 (1994).) Like taxol, the epothilones are thought to exert their cytotoxicity by induction of microtubule assembly and stabilization. (Bollag et al. Cancer Res. 55, :2325-2333 (1995); Kowalski et al. J. Biol. Chem. 272, 2534-2541 (1997).) Epothilones are reported to be about 2000-5000 times more potent than Taxol with respect to the stabilization of microtubules. Despite the marked structural differences between the epothilones and Taxol™, the epothilones were found to bind to the same region on microtubules and to displace Taxol™ from its binding site. (Grever et al. Seminars in Oncology 1992, 19, 622-638; Bollag et al. Cancer Res. 1995, 55, 2325-2333; Kowalski et al. J. Biol. Chem. 1997, 272, 2534-2541; Horwitz et al. Nature 1979, 277, 665-667; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1994, 33, 15-44.) Epothilones A and B have generated intense interest amongst chemists, biologists and clinicians due to their novel molecular architecture, important biological action and intriguing mechanism of action. (Höfle et al. Angew. Chem. Int. Ed. Engl. 35, 1567-1569 (1996); Grever et al. Semin. Oncol. 19, 622-638 (1992); Bollag et al. Cancer Res. 55, 2325-2333 (1995); Kowalski et al. J. Biol. Chem. 272, 2534-2541 (1997); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 35, 2399-2401 (1996); Meng et al. J. Org. Chem. 61, 7998-7999 (1996); Bertinato et al. J. Org. Chem. 61, 8000-8001 (1996); Schinzer et al. Chem. Eur. J. 2, 1477-1482 (1996); Mulzer et al. Tetrahedron Lett. 37, 9179-9182 (1996); Claus et al. Tetrahedron Lett. 38, 1359-1362 (1997); Gabriel et al. Tetrahedron Lett. 38, 1363-1366 (1997); Balog et al. Angew. Chem. Int. Ed. Engl. 35, 2801-2803 (1996); Yang et al. Angew. Chem. Int. Ed. Engl. 36, 166-168 (1997); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 36, 525-527 (1997); Schinzer et al. Angew. Chem. Int. Ed. Engl. 36, 523-524 (1997); Meng et al. J. Am. Chem. Soc. 119, 2733-2734 (1997).)
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.
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
The invention is directed to epothilone analogs and processes and intermediates for making same.
One aspect of the invention is directed to an epothilone analog represented by the following structure:
In a preferred embodiment, n is one. However, in alternative embodiments n may be as large as five. R
1
is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R
2
is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. 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), and —CH
2
R
5
. R
5
is a radical selected from the group consisting of —OH, —O-Trityl, —O—(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, and —CH
2
CO
2
H. R
4
is a radical selected from the group represented by the formulas:
However, there is a proviso that if R
3
is either methyl or hydrogen and R
4
is represented by the following formula:
then R
1
and R
2
cannot be simultaneously hydrogen. Preferred epothilone analogs of this aspect of the invention include compounds represented by the following structures:
Another aspect of the invention is directed to an epothilone analog represented by the following structure:
In a preferred embodiment, n is one. However, in alternative embodiments n may be as large as five. R
1
is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R
2
is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. 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), and —CH
2
R
5
. R
5
is a radical selected from the group consisting of —OH, —O-Trityl, —O-(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, and —CH
2
CO
2
H. R
4
is a radical selected from the group represented by the formulas:
However, there is a proviso that, if R
3
is selected from the group consisting of methyl and hydrogen and R
4
is represented by the following formula:
Then R
1
and R
2
cannot be simultaneously hydrogen. Preferred embodiments of this aspect of the invention include epothilone analogs represented by the following structure:
Another aspect of the invention is directed to an epothilone analog represented by the following structure:
In the above structure, R
1
is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R
2
is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R
3
is a radical selected from the group consisting of hydrogen and methyl. R
4
is a radical selected from the group represented by the formulas:
R
5
is a radical selected from the group consisting of hydrogen, methylene and methyl. R
6
is a radical selected from the group consisting of hydrogen, methylene and methyl. R
7
is a radical selected from the group consisting of hydrogen and methyl. However, there are several provisos. If R
5
is methylene, then R
6
is methylene. If R
5
and R
6
are methy

Affiliated with

Also associated with

Rating

Epothilone analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Epothilone analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Epothilone analogs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2914902