Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-24
2003-12-09
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S235000
Reexamination Certificate
active
06660758
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, their use for the therapy of diseases or for the manufacture of pharmaceutical preparations for the treatment of diseases, as well as to novel intermediates used in the synthesis of said compounds.
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.
SUMMARY OF THE INVENTION
The invention provides new ways of synthesis for epothilone derivatives with advantageous pharmacological properties, especially due to better activities when compared with Taxol or (especially with regard to the preferred compounds) comparable or better activities than than epothilones A or B, which, without said methods, would have been inaccessible, as well as new synthetic methods for the synthesis of epothilone A and epothilone B.
In detail, the invention is directed to analogs of epothilone. More particularly, the invention is directed to compounds represented by the following structure (formula (I)):
wherein n is 1 to 5, preferably 3 or in a broader aspect of the invention 1. In a preferred embodiment, either R* is —OR
1
and R** is hydrogen, or R* and R** together form a further bond so that a double bond is present between the two carbon atoms carrying R* and R**; R
1
is a radical selected from the group consisting of hydrogen (preferred) or methyl, or (in a broader aspect of the invention) a protecting group, especially from the group comprising tert-butyldimethylsilyl, trimethylsilyl, acetyl, benzoyl, and tertbutoxycarbonyl; R
2
is a radical selected from the group consisting of hydrogen, methylene and (preferably) methyl; R
3
is a radical selected from the group consisting of hydrogen, methylene and (preferably) methyl; R
4
is a radical selected from the group consisting of hydrogen (preferred) or methyl, or is a protecting group, preferably selected from the group consisting of tertbutyldimethylsilyl, trimethylsilyl, acetyl, benzoyl, and tertbutoxycarbonyl; R
5
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), —CON(methyl)
2
, —CON(ethyl)
2
, —CONH(benzyl), —CH═CH
2
, HC≡C—, and —CH
2
R
11
; 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—CO—C(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
, —NHCO—C(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, —CH
2
CO
2
H and methyl; R
6
is absent, methylene, or oxygen; R
7
is hydrogen; R
8
is a radical selected from the group represented by the for-mulas:
wherein R
9
is a radical selected from the group consisting of hydrogen and methyl; R
10
is a radical selected from the group represented by the formulas:
and (in a broader aspect of the invention)
wherein Rx is acyl, especially lower alkanoyl, such as acetyl;
R
12
is a radical selected from the group consisting of hydrogen, methyl or a protecting group, preferably tertbutyldiphenylsilyl, tertbutyldimethylsilyl, trimethylsilyl, acetyl, benzoyl, tert-butoxycarbonyl and a group represented by any on of the following formulae
or (in a broader aspect of the invention) a salt thereof where a salt-forming group is present.
Preferably, the compound of the formula I has the formula IA
wherein the moieties and symbols have the manings just defined for a compound of the formula I.
In the above structures, “a” can be either absent or a single bond; “b” can be either a single or double bond; “c” can be either absent or a single bond; “d” can be either absent or a single bond. However, the following provisos pertain:
1. If R
2
is methylene, then R
3
is methylene;
2. if R
2
and R
3
are both methylene, then “a” is a single bond;
3. if R
2
and R
3
are selected from the group consisting of hydrogen and methyl, then the single bond “a” is absent;
4. if n is 3, R
2
is methyl, R
3
is methyl, R
5
is selected from the group consisting of methyl and hydrogen, R
6
is oxygen, R
7
is hydrogen, R
8
is represented by the formula:
wherein R
9
is hydrogen, and R
10
is represented by the formula
then R
1
and R
4
cannot both be simultaneously hydrogen or methyl or acetyl;
5. if R
6
is oxygen, then “c” and “d” are both a single bond and “b” is a single bond;
6. if R
6
is absent, then “c” and “d” are absent and “b” is a double bond;
7. if “b” is a double bond then R
6
, “c”, and “d” are absent;
Especially preferred is the use of said compounds for the treatment of resistant (especially drug resistant) tumours or for the preparation
Finlay M. Ray
He Yun
King Nigel Paul
Nicolaou Kyriacos C.
Ninkovic Sacha
Gerstl Robert
Lewis Donald G.
The Scripps Research Institute
LandOfFree
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.
Profile ID: LFUS-PAI-O-3172957