Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1999-12-21
2004-08-24
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S118000, C435S119000, C435S121000, C435S123000
Reexamination Certificate
active
06780620
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a microbiological method for the preparation of an epothilone.
BACKGROUND OF INVENTION
Epothilones are macrolide compounds that find utility in the pharmaceutical field. For example, epothilones A and B having the structures:
have been found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Bollag et al.,
Cancer Res
., Vol. 55, No. 11, 2325-2333 (1995).
Epothilones A and B are natural anticancer agents produced by
Sorangium cellulosum
that were first isolated and characterized by Hofle et al., DE 4138042; WO 93/10121
; Angew. Chem. Int. Ed. Engl
. Vol. 35, No 13/14, 1567-1569 (1996); and
J. Antibiot
., Vol. 49, No. 6, 560-563 (1996). Subsequently, the total syntheses of epothilones A and B have been published by Balog et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 35, No. 23/24, 2801-2803, 1996; Meng et al.,
J. Am. Chem. Soc
., Vol. 119, No. 42, 10073-10092 (1997); Nicolaou et al.,
J. Am. Chem. Soc
., Vol. 119, No. 34, 7974-7991 (1997); Schinzer et al.,
Angew. Chem. Int. Ed. Eng
., Vol. 36, No. 5, 523-524 (1997); and Yang et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, No. 1/2, 166-168, 1997. PCT WO98/25929 disclosed the methods for chemical synthesis of epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs. The structure and production from
Sorangium cellulosum
DSM 6773 of epothilones C, D, E, and F was disclosed in WO98/22461.
SUMMARY OF THE INVENTION
The present invention relate s to a method for obtaining epothilones with desired substituents at a terminal carbon position. In particular, the present invention provides a method for the preparation of hydroxyalkyl-bearing epothilones, which compounds find utility as antitumor agents and as starting materials in the preparation of other epothilone analogs.
One embodiment of the invention provides a method for the preparation of at least one epothilone of the following formula I
HO—CH
2
—(A
1
)
n
—(Q)
m
—(A
2
)
o
—E (I)
where
A
1
and A
2
are independently selected from the group of optionally substituted C
1
-C
3
alkyl and alkenyl;
Q is an optionally substituted ring system containing one to three rings and at least one carbon to carbon double bond in at least one ring;
n, m, and o are integers selected from the group consisting of zero and 1, where at least one of m or n or o is 1; and
E is an epothilone core;
comprising the steps of contacting at least one epothilone of the following formula II
CH
3
—(A
1
)
n
—(Q)
m
—(A
2
)
o
—E (II)
where A
1
, Q, A
2
, E, n, m, and o are defined as above;
with a microorganism, or an enzyme derived therefrom, which is capable of selectively catalyzing the hydroxylation of formula II, and effecting said hydroxylation.
In another embodiment, the present invention provides a method for the preparation of at least one epothilone of the following formula III:
where
Q is selected from the group consisting of
G
1
is the following formula V
HO—CH
2
—(A
1
)
n
—(Q)
m
—(A
2
)
o
(V)
where
A
1
and A
2
are independently selected from the group of optionally substituted C
1
-C
3
alkyl and alkenyl;
Q is an optionally substituted ring system containing one to three rings and at least one carbon to carbon double bond in at least one ring;
n, m, and o are integers independently selected from the group consisting of zero and 1, where at least one of m or n or o is 1;
W is O or NR
6
;
X is selected from the group consisting of O; H, OR
7
;
M is O, S, NR
8
, CR
9
R
10
;
B
1
and B
2
are selected from the group consisting of OR
11
, OCOR
12
;
R
1
-R
5
and R
12
-R
17
are selected from the group consisting of H, alkyl, substituted alkyl, aryl, and heterocyclo, and wherein when R
1
and R
2
are alkyl they can be joined to form a cycloalkyl;
R
6
is selected from the group consisting of H, alkyl, and substituted alkyl;
R
7
and R
11
are selected from the group consisting of H, alkyl, substituted alkyl, trialkylsilyl, alkyldiarylsilyl, and dialkylarylsilyl;
R
8
is selected from the group consisting of H, alkyl, substituted alkyl, R
13
C═O, R
14
OC═O and R
15
SO
2
;
R
9
and R
10
are selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R
16
C═O, and R
17
OC═O;
the pharmaceutically acceptable salts thereof and any hydrates, solvates, or geometric, optical and stereoisomers thereof;
comprising the steps of contacting at least one epothilone of the following formula IV:
where
Q, W, X, M, B
1
, B
2
, and R
1
-R
17
are as defined above;
G
2
is the following formula VI
CH
3
—(A
1
)
n
—(Q)
m
—(A
2
)
o
(VI)
where A
1
, Q, A
2
, n, m, and o are defined as above;
the pharmaceutically acceptable salts thereof and any hydrates, solvates, or geometric, optical and stereoisomers thereof;
with a microorganism or enzyme derived therefrom capable of selectively catalyzing the hydroxylation of G
2
to G
1
, and effecting said hydroxylation.
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IUBMB Enzyme Nomenclature Web Site: http://www.chem.qtnul.ac.uk/iubmb/enzyme/ECI/14/14/1.html12/1/03.*
U. Bornscheuer, Biotechnology and Bioengineering, vol. 58, No. 5, pp. 554-559, 1998.
Nicolaou et al., “Total Synthesis of 26-Hydroxy-Epothilone B and Related Analogs Via a Macrolactonization Based Strategy”, Tetrahedron, 54, 7127-7166 (1998).
Nicolaou et al., “Total Synthesis of 26-Hydroxyepothilone B and Related Analogues”, Chem. Commun., 24, 2343-2344 (1997).
U.S. patent application Ser. No. 08/856,533, Nicolaou et al., filed May 14, 1997.
U.S. patent application Ser. No. 08/923,869, Nicolaou et al., filed Sep. 4, 1997.
U.S. patent application Ser. No. 60/032,864, Nicolaou et al., filed Dec. 13, 1996.
Balog, A., et al., “Total Synthesis of (−)-Epothilone A”,Angew. Chem. Int. Ed. Engl., vol. 35, No. 23/24, 2801-2803 (1996).
Bertini, F., et al., “Alkenes from Epoxides by Reductive Elimination with Magnesium Bromide-Magnesium Amalgam”,Chem. Commun., 144 (1970).
Bollag, D.M., et al., “Epothilones, A New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action”,Cancer Res. 55, No. 11, 2325-2333 (1995).
Fujisawa, T., et al., “Deoxygenation of Epoxides to Olefins with FeCl3—n-BuLi System”,Chem. Lett., 883-886 (1974).
Fujiwara, Y., et al., “Reductive Coupling of Carbonyl Compounds to Olefins by Tungsten Hexachloride-Lithium Aluminum Hydride and Some Tungsten and Molybdenum Carbonyls”,J. Org. Chem., vol. 43, No. 12, 2477-2479 (1978).
Gladysz, J. A., et al., “Deoxygenation of Epoxides by Metal Atom Cocondensation”,J. Org. Chem., vol. 41, No. 22, 3647-3648 (1976).
Hofle, G., et al., “Epothilone A and B—Novel 16-Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution”,Angew. Chem. Int. Ed. Engl., vol. 35, No. 13/14, 1567-1569 (1996)
Huang Xiaohua
Lam Kin Sing
Li Wenying
Matson James A.
McClure Grace A.
Bristol--Myers Squibb Company
Lilling Herbert J.
Patel Rena
Switzer Joan
Winslow Anastasia P.
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