Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-02-01
2003-02-11
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C548S181000
Reexamination Certificate
active
06518421
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of certain epothilone analogs, including novel intermediates, which is characterized by a significantly enhanced yield.
BACKGROUND OF THE INVENTION
Epothilones are macrolide compounds that find utility in the pharmaceutical field. For example, epothilones A and B having the structures:
epothilone A R═H
epothilone B R═Me
may be 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 Hofle, G., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 35, No.13/14, 1567-1569 (1996); WO93/10121 published May 27, 1993; and WO97/19086 published May 29, 1997.
Derivatives and analogs of epothilones A and B have been synthesized and may be used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Id.; Nicolaou, K. C., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, No. 19, 2097-2103 (1997); and Su, D.-S., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, No. 19, 2093-2097 (1997).
Analogs of the epothilones that have been found to have advantageous activity are represented by the following structure
wherein Q, and R
1
through R
6
have the meanings given herein below. An improved synthesis for these analogs involving novel intermediates is provided in accordance with the present invention.
SUMMARY OF THE INVENTION
The present invention is directed to a process for the preparation of compounds represented by formulas I and II wherein Q, Z, and R
1
through R
6
are as defined below.
The compounds represented by formula I are novel intermediates for the preparation of epothilone analogs that are useful in the treatment of a variety of cancers and other abnormal proliferative diseases. Compounds represented by formula I may be utilized to prepare epothilone analogs represented by formula II which are useful as anticancer agents.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention provides an advantageous synthesis for the compounds represented by formula II including the preparation of novel ring opened epothilone intermediate compounds represented by formula I.
As used in formulas I and II, and throughout the specification, the meaning of the symbol Q is:
M is selected from the group consisting of oxygen, sulfur, NR
8
, and CR
9
R
10
;
Z is selected from the group consisting of
R
1
-R
5
, R
7
, and R
11
-R
15
are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R
1
and R
2
are alkyl, they can be joined to form a cycloalkyl;
R
6
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;
R
8
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R
11
C═O, R
12
OC═O and R
13
SO
2
;
R
9
and R
10
are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R
14
C═O, and R
15
OC═O; and
R
16
, R
17
, and R
18
are independently selected from the group consisting of alkyl, aryl, and aralkyl.
The process of the present invention is advantageous in that only two steps are required to prepare the epothilone analogs from the epothilone starting material, for example, epothilone B. Two further distinct advantages of the process of the present invention are that the yields of crystallized compounds represented by formula II are significantly higher than those previously realized utilizing the free acid of the compound represented by formula I as the intermediate compound, and the fact that the preparation of the intermediate is amendable to being carried out in one step. A further advantage of this process is that it can progress from the epothilone starting material to the epothilone represented by formula II without the need to isolate and purify an intermediate. Those skilled in the art will immediately recognize the economic benefits of such a process.
Definitions
The following are definitions of various terms used herein to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “epothilone”, as used herein, denotes compounds containing an epothilone core and a side chain group as defined herein. The term “epothilone core”, as used herein, denotes a moiety containing the core structure (with the numbering of ring system positions used herein shown):
wherein the substituents are as defined herein and where
X is selected from the group consisting of C═O, CH
2
and CHOR
19
;
B
1
and B
2
are selected from the group consisting of OR
20
and OCOR
21
;
R
19
and R
20
are selected from the group consisting of hydrogen, alkyl, substituted alkyl, trialkylsilyl, alkyldiarylsilyl, and dialkylarylsilyl; and
R
21
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, and heterocyclo.
The term “side chain group” refers to substituent G as defined by the following formula
Y
m
—A—
where
A is optionally substituted alkenyl;
Y 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; and
m is zero or 1.
The term “alkyl” refers to optionally substituted straight- or branched-chain saturated hydrocarbon groups having from 1 to 20 carbon atoms, preferably from 1 to 7 carbon atoms. The expression “lower alkyl” refers to optionally substituted alkyl groups having from 1 to 4 carbon atoms.
The term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryl, aryloxy, aralkyl, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amino in which the two substituents on the amino group are selected from alkyl, aryl, aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO
2
NH
2
), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH
2
), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or instances where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Wherein, as noted above, the substituents themselves are further substituted, such further substituents are selected from the group consisting of halogen, alkyl, alkoxy, aryl and aralkyl. The definitions given herein for alkyl and substituted alkyl apply as well to the alkyl portion of alkoxy groups.
The term “alkenyl” refers to optionally substituted unsaturated aliphatic hydrocarbon groups having from one to nine carbons and one or more double bonds. Substituents may include one or more substituent groups as described above for substituted alkyl.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “ring system” refers to an optionally substituted ring system containing one to three rings and at least one carbon to carbon double bond in at least one ring. Exemplary ring systems include, but are not limited to, an aryl or a partially or filly unsaturated heterocyclic ring system, which may be optionally substituted.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having from 6 to 12 carbon atoms in the ring portion, for example, phenyl, naphthyl,
Guo Zhenrong
Li Wen Sen
Swaminathan Shankar
Thornton John E.
Bristol--Myers Squibb Company
Kifle Bruck
Patel Rena
LandOfFree
Process for the preparation of 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 Process for the preparation of epothilone analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of epothilone analogs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3179004