Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-13
2003-02-04
Powers, Flona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S214000, C549S220000
Reexamination Certificate
active
06515151
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the preparation of sidechain-bearing taxanes and intermediates thereof, and to the novel compounds prepared by these methods.
BACKGROUND OF THE INVENTION
Taxanes are diterpene compounds which find utility in the pharmaceutical field. For example, taxol, a taxane having the structure:
where Ph is phenyl, Ac is acetyl and Bz is benzoyl, has been found to be an effective anticancer agent. Naturally occurring taxanes such as taxol may be found in plant materials, and have been isolated therefrom. Such taxanes may, however, be present in plant materials in relatively small amounts so that, in the case of taxol, for example, large numbers of the slow-growing yew trees forming a source for the compound may be required. The art has thus continued to search for synthetic, including semi-synthetic routes for the preparation of taxanes such as taxol and analogs thereof, as well as routes for the preparation of intermediates used in the preparation of these compounds.
SUMMARY OF THE INVENTION
The present invention provides a novel, overall method for the preparation of novel sidechain-bearing taxanes, comprising the following steps (a) through (e):
(a) preparing an oxazoline compound of the following formula I or a salt thereof:
where
R
1
is R
5
, R
7
—O—, R
7
—S—, or (R
5
)(R
6
)N—;
R
2
is R
7
—O—, R
7
—S—, or (R
5
)(R
6
)N—;
R
3
and R
4
are independently R
5
, R
5
—O—C(O)—, or (R
5
)(R
6
)N—C(O)—;
R
5
and R
6
are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclo; and
R
7
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo;
(b) converting the oxazoline of formula I or salt thereof to an oxazoline of the formula II or a salt thereof:
where R
1
, R
3
and R
4
are as defined above;
(c) coupling the oxazoline of the formula II or salt thereof with a taxane having a hydroxyl group directly bonded to C-13 thereof, or salt thereof, to form an oxazoline sidechain-bearing taxane of the following formula III or a salt thereof:
where R
1
, R
3
and R
4
are as defined above, and T is a taxane moiety preferably a compound of Formula IX bonded directly through C-13 of said moiety;
(d) contacting the oxazoline sidechain-bearing taxane of the formula III or salt thereof with an aqueous acid capable of opening the oxazoline ring of said compound of the formula III or salt thereof to form a sidechain-bearing taxane of the following formula X or salt thereof:
where R
1
, R
3
, R
4
and T are as defined above, and the acid salt at the amine group in said formula X is formed by contact with said ring-opening acid; and
(e) contacting said sidechain-bearing taxane of the formula X or salt thereof with a base to form a sidechain-bearing taxane of the following formula IV or salt thereof:
where R
1
, R
3
, R
4
and T are as defined above.
In addition, the present invention provides the individual methods of each of steps (a) through (e) which are novel methods, and the novel compounds of the formulae I, II, III, IV, IX and X and salts and hydrates thereof as described following. Also included are novel prodrugs of these compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described further as follows.
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH
2
—CO—), substituted carbamoyl ((R
5
)(R
6
)N—CO— where R
5
or R
6
are as defined above, except that at least one of R
5
or R
6
is not hydrogen), amino (—NH
2
), heterocyclo, mono- or dialkylamino, or thiol (—SH).
The terms “lower alk” or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The terms “alkoxy” or “alkylthio” denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively. The term “alkyloxycarbonyl”, as used herein, denotes an alkoxy group bonded through a carbonyl group. The term “alkylcarbonyl”, as used herein, denotes an alkyl group bonded through a carbonyl group. The term “alkylcarbonyloxy”, as used herein, denotes an alkyl group bonded through a carbonyl group which is, in turn, bonded through an oxygen linkage. The terms “monoalkylamino” or “dialkylamino” denote an amino group substituted by one or two alkyl groups as described above, respectively.
The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH
2
—CO—), substituted carbamoyl ((R
5
)(R
6
)N—CO— where R
5
or R
6
are as defined above, except that at least one of R
5
or R
6
is not hydrogen), amino (—NH
2
), heterocyclo, mono- or dialkylamino, or thiol (—SH).
The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH
2
—CO—), substituted carbamoyl ((R
5
)(R
6
)N—CO— where R
5
or R
6
are as defined above, except that at least one of R
5
or R
6
is not hydrogen), amino (—NH
2
), heterocyclo, mono- or dialkylamino, or thiol (—SH).
The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “cycloalkenyl”, as used herein alone or as part of another group, denotes such optionally substituted groups as described above for cycloalkyl, further containing at least one carbon to carbon double bond forming a partially unsaturated ring.
The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include phenyl, biphenyl, and naphthyl. Exemplary substituents include one or more, preferably three or fewer, nitro groups, alkyl groups as described above or groups described above as alkyl
Chen Shu-Hui
Kucera David J.
Moniot Jerome L.
Poss Michael A.
Thottahil John K.
Bristol--Myers Squibb Company
Peist Kenneth W.
Powers Flona T.
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