C10 carbonate substituted taxanes

Details C10 carbonate substituted taxanes C10 carbonate substituted taxanes

2001-02-02

2003-12-09

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S337000, C514S444000, C514S471000, C514S473000, C514S449000, C549S060000, C549S471000, C549S510000, C549S511000

Reexamination Certificate

active

06660866

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is directed to novel taxanes which have exceptional utility as antitumor agents.
The taxane family of terpenes, of which baccatin III and taxol are members, has been the subject of considerable interest in both the biological and chemical arts. Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2′R, 3′S configuration and the following structural formula:
wherein Ac is acetyl.
Colin et al. reported in U.S. Pat. No. 4,814,470 that certain taxol analogs have an activity significantly greater than that of taxol. One of these analogs, commonly referred to as docetaxel, has the following structural formula:
Although taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various doses. Accordingly, a need remains for additional chemotherapeutic agents with improved efficacy and less toxicity.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity. In general, these taxanes possess a carbonate substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and C(13) side chain substituents.
Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutically acceptable carrier, and to methods of administration.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In one embodiment of the present invention, the taxanes of the present invention correspond to structure (1):
wherein
R
2
is acyloxy;
R
7
is hydroxy;
R
9
is keto, hydroxy, or acyloxy;
R
10
is carbonate;
R
14
is hydrido or hydroxy;
X
3
is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo, wherein alkyl comprises at least two carbon atoms;
X
5
is —COX
10
, —COOX
10
, or —CONHX
10
;
X
10
is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
Ac is acetyl; and
R
7
, R
9
, and R
10
independently have the alpha or beta stereochemical configuration.
In one embodiment, R
2
is an ester (R
2a
C(O)O—), a carbamate (R
2a
R
2b
NC(O)O—), a carbonate (R
2a
OC(O)O—), or a thiocarbonate (R
2a
SC(O)O—) wherein R
2a
and R
2b
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R
2
is an ester (R
2a
C(O)O—), wherein R
2a
is aryl or heteroaromatic. In another preferred embodiment, R
2
is an ester (R
2a
C(O)O—), wherein R
2a
is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R
2
is benzoyloxy.
While R
9
is keto in one embodiment of the present invention, in other embodiments R
9
may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, &agr;- or &bgr;-hydroxy or &agr;- or &bgr;-acyloxy. For example, when R
9
is acyloxy, it may be an ester (R
9a
C(O)O—), a carbamate (R
9a
R
9b
NC(O)O—), a carbonate (R
9a
OC(O)O—), or a thiocarbonate (R
9a
SC(O)O—) wherein R
9a
and R
9b
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R
9
is an ester (R
9a
C(O)O—), R
9a
is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic. Still more preferably, R
9
is an ester (R
9a
C(O)O), wherein R
9a
is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl. In one embodiment R
9
is (R
9a
C(O)O—) wherein R
9a
is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic). In another embodiment R
9
is (R
9a
C(O)O—) wherein R
9a
is substituted methyl, substituted ethyl, substituted propyl (straight, branched or cyclic), substituted butyl (straight, branched or cyclic), substituted pentyl, (straight, branched or cyclic), or substituted hexyl (straight, branched or cyclic) wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
In one embodiment, R
10
is R
10a
OCOO— wherein R
10a
is (i) substituted or unsubstituted C
1
to C
8
alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C
2
to C
8
alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C
2
to C
8
alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heterocyclo such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, R
10a
is methyl, ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. In another embodiment, R
10a
is substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or substituted thienyl wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
Exemplary X
3
substituents include substituted or unsubstituted C
2
to C
8
alkyl, substituted or unsubstituted C
2
to C
8
alkenyl, substituted or unsubstituted C
2
to C
8
alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X
3
substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
Exemplary X
5
substituents include —COX
10
, —COOX
10
or —CONHX
10
wherein X
10
is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X
5
substituents include —COX
10
, —COOX
10
or —CONHX
10
wherein X
10
is (i) substituted or unsubstituted C
1
to C
8
alkyl such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C
2
to C
8
alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight, branched or cyclic), butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic); (iii) substituted or unsubstituted C
2
to C
8
alkynyl such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or hexynyl (straight or branched); (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous contai

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