Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-02
2003-12-16
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S471000, C514S473000, C514S449000, C546S281700, C549S060000, C549S471000, C549S510000, C549S511000
Reexamination Certificate
active
06664275
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 heterosubstituted acetate substituent at C-10, a hydroxy substituent at C-7 and a range of C-3′ 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 heterosubstituted acetate;
R
14
is hydrido or hydroxy;
X
3
is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
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, subsituted or unsubstituted alkenyl, subsituted or unsubstituted aryl or subsituted or unsubstituted heteroaromatic. Still more preferably, R
9
is an ester (R
9a
C(O)O—), wherein R
9a
is substituted or unsubstituted phenyl, subsituted or unsubstituted furyl, subsituted or unsubstituted thienyl, or subsituted 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
C(O)O— wherein R
10a
is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R
10a
is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R
10
substituents include R
10a
COO— wherein R
10a
is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.
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 containing moieties.
In one embodiment of the present invention, the taxane corresponds to structure 1, X
5
is —COX
10
wherein X
10
is phenyl or —COOX
10
wherein X
10
is t-butoxycarbonyl, and R
10
is R
10a
C(O)O— wherein R
10a
is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1, X
5
is —COX
10
wherein X
10
is phenyl or —COOX
10
wherein X
10
is t-butoxycarbonyl, and R
10
is R
10a
C(O)O— wherein R
10a
is acyloxymethyl, preferably acetoxymethyl.
In another embodiment of the present invention, the taxane corresponds to structure 1, X
5
is —COX
10
where
FSU Research Foundation, Inc.
Senniger Powers Leavitt & Roedel
Trinh Ba K.
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