Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-05-05
2003-04-08
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06545168
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to novel taxanes which have utility as antitumor agents and to a process for their preparation.
The taxane family of terpenes, of which baccatin III and taxol are members, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of tumor-inhibiting activity. Taxol has a 2′R, 3′S configuration and the following structural formula:
wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
Colin et al. reported in U.S. Pat. No. 4,814,470 that taxol derivatives having the structural formula (II) below, have an activity significantly greater than that of taxol (I).
R′ represents hydrogen or acetyl and one of R″ and R′″ represents hydroxy and the other represents tert-butoxycarbonylamino and their stereoisomeric forms, and mixtures thereof. The compound of this formula in which R″ is hydroxy, R′″ is tert-butoxycarbonylamino having the 2′R, 3′S configuration is commonly referred to as taxotere.
Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of novel taxanes which are valuable anti-tumor agents and a process for their preparation.
Briefly, therefore, the present invention is directed to a process for the preparation of 1-deoxy baccatin III, 1-deoxy taxol and 1-deoxy taxol analogs. The process comprises at least one of the following steps:
(a) reacting a compound having the formula:
with a peracid such as metachloroperbenzoic acid to form a compound having the formula:
wherein P
10
is a silyl hydroxy protecting group such as triethylsilyl or an acyl group such as benzoyl. In this reaction, the protected hydroxy group —OP
10
migrates to the adjacent carbon and becomes —OP
9
with P
9
being the same as P
10
;
(b) subjecting a compound having the formula:
to an epoxy alcohol fragmentation consisting of (ia) epoxidation of an olefinic residue with a hydroperoxide, preferably t-BuOOH, in the presence of a transition metal catalyst, preferably titanium tetraisopropoxide, or (ib) treatment of the olefinic residue with a peracid such as peracetic acid followed by (ii) addition of a sulfide, preferably dimethyl sulfide, followed by heating in the presence of a transition metal catalyst, preferably titanium tetraisopropoxide, to form a compound having the formula:
wherein P
9
is a hydroxyl protecting group such as a silyl group, ketal, acetal, or ether which does not contain a reactive functionality;
(c) reacting a compound having the formula:
with a vinyl organometallic reagent to form a compound having the formula:
(d) reacting a compound having the formula:
with a paladium catalyst to form a compound having the formula:
(e) reacting a compound having the formula:
with a base, most preferably BaO in methanol, and protecting the C7 hydroxy substituent, for example, by reacting the product with TESOTf, to form a compound having the formula:
(f) reacting a compound having the formula:
with SeO
2
to form a compound having the formula:
wherein E
7
is hydrogen or a hydroxy protecting group, and P
2
, P
7
, P
9
, P
10
and P
13
are hydroxy protecting groups as hereinafter defined.
In general, the process of the present invention may be used to prepare 1-deoxy baccatin III, 1-deoxy taxol and 1-deoxy taxol analogs having the formula:
wherein
M comprises ammonium or is a metal;
R
2
is —OT
2
, —OCOZ
2
, or —OCOOZ
2
;
R
4
is —OT
4
, —OCOZ
4
, or —OCOOZ
4
;
R
6
is hydrogen, keto, —OT
6
, —OCOZ
6
or —OCOOZ
6
;
R
7
is hydrogen, halogen, —OT
7
, —OCOZ
7
or —OCOOZ
7
;
R
9
is hydrogen, keto, —OT
9
, —OCOZ
9
or —OCOOZ
9
;
R
10
is hydrogen, keto, —OT
10
, —OCOZ
10
or —OCOOZ
10
;
R
6
, R
7
, R
9
, and R
10
independently have the alpha or beta stereochemical configuration;
R
13
is hydroxy, protected hydroxy, keto, MO— or
T
2
, T
4
, T
6
, T
7
, T
9
and T
10
are independently hydrogen or hydroxy protecting group;
X
1
is —OX
6
;
X
2
is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl;
X
3
and X
4
are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl;
X
5
is —COX
10
, —COOX
10
, —COSX
10
, or —CONX
8
X
10
;
X
6
is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
X
8
is hydrogen, hydrocarbon, heterosubstituted hydrocarbon;
X
10
is hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl; and
Z
2
, Z
4
, Z
6
, Z
7
, Z
9
and Z
10
are independently hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl.
The present invention is additionally directed to compounds having the formulae
wherein E
7
is hydrogen or a hydroxy protecting group; Bz is benzoyl; P
2
, P
3
, P
7
, P
9
, P
10
and P
13
are hydroxy protecting groups; and R
13
is as previously defined. These compounds are key intermediates in the synthesis of 1-deoxy baccatin III, 1-deoxy taxol and other analogs. The present invention is also directed to processes for the preparation of these key intermediates.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The process of the present invention enables the preparation of 1-deoxy taxol, 1-deoxy taxotere and analogs of 1-deoxy taxol and 1-deoxy taxotere from 1-deoxy baccatin III, 1-deoxy-10-deactylbaccatin III, or analogs thereof. In a preferred embodiment, these compounds have the formula:
wherein
M comprises ammonium or is a metal;
R
2
is —OCOZ
2
;
R
4
is —OCOZ
4
;
R
6
is hydrogen;
R
7
is hydrogen, —OT
7
, or —OCOZ
7
;
R
9
is hydrogen, keto, —OT
9
, —OCOZ
9
;
R
10
is hydrogen, keto, —OT
10
, or —OCOZ
10
;
R
13
is MO— or
T
7
, T
9
and T
10
are independently hydrogen or hydroxy protecting group;
X
1
is —OX
6
;
X
2
is hydrogen;
X
3
is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, or heteroaryl;
X
4
is hydrogen;
X
5
is —COX
10
or —COOX
10
;
X
6
is hydrogen or hydroxy protecting group;
X
10
is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, or heteroaryl; and
Z
2
is alkyl, substituted alkyl, phenyl, substituted phenyl, or heteroaryl;
Z
4
is phenyl, substituted phenyl, or heteroaryl; and
Z
7
, Z
9
and Z
10
are independently alkyl, substituted alkyl, phenyl, substituted phenyl, or heteroaryl.
An exemplary synthesis of 1-deoxy baccatin III is depicted in Reaction Scheme 1. The starting material, diol 1, can be prepared from patchino (commonly known as B-patchouline epoxide) which is commercially available. The patchino is first reacted with an organo-metallic, such as lithium t-butyl followed by oxidation with an organic peroxide, such as t-butylperoxide in the presence of titanium tetraisopropoxide to form a tertiary alcohol. The tertiary alcohol is then reacted with a Lewis acid, such as boron trifluoride at low temperature, in the range from 40° C. to −100° C.; in the presence of an acid, such as trifluoromethane sulfonic acid. A graphical depiction of this reaction scheme along with an experimental write-up for the preparation of diol 1 can be found in U.S. Pat. No. 4,876,399.
In this reaction scheme, P
2
is BOM; P
3
is TMS; P
7
is Ac in compounds 12-15 and TES in compounds 18-23; P
9
is TES in compounds 4, 5, 6 and 7, and TMS in compounds 8, 9, 10, 11 and 12; P
10
is TES, and P
13
is TBS in compounds 7 through 21 and TES in compounds 22 and 23. It should be understood, however, that P
2
, P
3
, P
7
, P
9
, P
10
and P
13
may be other hydroxy protecting groups.
In general, tetracyclic taxanes bearing C13
Holton Robert A.
Liang Feng
Somoza Carmen
Tang Suhan
Florida State University
Senniger Powers Leavitt & Roedel
Solola T. A.
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