Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-17
2004-09-21
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06794523
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to novel taxanes which have utility as antileukemia and antitumor agents.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and 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 structural formula (2) below, have an activity significantly greater than that of taxol (1).
R′ represents hydrogen or acetyl and one of R″ and R′″ represents hydroxy and the other represents tert-butoxy-carbonylaminlo and their stereoisomeric forms, and mixtures thereof. The compound of formula (2) in which R′ is hydrogen, 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 taxane derivatives which are valuable antileukemia and antitumor agents.
Briefly, therefore, the present invention is directed to taxane derivatives having a C13 side chain which includes an alkoxy or alkenoxy substituent, but which differs from taxotere with respect to at least one substituent. In a preferred embodiment, the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula:
wherein
X
1
is —OX
6
, —SX
7
, or —NX
8
X
9
;
X
2
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X
3
and X
4
are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X
5
is —COOX
10
;
X
6
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X
7
is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X
8
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X
9
is an amino protecting group;
X
10
is alkyl, alkenyl or aryl;
R
1
is hydrogen, hydroxy, protected hydroxy, or together with R
14
forms a carbonate;
R
2
is hydrogen, hydroxy, —OCOR
31
or together with R
2a
forms an oxo;
R
2a
is hydrogen or taken together with R
2
forms an oxo;
R
4
is hydrogen, together with R
4a
forms an oxo, oxirane or methylene, or together with R
5a
and the carbon atoms to which they are attached form an oxetane ring;
R
4a
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, —OCOR
30
, or together with R
4
forms an oxo, oxirane or methylene;
R
5
is hydrogen or together with R
5a
forms an oxo,
R
5a
is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R
5
forms an oxo, or together with R
4
and the carbon atoms to which they are attached form an oxetane ring;
R
6
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R
6a
forms an oxo;
R
6a
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R
6
forms an oxo;
R
7
is hydrogen or together with R
7a
forms an oxo,
R
7a
is hydrogen, halogen, protected hydroxy, —OR
28
, or together with R
7
forms an oxo;
R
9
is hydrogen or together with R
9a
forms an oxo,
R
9a
is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R
9
forms an oxo;
R
10
is hydrogen or together with R
10a
forms an oxo,
R
10a
is hydrogen, —OCOR
29
, hydroxy, or protected hydroxy, or together with R
10
forms an oxo;
R
14
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R
1
forms a carbonate;
R
14a
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R
28
is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative;
R
29
, R
30
, and R
31
are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl, provided, however, that when X
10
is t-butyl at least one of said other X
1
-X
9
or R
1
-R
31
has a value such that the structure of the taxane is different from that of taxotere.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
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Borman “New Family of Taxol, Taxotere Analogs Developed” Chem. & Engineering News, Science/Technology (Apr. 12, 1993) pp. 26-27.
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Chai Ki-byung
Holton Robert A.
Idmoumaz Hamid
Nadizadeh Hossain
Rengan Kasthuri
Florida State University
Senniger Powers Leavitt & Roedel
Trinh Ba K.
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