C2 substituted taxanes

Details C2 substituted taxanes C2 substituted taxanes

2001-12-12

2003-11-18

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

06649777

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.
Cohn 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-carbonylamino 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 C2 taxane derivatives. 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 —COX
10
, —COOX
10
, —COSX
10
, —CONX
8
X
10
, or —SO
2
X
11
;
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, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X
11
is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX
10
, or —NX
8
X
14
;
X
14
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R
1
is hydrogen, hydroxy, protected hydroxy or together with R
14
forms a carbonate;
R
2
is —OCOR
31
;
R
2a
is hydrogen;
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
and R
30
are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl, and
R
31
is substituted phenyl.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein “Ar” means aryl; “Ph” means phenyl; “Ac” means acetyl; “Et” means ethyl; “R” means alkyl unless otherwise defined; “Bu” means butyl; “Pr” means propyl; “TES” means triethylsilyl; “TMS” means trimethylsilyl; “TPAP” means tetrapropylammonium perruthenate; “DMAP” means p-dimethylamino pyridine; “DMF” means dimethylformamide; “LDA” means lithium diisopropylamide; “LHMDS” means lithium hexamethyldisilazide; “LAH” means lithium aluminum hydride; “Red-Al” means sodium bis(2-methoxyethoxy) aluminum hydride; “AIBN” means azo-(bis)-isobutyronitrile; “10-DAB” means 10-desacetylbaccatin III; FAR means 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means —OR wherein R is a hydroxy protecting group; sulfhydryl protecting group” includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; “amine protecting group” includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and “hydroxy protecting group” includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C
1-6
alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in “Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like.
The alkenyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
The alkynyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethynyl, propy

Affiliated with

Also associated with

Rating

C2 substituted taxanes does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with C2 substituted taxanes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C2 substituted taxanes will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3147400