9&bgr;-hydroxytetracyclic taxanes

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C549S511000

Reexamination Certificate

active

06710191

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of taxol, baccatin III and 10-desacetyl-baccatin III derivatives or other taxanes having new C9 functional groups.
Taxol is a natural product extracted from the bark of yew trees. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is currently undergoing clinical trials against ovarian, breast and other types of cancer in the United States and France and preliminary results have confirmed it as a most promising chemo-therapeutic agent. The structure of taxol and the numbering system conventionally used is shown below; this numbering system is also applicable to compounds used in the process of the present invention.
In Colin U.S. Pat. No. 4,814,470, it was reported that a taxol derivative, commonly referred to as taxotere, has an activity significantly greater than taxol. Taxotere has the following structure:
The tetracyclic core of taxol and taxotere bear a C9 keto substituent which, if modified, would lead to the preparation of a series of taxol analogs having improved water solubility. To date, however, the selective manipulation of the C9 keto group has presented a formidable problem.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a process for selectively manipulating the C9 keto substituent of baccatin III, 10-deactylbaccatin III and other taxanes; and the provision of such a process which is relatively straightforward.
Briefly, therefore, the present invention is directed to a process for the preparation of analogs or derivatives of taxol, baccatin III, 10-desacetyl baccatin III or other taxanes in which the C9 keto substituent is reduced to the corresponding hydroxy group. Optionally, the C9 hydroxy substituent may thereafter be selectively replaced by another functional group and/or other substituents of the taxane may be replaced by other functional groups to yield a taxane having the formula:
wherein
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 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;
R
9a
is hydrogen, hydroxy, protected hydroxy, or acyloxy;
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
13
is hydroxy, protected hydroxy or
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
29
, is hydrogen, acyl, or hydroxy protecting group;
R
29
, R
30
and R
31
are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;
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, or hydroxy protecting group;
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
; and
X
14
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
The present invention is additionally directed to a derivative of baccatin III or 10-desacetyl baccatin III having the following formula which is a key intermediate in the synthesis of a new series of tetracyclic taxanes
wherein R
2
, R
4a
, R
7a
, R
10a
and R
14
are as previously defined and R
13
is hydroxy or protected hydroxy.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
As used herein “Ar” means aryl; “Ph” means phenyl; “Ac” means acetyl; “Et” means ethyl; “R” means alkyl unless otherwise defined; “tBu” means t-butyl; “TES” means triethylsilyl; “TMS” means trimethylsilyl; “TPAP” means tetrapropylammonium perruthenate; “DMAP” means p-dimethylamino pyridine; “DMF” means dimethyl-formamide; “LDA” means lithium diisopropylamide; “LAH” means lithium aluminum hydride; “Red-Al” means sodium bis(2-methoxyethoxy) aluminum hydride; “10-DAB” means 10-desacetylbaccatin III; 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, 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-trichloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates have 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 hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.
The alkenyl groups described herein, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be str

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