Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1994-07-28
2001-03-13
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S449000, C514S471000, C549S472000, C549S473000, C549S511000
Reexamination Certificate
active
06201140
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions hereof, and their use as antitumor agents.
2. Background Art
Taxol® (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. 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 has been recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results. The results of paclitaxel clinical studies are reviewed in Rowinsky and Donehower, “The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics”
Pharmac. Ther.,
52:35-84, 1991.
Recently, a semi-synthetic analog of paclitaxel named Taxotere® has also been found to have good antitumor activity in animal models. Taxotere® is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and Taxotere® are shown below along with the conventional numbering system of taxane molecules; such numbering system is also employed in this application.
Taxol®: R=Ph; R′=acetyl
Taxotere®: R=t-butoxy; R′=hydrogen
The instant invention relates to a novel class of taxanes. More particularly they are 7-0 ethers of taxane derivatives.
SUMMARY OF THE INVENTION
The present invention relates to taxane derivatives having the formula (I):
wherein R
1
is hydrogen, C
1-8
alkyloxy, C
2-8
alkenyloxy, or C
2-8
alkynyloxy, each can be optionally substituted with hydroxy; R
2
is hydroxy, —OC(O)R
x
or —OC(O)OR
x
; R
4
and R
5
are independently C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, or —Z—R
6
; p is zero or one; Z is a direct bond, C
1-8
alkylene or C
2-8
alkenediyl; R
6
is aryl, substituted aryl, C
3-8
cycloalkyl or heteroaryl; and R
x
is C
1-8
alkyl optionally, substituted with one to six same or different halogen atoms, C
3-8
cycloalkyl or C
2-8
alkenyl; or R
x
is a radical of the formula
wherein D is a bond or C
1-8
alkyl; and R
a
, R
b
and R
c
are independently hydrogen, amino, C
1-8
alkylamino, di-C
1-8
alkylamino, halogen, C
1-8
alkyl, or C
1-8
alkyloxy.
Another aspect of the present invention provides a method for inhibiting tumor in a mammalian host which comprises administering to said mammalian host an antitumor effective amount of a compound of the formula (I).
Yet another aspect of the present invention provides a pharmaceutical composition (formulation) which comprises an antitumor effective amount of a compound of the formula (I) and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
In the application, unless otherwise specified explicitly or in context, the following definitions apply. “Alkyl” means a straight or branched saturated carbon chain having from one to eight carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, n-hexyl, n-heptyl, and n-octyl. “Alkylene” means alkyl with two points of attachment; examples include methylene, ethylene, and propylene. “Alkenyl” means a straight or branched carbon chain having at least one carbon—carbon double bond, and having from two to eight carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. “Alkenediyl” refers to alkenyl with two points of attachment; examples include ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-dinyl, 2-hexene-1,6-diyl, and the like groups. “Alkynyl” means a straight or branched carbon chain having at least one carbon—carbon triple bond, and from two to eight carbon atoms; examples include ethynyl, propynyl, butynyl, and hexynyl.
“Aryl” means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and naphthyl. “Substituted aryl” means aryl substituted with at least one group selected from C
1-8
alkanoyloxy, hydroxy, halogen, C
1-8
alkyl, trifluoromethyl, C
1-8
alkoxy (alkyloxy), aryl, C
2-8
alkenyl, C
1-8
alkanoyl, nitro, amino, and amido. “Halogen” means fluorine, chlorine, bromine, and iodine.
“Methylthiomethyl” (also abbreviated as MTM) refers to the group —CH
2
SCH
3
.
“Heteroaryl” means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, and like rings.
“Hydroxy protecting groups” include, 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, and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl, and p-nitrophenyl. Additional examples of hydroxy protecting groups may be found in standard reference works such as Greene and Wuts,
Protective Groups in Organic Synthesis,
2d Ed., 1991, John Wiley & Sons, and McOmie,
Protective Groups in Organic Chemistry,
1975, Plenum Press. Methods for introducing and removing protecting groups are also found in such textbooks.
“Taxane” denotes moieties containing the twenty carbon taxane core framework represented by the structural formula shown below with the absolute configuration.
The numbering system shown above is one used in conventional taxane nomenclature, and is followed throughout the application. For example, the notation C1 refers to the carbon atom labelled as “1”; C5-C20 oxetane refers to an oxetane ring formed by the carbon atoms labelled as 4, 5 and 20 with an oxygen atom.
A compound of formula (I) can be prepared by a process of Scheme I. In Scheme I, 7-O-methylthiomethyl is either (1) reduced to 7-O-methyl with Raney Nickel; or (2) reacted with R
3
OH, in which R
3
is C
1-8
alkyloxy, C
2-8
alkenyloxy or C
2-8
alkynyloxy, each can optionally be substituted with hydroxy, in the presence of NIS with triflate as a catalyst. Preferred triflate is silver triflate or trialkylsilyltriflate. An analogous reaction of an alcohol with methylthiomethyloxy group in the presence of NIS was reported by Veeneman et al, in
Tetrahedron,
1991, v47, pp. 1547-1562, the relevant portions thereof are hereby incorporated by reference.
A starting compound of formula (II) can be readily available by either process of Scheme IIa or IIb.
Scheme IIa depicts essentially a coupling as described in EP Application 400,971 published Dec. 5, 1990 (now U.S. Pat. No. 5,175,315) and U.S. Pat. No. 5,229,526. To summerize, the process as disclosed in EP 400,971 (the Holton process) involves reacting 1-benzoyl-3-(1-ethoxy)ethoxy-4-phenyl-2-azetidinone with 7-O-triethylsilylbaccatin III in the presence of N,N-dimethylaminopyridine and pyridine at 25° C. for 12 hours; paclitaxel is obtained after the various hydroxy protecting groups are removed. An improvement of the Holton process is reported by Ojima et al in “New and Efficient Approaches to the Semisynthesis of Taxol and its C-13 Side Chain Analogs by Means of &bgr;-Lactam Synthon Method”
Tetrahedron,
1992, 48(34):6985-7012. Ojimals process involves first generating the sodium salt of 7-O-triethylsilylbaccatin III with sodium hydride; this salt is then reacted with chiral 1-benzoyl-3-(1-ethyoxy)ethoxy-4-phenyl-2-azetidinone to provide paclitaxel after removal of the hydroxy protecting groups. In U.S. Pat. No. 5,229,
Wittman Mark D.
Wong Henry
Bristol--Myers Squibb Company
DuBoff Samuel J.
Han William T.
Trinh Ba K.
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