Phosphonooxymethyl ethers of taxane derivatives

Details Phosphonooxymethyl ethers of taxane derivatives Phosphonooxymethyl ethers of taxane derivatives

1997-06-06

2002-09-24

Trinh, Ba K. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S510000, C549S511000

Reexamination Certificate

active

06455575

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 thereof, 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 was 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; the conventional numbering system of the paclitaxel molecule is provided.
One drawback of paclitaxel is its very limited water solubility requiring it to be formulated in nonaqueous pharmaceutical vehicles. One commonly used carrier is Cremophor EL which may itself have undesirable side effects in man. Accordingly, a number of research teams have prepared water-soluble derivatives of paclitaxel which are disclosed in the following references:
(a) Haugwitz et al, U.S. Pat. No. 4,942,184;
(b) Kingston et al, U.S. Pat. No. 5,059,699;
(c) Stella et al, U.S. Pat. No. 4,960,790;
(d) European Patent Application 0,558,959 A1 published Sep. 8, 1993;
(e) Vyas et al,
Bioorganic & Medicinal Chemistry Letters,
1993, 3:1357-1360; and
(f) Nicolaou et al,
Nature,
1993, 364:464-466
Compounds of the present invention are phosphonooxymethyl ethers of taxane derivatives and pharmaceutically acceptable salts thereof. The water solubility of the salts facilitates preparation of pharmaceutical formulations.
SUMMARY OF THE INVENTION
The present invention relates to taxane derivatives having the formula (A):
T—[OCH
2
(OCH
2
)
m
OP(O)(OH)
2
]
n
  (A)
wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2-hydroxypropanoyloxy group; n is 1, 2 or 3; m is 0 or an integer from 1 to 6 inclusive; or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention provides taxane derivatives having the formula (B):
T′—[OCH
2
(OCH
2
)
m
SCH
3
]
n
  (B)
wherein T′ is T in which non-reacting hydroxy groups have been blocked, m and n are as defined under formula (A).
Yet another aspect of the present invention provides intermediates having the formula (C):
T′—[OCH
2
(OCH
2
)
m
OP(O)(OR
y
)
2
]
n
  (C)
wherein T′, m and n are as defined under formula (A), and R
y
is a phosphono protecting group.
Another aspect of the present invention provides compounds of the formula (D):
13—OH—txn—[OCH
2
(OCH
2
)
m
SCH
3
]
n
  (D)
wherein m and n are as defined above; and txn is a taxane moiety; or a C13 metal alkoxide thereof.
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 formula (A).
Further 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 (B′):
wherein R
1b′
is hydroxy, —OC(O)R
x
or —OC(O)OR
x
; R
3b′
is hydrogen, hydroxy, —OC(O)OR
x
, C
1-6
alkyloxy or —OC(O)R
x
; one of R
6b′
or R
7b′
is hydrogen and the other is hydroxy or C
1-6
alkanoyloxy; or R
6b′
and R
7b′
together form an oxo group; R
4
and R
5
are independently C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, or —Z—R
6
; Z is a direct bond, C
1-6
alkyl or C
2-6
alkenyl; R
6
is aryl, substituted aryl, C
3-6
cycloalkyl or heteroaryl; p is 0 or 1; R
x
is C
1-6
alkyl optionally, substituted with one to six same or different halogen atoms, C
3-6
cycloalkyl, C
2-6
alkenyl or hydroxy; or R
x
is a radical of the formula
wherein D is a bond or C
1-6
alkyl; and R
a
, R
b
and R
c
are independently hydrogen, amino, C
1-6
alkylamino, di-C
1-6
alkylamino, halogen, C
1-6
alkyl, or C
1-6
alkoxy.
Thus, another aspect of the present invention provides a pharmaceutical composition which comprises an antitumor effective amount of a compound of formula (B′) or (A) 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 six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, and n-hexyl. “Alkenyl” means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to six carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. “Alkynyl” means a straight or branched carbon chain having at least one carbon-carbon triple bond, and from two to six 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
1-6
alkanoyloxy, hydroxy, halogen, C
1-6
alkyl, trifluoromethyl, C
1-6
alkoxy, aryl, C
2-6
alkenyl, C
1-6
alkanoyl, nitro, amino, and amido. “Halogen” means fluorine, chlorine, bromine, and iodine.
“Phosphono-” means the group —P(O) (OH)
2
and “phosphonooxymethoxy” or “phosphonooxymethyl ether” means generically the group —OCH
2
(OCH
2
)
m
OP(O) (OH)
2
. “(Methylthio)thiocarbonyl” means the group —C(S)SCH
3
. “Methylthiomethyl” (also abbreviated as MTM) generically refers to the group —CH
2
SCH
3
.
“Taxane moiety” (also abbreviated as txn) 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; and C9 oxy refers to an oxygen atom attached to the carbon atom labelled as “9”, said oxygen atom may be an oxo group, &agr;- or &bgr;-hydroxy, or &agr;- or &bgr;-acyloxy.
“Substituted 3-amino-2-hydroxypropanoyloxy” denotes a residue represented by the formula
(X is a nonhydrogen group and X′ is hydrogen or a non-hydrogen group.) The stereochemistry of this residue is the same as the paclitaxel sidechain. This group is sometimes referred to in the application as the “C13 sidechain.”
“Taxane derivative” (abbreviated as T) refers to a compound having a taxane moiety bearing a C13 sidechain.
“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.
“Phosphono protecting groups” means moieties which can be employed to block or protect the phosphono functional group; preferably such protecting grou

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