Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-31
2003-07-15
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06593482
ABSTRACT:
The present invention relates to methods of preparing new taxoids of general formula:
in which:
Z represents a hydrogen atom or a radical of general formula:
in which:
R
1
represents a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl radicals, a thenoyl or furoyl radical or a radical R
2
—O—C(═O)— in which
R
2
represents:
an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, a phenyl radical (unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms), cyano radicals, carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms;
a phenyl or an &agr;- or &bgr;-naphthyl radical radical, which is unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, and a 5-membered aromatic heterocyclic radical;
R
3
represents a phenyl radical;
R
4
represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms in an unbranched or branched chain, this radical being unsubstituted or substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms, or alternatively R
4
represents a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms, or alternatively R
4
represents a benzoyloxy radical; and
R
5
represents an alkoxy radical containing 1 to 4 carbon atoms in an unbranched or branched chain, substituted by an alkylthio radical containing 1 to 4 carbon atoms.
Preferably, the radical R
4
represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms, or a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms.
More especially, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which
R
1
represents a benzoyl radical, or a radical R
2
—O—C (═O)— in which
R
2
represents a tert-butyl radical, and
R
3
represents a phenyl radical, and
R
4
represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 4 carbon atoms, and
R
5
represents an alkoxy group containing 1 to 4 carbon atoms substituted by a methylthio radical.
Still more especially, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R
1
represents a benzoyl radical or a radical R
2
—O—C(═O)— in which R
2
represents a tert-butyl radical and R
3
represents a phenyl radical, R
4
represents an acetoxy, or a methoxyacetoxy radical, and R
5
represents a methylthiomethoxy radical.
The products of general formula (I) in which Z represents a radical of general formula (II) display noteworthy anti-tumor and anti-leukemic properties.
According to the present invention, the new products of general formula (I) in which Z represents a radical of general formula (II) may be obtained by esterification of a product of general formula:
in which R
4
and R
5
are defined as above, by means of an acid of general formula:
in which R
1
and R
3
are defined as above, and either R
6
represents a hydrogen atom and R
7
represents a group protecting the hydroxyl function, or R
6
and R
7
together form a saturated 5- or 6-membered heterocycle, or by means of a derivative of this acid, to obtain an ester of general formula:
in which R
1
, R
3
, R
4
, R
5
, R
6
and R
7
are defined as above, followed by replacement of the protective groups represented by R
7
and/or R
6
and R
7
by hydrogen atoms.
The esterification by means of a product of general formula (XII):
R′
4
−X
1
(XII)
in which R′
4
is such that R′
4
—O— is identical to R
4
defined as above but cannot represent a hydrogen atom or a hydroxyl radical, and in which X
1
represents a hydroxyl radical, may be performed in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between −10 and 90° C.
The esterification may also be carried out using a product of general formula (XII) in which X
1
represents a radical R
4
—O—, working in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between 0 and 90° C.
The esterification may also be carried out using a product of general formula (XII) in which X
1
represents a halogen atom, in the presence of a base (tertiary aliphatic amine), working in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between 0 and 80° C.
Preferably, R
6
represents a hydrogen atom and R
7
represents a group protecting the hydroxyl function, or alternatively R
6
and R
7
together form a saturated 5- or 6-membered heterocycle.
When R
6
represents a hydrogen atom, R
7
preferably represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, &bgr;-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl radical.
When R
6
and R
7
together form a heterocycle, the latter is preferably an oxazolidine ring optionally monosubstituted or gem-disubstituted at position 2.
Replacement of the protective groups R
7
and/or R
6
and R
7
by hydrogen atoms may be performed, depending on their nature, in the following manner:
1) when R
6
represents a hydrogen atom and R
7
represents a group protecting the hydroxyl function, replacement of the protective groups by hydrogen atoms is performed by means of an inorganic acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid) used alone or mixed, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitrites at a temperature of between −10 and 60° C.,
2) when R
6
and R
7
together form a saturated 5-or 6-membered heterocycle, and more especially an oxazolidine ring of general formula:
in which R
1
is defined as above and R
8
and R
9
, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an arylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R
8
represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted with a trihalomethyl radical such as trichloromethyl and R
9
represents a hydrogen atom, or alternatively R
8
and R
9
, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, replacement of the protective group formed by R
6
and R
7
by hydrogen atoms may be performed, depending on the meanings of R
1
, R
8
and R
9
, in the following manner:
a) when R
1
represents a tert-butoxycarbo
Bouchard Herve
Bourzat Jean-Dominique
Commerçon Alain
Ojima Iwao
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
Trinh Ba K.
LandOfFree
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