U.S. patent application number 09/985956 was filed with the patent office on 2002-03-28 for methods for treating pathological conditions of abnormal cell proliferation.
This patent application is currently assigned to Aventis Pharma S.A.. Invention is credited to Bouchard, Herve, Bourzat, Jean-Dominique, Commercon, Alain.
Application Number | 20020038038 09/985956 |
Document ID | / |
Family ID | 26231838 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020038038 |
Kind Code |
A1 |
Bouchard, Herve ; et
al. |
March 28, 2002 |
Methods for treating pathological conditions of abnormal cell
proliferation
Abstract
New taxoids of general formula (I): 1 their preparation and
pharmaceutical compositions containing them. The new products of
general formula (I) in which Z represents a radical of general
formula (II): 2 display noteworthy antitumor and antileukemic
properties.
Inventors: |
Bouchard, Herve;
(Ivry-sur-Seine, FR) ; Bourzat, Jean-Dominique;
(Vincennes, FR) ; Commercon, Alain;
(Vitry-sur-Seine, FR) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT &
DUNNER LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Assignee: |
Aventis Pharma S.A.
|
Family ID: |
26231838 |
Appl. No.: |
09/985956 |
Filed: |
September 25, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09985956 |
Sep 25, 2001 |
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09066929 |
Apr 28, 1998 |
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09066929 |
Apr 28, 1998 |
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08622011 |
Mar 26, 1996 |
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5847170 |
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60010144 |
Jan 17, 1996 |
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Current U.S.
Class: |
549/60 ; 549/472;
549/510 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 305/14 20130101; Y02P 20/55 20151101; A61P 35/02 20180101 |
Class at
Publication: |
549/60 ; 549/510;
549/472 |
International
Class: |
C07D 49/02; C07D
35/14 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 1995 |
FR |
95 03545 |
Dec 22, 1995 |
FR |
95 15381 |
Claims
We claim:
1. A taxoid of the formula (I): 23in which: Z represents a hydrogen
atom or a radical of formula (II): 24in which: R.sub.1 represents a
benzoyl radical optionally substituted with one or more identical
or different atoms or radicals selected from halogen atoms, alkyl
radicals containing 1 to 4 carbon atoms, alkoxy radicals containing
1 to 4 carbon atoms, trifluoromethyl radicals, a thenoyl radical, a
furoyl radical, and a radical R.sub.2--O--CO-- in which R.sub.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 or a bicycloalkyl radical containing 7 to 10 carbon atoms,
these radicals being optionally substituted with one or more
substituents selected from halogen atoms; hydroxyl radicals; alkoxy
radicals containing 1 to 4 carbon atoms; dialkylamino radicals in
which each alkyl portion contains 1 to 4 carbon atoms; piperidino
radicals; morpholino radicals; 1-piperazinyl radicals optionally
substituted at position 4 with an alkyl radical containing 1 to 4
carbon atoms or with a phenylalkyl radical in which the alkyl
portion contains 1 to 4 carbon atoms; cycloalkyl radicals
containing 3 to 6 carbon atoms; cycloalkenyl radicals containing 4
to 6 carbon atoms; phenyl radicals optionally 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 .alpha.- or .beta.-naphthyl radical
optionally 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, or a 5-membered
aromatic heterocyclic radical, or a saturated heterocyclic radical
containing 4 to 6 carbon atoms, optionally substituted with one or
more alkyl radicals containing 1 to 4 carbon atoms, R.sub.3
represents an unbranched or branched alkyl radical containing 1 to
8 carbon atoms, an unbranched or branched alkenyl radical
containing 2 to 8 carbon atoms, an unbranched or branched alkynyl
radical containing 2 to 8 carbon atoms, a cycloalkyl radical
containing 3 to 6 carbon atoms, a phenyl or .alpha.- or
.beta.-naphthyl radical optionally substituted with one or more
atoms or radicals selected from halogen atoms, alkyl, alkenyl,
alkynyl, aryl aralkyl, alkoxy, alkylthio, aryloxy, arylthio,
hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino,
aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino,
carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or a
5-membered aromatic heterocycle containing one or more identical or
different hetero atoms selected from nitrogen, oxygen and sulphur
atoms and optionally substituted with one or more identical or
different substituents selected from halogen atoms, alkyl, aryl,
amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl,
arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl and alkoxycarbonyl radicals, with the proviso
that, in the substituents of the phenyl, .alpha.- or
.beta.-naphthyl and aromatic heterocyclic radicals, the alkyl
radicals and the alkyl portions of the other radicals contain 1 to
4 carbon atoms, and the alkenyl and alkynyl radicals contain 2 to 8
carbon atoms, and the aryl radicals are phenyl or .alpha.- or
.beta.-naphthyl radicals, R.sub.4 represents an alkoxy radical
containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain, an alkynyloxy radical containing 3 to
6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy
radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 4 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 1 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, R.sub.5 represents an alkoxy radical containing 1 to
6 carbon atoms in an unbranched or branched chain optionally
substituted with an alkoxy radical containing 1 to 4 carbon atoms,
an alkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy
radical containing 3 to 6 carbon atoms, a cycloalkyloxy radical
containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 3 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 2 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical, or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms.
2. A taxoid according to claim 1, wherein Z represents a hydrogen
atom or a radical of formula (II) in which R.sub.1 represents a
benzoyl radical or a radical R.sub.2--O--CO-- in which R.sub.2
represents a tert-butyl radical, R.sub.3 represents an alkyl
radical containing 1 to 6 carbon atoms; an alkenyl radical
containing 2 to 6 carbon atoms; a cycloalkyl radical containing 3
to 6 carbon atoms; a phenyl radical optionally substituted with one
or more identical or different atoms or radicals selected from
halogen atoms, alkyl, alkoxy, dialkylamino, acylamino,
alkoxycarbonylamino and trifluoromethyl radicals; or a 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl radical, and R.sub.4 and R.sub.5, which may be
identical or different, each represent an unbranched or branched
alkoxy radical containing 1 to 6 carbon atoms.
3. A taxoid according to claim 1, wherein Z represents a hydrogen
atom or a radical of formula (II) in which R.sub.1 represents a
benzoyl radical or a radical R.sub.2--O--CO-- in which R.sub.2
represents a tert-butyl radical, R.sub.3 represents an isobutyl,
isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl
radical, and R.sub.4 and R.sub.5, which may be identical or
different, each represent a methoxy, ethoxy or propoxy radical.
4. A taxoid according to claim 1, wherein when R.sub.2 represents a
5-membered aromatic heterocyclic radical, said radical is a furyl
or thienyl radical.
5. A process for preparing the taxoid according to claim 1, wherein
Z represents a radical of formula (II), said process comprising:
esterifying a product of formula (III): 25in which R.sub.4 and
R.sub.5 are defined as in claim 1 with an acid of formula (IV):
26in which R.sub.1 and R.sub.3 are defined as above, and either
R.sub.6 represents a hydrogen atom and R.sub.7 represents a group
protecting the hydroxyl function, or R.sub.6 and R.sub.7 together
form a saturated 5- or 6-membered heterocycle, or with a derivative
of said acid, to obtain an ester of formula (V): 27in which
R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are defined
as above, and replacing the protective group(s) of said ester of
formula (V), represented by R.sub.7 or R.sub.6 and R.sub.7, by
hydrogen atoms.
6. A process according to claim 5, wherein said esterifying step is
performed with an acid of formula (IV) in the presence of a
condensing agent and an activating agent in an organic solvent at a
temperature of from -10 to 90.degree. C.
7. A process according to claim 5, wherein said esterifying step is
performed with an acid of formula (IV) in the form of the
symmetrical anhydride thereof, in the presence of an activating
agent in an organic solvent at a temperature of from 0 to
90.degree. C.
8. A process according to claim 5, wherein said esterifying step is
performed with the acid of formula (IV) in halide form or in the
form of a mixed anhydride with an aliphatic or aromatic acid,
optionally prepared in situ, in the presence of a base, in an
organic solvent at a temperature of from 0 to 80.degree. C.
9. A process according to claim 5, further comprising replacing the
protective group(s) R.sub.7 or R.sub.6 and R.sub.7 by hydrogen
atoms, wherein: 1) when R.sub.6 represents a hydrogen atom and
R.sub.7 represents a group protecting the hydroxyl function, said
replacing the protective groups by hydrogen atoms is accomplished
with at least one inorganic or organic acid in an organic solvent
selected from alcohols, ethers, esters, aliphatic hydrocarbons,
halogenated aliphatic hydrocarbons, aromatic hydrocarbons and
nitrites at a temperature from -10 to 60.degree. C., or with a
source of fluoride ions, or with catalytic hydrogenation, 2) when
R.sub.6 and R.sub.7 together form a saturated 5- or 6-membered
heterocycle of formula (VI): 28in which R.sub.1 is defined as above
and R.sub.8 and R.sub.8, which may be identical or different,
represent a hydrogen atom or an alkyl radical containing 1 to 4
carbon atoms, or an aralkyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, or an aryl radical, or alternatively
R.sub.6 represents an alkoxy radical containing 1 to 4 carbon atoms
or a trihalomethyl radical or a phenyl radical substituted with a
trihalomethyl radical and R.sub.9 represents a hydrogen atom, or
alternatively R.sub.8 and R.sub.9, together with the carbon atom to
which they are linked, form a 4- to 7-membered ring, wherein when:
a) R.sub.1 represents a tert-butoxycarbonyl radical and R.sub.6 and
R.sub.9, which may be identical or different, represent an alkyl
radical or an aralkyl or aryl radical, or alternatively R.sub.6
represents a trihalomethyl radical or a phenyl radical substituted
with a trihalomethyl radical and R.sub.9 represents a hydrogen
atom, or alternatively R.sub.6, and R.sub.9 together form a 4- to
7-membered ring, the ester of formula (V) is treated with an
inorganic or organic acid, and where appropriate, in an organic
solvent, to obtain the product of formula (VII): 29in which
R.sub.3, R.sub.4 and R.sub.5 are defined as above, and said product
of formula (VII) is acylated with benzoyl chloride in which the
phenyl ring is optionally substituted or thenoyl chloride, or
furoyl chloride or a product of formula (VIII): R.sub.2--O--CO--X
(VIII) in which R.sub.2 is defined in claim 1 and X represents a
halogen atom or a residue --O--R.sub.2 or --O--CO--O--R.sub.2, to
obtain a product of formula (I) in which Z represents a radical of
formula (II), b) when R.sub.1 represents an optionally substituted
benzoyl radical a thenoyl or furoyl radical or a radical
R.sub.2O--CO-- in which R.sub.2 is defined as above, R.sub.8
represents a hydrogen atom or an alkoxy radical containing 1 to 4
carbon atoms or a phenyl radical substituted with one or more
alkoxy radicals containing 1 to 4 carbon atoms and R.sub.9
represents a hydrogen atom, the protective group formed by R.sub.6
and R.sub.7 is replaced by hydrogen atoms in the presence of at
least one inorganic or organic acid in a stoichiometric or
catalytic amount, and in an organic solvent selected from alcohols,
ethers, esters, aliphatic hydrocarbons, halogenated aliphatic
hydrocarbons and aromatic hydrocarbons at a temperature of from -10
to 60.degree. C.
10. A process according to claim 9, wherein when R.sub.6 and
R.sub.7 together form a saturated 5- or 6-membered heterocycle of
formula (VI), and R.sub.6 and R.sub.9, which may be identical or
different, represent an aralkyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, the aryl portion of said aralkyl
radical represents a phenyl radical optionally substituted with one
or more alkoxy radicals containing 1 to 4 carbon atoms.
11. A process according to claim 9, wherein when R.sub.6 and
R.sub.7 together form a saturated 5- or 6-membered heterocycle of
formula (VI), and R.sub.8 and R.sub.9, which may be identical or
different, represent an aryl radical, said aryl radical is a phenyl
radical optionally substituted with one or more alkoxy radicals
containing 1 to 4 carbon atoms.
12. A process according to claim 9, wherein said temperature ranges
from 15 to 30.degree. C.
13. A process for preparing a new taxoid according to claim 1,
wherein Z represents a hydrogen atom and R.sub.4 and R.sub.5 are
defined as in claim 1, said process comprising: treating
10-deacetylbaccatin III of formula (IX): 30with a silyl halide of
formula: (R).sub.3--Si--Hal (X) in which the symbols R, which may
be identical or different, represent an alkyl radical containing 1
to 6 carbon atoms, optionally substituted with a phenyl radical, a
cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl
radical, to obtain a product of formula (XI): 31in which R is
defined as above treating said product of formula (XI) with a
product of formula: R'.sub.4--X.sub.1 (XII) in which R'.sub.4
represents a radical such that R'.sub.4--O is identical to R.sub.4
defined as in claim 1 and X, represents a halogen atom or a
reactive ester residue, to obtain a product of formula (XIII): 32in
which R and R.sub.4 are defined as above, replacing the silyl
protective groups of said product of formula (XIII) by hydrogen
atoms to obtain a product of formula (XIV): 33in which R.sub.4 is
defined as above, and etherifying said compound of formula (XIV)
selectively at position 7 with a product of formula (XV):
R'.sub.5--X.sub.2 (XV) in which R'.sub.5 represents a radical such
that R'.sub.5--O is identical to R.sub.5 defined as in claim 1 and
X.sub.2 represents a reactive ester residue or a halogen atom, to
give the product of formula (I) in which 2 represents a hydrogen
atom.
14. A process for preparing a product according to claim 1, wherein
Z represents a radical of formula (II) and R.sub.4 and R.sub.5 are
defined as in claim 1, said process comprising: treating a product
of formula (XVI): 34in which R.sub.1, R.sub.3, R.sub.6 and R.sub.7
are defined as in claim 1, with a product of formula (X):
(R).sub.3Si--Hal (X) in which the symbols R, which may be identical
or different, represent an alkyl radical containing 1 to 6 carbon
atoms, optionally substituted with a phenyl radical, or a
cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl
radical, to obtain a product of formula (XVII): 35in which R,
R.sub.1, R.sub.3, R.sub.6 and R.sub.7 are defined as above,
functionalizing said compound of formula (XVII) at position 10 with
a product of formula: R'.sub.4--X.sub.1 (XII) in which R'.sub.4
represents a radical such that R'.sub.4--O is identical to R.sub.4
defined as in claim 1 and X.sub.1 represents a halogen atom or a
reactive ester residue, to give a product of formula (XVIII): 36in
which R, R.sub.1, R.sub.3, R.sub.4, R.sub.6 and R.sub.7 are defined
as above, replacing the silyl protective group of said product of
formula (XVIII) by a hydrogen atom to give a product of formula
(XIX): 37which, when reacted with a product of formula (XV), yields
the product of formula (V), and replacing the protective groups of
formula (V) with hydrogen atoms to give a product of formula (I) in
which Z represents a radical of formula (II).
15. A process for preparing a product according to claim 1,
comprising reacting activated Raney nickel, in the presence of an
aliphatic alcohol containing 1 to 3 carbon atoms or an ether, with
a product of formula (XXI): 38in which R.sub.4 is defined as in
claim 1, and R' and R", which may be identical or different,
represent a hydrogen atom or an alkyl radical containing 1 to 6
carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, an
alkynyl radical containing 3 to 6 carbon atoms, a cycloalkyl
radical containing 2 to 6 carbon atoms or a cycloalkenyl radical
containing 3 to 6 carbon atoms, optionally substituted, or
alternatively R' and R", together with the carbon atom to which
they are linked, form a cycloalkyl radical containing 3 to 6 carbon
atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, and
Z.sub.1 represents a hydrogen atom or a radical of formula (XXII):
39in which R.sub.1 and R.sub.3 are defined in claim 1 and either
R.sub.6 represents a hydrogen atom and R.sub.7 represents a group
protecting the hydroxyl function, or R.sub.6 and R.sub.7 together
form a saturated 5- or 6-membered heterocycle, to obtain a product
of formula (XXIII): 40followed, when Z.sub.1 represents a radical
of formula (XXII), by replacing the protective group(s) represented
by R.sub.6 or R.sub.6 and R.sub.7 by hydrogen atoms under the
conditions of claim 9.
16. A preparation process according to claim 15, wherein said
process is carried out at a temperature of from -10 to 60.degree.
C.
17.
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy--
7.beta., 10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
18.
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-1.beta.-hydroxy-5.beta.,20-epoxy--
7.beta.-methoxy-10.beta.-ethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
19.
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-1.beta.-hydroxy-5.beta.,20-epoxy--
7.beta.-methoxy-10.beta.-(1-propyl)oxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
20. A pharmaceutical composition comprising at least one product
according to claim 1 wherein Z represents a radical of formula
(II), in combination with one or more pharmaceutically acceptable
diluents or adjuvants and optionally one or more compatible and
pharmacologically active compounds.
21. A pharmaceutical composition comprising at least the product
according to claim 17 in combination with one or more
pharmaceutically acceptable diluents or adjuvants and optionally
one or more compatible and pharmacologically active compounds.
22. A pharmaceutical composition comprising at least the product
according to claim 18 in combination with one or more
pharmaceutically acceptable diluents or adjuvants and optionally
one or more compatible and pharmacologically active compounds.
23. A pharmaceutical composition comprising at least the product
according to claim 19 in combination with one or more
pharmaceutically acceptable diluents or adjuvants and optionally
one or more compatible and pharmacologically active compounds.
24. An ester of the formula (V): 41wherein R.sub.1 represents a
benzoyl radical optionally substituted with one or more identical
or different atoms or radicals selected from halogen atoms, alkyl
radicals containing 1 to 4 carbon atoms, alkoxy radicals containing
1 to 4 carbon atoms, trifluoromethyl radicals, a thenoyl radical, a
furoyl radical, and a radical R.sub.2--O--CO-- in which R.sub.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 or a bicycloalkyl radical containing 7 to 10 carbon atoms,
these radicals being optionally substituted with one or more
substituents selected from halogen atoms; hydroxyl radicals; alkoxy
radicals containing 1 to 4 carbon atoms; dialkylamino radicals in
which each alkyl portion contains 1 to 4 carbon atoms; piperidino
radicals; morpholino radicals; 1-piperazinyl radicals optionally
substituted at position 4 with an alkyl radical containing 1 to 4
carbon atoms or with a phenylalkyl radical in which the alkyl
portion contains 1 to 4 carbon atoms; cycloalkyl radicals
containing 3 to 6 carbon atoms; cycloalkenyl radicals containing 4
to 6 carbon atoms; phenyl radicals optionally 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 .alpha.- or .beta.-naphthyl radical
optionally 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, a 5-membered
aromatic heterocyclic radical, or a saturated heterocyclic radical
containing 4 to 6 carbon atoms, optionally substituted with one or
more alkyl radicals containing 1 to 4 carbon atoms, R.sub.3
represents an unbranched or branched alkyl radical containing 1 to
8 carbon atoms, an unbranched or branched alkenyl radical
containing 2 to 8 carbon atoms, an unbranched or branched alkynyl
radical containing 2 to 8 carbon atoms, a cycloalkyl radical
containing 3 to 6 carbon atoms, a phenyl or .alpha.- or
.beta.-naphthyl radical optionally substituted with one or more
atoms or radicals selected from halogen atoms, alkyl, alkenyl,
alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio,
hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino,
aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino,
carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or a
5-membered aromatic heterocycle containing one or more identical or
different hetero atoms selected from nitrogen, oxygen and sulphur
atoms and optionally substituted with one or more identical or
different substituents selected from halogen atoms, alkyl, aryl,
amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl,
arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl and alkoxycarbonyl radicals, with the proviso
that, in the substituents of the phenyl, .alpha.- or
.beta.-naphthyl and aromatic heterocyclic radicals, the alkyl
radicals and the alkyl portions of the other radicals contain 1 to
4 carbon atoms, and the alkenyl and alkynyl radicals contain 2 to 8
carbon atoms, and the aryl radicals are phenyl or .alpha.- or
.beta.-naphthyl radicals, R.sub.4 represents an alkoxy radical
containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain, an alkynyloxy radical containing 3 to
6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy
radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 4 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 1 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, R.sub.5 represents an alkoxy radical containing 1 to
6 carbon atoms in an unbranched or branched chain optionally
substituted with an alkoxy radical containing 1 to 4 carbon atoms,
an alkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy
radical containing 3 to 6 carbon atoms, a radical containing 3 to 6
carbon atoms, these radicals being optionally substituted with at
least one substituent selected from halogen atoms, an alkoxy
radical containing 1 to 4 carbon atoms, an alkylthio radical
containing 2 to 4 carbon atoms, a carboxyl radical, an
alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4
carbon atoms, a cyano radical, a carbamoyl radical, an
N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical, or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and either R.sub.6 represents a hydrogen atom and
R.sub.7 represents a group protecting the hydroxyl function, or
R.sub.6 and R.sub.7 together form a saturated 5- or 6-membered
heterocycle.
25. An ester of formula (VII): 42wherein R.sub.3 represents an
unbranched or branched alkyl radical containing 1 to 8 carbon
atoms, an unbranched or branched alkenyl radical containing 2 to 8
carbon atoms, an unbranched or branched alkynyl radical containing
2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon
atoms, a phenyl or .alpha.- or .beta.-naphthyl radical optionally
substituted with one or more atoms or radicals selected from
halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy,
alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto,
formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino,
alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,
alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl
radicals, or a 5-membered aromatic, heterocycle containing one or
more identical or different hetero atoms selected from nitrogen,
oxygen and sulphur atoms and optionally substituted with one or
more identical or different substituents selected from halogen
atoms, alkyl, aryl, amino, alkylamino, dialkylamino,
alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl
radicals, with the proviso that, in the substituents of the phenyl,
.alpha.- or .beta.-naphthyl and aromatic heterocyclic radicals, the
alkyl radicals and the alkyl portions of the other radicals contain
1 to 4 carbon atoms, and the alkenyl and alkynyl radicals contain 2
to 8 carbon atoms, and the aryl radicals are phenyl or .alpha.- or
.beta.-naphthyl radicals, R.sub.4 represents an alkoxy radical
containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain, an alkynyloxy radical containing 3 to
6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy
radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 4 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 1 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and R.sub.5 represents an alkoxy radical containing 1
to 6 carbon atoms in an unbranched or branched chain optionally
substituted with an alkoxy radical containing 1 to 4 carbon atoms,
an alkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy
radical containing 3 to 6 carbon atoms, a cycloalkyloxy radical
containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 3 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 2 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical, or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms.
26. A method comprising the step of etherifying selectively at
position 7 a compound of the formula (XIV): 43wherein R.sub.4
represents an alkoxy radical containing 1 to 6 carbon atoms in an
unbranched or branched chain, an alkenyloxy radical containing 3 to
6 carbon atoms in an unbranched or branched chain, an alkynyloxy
radical containing 3 to 6 carbon atoms in an unbranched or branched
chain, a cycloalkyloxy radical containing 3 to 6 carbon atoms or a
cycloalkenyloxy radical containing 4 to 6 carbon atoms, these
radicals being optionally substituted with at least one substituent
selected from halogen atoms, an alkoxy radical containing 1 to 4
carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms,
a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl
portion contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl
radical, an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl
radical in which each alkyl portion contains 1 to 4 carbon atoms
or, both alkyl portions, together with the nitrogen atom to which
they are linked, form a saturated 5- or 6-membered heterocyclic
radical optionally containing a second hetero atom selected from
oxygen, sulphur and nitrogen atoms, optionally substituted with an
alkyl radical containing 1 to 4 carbon atoms, a phenyl radical or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, with a compound of the formula (XV):
R'.sub.5--X.sub.2 wherein R'.sub.5 represents a radical such that
R'.sub.5--O represents an alkoxy radical containing 1 to 6 carbon
atoms in an unbranched or branched chain optionally substituted
with an alkoxy radical containing 1 to 4 carbon atoms, an
alkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy
radical containing 3 to 6 carbon atoms, a cycloalkyloxy radical
containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 3 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 2 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical, or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and X.sub.2 represents a reactive ester residue or a
halogen atom, to produce a compound of the formula (I): 44wherein Z
is hydrogen, R.sub.4 is as defined above, and R.sub.5 is identical
to R'.sub.5 as defined above.
27. A method comprising the step of reacting a product of the
formula (XV): R'.sub.5--X.sub.2 wherein R'.sub.5 represents a
radical such that R'.sub.5--O represents an alkoxy radical
containing 1 to 6 carbon atoms in an unbranched or branched chain
optionally substituted with an alkoxy radical containing 1 to 4
carbon atoms, an alkenyloxy radical containing 3 to 6 carbon atoms,
an alkynyloxy radical containing 3 to 6 carbon atoms, a
cycloalkyloxy radical containing 3 to 6 carbon atoms or a
cycloalkenyloxy radical containing 3 to 6 carbon atoms, these
radicals being optionally substituted with at least one substituent
selected from halogen atoms, an alkoxy radical containing 1 to 4
carbon atoms, an alkylthio radical containing 2 to 4 carbon atoms,
a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl
portion contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl
radical, an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl
radical in which each alkyl portion contains 1 to 4 carbon atoms
or, both alkyl portions, together with the nitrogen atom to which
they are linked, form a saturated 5- or 6-membered heterocyclic
radical optionally containing a second hetero atom selected from
oxygen, sulphur and nitrogen atoms, optionally substituted with an
alkyl radical containing 1 to 4 carbon atoms, a phenyl radical, or
a phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and X.sub.2 represents a reactive ester residue or a
halogen atom, with a compound of the formula (XIX): 45wherein
R.sub.1 represents a benzoyl radical optionally substituted with
one or more identical or different atoms or radicals selected from
halogen atoms, alkyl radicals containing 1 to 4 carbon atoms,
alkoxy radicals containing 1 to 4 carbon atoms, trifluoromethyl
radicals, a thenoyl radical, a furoyl radical, and a radical
R.sub.2--O--CO-- in which R.sub.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 or a bicycloalkyl radical
containing 7 to 10 carbon atoms, these radicals being optionally
substituted with one or more substituents selected from halogen
atoms; hydroxyl radicals; alkoxy radicals containing 1 to 4 carbon
atoms; dialkylamino radicals in which each alkyl portion contains 1
to 4 carbon atoms; piperidino radicals; morpholino radicals;
1-piperazinyl radicals optionally substituted at position 4 with an
alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl
radical in which the alkyl portion contains 1 to 4 carbon atoms;
cycloalkyl radicals containing 3 to 6 carbon atoms; cycloalkenyl
radicals containing 4 to 6 carbon atoms; phenyl radicals optionally
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 .alpha.- or
.beta.-naphthyl radical optionally 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, a 5-membered aromatic heterocyclic radical, or a
saturated heterocyclic radical containing 4 to 6 carbon atoms,
optionally substituted with one or more alkyl radicals containing 1
to 4 carbon atoms, R.sub.3 represents an unbranched or branched
alkyl radical containing 1 to 8 carbon atoms, an unbranched or
branched alkenyl radical containing 2 to 8 carbon atoms, an
unbranched or branched alkynyl radical containing 2 to 8 carbon
atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a
phenyl or .alpha.- or .beta.-naphthyl radical optionally
substituted with one or more atoms or radicals selected from
halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy,
alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto,
formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino,
alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,
alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl
radicals, or a 5-membered aromatic heterocycle containing one or
more identical or different hetero atoms selected from nitrogen,
oxygen and sulphur atoms and optionally substituted with one or
more identical or different substituents selected from halogen
atoms, alkyl, aryl, amino, alkylamino, dialkylamino,
alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl
radicals, with the proviso that, in the substituents of the phenyl,
.alpha.- or .beta.-naphthyl and aromatic heterocyclic radicals, the
alkyl radicals and the alkyl portions of the other radicals contain
1 to 4 carbon atoms, and the alkenyl and alkynyl radicals contain 2
to 8 carbon atoms, and the aryl radicals are phenyl or .alpha.- or
.beta.-naphthyl radicals, R.sub.4 represents an alkoxy radical
containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain, an alkynyloxy radical containing 3 to
6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy
radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 4 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 1 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and either R.sub.6 represents a hydrogen atom and
R.sub.7 represents a group protecting the hydroxyl function, or
R.sub.6 and R.sub.7 together form a saturated 5- or 6-membered
heterocycle, to form a compound of the formula (V): 46wherein
R.sub.5 represents an alkoxy radical containing 1 to 6 carbon atoms
in an unbranched or branched chain optionally substituted with an
alkoxy radical containing 1 to 4 carbon atoms, an alkenyloxy
radical containing 3 to 6 carbon atoms, an alkynyloxy radical
containing 3 to 6 carbon atoms, a cycloalkyloxy radical containing
3 to 6 carbon atoms or a cycloalkenyloxy radical containing 3 to 6
carbon atoms, these radicals being optionally substituted with at
least one substituent selected from halogen atoms, an alkoxy
radical containing 1 to 4 carbon atoms, an alkylthio radical
containing 2 to 4 carbon atoms, a carboxyl radical, an
alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4
carbon atoms, a cyano radical, a carbamoyl radical, an
N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical, or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and R.sub.1, R.sub.3, R.sub.4, R.sub.6, and R.sub.7
are as defined above.
28. A method comprising the step of replacing with hydrogen atom(s)
group(s) R.sub.6 and R.sub.7 in a compound of the formula (V):
47wherein: R.sub.1 represents a benzoyl radical optionally
substituted with one or more identical or different atoms or
radicals selected from halogen atoms, alkyl radicals containing 1
to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms,
trifluoromethyl radicals, a thenoyl radical, a furoyl radical, and
a radical R.sub.2--O--CO-- in which R.sub.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 or a
bicycloalkyl radical containing 7 to 10 carbon atoms, these
radicals being optionally substituted with one or more substituents
selected from halogen atoms; hydroxyl radicals; alkoxy radicals
containing 1 to 4 carbon atoms; dialkylamino radicals in which each
alkyl portion contains 1 to 4 carbon atoms; piperidino radicals;
morpholino radicals; 1-piperazinyl radicals optionally substituted
at position 4 with an alkyl radical containing 1 to 4 carbon atoms
or with a phenylalkyl radical in which the alkyl portion contains 1
to 4 carbon atoms; cycloalkyl radicals containing 3 to 6 carbon
atoms; cycloalkenyl radicals containing 4 to 6 carbon atoms; phenyl
radicals optionally 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 carbons atoms, a phenyl or
.alpha.- or .beta.-naphthyl radical optionally 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, a 5-membered aromatic heterocyclic
radical, or a saturated heterocyclic radical containing 4 to 6
carbon atoms, optionally substituted with one or more alkyl
radicals containing 1 to 4 carbon atoms, R.sub.3 represents an
unbranched or branched alkyl radical containing 1 to 8 carbon
atoms, an unbranched or branched alkenyl radical containing 2 to 8
carbon atoms, an unbranched or branched alkynyl radical containing
2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon
atoms, a phenyl or .alpha.- or .beta.-naphthyl radical optionally
substituted with one or more atoms or radicals selected from
halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy,
alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto,
formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino,
alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,
alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl
radicals, or a 5-membered aromatic heterocycle containing one or
more identical or different hetero atoms selected from nitrogen,
oxygen and sulphur atoms and optionally substituted with one or
more identical or different substituents selected from halogen
atoms, alkyl, aryl, amino, alkylamino, dialkylamino,
alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl
radicals, with the proviso that, in the substituents of the phenyl,
.alpha.- or .beta.-naphthyl and aromatic heterocyclic radicals, the
alkyl radicals and the alkyl portions of the other radicals contain
1 to 4 carbon atoms, and the alkenyl and alkynyl radicals contain 2
to 8 carbon atoms, and the aryl radicals are phenyl or .alpha.- or
.beta.-naphthyl radicals, R.sub.4 represents an alkoxy radical
containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain, an alkynyloxy radical containing 3 to
6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy
radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 4 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 1 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, R.sub.5 represents an alkoxy radical containing 1 to
6 carbon atoms in an unbranched or branched chain optionally
substituted with an alkoxy radical containing 1 to 4 carbon atoms,
an alkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy
radical containing 3 to 6 carbon atoms, a cycloalkyloxy radical
containing 3 to 6 carbon atoms or a cycloalkenyloxy radical
containing 3 to 6 carbon atoms, these radicals being optionally
substituted with at least one substituent selected from halogen
atoms, an alkoxy radical containing 1 to 4 carbon atoms, an
alkylthio radical containing 2 to 4 carbon atoms, a carboxyl
radical, an alkyloxycarbonyl radical in which the alkyl portion
contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical,
an N-alkylcarbamoyl radical, and an N,N-dialkylcarbamoyl radical in
which each alkyl portion contains 1 to 4 carbon atoms or, both
alkyl portions, together with the nitrogen atom to which they are
linked, form a saturated 5- or 6-membered heterocyclic radical
optionally containing a second hetero atom selected from oxygen,
sulphur and nitrogen atoms, optionally substituted with an alkyl
radical containing 1 to 4 carbon atoms, a phenyl radical, or a
phenylalkyl radical in which the alkyl portion contains 1 to 4
carbon atoms, and either R.sub.6 represents a hydrogen atom and
R.sub.7 represents a group protecting the hydroxyl function, or
R.sub.6 and R7 together form a saturated 5- or 6-membered
heterocycle, by treating the compound of formula (V) with an
organic or inorganic acid, where appropriate in an organic solvent
to obtain a compound of the formula (VII): 48wherein R.sub.3,
R.sub.4, and R.sub.5 are as defined above.
29. A process according to claim 9, wherein said source of fluoride
ions is a hydrofluoric acid/triethylamine complex.
30. A process according to claim 9, wherein said trihalomethyl
radical is trichloromethyl.
31. A process according to claim 9, wherein when said ester of
formula (V) is treated in an organic solvent, said organic solvent
is an alcohol.
Description
[0001] The present invention relates to new taxoids of general
formula (I) 3
[0002] in which:
[0003] Z represents a hydrogen atom or a radical of general formula
(II): 4
[0004] in which:
[0005] R.sub.1 represents
[0006] a benzoyl radical optionally substituted with one or more
identical or different atoms or radicals selected from halogen
atoms, alkyl radicals containing 1 to 4 carbon atoms, alkoxy
radicals containing 1 to 4 carbon atoms and trifluoromethyl
radicals,
[0007] a thenoyl or furoyl radical or
[0008] a radical R.sub.2--O--CO-- in which R.sub.2 represents:
[0009] an alkyl radical containing 1 to 8 carbon atoms,
[0010] an alkenyl radical containing 2 to 8 carbon atoms,
[0011] an alkynyl radical containing 3 to 8 carbon atoms,
[0012] a cycloalkyl radical containing 3 to 6 carbon atoms,
[0013] a cycloalkenyl radical containing 4 to 6 carbon atoms or
[0014] a bicycloalkyl radical containing 7 to 10 carbon atoms,
[0015] these radicals being optionally substituted with one or more
substituents selected from halogen atoms, hydroxyl radicals, alkoxy
radicals containing 1 to 4 carbon atoms, dialkylamino radicals in
which each alkyl portion contains 1 to 4 carbon atoms, piperidino
radicals, morpholino radicals, 1-piperazinyl radicals, said
piperazinyl radicals being optionally substituted at position 4
with an alkyl radical containing 1 to 4 carbon atoms or with a
phenylalkyl radical in which the alkyl portion contains 1 to .4
carbon atoms, cycloalkyl radicals containing 3 to 6 carbon atoms,
cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl
radicals, said phenyl radicals being optionally 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,
[0016] a phenyl or .alpha.- or .beta.-naphthyl radical optionally
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,
[0017] a 5-membered aromatic heterocyclic radical preferably
selected from furyl and thienyl radicals,
[0018] or a saturated heterocyclic radical containing 4 to 6 carbon
atoms, optionally substituted with one or more alkyl radicals
containing 1 to 4 carbon atoms,
[0019] R.sub.3 represents
[0020] an unbranched or branched alkyl radical containing 1 to 8
carbon atoms,
[0021] an unbranched or branched alkenyl radical containing 2 to 8
carbon atoms,
[0022] an unbranched or branched alkynyl radical containing 2 to 8
carbon atoms,
[0023] a cycloalkyl radical containing 3 to 6 carbon atoms,
[0024] a phenyl or .alpha.- or .beta.-naphthyl radical optionally
substituted with one or more atoms or radicals selected from
halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy,
alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto,
formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino,
alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,
alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl
radicals,
[0025] or a 5-membered aromatic heterocycle containing one or more
identical or different hetero atoms selected from nitrogen, oxygen
and sulphur atoms and optionally substituted with one or more
identical or different substituents selected from halogen atoms,
alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino,
acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl,
dialkylcarbamoyl and alkoxycarbonyl radicals,
[0026] with the understanding that, in the substituents of the
phenyl, .alpha.- or .beta.-naphthyl and aromatic heterocyclic
radicals, the alkyl radicals and the alkyl portions of the other
radicals contain 1 to 4 carbon atoms, the alkenyl and alkynyl
radicals contain 2 to 8 carbon atoms, and the aryl radicals are
phenyl or .alpha.- or .beta.-naphthyl radicals,
[0027] R.sub.4 represents
[0028] an alkoxy radical containing 1 to 6 carbon atoms in an
unbranched or branched chain,
[0029] an alkenyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain,
[0030] an alkynyloxy radical containing 3 to 6 carbon atoms in an
unbranched or branched chain,
[0031] a cycloalkyloxy radical containing 3 to 6 carbon atoms
or
[0032] a cycloalkenyloxy radical containing 4 to 6 carbon
atoms,
[0033] these radicals being optionally substituted with one or more
substituents selected from halogen atoms, an alkoxy radical
containing 1 to 4 carbon atoms, an alkylthio radical containing 1
to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical
in which the alkyl portion contains 1 to 4 carbon atoms, a cyano
radical, a carbamoyl radical, an N-alkylcarbamoyl radical and a
N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1
to 4 carbon atoms, or both alkyl portions, together with the
nitrogen atom to which they are linked, form a saturated 5- or
6-membered heterocyclic radical optionally containing a second
hetero atom selected from oxygen, sulphur and nitrogen atoms, said
saturated 5- or 6-membered heterocyclic radical optionally being
substituted with a substituent selected from an alkyl radical
containing 1 to 4 carbon atoms, a phenyl radical, and a phenylalkyl
radical in which the alkyl portion contains 1 to 4 carbon
atoms,
[0034] R.sub.5 represents
[0035] an alkoxy radical containing 1 to 6 carbon atoms in an
unbranched or branched chain,
[0036] an alkenyloxy radical containing 3 to 6 carbon atoms,
[0037] an alkynyloxy radical containing 3 to 6 carbon atoms,
[0038] a cycloalkyloxy radical containing 3 to 6 carbon atoms
or
[0039] a cycloalkenyloxy radical containing 3 to 6 carbon
atoms,
[0040] these radicals being optionally substituted with at least
one substituent selected from halogen atoms, an alkoxy radical
containing 1 to 4 carbon atoms, an alkylthio radical containing 2
to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical
in which the alkyl portion contains 1 to 4 carbon atoms, a cyano
radical, a carbamoyl radical, an N-alkylcarbamoyl radical, and a
N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1
to 4 carbon atoms or, with the nitrogen atom to which it is linked,
forms a saturated 5- or 6-membered heterocyclic radical optionally
containing a second hetero atom selected from oxygen, sulphur and
nitrogen atoms, optionally substituted with a substituent selected
from an alkyl radical containing 1 to 4 carbon atoms, a phenyl
radical and a phenylalkyl radical in which the alkyl portion
contains 1 to 4 carbon atoms.
[0041] Preferably, the aryl radicals which can be represented by
R.sub.3 are phenyl or .alpha.- or .beta.-naphthyl radicals
optionally substituted with one or more atoms or radicals selected
from halogen atoms (fluorine, chlorine, bromine, iodine) alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy,
arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl,
acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino,
dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,
dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, on the
understanding that the alkyl radicals and the alkyl portions of the
other radicals contain 1 to 4 carbon atoms, that the alkenyl and
alkynyl radicals contain 2 to 8 carbon atoms and that the aryl
radicals are phenyl or .alpha.- or .beta.-naphthyl radicals.
[0042] Preferably, the heterocyclic radicals which can be
represented by R.sub.3 are 5-membered aromatic heterocyclic
radicals containing one or more identical or different atoms
selected from nitrogen, oxygen and sulphur atoms, optionally
substituted with one or more identical or different substituents
selected from halogen atoms (fluorine, chlorine, bromine, iodine),
alkyl radicals containing 1 to 4 carbon atoms, aryl radicals
containing 6 or 10 carbon atoms, alkoxy radicals containing 1 to 4
carbon atoms, aryloxy radicals containing 6 or 10 carbon atoms,
amino radicals, alkylamino radicals containing 1 to 4 carbon atoms,
dialkylamino radicals in which each alkyl portion contains 1 to 4
carbon atoms, acylamino radicals in which the acyl portion contains
1 to 4 carbon atoms,
[0043] alkoxycarbonylamino radicals containing 1 to 4 carbon atoms,
acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals
in which the aryl portion contains 6 or 10 carbon atoms, cyano
radicals, carboxyl radicals, carbamoyl radicals, alkylcarbamoyl
radicals in which the alkyl portion contains 1 to 4 carbon atoms,
dialkylcarbamoyl radicals in which each alkyl portion contains 1 to
4 carbon atoms, and alkoxycarbonyl radicals in which the alkoxy
portion contains 1 to 4 carbon atoms.
[0044] Preferably, the radicals R.sub.4 and R.sub.5, which may be
identical or different, represent unbranched or branched alkoxy
radicals containing 1 to 6 carbon atoms, optionally substituted
with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl,
ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-pyrrolidinocarbonyl or N-piperidinocarbonyl radical.
[0045] More particularly, 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.sub.1
represents a benzoyl radical or a radical R.sub.2--O--CO-- in which
R.sub.2 represents a tert-butyl radical and R.sub.3 represents an
alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical
containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3
to 6 carbon atoms, a phenyl radical optionally substituted with one
or more identical or different atoms or radicals selected from from
halogen atoms (fluorine, chlorine), alkyl (methyl), alkoxy
(methoxy), dialkylamino (dimethylamino), acylamino (acetylamino),
alkoxycarbonylamino (tert-butoxycarbonylamino), trifluoromethyl, a
2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a
3-thienyl radical, a 2-thiazolyl radical, a 4-thiazolyl radical,
and a 5- thiazolyl radical, and R.sub.4 and R.sub.5, which may be
identical or different, each represent an unbranched or branched
alkoxy radical containing 1 to 6 carbon atoms.
[0046] Still more particularly, 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.sub.1
represents a benzoyl radical or a radical R.sub.2--O--CO-- in which
R.sub.2 represents a tert-butyl radical and R.sub.3 represents an
isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or
5-thiazolyl radical, and R.sub.4 and R.sub.5, which may be
identical or different, each represent a methoxy, ethoxy or propoxy
radical.
[0047] The products of general formula (I) in which Z represents a
radical of general formula (II) display noteworthy antitumour and
antileukaemic properties.
[0048] 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 (III) 5
[0049] in which R.sub.4 and R.sub.5 are defined as above, by means
of an acid of general formula (IV): 6
[0050] in which R.sub.1 and R.sub.3 are defined as above, and
either R.sub.6 represents a hydrogen atom and R.sub.7 represents a
group protecting the hydroxyl function, or R.sub.6 and R.sub.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
(V) 7
[0051] in which R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and
R.sub.7 are defined as above, followed by replacement of the
protective groups represented by R.sub.7 and/or R.sub.6 and R.sub.7
by hydrogen atoms.
[0052] The esterification by means of an acid of general formula
(IV) 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 from -10 to
90.degree. C.
[0053] The esterification may also be carried out using the acid of
general formula (IV) in the form of the symmetrical anhydride,
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 from 0 to 90.degree. C.
[0054] The esterification may also be carried out using the acid of
general formula (IV) in halide form or in the form of a mixed
anhydride with an aliphatic or aromatic acid, optionally prepared
in situ, in the presence of a base (tertiary aliphatic amine),
working in an organic solvent (ethers, esters, ketones, nitrites,
aliphatic hydrocarbons, halogenated aliphatic hydrocarbons,
aromatic hydrocarbons) at a temperature of from 0 to 80.degree.
C.
[0055] Preferably, R.sub.6 represents a hydrogen atom and R.sub.7
represents a group protecting the hydroxyl function, or
alternatively R.sub.6 and R.sub.7 together form a saturated 5- or
6-membered heterocycle.
[0056] When R.sub.6 represents a hydrogen atom, R.sub.7 preferably
represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl,
trimethylsilyl, triethylsilyl, .beta.-trimethylsilylethoxymethyl,
benzyloxycarbonyl or tetrahydropyranyl radical.
[0057] When R.sub.6 and R.sub.7 together form a heterocycle, the
latter is preferably an oxazolidine ring optionally monosubstituted
or gem-disubstituted at position 2.
[0058] Replacement of the protective groups R.sub.7 and/or R.sub.6
and R.sub.7 by hydrogen atoms may be performed, depending on their
nature, in the following manner:
[0059] 1) when R.sub.6 represents a hydrogen atom and R.sub.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, sulphuric acid, hydrofluoric
acid) or organic acid (acetic acid, methanesulphonic acid,
trifluoromethanesulphonic acid, p-toluenesulphonic 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
from -10 to 60.degree. C., or by means of a source of fluoride ions
such as a hydrofluorine acid/triethylamine complex, or by catalytic
hydrogenation,
[0060] 2) when R.sub.6 and R.sub.7 together form a saturated 5- or
6-membered heterocycle, and more especially an oxazolidine ring of
general formula (VI): 8
[0061] in which R.sub.1 is defined as above and R.sub.8 and
R.sub.9, which may be identical or different, represent a hydrogen
atom or an alkyl radical containing 1 to 4 carbon atoms, or an
aralkyl 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.sub.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.sub.9 represents a hydrogen atom, or alternatively R.sub.8
and R.sub.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.sub.6 and R.sub.7 by hydrogen atoms may be
performed, depending on the meanings of R.sub.1, R.sub.8 and
R.sub.9, in the following manner:
[0062] a) when R.sub.1 represents a tert-butoxycarbonyl radical and
R.sub.8 and R.sub.9, which may be identical or different, represent
an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical,
or alternatively R.sub.8 represents a trihalomethyl radical or a
phenyl radical substituted with a trihalomethyl radical and R.sub.9
represents a hydrogen atom, or alternatively R.sub.8 and R.sub.9
together form a 4- to 7-membered ring, treatment of the ester of
general formula (V) with an inorganic or organic acid, where
appropriate in an organic solvent such as an alcohol, yields the
product of general formula (VII): 9
[0063] in which R.sub.3, R.sub.4 and R.sub.5 are defined as above,
which is acylated by means of benzoyl chloride in which the phenyl
ring is optionally substituted or by means of thenoyl chloride, of
furoyl chloride or of a product of general formula.
R.sub.2--O--CO--X (VIII)
[0064] in which R.sub.2 is defined as above and X represents a
halogen atom (fluorine, chlorine) or a residue --O--R.sub.2 or
--O--CO--O--R.sub.2, to obtain a product of general formula (I) in
which Z represents a radical of general formula (II).
[0065] Preferably, the product of general formula (V) is treated
with formic acid at a temperature in the region of 20.degree. C. to
yield the product of general formula (VII).
[0066] Preferably, the acylation of the product of general formula
(VII) by means of a benzoyl chloride in which the phenyl radical is
optionally substituted or by means of thenoyl chloride, of furoyl
chloride or of a product of general formula (VIII) is performed in
an inert organic solvent chosen from esters such as ethyl acetate,
isopropyl acetate or n-butyl acetate and halogenated aliphatic
hydrocarbons such as dichloromethane or 1,2-dichloroethane, in the
presence of an inorganic base such as sodium bicarbonate or an
organic base such as triethylamine. The reaction is performed at a
temperature of from 0 to 50.degree. C., and preferably at about
20.degree. C.
[0067] b) when R.sub.1 represents an optionally substituted benzoyl
radical, a thenoyl or furoyl radical or a radical R.sub.2O--CO-- in
which R.sub.2 is defined as above, R.sub.8 represents a hydrogen
atom or an alkoxy radical containing 1 to 4 carbon atoms or a
phenyl radical substituted with one or more alkoxy radicals
containing 1 to 4 carbon atoms and R.sub.9 represents a hydrogen
atom, replacement of the protective group formed by R.sub.6 and
R.sub.7 by hydrogen atoms is performed in the presence of an
inorganic acid (hydrochloric acid, sulphuric acid) or organic acid
(acetic acid, methanesulphonic acid, trifluoromethanesulphonic
acid, p-toluenesulphonic acid) used alone or mixed in a
stoichiometric or catalytic amount, working in an organic solvent
chosen from alcohols, ethers, esters, aliphatic hydrocarbons,
halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a
temperature of from -10 to 60.degree. C., and preferably from 15 to
30.degree. C.
[0068] According to the invention, the products of general formula
(III), that is to say the products of general formula (I) in which
Z represents a hydrogen atom and R.sub.4 and R.sub.5 are defined as
above, may be obtained from 10-deacetylbaccatin III of formula
(IX): 10
[0069] It can be especially advantageous to protect the hydroxyl
functions at the positions 7 and 13 selectively, for example in the
form of a silyl diether which may be obtained by the action of a
silyl halide of general formula:
(R).sub.3--Si--Hal (X)
[0070] in which the symbols R, which may be identical or different,
represent an alkyl radical containing 1 to 6 carbon atoms,
optionally substituted with a phenyl radical, or a cycloalkyl
radical containing 3 to 6 carbon atoms or a phenyl radical, on
10-deacetylbaccatin III, to obtain a product of general formula
(XI): 11
[0071] in which R is defined as above, followed by the action of a
product of general formula:
R'.sub.4--X.sub.1 (XII)
[0072] in which R'.sub.4 represents a radical such that R'.sub.4--O
is identical to R.sub.4 defined as above and X, represents a
reactive ester residue such as a sulphuric or sulphonic ester
residue or a halogen atom, to obtain a product of general formula
(XIII): 12
[0073] in which R and R.sub.4 are defined as above, the silyl
protective groups of which are replaced by hydrogen atoms to obtain
a product of general formula (XIV): 13
[0074] in which R.sub.4 is defined as above, which is etherified
selectively at position 7 by the action of a product of general
formula:
R'.sub.5--X.sub.2 (XV)
[0075] in which R'.sub.5 represents a radical such that R'.sub.5--O
is identical to R.sub.5 defined as above and X.sub.2 represents a
halogen atom or a reactive ester residue such as a sulphuric or
sulphonic ester residue, to give the product of general formula
(III)
[0076] Generally, the action of a silyl derivative of general
formula (X) on 10-deacetylbaccatin III is performed in pyridine or
triethylamine, where appropriate in the presence of an organic
solvent such as an aromatic hydrocarbon, for instance benzene,
toluene or xylenes, at a temperature between 0.degree. C. and the
refluxing temperature of the reaction mixture.
[0077] Generally, the action of a product of general formula (XII)
on a product of general formula (XI) is performed, after metalation
of the hydroxyl function at position 10 by means of an alkali metal
hydride, such as sodium hydride, an alkali metal amide, such as
lithium amide, or an alkali metal alkylide, such as butyllithium,
working in an organic solvent, such as dimethylformamide or
tetrahydrofuran, at a temperature of from 0 to 50.degree. C.
[0078] Generally, the replacement of the silyl protective groups of
the product of general formula (XIII) by hydrogen atoms is
performed by means of an acid such as hydrofluoric acid or
trifluoroacetic acid in the presence of a base such as
triethylamine or pyridine optionally substituted with one or more
alkyl radicals containing 1 to 4 carbon atoms, the base optionally
being combined with an inert organic solvent such as a nitrile, for
instance acetonitrile, or a halogenated aliphatic hydrocarbon, such
as dichloromethane, at a temperature of from 0 to 80.degree. C.
[0079] Generally, the action of a product of general formula (XV)
on a product of general formula (XIV) is performed under the
conditions described above for the action of a product of general
formula (XII) on a product of general formula (XI).
[0080] According to the invention, the products of general formula
(I) in which Z represents a radical of general formula (II),
R.sub.4 is defined as above and R.sub.5 is defined as above may be
obtained from a product of general formula (XVI): 14
[0081] in which R.sub.1, R.sub.3, R.sub.6 and R.sub.7 are defined
as above, by silylation at position 7 by means of a product of
general formula (X), to obtain a product of general formula (XVII):
15
[0082] in which R, R.sub.1, R.sub.3, R.sub.6 and R.sub.7 are
defined as above, which is functionalized at position 10 by means
of a product of general formula (XII) to give a product of general
formula (XVIII): 16
[0083] in which R, R.sub.1, R.sub.3, R.sub.4, R.sub.6 and R.sub.7
are defined as above, the silyl protective group of which is
replaced by a hydrogen atom to give a product of general formula
(XIX): 17
[0084] which, by the action of a product of general formula (XV),
yields the product of general formula (V), the protective groups of
which are replaced by hydrogen atoms to give a product of general
formula (I) in which Z represents a radical of general formula
(II).
[0085] The reactions used for silylation, functionalization and
replacement of the protective groups by hydrogen atoms are
performed under conditions similar to those described above.
[0086] The products of general formula (XVI) may be obtained under
the conditions described in European Patent EP 0,336,841 and
international Applications PCT WO 92/09589 and WO 94/07878, the
disclosures of which are hereby incorporated by reference in their
entirety, or from the products of general formula (XX): 18
[0087] in which R.sub.1 and R.sub.3 are defined as above, according
to known methods for protecting the hydroxyl function of the side
chain without affecting the remainder of the molecule.
[0088] According to the invention, the products of general formula
(I) in which Z represents a hydrogen atom or a radical of general
formula (II) may be obtained by the action of activated Raney
nickel, in the presence of an aliphatic alcohol containing 1 to 3
carbon atoms or an ether such as tetrahydrofuran or dioxane, on a
product of general formula (XXI): 19
[0089] in which R.sub.4 is defined as above and R' and R", which
may be identical or different, represent a hydrogen atom or an
alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical
containing 2 to 6 carbon atoms, an alkynyl radical containing 2 to
6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms
or a cycloalkenyl radical containing 3 to 6 carbon atoms,
optionally substituted, or alternatively R' and R", together with
the carbon atom to which they are linked, form a cycloalkyl radical
containing 3 to 6 carbon atoms or a cycloalkenyl radical containing
4 to 6 carbon atoms, and Z.sub.1 represents a hydrogen atom or a
radical of general formula (XXII): 20
[0090] in which R.sub.1, R.sub.3, R.sub.6 and R.sub.7, are defined
as above, and, to obtain a product of general formula (XXIII):
21
[0091] followed, when Z.sub.1 represents a radical of general
formula (XXII), that is to say when the product of general formula
(XXIII) is identical to the product of general formula (V), by
replacement of the protective groups represented by R.sub.6 and/or
R.sub.6 and R.sub.7 by hydrogen atoms under the conditions
described above.
[0092] Generally, the action of activated Raney nickel in the
presence of an aliphatic alcohol or an ether is performed at a
temperature of from -10 to 60.degree. C.
[0093] According to the invention, the product of general formula
(XXI) in which Z.sub.1 and R.sub.4 are defined as above may be
obtained by the action of a sulphoxide of general formula (XXIV):
22
[0094] in which R' and R" are defined as above, on a product of
general formula (XIX).
[0095] Generally, the reaction of the sulphoxide of general formula
(XXIV), preferably dimethyl sulphoxide, with the product of general
formula (XIX) is performed in the presence of a mixture of acetic
acid and acetic anhydride or a derivative of acetic acid such as a
haloacetic acid at a temperature of from 0.degree. to 50.degree.
C., and preferably at about 25.degree. C.
[0096] The new products of general formula (I) obtained by carrying
out the processes according to the invention may be purified
according to known methods such as crystallization or
chromatography.
[0097] The products of general formula (I) in which Z represents a
radical of general formula (II) display noteworthy biological
properties.
[0098] In vitro, measurement of the biological activity is
performed on tubulin extracted from pig's brain by the method of M.
L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768
(1973). Study of the depolymerization of microtubules to tubulin is
performed according to the method of G. Chauvire et al., C.R. Acad.
Sci., 293, series II, 501-503 (1981). In this study, the products
of general formula (I) in which Z represents a radical of general
formula (II) were shown to be at least as active as taxol and
Taxotere.
[0099] In vivo, the products of general formula (I) in which Z
represents a radical of general formula (II) were shown to be
active in mice grafted with B16 melanoma at doses of from 1 to 30
mg/kg administered intraperitoneally, as well as on other liquid or
solid tumours.
[0100] The new products have antitumour properties, and more
especially activity against tumours which are resistant to
Taxol.RTM. or to Taxotere.RTM.. Such tumours comprise colon tumours
which have a high expression of the mdr 1 gene (multiple drug
resistance gene). Multiple drug resistance is a customary term
relating to the resistance of a tumour to different products having
different structures and mechanisms of action. Taxoids are
generally known to be strongly recognized by experimental tumours
such as P388/DOX, a cell line selected for its resistance to
doxorubicin (DOX) which expresses mdr 1.
[0101] The examples which follow illustrate the present
invention.
EXAMPLE 1
[0102] 126 mg of dicyclohexylcarbodiimide and then 14 mg of
4-(N,N-dimethylamino)pyridine were added successively at a
temperature in the region of 20.degree. C. to a suspension
containing 217.8 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,
13.alpha.-dihydroxy-7.beta., 10.beta.-dimethoxy-9-oxo-11-taxene,
200 mg of
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3oxazo-
lidine-5-carboxylic acid and 50 mg of powdered 4 .ANG. molecular
sieve in 2 cm.sup.3 of ethyl acetate. The suspension obtained was
stirred at a temperature in the region of 20.degree. C. under an
argon atmosphere for 16 hours, and then concentrated to dryness
under reduced pressure (0.27 kPa) at a temperature in the region of
40.degree. C. The residue obtained was purified by chromatography
at atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained
in a column 2 cm in diameter (elution gradient: ethyl
acetate/dichloromethane from 10:90 to 40:60 by volume), collecting
10-cm.sup.3 fractions. Fractions containing only the desired
product were pooled and concentrated to dryness under reduced
pressure (0.27 kPa) at 40.degree. C. for 2 hours. 271.8 mg of
4.alpha.-acetoxy-2.alpha.-benzoylo-
xy-5.beta.,20-epoxy-1.beta.-hydroxy-7.beta.,10.beta.-dimethoxy-9-oxo-11-ta-
xen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-ph-
enyl-1,3-oxazolidine-5-carboxylate were thereby obtained in the
form of a white solid, the characteristics of which were as
follows:
[0103] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3 with a few drops
of CD.sub.3OD--d.sub.4: chemical shifts .delta. in ppm; coupling
constants J in Hz): 1.02 (s, 9H: C(CH.sub.3).sub.3); 1.10 (s, 3H:
CH.sub.3); 1.17 (s, 3}: CH.sub.3); 1.63 (s, 3H: CH.sub.3); from
1.65 to 1.85 and 2.60 (2 mts, 1H each; CH.sub.2 at position 6);
1.78 (unres. comp., 3H: CH.sub.3); 2.02 and 2.15 (2 dd, J=14 and 9,
1H each: CH.sub.2 at position 14); 2.14 (s, 3H: CH.sub.3); 3.22 and
3.35 (2 s, 3H each: OCH.sub.3); 3.64 (d, J=7, 1H: H at position 3);
3.73 (mt, 1H: H at position 7); 3.76 (s, 3H: ArOCH.sub.3); 4.06 and
4.16 (2 d, J=8.5, 1 H each; CH.sub.2 at position 20); 4.53 (d, J=5,
1H: H at position 2'); 4.67 (s, 1H: H at position 10); 4.85 (broad
d, J=10, 1H: H at position 5); 5.36 (mt, 1H: H at position 3');
5.52 (d, J=7, 1H: H at position 2); 6.07 (mt, 1H: H at position
13); 6.33 (unres. comp., 1H: H at position 5'); 6.88 (d, J=8, 2H:
aromatic H at the ortho position with respect to OCH.sub.3); from
7.25 to 7.40 (mt, 7H: aromatic H at position 3' and aromatic H at
the meta position with respect to OCH.sub.3); 7.43 (t, J=7.5, 2H:
OCOC.sub.6H.sub.5 H at the meta position); 7.58 (t, J=7.5, 1H:
OCOC.sub.6H.sub.5 H at the para position); 7.96 (d, J=7.5, 2H:
OCOC.sub.6H.sub.5 H at the ortho position).
[0104] A solution of 446.3 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.be-
ta.,20-epoxy-1.beta.-hydroxy-7.beta.,10.beta.-dimethoxy-9-oxo-11-taxen-13.-
alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,-
3-oxazolidine-5-carboxylate in 11.6 cm.sup.3 of a 0.1N solution of
hydrogen chloride in ethanol was stirred constantly at a
temperature in the region of 0.degree. C. for 16 hours under an
argon atmosphere. The reaction mixture was then diluted with 40
cm.sup.3 of dichloromethane and 5 cm.sup.3 of distilled water.
After settling had taken place, the aqueous phase was separated and
extracted with 5 cm.sup.3 of dichloromethane. The organic phases
were combined, dried over magnesium sulphate, filtered through
sintered glass and then concentrated to dryness under reduced
pressure (0.27 kPa) at a temperature in the region of 40.degree. C.
424.2 mg of a pale yellow solid were obtained, which product was
purified by preparative thin-layer chromatography [12 Merck
preparative silica gel 60F.sub.254 plates, thickness 1 mm,
application in solution in a methanol/dichloromethane (5:95 by
volume) mixture, eluting with a methanol/dichloromethane (5:95 by
volume) mixture]. After elution of the zone corresponding to the
main product with a methanol/dichloromethane (15:85 by volume)
mixture, filtration through sintered glass and evaporation of the
solvents under reduced pressure (0.27 kPa) at a temperature in the
region of 40.degree. C., 126 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy-7.b-
eta.,10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate were
obtained in the form of an ivory-coloured foam, the characteristics
of which were as follows:
[0105] optical rotation [.alpha.].sub.20.sup.o=-32.9 (c=0.5;
methanol)
[0106] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemical shifts
.delta. in ppm; coupling constants J in Hz): 1.23 (s, 3H:
CH.sub.3); 1.25 (s, 3H: CH.sub.3); 1.39 (s, 9H: C(CH.sub.3).sub.3);
1.70 (s, 1H: OH at position 1); 1.75 (s, 3H: CH.sub.3); 1.82 and
2.72 (2 mts, 1H each: CH.sub.2 at position 6); 1.91 (s, 3H:
CH.sub.3); 2.31 (limiting AB, 2H: CH.sub.2 at position 14); 2.39
(s, 3H: COCH.sub.3); 3.33 and 3.48 (2 s, 3H each: OCH.sub.3); 3.48
(mt, 1H: OH at position 2'); 3.85 (d, J=7, 1H: H 3); 3.88 (dd, J=11
and 7, 1H: H 7); 4.20 and 4.33 (2 d, J=8.5, 1H each: CH.sub.2 at
position 20); 4.65 (mt, 1H: H at position 2'); 4.83 (s, 1H: H at
position 10): 5.00 (broad d, J=10, 1H: H at position 5); 5.30
(broad d, J=10, 1H: H at position 3'); 5.47 (d, J=10, 1H: CONH);
5.66 (d, J=7, 1H: H at position 2); 6.24 (broad t, J=9, 1H: H at
position 13); from 7.30 to 7.50 (mt, 5H aromatic H at position 3');
7.52 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position); 7.63
(t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position); B.12 (d,
J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0107]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.,
13.alpha.-dihydroxy-7.beta., 10.beta.-dimethoxy-9-oxo-11-taxene (or
7.beta., 10.beta.-dimethoxy-10deacetoxybaccatin III) was prepared
in the following manner:
[0108] 86 mg of sodium hydride at a concentration of 50% by weight
in liquid paraffin were added portionwise to a solution, maintained
under an argon atmosphere, at a temperature in the region of
0.degree. C., of 500 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.bet-
a.,13.alpha.-trihydroxy-10.beta.-methoxy-9oxo-11-taxene in 5
cm.sup.3 of iodomethane and 0.5 cm.sup.3 of dimethylformamide.
After 45 minutes at a temperature in the region of 0.degree. C.,
the reaction mixture was diluted with 50 cm.sup.3 of ethyl acetate
and 8 cm.sup.3 of distilled water. After settling had taken place,
the organic phase was separated and washed with twice 8 cm.sup.3 of
distilled water and then 8 cm.sup.3 of saturated aqueous sodium
chloride solution, dried over magnesium sulphate, filtered through
sintered glass and concentrated to dryness under reduced pressure
(0.27 kPa) at a temperature in the region of 40.degree. C. 570 mg
of a pale yellow solid were thereby obtained, which product was
purified by chromatography at atmospheric pressure on 50 g of
silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter,
eluting with a methanol/dichloromethane (2:98 by volume) mixture
and collecting 10-cm.sup.3 fractions. Fractions containing only the
desired product were pooled and concentrated to dryness under
reduced pressure (0.27 kPa) at 40.degree. C. for 2 hours. 380 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-
-5.beta.,20-epoxy-1.beta.,13.alpha.-dihydroxy-7.beta.,
10.beta.-dimethoxy-9oxo-11-taxene were thereby obtained in the form
of a pale yellow solid, the characteristics of which were as
follows:
[0109] .sup.1H NMR spectrum (400 MHz; CDCl,; with a few drops of
CD.sub.30D-d.sub.4; chemical shifts 5 in ppm; coupling constants J
in Hz): 1.03 (s, 3H: CH5); 1.11 (s, 3H: CH.sub.3); 1.65 (s, 3H:
CH.sub.3): 1.72 and 2.67 (2 mts, 1H each: CH.sub.2 at position 6);
2.05 (s, 3H: CH.sub.3): 2.21 (limiting AB, J=14 and 9, 2H: CH.sub.2
at position 14); 2.25 (s, 3H: COCH.sub.3); 3.26 and 3.40 (2 s, 3H
each: OCH.sub.3); 3.85 (d, J=7, 1H: H at position 3); 3.89 (dd,
J=11 and 6.5, 1H: H at position 7); 4.12 and 4.25 (2 d, J=8.5, 1H
each: CH.sub.2 at position 20); 4.78 (broad t, J=9, 11H: H at
position 13); 4.83 (s, 1H: H at position 10); 4.98 (broad d, J=10,
1H: H at position 5); 5.53 (d, J=7, 1H: H at position 2); 7.43 (t,
J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position); 7.56 (t,
J=7.5, 1H: OCOC.sub.6H, H at the para position); 8.05 (d, J=7.5,
2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0110]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.bet-
a., 13.alpha.-trihydroxy-10.beta.-methoxy-9-oxo-11-taxene (or
10.beta.-methoxy-10-deacetoxybaccatin III) was prepared in the
following manner:
[0111] 50 cm.sup.3 of hydrogen fluoride/triethylamine complex
(3HF.Et.sub.3N) were added slowly to a solution, maintained under
an argon atmosphere, at a temperature in the region of 0.degree.
C., of 3.62 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydrox-
y-10.beta.-methoxy-9oxo-7.beta.,13.alpha.-bis(triethylsilyoxy)-11-taxene
in 30 cm.sup.3 of dichloromethane. After 48 hours at a temperature
in the region of 20.degree. C., the reaction mixture was poured
into a suspension of 100 cm.sup.3 of supersaturated aqueous sodium
hydrogen carbonate solution maintained at a temperature in the
region of 0.degree. C. After settling had taken place, the aqueous
phase was separated and re-extracted with three times 80 cm.sup.3
of dichloromethane and then twice 80 cm.sup.3 of ethyl acetate. The
organic phases were combined, dried over magnesium sulphate,
filtered through magnesium sulphate and concentrated to dryness
under reduced pressure (0.27 kPa) at a temperature in the region of
40.degree. C. 3.45 g of a yellow foam were thereby obtained, which
product was purified by chromatography at atmospheric pressure on
150 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in
diameter, eluting with a methanol/dichloromethane (5:95 by volume)
mixture and collecting 35-cm.sup.3 fractions. Fractions containing
only the desired product were pooled and concentrated to dryness
under reduced pressure (0.27 kPa) at 40.degree. C. for 2 hours.
1.97 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7-
.beta.,13.alpha.-trihydroxy-10.beta.-methoxy-9-oxo-11-taxene were
thereby obtained in the form of a white solid, the characteristics
of which were as follows:
[0112] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemical shifts
.delta. in ppm: coupling constants J in Hz): 1.10 (s, 3H:
CH.sub.3); 1.19 (s, 3H: CH.sub.3); 1.48 (d, J=8.5, 1H: OH at
position 13); 1.70 (s, 3H: CH.sub.3); 1.81 and 2.61 (2 mts, 1H
each: CH.sub.2 at position 6); 2.09 (d, J=5, 1H: OH at position 7);
2.11 (s, 3H: CH.sub.3); 2.30 (s, 3H: COCH.sub.3); 2.32 (d, J=9, 2H:
CH.sub.2 at position 14); 3.48 (s, 3H: OCH.sub.3); 3.97 (d, J=7,
1H: H at position 3); 4.18 and 4.33 (2 d, J=8.5, 1H each: CH.sub.2
at position 20); 4.31 (mt, 1H: H at position 7); 4.93 (mt, 1H: H at
position 13); 4.99 (s, .sub.1 H: H at position 10); 5.01 (broad d,
J=10, 1H: H at position 5); 5.66 (d, J=7, 1H: H at position 2);
7.49 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position); 7.63
(t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position); 8.12 (d,
J=7.5, 2H: OCOC.sub.8H.sub.5 H at the ortho position).
[0113]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.bet-
a., 13.alpha.-trihydroxy-10.beta.-methoxy-9-oxo-11-taxene (or
10.beta.-methoxy-10-deacetoxybaccatin III) was prepared in the
following manner:
[0114] 375 mg of sodium hydride at a concentration of 50% by weight
in liquid paraffin were added portionwise to a solution, maintained
under an argon atmosphere, at a temperature in the region of
0.degree. C., of 5 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,
10.beta.-hydroxy-9oxo-7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-taxene in 25 cm.sup.3 of
iodomethane. The solution was stirred constantly for 45 minutes at
a temperature in the region of 0.degree. C., and then for 5 hours
30 minutes at a temperature in the region of 20.degree. C. The
reaction mixture was cooled again to a temperature in the region of
0.degree. C., and 125 mg of sodium hydride at a concentration of
50% by weight in liquid paraffin were added portionwise. After 1
hour at 20.degree. C. and then 18 hours at 5.degree. C., the
reaction mixture was diluted by adding 50 cm.sup.3 of
dichloromethane and poured into 50 cm.sup.3 of saturated aqueous
ammonium chloride solution, and settling was allowed to take place.
The aqueous phase was separated and extracted with twice 30
cm.sup.3 of dichloroemethane, and the organic phases were then
combined, washed with 10 cm.sup.3 of distilled water, dried over
magnesium sulphate, filtered through sintered glass and
concentrated to dryness under reduced pressure (0.27 kPa) at a
temperature in the region of 40.degree. C. 5.15 g of a yellow foam
were thereby obtained, which product was purified by chromatography
at atmospheric pressure on 300 g of silica (0.063-0.2 mm) contained
in a column 5 cm in diameter (elution gradient: ethyl
acetate/dichloromethane from 0:100 to 10:90 by volume), collecting
30-cm.sup.3 fractions. Fractions containing only the desired
product were pooled and concentrated to dryness under reduced
pressure (0.27 kPa) at 40.degree. C. for 2 hours. 3.62 9 of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy-10.-
beta.-methoxy-9-oxo7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-taxene were thereby obtained in
the form of a pale yellow foam, the characteristics of which were
as follows:
[0115] .sup.1H NMR spectrum (600 MHz; CDCl.sub.3; chemical shifts
.delta. in ppm; coupling constants J in Hz): 0.58 and 0.69 (2 mts,
6H each: ethyl CH.sub.2); 0.97 and 1.04 (2 t, J=7.5, 9H each: ethyl
CH.sub.3); 1.15 (s, 3H: CH.sub.3); 1.18 (s, 3H: CH.sub.3); 1.58 (s,
1H: OH at position 1); 1.68 (s, 3H: CH.sub.3); 1.89 and 2.48 (2
mts, 1H each: CH.sub.2 at position 6); 2.04 (s, 3H: CH.); 2.15 and
2.23 (2 dd, J=16 and 9, 1H each: CH.sub.2 at position 14); 2.29 (s,
3H: COCH.sub.3); 3.40 (s, 3H: OCH.sub.3); 3.83 (d, J=7, 1H: H: H at
position 13); 4.15 and 4.30 (2 d, J=8.5, 1H each: CH.sub.2 at
position 20); 4.43 (dd, J=11 and 7, 1H: H at position 7); 4.91 (s,
1H: H at position 10); 4.96 (broad d, J=10, 1H at position 5); 5.01
(broad t, J=9, 1H: H at position 13); 5.62 (d, J=7, 1H: H at
position 2); 7.46 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta
position); 7.60 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para
position); 8.09 (d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho
position).
[0116]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,10.be-
ta.-dihydroxy-9-oxo-7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-taxene (or 10-deacetyl-7,
13-bis(triethylsilyl)baccatin III) was prepared in the following
manner:
[0117] 10.8 cm.sup.3 of triethylsilyl chloride were added to a
solution, maintained under an argon atmosphere, at a temperature in
the region of 20.degree. C., of 14 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-
epoxy-1.beta.,7.beta.,10.beta.,13.alpha.-tetrahydroxy-9-oxo-11-taxene
(10 eacetylbaccatin III) in 50 cm.sup.3 of anhydrous pyridine.
After 17 hours at a temperature in the region of 20.degree. C., the
reaction mixture was brought to a temperature in the region of
115.degree. C. and 10.8 cm.sup.3 of triethylsilyl chloride were
then added. After 3 hours 15 minutes at a temperature in the region
of 115.degree. C., the reaction mixture was brought back to a
temperature in the region of 20.degree. C. and diluted with 30
cm.sup.3 of ethyl acetate and 100 cm.sup.3 of distilled water.
After settling took place, the aqueous phase was separated and
extracted with twice 50 cm.sup.3 of ethyl acetate. The organic
phases were combined, washed with 50 cm.sup.3 of saturated aqueous
sodium chloride solution, dried over magnesium sulphate, filtered
through sintered glass and then concentrated to dryness under
reduced pressure (0.27 kPa) at a temperature in the region of
40.degree. C. 63.1 g of a brown oil were thereby obtained, which
product was purified by chromatography at atmospheric pressure on
800 g of silica (0.063-0.2 mm) contained in a column 7 cm in
diameter (elution gradient: ethyl acetate/dichloromethane from
0:100 to 5:95 by volume), collecting 60-cm.sup.3 fractions.
Fractions containing only the desired product were pooled and
concentrated to dryness under reduced pressure (0.27 kPa) at
40.degree. C for 2 hours. 9.77 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-- 5.beta.,20-epoxy-1.beta.,
10.beta.-dihydroxy-9-oxo-7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-taxene were thereby obtained in
the form of a cream-coloured foam, the characteristics of which
were as follows:
[0118] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm; coupling constants J in Hz): 0.55 and 0.68 (2 mts,
6H each: ethyl CH.sub.2); 0.94 and 1.03 (2 t, J=7.5, 9H each: ethyl
CH.sub.3); 1.08 (s, 3H: CH.sub.3); 1.17 (s, 3H: CH.sub.3); 1.58 (s,
1H: OH at position 1); 1.73 (s, 3H: CH.sub.3); 1.91 and 2.57 (2
mts, 1H each: CH.sub.2 at position 2); 2.04 (s, 3H: CH.sub.3); 2.12
and 2.23 (2 dd, J=16 and 9, 1H each: CH.sub.2 at position 14); 2.30
(s, 3H: COCH.sub.3); 3.88 (d, J=7, 1H H at position 3); 4.16 and
4.32 (2 d, J=8.5, 1 H each: CH.sub.2 at position 20); 4.27 (d, J=1,
1H: OH at position 10); 4.40 (dd, J=11 and 7, 1H: H at position 7);
4.95 (broad d, J=10, 1,H: H at position 5); 4.95 (mt, 1H: H at
position 13): 5.16 (d, J=1, 1H: H at position 10); 5.60 (d, J=7,
1H: H at position 2); 7.46 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at
the meta position); 7.60 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the
para position); 8.09 (d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the
ortho position).
EXAMPLE2
[0119] 340 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.b-
eta.-hydroxy-7.beta.,
10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazoli-
dine-5-carboxylate were dissolved in 8 cm.sup.3 of a 0.1N ethanolic
solution of hydrochloric acid containing 1% of water. The solution
thereby obtained was stirred for 13 hours at a temperature in the
region of 20.degree. C. and then for 80 hours at 4.degree. C., and
20 cm.sup.3 of dichloromethane were added. The organic phase was
separated after settling had taken place and washed successively
with 3 times 5 cm.sup.3 of saturated aqueous sodium hydrogen
carbonate solution, dried over magnesium sulphate, filtered and
concentrated to dryness under reduced pressure (2.7 kPa) at
40.degree. C. 300 mg of a white foam were obtained, which product
was purified by chromatography on silica gel deposited on plates
[gel 1 mm thick, plates 20.times.20 cm, eluent:
dichloromethane/methanol (95:5 by volume)] in 80-mg fractions (4
plates). After localization with UV rays of the zone corresponding
to the adsorbed desired product, this zone was scraped off, and the
silica collected was washed on sintered glass with 10 times 5
cm.sup.3 of ethyl acetate. The filtrates were combined and
concentrated to dryness under reduced pressure (2.7 kPa) at
40.degree. C. A white foam was obtained, which was repurified
according to the same technique [3 plates: 20.times.20.times.1 mm;
eluent: dichloromethane/ethyl acetate (90:10 by volume)).
[0120] 205 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.b-
eta.-hydroxy-7.beta.,
10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
were thereby obtained in the form of a white foam, the
characteristics of which were as follows:
[0121] optical rotation: [.alpha.].sub.20.sup.D=-33 (c=0.5;
methanol).
[0122] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm; coupling constants J in Hz): 1.23 (s, 3H:
--CH.sub.3); 1.25 (s, 3H: --CH.sub.3); 1.39 [s, 9H:
--C(CH.sub.3),]; 1.70 ,(s, 1H: --OH at position 1); 1.75 (s, 3H:
--CH.sub.3); 1.82 and 2.72 (2 mts, 1H each: --CH.sub.2 at position
6); 1.91 (s, 3H: --CH.sub.3); 2.31 (limiting AB, 2H: --CH.sub.2 at
position 14); 2.39 (s, 3H: --COCH.sub.3); 3.33 and 3.48 (2 s, 3H
each: --OCH.sub.3); 3.48 (mt, 1H: OH at position 2'); 3.85 (d, J=7,
1H: --H at position 3); 3.88 (dd, J=11 and 7, 1H: --H at position
7); 4.20 and 4.33 (2d, J=8.5, 1H each: --CH.sub.2 at position 20);
4.65 (mt, 1H: --H at position 2'); 4.83 (s, 1H: --H at position
10); 5.00 (broad d, J=10, 1H: --H at position 5); 5.30 (broad d,
J=10. 1H: --H at position 3'); 5.47 (d, J=10, 1H: --CONH--); 5 66
(d, J=7, 1H: --H at position 2); 6.24 (broad t, J=9, 1H: --H at
position 13); from 7.30 to 7.50 (mt, 5H: -C.sub.6H.sub.5 at
position 3'); 7.52 [t, J=7.5, 2H: --OCOC.sub.6H.sub.5 (--H at
position 3 and H at position 5)]; 7.63 [t, J=7.5, 1H:
--OCOC.sub.6H.sub.5 (--H at position 4)]; 8.12 [d, J=7.5, 2H:
--OCOC.sub.6H5 (--H at position 2 and H at position 6)].
[0123]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydro-
xy-7.beta., 10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazoli-
dine-5-carboxylate was prepared in the following manner:
[0124] 100 cm.sup.3 of an ethanolic suspension of activated nickel
according to Raney (obtained from 80 cm.sup.3 of the approximately
50% commercial aqueous suspension by successive washing, to a pH in
the region of 7, with 15 times 100 cm.sup.3 of distilled water and
with 5 times 100 cm.sup.3 of ethanol) were added at a temperature
in the region of 20.degree. C. to a solution, maintained under an
argon atmosphere and kept stirring, of 1 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20--
epoxy-1.beta.-hydroxy-7.beta.,
10.beta.-bis(methylthiomethoxy)-9-oxo-11-ta- xen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-ph-
enyl-1,3oxazolidine-5-carboxylate in 100 cm.sup.3 of anhydrous
ethanol. The reaction medium was kept stirring for 24 hours at a
temperature in the region of 20.degree. C. and then filtered
through sintered glass. The, sintered glass was washed with 4 times
80 cm.sup.3 of ethanol, and the filtrates were combined and
concentrated to dryness under reduced pressure (2.7 kPa) at
40.degree. C. 710 mg of a yellow foam were obtained, which product
was purified by chromatography on 60 g of silica (0.063-0.2 mm)
contained in a column 2.5 cm in diameter [eluent:
dichloromethane/ethyl acetate (90:10 by volume)], collecting
6-cm.sup.3 fractions. Fractions containing only the desired product
are pooled and concentrated to dryness under reduced pressure (2.7
kPa) at 40.degree. C. 350 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.-hy-
droxy-7.beta., 10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3oxazolidin-
e5carboxylate were thereby obtained in the form of a white
foam.
[0125]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy5.beta.,20-epoxy-1.beta.-hydrox-
y-7.beta.,
10.beta.-bis(methylthiomethoxy)-9-oxo11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxy-phenyl)-4-phenyl-1,3-oxazol-
idine-5-carboxylate was prepared in the following manner:
[0126] 2.3 cm.sup.3 of acetic acid and 7.55 cm.sup.3 of acetic
anhydride were added at a temperature in the region of 20.degree.
C. to a solution, maintained under an argon atmosphere and kept
stirring, of 3.1 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-7.beta.,10.-
beta.-trihydroxy-9-oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbo-
nyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate
dissolved in 102 cm.sup.3 of dimethyl sulphoxide. The reaction
mixture was kept stirring for 7 days at a temperature in the region
of 20.degree. C., and then poured into a mixture of 500 cm.sup.3 of
distilled water and 250 cm.sup.3 of dichloromethane. 30 cm.sup.3 of
saturated aqueous potassium carbonate solution were then added with
efficient stirring to a pH in the region of 7. After 10 minutes of
stirring, the organic phase was separated after settling had taken
place and the aqueous phase was re-extracted with twice 250
cm.sup.3 of dichloromethane. The organic phases were combined,
washed with 250 cm.sup.3 of distilled water, dried over magnesium
sulphate, filtered and concentrated to dryness under reduced
pressure (2.7 kPa) at 40.degree. C. 5.2 g of a pale yellow oil were
obtained, which product was purified by chromatography on 200 g of
silica (0.063-0.4 mm) contained in a column 3 cm in diameter
[eluent: dichloromethane/methanol (99:1 by volume)], collecting
50-cm.sup.3 fractions. Fractions containing only the desired
product were pooled and concentrated to dryness under reduced
pressure (2.7 kPa) at 40.degree. C. 1.25 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-h-
ydroxy-7.beta.,
10.beta.-bis(methylthiomethoxy)-9oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazoli-
dine-5-carboxylate were thereby obtained in the form of a white
foam.
[0127]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-10.beta.,7.bet-
a.,10.beta.-trihydroxy-9-oxo-11-taxen-13.alpha.-yl (2R,4S,
5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5--
carboxylate was prepared in the following manner:
[0128] A solution of 5.1 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.-
,20-epoxy-1.beta.-hydroxy-9-oxo-7.beta.,
10.beta.-bis(2,2,2-trichloroethox-
ycarbonyloxy)-11-taxen-13.alpha.-yl (2R,4S, 5R
)-3-tert-butoxycarbonyl-2-(-
4methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate in a mixture
of 100 cm.sup.3 of methanol and 100 cm.sup.3 of acetic acid was
heated, with stirring and under an argon atmosphere, to a
temperature in the region of 60.degree. C., and 10 g of powdered
zinc were then added. The reaction mixture was then stirred for 15
minutes at 60.degree. C., thereafter cooled to a temperature in the
region of 20.degree. C. and filtered through sintered glass lined
with Celite. The sintered glass was washed with twice 15 cm.sup.3
of methanol. The filtrate was concentrated to dryness under reduced
pressure (2.7 kPa) at a temperature in the region of 40.degree. C.
50 cm.sup.3 of ethyl acetate and 25 cm.sup.3 of saturated aqueous
sodium hydrogen carbonate solution were added to the residue. The
organic phase was separated after settling had taken place and
washed successively with 25 cm.sup.3 of saturated aqueous sodium
hydrogen carbonate solution and with 25 cm.sup.3 of distilled
water, then dried over magnesium sulphate, filtered through
sintered glass and concentrated to dryness under reduced pressure
(2.7 kPa) at 40.degree. C. 3.1 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.-
beta., 10.beta.-trihydroxy-9-oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazoli-
dine-5-carboxylate were thereby obtained in the form of a white
foam.
[0129]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.-hydrox-
y-9-oxo-7.beta.,
10.beta.-bis(2,2,2-trichloroethoxy-carbonyloxy)-11-taxen--
13.alpha.-yl (2R,4S, 5R
)-3-tert-butoxy-carbonyl-2-(4-methoxyphenyl)-4-phe-
nyl-1,3-oxazolidine-5-carboxylate was prepared under the conditions
described in Patent WO 94/07878, the disclosure of which is
specifically incorporated by reference herein.
EXAMPLE 3
[0130] 76 mg of dicyclohexylcarbodiimide and then 8.5 mg of
4-(N,N-dimethylamino)pyridine were added successively at a
temperature in the region of 20.degree. C. to a suspension
containing 135 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-ethoxy-1.b-
eta., 13.alpha.-dihydroxy-7.beta.-methoxy-9-oxo-11-taxene, 120 mg
of (2R,4S,
5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazol-
idine-5-carboxylic acid and 50 mg of powdered 4 .ANG. molecular
sieve in 1 cm.sup.3 of anhydrous toluene. The suspension obtained
was stirred at a temperature in the region of 20.degree. C. under
an argon atmosphere for 1 hour, and then purified by direct
application to a column for chromatography at atmospheric pressure
on 30 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in
diameter (elution gradient: ethyl acetate/dichloromethane from 2:98
to 10:90 by volume), collecting 10-cm.sup.3 fractions. Fractions
containing only the desired product were pooled and concentrated to
dryness under reduced pressure (2.7 kPa) at 40.degree. C. for 2
hours. 320.6 mg of a white solid were thereby obtained, which
product was purified by preparative thin-layer chromatography: 10
Merck preparative silica gel 60F.sub.254 plates, thickness 0.5 mm,
application in solution in dichloromethane, eluting with a
methanol/dichloromethane (3:97 by volume) mixture. After elution of
the zones corresponding to the main products with a
methanol/dichloromethane (15:85 by volume) mixture, filtration
through cotton wool and then evaporation of the solvents under
reduced pressure (2.7 kPa) at a temperature in the region of
40.degree. C., 47.7 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-ethoxy-1.b-
eta., 13.beta.-dihydroxy-7.beta.-methoxy-9-oxo-11-taxene were
obtained in the form of a cream-coloured solid and 37 mg of
4.alpha.-acetoxy-2.alpha.-
-benzoyloxy-5.beta.,20-epoxy-10.beta.-ethoxy-1.beta.-hydroxy-7.beta.-metho-
xy-9-oxo-11-taxen-13.alpha.-yl (2R,4S,
5R)-3-tert-butoxycarbonyl-2-(4-meth-
oxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate were obtained in
the form of a white foam, the characteristics of which
5-carboxylate product were as follows:
[0131] .sup.1H NMR spectrum (600 MHz; CDCl.sub.3; at a temperature
of 333 K; chemical shifts .delta. in ppm; coupling constants J in
Hz): 1.09 (s, 9H: C(CH.sub.3).sub.3; 1.19 (s, 3H: CH.sub.3), 1.21
(s, 3H: CH.sub.3); 1.27 (t, J=7, 3H: ethyl CH.sub.3); 1.43 (s, 1H:
OH at position 1); 1.62 (s, 3H: CH.sub.3); 1.68 (s, 3H: CH.sub.3);
1.77 and 2.63 (2 mts, 1H each: CH.sub.2 at position 6); 1.86 (s,
3H: COCH.sub.3); 2.13 and 2.22 (2 dd, J=16 and 9, 1H each: CH.sub.2
at position 14); 3.27 (s, 3H: OCH.sub.3); 3.45 and 3.68 (2 mts, 1H
each: ethyl CH.sub.2); 3.76 (d, J=7, 1H: H3); 3.81 (s, 3H:
ArOCH.sub.3); 3.85 (dd, J=11 and 7, 1H: H at position 7); 4.13 and
4.23 (2 d, J=8.5, 1H each: CH.sub.2 at position 20); 4.58 (d,
J=4.5, 1H: H at position 2'); 4.83 (s, 1H: H at position 10); 4.90
(broad d, J=10, 1H: H at position 5); 5.46 (d, J=4.5, 1H: H at
position 3'); 5.60 (d, J=7 Hz, 1H: H2); 6.13 (broad t, J=9 Hz, 1H:
H13); 6.38 (s, 1H: H5'); 6.92 (d, J=8.5, 2H: aromatic H at the
ortho position with respect to OCH.sub.3); from 7.30 to 7.50 (mt,
9H: aromatic H at position 3'-aromatic H at the meta position with
respect to OCH.sub.3 and OCOC.sub.6H.sub.5 H at the meta position);
7.59 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position); 8.03
(d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0132] A solution of 46 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.-
,20-epoxy-10.beta.-ethoxy-1.beta.-hydroxy-7.beta.-methoxy-9-oxo-11-taxen-1-
3.alpha.-yl (2R,4S,
5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-
-1,3-oxazolidine-5-carboxylate in 0.5 cm.sup.3 of ethyl acetate and
0.004 cm.sup.3 of concentrated 37% hydrochloric acid was kept
stirring at a temperature in the region of 20.degree. C. for 1.5
hours under an argon atmosphere. The reaction mixture was then
purified by preparative thin-layer chromatography: application of
the crude reaction mixture to 5 Merck preparative silica gel
60F.sub.254 plates, thickness 0.5 mm, eluting with a
methanol/dichloromethane (4:96 by volume) mixture. After elution of
the zone corresponding to the main product with a
methanol/dichloromethane (15:85 by volume) mixture, filtration
through cotton wool and then evaporation of the solvents under
reduced pressure (2.7 kPa) at a temperature in the region of
40.degree. C., 28.5 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-10.beta.-ethoxy-1.be-
ta.-hydroxy-7.beta.-methoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
were obtained in the form of an ivory-coloured foam, the
characteristics of which were as follows:
[0133] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm; coupling constants J in Hz): 1.22 (s, 3H: CH); 1.25
(s, 3H: CH.sub.3); 1.32 (t, J=7, 3H: ethyl CH.sub.3); 1.38 (s, 9H:
C(CH.sub.3).sub.3; 1.64 (s, 1H: OH at position 1): 1.73 (s, 3H:
CH.sub.3); 1.80 and 2.70 (2 mts, 1H each: CH.sub.2 at position 6);
1.88 (s, 3H CH.sub.3); 2.30 (mt, 2H: CH.sub.2 at position 14); 2.38
(s, 3H: COCH.sub.3); 3.31 (s, 3H: OCH.sub.3); 3.44 (unres. comp.,
1H: OH at position 2'); 3.50 and 3.70 (2 mts, 1H each. ethyl
OCH.sub.2); 3.84 (d, J=7.5, 1H: H at position 3); 3.87 (dd, J=11
and 6.5, 1H: H at position 7); 4.18 and 4.32 (2 d, J=8.5, 1H each:
CH.sub.2 at position 20); 4.64 (mt, 1H: H at position 2'); 4.90 (s,
1H: H at position 10); 4.98 (broad d, J=10, 1H: H at position s);
5.28 (broad d, J=10, 1H: H at position 3'); 5.42 (d, J 10, 1H:
CONH); 5.64 (d, J=7.5, 1H: H at position 2); 6.22 (broad t, J=9,
1H: H at position 13); from 7.25 to 7.45 (mt, 5H aromatic H at
position 3'); 7.50 (d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta
position): 7.62 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para
position); 8.12 (d J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho
position).
[0134]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-10.beta.-ethox-
y-1.beta., 13.alpha.-dihydroxy-7.beta.-methoxy-9-oxo-11-taxene (or
10.beta.-ethoxy-7.beta.-methoxy-10-deacetoxybaccatin III) may be
prepared in the following manner:
[0135] 43 mg of sodium hydride at a concentration of 50% by weight
in liquid paraffin were added portionwise to a solution, maintained
under an argon atmosphere, at a temperature in the region of
0.degree. C., of 235 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.,7.beta-
.,13.alpha.-trihydroxy-10.beta.-ethoxy-9-oxo-11-taxene in 2.5
cm.sup.3 of iodomethane and 1 cm.sup.3 of dimethylformamide After
30 minutes at a temperature in the region of 0.degree. C., the
reaction mixture was diluted with 40 cm.sup.3 of ethyl acetate, 6
cm.sup.3 of distilled water and 8 cm.sup.3 of saturated aqueous
ammonium chloride solution. After settling had taken place, the
organic phase was separated and washed with three times 8 cm.sup.3
of distilled water and then 8 cm.sup.3 of saturated aqueous NaCl
solution, dried over magnesium sulphate, filtered through sintered
glass and concentrated to dryness under reduced pressure (2.7 kPa)
at a temperature in the region of 40.degree. C. 268 mg of a yellow
solid were thereby obtained, which product was purified by
chromatography at atmospheric pressure on 30 g of silica (0.063-0.2
mm) contained in a column 2.5 cm in diameter (elution gradient:
ethyl acetate/dichloromethane from 0:100 to 15:85 by volume),
collecting 10-cm.sup.3 fractions. Fractions containing only the
desired product were pooled and concentrated to dryness under
reduced pressure (0.27 kPa) at 40.degree. C. for 2 hours. 380 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-
-5.beta.,20-epoxy-10.beta.-ethoxy-1.beta.,
13.alpha.-dihydroxy-7.beta.-met- hoxy-9-oxo-11-taxene are thereby
obtained in the form of a white powder, the characteristics of
which were as follows:
[0136] .sup.1H NMR spectrum (300 MHz; CDCl.sub.3 with the addition
of a few drops of CD.sub.3OD-d.sub.4; chemicals shifts .delta. in
ppm, coupling constants J in Hz): 0.99 (s, 3H: CH.sub.3); 1.09 (s,
3H: CH.sub.3); 1.22 (t, J=7, 3H: ethyl CH.); 1.62 (s, 3H:
CH.sub.3); 1.68 and 2.66 (2 mts, 1H each: CH.sub.26); 2.03 (s, 3H:
CH.sub.3); 2.13 and 2.22 (2 dd, J=16 and 9, 1H each: CH.sub.2 at
position 14); 2.23 (s, 3H: COCH.sub.3); 3.23 (s, 3H: OCH.sub.3);
from 3.40 to 3.65 (mt, 2H: ethyl CH.sub.2); 3.84 (d, J=7.5, 1H: H
at position 3); 3.88 (dd, J=10 and 6.5, 1H: H at position 7); 4.10
and 4.23 (2 d, J=8.5, 1 H each: CH.sub.2 20); 4.75 (broad t, J=9,
1H: H at position 13); 4.90 (s, 1H: H at position 10); 4.97 (broad
d, J=10, 1H. H at position 5); 5.51 (d, J=7.5, 1H: H at position
2); 7.42 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position);
7.53 (t, J=7.5, 1H: OCOC6H.sub.5 H at the para position); 8.03 (d,
J=7.5. 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0137]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.bet-
a., 13.alpha.-trihydroxy-10.beta.-methoxy-9-oxo-11-taxene (or
10.beta.-methoxy-10-deacetoxybaccatin III) was prepared in the
following manner:
[0138] 9 cm.sup.3 of hydrogen fluoride/triethylamine complex
(3HF.Et.sub.3N) were added to a solution, maintained under an argon
atmosphere, at a temperature in the region of 20.degree. C., of 591
mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.,hydroxy-10.b-
eta.-ethoxy-9-oxo-7.beta.,13.alpha.-bis(triethylsilyloxy)-11-taxene
in 6 cm.sup.3 of dichloromethane. After 21 hours at a temperature
in the region of 20.degree. C., the reaction mixture was diluted
with 40 cm.sup.3 of dichloromethane and poured into a suspension of
40 cm.sup.3 of supersaturated aqueous sodium hydrogen carbonate
solution maintained at a temperature in the region of 0.degree. C.
After dilution with 10 cm.sup.3 of distilled water and when
settling had taken place, the aqueous phase was separated and
re-extracted with twice 20 cm.sup.3 of diethyl ether. The organic
phases were combined, washed with 20 cm.sup.3 of distilled water
and 20 cm.sup.3 of saturated aqueous sodium chloride solution,
dried over magnesium sulphate, filtered through magnesium sulphate
and concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature in the region of 40.degree. C. 370 mg of a pale yellow
foam were thereby obtained, which product is purified by
chromatography at atmospheric pressure on 35 g of silica (0.063-0.2
mm) contained in a column 2.5 cm in diameter, eluting with a
methanol/dichloromethane (2:98 by volume) mixture and collecting
15-cm.sup.3 fractions. Fractions containing only the desired
product were pooled and concentrated to dryness under reduced
pressure (2.7 kPa) at 40.degree. C. for 2 hours. 236.2 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-
,7.beta.,13.alpha.-trihydroxy-10.beta.-ethoxy-9-oxo-11taxene were
thereby obtained in the form of a white solid, the characteristics
of which were as follows:
[0139] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3: chemicals shifts
.delta. in ppm, coupling constants J in Hz): 1.08 (s, 3H:
CH.sub.3); 1.19 (s, 3H: CH.sub.3): 1.29 (t. J=7.5, 3H: ethyl
CH.sub.3); 1.38 (d, J=9, 1H: OH at position 7); 1.59 (s, 1H: OH at
position 1); 1.69 (s, 3H: CH.sub.3); 1.82 and 2.62 (2 mts, 1H each:
CH.sub.2 at position 6); 2.02 (d, J=5, 1H: OH at position 13); 2.08
(s, 3H: CH.sub.3); 2.30 (s, 3H: COCH.sub.3); 2.32 (d, J=9, 2H:
CH.sub.2 at position 14); 3.56 and 3.67 (2 mts, 1H each: ethyl
OCH.sub.2); 3.98 (d, J=7, 1H: H at position 3); 4.18 and 4.33 (2 d,
J=8.5 Hz, 1H each: CH.sub.220); 4.30 (mt, 1H: H7); 4.90 (mt, 1H: H
at position 13); 4.99 (dd, J=10 and 1.5, 1H: H at position 5); 5.05
(s, 1H: H at position 10); 5.66 (d, J=7, 1H: H at position 2); 7.49
(t, J=7.5, 2H: OCOC.sub.8H.sub.5 H at the meta position); 7.63 (t,
J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position); 8.12 (d,
J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0140]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydro-
xy-10.beta.-ethoxy-9-oxo-7.beta.,13.alpha.-bis(triethylsilyloxy)-11
-taxene (or
10.beta.-ethoxy-10-deacetoxy-7,13-bis(triethylsilyl)baccatin III)
was prepared in the following manner:
[0141] 93 mg of sodium hydride at a concentration of 50% by weight
of liquid paraffin were added portionwise to a solution, maintained
under an argon atmosphere, at a temperature in the region of
20.degree. C., of 1 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.,10.beta.--
dihydroxy-9-oxo-7.beta., 13.alpha.-bis(triethylsilyloxy)-11-taxene
in 3 cm.sup.3 of iodoethane and 4 cm.sup.3 of dimethylformamide.
The solution was kept stirring for 17 hours at a temperature in the
region of 20.degree. C., and 93 mg of sodium hydride at a
concentration of 50% by weight in liquid paraffin was then added
portionwise. After 50 minutes at a temperature in the region of
20.degree. C., the reaction mixture was diluted with 100 cm.sup.3
of ethyl acetate and 10 cm.sup.3 of saturated aqueous ammonium
chloride solution. The organic phase was separated after settling
had taken place and washed with six times 10 cm.sup.3 of distilled
water and then 10 cm.sup.3 of saturated aqueous sodium chloride
solution, dried over magnesium sulphate, filtered through sintered
glass and concentrated to dryness under reduced pressure (2.7 kPa)
at a temperature in the region of 40.degree. C. 1.2 g of a yellow
foam were thereby obtained, which product was purified by
chromatography at atmospheric pressure on 150 g of silica
(0.063-0.2 mm) contained in a column 3.5 cm in diameter, eluting
with an ethyl acetate/dichloromethane (2:98, then 5:95 by volume)
mixture and collecting 15-cm.sup.3 fractions. Fractions containing
only the desired products were pooled and concentrated to dryness
under reduced pressure (0.27 kPa) at 40.degree. C. for 2 hours.
379.2 mg of 4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,-
20-epoxy-1.beta.,10.beta.-dihydroxy-9-oxo-7.beta.,13.alpha.-bis(triethylsi-
lyloxy)-11-taxene were thereby obtained in the form of a pale
yellow foam and 430 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5,20-epoxy-1.beta.-hyd-
roxy-10.beta.-ethoxy-9-oxo-7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-tax- ene were thereby obtained
in the form of a white foam, the characteristics of which
10-.beta.-ethoxy product were as follows:
[0142] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemical shifts
.delta. in ppm, coupling constants J in Hz): 0.57 and 0.70 (2 mts,
6H each; ethyl CH.sub.2); 0.97 and 1.03 (2 t, J=7.5, 9H each: ethyl
CH.sub.3); 1.13 (s, 3H: CH.sub.3); 1.20 (s, 3H: CH.sub.3); 1.29 (t,
J=7.5, 3H: CH.sub.3 of ethoxy at position 10); 1.58 (s, 1H: OH at
position 1); 1.66 (s, 3H: CH.sub.3); 1.89 and 2.58 (2 mts, 1H each:
CH.sub.2 at position 2); 2.03 (s, 3H: CH.sub.3); 2.13 and 2.23 (2
dd, J=16 and 9, 1H each: CH.sub.2 at position 14); 2.30 (s, 3H:
COCH.sub.3); 3.53 (mt, 2H: CH.sub.2 of ethoxy at position 10): 3.84
(d, J=7, 1H: H at position 3); 4.15 and 4.30 (2 d, J=8.5, 1 H each:
CH.sub.2 at position 20); 4.43 (dd, J=11 and 6.5, 1H: H at position
7); from 4.90 to 5.00 (mt, 2H: H at position 13 and H at position
5), 5.01 (s, 1H: H at position 10); 5.61 (d, J=7, 1H: H at position
2); 7.48 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position);
7.61 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position); 8.10
(d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
EXAMPLE4
[0143] 65 mg of dicyclohexylcarbodiimide and then 7 mg of
4-(N,N-dimethylaminopyridine were added successively at a
temperature in the region of 20.degree. C. to a suspension
containing 115 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-(1.alpha.--
propyl)oxy-1.beta.,
13.alpha.-dihydroxy-7.beta.-methoxy-9-oxo-11-taxene and 100 mg of
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4pheny-
l-1,3-oxazolidine-5-carboxylic acid in 1 cm.sup.3 of anhydrous
toluene. The suspension obtained was stirred at a temperature in
the region of 20.degree. C. under an argon atmosphere for 1 hour,
and then purified by direct application to a column for
chromatography at atmospheric pressure on 30 g of silica (0.063-0.2
mm) contained in a column 2.5 cm in diameter (elution gradient:
ethyl acetate/dichloromethane from 2:98 to 10: 90 by volume),
collecting 10-cm.sup.3 fractions. Fractions containing only the
desired product were pooled and concentrated to dryness under
reduced pressure (2.7 kPa) at 40.degree. C. for 2 hours. 276.2 mg
of a white solid were thereby obtained, which product was purified
by preparative thin-layer chromatography: 10 Merck preparative
silica gel 60F.sub.254 plates, thickness 0.5 mm, application in
solution in dichloromethane, eluting with a
methanol/dichloromethane (3:97 by volume) mixture. After elution of
the zones corresponding to the main products with a
methanol/dichloromethane (15:85 by volume) mixture, filtration
through cotton wool and then evaporation of the solvents under
reduced pressure (2.7 kPa) at a temperature in the region of
40.degree. C., 84.8 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-(1-propyl)-
oxy-1 -hydroxy-7 0-methoxy-9- oxo-11-taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazoli-
dine-5-carboxylate were obtained in the form of a white foam, the
characteristics of which were as follows:
[0144] .sup.1H NMR spectrum (300 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm; coupling constants J in Hz): 0.97 (t, J=7, 3H:
propyl CH.sub.3); 1.07 (s, 9H: C(CH.sub.3).sub.3), 1.19 (s, 6H:
CH.sub.3); from 1.50 to 1.80 (mt, 3H: OH at position 1 and central
CH.sub.2 of propyl); 1.60 (s, 3H: CH.sub.3); 1.70 (s, 3H:
CH.sub.3); 1.78 and 2.63 (2 mts, 1H each: CH.sub.2 at position 6);
1.82 (unres. comp. 3H: COCH.sub.3); 2.07 and 2.19 (2 dd, J=16 and
9, 1H each:,CH.sub.2 at position 14); 3.26 (s, 3H: OCH.sub.3); 3.30
and 3.58 (2 mts, 1H each: propyl OCH.sub.2); 3.73 (d, J=7.5, 1H: H
at position 3); 3.81 (s, 3H: ArOCH.sub.3); 3.81 (mt, 1H: H at
position 7); 4.09 and 4.23 (2 d, J=8.5, 1H each: CH.sub.2 at
position 20): 4.57 (d, J=4.5, 1H: H at position 2'); 4.79 (s, 1H: H
at position 10); 4.90 (broad d, J=10, 1H: H at position 5); 5.40
(unres. comp. 1H: H at position 3'); 5.58 (d, J=7 5, 1H: H at
position 2); 6.13 (broad t, J=9, 1H: H at position 13); 6.40
(spread unres. comp. 1H: H at position 5'); 6.92 (d, J=8.5, 2H:
aromatic H at the ortho position with respect to OCH.sub.3); from
7.30 to 7.60 (mt, 9H: aromatic H at position 3'-aromatic H at the
meta position with respect to OCH.sub.3 and OCOC.sub.6H.sub.5 meta
H); 7.63 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position);
8.03 (d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0145]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-(1-p-
ropyl)oxy-1.beta.-hydroxy-7.beta.-methoxy-9-oxo-11-taxen-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate was
prepared in the following manner:
[0146] A solution of 84 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.-
,20-epoxy-10.beta.-(1-propyl)oxy-1.beta.-hydroxy-7.beta.-methoxy-9-oxo-11--
taxen-13.alpha.-yl
(2R,4S,5R)-3-tert-butoxy-carbonyl-2-(4-methoxyphenyl)-4-
-phenyl-1,3-oxazolidine-5-carboxylate in 0.84 cm.sup.3 of ethyl
acetate and 0.0071 cm.sup.3 of concentrated 37% hydrochloric acid
was kept stirring at a temperature in the region of 20.degree. C.
for 1 hour under an argon atmosphere. The reaction mixture was then
purified by preparative thin-layer chromatography: application of
the crude reaction mixture to 6 Merck preparative silica gel
60F.sub.254 plates, thickness 0.5 mm, eluting with a
methanol/acetonitrile dichloromethane (3:7:90 by volume) mixture.
After elution of the zone corresponding to the main product with a
methanol/dichloromethane (15:85 by volume) mixture, filtration
through cotton wool and then evaporation of the solvents under
reduced pressure (2.7 kPa) at a temperature in the region of
40.degree. C., 27 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.bet-
a.-(1-propyl)oxy-1.beta.-hydroxy-7.beta.-methoxy-9-oxo-11-taxen-13.alpha.--
yl (2R,3S)-3tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate
were obtained in the form of a white foam, the characteristics of
which are as follows:
[0147] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm; coupling constants J in Hz): 0.99 (t, J=7, 3H:
propyl CH.sub.3); 1.22 (s, 3H: CH.sub.3); 1.25 (s, 3H: CH.sub.3);
1.38 (s, 9H: C(CH.sub.3).sub.3; 1.64 (s, 1H: OH at position 1);
1.69 (mt, 2H: central CH.sub.2 of propyl); 1.73 (s, 3H: CH.sub.3);
1.80 and 2.70 (2 mts, 1H each: CH.sub.2 at position 6); 1.88 (s,
3H: CH.sub.3); 2.30 (mt, 2H: CH.sub.2 at position 14); 2.38 (s, 3H:
COCH.sub.3); 3.31 (s, 3H: OCH.sub.3); 3.36 and 3.64 (2 mts, 1H
each: propyl OCH.sub.2); 3.44 (unres. comp. 1H: OH at position 2');
3.84 (d, J=7.5, Hz, 1H: H at position 3); 3.87 (dd, J=11 and 6.5,
1H: H at position 7); 4.18 and 4.30 (2 d, J=8.5, 1H each: CH.sub.2
at position 20); 4.64 (mt, 1H: H at position 2'); 4.89 (s, 1H: H at
position 10); 4.98 (broad d, J=10, 1H: H at position 5); 5.28
(broad d, J=10, 1H: H at position 3'); 5.42 (d, J=10, 1H: CONH);
5.64 (d, J=7.5, 1H: H at position 2); 6.22 (broad t, J=9, 1H: H at
position 13); from 7.25 to 7.45 (mt, 5H: aromatic H at position
3'); 7.50 (d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position);
7.61 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para position); 8.12
(d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0148]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-(1-p-
ropyl)oxy-1.beta.,
13.alpha.-dihydroxy-7.beta.-methoxy-9-oxo-11-taxene (or
10.beta.-(1-propyl)oxy-7.beta.-methoxy-10-deacetoxybaccatin III)
was prepared in the following manner:
[0149] 30 mg of sodium hydride at a concentration of 50% by weight
in liquid paraffin were added portionwise to a solution, maintained
under an argon atmosphere, at a temperature in the region of
0.degree. C., of 165 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.bet-
a.,13.alpha.-trihydroxy-10.beta.-(1-propyl)oxy-9-oxo-11-taxene in
1.7 cm.sup.3 of iodomethane and 1 cm.sup.3 of dimethylformamide.
After 30 minutes at a temperature in the region of 0.degree. C.,
the reaction mixture was diluted with 40 cm.sup.3 of ethyl acetate,
5 cm.sup.3 of distilled water and 7 cm.sup.3 of saturated aqueous
ammonium chloride solution. After settling had taken place, the
organic phase was separated and washed with three times 7 cm.sup.3
of distilled water and then 7 cm.sup.3 of saturated aqueous sodium
chloride solution, dried over magnesium sulphate, filtered through
sintered glass and concentrated to dryness under reduced pressure
(2.7 kPa) at a temperature in the region of 40.degree. C. 224 mg of
the yellow solid were thereby obtained, which product was purified
by chromatography at atmospheric pressure on 20 g of silica
(0.063-0.2 mm) contained in a column 2.5 cm in diameter (elution
gradient: ethyl acetate/dichloromethane from 0:100 to 15:85 by
volume), collecting 10-cm.sup.3 fractions. Fractions containing
only the desired product were pooled and concentrated to dryness
under reduced pressure (0.27 kPa) at 40.degree. C. for 2 hours.
117.5 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-10.beta.-(1-propyl)-
oxy-1.beta., 13.alpha.-dihydroxy-7.beta.-methoxy-9-oxo-11-taxene
were thereby obtained in the form of a white foam, the
characteristics of which were as follows:
[0150] .sup.1H NMR spectrum (300 MHz; CDCl.sub.3: chemicals shifts
.delta. in ppm, coupling constants J in Hz): 0.98 (t, J=7, 3H:
propyl CH.sub.3); 1.05 (s, 3H: CH.sub.3); 1.19 (s, 3H: CH.sub.3);
from 1.60 to 1.80 (mt, 2H: central CH.sub.2 of propyl); from 1.65
to 1.85 and 2.66 (2 mts, 1H each: CH.sub.2 at position 6); 1.72 (s,
3H: CH.sub.3); 2.10 (s, 3H: CH.sub.3); from 2.05 to 2.35 (mt 2H:
CH.sub.2 at position 14); 2.28 (s, 3H: COCH.sub.3); 3.32 (s, 3H:
OCH.sub.3); 3.45 and 3.65 (2 mts, 1H each, propyl OCH.sub.2); 3.92
(d, J 7.5, 1H: H3); 3.93 (dd, J=11 and 6, 1H: H at position 7);
4.16 and 4.32 (2 d, J=8.5, 1H each: CH.sub.2 at position 20); 4.90
(mt, 1H: H at position 13); 4.94 (s, 1H: H at position 10); 5.03
(broad d, J=10, 1H: H at position 5); 5.60 (d, J=7.5, 1H: H at
position 2); 7.48 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta
position); 7.62 (t, J=7.5, 1H: OCOC.sub.6H.sub.5 H at the para
position); 8.11 (d, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho
position).
[0151]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,7.bet-
a.,13.alpha.-trihydroxy-10.beta.-(1-propyl)oxy-9-oxo-11-taxene (or
10(1 -propyl)oxy-10deacetoxybaccatin III) was prepared in the
following manner:
[0152] 8.75 cm.sup.3 of hydrogen fluoride/triethylamine complex
(3HF.Et.sub.3N) were added to a solution, maintained under an argon
atmosphere, at a temperature in the region of 20.degree. C., of 585
mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20epoxy-1.beta.-hydroxy-10.b-
eta.-(1-propyl)oxy-9-oxo-7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-taxen- e in 6 cm.sup.3 of
dichloromethane. After 24 hours at a temperature in the region of
20.degree. C., the reaction mixture was diluted with 30 cm.sup.3 of
dichloromethane and poured into a suspension of 30 cm.sup.3 of
supersaturated aqueous sodium hydrogen carbonate solution
maintained at a temperature in the region of 0.degree. C. After
dilution with 10 cm.sup.3 of distilled water and when settling had
taken place, the aqueous phase was separated and re-extracted with
twice 20 cm.sup.3 of diethyl ether. The organic phases were
combined, washed with 20 cm.sup.3 of distilled water and 20
cm.sup.3 of saturated aqueous sodium chloride solution, dried over
magnesium sulphate, filtered through magnesium sulphate and
concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature in the region of 40.degree. C. 500 mg of a pale yellow
foam were thereby obtained, which product was purified by
chromatography at atmospheric pressure on 40 g of silica (0.063-0.2
mm) contained in a column 2.5 cm in diameter, eluting with a
methanol/dichloromethane (2:98 by volume) mixture and collecting
15-cm.sup.3 fractions. Fractions containing only the desired
product were pooled and concentrated to dryness under reduced
pressure (2.7 kPa) at 40.degree. C. for 2 hours. 373.8 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-
,7.beta.,13.alpha.-trihydroxy-10.beta.-(1-propyl)oxy-9-oxo-11-taxene
were thereby obtained in the form of a white solid, the
characteristics of which were as follows:
[0153] .sup.1H NMR spectrum (300 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm, coupling constants J in Hz): 0.95 (t, J=7, 3H:
propyl CH.sub.3); 1.06 (s, 3H: CH.sub.3); 1.22 (s, 3H: CH.sub.3);
1.45 (d, J=7.5, 1H: OH at position 7); from 1.60 to 1.80 (mt, 2H:
central CH.sub.2 of propyl); 1.67 (s, 3H: CH.sub.3); 1.83 and 2.62
(2 mts, 1H each: CH.sub.2 at position 6); 2.05 (s, 3H: CH.sub.3);
2.05 (mt, 1H: OH at position 13); 2.27 (limiting AB, 2H: CH.sub.2
at position 4); 2.28 (s, 3H: COCH.sub.3); 3.40 and 3.57 (2 mts, 1H
each: propyl OCH.sub.2); 3.97 (d, J=7.5, 1H: H at position 3); 4.15
and 4.30 (2 d, J=8.5, 1H each: CH.sub.2 at position 20); 4.28 (mt,
1H: H at position 7); 4.90 (mt, 1H: H at position 13); 4.98 (broad
d, J=10, 1H, H at position 5); 5.03 (s, 1H: H at position 10); 5.65
(d, J=7.5, 1H: H at position 2); 7.50 (t, J=7.5, 2H:
OCOC.sub.6H.sub.5 H at the meta position); 7.60 (t, J=7.5, 1H:
OCOC.sub.6H.sub.5 H at the para position); 8.00 (d, J=7.5, 2H:
OCOC.sub.6H.sub.5 H at the ortho position).
[0154]
4.alpha.-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydro-
xy-10.beta.-(1-propyl)oxy-9-oxo-7.beta.,
13.alpha.-bis(triethyl-silyloxy)-- 11-taxene (or
10.beta.-(1-propyl)oxy-10-deacetoxy-7,13bis(triethylsilyl)ba-
ccatin III) was prepared in the following manner:
[0155] 93 mg of sodium hydride at a concentration of 50% by weight
in liquid paraffin were added portionwise to a solution, maintained
under an argon atmosphere, at a temperature in the region of
20.degree. C., of 1 g of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.,
10.beta.-dihydroxy-9-oxo-7.beta.,
13.alpha.-bis(triethylsilyloxy)-11-taxe- ne in 3 cm.sup.3 of
iodoethane and 4 cm.sup.3 of dimethylformamide. The solution was
kept stirring for 19 hours at a temperature in the region of
20.degree. C., and 93 mg of sodium hydride at a concentration of
50% by weight in liquid paraffin were then added portionwise. After
3 hours at a temperature in the region of 20.degree. C., the
reaction mixture was diluted with 100 cm.sup.3 of ethyl acetate and
10 cm.sup.3 of saturated aqueous ammonium chloride solution. The
organic phase was separated after settling had taken place and
washed with six times 10 cm.sup.3 of distilled water and then 10
cm.sup.3 of saturated aqueous sodium chloride solution, dried over
magnesium sulphate, filtered through sintered glass and
concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature in the region of 40.degree. C. 1.32 g of a pale yellow
foam were thereby obtained, which product was purified by
chromatography at atmospheric pressure on 150 g of silica
(0.063-0.2 mm) contained in a column 3.5 cm in diameter, eluting
with an ethyl acetate/dichloromethane (2:98, then 5:95 by volume)
mixture and collecting 15-cm.sup.3 fractions. Fractions containing
only the desired products were pooled and concentrated to dryness
under reduced pressure (0.27 kPa) at 40.degree. C. for 2 hours.
376.3 mg of 4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,-
20-epoxy-1.beta.,
10.beta.-dihydroxy-9-oxo-7.beta.,13.alpha.-bis(triethyls-
ilyloxy)-11-taxene were thereby obtained in the form of a pale
yellow foam and 395.3 mg of
4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.b-
eta.-hydroxy-10.beta.-(1-propyl)oxy-9-oxo-7.beta.,
13.alpha.-bis(triethyls- ilyloxy)-11-taxene were thereby obtained
in the form of a pale yellow foam, the characteristics of which
were as follows:
[0156] .sup.1H NMR spectrum (400 MHz; CDCl.sub.3; chemicals shifts
.delta. in ppm; coupling constants J in Hz): 0.57 and 0.70 (2 mts,
6H each: ethyl CH.sub.2); 0.94 and 1.03 (2 t, J=7.5, 9H each: ethyl
CH.sub.3); 0.94 (t, J=7.5, 3H: propyl CH.sub.3); 1.14 (s, 3H:
CH.sub.3); 1.21 (s, 3H: CH.sub.3); 1.67 (s, 3H: CH.sub.3); 1.69
(mt, 2H: central CH.sub.2 of propyl); 1.88 and 2.48 (2 mts, 1H
each: CH.sub.2 at position 6); 2.03 (s, 3H: CH.sub.3); 2.13 and
2.23 (2 dd, J=16 and 9, 1H each: CH.sub.2 at position 14); 2.30 (s,
3H: COCH.sub.3); 3.40 (mt, 2H: propyl OCH.sub.2); 3.84 (d, J=7.5.
1H: H at position 3); 4.16 and 4.30 (2 d, J=8.5, 1H each: CH.sub.2
at position 20); 4.44 (dd, J=11 and 6.5, 1H: H at position 7); 4.96
(broad d, J=10 Hz, 1H: H5); 4.97 (s, 1H: H 10); 4.99 (broad t,
J=9Hz, 1H: H at position 13); 5.62 (d, J=7.5, 1H: H at position 2);
7.48 (t, J=7.5, 2H: OCOC.sub.6H.sub.5 H at the meta position); 7.60
(t, J=7.5, 1H: OCOC6H.sub.5 H at the para position); 8.10 (d,
J=7.5, 2H: OCOC.sub.6H.sub.5 H at the ortho position).
[0157] The new products of general formula (I) in which Z
represents a radical of general formula (II) manifest significant
inhibitory activity with respect to abnormal cell proliferation,
and possess therapeutic properties permitting the treatment of
patients having pathological conditions associated with abnormal
cell proliferation. The pathological conditions include the
abnormal cell proliferation of malignant or non-malignant cells of
various tissues and/or organs, comprising, without implied
limitation, muscle, bone or connective tissue, the skin, brain,
lungs, sex organs, the lymphatic or renal systems, mammary or blood
cells, liver, the digestive system, pancreas and thyroid or adrenal
glands. These pathological conditions can also include psoriasis,
solid tumours, cancers of the ovary, breast, brain, prostate,
colon, stomach, kidney or testicles, Kaposi's sarcoma,
cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour,
Hodgkin's disease, melanoma, multiple myeloma, chronic lymphocytic
leukaemia and acute or chronic granulocytic lymphoma.
[0158] The new products according to the invention are especially
useful for the treatment of cancer of the ovary. The products
according to the invention may be used to prevent or delay the
appearance or reappearance of the pathological conditions, or to
treat these pathological conditions.
[0159] The products according to the invention may be administered
to a patient according to different dosage forms suited to the
chosen administration route, which is preferably the parenteral
route. Parenteral administration comprises intravenous,
intraperitoneal, intramuscular or subcutaneous administration.
Intraperitoneal or intravenous administration is more especially
preferred.
[0160] The present invention also comprises pharmaceutical
compositions containing at least one product of general formula
(I), in a sufficient amount suitable for use in human or veterinary
therapy. The compositions may be prepared according to the
customary methods, using one or more pharmaceutically acceptable
adjuvants, vehicles or excipients. Suitable vehicles include
diluents, sterile aqueous media and various non-toxic solvents.
Preferably, the compositions take the form of aqueous solutions or
suspensions, injectable solutions which can contain emulsifying
agents, colourings, preservatives or stabilizers. However, the
compositions can also take the form of tablets, pills, powders or
granules which can be administered orally.
[0161] The choice of adjuvants or excipients may be determined by
the solubility and the chemical properties of the product, the
particular mode of administration and good pharmaceutical
practice.
[0162] For parenteral administration, sterile, aqueous or
non-aqueous solutions or suspensions are used. For the preparation
of non-aqueous solutions or suspensions, natural vegetable oils
such as olive oil, sesame oil or liquid petroleum, or injectable
organic esters such as ethyl oleate, may be used, The sterile
aqueous solutions can consist of a solution of a pharmaceutically
acceptable salt dissolved in water. The aqueous solutions are
suitable for intravenous administration provided the pH is
appropriately adjusted and the solution is made isotonic, for
example with a sufficient amount of sodium chloride or glucose. The
sterilization may be carried out by heating or by any other means
which does not adversely affect the composition.
[0163] It is clearly understood that all the products participating
in the compositions according to the invention must be pure and
non-toxic in the amounts used.
[0164] The compositions can contain at least 0.01% of
therapeutically active product. The amount of active product in a
composition is such that a suitable dosage can be prescribed.
Preferably, the compositions are prepared in such a way that a
single dose contains from 0.01 to 1000 mg approximately of active
product for parenteral administration.
[0165] The therapeutic treatment may be performed concurrently with
other therapeutic treatments including antineoplastic drugs,
monoclonal antibodies, immunotherapy or radiotherapy or biological
response modifiers. The response modifiers include, without implied
limitation, lymphokines and cytokines such as interleukins,
interferons (.alpha., .beta. or .delta.) and TNF.
[0166] Other chemotherapeutic agents which are useful in the
treatment of disorders due to abnormal cell proliferation include,
without implied limitation, alkylating agents, for instance
nitrogen mustards such as mechlorethamine, cyclophosphamide,
melphalan and chlorambucil, alkyl sulphonates such as busulfan,
nitrosoureas such as carmustine, lomustine, semustine and
streptozocin, triazenes such as dacarbazine, antimetabolites such
as folic acid analogues, for instance methotrexate, pyrimidine
analogues such as fluorouracil and cytarabine, purine analogues
such as mercaptopurine and thioguanine, natural products, for
instance vinca alkaloids such as vinblastine, vincristine and
vindesine, epipodophyllotoxins such as etoposide and teniposide,
antibiotics such as dactinomycin, daunorubicin, doxorubicin,
bleomycin, plicamycin and mitomycin, enzymes such as
L-asparaginase, various agents such as coordination complexes of
platinum, for instance cisplatin, substituted ureas such as
hydroxyurea, methylhydrazine derivatives such as procarbazine,
adrenocortical suppressants such as mitotane and aminoglutethimide,
hormones and antagonists such as adrenocorticosteroids such as
prednisone, progestins such as hydroxyprogesterone caproate,
methoxyprogesterone acetate and megestrol acetate, oestrogens such
as diethylstilboestrol and ethynyloestradiol, antioestrogens such
as tamoxifen, and androgens such as testosterone propionate and
fluoxymesterone.
[0167] The doses used for carrying out the methods according to the
invention are those which permit a prophylactic treatment or a
maximum therapeutic response. The doses vary according to the
administration form, the particular product selected and features
distinctive to the subject to be treated. In general, the doses are
those which are therapeutically effective for the treatment of
disorders due to abnormal cell proliferation.
[0168] The products according to the invention may be administered
as often as necessary to obtain the desired therapeutic effect.
Some patients may respond rapidly to relatively high or low doses,
and then require low or zero maintenance doses. Generally, low
doses will be used at the beginning of the treatment and, if
necessary, increasingly stronger doses will be administered until
an optimum effect is obtained.
[0169] For other patients, it may be necessary to administer
maintenance doses 1 to 8 times a day, and preferably 1 to 4 times,
according to the physiological requirements of the patient in
question. It is also possible that some patients may require the
use of only one to two daily administrations.
[0170] In man, the doses generally range from 0.01 to 200 mg/kg.
For intraperitoneal administration, the doses will generally range
from 0.1 to 100 mg/kg, preferably from 0.5 to 50 mg/kg and still
more specifically from 1 to 10 mg/kg. For intravenous
administration, the doses generally range from 0.1 to 50 mg/kg,
preferably from 0.1 to 5 mg/kg and still more specifically from 1
to 2 mg/kg. It is understood that, in order to choose the most
suitable dosage, account should be taken of the administration
route, the patient's weight, general state of health and age and
all factors which may influence the efficacy of the treatment.
[0171] The example which follows illustrates a composition
according to the invention.
EXAMPLE
[0172] 40 mg of the product obtained in Example 1 are dissolved in
1 cm.sup.3 of Emulphor EL 620 and 1 cm.sup.3 of ethanol, and the
solution is then diluted by adding 18 cm.sup.3 of physiological
saline. The composition is administered by perfusion over 1 hour by
introduction in physiological solution.
* * * * *