DERIVES C9 DU TAXANE; COMPOSITIONS PHARMACEUTIQUES A BASE DE CES DERIVES

C9 TAXANE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abrégé anglais

Taxane derivatives, useful as anti-tumor and anti-leukenia agents, having
alternative C9 substituents wherein the substituents are
selected from a group consisting of hydrogen, hydroxy, protected hydroxy and
acyloxy.

Revendications

51
CLAIMS:
1. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,

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C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14:
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo,
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C1-C15 heteroaryl , hydroxy, protected
hydroxy or together with R6 forms an oxo;

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R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and
R29, R30 and R31 are independently hydrogen C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.
2. The taxane derivative of claim 1 wherein R31 is
selected from the group consisting of
<IMGS>

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and Z is C1-C15 alkyl, hydroxy, alkoxy, halogen, or
trifluoromethyl.
3. The taxane derivative of claim 2 wherein Z is methyl
or methoxy.
4. The taxane derivative of claim 1 wherein R9a is
hydrogen.
5. The taxane derivative of claim 1 wherein R9a is
.beta.-hydroxy.
6. The taxane derivative of claim 1 wherein R9a is
acetoxy.
7. The taxane derivative of claim 1 wherein R14 and R14a
are hydrogen, R10 is hydrogen, R10a is hydroxy or acetoxy, R9a is
hydrogen or .beta.-hydroxy, R7 is hydrogen, R7a is hydroxy, R5 is
hydrogen, R5a and R4 and the carbons to which they are attached
form an oxetane ring, R4a is acetoxy, R2a is hydrogen, R2 is
benzoyloxy, R1 is hydroxy, X1 is -OH, X2 is hydrogen, X3 is
phenyl, X4 is hydrogen, X5 is -COX10, X10 is phenyl or t-butoxy
and the taxane has the 2'R, 3'S configuration.
8. The taxane derivative of claim 1 wherein R14 and R14a
are hydrogen, R10 is hydrogen, R10a is hydroxy or acetoxy, R9a is
hydrogen, .beta.-hydroxy or .beta.-acetoxy, R7 is hydrogen, R7a is
hydroxy, R5 is hydrogen, R5a and R4 and the carbons to which they
are attached form an oxetane ring, R4a is acetoxy, R1 is
hydroxy, X1 is -OH, X2 is hydrogen, X3 is C1-C15 alkyl or C2-C15
alkenyl, X4 is hydrogen, X5 is -COX10, X10 is phenyl, tert-, iso-
or n-butoxy, ethoxy, iso- or n-propoxy, cyclohexyloxy,
allyloxy, crotyloxy, 1,3-diethoxy-2-propoxy, 2-methoxyethoxy,
amyloxy, neopentyloxy, PhCH2O-, -NPh2, -NHnPr, -NHPh, and -NHEt.

55
9. A pharmaceutical composition which contains the
taxane derivative of claim 1 and one or more pharmacologically
acceptable, inert or physiologically active diluents or
adjuvants.
10. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, - SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl or
substituted phenyl, substituted with an C1-C15 alkyl, C2-C15
alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl group,
provided, however that X3 is other than phenyl when X4 is
hydrogen, and X4 is other than phenyl when X3 is hydrogen;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
alkenyl, X4 is hydrogen, X5

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X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C1-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-
C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl , cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo,

57
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl or C5-C15 heteroaryl, hydrogen, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and

58
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.
11. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
as is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;

59
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, or -OCOR31, or together with
R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;

60
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with. R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.

61
12. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;

62
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14:
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;

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R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen. or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
R28 is hydrogen, aryl, or a hydroxy protecting group;
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl, provided, however, that R31 is not
unsubstituted phenyl.

64
13. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl , C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,

65
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 alkynyl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen or together with R4d forms an oxo;
oxirane or methylene;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo,
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
or together with R5 forms an oxo;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;

66
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.
14. A taxane derivative having the formula
<IMG>

67
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;

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R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, o:r together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;

69
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, or C5-C15 heteroaryl, hydroxy protected hydroxy or
together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.
15. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;

70
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, ar C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy, or
together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or

71
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is acyl, or a hydroxy protecting group; and

72
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.
16. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently :hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX12, -COOX10, -COSX10, -CONX8X10 or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;

73
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C1-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15, heteroaryl, or heterosubstituted C1-C15; alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl. C5-C15 heteroaryl, -OX10, or -NX8X14;
X12 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl,
provided, however, that X12 is other than unsubstituted phenyl;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, -C6-15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;

74
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and
R29, R30 and R31 are independently hydrogen, C1-C15
alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.

75
17. A taxane derivative having the formula
<IMG>
wherein
X1 is -OX6, -SX7, or -NXSX9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10 or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting
group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15
aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted
C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15
heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;

76
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl,
C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together
with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a
forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with R5a and the carbon atoms
to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or
-OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo,
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy,
together with R5 forms an oxo, or together with R4 and the
carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R6 forms an oxo;
R7 is hydrogen. or together with R7a forms an oxo;

R7a is hydrogen, halogen, protected hydroxy, or -OR28,
or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or
.beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected
hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15
alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, aryl, or a hydroxy protecting group;
R29 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C-C15
alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl,
provided, however, that R29 is other than methyl; and
R30 and R31 area independently hydrogen, C1-C15 alkyl,
C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or
monocyclic C5-C15 heteroaryl.
18. The taxane derivative of claim 1 wherein R10a is other
than hydroxy.
19. The taxane derivative of claim 1 wherein X5 is -COX10,
-COSX10, -CONX8X10, or -SO2X11, with X8 and X11 as defined above
and X10 being other than phenyl, or X5 is -COOX10 with X10 being
other than butyl.

78
20. A taxane derivative having the formu a
<IMG>
wherein
X1, R1 and R7 are hydroxy;
X3 is furyl, thienyl, isobutenyl, or phenyl;
X5 is -COX10;
X10 is butoxy or phenyl;
R2 is benzoyloxy;
R4 together with R5a and the carbon atoms to which
they are attached form an oxetane ring;
R4a is acetoxy;
R9a is hydrogen or .beta.-hydroxy;
R10 is hydrogen or together with R10 forms an oxo;
R10a is hydroxy or together with R10 forms an oxo; and
X2, X4, R2a, R5, R7a, R9, R14 and R14a, are hydrogen.
21. The taxane derivative of claim 20 wherein X10 is
t-butoxy, R9a is hydrogen, and R10 and R10a form an oxo.
22. The taxane derivative of claim 20 wherein X10 is t-
butoxy, R9a is .beta.-hydroxy, R10 is hydrogen, and R10a is hydroxy.

Description

CA 02156908 2001-02-13
64725-651
1
C9 TAXANE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM
BACKGROUND OF THE INVENTION
The present invention is directed to novel taxanes
which have utility as antileukemia and antitumor agents.
The taxane family of terpenes, of which taxol* is a
member, has attracted considerable interest in both the
biological and chemical arts. Taxol* is a promising cancer
chemotherapeutic agent with a broad spectrum of antileukemic
and tumor-inhibiting activity. Taxol* has a 2'R, 3'S
configL,v ~ .on and the f~~llowing structural form»~
OAc
,e 0
s 0 'ri
C6HSCONH 0 "
10 9
.~t ~,,,~1~ ,7
01111 13 15~ 16 8 7
C6H5 =_ )
CH Z ,~ , s/
0 H H \y
1 ~ -_ 0~~., c ~2 a' 0
~~HSC00
(_
Wherein ac is acetyl. Because of this promising .~ctivicy,
taxol* is currently undergoing clinical trials in both France
and the and the United States.
Colin et al. reported in U.S. Patent No. 4,814,470
that taxol* derivative; having structural formula (2) below,
have an activity sign~f:icantly greater than that of taxol* (1).
q o 0 oh
co-o
I
2 ~CH-Ga ~ .
I . _ ~0
r u~,,u_c~ . . nu , a
OCOCH3
,''OCOCSHg
*Trade-mar'.

CA 02156908 2001-02-13
64725-651
2
R' represents hydrogen or acetyl and one of R " and R " '
represents hydroxy and t:he other represents tert-butoxy-
carbonylamino and their stereoisomeric forms, and mixtures
thereof. The compound of formula (2) :in which R' is hydrogen,
R " is hydroxy, R " ' is tert-butoxy-carbonylamino having the
2'R, 3'S configuration is commonly referred to as taxotere.
Although taxo7_ and taxotere are promising
chemotherapeutic agents, they are not universally effective.
Accordingly, a need remains for additional chemotherapeutic
agents.
SUMMARY OF THE INVENTI01'd
Among the objects of the present invention,
therefore, is the provi~~ion of novel t<~xane derivatives which
are valuable antileukem=_a and antitumor agents.
Briefly, therefore, the present invention is directed
to C9 taxane derivative:;. In a preferred embodiment, the
taxane derivative has a tricyclic or tetracyclic core and
corresponds to the formula:

PCT/US94102210
WO 94!20088
3
Fi~~a
,e R10/ R9
"~~ R9a R~
,z ,o /
g 19
X5\N~ 2 '.~OIIII ~~ " R7a
' ~ ~ ~" '
6
S~Rsa
R~ R5a
R2a R R5
R~4a 4e
R2 Rq (3)
wherein
X1 i s -OX6 , -SX~ , or -N.~BXg ;
Xz is hydrogen, alkyl, alkenyl, alkynyl, aryl,
or heteroaryl;
X3 and X4 are independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, or heteroaryl;
XS is -COXlo, -COOXlo, -COSXlo, -CONXBXlo,
or -SOZXll ;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, hydroxy protecting group, or a functional
group which increases the water solubility of the taxane
derivative;
X, is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl,
aryl or heteroaryl;
X9 is an amino protecting group;
Xlo is alkyl, alkenyl, alkynyl, aryl,
heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl,
aryl or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl,
heteroaryl , -OXio , or -NXaXl4
X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
or heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or
together with R14 forms a carbonate;

WO 94/20088 ~ PCTIUS94102210
~~,~6 .
4
RZ is hydrogen, hydroxy, -OCOR31, or together
with RZa forms an oxo;
R2a is hydrogen or together with Rz forms an
oxo;
R4 is hydrogen, together with R4a forms an oxo,
oxirane or methylene, or together with Rsa and the carbon
atoms to which they are attached form an oxetane ring;
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cyano, hydroxy, -OCOR3o, or together with R4
forms an oxo, oxirane or methylene;
RS is hydrogen or together with Rsa forms an
oxo,
Rsa is hydrogen, hydroxy, protected hydroxy,
acyloxy, together with RS forms an oxo, or together with
R4 and the carbon atoms to which they are attached form
an oxetane ring;
R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
or heteroazyl, hydroxy, protected hydroxy or together
with R6a forms an oxo;
R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl,
or heteroaryl, hydroxy, protected hydroxy or together
with R6 forms an oxo;
R~ is hydrogen or together with Rya forms an
oxo,
Rya is hydrogen, halogen, protected hydroxy,
-ORZB, or together with R, forms an oxo;
R9 is hydrogen;
R9a is hydrogen, hydroxy, protected hydroxy, or
acyloxy;
Rlo is hydrogen or together with Rloa forms an
oxo,
Rloa is hydrogen, -OCOR29, hydroxy, or protected
hydroxy, or together with Rlo forms an oxo;
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl,
or heteroaryl, hydroxy, protected hydroxy or together
with R1 forms a carbonate;

WO 94/20088 ~ 21 ~ 6 9 Q ~ PCT/US94102210
Rl4a is hydrogen, alkyl, alkenyl, alkynyl, aryl,
or heteroaryl;
. Rz8 is hydrogen, aryl, :hydroxy protecting group
or a functional group which incrEsa::es the solubility of
5 the taxane derivative; and
Rz9~ Rso and R31 are independently hydrogen,
alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic
heteroaryl.
Other objects and features of this invention
will be in part apparent and in part pointed out
hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein "Ar" means aryl; "Ph" means
phenyl; "Ac" means acetyl; "Et" rneans ethyl; "R" means
alkyl unless otherwise defined; "Bu" means butyl; "Pr"
means propyl; "TES" means triethylsilyl; "TMS" means
trimethylsilyl; "TPAP" means tet~:apropylammonium
perruthenate; "DMAP" means p-dimethylamino pyridine;
"DMF" means dimethylformamide; "LDA" means lithium
diisopropylamide; "LHMDS" means Lithium hexamethyl-
disilazide; "LAH" means lithium aluminum hydride; "Red-
Al" means sodium bis(2-methoxyethoxy) aluminum hydride;
"AIBN" means azo-(bis)-isobutyronitrile; "10-DAB" means
10-desacetylbaccatin III; FAR means 2-chloro-1,1,2-
trifluorotriethylamine; protected hydroxy means -OR
wherein R is a hydroxy protecting group; sulfhydryl
protecting group" includes, but is not limited to,
hemithioacetals such as 1-ethoxyethyl and methoxymethyl,
thioesters, or thiocarbonates; "amine protecting group"
includes, but is not limited to, carbamates, for example,
2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and
"hydroxy protecting group" includes, but is not limited
to, ethers such as methyl, t-butyl, benzyl, p-methoxy-
benzyl, p-nitrobenzyl, allyl, tri:tyl, methoxymethyl, 2-
methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetra-

WO 94/20088 ~ PCTIUS94102210
~690~
.. ~,'~
6
hydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl
ethers such as trimethylsilyl ether, triethylsilyl ether,
dimethylarylsilyl ether, triisopropylsilyl ether and
t-butyldimethylsilyl ether; esters such as benzoyl,
acetyl, phenylacetyl, form~~~,~ mono-, di-, and trihalo-
acetyl such as chloroacetyl~, dichloroacetyl, trichloro-
acetyl, trifluoroacetyl; and carbonates including but not
limited to alkyl carbonates having from one to six carbon
atoms such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl
carbonates having from one to six carbon atoms and
substituted with one or more halogen atoms such as
2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl;
alkenyl carbonates having from two to six carbon atoms
such as vinyl and allyl; cycloalkyl carbonates having
from three to six carbon atoms such as cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or
benzyl carbonates optionally substituted on the ring with
one or more C1_6 alkoxy, or nitro. Other hydroxyl,
sulfhydryl and amine protecting groups may be found in
"Protective Groups in Organic Synthesis" by T. W. Greene,
John Wiley and Sons, 1981.
The alkyl groups described herein, either alone
or with the various substituents defined herein are
preferably lower alkyl containing from one to six carbon
atoms in the principal chain and up to 15 carbon atoms.
They may be substituted, straight, branched chain or
cyclic and include methyl, ethyl, propyl, isopropyl,
butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and
the like.
The alkenyl groups described herein, either
alone or with the various substituents defined herein are
preferably lower alkenyl containing from two to six
carbon atoms in the principal chain and up to 15 carbon
atoms. They may be substituted, straight or branched

PCTlUS94/02210
WO 94120088
7
chain and include ethenyl, propenyl, isopropenyl,
butenyl, isobutenyl, hexenyl, and the like.
The alkynyl groups described herein, either
alone or with the various substituents defined herein are
preferably lower alkynyl containing from two to six
carbon atoms in the principal chain and up to 15 carbon
atoms. They may be substituted, straight or branched
chain and include ethynyl, propy:nyl, butynyl, isobutynyl,
hexynyl, and the like.
The aryl moieties described herein, either
alone or with various substituents, contain from 6 to 15
carbon atoms and include phenyl. Substituents include
alkanoxy, protected hydroxy, halogen, alkyl, aryl,
alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl
is the more preferred aryl.
The heteroaryl moietiea described herein,
either alone or with various subatituents, contain from 5
to 15 atoms and include, furyl, t:hienyl, pyridyl and the
like. Substituents include alkanoxy, protected hydroxy,
halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro,
amino, and amido.
The acyloxy groups described herein contain
alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
The substituents of the substituted alkyl,
alkenyl, alkynyl, aryl, and heteroaryl groups and
moieties described herein, may be alkyl, alkenyl,
alkynyl, aryl, heteroaryl and/or may contain nitrogen,
oxygen, sulfur, halogens and inc7.ude, for example, lower
alkoxy such as methoxy, ethoxy, butoxy, halogen such as
chloro or fluoro, nitro, amino, and keto.
In accordance with the present invention, it
has been discovered that compounds corresponding to
structural formula 3 show remarkable properties, _in
vitro, and are valuable antileuke~mia and antitumor
agents. Their biological activity has been determined _in
vitro, using tubulin assays according to the method of

WO 94/20088 ~ PCTIUS94102210
8
Parness et al., J. Cell Biolocty, 91: 479-487 (1981) and
human cancer cell lines, and is comparable to that
exhibited by taxol and taxotere.
In a preferred embodimerr~ cf the present
invention, the taxane has a s~;ri~,eture corresponding to
taxol or taxotere except fog=:the C9 substituents, R9,
which is hydrogen and R9a, which is hydrogen, hydroxy, or
acyloxy (such as acetoxy). That is, RZa is hydrogen, RZ
is benzoyloxy, R14 and Rl4a are hydrogen, Rlo is hydrogen,
Rloa is hydroxy or acetoxy, R7 is hydrogen, Rya is hydroxy,
RS is hydrogen, Rsa and R4 and the carbons to which they
are attached form an oxetane ring, R4a is acetoxy, R1 is
hydroxy, X1 is -OH, XZ is hydrogen, X3 is phenyl, X4 is
hydrogen, XS is -COXlo, Xlo is phenyl or t-butoxy and the
taxane has the 2'R, 3'S configuration.
In other embodiments of the present invention,
the taxane has a structure which differs from that of
taxol or taxotere with respect to the C9 substituent and
at least one other substituent. For example, R2 may be
hydroxy or -OCOR31 wherein R31 is hydrogen, alkyl or
selected from the group comprising
z
z z z
s o 0 0
. . ~Z , and
and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoro-
methyl. RQa may be hydroxy or acyloxy (other than
acetoxy) Rya may be hydrogen and R~ may be acetoxy or
other acyloxy or halogen, Rloa and Rlo may each be hydrogen
or together form an oxo; X3 may be selected from
isobutenyl, isopropyl, cyclopropyl, n-butyl, t-butyl,
cyclobutyl, cyclohexyl, furyl, thienyl, pyridyl or the
substituted derivatives thereof, XS may be -COXIo or
-COOXlo and Xlo may be selected from furyl, thienyl, alkyl

WO 94/20088 ~ PCTIUS94102210
9
substituted furyl or thienyl, pyridyl, tert-, iso- or n-
butyl, ethyl, iso- or n-propyl, cyclopropyl, cyclohexyl,
allyl, crotyl, ~1;3-diethoxy-2-propyl, 2-methoxyethyl,
amyl, neopentyl, RYiCH20-, -NPh2, -NHnPr, -NHPh, and -NHEt .
Taxanes having the genesral formula 3 may be
obtained by reacting a i3-lactam with alkoxides having the
taxane tricyclic or tetracyclic nucleus and a C-13
metallic oxide substituent to form compounds having a
i3-amido ester substituent at C-13. The i3-lactams have
the following structural formula:;
X5\N ~0
~ z
~ 3
X4 X1
X3 X2
wherein X1 - XS are as defined above.
The i3-lactams can be prepared from readily
available materials, as is illustrated in schemes A and B
below:
Scheme A
0 CH30
0~ X4 /N / _ a
CI
+ '' 0
X3
OCH3 N
X 4 iiii
X OAc
3
b
X 0 H 0 H 0
5\N /~ a 'N /~ cd \N
----
X4 1 XQ -~C 1 X4
BOAC
3 X2 3 X2 3

WO 94!20088 PCTIUS94102210
Scheme B
0 X'1 OLi
f
1
0 E t --r X ~.O~E t
X2
H 0
vN ~~
X4 X1
N-TMS
X3X4C0 ~ X3~~ X3 X2
IX~ a
Xg 0
\N
X4 1
X3 X2
reagents: (a) triethylamine, CHzCl2, 25oC, 18h; (b) 4
equiv ceric ammonium nitrate, CH3CN, -10~C, 10 min; (c)
5 KOH, THF, H20, O~C, 30 min, or pyrolidine, pyridine, 25
°C, 3h, (d) TESC1, pyridine, 25 °C, 30 min or 2-
methoxypropene toluene sulfonic acid (cat.), THF, OaC,
2h; (e) n-butyllithium, THF, -78 °C, 30 min; and an acyl
chloride or chloroformate (XS = -COXIO)., sulfonyl chloride
10 (XS = -COSXlo) or isocyanate (XS = -CONXaXlo) ; ( f ) lithium
diisopropyl amide, THF -78aC to -50oC; (g) lithium hexa-
methyldisilazide, THF -78oC to O~C; (h) THF, -78oC to
25~C, 12h.
The starting materials are readily available.
In scheme A, oc-acetoxy acetyl chloride is prepared from
glycolic acid, and, in the presence of a tertiary amine,
it cyclocondenses with imines prepared from aldehydes and
p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-
arylazetidin-2-ones. The p-methoxyphenyl group can be
readily removed through oxidation with ceric ammonium
nitrate, and the acyloxy group can be hydrolyzed under

WO 94/20088 ~ 21 ~ 6 9 O g pCT/US94/02210
11
standard conditions familiar to those experienced in the
art to provide 3-hydroxy-4-arylazetidin-2-ones. In
Scheme B, ethyl-oc-triethylsilyloxyacetate is readily
prepared from glycolic acid.
In Schemes A and B, X1 is preferably -OX6 and X6
is a hydroxy protecting group. Protecting groups such as
2-methoxypropyl ("MOP"), 1-ethoxyethyl ("EE") are
preferred, but a variety of other standard protecting
groups such as the triethylsilyl group or other trialkyl
(or aryl) silyl groups may be used. As noted above,
additional hydroxy protecting groups and the synthesis
thereof may be found in "Protective groups in Organic
Synthesis" by T.W. Greene, John Wiley & Sons, 1981.
The racemic i3-lactams :may be resolved into the
pure enantiomers prior to protection by reczystallization
of the corresponding 2-methoxy-2-(trifluoromethyl)
phenylacetic esters. However, the reaction described
hereinbelow in which the i3-amido ester side chain is
attached has the advantage of being highly diastereo-
selective, thus permitting the use of a racemic mixture
of side chain precursor.
The alkoxides having t:he tricyclic or tetra-
cyclic taxane nucleus and a C-13 metallic oxide or
ammonium oxide substituent have the following structural
formula:
R~~s
~e R~o~R9
Rsa R~
~z ~o
s ~s
MOIIIII ~~ '~ ~R~a
R
s
R 14 z 3 , ~s~R s a
R~ ~, ~RSa
Rpa ~R4a R5
R~4a Rz R4

WO 94120088 ~ PCTIUS94/02210
21569Q$
12
wherein R1 - RIQa are as previously defined and M
comprises ammonium or is a metal optionally selected from
the group comprisir_g Group IA, Group IIA and transition
metals, and prefer~biy, Li, Mg, Na, K or Ti. Most
preferably, the alkoxide has the tetracyclic taxane
nucleus and corresponds to the structural formula:
R ~ n a R "
p
MOIIiII Rya
~r a
wherein M, R2, R4a, R~, Rya, R9, R9a, R10, and Rloa are as
previously defined.
The alkoxides can be prepared by reacting an
alcohol having the taxane nucleus and a C-13 hydroxyl
group with an organometallic compound in a suitable
solvent. Most preferably, the alcohol is a protected
baccatin III, in particular, 7-O-triethylsilyl baccatin
III (which can be obtained as described by Greene, et al.
in JACS 110: 5917 (1988) or by other routes) or 7,10-bis-
O-triethylsilyl baccatin III.
As reported in Greene et al., 10-deacetyl
baccatin III is converted to 7-0-triethylsilyl-10-
deacetyl baccatin III according to the following reaction
scheme:

WO 94/20088 ~ PCTIUS94102210
21~s9o$
13
OH
~0 OH
CH3 10 ~H3
- CH3 7
H 0 -- 13
'CH3~
H . 0
OH ~ '
OCOCH3
OCOC6H5
1 . ~ C2H5] ,3S i C I , CSHSN
2. CH3COC1, CSHSN
OR
CH /~ 0S i ~ C2H5] 3
3
~H3
_ CH3 .7
H 0 -- 13
CH3~ ~a
~0
H
OH ~ OCOCH3
OCOC6H5
(4) a, R=:H
b, R=:COCH3
Under what is reported to be carefully optimized
5 conditions, 10-deacetyl baccatin III is reacted with 20
equivalents of (CZHS) 3SiC1 at 23oC under an argon
atmosphere for 20 hours in the presence of 50 ml of
pyridine/mmol of 10-deacetyl bac;catin III to provide
7-triethylsilyl-10-deacetyl bacc;atin III (4a) as a
10 reaction product in 84-86~ yield after purification. The
reaction product may then optionally be acetylated with 5
equivalents of CH3COCl and 25 mL of pyridine/mmol of 4a at
0 oC under an argon atmosphere f:or 48 hours to provide
86o yield of 7-0-triethylsilyl baccatin III (4b).
Greene, et al. in JACS 110, 5917 at 5918 (1988).
The 7-protected baccat:in III (4b) is reacted
with an organometallic compound such as LHNa7S in a
solvent such as tetrahydrofuran (THF), to form the metal

WO 94120088 ~ ~ ~ , PCTIUS94102210
X15 69
14
alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III as
shown in the following reaction scheme:
OR
CH3 r .0
- C~~CH3 OS t ~ CZHS] 3
LHMDS + HO---13
~~CH3 7
OH '
1 H ,
0
OCOCH3
OCOC6H5
THF
OR
CH3 0
1 CH ~CH3 OS t [ CzHS] 9
L i 0 --- 13
~CH~~
OH ;
H ,
OCOCH.,
OCOC6H5
As shown in the following reaction scheme,
13-0-lithium-7-O-triethylsilyl baccatin III reacts with a
i~-lactam in which X1 is preferably -OX6, (X6 being a
hydroxy protecting group) and XZ - XS are as previously
defined to provide an intermediate in which the C-7 and
C-2' hydroxyl groups are protected. The protecting
groups are then hydrolyzed under mild conditions so as
not to disturb the ester linkage or the taxane
substituents.

WO 94!20088 ~ - ~ PCTIUS94l02210
Ac0
0
- ' OTES
M OI I I I I ~// X 5\
N
HO _
PhC00
ACO 0 X3 X,4 XZ X1
~1] THF
~2] HF, Pyridine, CH3CN
Ac0
' 0
X4 X3 0
X5~ ~ - ~ OH
N OIIII~
//i/
H X1 X2
HO
PhC00
Ac
Both the conversion of the alcohol to the
alkoxide and the ultimate synthesis of the taxane
derivative can take place in the same reaction vessel.
5 Preferably, the i3-lactam is added to the reaction vessel
after formation therein of the alkoxide.
Compounds of formula 3 of the instant invention
are useful for inhibiting tumor growth in animals
including humans and are preferably administered in the
10 form of a pharmaceutical composition comprising an
effective antitumor amount of compound of the instant
invention in combination with a pharmaceutically
acceptable carrier or diluent.
Antitumor compositions herein may be made up in
15 any suitable form appropriate for desired use; e.g.,
oral, parenteral or topical administration. Examples of
parenteral administration are in.tramuscular, intravenous,
intraperitoneal, rectal and subcutaneous administration.

WO 94!20088 2,~~ PCT/US94102210
16
The diluent or carrier ingredients should not
be such as to diminish the the~~~~eutic effects of the
antitumor compounds.
Suitable dosage forms for oral use include
tablets, dispersible powders, granules, capsules,
suspensions, syrups, and elixirs. Inert diluents and
carriers for tablets include, for example, calcium
carbonate, sodium carbonate, lactose and talc. Tablets
may also contain granulating and disintegrating agents
such as starch and alginic acid, binding agents such as
starch, gelatin and acacia, and lubricating agents such
as magnesium stearate, stearic acid and talc. Tablets
may be uncoated or may be coated by unknown techniques;
e.g., to delay disintegration and absorption. Inert
diluents and carriers which may be used in capsules
include, for example, calcium carbonate, calcium
phosphate and kaolin. Suspensions, syrups and elixirs
may contain conventional excipients, for example, methyl
cellulose, tragacanth, sodium alginate; wetting agents,
such as lecithin and polyoxyethylene stearate; and
preservatives, e.g., ethyl- p-hydroxybenzoate.
Dosage forms suitable for parenteral adminis-
tration include solutions, suspensions, dispersions,
emulsions and the like. They may also be manufactured in
the form of sterile solid compositions which can be
dissolved or suspended in sterile injectable medium
immediately before use. They may contain suspending or
dispersing agents known in the art.
The water solubility of compounds of formula
t3) may be improved by modification of the C2' and/or C7
substituents. For instance, water solubility may be
increased if X1 is -OX6 and Rya is -ORze, and X6 and R28 are
independently hydrogen or -COGCOR1 wherein:
G is ethylene, propylene, -CH=CH-, 1,2-cyclo-
hexylene, or 1,2-phenylene;
Ri - OH base, NRZR3, OR3, SR3, OCH-,CONR4R', or OH;

CA 02156908 2001-02-13
64725-651
17
Rz - hydrogen, methyl
R3 - ( CHZ ) nNR6R.~ ~ ( CHz ) nN~R6R~R8Xo
n = 1 to 3
R4 - hydrogen, lower alkyl containing 1 to 4 carbons
RS - hydrogen, lower alkyl containing 1 to 4 carbons,
benzy, hydroxyethyl, CHzCO2H, dimethylaminoethyl
R6R' - lower a:Lkyl containing 1 or 2 carbons, benzyl
or R6 and
R' '~~Gether with the nitrogen atom c' NR6R' form the
f v ~~ving rinds
U C~
C~
C~
g N
"ri3
k~ - lower alkyl containing :L or 2 .~-Nuns, benzyl
1=, X° - halide
base = NH3 , ( FiOC2H4 ) 3N , N ( CH3 ) 3 , CH3N ( CZH40H ) z ,
NHz (CHz) 6NHz, N-methylglucamine, NaOH, KOH.
The preparation of compounds in which X1 or Xz is
-COGCOR is set forth in Haugwitz U.S. Patent 4,942,184.

CA 02156908 2001-02-13
64725-651
17a
Alternatively, solubility may be increased when X1 is
-OX6 and X6 is a radical having the formula -COCX=CHX or
-COX-CHX-CHX-S020-M wherein X is hydrogen, alkyl or aryl and M
is hydrogen, alkaline metal or an ammonio group as described in
Kingston et al., U.S. Patent No. 5,059,699.
Taxanes having alternative C9 substituents may be
prepared by selectively reducing the C9 keto

PCTlUS94102210
WO 94120088
18
substituent to yield the corresponding C9 (3-hydroxy
derivative. The reducing agent is preferably a
borohydride and, most preferably; tetrabutylammonium-
borohydride (Bu4NBH4) or Lriac'etoxyborohydride.
As illustrated iri Reaction Scheme 1, the
reaction of baccatin III with Bu4NBH4 in methylene
chloride yields 9-desoxo-9(3-hydroxybaccatin III 5. After
the C7 hydroxy group is protected with the triethylsilyl
protecting group, for example, a suitable side chain may
be attached to 7-protected-9i3-hydroxy derivative 6 as
elsewhere described herein. Removal of the remaining
protecting groups thus yields 9i3-hydroxy-desoxo taxol or
other 9(3-hydroxytetracylic taxane having a C13 side
chain.

WO 94/20088 ' .: PCT/US94/02210
19
REACTION SCHEME 1
OAc OAc
0 OH
OH - OH
HO~i~~ HOIi~~~
'~i 6u4N8H4 ~~i
HO CH2C12 HO
.; ' '
Ph~o c0~' '0 Ph~O c0~~'' 'O
0
TESCI
ET3N
OAc
OH
- OTES
HOW ~~
~i
HO
Ph~ Ac0 0
\\0
6
Alternatively; the C13 hydroxy group of 7-
protected-9(3-hydroxy derivative 6~ may be protected with
trimethylsilyl or other protecting group which can be
selectively removed relative to t:he C7 hydroxy protecting
group as illustrated in Reaction Scheme 2, to enable
further selective manipulation of: the various
substituents of the taxane. For example, reaction of
7,13-protected-9(3-hydroxy derivative 7 with KH causes the
acetate group to migrate from C1C) to C9 and the hydroxy
group to migrate from C9 to C10, thereby yielding 10-
desacetyl derivative 8. Protection of the C10 hydroxy
group of 10-desacetyl derivative 8 with triethylsilyl
yields derivative 9. Selective removal of the C13

WO 94/20088 ~ PCTIUS94102210
- 20
hydroxy protecting group from derivative 9 yields
derivative 10 to which a suitable side chain may be
attached as described abov:~:

WO 94/20088 - PCTIUS94/02210
_ 21~~690~3
REACTION SCHEME 2
OAC OAC
OH OH
- OTES - OTES
HOm~~ TMSO1~~
'~i '~i
1] TMSCI, Et3N
_ ~ _ _ /
0 ~~~ 0 ~~~~'-~~
PhH AcO~\~0 PhH Ac0~~~0
~0 ~0
6 7
2] KH
OTES OH
OAC OAc
- OTES - OTES
TMSOIi~~~ TMSOIi~~~
TESCI
O ~~~ E T N 0 .~~
phH ACO~\~0 3 PhH Ac0~~0
~0 ~0
g 8
HF
pyridine
OTES
OAC
/-\ - T I OTES
HOIi~
H
0 \~~~
P h A c 0 1--- 0
~0
As shown in Reaction Scheme 3, 10-oxo
derivative 11 can be provided by oxidation of 10-

WO 94120088 2 ~,~ PCTIUS94I02210
22
desacetyl derivative 8. Thereafter, the C13 hydroxy
protecting group can be se~~e~tively removed followed by
attachment of a side chain as described above to yield 9-
acetox_y-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic
taxanes having a C13 side chain. Alternatively, the C9
acetate group can be selectively removed by reduction of
10-oxo derivative 11 with a reducing agent such as
samarium diiodide to yield 9-desoxo-10-oxo derivative 12
from which the C13 hydroxy protecting group can be
selectively removed followed by attachment of a side
chain as described above to yield 9-desoxo-10-oxo-taxol
or other 9-desoxo-10-oxotetracylic taxanes having a C13
side chain.
REACTION SCHEME 3
OH
\ ~ OAc
- OTES
TMS011~~~ - OTES
TPAP TMSOI~~~~
....~i
H
H __
ph~ Ac0 0 ~0
p h---r( A c 0 0
~~0
5mI2
0
TES
TMSOW ~~
HQ
0
Ph~ Ac0
~~0
is
Reaction Scheme 4 illustrates a reaction in
which 10-DAB is reduced to yield pentaol 13. The C7 and

WO 94/20088 ~ PCTlUS94102210
23
C10 hydroxyl groups of pentaol 13 can then be selectively
protected with the triethylsilyl or another protecting
group to produce triol 14 to which a C13 side chain can
be attached as described above or, alternativ~:ly, after
further modification of the tetracylic substituents.
REACTION SCHEME 4
OH OH
H
H /-\ ~~( ~ OH
HOIm~( ~ V / HCllm~
Bu4NBH4 W
H CH2C12 H
p' ~~. p
ph~ Ac0 0 Ph~ ACO
\\0 \\0
TESCI
ET3N
OTES
\ 1 off
HCIW ~~
-\ ~~( / OTES
Hd
0
Ph~ ACO
'1 4
Taxanes having C9 and/or C10 acyloxy
substituents other than acetate can be prepared using 10
DAB as a starting material as illustrated in Reaction
Scheme 5. Reaction of 10-DAB with triethylsilyl chloride
in pyridine yields 7-protected 10-DAB 15. The C10
hydroxy substituent of 7-protected 10-DAB 15 may then be
readily acylated with any standard acylating agent to
yield derivative 16 having a new C10 acyloxy substituent.
Selective reduction of the C9 ket.o substituent of

WO 94/20088 ~ PCTIUS94102210
.~~~,9~8
2
24
derivative 16 yields 9i3-hydroxy derivative 17 to which a
C13 side chain may be attac~laed. Alternatively, the C10
and C9 groups can be caused to migrate as set forth in
Reaction Scheme 2, above.
REACTION SCHEME 5
OH OH
1 .0 \ ~ 0
- ' OH - ' OTES
HOIIII i TESC I HOIIII
pyrtdtne
H 0 ~ H~ \\'~ H 0 ~ H~~\'
0 ~ 0
ph~ ACO 0 Ph~ ACO 0
\'0 '\0
Acylatlng
agent
OCOR29 OCOR29
~H ~ ~ 0
- OTES - OTES
HOIIII , 1] HF HOIIII
2] BugNBH4
H 0 o H~~'\\~~ 3 ] T E S C 1 H 0 ~ H ''\\~
ph~ Ac0 0 Ph~ Ac0 0
\\0 \\0
'I 7 'i 6
Taxanes having alternative C2 and/or C4 esters
can be prepared using baccatin III and 10-DAB as starting
materials. The C2 and/or C4 esters of baccatin III and
10-DAB can be selectively reduced to the corresponding
alcohol(s) using reducing agents such as LAH or Red-A1,
and new esters can thereafter be substituted using
standard acylating agents such as anhydrides and acid
chlorides in combination with an amine such as pyridine,
triethylamine, DMAP, or diisopropyl ethyl amine.
Alternatively, the C2 and/or C4 alcohols may be converted

W0 94/20088 ~ ~ PCTIUS94I02210
to new C2 and/or C4 esters through formation of the
corresponding alkoxide by treatment of the alcohol with a
suitable base such as LDA followed by an acylating agent
such as an acid chloride.
5 Baccatin III and 10-DAB analogs having
different substituents at C2 and/or C4 can be prepared as
set forth in Reaction Schemes 6-10. To simplify the
description, 10-DAB is used as th.e starting material. It
should be understood, however, that baccatin III
10 derivatives or analogs may be produced using the same
series of reactions (except for the protection of the C10
hydroxy group) by simply replacing 10-DAB with baccatin
III as the starting material. Derivatives of the
baccatin III and 10-DAB analogs having different
15 substituents at C9 and at least one other position, for
instance C1, C2, C4, C7, C10 and C13, can then be
prepared by carrying out any of the other reactions
described herein and any others which are within the
level of skill in the art.
20 In Reaction Scheme 6, protected 10-DAB 3 is
converted to the triol 18 with lithium aluminum hydride.
Triol 18 is then converted to the corresponding C4 ester
using C12C0 in pyridine followed by a nucleophilic agent
(e. g., Grignard reagents or alkyllithium reagents).

WO 94!20088 PCTIUS94102210
26
Scheme 6
OTES
0 OTES
- 0
OTES - ~ OTES
TMS01111 ii,~~ LAH TMSOIIIII
H 0 = Lj
HO
Ph~ ACO~ 0 HO ~~ '
H 0 '0
8 'I 8
cizco
pyrtdine
OTES OTES
0 0
- ~ OTES - ~ OTES
TMS01111 , TMSOIIII
~~ii R3~Lt or
HO __ ~ R31Mg8r 0
0 H v ~0 v
~ H0~\~0 HO 0
R 3 1 \'
2 0 'i g
Deprotonation of trio! 18 with LDA followed by
introduction of an acid chloride selectively gives the C4
ester. For example, when acetyl chloride was used, trio!
18 was converted to 1,2 diol 4 as set forth in Reaction
Scheme 7.
Trio! 18 can also readily be converted to the
1,2 carbonate 19. Acetylation of carbonate 19 under
vigorous standard conditions provides carbonate 21 as
described in Reaction Scheme 8; addition of alkyllithiums
or Grignard reagents to carbonate 19 provides the C2
ester having a free hydroxyl group at C4 as set forth in
Reaction Scheme 6.

WO 94!20088 ~ PCTIUS94/02210
~15690~8
27
Scheme 7
OTES
_ p OTES
- ~ OTES LDA 0
TMSOI1111 - ~ OTES
' i,~~ R3~COC I TMSOIIII ,
iii
HO
H~ H'y HO s H
~~\~0 H 0
HO R3oC00~ ,0
'1 8 4
Scheme 8
OTES
0 OTES
0
OTES CI CO
TMSOIIIII 2 - ~ OTES
Pyridine TMS01111
iii
i
HO
H0 H~w~ 0 = H
HO 0 ~~ Ow
8 0~ H o~ o
'i 9
AC20
OMAP
OTES
0
OTES
TMSOIIII
i,
0
0 H w
O/ AcO~ 0
2 'I
As set forth in Reaction Scheme 9, other C4
substituents can be provided by rE=acting carbonate 19
with an acid chloride and a tertiary amine to yield
carbonate 22 which is then reacted with alkyllithiums or

WO 94/20088 5 ~ ' PCTIUS94102210
28
Grignard reagents to provide 10-DAB derivatives having
new substituents at C2.
Scheme ~a
OTES OTES
v 1 ,,° \ . 0
- ~ OTES CIZCO - ~ ~ OTES
TMS011111 ,~~ pyr i d i ne TMSOIIII
~~~i~
H0 ~
H 0 H 0\~~~~0 0 H y\
H0 0
0
R30COC1
pyridine
DMAP
OTES OTES
i~ \ ~ 0
- i OTES - ~~ OTES
TMSOIIIII ~~~ R L t or TMS01111
ii 3 ~ iii
r
HO = H ' R3~MgBr 0
R3~C00 'w Q H
R C00 ~0
30 ~~oC00
0
22
Alternatively, baccatin III may be used as a
starting material and reacted as shown in Reaction Scheme
10. After being protected at C7 and C13, baccatin III is
reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol
24 is converted to carbonate 25 using C12C0 and pyridine,
and carbonate 25 is acylated at C10 with an acid chloride
and pyridine to produce carbonate 26 (as shown) or with
acetic anhydride and pyridine (not shown). Acetylation
of carbonate 26 under vigorous standard conditions
provides carbonate 27 which is then reacted with alkyl
lithiums to provide the baccatin III derivatives having
new substituents at C2 and C10.

j ';. I
WO 94120088 ~ PCTIUS94102210
~~.~69~~~
29
Scheme 10
OAc OAC
0 ' 0
_ ~ OH
OTES
HOIIII TMSOIII11
1] TESCI, PY
HO = H ~~ 2] TMSCI, OMAP HO = _
ph~0AC0~''' 0 I m i dazo I e, OMF Ph ACO~''\ 0
~0
LAH
OH
0 OH
0
OTES
TMSOIIII _~ C I zC0 - ~ OTES
~~i, pyr t d i ne TMSOIItI
viiii
0
~ H''\~ HO _=
H0~ ~~0 HO H w
0 H 0~ 0
2 S 24
R29COC I
pyrtdtne

CA 02156908 2001-02-13
64725-651
ocoaz9 cc~a~a
1 0 \ 1 ,
OZ'ES
TMSOIIII i~~~\~~ pMAP TMSOIIIIC ~ _~~°TES
~ ~_.- ~ 0 _.. s
-H'~ Hy
5 ~0 H0~ 0 ~~ ACO~\
° 27
° 26
R3~Li
10 OCORzg
o
TMSOIIII
-\ _ ~Y I OTES
HO
° H W~~ -,
15 R3~'~ Ac0
0
10-desacetoxy derivatives of baccatin III and
10-desoxy derivatives oi= 10-DAB may be prepared by reacting
baccatin III or 10-DAB (or their derivatives) with samarium
2C diiodide. Reaction between the tetracyclic taxane having C10
leaving group and samarium diiodide may be carried out at 0°C in
a solvent such as tetralz:ydrofuran. Advantageously, the
samarium diiodide selectively abstracts the C10 leaving group;
C13 side chains and oths=_r substituents on the tetracyclic
25 nucleus remain undisturbed. Thereafter, the C9 keto
substituent may be reduced to provide the corresponding
9-desoxo-9(3-hydroxy-10-desacetyoxy or 10-desoxy derivatives as
otherwise described herein.
C7 dihydro and other C7 substituted taxanes can be
30 prepared as set forth in Reaction Schemes 11, 12 and 12a.

WO 94/20088 ~ PCTIUS94102210
31
REACTION SCHEME 11
OAc OAc
0 0 S
~ ~ C
- 0H - O
H01111 NaH HOIIII "SCH3
~ ~
CS2
HO ~ H HO
CH31
~
0 ~ 0 H ~~~
Ph~ ~~ Ph~ Ac0 0
Ac0
~~0 ~~0
nBu3SnH
AIBN at]
[c
toluene (reflux]
OAC
a ~ _0
HOII11
iii
HO
0
Ph~ Ac0
'\0

WO 94J20088 ~ PCTIUS94J02210
X69
~1
32
REACTION SCHEME 12
OAc OAc
0 0
- ~ OH - ~ F
HOIi~~~ HOI~~~~
FAR '~i
H _ H
/0 ~~~ 0
Ph~ Ac0 0 Ph~ Ac0 0
\\0 \\0
OAc OAc
0 0
- ~ OH - ~ CI
HOIi~~~ H01~~~~
MsC I
Et3N
H = Et3NHCl H
0 ~~~ 0
Ph~ Ac0 0 Ph~ AcO~
\\0 \\0

PCT/US94I02210
WO 94/20088 ~ _ 215 6 9 Q
33
REACTION SCHEME 12a
a o
OAC OAC
- OTES - OTES
TMSOIIIII //~/ HF, pY HOIIIII
HO = \~ HO
0 \~~~ 0
ph~ Ac0 0 Ph~ Ac0
0 1 1 \\0
LHMOS
0
OAC
OTES X5~
L i O I I I I I ,~~ N
ii
HO
0 w X3 X4 X2 X1
Ph~ AcO~ 0
[ 1J THF
[2~ HF, Pyr id i ne, CH3CN
OH
X4 X3 0 0
X5~ I - ~ OAC
N ~ 01111 //
////
H X1 X2
HO ~
PhC00
A C O ~~..--0
As shown in Reaction Scheme 12, Baccatin III
may be converted into 7-fluoro baccatin III by treatment
with FAR at room temperature in THF solution. Other
baccatin derivatives with a free C7 hydroxyl group behave
similarly. Alternatively, 7-chloro baccatin III can be
prepared by treatment of baccatin III with methane
sulfonyl chloride and triethylamine in methylene chloride
solution containing an excess of triethylamine hydro-
chloride.

WO 94/20088 . PCTIUS94102210
34
Taxanes having C7 ac~loxy substituents can be
prepared as set forth in F~-e'~ction Scheme 12a, 7,13-
protected 1U-oxo-derivative 11 is converted to its
corresponding C13 alkoxide by selectively removing the
Cl3 protecting group and replacing it with a metal such
as lithium. The alkoxide is then reacted with a ~i-lactam
or other side chain precursor. Subsequent hydrolysis of
the C7 protecting groups causes a migration of the C7
hydroxy substituent to C10, migration of the C10 oxo
substituent to C9, and migration of the C9 acyloxy
substituent to C7.
A wide variety of tricyclic taxanes are
naturally occurring, and through manipulations analogous
to those described herein, an appropriate side chain can
be attached to the C13 oxygen of these substances.
Alternatively, as shown in Reaction Scheme 13, 7-O-
triethylsilyl baccatin III can be converted to a
tricyclic taxane through the action of trimethyloxonium
tetrafluoroborate in methylene chloride solution. The
product diol then reacts with lead tetraacetate to
provide the corresponding C4 ketone.

PCT/US94102210
WO 94/20088 . _ ~ I ~ ~ 9 0 g
REACTION SCHEME 13
OAC OAc
0 0
- ~ OTES - ~ OTES
HOl ,. ~~ Me308F4 HOl ,.
Hd _ ~ Hd __
Ph~ AcO~~', O ph~0 HO~'' /'~OAc
~~0 ~~0 H O
Pb[OAc~4
OAc
\ ~ 0
-~ ~~ OTES
HOIi~~~ /
Hd __
0
0 OAc
\\0
Recently a hydroxylated taxane (14-hydroxy-10-
deacetylbaccatin III) has been discovered in an extract
5 of yew needles (C&EN, p 36-37, April 12, 1993).
Derivatives of this hydroxylated taxane having the
various C2, C4, etc. functional groups described above
may also be prepared by using this hydroxylated taxane.
In addition, the C14 hydroxy group together with the C1
10 hydroxy group of 10-DAB can be converted to a 1,2-
carbonate as described in C&EN or it may be converted to
a variety of esters or other functional groups as
otherwise described herein in connection with the C2, C4,
C9 and C10 substituents.
15 The following examples are provided to more
fully illustrate the invention.

WO 94120088 ~ PCT/LTS94102210
~.~~ 69 a~
36
EXAMPLE:'-.2
OH
0 Ph 0 OH
OH
~~~~ 0 i ~ i i
t B a 0 N _ i,~~
- i
H OH
HO = H
OAcO~\~0
P h~
~~0
(67-3 )
Preparation of 10-deacetyl-9-desoxo-9(3-hydroxy-N-
debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7,10-(bis)triethylsilyl-10-
deacetyl-9-desoxo-9~i-hydroxy baccatin III (95 mg, 0.123
mmol) in 1 mL of THF at -45 °C was added dropwise 0.250 mL
of a 0.98M solution of (TMS)2NLi in THF. After 1 h at
-45 °C, a solution of cis-1-(t-butoxycarbonyl)-3-triethyl-
silyloxy-4-phenylazetidin-2-one (137 mg, 0.37 mmol) in 1
mL of THF was added dropwise to the mixture. The
solution was gradually warmed to 0 °C during 6h before 1
mL of aqueous solution was added. The mixture was
partitioned between saturated aqueous NaHCO, and ethyl
acetate. Evaporation of the organic layer gave a residue
which was purified by flash chromatography to afford 127
mg of (2'R,3'S)-2',7,10-(tris)triethylsilyl-10-deacetyl-
9-desoxo-9~3-hydroxy-N-debenzoyl-N-(t-butoxycarbonyl)
taxol and 8 mg of the (2'S,3'R) isomer.
To a solution of 90 mg of the major compound
obtained from the previous reaction in 1.5 mL of
acetonitrile and 2 mL of pyridine at 0 °C was added 0.8 mL
of 48% aqueous HF. The mixture was stirred at 0 °C for 3
h, then at 2S °C for 24 h, and partitioned between
saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 71 mg of

,, WO 94!20088 21 ~ ~ 9 0 ~ PCTIUS94102210
37
material which was purified by flash chromatography to
give 58 mg (92~) of 10-deacetyl-9-desoxo-9(3-hydroxy-N-
debenzoyl-N-(t-butoxycarbonyl) taxol, which was
recrystallizeci rrom ethyl acetate/ether/hexane.
m.p. 160-161 °C; [a]"Na -18.75 ° (c 0.08 , CHC1,) .
1H NMR (CD,OD, 500 MHz) 8 8.10 (d, J = 7.0 Hz, 2H,
benzoate ortho), 7.61 (m, 1H, benzoate, para), 7.50 (m,
2H, benzoate, meta), 7.41 (d, J = 8.0 Hz, 2H, phenyl,
ortho), 7.36 (m, 2H, phenyl, meta), 7.28 (m, 1H, phenyl,
para) , 6.18 (m, 1H, H13 ) ; 6 .18 (d, J = 5 . 5 Hz, 1H, H2 (3) ,
5.18 (br s, 1H, H3'), 5.10 (d, J = 5.5 Hz, 1H, H10), 4.99
(d, J = 8.2 Hz, 1H, H5), 4.91 (d, J = 9.3 Hz, 1H, NH),
4.59 (br s, 1H, H2'), 4.51 (d, J = 5.5 Hz, 1H, H9),
4.22(d, J = 8.0 Hz, 1H, H2Oa), 4.16 (d, J = 8.0 Hz, 1H,
H20~i), 3.86 (dd, J = 9.5, 7.5 Hz, 1H, H7), 3.13 (d, J =
5.5 Hz, 1H, H3), 2.48 (m, 1H, H6a), 2.29 (m, 1H, Hl4a),
2.28 (s, 3H, 4Ac), 2.19 (m , 1H, H14~), 1.85 (ddd, J =
15.1, 9.6, 1.4 Hz, 1H, H6(3), 1.79 (s, 3H, Mel6), 1.78
(s, 3H, MelB), 1.61 (s, 3H, Mel9H), 1.42 (s, 9H, t-Bu),
1.29 (s, 3H, Mel7).

WO 94/20088 PCT/US94/02210
~~ 6~
38
EXi'~PLE 2
off
0 p OH
_ OH
t8u0~N _ Otitt
- ~~i
H OH
OAcO
0
(70-2)
Preparation of 3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-
N-(t-butoxycarbonyl)-9-desoxo-9~3-hydroxy-10-desacetyl
taxol.
To a solution of 7,10-(bis)-O-triethylsilyl-9-
desoxo-9(3-hydroxy-10-deacetyl baccatin (III) (70.0 mg,
0.09 mmol) in 1.0 mL of THF at -45°C was added dropwise
0.10 mL of a 0.98 M solution of LiN(SiMe3)2 in hexane.
After 0.5 h at -45 °C, a solution of cis-1-t-butoxy-
carbonyl-3-triethylsilyloxy-4-(2-thienyl)azetidin-2-one
(103.8 mg, 0.27 mmol) in 1.0 mL of THF was added dropwise
to the mixture. The solution was warmed to 0 °C and kept
at that temperature for 1 h before 1 mL of a 10o solution
of AcOH in THF was added. The mixture was partitioned
between saturated aqueous NaHCO, and 60/40 ethyl acetate/
hexane. Evaporation of the organic layer gave a residue
which was purified by filtration through silica gel to
give 97.4 mg of a mixture containing (2'R,3'S)-2',7,10-
(tris)-0-triethylsilyl-3'-desphenyl-3'-(2-thienyl)-N-
desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-
desacetyl taxol and a small amount of the (2'S,3'R)
Isomer.
To a solution of 97.4 mg (0.084 mmol) of the
mixture obtained from the previous reaction in 13.5 mL of
acetonitrile and 0.57 mL of pyridine at 0 °C was added

i;
~ms9os
WO 94120088 ~ PCTlUS94l02210
39
1.92 mL of 48o aqueous FiF. The mixture was stirred at 0
°C for 3 h, then at 25 °C for 13 h, and partitioned
between saturated aqueous sodium bicarbonate and ethyl
acetate. Evaporation of the ethyl acecate solution gave
69.4 mg of material which was purified by flash
chromatography to give 63.1 mg (89~) of 3'-desphenyl-
3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-
desoxo-9~3-hydroxy-10-desacetyl taxol, which was
recrystallized from methanol/water.
m.p.146-148°C; [a]=SNa -54.2° (c 0.0026, CHC1,) .
1H NMR (MeOH, 300 MHz) 8 8.11(d, J=7.1 Hz, 2H, benzoate
ortho), 7.61(m, 1H, benzoate para), 7.48(m, 2H, benzoate
meta), 7.25(dd, J=5.4, 1.2 Hz, 1H, thienyl), 7.14(d,
J=3.3 Hz, 1H, thienyl), 7.03(dd, J=5.4, 3.9 Hz, 1H,
thienyl), 6.18(m, 1H, H13), 6.18(d, J=5.5 Hz, 1H, H2),
5.23(br s, 1H, H3'), 5.07(d, J=5.5 Hz, 1H, H10), 4.97(d,
J=8.1 Hz, 1H, H5), 4.84(d, J=9.3 hz, 1H, NH), 4.52(br s,
1H, H2'), 4.50(d, J=5.5 Hz, 1H, H9), 4.23(d, J=8.1, 1H,
H20a), 4.16(d, J=8.1 Hz, 1H, H20(3), 3.92(dd, J=9.4, 7.5
Hz, 1H, H7), 3.13(d, J=5.5 Hz, H3), 2.47(m, 1H, H6a),
2.26(m, 1H, Hl4a), 2.27(s, 3H, 4Ac), 2:16(m, 1H, H14(3),
1.84(ddd, J=15.1, 9.4, 1.2 Hz, H6~i), 1.79(s, 3H, Mel6),
1.76(s, 3H, Mel8), 1.62(s, 3H, Mel9) 1.39(s, 9H, 3Me
t-butoxy), 1.27(s, 3H, Mel7).

WO 94/20088 ' PCTlUS94102210
EXAMPLE ~.'3
0H
0 0 OH
OH
tBuO N Oltil
iii
H OH
H0 ~ H
OACO\~0
Ph
0
(70-3)
Preparation of 3'-desphenyl-3'-(2-furyl)-N-desbenzoyl-
5 N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl
taxol.
To a solution of 7,10-(bis)-O-triethylsilyl-9-
desoxo-9~i-hydroxy-10-deacetyl baccatin (III) (70.0 mg,
0.09 mmol) in 1.0 mL of THF at -45 °C was added dropwise
10 0.10 mL of a 0.98 M solution of LiN(SiMe3)~ in hexane.
After 0.5 h at -45 °C, a solution of cis-1-t-butoxy-
carbonyl-3-triethylsilyloxy-4-(2-furyl)azetidin-2-one
(99.5 mg, 0.27 mmol) in 1.0 mL of THF was added dropwise
to the mixture. The solution was warmed to 0 °C and kept
15 at that temperature for 1 h before 1 mL of a 10% solution
of AcOH in THF was added. The mixture was partitioned
between saturated aqueous NaHCO, and 60/40 ethyl acetate/
hexane. Evaporation of the organic layer gave a residue
which was purified by filtration through silica gel to
20 give 94.3 mg of a mixture containing (2'R,3'S)-
2',7,10-(tris)-0-triethylsilyl-3'-desphenyl-3'-(2-furyl)-
N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-
10-desacetyl taxol and a small amount of the (2'S,3'R)
isomer.
25 To a solution of 94.3 mg (0.082 mmol) of the
mixture obtained from the previous reaction in 13.5 mL of
acetonitrile and 0.57 mL of pyridine at 0 °C was added

PCTlUS94102210
WO 94!20088
41
1.92 mL of 48~ aqueous HF. The mixture was stirred at 0
°C for 3 h, then at 25 °C for 13 h, and partitioned
between saturated aqueous sodium bicarbonate and ethyl
acetate. Evaporation of the ethyl acetate solution gave
72.3 mg of material which was purified by flash
chromatography to give 59.1 mg (89~) of 3'-desphenyl-3'-
(2-furyl)-N-desbenzoyl-N-Et-butoxycarbonyl)-9-desoxo-
9~3-hydroxy-10-desacetyl taxol, which was reczystallized
from methanol/water.
m.p.144-146°C; [a]=SNa -54.0° (c 0.0028, CHC1,) .
1H NMR (MeOH, 300 MHz) 8 8.10(d, J=7.1 Hz, 2H, benzoate
ortho), 7.60(m, 1H, benzoate para), 7.51(m, 2H, benzoate
meta) , 7 . 40 (m, 1H, fury! ) , 6 .37 (m, 1H, fury! ) , 6 . 34 (m,
1H, fury!), 6.17(m, 1H, H13), 6.16(d, J=5.4 Hz, 1H,
H2), 5.24(br s., 1H, H3'), 5.11(d, J=5.5 Hz, 1H, H10),
4.86(d, J=8.1 Hz, 1H, H5), 4.83(d, J=9.3 hz, 1H, NH),
4.50(d, J=5.5 Hz, 1H, H9), 4.45(br s, 1H, H2'), 4.21(d,
J=8.1, 1H, H20a), 4.13(d, J=8.1 Hz, 1H, H20(3), 3.92(dd,
J=9.4, 7.5 Hz, 1H, H7), 3.11(d, J=5.5 Hz, H3), 2.46(m, 1H,
H6oc) , 2 .24 (m, 1H, Hl4oc) , 2 .21 (s, 3H, 4Ac) , 2 .15 (m, 1H,
H14(3) , 1.79 (ddd, J=15.1, 9.4, 1.2 Hz, H6(3) , 1.77 (s, 3H,
Mel6), 1.73(s, 3H, Mel8), 1.61(s, 3H, Mel9), 1.37(s, 9H,
3Me t-buthoxy), 1.26(s, 3H, Mel7).

WO 94120088 ~ PCTIUS94102210
~~~ ~90~
42
EXAMPLE.4
OH
p \ p OH
off
taao i = o....
H OH _
(70-4)
Preparation of 3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-
N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl
taxol.
To a solution of 7,10-(bis)-O-triethylsilyl-9-
desoxo-9(3-hydroxy-10-deacetyl baccatin (III) (70.0 mg,
0.09 mmol) in 1.0 mL of THF at -45 °C was added dropwise
0.10 mL of a 0.98 M solution of LiN(SiMe3)z in hexane.
After 0.5 h at -45 °C, a solution of cis-1-(t-butoxy-
carbonyl)-3-(2-methoxyisopropyloxy)-4-(isobutenyl)-
azetidin-2-one (84.5 mg, 0.27 mmol) in 1.0 mL of THF was
added dropwise to the mixture. The solution was warmed to
0 °C and kept at that temperature for 1 h before 1 mL of a
10o solution of AcOH in THF was added. The mixture was
partitioned between saturated aqueous NaHCO, and 60/40
ethyl acetate/hexane. Evaporation of the organic layer
gave a residue which was purified by filtration through
silica gel to give 88.3 mg of a mixture containing
(2'R,3'S)-2',7,10-(tris)-0-triethylsilyl-3'-desphenyl-
3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-
9-desoxo-9~i-hydroxy-10-desacetyl taxol and a small amount
of the (2'S,3'R) isomer.
To a solution of 88.3 mg (0.080 mmol) of the.
mixture obtained from the previous reaction in 13.5 mL of
acetonitrile and 0.55 mL of pyridine at 0 °C was added

WO 94/20088 ~ PCTIUS94l02210
_216948
43
1.90 mL of 48o aqueous HF. The mixture was stirred at 0
°C for 3 h, then at 25 °C for 13 h, and partitioned
between saturated aqueous sodium bicarbonate and ethyl
acetate. Evaporation of the ethyl acetate solution gave
. 5 67.2 mg of material which was purified by flash
chromatography to give 52.7 mg (82%) of 3'-desphenyl-
3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-
desoxo-9(3-hydroxy-10-desacetyl taxol, which was
recrystallized from methanol/water.
m.p.138-140°C; [a]=SNa -55.2° (c 0.0026, CHC1,) .
1H NMR (MeOH, 300 MHz) 8 8.11(d, J=7.1 Hz, 2H, benzoate
ortho), 7.61(m, 1H, benzoate para), 7.48(m, 2H, benzoate
meta), 6.13(m, 1H, H13), 6.12(m, 1H, H2), 5.21(br s.,
1H, H3'), 5.02(d, J=5.3 Hz, 1H, H10), 4.93(d, J=8.1 Hz,
1H, H5), 4.85(d, J=9.1 hz, 1H, NH), 4.84(d, J=8.5 Hz, 1H,
MezC=CH-), 4.50(br s, 1H, H2'), 4.50(d, J=5.5 Hz, 1H, H9),
4.22(d, J=8.1, 1H, H20a), 4.18(d, J=8.1 Hz, 1H, H20(3),
3.89(dd, J=9.4, 7.5 Hz, 1H, H7), 3.12(d, J=5.5 Hz, H3),
2.45(m, 1H, H6a), 2.31(m, 1H, Hl4a), 2.29(s, 3H, 4Ac),
2 .18 (m, 1H, H14(3), 1.85 (ddd, J=15.1, 9.4, 1.2 Hz, H6(3) ,
1.81(s, 3H, Mel6), 1.76(s, 3H, Mel8), 1.72(s, 6H, 2Me
from isobuthenyl), 1.61(s, 3H, Mel9), 1.39(s, 9H, 3Me
t-buthoxy), 1.26(s, 3H, Mel7).

WO 94/20088 ~ PCTIUS94102210
44
EXANlP~E 5
0
Ph 0
- OH
t8u0 N OIIII
iiiii
H OH
H0 __
H
Ph 0 ~ 0
0 Ac0
(74-3)
Preparation of N-desbenzoyl-N-(t-butoxycarbonyl)-9-
desoxo-10-desacetoxy-10-keto taxol.
To a solution of 7-0-triethylsilyl-9-desoxo-10-
desacetoxy-10-keto baccatin (III) (30.0 mg, 0.047 mmol)
in 0.5 mL of THF at -45 °C was added dropwise 0.05 mL of a
0.98 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at
-45 °C, a solution of cis-1-t-butoxycarbonyl-3-triethyl-
silyloxy-4-phenylazetidin-2-one (53.1 mg, 0.14 mmol) in
0.5 mL of THF was added dropwise to the mixture. The
solution was warmed to 0 °C and kept at that temperature
for 1 h before 1 mL of a 10% solution of AcOH in THF was
added. The mixture was partitioned between saturated
aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation
of the organic layer gave a residue which was purified by
filtration through silica gel to give 43.7mg of a mixture
containing (2'R,3'S)-2',7-(bis)-O-triethylsilyl-N-
desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-
10-keto taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 43.7 mg (0.042 mmol) of the
mixture obtained from the previous reaction in 4.0 mL of
acetonitrile and 0.20 mL of pyridine at 0 °C was added
0.50 mL of 48% aqueous HF. The mixture was stirred at 0
°C for 3 h, then at 25 °C for 13 h, and partitioned

WO 94J20088 ~ PCTIUS94102210
between saturated aqueous sodium bicarbonate and ethyl
acetate. Evaporation of the ethyl acetate solution gave
- 33.2 mg of material which was purified by flash
chromatography to give 24.1 mg (73 0) of i~1-desbenzoyl-
5 N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto
taxol, which was recrystallized from methanol/wate.r.
m.p.162-165°C; [oc]=5Na -58.7° (c 0.0025, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.11(d, J=7.1 Hz, 2H, benzoate
ortho), 7.63(m, 1H, benzoate para), 7.50(m, 2H, benzoate
10 meta), 7.40-7.29(m, 5H, benzoate, phenyl), 6.11(td,
J=7.8, 1.0 Hz, 1H, H13), 5.94(d, J=6.4 Hz, 1H, H2),
5.52(d, J=9.8 Hz, 1H, H3'), 5.27(d, J=9.3 Hz, 1H, NH),
4.93(dd, J=8.8 Hz, 1H, H5), 4.64(br s, 1H, H2'), 4.32(d,
J=8.3 Hz, 1H, H20oc), 4.18(d, J=8.3 Hz, 1H, H20(3), 3.88(br
15 s, 1H, 2'OH), 3.71(m, 1H, H7), 3.11(d, J=5.1 Hz, 1H, H3),
3 .10 (d, J=15:7 Hz, H9oc), 2 .88 (d, J=16.1, 1H, H9(3), 2 . 54 (m,
1H, H6oc) , 2 .44 (m, 1H, H14(3) , 2.29 (s, 3H, 4Ac) , 2.26 (m, 1H,
Hl4oc), 2.02(br s, 1H, 7 OH), 1.88(s, 1H, 1 OH), 1.80(m,
1H, H6(3), 1.65( s, 3H, Mel8), 1.55(s, 3H, Mel6), 1.46(s,
20 3H, Mel9), 1.35(s, 9H, 3Me t-butoxy), 1.29(s, 3H,
Mel7).(74-4)

WO 94120088 ~ PCTIUS94102210
46
EXAMPLE 6.
0
0 \ 0
OH
tBuO~N _ 01111
H OH
HO
0
Ph~ _, 0
'1p ACO
(74-4)
Preparation of 3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-
N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto
taxol.
To a solution of 7-O-triethylsilyl-9-desoxo-10-
desacetoxy-10-keto baccatin (III) (30.0 mg, 0.047 mmol)
in 0.5 rnL of THF at -45 °C was added dropwise 0.05 mL of a
0.98 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at
-45 °C, a solution of cis-1-t-butoxycarbonyl-3-(2-methoxy-
isopropyloxy)-4-(isobutenyl) azetidin-2-one (44.1 mg,
0.141 mmol) in 0.5 mL of THF was added dropwise to the
mixture. The solution was warmed to 0 °C and kept at that
temperature for 1 h before 1 mL of a 10% solution of AcOH
in THF was added. The mixture was partitioned between
saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.
Evaporation of the organic layer gave a residue which was
purified by filtration through silica gel to give 40.8 mg
of a mixture containing (2'R,3'S)-2'-O-(2-methoxy-
isopropyl)-7-O-triethylsilyl-3'-desphenyl-3'-(iso-
butenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-
desacetoxy-10-keto taxol and a small amount of the
(2'S,3'R) isomer.
To a solution of 40.8 mg (0.043 mmol) of the
mixture obtained from the previous reaction in 4 mL of
acetonitrile and 0.2 mL of pyridine at 0 °C was added 0.5

WO 94/20088 ' PCTlUS94l02210
47
mL of 48o aqueous HF. The mixture was stirred at 0 °C for
3 h, then at 25 °C for 13 h, and partitioned between
saturated aqueous sodium bicarbonate and ethyl acetate.
F~aaporation of the ethyl acetate solution gave 34.4 mg of
material which was purified by flash chromatography to
give 23.0 mg (700) of 3'-desphenyl-3'-(isobutenyl)-N-
desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-
10-keto taxol, which was recrystallized from
methanol/water.
m.p.149-153°C; [a]"Na -56.3° (c 0.0025, CHC1,) .
IH NMR (CDC1" 300 MHz) 8 8.12(d, J=7.2 Hz, 2H, benzoate
ortho), 7.64(m, 1H, benzoate para), 7.51(m, 2H, benzoate
meta), 6.12(t, J=7.5 Hz, 1H, H13), 5.95(d, J=6.2 Hz, 1H,
H2), 5.30(d, J=8.9 Hz, 1H, NH), 4.94(d, J=8.2 Hz, 1H,
H5), 4.88(d, J=8.9 Hz, 1H, MezC=CH-), 4.79(td, J=8.9, 2.4
Hz, 1H, H3'), 4.34(d, J=8.2 Hz, 1H, H20a), 4.27(dd,
J=5.5, 2.7 Hz, 1H, H2'), 4.19(d, J=8.2 Hz, 1H, H20(3) "
3.73(m, 1H, H7), 3.67(br s, 1H, 2'OH), 3.13(d, J=5.1 Hz,
1H, H3), 3.12(d, J=15.7 Hz, 1H, H9a), 2.90(d, J=15.7 Hz,
1H, H9~3) , 2 . 55 (m, 1H, H6a), 2.47(m, 1H, H14~3), 2 . 32 ( s, 3H,
4Ac), 2.28(m, 1H, Hl4a), 2.04(br s, 1H, 7 OH), 1.88(s,
1H, 1 OH), 1.82 (m, 1H, H6(3), 1.79 (s, 3H, Mel8) , 1.76 (s,
6H, 2Me from isobuthenyl), 1.57(s, 3H, Mel6), 1.47 (s, 3H,
Mel9); 1.40(s, 9H, 3Me t-buthoxy) 1.30(s, 3H,
Mel7).(75-1)

WO 94/20088 ~ PCTIUS94I02210
,~~69~~
48
EXAMPLE 7
0
0 0
off
te~o i = o~~~~
H OH
Ph OACO~ VO
0
(75-1)
Preparation of 3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-
N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto
taxol.
To a solution of 7-0-triethylsilyl-9-desoxo-10-
desacetoxy-10-keto baccatin (III) (25.0 mg, 0.039 mmol)
in 0.5 mL of THF at -45 °C was added dropwise 0.05 mL of a
0.98 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at
-45 °C, a solution of cis-1-t-butoxycarbonyl-3-triethyl-
silyloxy-4-(2-thienyl)azetidin-2-one (45.0 mg, 0.117
mmol) in 0.5 mL of THF was added dropwise to the mixture.
The solution was warmed to 0 °C and kept at that
temperature for 1 h before 1 mL of a 10% solution of AcOH
in THF was added. The mixture was partitioned between
saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.
Evaporation of the organic layer gave a residue which was
purified by filtration through silica gel to give 36.2 mg
of a mixture containing (2'R,3'S)-2',7-(bis)-O-triethyl-
silyl-3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-
butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol and
a small amount of the (2'S,3'R) isomer.
To a solution of 36.2 mg (0.035 mmol) of the
mixture obtained from the previous reaction in 3.0 mL of
acetonitrile and 0.15 mL of pyridine at 0°C was added 0.45
mL of 48% aqueous HF. The mixture was stirred at 0 °C for

WO 94120088 PCTlUS94102210
49
3 h, then at 25 °C for 13 h, and partitioned between
saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl,acetate solution gave 29.4 mg of
material which was purified by flash chromatography to
give 24.3 mg (87~) of 3'-desphenyl-3'-(2-thienyl)-N-
desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-
10-keto taxol, which was recrystallized from
methanol/water.
m.p.163-169°C; [a]=SNa -54.2° (c 0.0023, CHCl,) .
1H NMR (CDC1" 300 MHz) 8 8.12(d, J=7.3 Hz, 2H, benzoate
ortho), 7.64(m, 1H, benzoate para), 7.51(m, 2H, benzoate
meta), 7.26(m, 1H, thienyl), 7.10(d, J=3.4 Hz, IH,
thienyl), 6.99(dd, J=5.1, 3.4 Hz, 1H, thienyl), 6.12(td,
J=6.1, 1.0 Hz, 1H, H13), 5.95(d, J=5.9 Hz, 1H, H2),
5.50(d, J=4.4 Hz, 1H, NH), 5.42(d, J=9.8 Hz, 1H, H3'),
4.94(d, J=8.3 Hz, 1H, H5), 4.64(dd, J=4.2, 2.0 Hz, 1H,
2'), 4.33(d, J=7.8 Hz, 1H, H20a), 4.18(d, J=7.8 Hz, 1H,
H20(3), 3.90(br s, 1H, 2'OH), 3.73(m, 1H, H7), 3.11(d,
J=15.8 Hz, H9a), 3.09(d, J=5.1 Hz, 1H, H3), 2.90(d,
J=15 . 6 Hz, 1H, H9~i), 2 .54 (m, 1H, H6a) , 2 .45 (m, 1H, H14(3) ,
2.31(s, 3H, 4Ac), 2.28(m, 1H, Hl4a)" 2.01(br s, 1H, 7
OH), 1.88(s, 1H, 1 OH), 1.83(m, 1H, H6(3), 1.69(s, 3H,
Mel8), 1.56(s, 3H, Mel6), 1.46(s, 3H, Mel9), 1.40(s, 9H,
3Me t-buthoxy), 1.29(s, 3H, Mel7).
EXAMPLE 8
Taxanes 67-3, 70-2, 70-3, 70-4, 75-1, 74-4, and
74-3 of Examples 1-7 were evaluated in in vitro
cytotoxicity activity against human colon carcinoma cells
HCT-116. Cytotoxicity was assessed in HCT116 human colon
carcinoma cells by XTT (2,3-bis(2-methoxy-4-nitro-5-
sulfophenyl)-5-[(phenyl-amino)carbonyl]-2H-tetrazolium
hydroxide) assay (Scudiero et al, "Evaluation of a

WO 94120088 - PCT/US94102210
soluble tetrazolium/ formazan assay for cell growth and
drug sensitivity in culture:, using human and other tumor
cell lines", Cancer Res,.~4°8':4827-4833, 1988). Cells were
plated at 4000 cells/~well in 96 well microtiter plates
5 and 24 hours later drugs were added and serial diluted.
The cells were incubated at 37oC for 72 hours at which
time the tetrazolium dye, XTT, was added. A dehydro-
genase enzyme in live cells reduces the XTT to a form
that absorbs light at 450 nm which can be quantitated
10 spectrophotometrically. The greater the absorbance the
greater the number of live cells. The results are
expressed as an ICSo which is the drug concentration
required to inhibit cell proliferation (i.e. absorbance
at 450 nm) to 50% of that of untreated control cells.
15 All compounds had an ICSO less than 0.1,
indicating that they are all cytotoxically active.

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