U.S. patent application number 10/210018 was filed with the patent office on 2003-02-20 for 2-aroyl-4-acyl paclitaxel (taxol) analogs.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Chordia, Mahendra Devichand, Jagtap, Prakash G., Kadow, John, Kingston, David George Ian.
Application Number | 20030036661 10/210018 |
Document ID | / |
Family ID | 22094031 |
Filed Date | 2003-02-20 |
United States Patent
Application |
20030036661 |
Kind Code |
A1 |
Kingston, David George Ian ;
et al. |
February 20, 2003 |
2-Aroyl-4-acyl paclitaxel (taxol) analogs
Abstract
2-debenzoyl-4-deacetyl paclitaxel, antineoplastic analogs
thereof and intermediates are taught, as well as the formation of
the compound, analogs and intermediates. The compound, analogs and
intermediates may be used to form pharmaceutical compositions
having anti-neoplastic activity. Further, the compound, analogs and
intermediates may be used to treat cancer when applied in an
effective amount by means such as a pharmaceutical composition.
Inventors: |
Kingston, David George Ian;
(Blacksburg, VA) ; Chordia, Mahendra Devichand;
(Charlottesville, VA) ; Jagtap, Prakash G.;
(Blacksburg, VA) ; Kadow, John; (Wallingford,
CT) |
Correspondence
Address: |
FITZPATRICK CELLA HARPER & SCINTO
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
US
|
Assignee: |
Bristol-Myers Squibb
Company
Princeton
NJ
|
Family ID: |
22094031 |
Appl. No.: |
10/210018 |
Filed: |
August 2, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10210018 |
Aug 2, 2002 |
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09223193 |
Dec 30, 1998 |
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6476242 |
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Current U.S.
Class: |
549/510 |
Current CPC
Class: |
C07D 493/10 20130101;
A61P 35/00 20180101; C07D 305/14 20130101 |
Class at
Publication: |
549/510 |
International
Class: |
C07D 35/14 |
Claims
1. An antineoplastic analog of paclitaxel, or a pharmaceutically
acceptable salt thereof, comprising the formula: 11wherein R.sub.6
is a substituted benzoyloxy group and R.sub.5 is selected from the
group consisting of an acyloxy group, an S-alkyl and
S-aryldithiocarboxyoxy group, wherein the acyloxy group is not
acetyloxy.
2. The analog of claim 1, wherein said substituents on the
benzoyloxy group are independently selected from the group
consisting of hydrogen, hydroxyl, halogens, alkyls, alkoxys, nitro,
cyano, azido, thiol, alkyl thiols, acyls, acyloxy,
alkoxycarbonyloxys, diatomics, and linear triatomics.
3. The analog of claim 1, wherein said acyloxy group is selected
from the group consisting of alkylcarbonyloxy, arylcarbonyloxy,
substituted arylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, and alkoxycarbonyloxy.
4. The analogs of claim 1, wherein the alkyl group of said
S-alkyldithiocarboxyoxy group is selected from the group consisting
of alkyl, cycloalkyl, and heterocycloalkyl.
5. The analog of claim 1, wherein the aryl group of said
S-aryldithiocarboxyoxy group is selected from the group consisting
of phenyl, substituted phenyl, and heteroaryl.
6. An antineoplastic compound, or a pharmaceutically acceptable
salt thereof, comprising the general formula: 12wherein R.sub.1 is
an aryl or substituted aryl; R.sub.2 is an aryl or substituted
aryl; R.sub.3 is selected from the group consisting of H, OH, and
OC(O)R.sub.a, R.sub.4 is selected from the group consisting of H,
OH, oxyprotecting group (i.e. triethylsiloxy), OR.sub.b, and
OC(O)R.sub.c, and wherein R.sub.a, R.sub.b, and R.sub.c are
independently selected from the group consisting of alkyls, aryls,
and substituted aryls; R.sub.5 is selected from the group OH,
OC(O)R.sub.d, OC(O)OR.sub.e and OC(S)SR.sub.f; and R.sub.6 is
selected from the group H and OC(O)R.sub.g, where R.sub.d, R.sub.e,
R.sub.f and R.sub.g are independently selected from the group
consisting of alkyls, cycloalkyls, heterocycloalkyls,
heterocycloaryls, alkenyls, alkynyls, aryls, and substituted
aryls.
7. The compound of claim 6, wherein R.sub.4 is OH and R.sub.3 is
OC(O)CH.sub.3.
8. The compound of claim 7, wherein R.sub.5 is OC(O)R.sub.d.
9. The compound of claim 8 wherein R.sub.d is selected from the
group consisting of alkyl, cycloalkyl and alkoxy.
10. The compound of claim 8, wherein R.sub.6 is OC(O)R.sub.g.
11. The compound of claim 10 wherein R.sub.g is an aryl or
substituted aryl.
12. The compound of claim 7, wherein R.sub.1 and R.sub.2 are both
phenyl.
13. The compound of claim 12, wherein R.sub.5 is
cyclopropylcarbonyloxy.
14. The compound of claim 13, wherein R.sub.6 is selected from the
group consisting of m-azidobenzoyloxy, m-methoxybenzoyloxy,
m-chlorobenzoyloxy, 3,5-dichlorobenzoyloxy, 3,5-difluorobenzoyloxy,
and 2,5-dimethoxybenzoyloxy.
15. The compound of claim 12, wherein R.sub.5 is
methoxycarbonyloxy.
16. The compound of claim 15, wherein R.sub.6 is selected from the
group consisting of m-methylbenzoylozxy, m-methoxybenzoyloxy, and
m-chlorobenzoyloxy.
17. The compound of claim 10, wherein R.sub.5 is
S-methyldithiocarboxyoxy.
18. The compound of claim 17, wherein R.sub.6 is selected from the
group consisting of m-methoxybenzoyl, m-chlorobenzoyloxy, and
m-azidobenzoyloxy.
19. A pharmaceutical composition, comprising an effective amount of
the analog of claim 1.
20. A pharmaceutical composition comprising an effective amount of
the compound of claim 6.
21. A method for treating cancer, comprising administering an
effective amount of the analog of claim 1.
22. A method of treating cancer comprising administering an
effective amount of the compound of claim 6.
23. A first paclitaxel analog compound having a protecting group at
each of the positions C-2' and C-7 and having OH groups at
positions C-2 and C-4, wherein said analog has the formula:
13wherein R.sub.1 and R.sub.2 are independently selected from the
group consisting of aryl, substituted aryl and heteroaryl; R.sub.3
is hydroxy or acyloxy; R.sub.4 is trialkylsilyl; and R.sub.7 is
trialkylsilyl.
24. An intermediate of claim 23 wherein R.sub.1 and R.sub.2 are
phenyl, R.sub.3 is acetoxy, R.sub.4 is triethylsilyl, and R.sub.7
is t-butyldimethylsilyl.
25. A method of making the first paclitaxel analog compound of
claim 23, comprising reacting
2'-t-butyldimethylsilyl-7-triethylsilylpaclitaxel with Triton B in
dichloromethane.
26. A second paclitaxel analog compound consisting of a cyclic
carbonate intermediate of the first paclitaxel analog compound of
claim 23, wherein the second paclitaxel analog compound has the
formula: 14
27. An intermediate of the second paclitaxel analog of claim 26,
wherein R.sub.1 and R.sub.2 are phenyl, R.sub.3 is acetoxy, R.sub.4
is triethylsilyl, and R.sub.7 is t-butyldimethylsilyl.
28. A method of synthesizing the intermediate of claim 27,
comprising reacting
2'-t-butyldimethylsilyl-2-debenzoyl-4-deacetyl-7-triethylsilylpa-
clitaxel with carbonyldiimidazole or triphosgene.
29. A third paclitaxel analog compound consisting of the 4-acyl
intermediate of the second paclitaxel analog compound of claim 26,
wherein the third paclitaxel analog compound has the following
formula: 15wherein R.sub.5 is selected from the group consisting of
alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls.
30. An intermediate of the third paclitaxel analog compound of
claim 29 wherein R.sub.1 and R.sub.2 are phenyl, R.sub.3 is
acetoxy, R.sub.4 is triethylsilyl, and R.sub.7 is
t-butyldimethylsilyl.
31. A method of synthesizing the intermediate of a third paclitaxel
analog compound: 16wherein R.sub.1 and R.sub.2 are independently
selected from the group consisting of aryl, substituted aryl or
heteroaryl; R.sub.3 is hydroxy or acyloxy; R.sub.4 is
trialkylsilyl; R.sub.5 is selected from the group consisting of
alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls; and R.sub.7 is
trialkylsilyl, comprising reacting the intermediate of claim 27
with a carboxylic acid in the presence of DCC and DMAP.
32. A fourth paclitaxel analog compound consisting of the 2-acyl
intermediate of the first paclitaxel analog compound of claim 23,
wherein the fourth paclitaxel analog compound has the following
formula: 17wherein R.sub.6 is selected from the group consisting of
alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls.
33. An intermediate of the fourth paclitaxel analog compound of
claim 32, wherein R.sub.1 and R.sub.2 are phenyl, R.sub.3 is
acetoxy, R.sub.4 is triethylsilyl, and R.sub.7 is
t-butyldimethylsilyl.
34. A method of synthesizing the intermediate of claim 33,
comprising reacting
2'-t-butyldimethylsilyl-2-debenzoyl-4-deacetyl-7-triethylsilylpa-
clitaxel with a carboxylic acid (R.sub.6COOH) in the presence of
DCC and DMAP.
35. A fifth paclitaxel analog compound consisting of a diprotected
paclitaxel analog with the composition: 18wherein R.sub.1 and
R.sub.2 are independently selected from the group consisting of
aryl, substituted aryl or heteroaryl; R.sub.3 is hydroxy or
acyloxy; R.sub.4 is trialkylsilyl; R.sub.5 and R.sub.6 are
independently selected from the group consisting of alkyls,
cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls; and R.sub.7 is
trialkylsilyl.
36. The intermediate of claim 35 wherein R.sub.1 and R.sub.2 are
phenyl, R.sub.3 is acetoxy, R.sub.4 is triethylsilyl, and R.sub.7
is t-butyldimethylsilyl.
37. A method of synthesizing the intermediate of claim 36,
comprising reacting
2'-t-butyldimethylsilyl-4-deacetyl-7-triethylsilylpaclitaxel with a
carboxylic acid under forcing conditions in the presence of DCC and
DMAP.
38. A second method of synthesizing a fifth paclitaxel analog
compound consisting of a diprotected paclitaxel analog with the
composition: 19wherein R.sub.1 and R.sub.2 are phenyl, R.sub.3 is
acetoxy, R.sub.4 is triethylsilyl, R.sub.5 and R.sub.6 are
independently selected from the group consisting of alkyls,
cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls, and R.sub.7 is
t-butyldimethylsilyl, comprising reacting the intermediate of claim
29 with lithium hydroxide followed by a carboxylic acid
(R.sub.6COOH), DCC and DMAP.
39. An antineoplastic pcalitaxel analog as shown in Table 1, or a
pharmaceutically acceptable salt thereof.
Description
FIELD OF INVENTION
[0001] The present invention relates to 2-debenzoyl-4-deacetyl
paclitaxel, 2-debenzoyl-4-deacetyl-2,4-diacyl paclitaxel analogs
thereof, and methods for making the same.
BACKGROUND OF THE INVENTION
[0002] The natural product paclitaxel (1) (Taxol.RTM.) is an
effective antitumor drug with demonstrated clinical activity
against breast and ovarian cancer, as well as indicated activity
against non-small cell lung cancer (24, 25). Studies of use against
various other cancers show promising results. Recent studies have
elucidated the unique mode of action of paclitaxel, which involves
abnormal polymerization of tubulin and disruption of mitosis. Taxol
was first isolated and its structure reported by Wani, et al. (26).
1
[0003] Taxol is found in the stem bark of the western yew, Taxus
brevifolia, as well as in T. baccata and T. cuspidata. Therefore,
there is a limited natural supply of paclitaxel.
[0004] Because of the limited availability of paclitaxel and the
high demand due to its efficacy against various types of cancer,
other derivatives and analogs of paclitaxel have been sought. The
relative scarcity of such analogs in relation to their importance
as potential anti-cancer agents is due to several factors,
including the large size and complexity of paclitaxel compounds,
the presence of multiple reactive sites and the presence of many
stereospecific sites, making synthesis of even close analogs
difficult.
[0005] Because it is believed that the tetracyclic taxane nucleus
is an important feature in establishing the antineoplastic activity
of paclitaxel and analogs thereof, it is desired to alter the ring
substituents without disrupting the tetracyclic nucleus in order to
develop antineoplastically active derivatives of paclitaxel. The
complexity of paclitaxel and its analogs makes it difficult to
selectively alter substituents.
[0006] The only disclosed preparations of taxol analogs retaining
the tetracyclic taxane nucleus are those analogs modified at the
C-1, C-2, C-4, C-7 and C-13 positions, and derivatives having a
protecting group or a hydroxyl group at the C-10 position (27).
However, it has been demonstrated that analogs with improved
activity can be prepared by modifications at various functional
groups, and several investigators have prepared paclitaxel analogs
modified at the 2-position (1-10), at the 4-position (11-15), at
the 7-position (16-19), at the 9 and 10 positions (20-21) and at
the 14-position (22), among others. Baccatin III derivatives
(baccatin III is the taxane core of paclitaxel) have also been
prepared with substitutions at C-2 and/or C-4 (23).
[0007] In particular, analogs at the C-2 position have been
prepared by Chaudhary et al. (1,3) using a phase-transfer catalyst
to prepare 2-debenzoylpaclitaxel followed by reacylation with a
carboxylic acid in the presence of dicyclhexylcarbodiimide (DCC)
and pyrollidinopyridine (PP). Similar chemistry has more recently
been reported by Georg et al. (2,5,6,13), who used potassium
t-butoxide as the base and reacylated in the presence of
1,3-dicyclohexylcarbodiimide (DCC) and N,N-dimethylaminopyridine
(DMAP). Nicolaou (4,7) has shown that 2-debenzoylpaclitaxels can be
prepared from 10-deacetylbaccatin III by a process involving
protection at C-7, oxidation at C-13, selective debenzoylation at
C-2, formation of the cyclic 1,2-carbonate derivative, reaction
with an aryllithium, reduction at C-13, and finally coupling of the
C-13 side chain. A different route to 2-debenzoyl taxoids was
developed by Pulicani et al. (8), who were able to prepare
2-debenzoyl docetaxel and certain derivatives by electrochemical
reduction of docetaxel followed by reacylation with Butyllithium
and an acid chloride. Yet another, albeit restricted, synthesis of
certain 2-acyl paclitaxel analogs was achieved by Ojima et al. (9)
and Boge et al. (10), who independently hydrogenated baccatin III
to its 2-cyclohexylcarbonyl derivative, and then attached the C-13
ester side chain. 2-Debenzoylbaccatin III was prepared by Datta et
al. (23) by treatment of 7,13-bis(triethylsilyl)baccatin III with
potassium t-butoxide.
[0008] 4-Deacetylpaclitaxel has been prepared by Neidigh et al.
(11) and independently by Georg et al. (12). Neidigh et al.
prepared 4-deacetylpaclitaxel by treatment of a protected
paclitaxel with base under various conditions, and also by a second
method in which a C-13 side chain was attached to a suitably
protected 4-deacetylbaccatin III. Georg et al. prepared
4-deacetylpaclitaxel by attachment of the C-13 side chain to a
protected deacetylbaccatin III. 4-Deacetylbaccatin III was also
prepared by Datta et al. (23) by treatment of
7-(triethylsilyl)baccatin III with potassium t-butoxide. C-4
deacetoxypaclitaxel was prepared by Chordia et al. (15) by
preparation of 2-debenzoyl-4-deacetyl paclitaxel by treatment of
2-t-butyldimethylsilyl-- 7-triethylsilylpaclitaxel with Triton B
(an organic-soluble base) followed by formation of the cyclic
1,2-carbonate, formation of a xanthate at C-4, opening of the
carbonate with phenyllithium, and deprotection.
[0009] Paclitaxels with modified C-4 acyl substituents have been
prepared by Chen et al. (14), who protected
7,13-di(triethylsilyl)baccatin III at C-1 with a dimethylsilyl
protecting group and then deacylated selectively at C-4 with
Red-A1. Subsequent reacylation using acid chloride and lithium
hexamethyldisilazide (LHDMS), followed by protecting group
manipulations and reacylation at C-13 with the paclitaxel side
chain (as its .beta.-lactam derivative) yielded a range of
4-acylpaclitaxel analogs. A 4-acyl analog of paclitaxel was also
prepared by Georg et al. (13), who treated
2'-t-butyldimethylsilyl-7-triethylsilylpaclitaxel with aqueous
potassium t-butoxide to give a 2-debenzoyl-4-deacetyl-2'-t-butyld-
imethylsilyl-7-triethylsilylpaclitaxel. This compound was converted
to its cyclic carbonate, acylated at C-4, and treated with
phenyllithium to yield a 4-isobutyroylpaclitaxel analog.
[0010] In spite of all the work that has been done on the
preparation of paclitaxel analog with C-2 and C-4 acyl
substituents, no work has been reported to date on the preparation
of derivatives with modified substituents at both C-2 and C-4. The
preparation of such derivatives is desirable because it is
anticipated that such derivatives will have antineoplastic
activity, like paclitaxel itself. Further, because previous work
has shown that both 2-acyl and 4-acyl analogs independently can
have improved activity over paclitaxel, it is thought that some
derivatives described herein will also have improved activity. It
is further contemplated that the derivatives described herein will
be easier to synthesize, will be more abundant, will have greater
solubility and/or will have fewer side effects than paclitaxel.
[0011] The preparation of analogs of paclitaxel is an important
endeavor, especially in view of paclitaxel's clinical activity and
limited supply. The preparation of analogs might result in the
synthesis of compounds with greater potency than paclitaxel (thus
reducing the need for the drug), compounds with superior
bioavailability, or compounds which are easier to synthesize than
paclitaxel from readily available sources.
SUMMARY OF THE INVENTION
[0012] The present application describes paclitaxel analogs which
have modified substituents at both the C-2 and C-4 positions, in
particular 2-debenzoyl-2-acyl-4-deacetyl-4-acyl paclitaxel analogs,
as well as procedures for preparing these compounds, and
intermediates which can be utilized in preparing these
compounds.
[0013] The compounds of the present invention have anti-neoplastic
activity and may be used to treat patients suffering from cancer,
or as intermediates for making compounds which can be used to treat
cancer. In a preferred embodiment, the paclitaxel analogs have
improved in vivo activities for use as anticancer agents, are more
soluble, and/or have fewer side effects than paclitaxel.
[0014] Compounds of the present invention include compounds having
the general formula: 2
[0015] wherein R.sub.1 is an aryl or substituted aryl; R.sub.2 is
an aryl or substituted aryl; R.sub.3 is selected from the group
consisting of H, OH, and OC(O)R.sub.a; R.sub.4 is selected from the
group consisting of H, OH, oxyprotecting group (i.e.
triethylsiloxy), OR.sub.b, and OC(O)R.sub.c, and wherein R.sub.a,
R.sub.b, and R.sub.c are independently selected from the group
consisting of alkyls, aryls, and substituted aryls; R.sub.5 is
selected from the group OH, OC(O)R.sub.d, OC(O)OR.sub.e and
OC(S)SR.sub.f; and R.sub.6 is selected from the group H and
OC(O)R.sub.g, where R.sub.d, R.sub.e, R.sub.f and R.sub.g are
independently selected from the group consisting of alkyls,
cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls. As used herein, substituted
aryl means an aryl independently substituted with one to five (but
preferably one to three) groups selected from C.sub.1-6
alkanoyloxy, hydroxy, halogen, C.sub.1-6 alkyl, trifluoromethyl,
C.sub.1-6 alkoxy, aryl, heteroaryl, C.sub.2-6 alkenyl, C.sub.1-6
alkanoyl, nitro, amino, cyano, azido, C.sub.1-6 alkylamino,
di-C.sub.1-6 alkylamino, and amido.
[0016] Preferred embodiments of the present invention include
compounds having the formula: 3
[0017] wherein Ar is a phenyl or substituted phenyl group and
R.sub.5 is an alkyl, cycloalkyl or an alkoxy group. Another
preferred embodiment includes compounds having the formula: 4
[0018] wherein Ar is a substituted phenyl and R.sub.7 is an alkyl,
substituted alkyl, aryl or substituted aryl group. As used herein,
a substituted phenyl group may be alkyl, alkenyl, alkynyl, aryl,
heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens
and include, for example, lower alkoxy such as methoxy, ethoxy,
butoxy; halogen such as chloro or fluoro; nitro; amino; and
keto.
BRIEF DESCRIPTION OF THE FIGURES
[0019] The figures are included to more clearly demonstrate the
nature of the invention.
[0020] FIG. 1 is an overview of paclitaxel analogs and
intermediates and the chemical reactions for converting one into
another.
[0021] FIG. 2 shows a selection of paclitaxel analogs and
intermediates and the chemical reactions for converting one into
another.
[0022] FIG. 3 shows a selection of paclitaxel analogs and
intermediates and the chemical reactions for converting one into
another.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention pertains to paclitaxel analogs having
modified substituents at the C2 and C4 positions. The removal of
both the benzoyl group at the C-2 position of paclitaxel and the
acetyl group at the C-4 position, and the replacement of these
groups with other acyl groups, yields paclitaxel analogs which are
contemplated to have such characteristics as improved
bioactivities, in particular, improved antineoplastic activity;
improved solubility; and/or fewer side effects than paclitaxel. In
addition, the paclitaxel analogs may be easier to synthesize than
paclitaxel and more abundant.
[0024] In particular, paclitaxel analogs having antineoplastic
activity of the formula: 5
[0025] are provided, wherein R.sub.1 is an aryl or substituted
aryl; R.sub.2 is an aryl or substituted aryl; R.sub.3 is selected
from the group consisting of H, OH, and OC(O)R.sub.a; R.sub.4 is
selected from the group consisting of H, OH, oxyprotecting group
(i.e. triethylsiloxy), OR.sub.b, and OC(O)R.sub.c, and wherein
R.sub.a, R.sub.b, and R.sub.c are independently selected from the
group consisting of alkyls, aryls, and substituted aryls; R.sub.5
is selected from the group OH, OC(O)R.sub.d, OC(O)OR.sub.e and
OC(S)SR.sub.f; and R.sub.6 is selected from the group H and
OC(O)R.sub.g, where R.sub.d, R.sub.e, R.sub.f and R.sub.g are
independently selected from the group consisting of alkyls,
cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls. As used herein, substituted
aryl means an aryl independently substituted with one to five (but
preferably one to three) groups selected from C.sub.1-6
alkanoyloxy, hydroxy, halogen, C.sub.1-6 alkyl, trifluoromethyl,
C.sub.1-6 alkoxy, aryl, heteroaryl, C.sub.2-6 alkenyl, C.sub.1-6
alkanoyl, nitro, amino, cyano, azido, C.sub.1-6 alkylamino,
di-C.sub.1-6 alkylamino, and amido.
[0026] In particular, it is desirable that R.sub.4 is OH and
R.sub.3 is OC(O)CH.sub.3. It is further desirable that R.sub.5 is
OC(O)R.sub.d and R.sub.d is preferably an alkyl, cycloalkyl or
alkoxy group. It is further preferred that, in addition to the
above, R.sub.6 is OC(O)R.sub.g and R.sub.g is preferably an aryl or
substituted aryl group. It is even further preferred that both
R.sub.1 and R.sub.2 be phenyl.
[0027] A further preferred analog is one wherein R.sub.4 is OH,
R.sub.3 is OC(O)CH.sub.3 and R.sub.5 and R.sub.6 are selected from
the following combinations:
[0028] 1) R.sub.5 is cyclopropylcarbonyloxy and R.sub.6 is selected
from the group consisting of m-methoxybenzoyloxy,
m-azidobenzoyloxy, m-chlorobenzoyloxy, 3,5-dichlorobenzoyloxy,
3,5-difluorobenzoyloxy, and 2,5-dimethoxybenzoyloxy;
[0029] 2) R.sub.5 is methoxycarbonyloxy and R.sub.6 is selected
from the group consisting of m-methylbenzoyloxy,
m-methoxybenzoyloxy and m-chlorobenzoyloxy; and
[0030] 3) R.sub.5 is S-methyldithiocarboxyoxy and R.sub.6 is
selected from the group consisting of m-methoxybenzoyl,
m-chlorobenzoyloxy and m-azidobenzoyloxy.
[0031] It is particularly preferred that the analogs of paclitaxel
have a substituted benzoyloxy group at the 2-position of the B-ring
and an acyloxy group or an S-alkyl or S-aryldithiocarboxyoxy group
at the 4-position of the C-ring, provided that the acyloxy group is
not acetyloxy. It is particularly preferred that the substituents
on the benzoyloxy group be selected from hydrogen, hydroxyl,
halogens, alkyls, alkoxys, nitro, cyano, azido, thiol, alkyl
thiols, acyls, acyloxy, alkoxycarbonyloxys, diatomics, and-linear
triatomics. It is further preferred that the acyloxy group be
selected from alkylcarbonyloxy, arylcarbonyloxy, substituted
arylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, and alkoxycarbonyloxy. The alkyl group
of S-alkyldithiocarboxyoxy should be selected from alkyl,
cycloalkyl, and heterocycloalkyl, while the aryl group of
S-aryldithiocarboxyoxy should be selected from phenyl, substituted
phenyl, and heteroaryl. As used herein, a substituted phenyl group
may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and/or may contain
nitrogen, oxygen, sulfur, halogens and include, for example, lower
alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or
fluoro; nitro; amino; and keto.
[0032] The analogs having the above general formula display an
inhibitory effect on abnormal cell proliferation, and have
therapeutic properties that make it possible to treat patients who
have pathological conditions associated with an abnormal cell
proliferation. The pathological conditions include the abnormal
cellular proliferation of malignant or non-malignant cells in
various tissues and/or organs, including, non-limitatively, muscle,
bone and/or conjunctive tissues; the skin, brain, lungs and sexual
organs; the lymphatic and/or renal system; mammary cells and/or
blood cells; the liver, digestive system, and pancreas; and the
thyroid and/or adrenal glands. These pathological conditions can
also include psoriasis; solid tumors; ovarian, breast, brain,
prostate, colon, stomach, kidney, and/or testicular cancer;
Karposi's sarcoma; cholangiocarcinoma; choriocarcinoma;
neuroblastoma; Wilm's tumor, Hodgkin's disease; melanomas; multiple
myelomas; chronic lymphocytic leukemias; and acute or chronic
granulocytic lymphomas. The paclitaxel analogs in accordance with
the invention are particularly useful in the treatment of
non-Hodgkin's lymphoma, multiple myeloma, melanoma, and ovarian,
urothelial, oesophageal, lung, and breast cancers. The paclitaxel
analogs can be utilized to prevent or delay the appearance or
reappearance, or to treat these pathological conditions.
[0033] The paclitaxel analogs can be made by the methods disclosed
herein and techniques from the conventional organic chemistry
repertoire. FIGS. 1-3, which depict processes by which compounds
within the scope of the above general formula can be made, are only
shown for the purpose of illustration and are not to be construed
as limiting the processes to make the compounds by any other
methods.
[0034] The present invention provides analogs useful as active
agents in effecting an antitumor or antineoplastic effect in a
tumor-bearing host. These analogs or their pharamaceutically
acceptable salts can be compounded into pharmaceutical formulations
for administration to cancer patients. Such formulations will
comprise one or more of the active agents of the present invention
in combination with pharamaceutically acceptable excipients and/or
adjuvants. Contemplated routes of administration are parenteral and
oral, though other acceptable means of administration will be
obvious to those of ordinary skill in the art.
[0035] The present invention further provides a method for
inhibiting, reducing, or eliminating tumors comprising
administering to a mammalian, especially a human, tumor bearing
host an antitumor effective amount of an analog of the general
formula shown above.
[0036] For treating a variety of tumors, the analogs of the present
invention are contemplated to be used in a manner similar to that
of paclitaxel, see e.g. Physician's Desk Reference, 49th Edition,
Medical Economics, p 682, 1995. The dosage, mode and schedule of
administration for the analogs of this invention are not
particularly restricted; an oncologist skilled in the art of cancer
treatment will be able to ascertain, without undue experimentation,
an appropriate treatment protocol for administering the analogs of
the present invention. Thus the analogs will be administered via
any suitable route of administration, in particular, parenterally
or orally. Parenteral administration includes intravenous,
intraperitoneal, intramuscular, and subcutaneous
administration.
[0037] The doses utilized to implement the methods of the present
invention will be similar to those used in administering
paclitaxel, taking into account the relative activity of the
analogs described herein. It is expected that one of ordinary skill
in the art will be able to discern suitable anti-tumor effective
doses and regimens for the efficacious administration of the
present paclitaxel analogs. It will be understood that such doses
vary, depending on the type of administration, the particular
product selected, and the profile and particular characteristics of
the patient to be treated. The desired doses will be those that are
therapeutically effective for the treatment of disorders caused by
abnormal cell proliferation. The analogs of the present invention
can be administered as often as necessary in order to obtain the
desired therapeutic effect. Some patients may respond rapidly to
relatively high or low doses, and then require mild maintenance or
no maintenance dose at all. When administered via IV, the dosage
may be, for example, in the range of about 20 to about 500
mg/m.sup.2 over 1 to 100 hours. Orally, the dosage may be in the
range of 5-1000 mg/kg/day of body weight. The actual dose used will
vary according to the particular composition formulated, the route
of administration, and the particular site, host and type of tumor
being treated. Many factors that modify the action of the drug will
be taken into account in determining the dosage including age,
weight, sex, diet and the physical condition of the patient.
[0038] The present invention also provides pharmaceutical
formulations (compositions) containing an antitumor effective
amount of the paclitaxel analogs of the above general formula in
combination with one or more pharmaceutically acceptable carriers,
excipients, diluents or adjuvants. The compositions can be prepared
in accordance with conventional methods. For example, paclitaxel is
formulated for parenteral administration in polyethoxylated castor
oil (Cremophor.RTM.). Examples of formulating paclitaxel or
derivatives thereof are also found in, for example, U.S. Pat. Nos.
4,960,790 and 4,814,470, and such examples can be followed to
formulate the compounds of this invention. For example, analogs of
the general formula might be formulated in the form of tablets,
pills, powder mixtures, capsules, injectables, storage stable
solutions, suppositories, emulsions, dispersions, food premix, and
in other suitable forms. They might also be manufactured in the
form of sterile solid compositions, for example, freeze dried
(lyophilized) and, if desired, combined with other pharmaceutically
acceptable excipients. Such solid compositions can be reconstituted
with sterile water, physiological saline, or a mixture of water and
an organic solvent, such as propylene glycol, ethanol, and the
like, or some other sterile injectable medium immediately before
use in parenteral administration.
[0039] Typical of pharmaceutically acceptable carriers are, for
example, manitol, urea, dextrans, lactose, potato and maize
starches, magnesium stearate, talc, vegetable oils, polyalkylene
glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium
carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate,
sodium carbonate, gelatin, potassium carbonate, silicic acid. The
pharmaceutical preparation may also contain nontoxic auxiliary
substances such as emulsifying, preserving, wetting agents, and the
like as for example, sorbitan monolaurate, triethanolamine oleate,
polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium
sulfosuccinate, and the like.
[0040] It is further desirable to formulate intermediates of
paclitaxel analogs for further study on the effectiveness of
paclitaxel derivatives against cancer and other diseases and to
facilitate the formation of various paclitaxel analogs. One
preferred intermediate is derived from the following paclitaxel
analog, which can be made by reacting
2'-t-butyldimethylsilyl-7-triethylsilylpaclitaxel with Triton B in
dichloromethane: 6
[0041] wherein the analog has a protecting group at each of the
positions C-2' and C-7 and having OH groups at positions C-2 and
C-4, and wherein R.sub.1 and R.sub.2 are independently selected
from the group consisting of aryl, substituted aryl and heteroaryl;
R.sub.3 is hydroxy or acyloxy; R.sub.4 is trialkylsilyl; and
R.sub.7 is trialkylsilyl. The intermediate preferably is of a
structure such that R.sub.1 and R.sub.2 are phenyl, R.sub.3 is
acetoxy, R.sub.4 is triethylsilyl, and R.sub.7 is
t-butyldimethylsilyl.
[0042] A second preferred intermediate is derived from the
following paclitaxel analog: 7
[0043] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of aryl, substituted aryl or heteroaryl;
R.sub.3 is hydroxy or acyloxy; R.sub.4 is trialkylsilyl; and
R.sub.7 is trialkylsilyl. The intermediate preferably is of a
structure such that R.sub.1 and R.sub.2 are phenyl, R.sub.3 is
acetoxy, R.sub.4 is triethylsilyl, and R.sub.7 is
t-butyldimethylsilyl. The second intermediate can be formed by
reacting 2'-t-butyldimethylsilyl-2-debenzoy-
l-4-deacetyl-7-triethylsilylpaclitaxel with carbonyldiimidazole or
triphosgene.
[0044] A third intermediate is derived from the following
paclitaxel analog: 8
[0045] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of aryl, substituted aryl or heteroaryl;
R.sub.3 is hydroxy or acyloxy; R.sub.4 is trialkylsilyl; R.sub.7 is
trialkylsilyl; and R.sub.5 is selected from the group consisting of
alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls. It is preferred that the
intermediate have a structure such that R.sub.1 and R.sub.2 are
phenyl, R.sub.3 is acetoxy, R.sub.4 is triethylsilyl, and R.sub.7
is t-butyldimethylsilyl. The third intermediate may be formed by
reacting the second intermediate with a carboxylic acid in the
presence of DCC and DMAP.
[0046] A fourth intermediate is derived from the following
paclitaxel analog: 9
[0047] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of aryl, substituted aryl or heteroaryl;
R.sub.3 is hydroxy or acyloxy; R.sub.4 is trialkylsilyl; R.sub.7 is
trialkylsilyl; and R.sub.6 is selected from alkyls, cycloalkyls,
heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and
substituted aryls. The intermediate preferably has a structure such
that R.sub.1 and R.sub.2 are phenyl, R.sub.3 is acetoxy, R.sub.4 is
triethylsilyl, and R.sub.7 is t-butyldimethylsilyl. This
intermediate may be synthesized by reacting
2'-t-butyldimethylsilyl-2-debenzoyl-4-deacetyl-7-triethylsilylpaclitaxel
with a carboxylic acid (R.sub.6COOH) in the presence of DCC and
DMAP.
[0048] A fifth intermediate may be formed from the paclitaxel
analog compound having the composition: 10
[0049] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of aryl, substituted aryl or heteroaryl;
R.sub.3 is hydroxy or acyloxy; R.sub.4 is trialkylsilyl; R.sub.5
and R.sub.6 are independently selected from the group consisting of
alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls,
alkynyls, aryls, and substituted aryls; and R.sub.7 is
trialkylsilyl. The intermediate preferably is of the structure
wherein R.sub.1 and R.sub.2 are phenyl, R.sub.3 is acetoxy, R.sub.4
is triethylsilyl, and R.sub.7 is t-butyldimethylsilyl. This
intermediate may be synthesized by reacting
2'-t-butyldimethylsilyl-4-deacetyl-7-triethylsilylpaclitaxel with a
carboxylic acid under forcing conditions in the presence of DCC and
DMAP. Alternatively, this intermediate may be synthesized by
reacting the third intermediate with lithium hydroxide followed by
a carboxylic acid (R.sub.6COOH), DCC and DMAP.
[0050] Two different methods have been developed for the synthesis
of paclitaxel analogs of the desired type.
[0051] In the first method, as illustrated in FIG. 1, paclitaxel
(1) is converted to its 2'-t-butyldimethylsilyl-7-triethylsilyl
derivative 2 by treatment in succession with t-butyldimethylsilyl
chloride/imidazole and then with triethylsilyl chloride/pyridine.
Treatment of 2 with Triton B under carefully defined conditions
(-78.degree. to -10.degree., CH.sub.2Cl.sub.2) gave the triol 3
(2-debenzoyl-4-deacetyl-2'-t-butyldime-
thylsilyl-7-triethylsilylpaclitaxel) as a key intermediate. This
intermediate has been prepared previously by us (15) and by Georg
(13).
[0052] Treatment of the triol 3 with a desired substituted benzoic
acid, such as m-methoxybenzoic acid, in the presence of DCC and
DMAP, yielded the 2-acyl derivative 4. If the conditions are
adjusted appropriately, the diacyl derivative 5, where R=Ar, can be
prepared in good yield. However, treatment of 4 with excess
carboxylic acid in the presence of DCC and DMAP yields the diacyl
derivative 5 in modest yield, where Ar and R are independently
selectable depending on the carboxylic acids used in the two
acylation steps.
[0053] Deprotection of 5 under standard conditions (dilute HCl or
HF/pyridine) yielded the diacyl paclitaxel analog 6.
[0054] In the second method, as also illustrated in FIG. 1,
paclitaxel (1) was converted as before to the triol 3. This triol
was then protected as the cyclic carbonate derivative 7 by
treatment with carbonyl diimidazole or triphosgene. Cyclic
carbonates of a related type have been prepared by Holton (U.S.
Pat. No. 5,399,726) and by Nicolaou (4,7); the carbonate 7 has
previously been prepared by us (15) and by Georg (13).
[0055] Acylation of the carbonate 7 with a selected acyl chloride
in the presence of lithium hexamethyldisilazide gave the 4-acyl
analog 8. This analog could be converted to the diprotected
2-acyl-4-acylpaclitaxel 5 in two ways. In the first method, 8 was
hydrolysed by lithium hydroxide in THF/H.sub.2O to yield the diol
9, which could be acylated under our standard conditions
(ArCOOH/DCC/DMAP) to give the diacyl analog 5. In the second
method, treatment of 8 with an aryllithium reagent converted it
directly to 5, as previously observed by Holton (U.S. Pat. No.
5,399,726), by Nicolaou (4,7), by ourselves (15), and by Georg
(13). Deprotection of 5 as previously described then yielded the
desired 2,4-diacylpaclitaxel analog 6.
[0056] Following the procedures described above, together with
procedures that are common in the art, such as those described in
Klein et al., J. Med. Chem., 38, pp 1482-1492 (1995), other analogs
within the scope of this invention can be synthesized, such as
those shown in the table below.
1TABLE 1 2-AROYL-4-ACYL PACLITAXEL ANALOGS Number BMS # Brief
Sample Name Tubulin Data anal/PT HCT116 116/VM46 anal/PT R/S ratio
181339 paclitaxel (PT) 6.9+/1.1 1 2 203 N.A. 101 MC-134-61 198235
2-(m-methoxybenzoyl)-4-MeOCO-PT 0.9 6,7, 4,4 867, >87 129
MG-134-45 198244 2-(m-methoxybz)-4-cyclo- propylCO-PT 1.3 2 40 20
MC-134-68 198245 2-(m-methylbenzoyl)-4-Me- OCO-PT 0.8 2.1 44 21
MC-134-180 198336 2-m-azido-4-cyclopropylCO-- PT MC-134-91 198336
2-m-azido-4-cyclopropylCO-PT 0.08 2.7, 1.1 28, <16 10.4
MC-134-191 198337 2-m-chloro-4-cyclopropylCO-PT MC-134-92 198337
2-m-chloro-4-cyclopropylCO-PT 0.06 1.7, 1.1 30, <16 18
MC-134-100 198638 2-m-chloro-4-MeOCO-PT 1.7+/-0.2 0.4 2.2 82 37
MC-134-239 200333 2-(m-azidobenzoyl-4-xanthyl)PT 250+/-0 42 0.0168
0.1348 11.02 8.03 MC-134-238 200334 2-(m-chlorobenzoyl-4-xa-
nthyl)PT 21+/-5.9 3.5 0.0057 0.0586 3.72 10.34 MC-134-229 200335
2-(m-methoxybenzoyl-4-xanthyl)PT 52+/-41 8.9 0.0047 0.0532 3.08
11.32 MC-134-248 200532 2-(2,4-difluorobz)-4-cyclopropylCO-PT
1.3+/-0.1 0.2 0.0021 0.0082 1.03 3.86 MC-134-250 200541
2-(2,5-dimethoxybz)-4-cy- clopropylCO-PT 3.4+/-0.8 0.5 0.0018
0.0451 0.78 25.06 MC 134-247 200545
2-(2,4-dichlorobz)-4-cyclopropylCO-PT 5.4+/-2.9 0.7 0.0025 0.0766
1.09 30.64 MC-134-277 200750 2-(m-Cl-benzoyl)-4-(m-Cl-benzoyl)PT
420+/-140 144 2427 2461 PJ-143-261 242855 2-(m-Azidobenzoyl)-4-MeO-
CO-PT PJ-143-263 242857 2-(3,3-Dimethylacryloyl)-4-MeOCO-PT
PJ-143-264 242861 2-(m-MeO-benzoyl)-4-t-BuOCO-PT
EXAMPLES
[0057] Materials and Methods:
[0058] General Methods.
[0059] Specific reaction conditions are described in more detail in
the following non-limiting examples. Certain methods used herein
are generally described in the Journal of Organic Chemistry, 51,
pp. 797-802 (1986) The term "standard workup" or "usual workup"
used herein includes extraction with a suitable solvent (usually
ethyl acetate or methylene chloride), washing the extract with
water, drying over magnesium sulfate or sodium sulfate, and
evaporation in vacuo. All technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art.
[0060] All chemicals were procured from Aldrich Chemical Company
and used without further purification. AU anhydrous reactions were
performed under argon. THF was dried over sodium/benzophenone. All
reactions were monitored by TLC (silicagel, GF) and analyzed with
UV light and developed with vanillin spray. .sup.1H NMR and
.sup.13C spectra were obtained in CDCl.sub.3 at 270 and 400 MHZ for
proton spectra and assigned primarily by comparison of chemical
shifts and coupling constants with those of related compounds and
by appropriate 2D NMR techniques. Coupling constants are reported
in Hz. .sup.13C spectra were assigned using HETCOR and DEPT
spectra. .sup.1H NMR spectra showed the presence of traces of ethyl
acetate; paclitaxel and its derivative retain ethylacetate very
tightly, and it cannot be removed completely even on prolonged
treatment in vacuo at 38.degree. C. Exact mass measurements were
performed at the Midwest Center for Mass Spectrometry, an NSF
Regional Instrumentation Facility. IUPAC nomenclature for
paclitaxel derivatives is used for title compounds.
[0061] 2'-O-TERT-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYLPACLITAXEL
(2): To a stirred solution of paclitaxel 1 (270 mg, 0.316 mmol) in
2.5 mL anhydrous DMF, imidazole (107 mg, 1.58 mmol) and
tert-butyldimethylsilyl chloride (238 mg, 1.58 mmol) were added.
The solution was heated at 60.degree. C. for 2 hours. The mixture
was cooled to room temperature, and additional amounts of imidazole
(107 mg, 1.58 mmol) and triethylsilyl chloride (150 .mu.L, 1.34
mmol) were added. After stirring at room temperature for one hour,
the reaction mixture was diluted with EtOAc and washed successively
with water and brine. Drying of the organic layer over
Na.sub.2SO.sub.4 and evaporation under reduced pressure yielded
crude material. Purification of the crude material by column
chromatography over silica gel (EtOAc:hexanes, 1:2) gave
2'-O-tert-butyldimethylsilyl-7-O-triethylsi- lylpaclitaxel (2) (325
mg, 95%) as an amorphous solid having the following
characteristics: m.p. 130-131.degree.; .sup.1H-NMR .delta.-0.20 (s,
3H, SiCH.sub.3), -0.02 (s, 3H, SiCH.sub.3), 0.62 (q, J=7.8, 6H,
SiCH.sub.2), 0.79 (s, 9H, tBu), 0.92 (t, J=7.8, 9H,
SiCH.sub.2CH.sub.3), 1.17 (s, 3H, C-16CH.sub.3), 1.21 (s, 3H,
C-17CH.sub.3), 1.70 (s, 3H, C-19CH.sub.3), 2.02 (bs, 3H,
C-18CH.sub.3), 2.16 (s, 3H, C-10 OAc), 2.40 (m, 1H, C-14H), 2.55
(m, 1H, C-6H), 2.58 (s, 3H, C-40Ac), 3.83 (d, J=7.0, 1H, C-3H),
4.19 (d, J=8.3, 1H, C-20H), 4.30 (d, J=8.3, 1H, C-20H), 4.48 (dd,
J=9.4,6.6, 1H, C-7H), 4.67 (d, J=2.1, 1H, C-2'H), 4.94 (bd, J=8.8,
1H, C-5H), 5.69 (d, J=7.0, 1H, C-2H), 5.74 (dd, J=9.0,2.1, 1H,
C-3'H), 6.26 (bt, 1H, C-13H), 6.45 (s, 1H, C-10H), 7.10 (d, J=8.9,
1H, C-3'NH), 7.30-7.60 (m, 11H, ArH), 7.74 (dd, J=8.5,1.5, 2H,
C-3'NBz orthoH), 8.13 (dd, J=8.5,1.4, 2H, C-2-OBz orthoH);
.sup.13C-NMR .delta.-5.86, -5.20, 5.27, 6.73, 10.11, 14.24, 18.11,
20.85, 21.50, 23.10, 25.49, 26.54, 35.55, 37.21, 43.31, 46.64,
55.63, 58.39, 71.36, 72.19, 74.92, 74.95, 75.10, 76.55, 78.82,
81.17, 84.22, 126.40, 126.97, 127.92, 128.68, 128.70, 128.71,
129.19, 130.20, 131.76, 133.60, 133.66, 134.03, 138.26, 140.14,
166.88, 167.03, 169.28, 170.13, 171.38, 201.67; fabms m/z (rel
int.) [M+H].sup.+ 1104 (5), 705 (3), 422 (40), 354 (12), 105 (100);
HRFABMS m/z [M+Na--H].sup.+ 1104.4936
(C.sub.59H.sub.79NO.sub.14Si.sub.2Na requires 1104.4937).
[0062]
2'-O-TERT-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBENZOYL-4-DEACET-
YLPACLITAXEL (3): To a solution of compound 2 (110.4, 0.1 mmol) in
anhydrous CH.sub.2Cl.sub.2 was added benzyltrimethyl ammonium
hydroxide (TritonB, 100 .mu.L, 40% w/w solution in methanol) at
-78.degree. C. The reaction mixture was stirred at -78.degree. C.
for 5 minutes and the cooling bath was removed to allow the
reaction mixture to warm to -10.degree. (ethylene glycol; dry ice
bath). The mixture was stirred at -10.degree. C. for one hour, and
the progress of the reaction was monitored with TLC. The TLC
analysis revealed first formation of more polar 2-debenzoyl
compound (Rf 0.3), that further converted to nonpolar
2-debenzoyl-4-deacetyl compound (Rf 0.5). After completion of the
reaction, the mixture was diluted with cold CH.sub.2Cl.sub.2
(-40.degree.) and quenched with 5 mL 0.1N HCl. The organic layer
was separated by washing successively with water, dilute
NaHCO.sub.3 and brine, and drying over Na.sub.2SO.sub.4.
Concentration under reduced pressure gave a crude residue that was
purified by PTLC (silica gel, 1000 m, ethylacetate:hexanes, 2:3) to
yield compound 3 (60.7 mg, 65%).
[0063] AROYLATION OF
2'-O-TERT-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBE-
NZOYL-4-DEACETYLPACLITAXEL (5a): To a mixture of m-chlorobenzoic
acid (26.6 mg, 0.16 mmol), DCC (39.6 mg, 0.18 mmol), 4-pyrrolidino
pyridine (1.0 mg, 0.006 mmol) in dry toluene (0.3 mL) was added
2-debenzoyl-4-deacetyl-4-acyl-2'-tert-butyl-7-triethylsilylpaclitaxel
(9) (20.0 mg, 0.02 mmol). The mixture was stirred at room
temperature for 10 hours. TLC analysis indicated formation of two
new compounds, both of which were non polar (Rf 0.5 and 0.4) as
compared to the starting material (Rf 0.3). The reaction mixture
was then diluted with EtOAc hexane (1:1, 10 mL) and filtered
through a pad of silica gel and celite. This pad was further washed
with EtOAc (2 mL). The filtrate was concentrated on a rotary
evaporator to give a crude product. Further purification using
preparative TLC (silica gel; 500 m, hexane:EtOAc; 2:1) gave the
less polar spot as the 2,4-di-(m-chlorobenzoyl)-paclitaxel
derivative 5a (6.0 mg, 23%) and the more polar spot as
2-(m-chlorobenzoyl)-2'-O-tert-butyldimethylsilyl-7-O-triethylsilypaclitax-
el (12.5 mg, 54%).
[0064] .sup.1H NMR of
2-(m-chlorobenzoyl)-4-deacetyl-2'-O-tert-butyldimeth-
ylsilyl-7-O-triethylsilyl-paclitaxel (4a): .delta.-0.23 (s, 3H,
SiCH.sub.3), 0.07 (s, 3H, SiCH.sub.3), 0.60 (q, J=7.8, 6H,
SiCH.sub.2), 0.83 (s, 9H, tBu), 0.93 (t, J=7.8, 9H,
SiCH.sub.2CH.sub.3), 1.06 (s, 3H, C-16CH.sub.3), 1.23 (s, 3H,
C-17CH.sub.3), 1.58(s, 3H, C-19CH.sub.3), 2.00 (m, 1H, C-6H), 2.16
(bs, 3H, C-18CH.sub.3), 2.19 (s, 3H, C-10 Oac), 2.30 (dd, 1H,
C-14H), 2.53 (m, 1H, C-6H), 2.79 (dd, 1H, C-14H), 3.45 (d, J=6.0,
1H, C-3H); 4.16 (m, 2H, C-7H and C-20H), 4.28 (d, J=8.3, 1H,
C-20H), 4.56 (d, J=1.2, 1H, C-2'H), 4.82 (s, 1H, C-4 OH), 4.91 (dd,
J=2.1,7.0, 1H, C-5H), 5.70 (d, J=6.0, 1H, C-2H), 5.91 (bt, 1H,
C-13H), 6.06 (bd, 1H, C-3'H), 6.48 (s, 1H, C-1OH), 7.60 (t, J=8.0,
1H, ArH), 7.30-7.66 (m, ArH), 8.14 (bs, 1H, ArH), 8.19 (dt, 1H,
ArH); .sup.13C-NMR .delta.-5.86, -5.51, 5.27, 6.75, 9.84, 16.10,
18.27, 18.90, 20.92, 25.52, 27.47, 35.08, 37.51, 43.02, 51.58,
55.03, 58.91, 71.57, 72.63, 74.34, 75.32, 75.52, 75.60, 77.20,
81.06, 87.55, 126.83, 126.99, 127.93, 128.34, 128.57, 128.81,
130.01, 130.36, 130.68, 131.80, 133.47, 134.66, 134.71, 136.00,
138.87, 139.24, 166.21, 167.80, 169.47, 170.20, 202.25.
[0065] .sup.1H and .sup.13C NMR spectrum of
2-(m-Chlorobenzoyl)-4-(m-chlor- benzoyl)-2-O-tert-butyldimethyl
silyl-7-O-triethylsilylpaclitaxel (5a): .sup.1H-NMR .delta.-0.11
(s, 3H, SiCH.sub.3), 0.03 (s, 3H, SiCH.sub.3), 0.62 (q, J=7.8, 6H,
SiCH.sub.2), 0.84 (s, 9H, tBu), 0.93 (t, J=7.8, 9H,
SiCH.sub.2CH.sub.3), 1.15 (s, 3H, C-16CH.sub.3), 1.23 (s, 3H,
C-17CH.sub.3), 1.74 (s, 3H, C-19CH.sub.3), 1.89 (bs, 3H,
C-18CH.sub.3), 1.95 (m, 1H, C-6H), 2.21 (dd, 1H, C-14 OAc), 2.41
(dd, 1H, C-14H), 2.56 (m, 1H, C-6H), 2.92 (d, 1H, C-2'H), 4.10 (d,
1H, C-3H), 4.32 (d, J=8.3, 1H, C-20H), 4.46 (d, J=8.3, 1H, C-20H),
4.62 (dd, J=9.4,6.6, 1H, C-7H), 4.91 (d, J=2.1, 1H, C-3'-H), 4.97,
(dd, J=8.8, 1H, C-5H), 5.78 (d, J=7.0, 1H, C-2H), 5.87 (bt, 1H,
C-13H), 6.51 (s, 1H, C-10H), 6.79 (d, J=8.9, 1H, C-3'NH), 6.98 (d,
2H, ArH), 7.30-7.66 (m, 11H, ArH), 8.13 (dt, J=8.5,1.4, 2H, ArH),
8.17 (dt, 2H, ArH), 8.21 (dt, 2H, ArH); .sup.13C-NMR .delta.-5.31,
-4.90, 5.27, 6.75, 10.16, 14.07, 18.13, 20.83, 21.80, 25.59, 26.44,
35.70, 37.20, 43.44, 46.61, 55.47, 58.42, 71.99, 72.72, 73.92,
74.87, 75.61, 76.61, 78.65, 82.62, 84.49, 126.80, 127.20, 127.65,
127.81, 128.23, 128.43, 128.64, 129.57, 129.82, 130.21, 130.24,
131.40, 131.61, 131.89, 133.30, 133.70, 134.14, 134.22, 134.78,
134.99, 138.05, 140.73, 164.47, 165.62, 166.97, 169.22, 172.43,
201.62.
[0066]
2'-TERT-BUTYLDIMETHYLSILYL-4-DEACETYL-2-DEBENZOYL-7-TRIETHYLSILYL-P-
ACLITAXEL 1,2-CARBONATE (7): Compound 3 (93:5 mg, 0.1 mmol)) was
dissolved in dry CH.sub.2Cl.sub.2 (0.3 mL) and pyridine (0.3 mL).
To this solution triphosgene (45.0 mg, 0.15 mmol) was added and the
mixture was stirred at room temperature for 4 hours. The reaction
mixture was then diluted with CH.sub.2Cl.sub.2 and washed with 0.1
N HCl, water and brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give a
crude product that was purified by PTLC (silica gel, 1000 m,
ethylacetate:hexanes, 1:3) to yield compound 7 (51.7 mg, 83%).
FABMS m/z (rel int.) [M+H].sup.+ 962.4(8), 904(3), 621(2), 400(90),
354(75), 105 (100); HRFABMS m/z [M+H].sup.+ 962.4512
(C.sub.51H.sub.71NO.sub.13Si.sub.2Na requires 961.4464).
[0067] 2'-TERT-BUTYLDIMETHYLSILYL-7-TRIETHYLSILYL -4-ACYLPACLITAXEL
1,2-CARBONATE DERIVATIVES (8): To a cooled (-78.degree. C.,
acetone, dry ice) solution of compound 7 (32.0 mg, 0.033 mmol) in
freshly distilled anhydrous THF (0.5 mL) was added lithium
hexamethyldisilamide (0.125 mmol) via syringe under argon. The
mixture was stirred at -78.degree. C. for 15 minutes. The
respective electrophile (acid chloride or chloroformate, 0.250
mmol) was added via syringe and the mixture was further stirred for
15 minutes at -78.degree. C. Then the reaction mixture was allowed
to warm to 0.degree. C. and diluted with EtOAc (5 mL) and quenched
with water. The organic layer was then washed with dil.HCl (1N),
dil.NaHCO.sub.3, water, and finally brine. The organic layer was
separated, dried over Na.sub.2SO.sub.4, and concentrated under
reduced pressure to yield the crude product. The crude product thus
obtained was purified using PTLC (silica gel, 500 m,
ethylacetate:hexanes, 1:3) to yield compounds 8 (80-90%).
[0068]
4-DEACETYL-4-(S-METHYLXANTHYL)-2'-TERT-BUTYLDIMETHYLSILYL-7-TRIETHY-
LSILYLPACLITAXEL 1,2-CARBONATE (8a):
4-Deacetyl-2'-tert-butyldimethylsilyl- -7-triethylsilylpaclitaxel
1,2-carbonate (7) (80.0 mg, 0.0825 mmol) was dissolved in freshly
distilled dry THF (0.5 mL). Sodium hydride (6.0 mg, 0.250 mmol) was
added at room temperature, followed by carbon disulfide (0.2 mL,
excess). After stirring for 5 minutes at room temperature, methyl
iodide (0.1 mL, excess) was added and stirred at room temperature.
The reaction was completed in 1 hour. The mixture was diluted with
EtOAc and washed with dil HCl, water and brine. The organic layer
was separated, dried over sodium sulfate and evaporated. The crude
product thus obtained was further purified with preparative TLC
(1000.mu., silicagel, 1:3 ethylacetate:hexanes) to yield amorphous
solid 8a (77.4 mg, 90%). FABMS m/z (rel int.) [M+H].sup.+ 1052 (7),
1022 (15), 514 (4), 400 (20), 354 (75), 105 (100); HRFABMS m/z
[M+H].sup.+ 1052.4120 (C.sub.53H.sub.73NO.sub.13S.sub.2Si.sub.2
requires 1052.4062).
[0069] REACTION OF
2'-TERT-BUTYLDIMETHYLSILYL-7-TRIETHYLSILYL-4-ACYLPACLIT- AXEL
1,2-CARBONATE DERIVATIVES (8) WITH LIOH/THF, WATER: A mixture of
the title compound 8 (60.0 mg, mmol) and LiOH (20.0 mmg, mmol) in
wet THF (0.5 mL, 2 or 3 drops of water) was stirred at room
temerature for 2-3 hours. Monitoring the reaction by TLC indicated
the formation of a low Rf (0.3) spot. The mixture was then diluted
with EtOAc and water. The organic layer was separated, washed with
brine, and evaporated to yield crude product. Purification of the
crude product by preparative TLC afforded the starting compound
(15.5 mg, 25%) as a non polar band and the 2-debenzoyl derivative 9
as a polar band (38.0 mg, 70%).
[0070] REACTION OF 4-(S-METHYLXANTHYL)-2'-TERT-BUTYLDIMETHYL
SILYL-7-TRIETHYLSILYLPACLITAXEL 1,2.CARBONATE (8a) WITH LIOH/THF,
WATER: A mixture of the title compound 8a (60.0 mg, mmol) and LiOH
(20.0 mmg, mmol) in wet THF (0.5 mL, 2 or 3 drops of water) was
stirred at room temperature for 2-3 hours. Monitoring the reaction
by TLC indicated the formation of a low Rf (0.3) spot. The mixture
was then diluted with EtOAc and water. The organic layer was
separated, washed with brine, and evaporated to yield crude
product. Purification of the crude product by preparative TLC
afforded the 2-debenzoyl-4-(S-methylxanthyl) derivative 9a as a
polar band (52.4 mg, 89%).
[0071] GENERAL PROCEDURE FOR AROYLATION OF
2-DEBENZOYL-4-DEACETYL-4-ACYLPA- CLITAXEL ANALOGS (5 and 5a): A
substituted benzoic acid (0.1 mmol) was taken in dry toluene (0.2
mL). To this solution DCC (20.6 mg, 0.1 mmol) and 4-pyrrolidino
pyridine (1.0 mg, 0.006 mmol) were added. The mixture was stirred
at room temperature for 5 minutes. To this mixture a
2-debenzoyl-4-deacetyl-4-acyl-2'-tert-butyl-7-triethylsilylpaclitaxel
analog (9) (10.0 mg, 0.01 mmol) was added. The reaction mixture was
stirred either at room temperature or heated on an oil bath at
60.degree. until the starting compound was consumed (TLC analysis,
generally 4-16hours). The reaction mixture was diluted with EtOAc
(10 mL) and filtered through a pad of silica gel and celite. This
pad was further washed with EtOAc (10 mL). The EtOAc filtrate was
concentrated on a rotary evaporator to give crude product. Further
purification using preparative TLC (silica gel; 500 m,
hexane:EtOAc; 2:1) gave 2-substituted
benzoyl-2'-tert-butyl-7-triethylsilypaclitaxel analogs 5 and 5a
respectively (60-90% yield).
[0072] GENERAL PROCEDURE FOR DEPROTECTION OF SILYL GROUPS OF
DERIVATIVES (5) BY METHANOL/HCL:
2-Debenzoyl-2-aroyl-4-deacetyl-4-acyl-2'-tert-butyl--
7-triethylsilyl paclitaxel 5 (0.005 mmol) was dissolved in freshly
prepared methanolic HCl (5%, v/v) solution. The mixture was kept
stirring at room temperature for 45-60 minutes. The mixture was
diluted with EtOAc (10 mL) and washed with dil. NaHCO.sub.3
solution, water and brine. The organic layer was dried over sodium
sulfate and concentrated to give crude product. Further
purification was carried out using preparative TLC to give
homogenous product 6 (70-90%).
[0073] GENERAL PROCEDURE FOR DEPROTECTION OF SILYL GROUPS OF
DERIVATIVES (5a) BY HF/PYRIDINE: To a solution of
2-debenzoyl-2-aroyl-4-deacetyl-4-(S- -methylxanthyl) derivatives 5a
(0.005 mmol) in dry THF (0.5 mL) was added HF/pyridine at room
temperature. The exothermic reaction mixture was then stirred at
room temperature for 2 hours. The reaction mixture was diluted with
EtOAc and washed with dil. NaHCO.sub.3, dil. HCl and finally brine.
The organic layer was separated, dried over Na.sub.2SO.sub.4, and
evaporated to yield crude material. Further purification by PTLC
afforded 2-debenzoyl-2-aroyl-4-deacetyl-4-(S-methylxanthyl)
paclitaxel analogs 6a.
[0074]
2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBENZOYL-4-DEACET-
YL-4-(METHOXYCARBONYL)-PACLITAXEL: To a solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-4-deacetyl-4-(-
methoxycarbonyl)-paclitaxel 1,2-carbonate (8b) (50 mg, 0.49 mmol)
in THF (1 mL) and water (0.1 mL), LiOH (20 mg, 0.64 mmol) was added
and stirred at room temperature for 1.5 hours. The mixture was
taken up in EtOAc (10 mL), washed with water and brine, and dried
over sodium sulfate. The residue obtained after concentration was
purified by PTLC (silica gel, 1000 .mu.M, EtOAc:hexane, 2:3) to
furnish 2'-O-tert-butyldimethylsilyl-7--
O-triethylsilyl-2-debenzoyl-4-deacetyl-4-(methoxycarbonyl)-paclitaxel
(9b) (20 mg, 59% yield based on the recovery of 15 mg unreacted
starting compound) and
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl--
4-deacetyl-paclitaxel (6 mg). .sup.1H NMR: .delta., -0.27 (s, 3H),
-0.06 (s, 3H), 0.54-0.60 (m, 6H), 0.79 (s, 9H), 0.89-0.96 (m, 9H),
1.03 (s, 3H), 1.09 (s, 3H), 1.22-1.27 (m, 1H), 1.85 (s, 3H),
1.86-1.95 (m, 1H), 2.04 (s, 3H), 2.08-2.14 (m, 1H), 2.12 (s, 3H),
2.25-2.29 (m, 1H), 2.45-2.53 (m, 1H), 3.24 (d, J=4.28 Hz, 1H), 3.30
(s, 1H), 3.52 (d, J=6.86 Hz, 1H), 3.86 (s, 3H), 3.92-3.95 (m, 1H),
4.37-4.41 (m, 1H), 4.52 (d, J=1.37 Hz, 1H), 4.65 (d, J=9.46 Hz,
1H), 4.70 (d, J=9.61 Hz, 1H), 4.98 (d, J=7.78 Hz, 1H), 5.70 (d,
J=9.31 Hz, 1H), 6.18 (dd, J=8.7, 8.24 Hz, 1H), 6.35 (s, 1H), 7.09
(d, J=9.46 Hz, 1H), 7.29-7.52 (m, 8H), 7.72 (d, J=7.17 Hz, 2H);
.sup.13 C NMR: .delta., -5.78, -5.25, 5.23, 6.71, 10.32, 14.21,
18.14, 20.81, 21.12, 25.42, 25.48. 26.26, 35.41, 37.24, 42.92,
46.73, 55.41, 55.87, 58.09, 71.46, 72.05, 73.75, 74.96, 75.14,
77.78, 78.03, 83.66, 84.26, 126.22, 126.62, 126.91, 126.99, 127.93,
128.49, 128.59, 128.83, 131.86, 134.17, 143.20, 138.41, 139.72,
152.91, 167.56, 169.24,171.51, 202.27; HRFABMS: m/z [M+H].sup.+
994.4822 (C.sub.52H.sub.76NO.sub.14Si.sub.2 requires 994.4802).
[0075]
2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBENZOYL-2-(3-AZI-
DO BENZOYL)-4-DEACETYL-4-(METHOXYCARBONYL)-PACLITAXEL (5b): To a
mixture of the
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-4-deace-
tyl-4-(methoxycarbonyl)-paclitaxel (10 mg, 0.01 mmol),
m-azidobenzoic acid (16 mg, 0.09 mmol) and pyrrolidinopyridine (1.0
mg) was added toluene (0.8 mL) and the reaction mixture was stirred
at room temperature for 24 hours and purified by PTLC (silica gel,
1000 .mu.M, EtOAc-hexane, 2:3) to yield
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-2-(3-azi-
dobenzoyl)-4-deacetyl-4-(methoxycarbonyl)-paclitaxel (9.0 mg, 79%).
.sup.1H NMR: .delta., -0.30 (s, 3H), -0.03 (s, 3H), 0.54-0.61 (m,
6H), 0.78 (s, 9H), 0.91-0.94 (m, 9H), 1.15 (s, 3H), 1.22 (s, 3H),
1.66-1.68 (m, 1H), 1.70 (s, 3H), 1.81 (s, 3H), 1.89-1.96 (m, 1H),
2.06 (s, 3H), 2.12-2.17 (m, 1H), 2.17 (s, 3H), 2.38-2.44 (m, 1H),
2.52-2.55 (m, 1H), 3.94 (d, J=6.87 Hz, 1H), 4.03 (s, 3H), 4.21 (d,
J=8.85 Hz, 1H), 4.37 (d, J=8.24 Hz, 1H), 4.43-4.48 (dd, J=6.87,
6.56 Hz, 1H), 4.67 (d, J=1.68 Hz, 1H), 5.10 (d, J=7.63 Hz, 1H),
5.71 (d, J=7.02 Hz, 1H), 5.77 (d, J=9.76 Hz, 1H), 6.20-6.24 (dd,
J=7.94, 9.16 Hz, 1H), 6.46 (s, 1H), 7.09 (d, J=9.31 Hz, 1H),
7.21-7.52 (m, 10H), 7.73-7.78 (d, J=7.17 Hz, 3H), 7.92 (d, J=7.78
Hz, 1H). .sup.13C NMR: .delta., -5.21, -5.25, 6.73, 10.09, 14.40,
18.11, 20.84, 21.09, 25.48, 26.50, 35.58, 32.12, 43.23, 46.71,
55.44, 56.47, 58.25, 70.86, 72.03, 75.01, 75.10, 75.25, 78.53,
83.17, 83.97, 120.45, 124.00, 126.49, 126.56, 126.93, 127.79.
128.57, 128.73, 130.25, 131.70, 133.65, 134.30, 140.43, 140.89,
152.56, 166.10, 166.91, 169.25, 171.51, 201.47. HRFABMS: m/z
[M+H].sup.+ 1139.5061 (calcd for
C.sub.59H.sub.79N.sub.4O.sub.15Si.sub.2, 1139.5080).
[0076]
2-DEBENZOYL-2-(3-AZIDOBENZOYL)-4-DEACETYL-4-(METHOXYCARBONYL)-PACLI-
TAXEL (6b): To a solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsily-
l-2-debenzoyl-2-(3-azido
benzoyl)-4-deacetyl-4-(methoxycarbonyl)-paclitaxe- l (8.0 mg, 0.007
mmol) in dry THF was added HF-pyridine (0.2 mL) in a Teflon vial.
The reaction mixture was stirred at room temperature for 2 hours.
The mixture was then diluted with EtOAc (10 mL) and washed
thoroughly with dilute sodium bicarbonate, dilute HCl, water and
finally brine. The organic layer was dried over sodium sulfate and
evaporated to yield crude product, which was purified by PTLC (500
.mu.M, 55% EtOAc/Hexane) to give
2-debenzoyl-2-(3-azidobenzoyl)-4-deacetyl-4-(methox-
ycarbonyl)-paclitaxel (6b, 6.3 mg, 98%) .sup.1H NMR: .delta., 1.14
(s, 3H), 1.24 (s, 3H), 1.67 (s, 3H), 1.85 (s, 3H), 1.88 (s, 1H),
1.89-1.93 (m, 1H), 2.24 (s, 3H), 2.35-2.57 (m, 4H), 3.57 (d, J=4.89
Hz, 1H), 3.77 (s, 3H), 3.84 (d, J=6.86 Hz, 1H), 4.20 (d, J=8.39 Hz,
1H), 4.34-4.41 (m, 2H), 4.47-4.79 (m, 1H), 4.99 (d, J=9.00 Hz, 1H),
5.69 (d, J=7.17 Hz, 1H), 5.80 (d, J=8.85 Hz, 1H), 6.18-6.22 (dd,
J=7.78, 9.00 Hz, 1H), 6.27 (s, 1H), 6.87 (d, J=9.01 Hz, 1H),
7.24-7.51 (m, 10H), 7.57 (d, J=7.63 Hz, 2H), 7.70 (d, J=7.02 Hz,
2H), 7.82-7.83 (m, 1H), 7.94 (d, J=7.79 Hz, 1H). HRFABMS: m/z
[M+H].sup.+ 911.3343 (C.sub.47H.sub.51N.sub.4O.sub.15 requires
911.3350).
[0077]
2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBENZOYL-2-(3,3-D-
IMETHYL-ACRYLOYL)-4-DEACETYL-4-(METHOXYCARBONYL)-PACLITAXEL (5c): A
mixture of the
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-
-4-deacetyl-4-(methoxycarbonyl)-paclitaxel (9b, 10 mg, 0.01 mmol),
3,3-dimethylacrylic acid (10 mg, 0.1 mmol) and pyrrolidinopyridine
(1.0 mg) in toluene (0.8 mL) was stirred at room temperature for 24
hours and purified by PTLC (silica gel, 1000 .mu.M, EtOAc hexane,
3:7) to yield
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-2-(3,3-dimethy-
lacryloyl)-4-deacetyl-4-(methoxycarbonyl)-paclitaxel (5c, 7.0 mg,
95% based on the recovery of 2 mg unreacted starting compound).
.sup.1H NMR: .delta., 0.35 (s, 3H), -0.04 (s, 3H), 0.52-0.62 (m,
6H), 0.78 (s, 9H), 0.87-0.93 (m, 9H), 1.14 (s, 3H), 1.18 (s, 3H),
1.25 (s, 3H), 1.67 (s, 3H), 1.89 (s, 3H), 1.97 (d, J=0.92 Hz, 3H),
2.02 (d, J=0.92 Hz, 3H), 1.91-2.22 (m, 3H), 2.16 (s, 3H), 2.19 (s,
3H), 2.52-2.55 (m, 1H), 3.78 (d, J=6.72 Hz, 1H), 4.00 (s, 3H), 4.22
(d, J=8.85 Hz, 1H), 4.39-4.43 (dd, J=6.86, 6.72 Hz, 1H), 4.52 (d,
J=8.39 Hz, 1H), 4.65 (d, J=1.68 Hz, 1H), 5.03 (d, J=7.62 Hz, 1H),
5.48 (d, J=6.72 Hz, 1H), 5.67-5.70 (m, 2H), 6.20-6.25 (dd, J=9.46,
9.76 Hz, 1H), 6.43 (s, 1H), 7.13 (d, J=8.70 Hz, 1H), 7.27-7.55 (m,
8H), 7.78 (d, J=6.92 Hz, 1H). HRFABMS: m/z [M+H].sup.+ 1076.5206
(calcd for C.sub.57H.sub.82NO.sub.15Si.sub.2, 1076.5223).
[0078] 2-DEBENZOYL-2-(3,3-DIMETHYL-ACRYLOYL)-4-DEACETYL-4-(METHYL
CARBONATE)-PACLITAXEL (6c): To a solution of
2'-O-tert-butyldimethylsilyl-
-7-O-triethylsilyl-2-debenzoyl-2-(3,3-dimethyl-acryloyl)-4-deacetyl-4-(met-
hoxycarbonyl)-paclitaxel (6.0 mg, 0.005 mmol) in dry THF (1 mL) was
added HF-pyridine (0.2 mL) in a Teflon vial. The reaction mixture
was stirred at room temperature for 2 hours. After usual workup the
residue obtained was purified by PTLC (500 .mu.M, 55% EtOAc/hexane)
to give 2-debenzoyl-2-(3,3-dimethyl
acryloyl)-4-deacetyl-4-(methoxycarbonyl)-pacl- itaxel (6c, 3.9 mg,
98%). .sup.1H NMR: .delta., 1.10 (s, 3H), 1.21 (s, 3H), 1.63 (s,
3H), 1.79 (d, J=1.22 Hz, 3H), 1.83 (s, 3H), 1.86-1.89 (m, 1H), 1.95
(d, J=1.07 Hz, 3H), 2.19 (s, 3H), 2.23 (s, 3H), 2.26-2.34 (m, 2H),
2.44 (d, J=4.27 Hz, 1H), 2.50-2.58 (m, 1H), 3.58 (d, J=4.27 Hz,
1H), 3.70 (d, J=6.71 Hz, 1H), 3.78 (s, 3H), 4.20 (d, J=8.24 Hz,
1H), 4.34 (m, 1H), 4.51 (d, J=8.85 Hz, 1H), 4.74-4.76 (dd, J=2.29,
2.13 Hz, 1H), 4.99 (d, J=7.79 Hz, 1H), 5.46 (d, J=6.71 Hz, 1H),
5.71 (s, 1H), 5.78 (d, J=8.85 Hz, 1H), 6.15 (m, 1H), 6.23 (s, 1H),
6.95 (d, J=9.77 Hz, 1H), 7.30-7.55 (m, 8H), 7.77 (d, J=7.02 Hz,
1H). HRFABMS: m/z [M+H].sup.+ 848.3501 (calcd for
C.sub.45H.sub.54NO.sub.15, 848.3493).
[0079] 2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBENZOYL
-4-DEACETYL-4-(tert-BUTOXY-CARBONYL)-PACLITAXEL 1,2-CARBONATE (8c):
To a stirred solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debe-
nzoyl-4-deacetyl-paclitaxel 1,2-carbonate (80 mg, 0.083 mmol), DMAP
(15 mg) in CH.sub.2Cl.sub.2 di-tert-butyldicarbonate (180 mg, 0.83
mmol) was added and the mixture was stirred at room temperature for
6 hours. It was diluted with CH.sub.2Cl.sub.2 (20 mL) and washed
throughly with water and brine. The organic layer was dried over
sodium sulfate and evaporated to yield crude product, which was
purified by PTLC (1000 .mu.M, EtOAc/hexane, 3:7) to give
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-
-2-debenzoyl-4-deacetyl-4-(tert-butoxycarbonyl)-paclitaxel
1,2-carbonate (8c, 82 mg, 93%). .sup.1H NMR: .delta., -0.41 (s,
3H), -0.03 (s, 3H), 0.55-0.60 (m, 6H), 0.79 (s, 9H), 0.90 (t,
J=8.24 Hz, 9H), 1.22 (s, 3H), 1.31 (s, 3H), 1.53 (s, 9H), 1.76 (s,
3H), 1.81-2.00 (m, 1H), 2.03 (s, 3H), 2.15 (s, 3H), 2.35-2.41 (m,
1H), 2.50-2.56 (dd, J=9.31, 9.46 Hz, 1H), 2.62-2.69 (m, 1H), 3.54
(d, J=5.80 Hz, 1H), 4.37-4.41 (dd, J=7.48, 7.17 Hz, 1H), 4.50-4.56
(dd, J=9.00, 5.96 Hz, 2H), 4.75-4.77 (m, 2H), 5.08 (d, J=8.55 Hz,
1H), 5.89 (d, J=9.31 Hz, 1H), 6.21-6.25 (dd, J=8.4, 8.24 Hz, 1H),
6.46 (s, 1H), 7.01 (d, J=9.31 Hz, 1H), 7.23-7.55 (m, 8H), 7.81 (d,
J=7.02 Hz, 1H). .sup.13C NMR: .delta., -5.89, -5.16, 5.19, 6.71,
10.16, 15.30, 17.98, 20.59, 20.72, 25.45, 25.55, 28.70, 32.78,
38.10, 41.39, 43.51, 55.29, 60.08, 69.19, 71.71, 75.18, 75.83,
80.90, 81.45, 83.81, 86.78. 89.97, 126.82, 127.05, 127.47, 128.24,
128.73, 131.17, 131.66, 134.40, 138.22, 143.76, 151.18, 152.40,
166.83, 169.02, 171.70, 201.90; HRFABMS: m/z [M+H].sup.+ 1062.5079
(calcd for C.sub.56H.sub.80NO.sub.15Si.sub.2, 1062.5066).
[0080]
2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-4-DEACETYL-4-(tert-B-
UTOXY-CARBONYL)-PACLITAXEL (5d) AND
2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIET-
HYLSILYL-10,4-DI-DEACETYL-4-(tert-BUTOXYCARBONYL)-PACLITAXEL (5e):
To a dry THF (1.5 mL) solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsil-
yl-2-debenzoyl-4-deacetyl-4-(tert-butoxy-carbonyl)-paclitaxel
1,2-carbonate (15 mg, 0.014 mmol) was added under argon a hexane
solution of phenyllithium (1.6 M, 78 .mu.L, 0.14 mmol). The
solution was stirred at -78.degree. C. for 20 min and 0.degree. C.
for 5 min. Then it was poured on a mixture of EtOAc (10 mL) and
dilute HCl (0.1 N, 2 mL). After standard workup, the residue was
purified on PTLC (500 .mu.M, EtOAc/hexane, 3:7) to give two
products: 2'-O-tert-butyldimethylsilyl-7-O-
-triethylsilyl-4-deacetyl-4-(tert-butoxycarbonyl)-paclitaxel (5d,
6.1 mg, 38%) and
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-10,4-di-deacetyl--
4-(tert-butoxy carbonyl)-paclitaxel (5e, 6.8 mg, 44%). Compound 5d:
.sup.1H NMR: .delta., -0.30 (s, 3H), -0.04 (s, 3H), 0.52-0.58 (m,
6H), 0.88 (s, 9H), 0.89-0.98 (m, 9H), 1.22 (s, 3H), 1.24 (s, 3H),
1.59 (s, 9H), 1.61 (s, 3H), 1.72 (s, 3H), 1.82-1.92 (m, 2H), 2.23
(s, 3H), 2.51-2.53 (m, 2H), 3.84 (d, J=6.40 Hz, 1H), 4.21 (d,
J=8.55 Hz, 1H), 4.35-4.42 (m, 2H), 4.68 (m, 1H), 4.98 (d, J=7.02
Hz, 1H), 5.73-5.79 (m, 2H), 6.12 (m, 1H), 6.41 (s, 1H), 7.13 (d,
J=9.00 Hz, 1H), 7.23-7.58 (m, 1H), 7.78 (d, J=7.02 Hz, 2H), 8.06
(d, J=7.02 Hz, 2H). Compound 5e: .sup.1H NMR: .delta., -0.32 (s,
3H), -0.04 (s, 3H), 0.55-0.61 (m, 6H), 0.87 (s, 9H), 0.88-0.97 (m,
9H), 1.08 (s, 3H), 1.12 (s, 3H), 1.57 (s, 9H), 1.71 (s, 3H),
1.70-1.92 (m, 2H), 2.21 (s, 3H), 2.53-2.58 (m, 2H), 3.90 (d, J=6.72
Hz, 1H), 4.26 (d, J=9.40 Hz, 1H), 4.32-4.45 (m, 2H), 4.64 (s, 1H),
4.98 (d, J=7.48 Hz, 1H), 4.76-4.80 (m, 2H), 6.12 (m, 1H), 7.12 (d,
J=9.00 Hz, 1H), 7.28-7.61 (m, 11H), 7.78 (d, J=7.02 Hz, 2H), 8.04
(d, J=7.02 Hz, 2H).
[0081] 4-DEACETYL-4-(tert-BUTOXYCARBONYL)-PACLITAXEL (6d): To a
solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-4-deacetyl-4-(tert-buto-
xycarbonyl)-paclitaxel (5d, 6.1 mg, 0.005 mmol) in dry THF (1 mL)
was added HF-Pyridine (0.4 mL) in a Teflon vial. The reaction
mixture was stirred at room temperature for 2 hours. After usual
workup, the residue obtained was purified by PTLC (500 .mu.M, 55%
EtOAc/hexane) to give 4-deacetyl-4-(tert-butoxycarbonyl)-paclitaxel
(4.3 mg, 89%). .sup.1H NMR: .delta., 1.14 (s, 3H), 1.23 (s, 3H),
1.51 (s, 9H), 1.61 (s, 3H), 1.73 (s, 3H), 1.74 (s, 1H), 1.84-1.90
(m, 2H), 2.24 (s, 3H), 2.39-2.43 (m, 1H), 2.48 (d, J=3.97 Hz, 1H),
2.50-2.54 (m, 1H), 3.73 (s, 1H), 3.81 (d, J=6.41 Hz, 1H), 3.92 (d,
J=3.82 Hz, 1H), 4.21 (d, J=8.55 Hz, 1H), 4.33 (m, 1H), 4.40 (d,
J=8.55 Hz, 1H), 4.80 (m, 1H), 4.98 (d, J=6.71 Hz, 1H), 5.70 (d,
J=7.13 Hz, 1H), 5.83 (d, J=6.71 Hz, 1H), 6.11-6.14 (m, 1H), 6.24
(s, 1H), 7.15-7.62 (m, 11H), 7.79 (d, J=7.32 Hz, 2H), 8.04 (d,
J=7.17 Hz, 2H). HRFABMS: m/z 934.3648 [M+Na].sup.+ (calcd for
C.sub.50H.sub.57NO.sub.15Na- , 934.3625).
[0082] 10,4-DI-DEACETYL-4-(tert-BUTOXYCARBONYL)-PACLITAXEL (6e): To
a solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-4,10-di-deacet-
yl-4-(tert-butoxycarbonyl)-paclitaxel (5e, 6.1 mg, 0.005 mmol) in
dry THF (1 mL) was added HF-pyridine (0.4 mL) in a Teflon vial. The
reaction mixture was stiffed at room temperature for 2 hours. After
usual workup, the residue obtained was purified by PTLC (500 .mu.M,
55% EtOAc/hexane) to give
10,4-dideacetyl-4-(tert-butoxycarbonyl)-paclitaxel (4.1 mg, 85%).
.sup.1H NMR: .delta., 1.11 (s, 3H), 1.20 (s, 3H), 1.52 (s, 9H),
1.71 (s, 3H), 1.68-1.89 (m, 2H), 2.39 (s, 3H), 2.39 (d, J=9.00 Hz,
2H), 2.52-2.59 (m, 1H), 3.90 (d, J=3.35 Hz, 1H), 3.92 (d, J=6.72
Hz, 1H), 4.13 (m, 1H), 4.17 (d, J=1.68 Hz, 1H), 4.26 (d, J=9.46 Hz,
1H), 4.78-4.80 (dd, J=2.59, 3.51 Hz, 1H), 4.96 (d, J=7.78 Hz, 1H),
5.17 (d, J=1.83 Hz, 1H), 5.71 (d, J=6.71 Hz, 1H), 5.83 (d, J=9.00
Hz, 1H), 6.06-6.09 (dd, J=7.02, 8.70 Hz, 1H), 7.25-7.51 (m, 10H),
7.60 (dd, J=7.47, 7.78 Hz, 1H), 7.79 (d, J=7.02 Hz, 2H), 8.03 (d,
J=7.02 Hz, 2H). HRFABMS: m/z [M+H].sup.+ 870.3698 (calcd for
C.sub.48H.sub.56NO.sub.14, 870.3700).
[0083]
2'-O-tert-BUTYLDIMETHYLSILYL-7-O-TRIETHYLSILYL-2-DEBENZOYL-2-(m-MET-
HOXY-BENZOYL)-4-DEACETYL-4-(tert-BUTOXYCARBONYL)-PACLITAXEL (5f):
To a dry THF (1.5 mL) solution of
2'-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-
-debenzoyl-1,2-carbonate-4-deacetyl-4-(tert-butoxy
carbonyl)-paclitaxel (15 mg, 0.014 mmol) was added under argon a
THF solution of m-methoxyphenyllithium [prepared from 1.6 M
n-butyllithium (90 .mu.L, 0.14 mmol) and m-bromoanisole (17 .mu.L,
0.14 mmol)]. The solution was stirred at -78.degree. C. for 20 min
and 0.degree. C. for 5 min. After standard workup, the residue was
purified on PTLC (500 .mu.M, EtOAc/hexane, 3:7) to give two
products 2'-O-tert-butyldimethylsilyl-7-O--
triethylsilyl-2-debenzoyl-2-(m-methoxybenzoyl)-4-deacetyl-4-(tert-butoxyca-
rbonyl)-paclitaxel (8.0 mg, 90%, based on the recovery of 7 mg
unreacted staring compound). .sup.1H NMR: .delta., -0.30 (s, 3H),
-0.03 (s, 3H), 0.51-0.59 (m, 6H), 0.82 (s, 9H), 0.95-0.99 (m, 9H),
1.22 (s, 3H), 1.59 (s, 9H), 1.71 (s, 3H), 1.91-2.04 (m, 1H), 2.03
(s, 3H), 2.19-2.24 (m, 1H), 2.21 (s, 3H), 2.48-2.52 (m, 2H), 3.81
(d, J=7.18 Hz, 1H), 3.93 (s, 3H), 4.22 (d, J=9.16 Hz, 1H),
4.42-4.56 (m, 2H), 4.64 (s, 1H), 4.98 (d, J=7.48 Hz, 1H), 5.72-5.78
(m, 2H), 6.16 (m, 1H), 6.44 (s, 1H), 7.11-7.52 (m, 10H), 7.71-7.78
(m, 4H).
[0084] 2-DEBENZOYL-2-(m-METHOXYBENZOYL)-4-DEACETYL-4-(tert-BUTOXY
CARBONYL)-PACLITAXEL (6f): To a solution of
2'-O-tert-butyldimethylsilyl--
7-O-triethylsilyl-2-debenzoyl-2-(m-methoxybenzoyl)-4-deacetyl-4-(tert-buto-
xycarbonyl)-paclitaxel (5f, 8.0 mg, 0.006 mmol) in dry THF (1 mL)
was added HF-pyridine (0.2 mL) in a Teflon vial. The reaction
mixture was stirred at room temperature for 1 hour. After usual
workup, the residue obtained was purified by PTLC (500 .mu.M, 55%
EtOAc/hexane) to give
2-debenzoyl-2-(m-methoxybenzoyl)-4-deacetyl-4-(tert-butoxycarbonyl)-pacli-
taxel (6f, 4.1 mg, 64%). .sup.1H NMR: .delta., 1.14 (s, 3H), 1.26
(s, 3H), 1.47 (s, 9H), 1.68 (s, 3H), 1.76 (s, 3H), 1.83 (s, 1H),
1.86-1.94 (m, 1H), 2.24 (s, 3H), 2.36-2.44 (m, 2H), 2.48 (d, J=3.97
Hz, 2H), 2.53-2.58 (m, 1H), 3.78 (d, J=7.17 Hz, 1H), 3.80 (d,
J=3.81 Hz, 1H), 3.87 (s, 3H), 4.21 (d, J=9.16 Hz, 1H), 4.38 (m,
1H), 4.41 (d, J=8.24 Hz, 1H), 4.80-4.81 (dd, J=2.29, 2.44 Hz, 1H),
4.96 (d, J=7.48 Hz, 1H), 5.68 (d, J=7.02 Hz, 1IH), 5.82 (d, J=11.14
Hz, 1H), 6.16 (m, 1H), 6.24 (s, 1H), 7.05 (d, J=9.00 Hz, 1H),
7.12-7.15 (m, 1H), 7.29-7.53 (m, 9H), 7.64 (d, J=7.02 Hz, 2H), 7.74
(d, J=7.02 Hz, 2H). HRFABMS: m/z [M+H].sup.+ 942.3912 (calcd for
C.sub.51H.sub.60NO.sub.16, 942.3912).
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