U.S. patent application number 09/528230 was filed with the patent office on 2001-10-18 for process for the preparation of aziridinyl epothilones from oxiranyl epothilones.
Invention is credited to Borzilleri, Robert M., Kim, Soong-Hoon, Regueiro-Ren, Alicia, Vite, Gregory D..
Application Number | 20010031880 09/528230 |
Document ID | / |
Family ID | 26825179 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031880 |
Kind Code |
A1 |
Borzilleri, Robert M. ; et
al. |
October 18, 2001 |
Process for the preparation of aziridinyl epothilones from oxiranyl
epothilones
Abstract
The present invention relates to a stereospecific process to
produce aziridinyl epothilones from oxiranyl epothilones and the
intermediates derived therein.
Inventors: |
Borzilleri, Robert M.; (New
Hope, PA) ; Kim, Soong-Hoon; (Lawrenceville, NJ)
; Regueiro-Ren, Alicia; (Plainsboro, NJ) ; Vite,
Gregory D.; (Titusville, NJ) |
Correspondence
Address: |
MARLA J MATHIAS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
26825179 |
Appl. No.: |
09/528230 |
Filed: |
March 17, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60126936 |
Mar 29, 1999 |
|
|
|
Current U.S.
Class: |
548/961 ;
549/214; 549/271 |
Current CPC
Class: |
C07D 491/04
20130101 |
Class at
Publication: |
548/961 ;
549/214; 549/271 |
International
Class: |
C07F 007/02; C07D
313/00; C07D 23/26 |
Claims
What is claimed:
1. A process for preparing a compound of structure VI 22wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 are selected from the
group H or alkyl and when R.sub.1 and R.sub.2 are alkyl can be
joined to form a cycloalkyl; R.sub.6 is selected from the group
consisting of H, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, or heterocyclo; R.sub.7 is selected from the group
consisting of alkyl, substituted alkyl, aryl, or substituted aryl;
and P.sub.1 is selected from the group H, alkyl, substituted alkyl,
alkanoyl, substituted alkanoyl, aroyl, substituted aroyl,
trialkylsilyl, aryl dialkylsilyl, diaryl alkylsilyl, triarylsilyl;
which comprises: (a) reacting a compound of structure I 23wherein
R.sub.1-6 and P.sub.1 are defined as above with at least one metal
halide salt to form structure II; 24(b) reacting the product of (a)
with at least one azide salt to form structure III; 25(c)
conducting a Mitsunobu reaction with the product of (b) wherein
R.sub.7 is defined as above to form the structure IV; 26(d)
cleaving the ester group of the product of (c) to form structure V;
27and (e) reducing and cyclizing the product of (d) with a reducing
agent to form the stereospecific form of structure VI.
2. The process of claim 1 wherein the product of step (c) or (d) is
deprotected prior to further reaction.
3. A compound of claim 1 having structure III: 28wherein R.sub.1-6
and P.sub.1 are defined therein.
4. A compound of claim 1 having structure IV: 29wherein R.sub.1-7
and P.sub.1 are defined therein.
5. A compound of claim 1 having structure V: 30wherein R.sub.1-6
and P.sub.1 are defined therein.
6. A process for preparing a compound of structure VI 31wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 are selected from the
group H or alkyl and when R.sub.1 and R.sub.2 are alkyl can be
joined to form a cycloalkyl; R.sub.6 is selected from the group
consisting of H, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, or heterocyclo; and P.sub.1 is selected from the group
H, alkyl, substituted alkyl, alkanoyl, substituted alkanoyl, aroyl,
substituted aroyl, trialkylsilyl, aryl dialkylsilyl, diaryl
alkylsilyl, triarylsilyl; which comprises: (a) reacting a compound
of structure V 32wherein R.sub.1-6 and P.sub.1 are defined as above
with an alkyl-, a substituted alkyl-, an aryl-, or a substitued
arylsulfonyl halide to form structure VII; 33and (b) reducing and
cyclizing the product of (a) wherein R.sub.7 is an alkyl,
substituted alkyl, aryl, or substitued aryl with a reducing agent
to form the stereospecific form of structure VI.
7. A compound of claim 6 having structure VII: 34wherein R.sub.1-7
and P.sub.1 are defined therein.
8. A process for preparing a compound of structure VI 35wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 are selected from the
group H or alkyl and when R.sub.1 and R.sub.2 are alkyl can be
joined to form a cycloalkyl; R.sub.6 is selected from the group
consisting of H, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, or heterocyclo; and P.sub.1 is selected from the group
H, alkyl, substituted alkyl, alkanoyl, substituted alkanoyl, aroyl,
substituted aroyl, trialkylsilyl, aryl dialkylsilyl, diaryl
alkylsilyl, triarylsilyl; which comprises: (a) reacting a compound
of structure III 36wherein R.sub.1-6 are defined above and P.sub.1
is a protecting group with triphenylphosphine and a carbon
tetrahalide to form structure VIII; 37and (b) reducing and
cyclizing the product of (a) wherein X is a halogen with a reducing
agent to form the stereospecific form of structure VI.
9. A compound of claim 8 having structure VIII: 38wherein R.sub.1-6
and P.sub.1 are defined therein.
10. A process for preparing a compound comprising: (a) reacting a
compound of structure I 39wherein: R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 are selected from the group H or alkyl and when
R.sub.1 and R.sub.2 are alkyl can be joined to form a cycloalkyl;
R.sub.6 is selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, cycloalkyl, or
heterocyclo; R.sub.7 is selected from the group consisting of
alkyl, substituted alkyl, aryl, or substituted aryl; and P.sub.1 is
selected from the group H, alkyl, substituted alkyl, alkanoyl,
substituted alkanoyl, aroyl, substituted aroyl, trialkylsilyl, aryl
dialkylsilyl, diaryl alkylsilyl, triarylsilyl; with at least one
metal halide salt to form structure II; 40(b) reacting the product
of (a) with at least one azide salt to form structure III; 41(c)
conducting a Mitsunobu reaction with the product of (b) to form the
structure IV; 42(d) cleaving the ester group of the product of (c)
to form structure V; 43and (e) reducing and cyclizing the product
of (d) with a reducing agent to form the stereospecific form of
structure VI. 44
Description
[0001] This application claims priority from provisional U.S.
application Ser. No. 60/126,936, filed Mar. 29, 1999, incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a stereospecific process
for the preparation of epothilone derivatives and intermediates
therefor.
BACKGROUND OF THE INVENTION
[0003] Epothilones are macrolide compounds which find utility in
the pharmaceutical field. For example, Epothilones A and B having
the structures: 1
[0004] have been found to exert microtubule-stabilizing effects
similar to paclitaxel (TAXOL.RTM.) and hence cytotoxic activity
against rapidly proliferating cells, such as, tumor cells or other
hyperproliferative cellular disease, see Angew. Chem. Int. Ed.
Engl., Vol. 35, No. 13/14, 1567-1569 (1996).
[0005] Derivatives and analogs of Epothilones A and B have been
synthesized and have been used to treat a variety of cancers and
other abnormal proliferative diseases. Such analogs are disclosed
in Hofle et al., Angew. Chem. Int. Ed. Engl., 35, No. 13/14 (1996);
WO93/10121 published May 27, 1993 and WO97/19086 published May 29,
1997; and Nicolaou et al., Angew Chem. Int. Ed. Engl., Vol. 36, No.
19, 2097-2103 (1997); and Su et al., Angew Chem. Int. Ed. Engl.,
Vol. 36, No. 19, 2093-2096 (1997).
[0006] For reasons of stability, it would be desirable to convert
the epoxide moiety of Epothilones A and B to their corresponding
aziridine form. However, conventional methods of affecting this
conversion, such as the methods of R. Zamboni and J. Rokach,
Tetrahedron Letters, 331-334 (1983); and Y. Ittah et al., J. Org.
Chem., 43, 4271-4273 (1978), result in a molecule having an
opposing stereoconfiguration. Applicants have now found a process
for synthesizing epothilones that retains the stereoconfiguration
of the starting material.
SUMMARY OF THE INVENTION
[0007] The present invention is a process for preparing
stereospecific aziridinyl epothilones and the intermediates derived
therein. The invention is directed to a process for preparing
compounds of structure VI 2
[0008] wherein:
[0009] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 are selected
from the group H or alkyl and when R.sub.1 and R.sub.2 are alkyl
can be joined to form a cycloalkyl;
[0010] R.sub.6 is selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, cycloalkyl, or
heterocyclo;
[0011] R.sup.7 is selected from the group consisting of alkyl,
substituted alkyl, aryl, or substituted aryl; and
[0012] P.sub.1 is selected from the group H, alkyl, substituted
alkyl, alkanoyl, substituted alkanoyl, aroyl, substituted aroyl,
trialkylsilyl, aryl dialkylsilyl, diaryl alkylsilyl,
triarylsilyl;
[0013] which comprises:
[0014] (a) reacting a compound of structure I 3
[0015] wherein R.sub.1-6 and P.sub.1 are defined as above with at
least one metal halide salt to form structure II; 4
[0016] (b) reacting the product of (a) with at least one azide salt
to form structure III; 5
[0017] (c) conducting a Mitsunobu reaction with the product of (b)
to form structure IV; 6
[0018] (d) cleaving the ester group of the product of (c) to form
structure V; 7
[0019] and
[0020] (e) reducing and cyclizing the product of (d) with a
reducing agent to form the stereospecific form of structure VI.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Definitions
[0022] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification, unless otherwise
limited in specific instances, either individually or as part of a
larger group.
[0023] The term "pharmaceutically active agent" or
"pharmaceutically active epothilone" refers to an epothilone that
is pharmacologically active in treating cancer or other diseases
described herein.
[0024] The term "alkyl" refers to optionally substituted, straight
or branched chain saturated hydrocarbon groups of 1 to 20 carbon
atoms, preferably 1 to 7 carbon atoms. The expression "lower alkyl"
refers to optionally substituted alkyl groups of 1 to 4 carbon
atoms.
[0025] The term "substituted alkyl" refers to an alkyl group
substituted by, for example, one to four substituents, such as,
halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy,
cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy,
amino, alkylamino, arylamino, aralkylamino, cycloalkylamino,
heterocycloamino, disubstituted amines in which the 2 amino
substituents are selected from alkyl, aryl or aralkyl,
alkanoylamino, aroylamino, aralkanoylamino, substituted
alkanoylamino, substituted arylamino, substituted aralkanoylamino,
thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio,
heterocyclothio, alkylthiono, arylthiono, aralkylthiono,
alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g.
SO.sub.2NH.sub.2), substituted sulfonamido, nitro, cyano, carboxy,
carbamyl (e.g. CONH.sub.2), substituted carbamyl (e.g. CONH alkyl,
CONH aryl, CONH aralkyl or cases where there are two substituents
on the nitrogen selected from alkyl, aryl or aralkyl),
alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos,
such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl,
pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above
where the substituent is further substituted it will be with
halogen, alkyl, alkoxy, aryl or aralkyl.
[0026] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6 to 12 carbon atoms in the ring portion,
such as phenyl, naphthyl, biphenyl and diphenyl groups, each of
which may be optionally substituted.
[0027] The term "substituted aryl" refers to an aryl group
substituted by, for example, one to four substituents such as
alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl,
hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl,
alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino,
heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio,
cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy,
carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,
alkysulfonyl, sulfonamido, aryloxy and the like. The substituent
may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl,
substituted aryl, substituted alkyl or aralkyl.
[0028] The term "aralkyl" refers to an aryl group bonded directly
through an alkyl group, such as benzyl.
[0029] The term "substituted alkene" and "substituted alkenyl"
refer to a moiety having a carbon to carbon double bond, which can
be part of a ring system, with at least one substituent being a
lower alkyl or substituted lower alkyl. Other substituents are as
defined for substituted alkyl.
[0030] The term "cycloalkyl" refers to a optionally substituted,
saturated cyclic hydrocarbon ring systems, preferably containing 1
to 3 rings and 3 to 7 carbons per ring which may be further fused
with an unsaturated C.sub.3-C.sub.7 carbocyclic ring. Exemplary
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
Exemplary substituents include one or more alkyl groups as
described above, or one or more groups described above as alkyl
substituents.
[0031] The terms "heterocycle", "heterocyclic" and "heterocyclo"
refer to an optionally substituted, unsaturated, partially
saturated, or fully saturated, aromatic or nonaromatic cyclic
group, for example, which is a 4 to 7 membered monocyclic, 7 to 11
membered bicyclic, or 10 to 15 membered tricyclic ring system,
which has at least one heteroatom in at least one carbon
atom-containing ring. Each ring of the heterocyclic group
containing a heteroatom may have 1, 2 or 3 heteroatoms selected
from nitrogen atoms, oxygen atoms and sulfur atoms, where the
nitrogen and sulfur heteroatoms may also optionally be oxidized and
the nitrogen heteroatoms may also optionally be quaternized. The
heterocyclic group may be attached at any heteroatom or carbon
atom.
[0032] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuiryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,
4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane
and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl,
thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
[0033] Exemplary bicyclic heterocyclic groups include
benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl,
quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,
benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl,
indazolyl, pyrrolopyridyl, furopyridinyl (such as
furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0034] Exemplary substituents include one or more alkyl groups as
described above or one or more groups described above as alkyl
substituents. Also included are smaller heterocyclos, such as,
epoxides and aziridines.
[0035] The term "alkanoyl" refers to --C(O)-alkyl.
[0036] The term "substituted alkanoyl" refers to --C(O)-substituted
alkyl.
[0037] The term "aroyl" refers to --C(O)-aryl.
[0038] The term "substituted aroyl" refers to --C(O)-substituted
aryl.
[0039] The term "trialkylsilyl" refers to --Si(alkyl).sub.3.
[0040] The term "aryl dialkylsilyl" refers to
--Si(alkyl).sub.2(aryl).
[0041] The term "diaryl alkylsilyl" refers to
--Si(aryl).sub.2(alkyl).
[0042] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0043] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0044] The compounds of formula VI may form salts with alkali
metals such as sodium, potassium and lithium, with alkaline earth
metals such as calcium and magnesium, with organic bases such as
dicyclohexylamine and tributylamine, with pyridine and amino acids
such as arginine, lysine and the like. Such salts can be obtained,
for example, by exchanging the carboxylic acid protons, if they
contain a carboxylic acid, from compounds of formula VI with the
desired ion in a medium in which the salt precipitates or in an
aqueous medium followed by evaporation. Other salts can be formed
as known to those skilled in the art.
[0045] The compounds of formula VI form salts with a variety of
organic and inorganic acids. Such salts include those formed with
hydrogen chloride, hydrogen bromide, methanesulfonic acid,
hydroxyethanesulfonic acid, sulfuric acid, acetic acid,
trifluoroacetic acid, maleic acid, benzenesulfonic acid,
toluenesulfonic acid and various others (e.g. nitrates, phosphates,
borates, tartrates, citrates, succinates, benzoates, ascorbates,
salicylates and the like). Such salts are formed by reacting a
compound of formula I through IV in an equivalent amount of the
acid in a medium in which the salt precipitates or in an aqueous
medium followed by evaporation.
[0046] In addition, zwitterions ("inner salts") can be formed and
are included within the term salts as used herein.
[0047] Prodrugs and solvates of the compounds of formula VI are
also contemplated herein. The term prodrug, as used herein, denotes
a compound which, upon administration to a subject, undergoes
chemical conversion by metabolic or chemical processes to yield a
compound of formula I through IV, or a salt and/or solvate thereof.
For example, compounds of formula I through IV may form a
carboxylate ester moiety. The carboxylate esters are conveniently
formed by esterifying any of the carboxylic acid functionalities
found on the disclosed ring structure(s). Solvates of the compounds
of formula I through IV are preferably hydrates.
[0048] Various forms of prodrugs are well known in the art. For
examples of such prodrug delivery derivatives, see:
[0049] a) Design of Prodrugs, H. Bundgaard (editor), Elsevier
(1985);
[0050] b) Methods in Enzymology, K. Widder et al. (editors),
Academic Press, Vol. 42, 309-396 (1985);
[0051] c) A Textbook of Drug Design and Development,
Krosgaard-Larsen and H. Bundgaard (editors), Chapter 5, "Design and
Application of Prodrugs," 113-191 (1991);
[0052] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38
(1992);
[0053] e) H. Bundgaard, J. of Pharm. Sciences, 77, 285 (1988);
and
[0054] f) N. Kakeya et al., Chem. Pharm. Bull., 32 692 (1984).
[0055] The compounds of the invention may exist as multiple
optical, geometric, and stereoisomers. While the compounds shown
herein are depicted for one optical orientation, included within
the present invention are all isomers and mixtures thereof.
[0056] Use and Utility
[0057] The compounds of the invention are microtubule-stabilizing
agents. They are thus useful in the treatment of a variety of
cancers and other proliferative diseases including, but not limited
to, the following;
[0058] carcinoma, including that of the bladder, breast, colon,
kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and
skin; including squamous cell carcinoma;
[0059] hematopoietic tumors of lymphoid lineage, including
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burketts lymphoma;
[0060] hematopoietic tumors of myeloid lineage, including acute and
chronic myelogenous leukemias and promyelocytic leukemia;
[0061] tumors of mesenchymal origin, including fibrosarcoma and
rhabdomyoscarcoma;
[0062] other tumors, including melanoma, seminoma,
tetratocarcinoma, neuroblastoma and glioma;
[0063] tumors of the central and peripheral nervous system,
including astrocytoma, neuroblastoma, glioma, and schwannomas;
[0064] tumors of mesenchymal origin, including fibrosarcoma,
rhabdomyoscaroma, and osteosarcoma; and
[0065] other tumors, including melanoma, xenoderma pigmentosum,
keratoactanthoma, seminoma, thyroid follicular cancer and
teratocarcinoma.
[0066] Compounds of the invention will also inhibit angiogenesis,
thereby affecting the growth of tumors and providing treatment of
tumors and tumor-related disorders. Such anti-angiogenesis
properties of the compounds of formula VI will also be useful in
the treatment of other conditions responsive to anti-angiogenesis
agents including, but not limited to, certain forms of blindness
related to retinal vascularization, arthritis, especially
inflammatory arthritis, multiple sclerosis, restinosis and
psoriasis.
[0067] Compounds of the invention will induce or inhibit apoptosis,
a physiological cell death process critical for normal development
and homeostasis. Alterations of apoptotic pathways contribute to
the pathogenesis of a variety of human diseases. Compounds of
formula VI, as modulators of apoptosis, will be useful in the
treatment of a variety of human diseases with aberrations in
apoptosis including, but not limited to, cancer and precancerous
lesions, immune response related diseases, viral infections,
degenerative diseases of the musculoskeletal system and kidney
disease.
[0068] Without wishing to be bound to any mechanism or morphology,
compounds of the invention may also be used to treat conditions
other than cancer or other proliferative diseases. Such conditions
include, but are not limited to viral infections such as
herpesvirus, poxyirus, Epstein-Barr virus, Sindbis virus and
adenovirus; autoimmune diseases such as systemic lupus
erythematosus, immune mediated glomerulonephritis, rheumatoid
arthritis, psoriasis, inflammatory bowel diseases and autoimmune
diabetes mellitus; neurodegenerative disorders such as Alzheimer's
disease, AIDS-related dementia, Parkinson's disease, amyotrophic
lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy
and cerebellar degeneration; AIDS; myelodysplastic syndromes;
aplastic anemia; ischemic injury associated myocardial infarctions;
stroke and reperfuision injury; restenosis; arrhythmia;
atherosclerosis; toxin-induced or alcohol induced liver diseases;
hematological diseases such as chronic anemia and aplastic anemia;
degenerative diseases of the musculoskeletal system such as
osteoporosis and arthritis; aspirin-sensitive rhinosinusitis;
cystic fibrosis; multiple sclerosis; kidney diseases; and cancer
pain.
[0069] The present invention thus provides a method of treating a
subject, preferably mammals and especially humans, in need of
treatment for any of the aforementioned conditions, especially
cancer or other proliferative diseases, comprising the step of
administering to a subject in need thereof of at least one compound
of formula I and II in an amount effective therefor. Other
therapeutic agents such as those described below may be employed
with the inventive compounds in the present method. In the method
of the present invention, such other therapeutic agent(s) may be
administered prior to, simultaneously with or following the
administration of the compound(s) of the present invention.
[0070] The effective amount of a compound of the present invention
may be determined by one of ordinary skill in the art, and includes
exemplary dosage amounts for a human of from about 0.05 to 200
mg/kg/day, which may be administered in a single dose or in the
form of individual divided doses, such as from 1 to 4 times per
day. Preferably the compounds are administered in a dosage of less
than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses. It
will be understood that the specific dose level and frequency of
dosage for any particular subject may be varied and will depend
upon a variety of factors including the activity of the specific
compound employed, the metabolic stability and length of action of
that compound, the species, age, body weight, general health, sex
and diet of the subject, the mode and time of administration, rate
of excretion, drug combination, and severity of the particular
condition. Preferred subjects for treatment include animals, most
preferably mammalian species such as humans, and domestic animals
such as dogs, cats and the like, subject to the aforementioned
disorders.
[0071] The present invention also provides a pharmaceutical
composition comprising at least one of the compounds of formula VI
capable of treating cancer or other proliferative diseases in an
amount effective therefor, and a pharmaceutically acceptable
vehicle or diluent. The compositions of the present invention may
contain other therapeutic agents as described below, and may be
formulated, for example, by employing conventional solid or liquid
vehicles or diluents, as well as pharmaceutical additives of a type
appropriate to the mode of desired administration (for example,
excipients, binders, preservatives, stabilizers, flavors, etc.)
according to techniques such as those well known in the art of
pharmaceutical formulation or called for by accepted pharmaceutical
practice.
[0072] The compounds of formula VI may be administered by any
suitable means, for example, orally, such as in the form of
tablets, capsules, granules or powders; sublingually; bucally;
parenterally, such as by subcutaneous, intravenous, intramuscular,
or intrastemal injection or infusion techniques (e.g., as sterile
injectable aqueous or non-aqueous solutions or suspensions);
nasally, such as by inhalation spray; topically, such as in the
form of a cream or ointment; or rectally such as in the form of
suppositories; in dosage unit formulations containing non-toxic,
pharmaceutically acceptable vehicles or diluents. The present
compounds may, for example, be administered in a form suitable for
immediate release or extended release. Immediate release or
extended release may be achieved by the use of suitable
pharmaceutical compositions comprising the present compounds, or,
particularly in the case of extended release, by the use of devices
such as subcutaneous implants or osmotic pumps. The present
compounds may also be administered liposomally. For example, the
active substance can be utilized in a composition such as a tablet,
capsule, solution or suspension containing about 5 to about 500 mg
per unit dosage of a compount or mixture of compounds of formula VI
or in a topical form (0.01 to 5% by weight compound of formula VI,
one to five treatments per day). They may be compounded in a
conventional manner with a physiologically acceptable vehicle or
carrier, excipient, binder, preservative, stabilizer, flavor, etc.,
or with a topical carrier. The compounds of formula VI can also be
formulated in compositions such as sterile solutions or suspensions
for parenteral administration. About 0.1 to 500 mg of a compound of
formula VI may be compounded with a physiologically acceptable
vehicle, carrier, excipient, binder preservative, stabilizer, etc.,
in a unit dosage form as called for by accepted pharmaceutical
practice. The amount of active sustance in these compositions or
preparations is preferably such that a suitable dosage in the range
indicated is obtained.
[0073] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. Molded tablets, compressed tablets or
freeze-dried tablets are exemplary forms which may be used.
Exemplary compositions include those formulating the present
compound(s) with fast dissolving diluents such as mannitol,
lactose, sucrose and/or cyclodextrins. Also included in such
formulations may be high molecular weight excipients such as
celluloses (avicel) or polyethylene glycols (PEG). Such
formulations may also include an excipient to aid mucosal adhesion
such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl
cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic
anhydride copolymer (e.g. Gantrez), and agents to control release
such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants,
glidants, flavors, coloring agents and stabilizers may also be
added for ease of fabrication and use.
[0074] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which may contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0075] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parentally acceptable diluents or solvents,
such as cremophor, mannitol, 1,3-butanediol, water, Ringer's
solution, an isotonic sodium chloride solution, or other suitable
dispersing or wetting and suspending agents, including synthetic
mono- or diglycerides, and fatty acids, including oleic acid.
[0076] Exemplary compositions for rectal administration include
suppositories which may contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperature, but liquify and/or dissolve in the rectal cavity to
release the drug.
[0077] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene). For example, the compounds of the invention may be
administered topically to treat plaques associated with psoriasis
and as such may be formulated as a cream or ointment.
[0078] The compounds of the invention may be administered either
alone or in combination with other anti-cancer and cytotoxic agents
and treatments useful in the treatment of cancer or other
proliferative diseases. Especially useful are anti-cancer and
cytotoxic drug combinations wherein the second drug chosen acts in
a different manner or different phase of the cell cycle, e.g. S
phase, than the present compounds of formula I and II which exert
their effects at the G.sub.2-M phase. Example classes of
anti-cancer and cytotoxic agents include, but are not limited to:
alkylating agents, such as nitorgen mustards, alkyl sulfonates,
nitrosoureas, ethylenimines, and triazenes; antimetabolites, such
as folate antagonists, purine analogues, and pyrimidine analogues;
antibiotics, such as anthracyclines, bleomycins, mitomycin,
dactinomycin, and plicamycin; enzymes, such as L-asparaginase;
farnesyl-protein transferase inhibitors; hormonal agents, such as
glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens,
progestins, and luteinizing hormone-releasing hormone anatagonists,
octreotide acetate; microtubule-disruptor agents, such as
ecteinascidins or their analogs and derivatives;
microtubule-stabilizing agents such as paclitaxel (Taxol.RTM.),
docetaxel (Taxotere.RTM.), and epothilones A-F or their analogs or
derivatives; plant-derived products, such as vinca alkaloids,
epipodophyllotoxins, taxanes; and topoisomerase inhibitors;
prenyl-protein transferase inhibitors; and miscellaneous agents
such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine,
platinum coordination complexes such as cisplatin and carboplatin;
and other agents used as anti-cancer and cytotoxic agents such as
biological response modifiers, growth factors; immune modulators,
and monoclonal antibodies. The compounds of the invention may also
be used in conjunction with radiation therapy.
[0079] Representative examples of these classes of anti-cancer and
cytotoxic agents include, but are not limited to, mechlorethamine
hydrochlordie, cyclophosphamide, chlorambucil, melphalan,
ifosfamide, busulfan, carmustin, lomustine, semustine,
streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine,
mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine,
fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin,
bleomycin sulfate, mitomycin C, actinomycin D, safracins,
saframycins, quinocarcins, discodermolides, vincristine,
vinblastine, vinorelbine tartrate, etoposide, teniposide,
paclitaxel, tamoxifen, estramustine, estramustine phosphate sodium,
flutamide, buserelin, leuprolide, pteridines, diyneses, levamisole,
aflacon, interferon, interleukins, aldesleukin, filgrastim,
sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride,
betamethosone, gemcitabine hydrochloride, altretamine, and topoteca
and any analogs or derivatives thereof.
[0080] Preferred members of these classes include, but are not
limited to paclitaxel, cisplatin, carboplatin, doxorubicin,
carminomycin, daunorubicin, aminopterin, methotrexate, methopterin,
mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil,
6-mercaptopurine, gemcitabine, cytosine arabinoside,
podophyllotoxin or podophyllotoxin derivatives such as etoposide,
etoposide phosphate or teniposide, melphalan, vinblastine,
vincristine, leurosidine, vindesine, and leurosine. Examples of
anti-cancer and other cytotoxic agents include the following:
[0081] epothilone derivatives as found in German Patent No.
4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO
99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692,
WO99/27890, and WO 99/28324; WO 99/43653, WO 99/54330, WO 99/54318,
WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253, and WO
00/00485; cyclin dependent kinase inhibitors as found in WO
99/24416; and prenyl-protein transferase inhibitors as found in WO
97/30992 and WO 98/54966.
[0082] The combinations of the present invention may also be
formulated or co-administered with other therapeutic agents that
are selected for their particular usefulness in administering
therapies associates with the aforementioned conditions. For
example, the compounds of the invention may be formulated with
agents to prevent nausea, hypersensitivity, and gastric irritation,
such as antiemetics, and H.sub.1 and H.sub.2 antihistaminics.
[0083] The above therapeutic agents, when employed in combination
with the compounds of the present invention, may be used in those
amounts indicated in the Physicians' Desk Reference (PDR) or as
otherwise determined by one of ordinary skill in the art.
Methods of Preparation
[0084] Compounds of the invention can be prepared from compounds
and by the methods described in the following schemes.
[0085] Compounds of formula VI can be prepared from compounds of
formula I as shown in Scheme 1. 8
[0086] The hydroxyl groups of formula I, where P.sub.1 is hydrogen,
R.sub.1-5 are methyl and R.sub.6 is 2-methyl-4-thiazolyl, can be
optionally protected, for example, with triethylsilyl ethers, using
methods known in the art. Other hydroxyl-protecting groups which
are known in the art, and defined above as P.sub.1, can also be
used (see T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, Inc., New York, 1991). A
compound of formula II, where X is a halogen, can be prepared from
a compound of formula I by treatment with a metal halide salt, such
as cesium halides, lithium halides, magnesium halides, and zinc
halides, and including but not limited to, lithium bromide,
magnesium bromide, zinc bromide, and zinc chloride. More
preferably, the metal halide salt is magnesium bromide. A compound
of formula III can be prepared from a compound of formula II by
treatment with an azide salt such as lithium azide, sodium azide,
tetraalkylammonium azide, or trialkylsilyl azide. Preferably the
azide salt is sodium azide. A compound of formula IV, where R. is
alkyl, substituted alkyl, aryl or substituted aryl, can be prepared
from a compound of formula III by a Mitsunobu reaction (see O.
Mitsunobu and M. Yamada, Bull. Chem. Soc. Japan 40: 2380 (1967))
using triphenylphosphine, an azodicarboxylate, and a carboxylic
acid such as 4-nitrobenzoic acid (see D. L. Hughes, Organic
Reactions, Volume 42, Edited by L. Paquette et al., John Wiley
& Sons, Inc., New York, 1992; and S. F. Martin and J. A. Dodge,
Tetrahedron Letters, 3017 (1991)). A compound of formula V can be
prepared from one of formula IV by hydrolysis or ammoniolysis of
the ester group using, for example, a solution of ammonia in
methanol. Other methods of ester cleavage, such as sodium
hydroxide, potassium cyanide in methanol, and potassium carbonate
in methanol, are well known in the art (see T. W. Greene and P. G.
M. Wuts, Protective Groups in Organic Synthesis, John Wiley &
Sons, Inc., New York, 1991, pp. 87-104). Optionally, a compound of
formula V, where P.sub.1 is a hydroxyl-protecting group can be
deprotected using trifluoroacetic acid in dichloromethane, or other
methods known in the art, such as hydrogen fluoride in
acetonitrile, tetra-n-butylammonium fluoride, or acetic acid in
THF/water. Hydroxyl-protecting groups may be alkanoyl, substituted
alkanoyl, aroyl, substituted aroyl, trialkylsilyl, aryl
dialkysilyl, diaryl alkylsilyl, or triarylsilyl. Preferably the
hydroxyl-protecting group is trialkylsilyl, more preferably the
protecting group is triethylsilyl. When P, is a protecting group
other than triethylsilyl, deprotection methods known in the art can
be used (see T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, Inc., New York, 1991,
pp.10-142). Reduction of the azido group and subsequent cyclization
of a compound of formula V with a reducing agent, such as a
triaryl- or trialkylphosphine provides a compound of formula VI,
where R.sub.1-5 are methyl and R.sub.6 is 2-methyl-4-thiazolyl.
9
[0087] Alternatively, a compound of formula V, where P.sub.1 is an
hydroxyl-protecting group and R.sub.8 is alkyl, substituted alkyl,
aryl, or substituted aryl can be converted to an alkyl-, a
substituted alkyl-, an aryl-, or a substituted arylsulfonate ester
VII by treatment with an alkyl-, a substituted alkyl-, an aryl-, or
a substituted arylsulfonyl chloride. Reduction of the azido group
and subsequent cyclization of a compound of formula VII using a
reducing agent such as a triaryl- or trialkylphosphine provides a
compound of the invention such as formula VI (where R.sub.1-5 are
methyl and R.sub.6 is 2-methyl-4-thiazolyl). Other azide reducing
agents are well known in the art including, but not limited to,
hydrogen, Lindlar's catalyst (Pd, CaCO.sub.3/Pb), tri-n-butyltin
hydride, stannous chloride, hydrogen sulfide, and
1,3-propanedithiol. 10
[0088] Alternatively, a compound of formula III where P.sub.1 is a
hydroxyl-protecting group, can be converted to a compound of
formula VIII where X is a halogen by treatment with, for example,
triphenylphosphine and a carbon tetrahalide. Alternative reagents
for the conversion of a hydroxyl group to a halogen are well known
in the art, such as thionyl chloride or phosphorous tribromide (see
R. C. Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989, pp. 352-359). Reduction of the
azido group and subsequent cyclization of a compound of formula
VIII using a reducing agent such as a triaryl- or trialkylphosphine
provides a compound of the invention such as VI (where R.sub.1-5,
are methyl and R.sub.6 is 2-methyl-4-thiazolyl). Other azide
reducing agents are well known in the art including, but not
limited to, hydrogen, Lindlar's catalyst (Pd, CaCO.sub.3/Pb),
tri-n-butyltin hydride, stannous chloride, hydrogen sulfide, and
1,3-propanedithiol.
EXAMPLE 1
[0089] 11
[0090]
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12--
tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyc-
lo[14.1.0]heptadecane-5,9-dione.
[0091] A.
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-8,8,10,12-Tetramethyl--
3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-7,11-bis[(triethylsily)oxy]-4-
,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione. 12
[0092] Et.sub.3SiCl (25 ml, 149 mmol) was added to Epothilone A
(10.39 g, 21 mmol), N,N-diisopropylethylamine (55 mL, 315 mmol),
and imidazole (7.15 g, 105 mmol) in DMF (75 mL) at 25.degree. C.
The reaction mixture was heated at 55.degree. C. for 6.5 hours and
concentrated in vacuo. The residue was then diluted with
CH.sub.2Cl.sub.2 (100 mL) and the organic extracts were washed with
NaHCO.sub.3 (30 mL), dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The residue was purified by flash chromatography
(SiO.sub.2, 5.0.times.30 cm, hexanes to 15% EtOAc/hexanes gradient
elution) to afford Compound A as a white solid (15.1 g, >95%).
MS (ESI.sup.+): (M+H).sup.+722.
[0093] B.
[4S-[4R*,7S*,8R*,9R*,13S*,14S*,16R*(E)]]-14-Bromo-13-hydroxy-5,5-
,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,8-bis[(tr-
iethylsilyl)oxy]-1-oxacyclohexadecane-2,6-dione. 13
[0094] To a solution of Compound A from above (2.0 g, 2.8 mmol) in
CH.sub.2Cl.sub.2 (30 mL) at -20.degree. C. under argon was added
MgBr.sub.2.OEt.sub.2 (3.times.1.1 g, 12 mmol total) in three
portions every two hours while maintaining an internal temperature
between -15 and -5.degree. C. After 7 hours, the reaction mixture
was quenched with pH 7 phosphate buffer (40 mL) and brine (40 mL),
carefully extracted with EtOAc (3.times.100 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
purified by flash chromatography (SiO.sub.2, 4.5.times.25 cm,
10-20% EtOAc/hexanes gradient elution) to afford Compound B as a
white solid [1.0 g, 45% (67% based on 0.6 g of recovered starting
material; <2% of the other C13--OH/C12--Br regioisomer was
detected]. MS (ESI.sup.+): (M+H).sup.+802.
[0095] C.
[4S-[4R*,7S*,8R*,9R*,13S*,14R*,16R*(E)]]-14-Azido-13-hydroxy-5,5-
,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,8-bis[(tr-
iethylsilyl)oxy]-1-oxacyclohexadecane-2,6-dione. 14
[0096] To a solution of Compound B from above (0.17 g, 0.21 mmol)
in DMF (2 mL) under argon was added sodium azide (0.14 g, 2.1 mmol)
and the resulting suspension was warmed to 43.degree. C. After 36
hours, the solvent was removed in vacuo and the residue was
directly purified by flash chromatography (SiO.sub.2, 2.5.times.15
cm, 10-20% EtOAc/hexanes gradient elution) to give Compound C (0.14
g, 88%) as a white foam. MS (ESI.sup.+): (M+H).sup.+765.
[0097] D.
[4S-[4R*,7S*,8R*,9R*,13R*,14R*,16R*(E)]]-14-Azido-5,5,7,9-tetram-
ethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-[(4-nitrobenzoyl)ox-
y]-4,8-bis[(triethylsilyl)oxy]-1-oxacyclohexadecane-2,6-dione.
15
[0098] To a solution of Compound C from above (0.10 g, 0.13 mmol)
in THF under argon was sequentially added 4-nitrobenzoic acid (55
mg, 0.33 mmol), triphenylphosphine (86 mg, 0.33 mmol), and diethyl
azodicarboxylate (52 mL, 0.33 mmol). The reaction mixture was
stirred at 25.degree. C. for 1.5 hours, concentrated in vacuo and
the residue was purified by flash chromatography (SiO.sub.2,
2.5.times.10 cm, 10-20% EtOAc/hexanes gradient elution) to afford
Compound D (0.10 g, 86%) as a white foam. MS (ESI.sup.+): 914.6
(M+H).sup.+.
[0099] E.
[4S-[4R*,7S*,8R*,9R*,13R*,14R*,16R*(E)]]-14-Azido-13-hydroxy-5,5-
,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,8-bis[(tr-
iethylsilyl)oxy]-1-oxacyclohexadecane-2,6-dione. 16
[0100] Compound D from above (0.10 g, 0.11 mmol) was treated with
2.0 M ammonia in methanol (1 mL) at 25.degree. C. under argon for
four hours. The solvent was removed in vacuo and the residue was
directly purified by flash chromatography (SiO.sub.2, 1.5.times.10
cm, 10-30% EtOAc/hexanes gradient elution) to afford Compound E (71
mg, 85%) as a white foam. MS (ESI.sup.+): 765.5 (M+H).sup.+; MS
(ESI.sup.-): 763.3 (M-H).sup.-.
[0101] F.
[4S-[4R*,7S*,8R*,9R*,13R*,14R*,16R*(E)]]-14-Azido-4,8,13-trihydr-
oxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-ox-
acyclohexadecane-2,6-dione. 17
[0102] Compound E (15 mg, 20 mmol) was treated with 20%
trifluoroacetic acid in methylene chloride (0.2 mL) at 0.degree. C.
under argon for ten minutes. The reaction mixture was concentrated
under a constant stream of nitrogen at 0.degree. C. and the residue
was purified by flash chromatography (SiO.sub.2, 1.times.5 cm, 0-5%
MeOH/CHCl.sub.3 gradient elution) to afford Compound F (9 mg, 86%)
as a film. MS (ESI.sup.+): 537.3 (M+H).sup.+.
[0103] G.
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,-
12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabi-
cyclo[14.1.0]heptadecane-5,9-dione. 18
[0104] To a solution of Compound F (9 mg, 17 .mu.mol) in THF (0.2
mL) under argon was added triphenylphosphine (18 mg, 67 .mu.mol).
The reaction mixture was warmed to 45.degree. C. for four hours,
and the solvent was removed under a constant flow of nitrogen. The
residue was purified by radial chromatography (1 mm SiO.sub.2 GF
rotor, 2-10% MeOH--CHCl.sub.3 gradient elution) to afford the title
compound (4 mg, 50%) as a film.
EXAMPLE 2
[0105]
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12--
tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyc-
lo[14.1.0]heptadecane-5,9-dione.
[0106] A.
[4S-[4R*,7S*,8R*,9R*,13S*,14R*,16R*(E)]]-14-Azido-5,5,7,9-tetram-
ethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-[(methylsulfonyl)ox-
y]-4,8-bis[(triethylsilyl)oxy]-1-oxacyclohexadecane-2,6-dione.
19
[0107] Compound 1E from above (1.047 g, 1.37 mmol) was dissolved in
CH.sub.2Cl.sub.2 (13 ml) and cooled at 0.degree. C. Triethylamine
(0.764 ml, 5.48 mmol) was added followed by methanesulfonylchloride
(0.318 ml, 4.11 mmol) and the mixture was stirred at room
temperature for three hours. The reaction was quenched with
saturated aqueous NaHCO.sub.3 (50 ml), the organic phase was
extracted with CH.sub.2Cl.sub.2 (3.times.50 ml) and dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to afford compound 2A
(1.130 g, 98%), which was used in step 2B without further
purification.
[0108] B.
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-8,8,10,12-Tetramethyl--
3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-7,11-bis[(triethylsilyl)oxy]--
4-oxa-17-azabicyclo [14.1.0]heptadecane-5,9-dione. 20
[0109] A solution of compound 2A from above (1.13 g, 1.34 mmol) was
dissolved in tetrahydrofuran-H.sub.2O (12:1, 24 mL) and treated
with trimethylphosphine (2.68 ml, 1M in THF) at room temperature
for three hours. Then the mixture was heated at 45.degree. C. for
10 hours to convert the remaining aminomesylate into the aziridine.
The volatiles were removed in vacuo and the residue was
chromatographed (SiO.sub.2, 50% ethyl acetate/Hexanes to 100% ethyl
acetate) to afford compound 1B (0.82 g, 85%).
[0110] C. [1S-[1R*,3R*(E),7R*,10
S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10-
,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azab-
icyclo[14.1.0]heptadecane-5,9-dione. 21
[0111] Compound 2B from above (3.44 g, 4.78 mmol) was dissolved in
CH.sub.2Cl.sub.2 (25 ml), cooled to -20.degree. C. and treated with
trifluoroacetic acid (20 ml, 10% in CH.sub.2Cl.sub.2). The reaction
was slowly warmed up to 0.degree. C. and after one hour was
quenched with a saturated aqueous solution of NaHCO.sub.3 (75 mL).
The organic phase was extracted with ethyl acetate (3.times.100 mL)
and CHCl.sub.3 (100 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by flash
chromatography (SiO.sub.2, CHCl.sub.3 to 10% methanol/CHCl.sub.3)
to afford compound 2C (2.12 g, 90%).
* * * * *