Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-17
2001-09-18
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S214000, C549S271000
Reexamination Certificate
active
06291684
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a stereospecific process for the preparation of epothilone derivatives and intermediates therefor.
BACKGROUND OF THE INVENTION
Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
have been found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) 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).
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 Suet al.,
Angew Chem. Int. Ed. Engl., Vol.
36, No. 19,2093-2096 (1997).
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
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
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
are selected from the group H or alkyl and when R
1
and R
2
are alkyl can be joined to form a cycloalkyl;
R
6
is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or heterocyclo;
R
7
is selected from the group consisting of alkyl, substituted alkyl, aryl, or substituted aryl; and
P
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
wherein R
1-6
and P
1
are defined as above with at least one metal halide salt to form structure II;
(b) reacting the product of (a) with at least one azide salt to form structure III;
(c) conducting a Mitsunobu reaction with the product of (b) to form structure IV; X
(d) cleaving the ester group of the product of (c) to form structure
and
(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
Definitions
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.
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.
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.
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, arylthijo, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO
2
NH
2
), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH
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.
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.
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.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
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.
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
3
-C
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.
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.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, 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, morphol
Borzilleri Robert M.
Kim Soong-Hoon
Regueiro-Ren Alicia
Vite Gregory D.
Bristol--Myers Squibb Company
Owens Amelia
Patel Rena
Switzer Joan E.
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