Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-05-21
2001-11-20
Kifle, Bruck (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C548S204000, C549S265000, C549S266000, C549S271000
Reexamination Certificate
active
06320045
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of olefinic epothilones from oxiranyl epothilones.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to a process for preparing compounds of formulas II and IV.
The compounds of formulas I-IV are useful in the treatment of a variety of cancers and other abnormal proliferative diseases. Compounds of formula I are disclosed in Hofle et al.,
Angew. Chem. Int. Ed. Engl
., 1996, 35, No 13/14, 1567; WO93/10121 published May 27, 1993, and WO97/19086 published May 29, 1997, and also Nicolaou et al.,
Angew Chem. Int. Ed. Engl
., 1997, 36, No. 19, 2097 and Su et al.,
Angew Chem. Int. Ed. Engl
., 1997, 36, No. 19, 2093. Compounds of formula III are disclosed in Hofle et al., WO 97/19086 published May 29, 1997. As used in formulas II and IV, and throughout the specification, the symbols have the following meanings:
W is O or NR
8
;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, are selected from the group H, alkyl, substituted alkyl, or aryl and when R
1
and R
2
are alkyl can be joined to form a cycloalkyl;
R
7
is selected from the group consisting of H, alkyl, substituted alkyl, aryl, cycloalkyl, or heterocyclo;
R
8
is H, alkyl, or substituted alkyl, OH, O-alkyl, O-substituted alkyl;
P
1
and P
2
are selected from the group, H, alkyl, substituted alkyl, alkanoyl, substituted alkanoyl, aroyl, substituted aroyl, trialkylsilyl, aryl dialkylsilyl, diaryl alkylsilyl, triarylsilyl.
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 “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression “lower alkyl” refers to unsubstituted 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, cycloalkyoxy, heterocylooxy, 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
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 “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
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 substituted.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
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 “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, fully saturated or unsaturated, 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, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
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.
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.
The term “alkanoyl” refers to —C(O)-alkyl.
The term “substituted alkanoyl” refers to —C(O)-substituted alkyl.
The term “aroyl” refers to —C(O)-aryl.
The term “substituted aroyl” refers to —C(O)-substituted aryl.
The term “trialkylsilyl” refers to —Si(alkyl)
3
.
The term “aryl dialkylsilyl” refers to —Si(alkyl)
2
(aryl).
The term “diaryl alkylsilyl” refers to —Si(aryl)
2
(alkyl).
The term “heteroatoms” shall include oxygen, sulfur and nitrogen.
The term “metallocene” refers to an organometallic coordination compounds obtained as a cyclopentadienyl derivative
Johnson James A.
Kim Soong-Hoon
Bristol--Myers Squibb Company
Kifle Bruck
Patel Rena
Switzer Joan E.
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