Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-06-11
2001-10-30
Berch, Mark L (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C549S510000, C549S214000
Reexamination Certificate
active
06310201
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel &bgr;-lactams. The &bgr;-lactams of the present invention find utility as intermediates in the preparation of sidechain-bearing taxanes such as taxol and taxol derivatives. The present invention also relates to novel methods of coupling &bgr;-lactams to form such sidechain-bearing taxanes, and to novel sidechain-bearing taxanes.
BACKGROUND OF THE INVENTION
Taxanes are diterpene compounds having utility in the pharmaceutical field. For example, taxol, a taxane having the structure:
where Ph is phenyl, Ac is acetyl and Bz is benzoyl, has been found to be an effective anticancer agent.
Naturally occurring taxanes such as taxol may be found in plant materials, and have been isolated therefrom. Such taxanes may, however, be present in plant materials in relatively small amounts so that, in the case of taxol, for example, large numbers of the slow-growing yew trees forming a source for the compound may be required. The art has thus continued to search for synthetic, including semi-synthetic routes for the preparation of naturally occurring taxanes such as taxol, as well as routes for the preparation of synthetic, pharmaceutically useful analogs thereof.
SUMMARY OF THE INVENTION
The present invention provides novel &bgr;-lactam compounds of the following formula I:
where
R
1
and R
2
are:
(i) both the same alkyl group;
(ii) together form a cycloalkyl group;
(iii) together form a cycloalkenyl group; or
(iv) together form a heterocyclo group;
R
3
is alkyl;
R
4
is aryl;
R
5
is hydrogen, arylcarbonyl, or alkyloxycarbonyl, and salts thereof.
The &bgr;-lactams of the present invention are useful as intermediates in the preparation of sidechain-bearing taxanes such as taxol and taxol derivatives. In particular, these compounds may be coupled with a taxane moiety to form the aforementioned sidechain.
As the stereochemistry of taxanes may affect their pharmaceutical activity, it is desirable to employ &bgr;-lactam intermediates which will provide the final taxane product with the stereochemistry sought. In the &bgr;-lactams of the present invention, the carbon marked with an asterisk in the above formula I is a non-asymmetric carbon. Where such a carbon center is asymmetric, a mixture of diastereomers can be formed. The &bgr;-lactams of the present invention provide superior results relative to &bgr;-lactams which contain an asymmetric carbon at the corresponding position since, when the latter compounds are prepared, or when they are coupled with a taxane moiety, products are formed as a mixture of stereoconfigurations. The formation of such a mixture of stereoisomers results in an inefficient use of the starting materials, and complicates separation and purification procedures.
The &bgr;-lactams of the formula I of the present invention are further advantageous in terms of the yield and purity of the final taxane product. In particular, the &bgr;-lactams of the present invention allow efficient conversion, and therefore use of lesser amounts, of starting materials, as well as simplified separation and purification procedures, when employed as intermediates in the preparation of sidechain-bearing taxanes.
The present invention also provides novel methods for using the aforementioned &bgr;-lactams of the formula I in the preparation of sidechain-bearing taxanes, and the novel sidechain-bearing taxanes prepared.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described further as follows.
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, carbamoyl (NH
2
—CO—), amino (—NH
2
), mono- or dialkylamino, or thiol (—SH).
The terms “lower alk” or “lower alkyl”, as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The terms “alkoxy” or “alkylthio”, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively. The term “alkyloxycarbonyl”, as used herein, denotes an alkoxy group bonded through a carbonyl group. The term “alkylcarbonyloxy”, as used herein, denotes an alkyl group bonded through a carbonyl group which is, in turn, bonded through an oxygen linkage. The terms “monoalkylamino” or “dialkylamino” denote an amino group substituted by one or two alkyl groups as described above, respectively.
The term “alkenyl”, as used herein alone or as part of another group, denotes such optionally substituted groups as described for alkyl, further containing at least one carbon to carbon double bond. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “alkynyl”, as used herein alone or as part of another group, denotes such optionally substituted groups as described for alkyl, further containing at least one carbon to carbon triple bond. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary unsubstituted such 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 term “cycloalkenyl”, as used herein alone or as part of another group, denotes such optionally substituted groups as described above for cycloalkyl, further containing at least one carbon to carbon double bond forming a partially unsaturated ring. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include phenyl, biphenyl, and naphthyl. Exemplary substituents include one or more, preferably three or fewer, nitro groups, alkyl groups as described above, or groups described above as alkyl substituents.
The term “arylcarbonyl”, as used herein alone or as part of another group, denotes an aryl group as described above bonded through a carbonyl group.
The terms “heterocyclo” or “heterocyclic”, as used herein alone or as part of another group, denote optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic groups having at least one heteroatom in at least one ring, preferably monocyclic or bicyclic groups having 5 or 6 atoms in each ring. The heterocyclo group may, for example, have 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring. Each heterocyclo group may be bonded through any carbon or heteroatom of the ring system. Exemplary heterocyclo groups include the following: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, azepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, and especially, tetrahydropyranyl (e.g. 4-tetrahydropyranyl). Exemplary substituents include one or more alkyl groups as described above, or o
Kucera David J.
Li Wen-Sen
Thottathil John K.
Trifunovich Ivan D.
Babajko Suzanne E.
Berch Mark L
Bristol--Myers Squibb Company
Lopez Gabriel
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