Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-03
2002-12-03
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S451000, C540S455000, C540S461000, C540S462000, C540S463000
Reexamination Certificate
active
06489314
ABSTRACT:
BACKGROUND
Epothilone A (R═H) and Epothilone B (R═CH
3
) are produced by
Sorangium cellulosum
strain So ce 90, the structures of which are shown below, and were the first of several epothilones to be isolated and characterized. Hofle et al., 1996,
Angew. Chem. Int. Ed. Engl.
35(13/14): 1567-1569.
Epothilone A and epothilone B possess many of the advantageous properties of taxol. As a result, there is significant interest in these and structurally related compounds as potential chemotherapeutic agents. The desoxy counterparts of epothilones A and B are known as epothilone C (R═H) and epothilone D (R═CH
3
), and also exhibit similar anti-tumor activity but with less cytotoxicity. The structures of epothilones C and D are shown below.
Although other naturally occurring epothilones have been described in the literature, these compounds are produced in exceedingly small amounts. For example, PCT publication WO 99/65913 describes 39 naturally occurring epothilones obtained from
Sorangium cellulosum
So ce 90 of which epothilones A, B, C, and D together account for approximately 98.9% of the total epothilones produced. The 35 other naturally occurring epothilone compounds together account for the remaining 1.1% and include epothilone C
6
(which may also be referred to as 10,11-dehydroepothilone C) and whose structure is shown below
Due to the increasing interest in epothilones as anti-cancer agents, novel derivatives of these compounds are needed and desired to more fully develop their therapeutic potential.
SUMMARY
The present invention relates to 16-membered macrocyclic compounds. In one aspect of the present invention, 16-membered macrocyclic compounds having a conjugated diene are provided. In another aspect of the present invention, compounds of the following formula
are provided wherein:
R
1
, R
2
, R
3
, and R
5
are each independently hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl or alkylaryl;
R
4
is hydrogen, C
1
-C
10
alkyl, C
1
-C
10
hydroxyalkyl, C
1
-C
10
haloalkyl, aryl, —C(═O)R
6
, —C(═O)OR
6
, —NR
6
R
7
where R
6
and R
7
are each independently hydrogen, C
1
-C
10
aliphatic, aryl or alkylaryl;
W is O, NR
8
where R
8
is hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl or alkylaryl;
X is O, CH
2
or a carbon-carbon double bond;
Y is absent or a C
1
-C
10
alkyl, C
2
-C
10
alkenyl, or C
2
-C
10
alkynyl; and
Ar is aryl; provided that 10,11-dehydroepothilone C is excluded. In another aspect of the present invention, methods for using the inventive compounds are provided.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to novel compounds that are useful for the treatment of cancer and other conditions characterized by abnormal cellular proliferation in a subject in need thereof.
Definitions
Statements regarding the scope of the present invention and definitions of terms used herein are listed below. The 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.
All stereoisomers of the inventive compounds are included within the scope of the invention, as pure compounds as well as mixtures thereof. Individual enantiomers, diastereomers, geometric isomers, and combinations and mixtures thereof are all encompassed by the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also encompassed within the scope of this invention.
Protected forms of the inventive compounds are included within the scope of the present invention. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999), which is incorporated herein by reference in its entirety. For example, a hydroxy protected form of the inventive compounds are those where at least one of the hydroxyl groups is protected by a hydroxy protecting group. Illustrative hydroxyl protecting groups include but not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethylthiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethyl silyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl and the like; acyl and aroyl such as acetyl, pivaloylbenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acylaryl and the like. Keto groups in the inventive compounds may similarly be protected.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs are functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a subject in need thereof. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, H. Bundgaard ed., Elsevier, 1985.
As used herein, the term “aliphatic” refers to saturated and unsaturated straight chained, branched chain, cyclic, or polycyclic hydrocarbons that may be optionally substituted at one or more positions. Illustrative examples of aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. The term “alkyl” refers to straight or branched chain saturated hydrocarbon substituent. “Alkenyl” refers to a straight or branched chain hydrocarbon substituent with at least one carbon-carbon double bond. “Alkynyl” refers to a straight or branched chain hydrocarbon substituent with at least one carbon-carbon triple bound.
The term “aryl” refers to monocyclic or polycyclic groups having at least one aromatic ring structure that optionally include one or more heteroatoms and preferably include three to fourteen carbon atoms. Aryl substituents may optionally be substituted at one or more positions. Illustrative examples of aryl groups include but are not limited to: furanyl, imidazolyl, indanyl, indenyl, indolyl, isooxazolyl, isoquinolinyl, naphthyl, oxazolyl, oxadiazolyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, quinolyl, quinoxalyl, tetrahydronaphththyl, tetrazolyl, thiazolyl, thienyl, and the like.
The aliphatic (i.e., alkyl, alkenyl, etc.) and aryl moieties may be optionally substituted with one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, and most preferably from one to two substituents. The definition of any substituent or variable at a particular location in a molecule is independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. Examples of suitable substituents include but are not limited to: alkyl, alkenyl, alkynyl, aryl, halo; trifluoromethyl; trifluoromethoxy; hydroxy; alkoxy; cycloalkoxy; heterocyclooxy; oxo; alkanoyl (—C(═O)-alkyl which is also referred to as “acyl”)); aryloxy; alkanoyloxy; amino; alkylamino; arylamino; aralkylamino; cycloalkylamino; heterocycloamino; disubstituted amines in which the two amino substituents are selected from alkyl, aryl, or aralkyl; alkanoylamino; aroylamino; aralkanoylamino; substituted alkanoylamino; substituted aryla
Ashley Gary
Metcalf Brian
Favorito Carolyn A.
Kaster Kevin
Kosan Biosciences, Inc.
Lentini David
Richter Johann
LandOfFree
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