Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-08
2003-12-30
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S451000, C514S452000, C514S453000, C514S456000, C514S460000, C540S488000, C549S267000, C549S268000, C549S269000, C549S270000, C549S271000
Reexamination Certificate
active
06670389
ABSTRACT:
BACKGROUND
Laulimalide (1) and isolaulimalide (2), also known as fijianolides, were originally isolated as cytotoxic agents from the Indonesian sponge Hyatella sp. (E. Quinoa et al., “Fijianolides, polyketide heterocycles from a marine sponge,”
J. Org. Chem.,
1988, 53, 3642; D. G. Corley et al., “Laulimalides. New potent cytotoxic macrolides from a marine sponge and a nudibranch predator,”
J. Org. Chem.
1988, 53, 3644-3646), and later found along with neolaulimalide (3) in the Okinawan sponge
Fasciospongia rimosa
(Jefford et al., “Structures and absolute configurations of the marine toxins, latrunculin A and laulimalide,” 1996,
Tetrahedron Letts.
37: 159-162; Higa et al., “Three new cytotoxic macrolides from a marine sponge,” PCT publication No. WO 97/10242). The absolute structure of natural (−)-laulimalide has been determined by X-ray crystallography.
A number of total syntheses of laulimalide have been reported. See Ghosh et al., 2001, “Total synthesis of microtubule-stabilizing agent (−)-laulimalide,”
J. Org. Chem.
66: 8973-8982; Paterson et al., 2001, “Total synthesis of microtubule-stabilizing agent (−)-laulimalide,”
Org. Letts.:
3149-3152; Enev et al., 2001, “Macrocyclization via allyl transfer: total synthesis of laulimalide,”
J. Am. Chem. Soc.
123: 10764-10765; Ghosh et al., 2000, “Total synthesis of(−)-laulimalide,”
J. Am. Chem. Soc.
122: 11027-11028.
A mechanism-based screening program aimed at isolating novel microtubule-directed anticancer agents revealed both laulimalide and isolaulimalide to be potent stabilizers of microtubules, similar to paclitaxel. See S. Mooberry et al., 1999,
Cancer Res.,
59, 653-660; Mooberry & Davidson, “Laulimalide compounds as microtubule stabilizing agents,” PCT Publication No. WO 01/54689, incorporated herein by reference.
Because of the problems associated with the use of paclitaxel such as low solubility and resistance, there is an increasing need for alternative anti-cancer compounds. The present invention provides such compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides laulimalide compounds, intermediates thereto and methods for their preparation, and methods for their use in the treatment of diseases characterized by cellular hyperproliferation.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be 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 the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
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 optionally substituted straight, branched or cyclic hydrocarbons comprising no unsaturation. “Alkenyl” refers to an optionally substituted straight, branched, or cyclic chain hydrocarbon with at least one carbon-carbon double bond. “Alkynyl” refers to an optionally substituted straight, branched, or cyclic hydrocarbon with at least one carbon-carbon triple bound. Substituted alkyl, substituted alkenyl, or substituted alkynyl refer to the respective alkyl, alkenyl or alkynyl group substituted by one or more substituents. Illustrative examples of substituents include but are not limited to alkyl, alkenyl, alkynyl, aryl, halo; trifluoromethyl; trifluoromethoxy; hydroxy; alkoxy; cycloalkoxy; heterocyclooxy; oxo (═O); alkanoyl (—C(═O)-alkyl); 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 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., —C(═O)NR′R″ where R′ and R″ are each independently hydrogen, alkyl, aryl, aralkyl and the like); alkoxycarbonyl, aryl, guanidino, and heterocyclo such as indoyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where applicable, the substituent may be further substituted such as with halogen, alkyl, alkoxy, aryl, or aralkyl and the like.
The term “aryl” refers to an optionally substituted aromatic ring having 6 to 12 carbon atoms and may include one or more heteroatoms such as N, S and O. Illustrative examples of aryl include but are not limited to biphenyl, furyl, imidazolyl, indolyl, isoquinolyl, naphthyl, oxazolyl, phenyl, pyridyl, pyrryl, quinolyl, quinoxalyl, tetrazoyl, thiazoyl, thienyl and the like. Substituted aryl refers to an aryl group substituted by, for example, one to four substituents such as substituted and unsubstituted alkyl, alkenyl, alkynyl, and aryl; halo; trifluoromethoxy; trifluoromethyl; hydroxy; alkoxy; cycloalkyloxy; heterocyclooxy; alkanoyl; alkanoyloxy; amino; alkylamino; aralkylamino; cycloalkylamino; heterocycloamino; dialkylamino; alkanoylamino; thio; alkylthio; cycloalkylthio; heterocyclothio; ureido; nitro; cyano; carboxy; carboxyalkyl; carbamyl; alkoxycarbonyl; alkylthiono; arylthiono; alkylsulfonyl; sulfonamido; aryloxy; and the like. The substituent may be further substituted, for example, by halo, hydroxy; alkyl, alkoxy; aryl, substituted aryl, substituted alkyl, substituted aralkyl, and the like.
The terms “halogen,” “halo”, or “halide” refer to fluorine, chlorine, bromine and iodine.
The term “subject” as used herein, refers to an animal, preferably a mammal, or, most preferably, a human, that is the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
In one aspect, the present invention provides compounds of the formula
wherein:
X is O or NR, wherein R is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl, alkylaryl, alkenylaryl, or alkynylaryl;
Z is O, CH
2
, or a bond;
R
1
is hydrogen, hydroxyl, C
1
-C
10
alkoxy, aryloxy, or alkylaryloxy;
R
2
is hydrogen, hydroxyl, C
1
-C
10
alkoxy, aryloxy, or alkylaryloxy; and
R
3
is cyclohexyl, 3-cyclohexenyl, phenyl, or a group of the formula
In one embodiment of the invention, the laulimalide compounds of formula (I) are provided
wherein:
X is O or NR, wherein R is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl, arylalkyl, arylalkenyl, or arylalkynyl;
R
1
is H, OH, C
1
-C
10
alkoxy, aryloxy, or alkylaryloxy;
R
2
is H, OH, C
1
-C
10
alkoxy, aryloxy, or alkylaryloxy; and
R
3
is cyclohexyl, 3-cyclohexenyl, phenyl, or a group of the formula
In another embodiment of the invention, compounds of formula (I) are provided wherein
X&b
Ashley Gary
Metcalf Brian
Ashley Gary W.
Favorito Carolyn A.
Kifle Bruck
Kosan Biosciences, Inc.
Lentini David P.
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