Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-31
2004-06-15
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S461000, C514S569000, C549S407000, C549S502000
Reexamination Certificate
active
06750247
ABSTRACT:
BACKGROUND OF THE INVENTION
Lipoxygenases are non-heme iron dioxygenase enzymes, which catalyze the hydroperoxidation of dieneoic and polyenoic fatty acids. Lipoxygenases are ubiquitous in mammals and include the 5-, 12-, and 15-lipoxygenases which respectively catalyze the insertion of oxygen at the C-5, C-12 and C-15 positions of arachidonic acid. The resulting leukotrienes and lipoxins provide signaling molecules associated with a variety of human diseases such as asthma, atherosclerosis, psoriasis and inflammatory bowel disease. Selective inhibitors for the human lipoxygenases thus are potentially useful as pharmacological agents, neutraceuticals and/or molecular tools.
Marine natural products have provided a variety of bioactive compounds, but relatively few marine natural products have been noted as being lipoxygenase inhibitors. The pseudopterosins are diterpene glycosides found in the Caribbean sea whip
Pseudopterogorgia elisabethae
, believed to have anti-inflammatory properties related to inhibition of cycloxygenase and lipoxygenase biosynthetic pathways (Look et al.,
J. Org. Chem
. 1986, 51, 5140; Jacobs et al.,
Pharm. Lett
. 1998, 62, 401). Fuscosides, which are diterpenoid glycosides from marine gorgonia, also have anti-inflammatory properties believed to be associated with lipoxygenase inhibition (Jacobsen et al.,
J. Pharmacol. Exp. Ther
. 1992, 262, 866).
The only sponge-derived lipoxygenase inhibitors to date are pentabromo biphenyl ethers (Fu et al.,
J. Nat. Prod
. 1995, 58, 609) isolated from cyanobacterial-containing sponges. The anti-inflammatory compound manoalide from
Luffariella variabilis
was initially identified as an inhibitor of 5-lipoxygenase (Devries et al.,
Biochem. Pharmacol
. 1988, 37, 2899), but the available 5-lipoxygenase assay used has been problematic, and subsequent studies (Cabre et al.,
Inflamm. Res
. 1996, 45, 218) show that manoalide has no lipoxygenase inhibitory properties.
There is a need for new selective inhibitors of human lipoxygenases, as well as other anti-inflammatory bioactive compounds usable for treatment of conditions associated with lipoxygenase and other conditions and diseases. The present invention satisfies these needs, as well as others, and overcomes deficiencies found in the background art.
SUMMARY OF THE INVENTION
The invention provides new compounds that are effective lipoxygenase inhibitors and effective therapeutic agents for methods and treatments for lipoxygenase mediated conditions and other diseases, disorders and conditions. The invention also provides pharmaceutical compositions and methods for inhibiting human lipoxygenases, treatments for lipoxygenase mediated conditions, and treatments for other diseases, disorders and conditions. The invention further provides pharmaceutical compositions and methods for increasing cell viability and prevention of cell damage associated with ischemia or hypoxic or anoxic events, and for treatment of ischemia, stroke, and inflammatory conditions generally.
The subject compounds, pharmaceutical compositions and methods comprise, or comprise the use of, subersic terpenoids, jaspic terpenoids, igemellic terpenoids, hippospongic terpenoids, halicondric terpenoids, dictyodendric terpenoids, and/or heteronemic terpenoids.
In some embodiments of the invention, the subject compounds, pharmaceutical compositions and methods may comprise or utilize compounds having the structure:
wherein R
1
comprises
and individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts thereof. In specific embodiments, the compounds, pharmaceutical compositions and methods may comprise or utilize (−)-(5R, 10R)-subersic acid, also named 4-hydroxy-3-[3-methyl-5-(2,5,5,8a -tetramethyl-3,4,4a,5,6,7,8,8a-octahydro-naphthalen-1-yl)-pent-2-enyl]-benzoic acid (1):
Substantially purified or isolated subersic terpenoid compounds isolated from Suberea sp. (Order: Verongida, Family: Aplysinellidae) are disclosed, including the novel compound (−)-(5R, 10R)-subersic acid (1), together with methods of isolation and purification thereof. These compounds are shown to be effective inhibitors of lipoxygenases, specifically human 15-lipoxygenase, and are demonstrated to increase cell viability under ischemic and anoxic conditions, and provide effective treatment for ischemia, congestive heart failure, stroke, and inflammatory conditions generally. Pharmaceutical methods and formulations using (−)-subersic acid (1) and other subersic terpenoids, either derived from natural source such sponge or marine organism, or prepared synthetically, are disclosed. An extract of Suberea sp. (Order: Verongida, Family: Aplysinellidae) is also demonstrated as a lipoxygenase inhibitor.
In other embodiments of the invention, the subject compounds, pharmaceutical compositions and methods may comprise or utilize compounds of the structure:
wherein R
1
comprises:
and individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts thereof. In specific embodiments, the subject compounds, pharmaceutical compositions and methods may comprise or utilize the novel compound (+)-(5S, 6S)-subersin, also named 3-[4-methyl-6-(1,2,6-trimethyl-cyclohex-2-enyl)-hex-3-enyl]-furan (2):
Substantially purified or isolated (+)-(5S, 6S)-subersin (2), together with methods of isolation and purification thereof, are disclosed. (+)-Subersin (2) is shown to be an effective inhibitor of lipoxygenases, specifically human 15-lipoxygenase, is demonstrated to increase cell viability under ischemic and anoxic conditions, and to provide effective treatment for ischemia, congestive heart failure, stroke, and inflammatory conditions generally. Pharmaceutical methods and formulations using (+)-subersin (2) and other subersic terpenoids, either derived from natural source such sponge or marine organism, or prepared synthetically, are disclosed.
In still other embodiments of the invention, the subject compounds, pharmaceutical compositions and methods may comprise or utilize compounds of the structure:
wherein R
1
comprises:
and wherein the 2,6,6-trimethyl cyclohexenyl moiety is unsaturated at either the 1- or 2- position, as well as individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts thereof. In specific embodiments, the subject compounds, pharmaceutical compositions and methods may comprise or utilize jaspaquinol, also named 2-[3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-1-enyl)-nona-2,6-dienyl]-benzene-1,4-diol (3):
Methods and pharmaceutical compositions for inhibiting lipoxygenases, treatment of lipoxygenase-mediated conditions, prevention of cell damage and promotion of cell viability under ischemic and/or anoxic conditions in mammals and other subjects, and treatment for ischemia, congestive heart failure, stroke, and inflammatory conditions generally, are shown for jaspaquinol (3) and other jaspic terpenoids. These methods and pharmaceutical preparations may comprise the use of one or more jaspic terpenoids derived from
Jaspis johnstoni, Jaspis splendens
or other Jaspis sp. sponge, or other marine organism or natural source, or which may be synthetically prepared.
In further embodiments of the invention, the subject compounds, pharmaceutical compositions and methods may comprise or utilize compounds of the structure:
wherein R
1
comprises:
and individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts thereof. In specific embodiments the compounds, pharmaceutical compositions and methods may comprise or utilize (−) jaspic acid, also named 4-hydroxy-3-[2,5,8a-trimethyl-5-(4-methyl-pent-3-enyl)-1,4,4a,5,6,7,8,8a-octahydro-naphthalen-1-ylmethyl]-benzoic acid (4):
Methods and pharmaceutical compositions for inhibiting lipoxygenases, treatment of lipoxygenase-mediated conditions, prevention of cell damage and promotion of cell viability under ischemic and/or anoxic conditions in mammals and other
Bobzin Steve
Brown Lesley
Carroll Jennifer
Crews Phillip
Holman Theodore
Bozicevic Field & Francis LLP
Dentz Bernard
Francis Carol L.
Galileo Laboratories, Inc.
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