Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-06
2003-11-25
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S468000, C549S469000, C549S468000, C549S460000
Reexamination Certificate
active
06653346
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to certain compounds having cytoprotective activity, and particularly to a series of benzofuran derivatives. The invention is also directed to formulations and methods for treating stroke, myocardial infarction and chronic heart failure, as well as other oxidative stress-related conditions that are typically responsive to cellular enzyme modulation. The invention is also directed to a method of treating inflammation by reducing C-reactive protein (CRP). The invention is also directed to cosmetic formulations for the treatment of skin inflammation and other skin disorders.
BACKGROUND INFORMATION
The present invention is concerned with cytoprotective compounds, which are benzofuran derivatives, said derivatives including steroisomers, mixtures of stereoisomers and therapeutically acceptable salts therof.
Compositions of the invention are active in certain experimental models that predict efficacy in, for example, certain ischemic or inflammatory conditions, including but not limited to stroke, myocardial infarction, congestive heart failure, and skin disorders characterized by inflammation or oxidative damage. The invention is therefore related to the use of the cytoprotective derivatives in such conditions.
2,3-Dihydro-5-oxy-4,6,7-trimethyl-2-optionally substituted alkyl benzofurans have been disclosed as antioxidizing pharmaceutical products having anti-ischemic properties in U.S. Pat. No. 5,114,966. Hydroxamines derivatives of 2,3-dihydrobenzofuran carboxy acids have been disclosed in U.S. Pat. No. 5,480,645. 2,3-Dihydrofuran derivatives useful in preventing and treating neovascularization have been disclosed in U.S. Pat. No. 5,719,167 and U.S. Pat. No. 5,798,356. 5-Hydroxybenzofurans have been disclosed for the treatment of a pathological cell proliferative disease in U.S. Pat. No. 5,674,876. A method of inhibiting mammalian leukotriene biosynthesis with 6-hydroxybenzofurans has been disclosed in U.S. Pat. No. 4,714,711.
While various agents have heretofore been provided for such conditions, it has, however, remained desired to provide new therapies for conditions characterized by oxidative stress, and particularly, for providing protection in the event of cerebral ischemia, ultraviolet exposure or inflammation; especially desired are agents that are effective even if first administered after a significant period of time (e.g., about 5 or more hours) following an ischemic or oxidative insult.
SUMMARY OF THE INVENTION
The present invention is concerned with certain novel and related cytoprotective compounds that are particularly active in restoring or preserving metabolic integrity in oxidatively competent cells that have been subjected to oxygen deprivation. Such compounds, predominantly benzofuran derivatives are useful in the manufacture of pharmaceutical compositions for treating a number of conditions characterized by oxidative stress, and particularly, in providing protection in the event of cerebral ischemia, ultraviolet exposure, or inflammation, even when administered a significant time interval after an ischemic or oxidative insult. In particular, the compositions of the present invention are useful in the treatment of stroke, as demonstrated by providing neuroprotection in a standard experimental model of focal cerebral ischemia. They are also useful in the treatment of myocardial ischemia (myocardial infarction), as well as other indications characterized by oxidative stress and/or inflammation, including, but not limited to, diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, chronic heart failure, rheumatoid arthritis, muscle fatigue, intermittent claudication, and for the preservation of allograft tissue for transplantation. Particularly with regard to dermatological conditions, the compounds, formulations and methods of the present invention are useful in regulating skin condition, regulating the signs of skin aging, and in treating a number of conditions, including, but not limited to preventing and protecting skin tissue against age-related damage or damage resulting from insults such as harmful (UV) radiation, stress and fatigue. These compounds, formulations and methods of the present invention are also useful in the treatment for example of contact dermatitis, acne, irritation including retinoid induced irritation, hirsutism, modulation of hair growth, disorders in pigmentation, or psoriasis, and can be used as bactericides, antifungal and antimicrobial agents. The compounds of the present invention also show activity for reducing elevated CRP levels associated with a number of diseases and disorders, including but not limited to, cardiovascular disease, diabetes and infectious diseases.
The present invention concerns the compounds represented by the Formula I:
wherein:
R
1
is: hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, (optionally substituted alkoxy)carbonyl, or halogen;
R
2
and R
3
are independently selected from optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted cycloalkyl;
R
4
is: hydrogen, optionally substituted aryl, (optionally substituted alkyl)carbonyl, (optionally substituted aryl)carbonyl, (optionally substituted heterocyclyl)carbonyl, (optionally substituted heterocyclylalkyl)carbonyl, (optionally substituted alkoxy)carbonyl, (optionally substituted alkenyloxy)carbonyl, (optionally substituted amino)carbonyo, carboxy, formyl, or hydroxy(optionally substituted)alkyl;
R
5
is: hydrogen, alkyl, alkenyl, (optionally substituted alkoxy)carbonyl, carboxy, (optionally substituted amino)carbonyl, or optionally substituted aryl;
provided that one of R
4
or R
5
is hydrogen, and that when R
4
is hydrogen R
5
is not hydrogen, and when R
5
is hydrogen R
4
is not hydrogen;
R is hydrogen, alkyl, acyl, phosphoryl, or polyalkoxy; or
R and R
1
with the atoms to which they are attached form an optionally substituted ring;
including single stereoisomers, mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof.
A preferred embodiment of this invention concerns the compounds of Formula I where R
2
and R
3
are (C
1
-C
6
)-alkyl, preferably methyl, and within that subset those compounds of Formula I wherein R is hydrogen.
In another embodiment, the invention concerns the compounds of Formula I wherein R
2
and R
3
are (C
1
-C
6
)-alkyl, preferably methyl, R is hydrogen, R
5
is hydrogen, and R
4
is optionally substituted aryl, (optionally substituted alkyl)carbonyl, (optionally substituted aryl)carbonyl, (optionally substituted heterocyclyl)carbonyl, (optionally substituted heterocyclylalkyl)carbonyl, (optionally substituted alkoxy)carbonyl, (optionally substituted alkenyloxy)carbonyl, (optionally substituted amino)carbony), carboxy, formyl, or hydroxy(optionally substituted)alkyl, especially wherein said aryl is unsubstituted phenyl or substituted phenyl with one or more substitutents selected from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano.
In another embodiment, the invention concerns the compounds of Formula I wherein R
2
and R
3
are (C
1
-C
6
)-alkyl, preferably methyl, R is hydrogen, R
4
is hydrogen, and R
5
is optionally substituted aryl, preferably unsubstituted phenyl or phenyl substituted with one or more substitutents selected from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano.
In another embodiment, the invention concerns the compounds of Formula I wherein R
2
and R
3
form a ring, preferably R and R
1
form a furan ring substituted with an unsubstituted phenyl or with a phenyl substituted with one or more substitutents selected from alkyl, alkenyl, hydroxy, alkoxy, nitro, cyano, carboxy, carboxyester, haloalkyl, and halo.
Certain embodiments of the invention provide novel and preferred combinations of the substituents groups pendant from the formulae of the different inventions.
In another aspect, the invention relates to pharmaceutical
Chen Jian
Wang Bing
Galileo Pharmaceuticals, Inc.
Lambkin Deborah C.
Pfister Gloria
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