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  Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methodsUSPTO Application #: 20060178356Title: Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods Abstract: Cytoprotective compounds, many of which are phenolic derivatives characterized by a substituted phenol having certain conjugated bonds, are useful in the treatment of 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. They are also useful in the manufacture of pharmaceutical and cosmetic formulations for the treatment of such conditions. (end of abstract)
Agent: Foley & Lardner LLP - Palo Alto, CA, US Inventors: Bing Wang, Yong-Kang Zhang, Jian Chen, Wei Zhang, Jiangao Song, Ughetta Del Balzo, Lesley Brown, Sekhar Boddupalli, Steven Bobzin, Sylvain Gilat, Guy Miller USPTO Applicaton #: 20060178356 - Class: 514184000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Heavy Metal Containing (including Salts) The Patent Description & Claims data below is from USPTO Patent Application 20060178356. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority of co-pending provisional applications U.S. Ser. No. 60/307,439, filed Jul. 23, 2001, and U.S. Ser. No. 60/353,702, filed Jan. 31, 2002, incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates to certain compounds having cytoprotective activity, and particularly to a series of phenolic 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. BACKGROUND INFORMATION [0003] The present invention is concerned with cytoprotective compounds, many of which are phenolic derivatives characterized by a substituted phenol having certain conjugated bonds, also referred to herein as a "conjugated phenol." [0004] 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. [0005] Various agents have heretofore been provided for such conditions. In one group of compounds, the substituted stilbenes (e.g., including resveratrol and its derivatives), many if not all of the possible positions have been disclosed as substituted with various moieties for use as cosmetics, antioxidants, fungicides and as pharmaceutical active agents for the treatment of dermatological conditions, inflammation, menopause, diabetes, cell growth inhibition, protection against UV damage, antimicrobial agents and the like (see, e.g., U.S. Pat. Nos. 4,992,468; 5,547,983; 5,565,191; and 6,147,121). It has, however, remained desired to provide new, improved and more specifically targeted therapies for conditions characterized by oxidative stress, and particularly, for providing protection in the event of cerebral ischemia or ultraviolet exposure; 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 [0006] 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 conjugated phenols (both synthetic and naturally occurring), are useful in the manufacture of pharmaceutical and cosmetic compositions for treating a number of conditions characterized by oxidative stress, and particularly, in providing protection in the event of cerebral ischemia or ultraviolet exposure, 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, neurodegenerative disorders such as Alzheimer's, dementia, and Parkinson's disease; diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, chronic heart failure, rheumatoid arthritis, inflammatory bowel syndrome, 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 contact dermatitis, acne, psoriasis, and in the prevention and protection of skin tissue against age-related damage or damage resulting from insults such as harmful (UV) radiation, stress and fatigue. [0007] The present invention concerns the compounds represented by Formulae I to V, particularly compounds embodying certain preferred combinations and permutations of substituent groups, including single stereoisomers, mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof. For example, the substituent group methoxymethoxy has been identified as conferring activity in various methods of treatment of the invention, in addition to serving as a protecting group in the synthesis of hydroxysubstituted compounds. Another preferred substituent group is alkenyl, represented by the formula H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an integer from 1 to 4 (most preferably n is 1 or 2, i.e., prenyl and geranyl). The invention further concerns the use of these compounds as active agents in practice of methods of treatment for a mammal suffering from a condition characterized by oxidative stress, their use in the manufacture of the pharmaceutical and/or cosmetic formulations of the invention, and their use as intermediates in the synthesis of active agents. [0008] With regard to Formula I: [0009] R is selected from: substituted alkenyl, optionally substituted aryl, (optionally substituted aryl)carbonyl, optionally substituted heteroaryl (including bipyridinyl metal complexes), optionally substituted heterocyclyl, or nitro; [0010] R' is selected from: hydrogen or (optionally substituted alkoxy)carbonyl; [0011] R.sup.1 to R.sup.5 are independently selected from: optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, (optionally substituted alkoxy)carbonyl, carboxy, cyano, halo, optionally substituted heteroaryl, hydrogen, hydroxy, nitro, nitrone, sulfonate; or [0012] two adjacent members of R.sup.1 to R.sup.5 are each O.sup.- and together are complexed with carbon or a metal; provided that at least one of R.sup.1 to R.sup.5 is not hydrogen. [0013] With regard to Formula II: [0014] R'' is selected from: optionally substituted anthracenone, substituted alkenyl, di-cyano, optionally substituted heteroaryl, or optionally substituted heterocyclyl; [0015] R.sup.6 to R.sup.10 are independently selected from: optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, (optionally substituted alkoxy)carbonyl, hydrogen, hydroxy and nitrone; or [0016] two adjacent members of R.sup.6 to R.sup.8 are each O.sup.- and together are complexed with carbon or a metal; provided that at least one of R.sup.6 to R.sup.10 is not hydrogen. Those skilled in the art will appreciate that many compounds analogous to those of Formula II, bearing a single bond to R'', can be employed in the methods of treatment of the present invention. [0017] Formula III, IV and V represent compounds of Formula I where two adjacent members of R.sup.1 to R.sup.5 (preferably R.sup.3 with R.sup.2 or R.sup.4) are each O.sup.- and together are complexed with a metal having one or more apical ligands, where the metal can optionally be further complexed with a second compound of Formula I forming dimers of such complexes: where: [0018] M is: a metal; [0019] L is: a ligand associated with a remaining free valence on M; [0020] n is: an integer from 1 to 3, corresponding to the remaining free valences on M and the number of associated ligands; [0021] R and R* are independently selected from: optionally substituted anthraquinone, substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or nitro; and [0022] R.sup.2, R.sup.4 and R.sup.4* are independently selected from: optionally substituted alkoxy, hydrogen, or hydroxy. [0023] Certain naturally occurring conjugated phenols and the like are also useful in the methods and compositions of the invention including: acetoxychavicol acetate, arachidin I, arachadin II, arachidin III, astringin, cis-gnetin, 1-(3,4,5-trimethoxyphenyl)-2-(4-methoxyphenyl)-ethanol, trans-(4,4'-diacetoxy-3,3'-dimethoxy)carboxystilbene, and trans-(4,4'-diacetoxy-3,3'-dimethoxy)stilbene, including single isomers, mixtures of isomers, and the pharmaceutically acceptable salts thereof. Other compounds of interest include (4-methoxyphenyl)-(benzo-1,3-dioxol-5-yl)-ethyne. [0024] As further described below, certain embodiments of the invention provide novel and preferred combinations of the substituents groups pendant from Formulae I to V. Also provided are methods of treatment for cardiovascular, cerebrovascular and neurologic, inflammatory and/or autoimmune, and dermatologic conditions characterized as involving oxidative stress, and certain preferred combinations of the substituent groups pendant from Formulae I to V for their respective treatment. [0025] In another aspect, the invention relates to a pharmaceutical and/or cosmetic compositions containing a therapeutically effective amount of a compound of any of Formulae I to V, an above-described naturally occurring conjugated phenol, or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. Particularly preferred are those pharmaceutical or cosmetic compositions wherein a compound of Formulae I to V is selected from the Preferred Compounds. [0026] In still another aspect, the invention relates to a method of treating stroke and other oxidative stress-related conditions that are responsive to cellular enzyme modulation such as cerebral ischemia, myocardial infarction, chronic heart failure and exposure to UV radiation in a mammal by administering to a mammal in need of such treatment (even a significant period of time following an ischemic or oxidative insult, such as about 5 or more hours) a therapeutically effective amount of a compound of any of Formulae I to V, an above-described naturally occurring conjugated phenol, or a pharmaceutically acceptable salt thereof. In a method for regulating skin condition, regulating the signs of skin aging, or for treating contact dermatitis, acne, psoriasis, age-related damage or damage resulting from harmful (UV) radiation, stress or fatigue, the invention entails topically administering to a mammal in need of such treatment a therapeutically effective amount of a compound of any of Formulae I to V, an above-described naturally occurring conjugated phenol, or a pharmaceutically acceptable salt thereof. Particularly preferred are those methods of treatment and uses in the manufacture of pharmaceutical and/or cosmetic compositions therefor, wherein a compound of Formulae I to V is selected from the Preferred Compounds. [0027] In yet another aspect, the invention relates to a method of promoting a product by directing a user to apply to the skin a pharmaceutical or cosmetic composition incorporating a compound of any of Formulae I to V, an above-described naturally occurring conjugated phenol, or a pharmaceutically acceptable salt thereof, for regulating skin condition, regulating the signs of skin aging, or for treating contact dermatitis, acne, psoriasis, age-related damage or damage resulting from harmful (UV) radiation, stress or fatigue. The invention also entails a product including instructions directing the user to apply a composition of the invention to the skin for regulating skin condition, regulating the signs of skin aging, or for treating contact dermatitis, acne, psoriasis, age-related damage or damage resulting from harmful (UV) radiation, stress or fatigue, where the composition incorporates a compound of any of Formulae I to V, an above-described naturally occurring conjugated phenol, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION Definitions [0028] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0029] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl," as defined below. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. [0030] Certain compound, reactant, or reaction parameter abbreviations are defined as follows: [0031] "DCM" refers to dichloromethane or methylene chloride [0032] "t-Bu" refers to t-butyl [0033] "DIC" refers to N,N-diisopropylcarbodiimide [0034] "DIPEA" refers to diisopropyl ethylamine [0035] "DMAP" refers to 4-N,N-dimethylamino pyridine [0036] "DMF" refers to N,N-dimethyl formamide [0037] "Eq." refers to equivalent [0038] "MeOH" refers to methanol [0039] "MOM" refers to methoxymethyl [0040] "OMOM" refers to methoxymethoxy [0041] "EtOH" refers to ethanol [0042] "PCC" refers to pyridinium chlorochromate [0043] "TBDMS" refers to t-butyl di-methyl silyl [0044] "THF" refers to tetrahydrofuran [0045] "TBAF" refers to tetrabutyl ammonium fluoride [0046] "TMEDA" refers to N,N,N',N'-tetramethylethylenediamine [0047] "CSA" refers to camphorsulfonic acid, and [0048] "EtOAc" refers to ethyl acetate. Continue reading... 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