WO2003066618A1 - Cytoprotective benzofuran derivatives - Google Patents
Cytoprotective benzofuran derivatives Download PDFInfo
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- WO2003066618A1 WO2003066618A1 PCT/US2003/003709 US0303709W WO03066618A1 WO 2003066618 A1 WO2003066618 A1 WO 2003066618A1 US 0303709 W US0303709 W US 0303709W WO 03066618 A1 WO03066618 A1 WO 03066618A1
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- dimethyl
- hydroxy
- benzofuran
- optionally substituted
- phenyl
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Definitions
- 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).
- CRP C-reactive protein
- the invention is also directed to cosmetic formulations for the treatment of skin inflammation and other skin disorders.
- 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 US 5,114,966.
- Hydroxamines derivatives of 2,3-dihydrobenzofuran carboxy acids have been disclosed in US 5,480,645.
- 2,3-Dihydrofuran derivatives useful in preventing and treating neovascularization have been disclosed in US 5,719,167 and US 5,798,356.
- 5-Hydroxybenzofurans have been disclosed for the treatment of a pathological cell proliferative disease in US 5,674,876.
- 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.
- 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.
- myocardial ischemia myocardial infarction
- 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.
- 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:
- 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)carbonyl, 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
- 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 ⁇ -C ⁇ )-alkyl, preferably methyl, and within that subset those compounds of Formula I wherein R is hydrogen.
- the invention concerns the compounds of Formula I wherein R 2 and R 3 are (C C 6 )-alkyl, preferably methyl, R is hydrogen, R 5 is hydrogen, and R 4 is optionally substituted aryl,
- the invention concerns the compounds of Formula I wherein R 2 and R 3 are (C 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.
- R 2 and R 3 are (C C 6 )-alkyl, preferably methyl
- R is hydrogen
- R 4 is hydrogen
- 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.
- the invention concerns the compounds of Formula I wherein R and R 1 form a ring, preferably R and R 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.
- the invention relates to pharmaceutical and/or cosmetic compositions containing a therapeutically effective amount of a compound of any of Formula I, 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 Formula I is selected from the Preferred
- Another aspect of the present invention concerns methods of treatment for a mammal suffering from a condition characterized by oxidative stress by administering a therapeutically effective amount of a compound represented by the Formula I including single stereoisomers, mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof.
- the invention relates to a method of treatment of a cardiovascular, cerebrovascular, neurologic, inflammatory, autoimmune, and/or dermatologic condition.
- the invention relates to a condition selected from stroke, cerebral ischemia, myocardial infarction, chronic heart failure, retinal ischemia, post-surgical cognitive diysfunctions, peripheral neuropathy, spinal cord injury, head injury and surgical trauma.
- the condition involves inflammatory or automimmune components.
- the invention relates to a method for treating dermatologic conditions characterized by oxidative stress including but not limited to regulating skin condition, regulating the signs of skin aging, contact dermatitis, acne, skin pigmentation, hair growth modulation, irritation including retinoid induced irritation, psoriasis, age-related damage and damage resulting from harmful (UV) radiation, stress, or fatigue.
- the compound of Formula I or composition thereof is administered topically.
- the condition is dermatologic, further comprising a method of promoting a product by directing a user to apply to the skin a pharmaceutical or cosmetic composition incorporating said compound of Formula I.
- 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 a therapeutically effective amount of a compound of any of Formula I, or a pharmaceutically acceptable salt thereof.
- the invention relates to a method of reducing levels of C-reactive protein
- CRP cardiovascular inflammatory condition
- respiratory inflammatory condition including but not limited to respiratory inflammatory condition, sepsis, diabetes, muscle fatigue, systemic lupus erythematosis (SLE), end stage renal disease (ERSD), periodontal disease, and inflammatory skin conditions.
- SLE systemic lupus erythematosis
- SLE systemic lupus erythematosis
- ERSD end stage renal disease
- periodontal disease inflammatory skin conditions.
- 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.
- DCM dichloromethane or methylene chloride
- t-Bu refers to t-butyl
- DCC refers to 1 ,3-dicyclohexylcarbodiimide
- DIPEA diisopropylcarbodiimide
- DMAP diisopropyl ethylamine
- DMF N-dimethylamino pyridine
- Eq refers to equivalent
- EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- MeOH refers to methanol
- THF tetrahydrofuran
- EtOAc ethyl acetate
- acyl refers to the groups -C(0)-H, -C(0)-(optionally substituted alkyl), -C(0)-(optionally substituted cycloalkyl), -C(0)-(optionally substituted alkenyl), -C(0)-(optionally substituted cycloalkenyl), -C(0)-(optionally substituted aryl), -C(0)-(optionally substituted heteroaryl) and -C(0)-(optionally substituted heterocyclyl).
- alkenyl refers to a monoradical branched or unbranched, unsaturated or polyunsatu rated hydrocarbon chain, having from about 2 to 20 carbon atoms, more preferably about 2 to 10 carbon atoms.
- This term is exemplified by groups such as ethenyl, but-2-enyl, 3-methyl-but-2-enyl (also referred to as “prenyl”), octa-2,6-dienyl, 3,7-dimethyl-octa-2,6-dienyl (also referred to as “geranyl”), and the like.
- substituted alkenyl refers to an alkenyl group in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is replaced by a substituent for example :hydroxy, alkoxy, carboxy, cyano, halogen or nitro.
- alkoxy refers to the groups -O-alkyl, -O-alkenyl, -O-cycloalkyl, -O-cycloalkenyl, and -O-alkynyl.
- Preferred alkoxy groups are -O-alkyl and -O-alkenyl and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, 3,7-dimethyl-octa-2,6-dieny!oxy and the like.
- substituted alkoxy refers to the groups - ⁇ -(substituted alkyl), - ⁇ -(substituted alkenyl),
- One preferred substituted alkoxy group is "polyalkoxy" or - ⁇ -(substituted alkylene)-alkoxy, and includes groups such as -OCH 2 OCH 3 , — OCH 2 CH 2 OCH 3 , and (or PEG) groups such as -0(CH 2 CH 2 ⁇ ) ⁇ CH 3 and -0(CH 2 CH 2 0) x H where x is an integer of about 2-20, preferably about 2-10, and more preferably about 2-5.
- alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from about 1 to 20 carbon atoms, more preferably about 1 to 10 carbon atoms, and even more preferably about 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
- One of the preferred optional substituents for alkyl is hydroxy, exemplified by hydroxyalkyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like; dihydroxyalkyl groups (glycols), such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, and the like; and those compounds known as polyethylene glycols, polypropylene glycols and polybutylene glycols, and the like.
- a preferred "substituted alkyl" wherein the substitutents form a ring is 6-hydroxy-3-methyl-[1 ,3]oxazinan-6-yl.
- amino refers to the group -NH 2 .
- substituted amino refers to the group -NHR or -NRR where each R is independently selected from the group: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, acyl, optionally substituted alkoxy, carboxy and alkoxycarbonyl, and wherein RR form with the nitrogen to which they are attached a cyclic amine optionally incorporating one or more additional heteroatoms selected from O, N and S.
- aryl refers to an aromatic cyclic hydrocarbon group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
- (optionally substituted alkoxy)carbonyl refers to the groups: -C(0)0-(optionally substituted alkyl), -C(0)0-(optionally substituted cycloalkyl), -C(0)0-(optionally substituted alkenyl), -C(0)0-(optionally substituted alkynyl), -C(0)0-(optionally substituted aryl), -C(0)0-(optionally substituted heteroaryl), and -C(0)0-(optionally substituted heterocyclyl). These moieties are also referred to as esters.
- (optionally substituted amino)carbonyl refers to the group -C(0)-(optionally substituted amino). This moiety is also referred to as a primary, secondary or tertiary carboxamide, and the "substituted amino” can be a cyclic amine.
- the term "compound of Formula I" is intended to encompass the derivatives of the invention as disclosed, and/or the pharmaceutically acceptable salts of such compounds.
- the compounds employed in this invention include the individual stereochemical isomers (arising from the selection of substituent groups) and mixtures of isomers.
- Cosmetics includes make-up, foundation, and skin care products.
- make-up refers to products that leave color on the face, including foundations, blacks and browns, i.e., mascara, concealers, eye liners, brow colors, eye shadows, blushers, lip colors, and so forth.
- the term “foundation” refers to liquid, creme, mousse, pancake, compact, concealer or like products that even out the overall coloring of the skin.
- skin care products refers to products used to treat or otherwise care for, moisturize, improve, or clean the skin.
- Products contemplated by the phrase “skin care products” include, but are not limited to, adhesives, bandages, toothpaste, anhydrous occlusive moisturizers, antiperspirants, deodorants, powder laundry detergent, fabric softener towels, occlusive drug delivery patches, nail polish, powders, tissues, wipes, solid emulsion compact, anhydrous hair conditioners medicated shampoos, scalp treatments and the like.
- CRP C-reactive protein
- CAVD cardiac allograft vasculopathy
- mastitis preclampsia
- inflammatory bowel conditions stroke
- tissue infarction lumbosciatic
- estrogen/progestin hormone replacement therapy HRT
- infection bacterial, viral and protozoan
- bacterial meningitis trauma; surgery; biomaterial implants; smoking; obesity; neurodegenerative diseases such as, Alzheimers; infectious disease, such as, for example, myocarditis, cardiomyopathy, acute endocarditis, pericarditis; atherosclerosis; Systemic Inflammatory Response Syndrome (SIRS)/sepsis; adult respiratory distress syndrome (ARDS); asthma; rheumatoid arthritis, osteoarth
- cycloalkyl refers to the monovalent saturated radical consisting of one or more rings, which can optionally be susbstituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino or sulfonyl, unless otherwise indicated.
- cycloalkyl radicals include but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, etc.
- halo or halogen refers to fluoro, chloro, bromo and iodo.
- heteroaryl refers to an aromatic cyclic hydrocarbon group having about 1 to 40 (preferably from about 3 to 15) carbon atoms and about 1 to 10 hetero atoms (preferably about 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen) within at least one ring.
- heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
- Preferred heteroaryls include pyridyl, [2,2']bipyridinyl, pyrrolyl and furyl.
- heterocycle refers to a monoradical, saturated or unsaturated, non-aromatic cyclic hydrocarbon group having about 1 to 40 (preferably from about 3 to 15) carbon atoms and about 1 to 10 hetero atoms (preferably about 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen) within the ring.
- heterocyclic groups can have a single ring or multiple condensed rings.
- Preferred heterocyclics include morpholino, piperidinyl, 1 ,3-oxazinane,and the like.
- heterocycloalkyl refers to the moiety "-alkylene-heterocycle” each having the meaning as defined herein.
- substituted heterocycloalkyl refers to the moiety "-(optionally substituted aklylene)-
- inflammation includes but is not limited to muscle fatigue, osteoarthritis, rheumatoid arthritits, inflammatory bowel syndrome or disorder, skin inflammation, such as atopic dermatitis, contact dermatitis, allergic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, atherosclerosis, thermal and radiation burns, acne, oily skin, wrinkles, excessive cellulite, excessive pore size, intrinsic skin aging, photo aging, photo damage, harmful UV damage, keratinization abnormalities, irritation including retinoid induced irritation, hirsutism, alopecia, dyspigmentation, inflammation due to wounds, scarring or stretch marks, loss of elasticity, skin atrophy and gingivitis.
- skin inflammation such as atopic dermatitis, contact dermatitis, allergic dermatitis, xerosis, eczema, rosacea, seborrhea, p
- ischemia refers to deficiency of blood to an organ or tissue due to functional constriction or actual obstruction of a blood vessel. Cerebral ischemia, also known as stroke, usually results from the interruption or reduction of blood and oxygen to the blood vessels of the brain; more rarely this may be the result of an hemorrhage. Signs of stroke include paralysis, slurred speech, general confusion, impairment of gait, cortical sensory loss over toes, foot and leg, and urinary incontinence, to name just a few. Many types of heart disease including cardiac arrhythmias or diseases due to cardiac structural abnormalities may produce cerebral emboli.
- Atrial fibrillation from any cause may result in emboli being produced which can migrate into the arteries of the brain.
- Emboli formation and migration can occur as a result of arteriosclerotic cardiovascular disease and myocardial infarction.
- Emboli formation is also a definite risk for intracardiac surgery and prosthetic valve replacement.
- Heart bypass surgery and angioplasty can result in the formation of microemboli which can migrate into the arteries of the brain and cause a series of occlusions in a number of arteries, resulting in mental impairment.
- Cerebral embolism is also the principal complication in the transplant of artificial hearts.
- the overall risk of stroke after any type of general surgery is 0.2 to 1 percent.
- the vegetations of acute and subacute bacterial endocarditis can give rise to emboli which can occlude a major intracranial artery.
- Populations at risk of ischemia include but are not limited to patients scheduled for coronary arterial bypass graft surgery (CABG), patients at risk for postoperative complications, patients with subarachnoid hemorrhage (SAH), patients with a first or second ischemic stroke, patients with acute ischemic stroke, patients undergoing cardiopulmonary resuscitation (CPR), patients with temporary lobectomy, patients with dominant hemisphere resection, patients receiving prophylactic brain radiation, patients with closed head trauma with neurological loss, patients with microvascular multi-infarct dementia, patients with homozygous and heterozygous MELAS
- personal care products refer to health and cosmetic beauty aid products generally recognized as being formulated for beautifying and grooming the skin and hair.
- personal care products include sunscreen products (e.g., lotions, skin creams, etc.), cosmetics, toiletries, and over-the- counter pharmaceutical products intended for topical usage.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the compounds of this invention and which are not biologically or otherwise undesirable.
- the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri (cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkeny
- Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene- sulfonic acid, salicylic acid, and the like.
- phosphoryl refers to the group -P(0)(OR") 2 , where R" is independently selected from hydrogen or alkyl and aryl, which group is sometimes also referred to as “phosphono” or as a “phosphate” or “phosphonic acid.”
- “Regulating skin condition” includes prophylactically regulating and/or therapeutically regulating skin condition, including visible and/or tactile discontinuities in skin such as, but not limited to, regulating visible and/or tactile discontinuities in the texture of skin, reducing post-inflammatory hyperpigmentation, regulating non-melanin discoloration of skin, regulating moisturization and barrier properties of skin, regulating epidermal differentiation of skin, regulating exfoliation of skin, thickening of skin to reduce skin atrophy, regulating the elasticity of skin, reducing oily skin, regulating cellulite in skin, regulating pruritus in skin, and promoting wound healing in skin.
- prophylactically regulating skin condition includes delaying, minimizing and/or preventing visible and/or tactile discontinuities in skin.
- therapeutically regulating skin condition includes ameliorating, e.g., diminishing, minimizing and/or effacing, discontinuities in skin.
- Regulating skin condition involves improving skin appearance and/or feel.
- Regulating skin condition includes modulation body/cranial hair growth, including retarding and/or preventing the growth of body and/or head hair.
- Regulating skin condition includes regulating irritation including retinoid induced irritation.
- regulating the skin includes the use of the compounds of the invention as bactericides, antifungal and antimicrobial agents.
- “Regulating the signs of skin aging” includes prophylactically regulating and/or therapeutically regulating one or more of such signs (similarly, regulating a given sign of skin aging, e.g., lines, wrinkles or pores, includes prophylactically regulating and/or therapeutically regulating that sign). As used herein, prophylactically regulating such signs includes delaying, minimizing and/or preventing signs of skin aging.
- therapeutically regulating such signs includes ameliorating, e.g., diminishing, minimizing and/or effacing signs of skin aging.
- “Signs of skin aging” include, but are not limited to, all outward visibly and tactilely perceptible manifestations as well as any other macro or micro effects due to skin aging. Such signs may be induced or caused by intrinsic factors or extrinsic factors, e.g., chronological aging and/or environmental damage (e.g., sunlight, UV, smoke, ozone, pollutants, stress, etc.).
- intrinsic factors or extrinsic factors e.g., chronological aging and/or environmental damage (e.g., sunlight, UV, smoke, ozone, pollutants, stress, etc.).
- These signs may result from processes which include, but are not limited to, the development of textural discontinuities such as wrinkles, including both fine superficial wrinkles and coarse deep wrinkles, skin lines, facial frown lines, expression lines, rhytides, dermatoheliosis, photodamage, premature skin aging, crevices, bumps, pits, large pores (e.g., associated with adnexal structures such as sweat gland ducts, sebaceous glands, or hair follicles), "orange-peel” skin appearance, dryness, scaliness, flakiness and/or other forms of skin unevenness or roughness; blemishes such as acne, pimples, breakouts; excess skin oil problems such as over production of sebum, oiliness, facial shine, foundation breakthrough; abnormal desquamation (or exfoliation) or abnormal epidermal differentiation (e.g., abnormal skin turnover) such as scaliness, flakiness, keratoses, hyperkeratinization; inadequate skin moisturization
- therapeutically effective amount refers to that amount of a compound of any of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
- the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
- treatment or “treating” means any treatment of a disease or disorder in a mammal, including:
- topical application means to apply or spread the compositions of the present invention onto the surface of the skin. Nomenclature
- Formula la represents the compound according to formula I where R, R 1 and R 5 are hydrogen, R 2 and R 3 are methyl, and R 4 is p-nitro-phenyl, and can be named 6,7-dimethyl-2-(4-nitro-phenyl)-benzofuran-5-ol.
- Formula lb represents the compound according to formula I where R, R 1 , and R 4 are hydrogen, R 2 and R 3 are methyl, and R 5 is phenyl, and can be named 6,7-dimethyl-3-phenyl-benzofuran-5-ol.
- solvent means a solvent inert under the conditions of the reaction being described in conjunction therewith.
- Solvents employed in synthesis of the compounds of the invention include, for example, methanol, acetone, water, acetonitrile, 1,4-dioxane, dimethylformamide (“DMF”), benzene, toluene, xylene, tetrahydrofuran (“THF”), chloroform, methylene chloride (or dichloromethane, (“DCM”)), diethyl ether, pyridine and the like, as well as mixtures thereof.
- DMF dimethylformamide
- DCM dichloromethane
- the solvents used in the reactions of the present invention are inert organic solvents.
- q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
- ambient temperature e.g., 20°C
- reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10°C to about 110°C (preferably from about 0°C to about 40°C; most preferably at about "room” or
- ambient temperature e.g., approximately 20°C
- ambient temperature e.g., approximately 20°C
- Parameters given in the Examples are intended to be specific, not approximate.
- Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
- suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
- the starting compounds e.g., 2,3-dimethylhydroquinone, are commercially available, e.g. from
- a 2,3- substituted hydroquinone of Formula 101 is treated with one equivalent of a 2-halo-1-substituted-ethanone, preferably 2-bromo-1-substituted-ethanone, most preferably 2-bromo-1 -substituted phenyl ethanone, in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate in a solvent such as acetone, THF, or DMF, to give 2-(4-hydroxy-2,3- substituted-phenoxy)-1-substituted-ethanone of Formula 102.
- a base such as sodium carbonate, potassium carbonate or cesium carbonate
- a solvent such as acetone, THF, or DMF
- Compound of Formula 102 can subsequently be treated with an acid such as polyphosphoric acid, hydrochloric acid, or sulfuric acid in an inert solvent such as toluene or xylene, to cyclise into a benzofuran compound of Formula 103.
- an acid such as polyphosphoric acid, hydrochloric acid, or sulfuric acid in an inert solvent such as toluene or xylene
- an inert solvent such as toluene or xylene
- a base such as sodium carbonate, potassium carbonate, or cesium carbonate
- a solvent such as acetone, THF, or DMF
- substituent groups (sub-grouped, respectively, in increasing order of preference) define compounds that are preferred as compositions of matter and compounds for use in the methods and pharmaceutical and cosmetic compositions according to the invention.
- R 1 is hydrogen or halogen Especially those where R is hydrogen.
- the compounds of any of Formula I where R 1 is hydrogen or halo o Preferably those where R 1 is hydrogen
- R 2 and R 3 are methyl o
- R 5 is optionally substituted aryl, wherein the substitutents are chosen from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano
- R 4 is para-substituted phenyl, wherein the substitutents are chosen from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano -
- R 4 is 4-nitrophenyl, 4-cyanophenyl and R 5 is hydrogen.
- R 4 is formyl, (optionally substituted alkyl)carbonyl,
- R 4 is alkylcarbonyl optionally substituted with halogen, hydroxy or heterocyclyl, especially substituted with morpholin-1-yl
- R 4 is selected from formyl, phenylcarbonyl, bromoacetyl, morpholin-1 -yl-acetyl, and acetyl; and R 5 is hydrogen o Especially those wherein R 4 is (optionally substituted alkoxy)carbonyl, (optionally substituted alkenyloxy)carbonyl, (optionally substituted amino)carbonyl, carboxy, or hydroxy(optionally substituted)alkyl;
- R 4 is (optionally substituted alkoxy)carbonyl, preferably those where the alkoxy is polyalkoxy, or optionally substituted alkenyloxy) carbonyl, preferably those where the alkenyloxy is geranyloxy.
- R 4 is (optionally substituted amino)carbonyl, preferably those wherein the amino is substituted with optionally substituted alkyl, especially hydroxyalkyl, or wherein the amino is a cyclic amine.
- R 4 is morpholin-1 -yl-carbonyl; bis-(2-hydroxy-ethyl)- amide, 2-hydroxy-ethyl-amide, carboxylic acid; carboxylic acid methyl ester; carboxylic acid 3,7-dimethyl-octa-2,6-dienyl ester; [2-(2-methoxy-ethoxy)- ethoxy]ethyl ester; and R 5 is hydrogen, o Especially those where R 4 are hydroxy (optionally substituted) alkyl • Particularly where R 4 is hydroxymethyl, 1-hydroxy-2-morpholiny-4-yl ethyl or 6- hydroxy-3-methyl-[1,3]oxazinan-6-yl.
- the compounds preferred for use in the invention include the following, as well as their stereoisomers, salts, and mixtures thereof (as appropriate):
- Acetic acid 2-(2-bromo-acetyl)-6,7-dimethyl-benzofuran-5-yl ester; 2-(1-Hydroxy-2-morpholin-4-yl-ethyl)-6,7-dimethyl-benzofuran-5-ol;
- CRP C-reactive protein
- cardiovascular diseases or disorders such as atrial fibrillation, unstable angina, coronary artery disease, peripheral artery disease, cardiac allograft vasculopathy (CAVD), mastitits, preclamplsia, inflammatory bowel conditions, stroke, tissue infarction, lumbosciatic, estrogen/progestin hormone replacement therapy (HRT); infection (bacterial, viral and protozoan), bacterial meningitis, trauma, surgery, biomaterial implants, smoking, obesity, neurodegenerative diseases such as Alzheimers, infectious disease such as for example myocarditis, cardiomyopathy, acute endocarditis orpericarditis, aatherosclerosis, sustemic inflammatory response (SIRS)/sepsis, adult respirtoru distress syndrome (ARDS), asthma, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosis,
- CRP C-reactive protein
- the compounds, formulations and methods of the present invention are useful in treating a number of dermatological conditions, including, but not limited to prevention and protecting skin tissue against age- related damage or damage resulting from insults such as harmful ultraviolet (UV) radiation, stress and fatigue.
- Such compounds, formulations and methods are likewise useful in hair care and treatments of the scalp, for example by incorporation in medicated shampoos, anhydrous hair conditioners and the like.
- Such compounds, formulations and methods are likewise useful in reduction of hair growth.
- UVB radiation having a wavelength of from about 290 nm to about 320 nm.
- UVB radiation having a wavelength of from about 290 nm to about 320 nm.
- UVA radiation having a wavelength of from about 320 nm to about 400 nm.
- This condition is characterized by wrinkling and pigment changes of the skin, along with other physical changes such as cracking, telangiectasis, solar dermatoses, ecchymoses, and loss of elasticity.
- Individuals, particularly those having light-skin who burn easily and tan poorly, who have had a great deal sun exposure in childhood can show the following gross cutaneous alterations in later adult life: wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling (hyperpigmentation) and various premalignant growths (often subclinical).
- photoaging Although the anatomical degradation of the skin is most advanced in the elderly, the destructive effects of excessive sun exposure are already evident by the second decade. Serious microscopic alterations of the epidermis and dermis occur decades before these become clinically visible. Wrinkling, yellowing, leatheriness and loss of elasticity are very late changes.
- compositions of the present invention are useful for regulating body and/or head hair growth, particularly for the reduction of hair growth.
- the composition should be applied to the area of the body where it is desired to inhibit hair growth.
- the composition can be applied to the face, particularly to the beard area of the face, i.e., the cheek, neck, upper lip, and chin.
- the composition can also be applied to the legs, arms, torso and armpit.
- the compostion is particularly suitable for the treatment of hirsutism.
- the composition should be applied onece or twice a day, or even more frequently, for at least three months to achieve a perceived reduction in hair growth.
- Other skin conditions that may benefit from the methods of the present invention include, but are not limited to, diaper rash, a common form of contact dermatitis and irritation occurring in infants, as well as adults, who wear diapers.
- U.S. Patent 6,211 ,186 incorporated herein by reference, describes possible etiologies and methods of treating this condition. It is generally thought that one or more fecal and lipolytic enzymes, as well as ammonia, bacteria, urine pH, overhydration and Candida albicans may be involved in the onset of skin irritation and inflammation associated with diaper rash.
- compositions and methods of the present invention may be useful in treating acne, a skin condition characterized by a profound inflammatory component, and irritation including retinoid iinduced irritation.
- compositions of the present invention are also useful for regulating skin condition, including visible and/or tactile discontinuities in skin (especially the skin surface; such discontinuities are generally undesired). Such discontinuities may be induced or caused by internal and/or external factors, and include the signs of skin aging described herein. Visible discontinuities include pigmentation disorders.
- the compositions of the present invention are useful for regulating signs of skin aging, especially visible and/or tactile discontinuities in skin texture associated with aging. It is to be understood that the present invention is not to be limited to regulation of the "signs of skin aging" that arise due to the above- mentioned mechanisms associated with skin aging, but is intended to include regulation of such signs irrespective of their mechanism of origin. Testing
- compositions incorporating compositions of the present invention are selected, using in vitro and/or in vivo animal models, for example, and used as therapeutic interventions in three exemplary indications, i.e., stroke, chronic heart failure and myocardial infarction.
- Neuronal cell lines such as the pheochromocytoma cell line, PC12, are also useful models for studying the effects of oxidative stress on the structure and function of neuron-specific proteins that are expressed in the cell lines. As many neuronal cell lines do not express all the properties of genuine neurons, primary neuronal cultures are now widely used as in vitro models in which to discern the processes that occur in intact brain.
- In vitro models of ischemia approximate oxygen and glucose deprivation that mimic in vivo conditions, for example, by placing neuronal cultures into large anaerobic or hypoxic chambers and exchanging culture medium with de-oxygenated and defined ionic composition media.
- NMDA neuronal glutamate receptors
- ROS reactive oxygen species
- the hippocampus is a source of a relatively homogenous population of neurons with well-characterized properties typical of central nervous system (CNS) neurons in general. Pyramidal neurons, the principal cell type in the hippocampus, have been estimated to account for 85% to 90% of the total neuronal population (Banker and Goslin, 1998, Culturing Nerve Cells, 2 nd edition. The MIT Press, Cambridge, Massachusetts).
- the hippocampus also exhibits a remarkable capacity for activity-dependent changes in synaptic function, such as long-term potentiation (Hawkins RD, Kandel ER, Siegelbaum SA. (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity [review], Ann. Rev Neurosci. 16:625-665.).
- anoxia/ischemia was induced in primary cultures of hippocampal neuronal cells, and compounds were tested for their ability to prevent cell death. Compounds found to have activity in such in vitro assays are then further tested in one or more animal models of cerebral ischemia ("stroke"), such as the middle cerebral artery occlusion (MCAO) model in rats.
- stroke animal models of cerebral ischemia
- MCAO middle cerebral artery occlusion
- Hippocampal cultures are typically prepared from 18- to 19-day fetal rats.
- pyramidal neurons which begins in the rat at about E15, is essentially complete.
- the brain tissue at this stage is relatively easy to dissociate, the meninges are removed readily, and the number of glial cells still is relatively modest (Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. (2000) Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture. J ⁇ /euroc/7em 74(1 ):114-124).
- a test compound is assessed for its ability to protect cells against one or more standard stressors, including hypoxia, as detailed in the Examples.
- desirable therapeutic compound candidates are effective in this model at concentrations less than about 1 mM and even more preferably, less than about 100 ⁇ M.
- effective it is meant that such compounds protect at least 20%, preferably 30%, more preferably 40% and even more preferably 50% or more of the cells tested from stressor-induced death.
- compounds that are effective in providing protection over a concentration a range of about 1 to 1000 ⁇ M would be expected to provide neuroprotection in vivo.
- Cerebral ischemic insults are modeled in animals by occluding vessels to, or within, the cranium (Molinari, G.F., 1986, in H.J.M. Barnett, et al., (Eds) Stroke: Pathophysiology, Diagnosis and Management, Vol. 1 , Churchill Livingstone, NY).
- the rat middle cerebral artery occlusion (MCAO) model is one of the most widely used techniques to induce transient focal cerebral ischemia approximating cerebral ischemic damage in humans, e.g., those who suffer from a stroke.
- the middle cerebral artery used as the ischemic trigger in this model is the most affected vessel in human stroke.
- the model also entails a period of reperfusion, which typically occurs in human stroke victims.
- MCAO involving a two-hour occlusion has been found to produce the maximum size of cortical infarction obtainable without increased mortality at twenty- four hours.
- a nylon filament is implanted into the right carotid artery of the rat.
- the rat is anesthetized, and the filament is advanced into the internal carotid artery 18-20 mm from the point of bifurcation of internal and external arteries and a suture is tightly ligated around the filament for a period of two hours.
- Test drugs can be administered any time during this process - before, during or after occlusion, and can be administered by one or more of a variety of means, including but not limited to intracerebroventricular (ICV) infusion, intravenous (IV) infusion, intraperitoneal (IP) administration, as well as enteral administration (e.g., gavage). Animals are maintained normothermic during the experiment, as described in the Examples. At a pre-determined time following occlusion and reperfusion, animals are sacrificed and their brains are removed and processed for assessment of damage as measured by infarct volume.
- ICV intracerebroventricular
- IV intravenous
- IP intraperitoneal
- enteral administration e.g., gavage
- compounds are considered to have activity in this model, if they provide a significant reduction in total infarct volume at a dose that is less than about 10 mg/kg, preferably less than 1 mg/kg, more preferably less than 100 ⁇ g/kg and even more preferably less than about 1 ⁇ g/kg, when administered ICV or IV.
- significant reduction of total infarct volume is meant a reduction of at least 20%, preferably at least 30%, more preferably at least 40%, and even more preferably about 50%, compared to control values.
- myocardial ischemia Preparation of myocardiocytes from neonatal rats is described in the Examples.
- Such cells are typically used to study molecular models of myocardial ischemia (Webster, KA, Discher, DJ & Bishopric, NH. 1995. J. Mol. Cell Cardiol. 27:453-458; Camilleri, L, Moins, N, Papon, J, Maublant, J, Bailly, P, de Riberolles, C & Veyre, A. 1997. Cell Biol. & Toxicol.
- compositions incorporating compositions of the present invention are selected, using in vitro and in vivo animal models and used as therapeutic interventions in dermatological indications.
- mediators include but are not limited to inflammatory cytokines, interleukin -l .beta., and tumor necrosis factor alpha (TNF.alpha.).
- mediators include but are not limited to inflammatory cytokines, interleukin -l .beta., and tumor necrosis factor alpha (TNF.alpha.).
- TNF.alpha tumor necrosis factor alpha
- Other molecules have been reported for use as markers of inflammation, including for example C-reactive protein (CRP), certain adhesion molecules, and proteins such as leukotriene, thromboxane and isoprostane.
- ELAM E-selectin
- CRP CRP assay exemplified in Example 9
- ELAM E-selectin
- CRP CRP assay exemplified in Example 9
- ELAM assay measures activity of test compounds in reducing espression of ELAM in acrivated endothelial cells.
- endothelial cells are crivated by adding known acrivalors such as lipopolysaccharides, TNF, or IL-1.beta., alone or in some combination.
- Activated cells produce ELAM, which can be measure unsing, for example, an E- selectin monoclonal antibody-based ELISA assay. In studies carried out in support of the present invention, ELAM production was decreased. In vivo evaluation of anti-inflammatory activity as described in Example
- Carrageenan-lnduced Paw Edema is a model of inflammation, which causes time-dependent edema formation following carrageenan administration into the intraplantar survace of a rat paw.
- the application of arachidonic acid (AA) to the ears of mice produces immediate vasodilatation and erythema, followed by the abrupt development of edema, which is maximal at 40 to 60 min. The onset of edema coincides with the extravasations of protein and leukocytes.
- Example 8 100) from the Mattek Corporation of Ashland, Mass., as dexcribed in Example 7.
- Cell cultures of neonatal foreskin are cultured in accordance with the manufacturer's directions, and are assayed for percent cellular viability by measuring the amount of 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye taken up by the cells.
- Activity with respect to hair growth inhibition is described in Example 8.
- the compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described.
- Administration of the compounds of the invention or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities.
- a daily dose is from about 0.01 to 2.0 mg/kg of body weight, preferably about 0.1 to .5 mg/kg of body weight, and most preferably about 0.3 to 1.0 mg/kg of body weight.
- the dosage range would be about 0.7 to 140 mg per day, preferably about 7.0 to 105 mg per day, and most preferably about 21 to 70 mg per day.
- the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
- compositions of the present invention are suitable for providing protection against the harmful effects of ultraviolet radiation, preferably in personal care products. More preferably, the compositions of the present invention are suitable for use as sunscreens to provide protection to human skin from the harmful effects of UV radiation, which include, but are not limited to, sunburn and premature aging of the skin.
- the present invention therefore also further relates to methods of protecting human skin from the harmful effects of UV radiation. Such methods generally involve attenuating or reducing the amount of UV radiation that reaches the skin's surface.
- the methods of treatment for the harmful effects of ultraviolet radiation also include administration of a composition of the invention after the exposure to UV radiation has already taken place.
- Topical application refers to application of the present compositions by spreading, spraying, etc. onto the surface of the skin. The exact amount applied may vary depending on the level of UV protection desired. From about 0.5 mg of composition per square centimeter of skin to about 25 mg of composition per square centimeter of skin are typically applied
- compositions of the invention may be employed in any skin care application where decreased inflammatory response is desirable
- compounds and compositions of the invention may be incorporated into leave-on and rinse-off acne preparations, facial milks and conditioners, shower gels, foaming and non-foaming facial cleansers, cosmetics, hand and body lotions, leave-on moisturizers, cosmetic and cleaning wipes, salves for poison ivy, chicken pox, or pruntis, or the like
- topical administration is preferred, however, systemic administration, as described elsewhere herein, is also possible
- Cosmetic compositions of the present invention are ideally suited for use in treating the skin and lips, especially in the form of a lipstick or lip balm for applying to the lips a permanent or semi-permanent color, ideally with a gloss or luster finish
- the cosmetic compositions can also be used in treating the skin and/or lips with a skin care agent for protection against exposure to adverse weather, including the
- the cosmetic compositions can accordingly be applied to the skin and/or lips in the traditional manner with or without a conventional holder or applicator to provide a decorative and/or protective film thereto
- any pharmaceutically acceptable mode of administration can be used
- the compounds of formula I can be administered either alone or in combination with other pharmaceutically acceptable excipients, including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like
- the compounds of formula I can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the prolonged administration of the compound at a predetermined rate, preferably in unit dosage forms suitable for single administration of precise dosages
- the compositions will typically include a conventional pharmaceutical carrier or excipient and a compound of formula I or a pharmaceutically acceptable salt thereof
- these compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, and the like, including, but not limited to anticoagulants, blood clot dissolvers, permeability enhancers and slow release formulations
- the pharmaceutically acceptable composition will contain about 0 1% to 90%, preferably about 0 5% to 50%, by weight of a compound or salt of formula I, the remainder being suitable pharmaceutical excipients, carriers, etc
- a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like
- excipients such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like
- Such compositions take the form of solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like
- compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like, a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
- a diluent such as lactose, sucrose, dicalcium phosphate, or the like
- a lubricant such as magnesium stearate or the like
- a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
- Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
- a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
- the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc.
- composition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount effective to alleviate the symptoms of the subject being treated.
- Dosage forms or compositions containing active ingredient in the range of 0.005% to 95% with the balance made up from non-toxic carrier may be prepared.
- a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum and the like.
- excipients such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum and the like.
- Such compositions take the form of solutions, suspensions, tablets, capsules, powders, sustained release formulations and the like.
- compositions may contain 0.01%-95% active ingredient, preferably 0.1-50%.
- the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
- a gelatin capsule Such diester solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239; and 4,410,545.
- the solution e.g. in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
- liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
- formulations include those set forth in U.S. Patents Nos. Re. 28,819 and 4,358,603.
- the formulation can be administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
- the formulation may be administered as a bolus or as a continuous intravenous infusion after onset of symptoms of stroke, myocardial infarction or chronic heart failure.
- Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
- Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
- Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
- the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
- a more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795.
- the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages.
- composition will comprise 0.2-2% of the active agent in solution.
- Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
- Formulations of the active compound or a salt may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
- the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
- Dermatologic formulations of the present invention typically comprise a cytoprotective derivative of any of Formula I and optionally, a polar solvent.
- Solvents suitable for use in the formulations of the present invention include any polar solvent capable of dissolving the cytoprotective derivative.
- Suitable polar solvents include: water; alcohols (such as ethanol, propyl alcohol, isopropyl alcohol, hexanol, and benzyl alcohol); polyols (such as propylene glycol, polypropylene glycol, butylene glycol, hexylene glycol, maltitol, sorbitol, and glycerine); and panthenol dissolved in glycerine, flavor oils and mixtures thereof.
- alcohols such as ethanol, propyl alcohol, isopropyl alcohol, hexanol, and benzyl alcohol
- polyols such as propylene glycol, polypropylene glycol, butylene glycol, hexylene glyco
- Exemplary polar solvents are polyhydric alcohols and water.
- preferred solvents include glycerine, panthenol in glycerine, glycols such as propylene glycol and butylene glycol, polyethylene glycols, water and mixtures thereof.
- Additional preferred polar solvents for use are alcohols, glycerine, panthenol, propylene glycol, butylene glycol, hexylene glycol and mixtures thereof.
- the formulations of the present invention will comprise from about 0.1% to about 80%, preferably from about 0.5% to about 60%, more preferably from about 1 % to about 30% and most preferably from about 3% to about 18% polar solvent.
- An emollient may also be added to the cosmetic/dermatological compositions of the present invention.
- the emollient component can comprise fats, oils, fatty alcohols, fatty acids and esters which aid application and adhesion, yield gloss and most importantly provide occlusive moisturization.
- Suitable emollients for use are isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco- glycerides, isononyl isononanoate, is
- Suitable emollients include polar emollient emulsifiers (such as linear or branched chained polyglycerol esters) and non-polar emollients.
- the emollient component typically comprises from about 1% to about 90%, preferably from about 10% to about 80%, more preferably from about 20% to about 70%, and most preferably from about 40% to about 60%, of the cosmetic composition.
- polar emollient any emollient emulsifier having at least one polar moiety and wherein the solubility (at 30 degrees C.) of the cytoprotective derivative compound in the polar emollient is greater than about 1.5%, preferably greater than about 2%, more preferably greater than about 3%.
- Suitable polar emollients include, but are not limited to, polyol ester and polyol ethers such as linear or branched chained polyglycerol esters and polyglycerol ethers.
- Nonlimiting examples of such emollients include PG3 diisosterate, polyglyceryl-2-sesquiisostearate, polyglyceryl-5-distearate, polyglyceryl-10- distearate, polyglyceryl-10-diisostearate, acetylated monoglycerides, glycerol esters, glycerol tricaprylate/caprate, glyceryl ricinoleate, glyceryl isostearate, glyceryl myristate, glyceryl linoleate, polyalkylene glycols such as PEG 600, monoglycerides, 2-monolaurin, sorbitan esters and mixtures thereof.
- non-polar emollient means any emollient emulsifier possessing no permanent electric moments.
- Suitable non-polar emollients include, but are not limited to, esters and linear or branched chained hydrocarbons.
- Non-limiting examples of such emollients isononyl isononanoate, isopropyl isostearate, octyl hydroxystearate, diisopropyl dimerate, lanolin oil, octyl palmitate, isopropyl palmitate, pariffins, isoparrifins, acetylated lanolin, sucrose fatty acid esters, isopropyl myristate, isopropyl stearate, mineral oil, silicone oils, dimethicone, allantoin, isohexadecane, isododecane, petrolatum, and mixtures thereof.
- the solubility of the compound in polar or non-polar emollients is determined according to methods known in the art.
- Suitable oils include esters, triglycerides, hydrocarbons and silicones. These can be a single material or a mixture of one or more materials. They will normally comprise from 0% to about 100%, preferably from about 5% to about 90%, and most preferably from about 70% to about 90% of the emollient component.
- Oils that act as emollients also impart viscosity, tackiness, and drag properties to cosmetic compositions such as lipstick.
- suitable oils include caprylic triglycerides; capric triglyceride; isostearic triglyceride; adipic triglyceride; propylene glycol myristyl acetate; lanolin; lanolin oil; polybutene; isopropyl palmitate; isopropyl myristate; isopropyl isostearate; diethyl sebacate; diisopropyl adipate; tocopheryl acetate; tocopheryl linoleate; hexadecyl stearate; ethyl lactate; cetyl oleate; cetyl ricinoleate; oleyl alcohol; hexadecyl alcohol; octyl hyroxystearate; octyl dodecan
- Suitable oils for use herein are acetylglycerides, octanoates, and decanoates of alcohols and polyalcohols, such as those of glycol and glycerol, the ricinoleates of alcohols and polyalcohols such as cetyl ricinoleate, PG-3 diisostearate, polyglycerol ethers, polyglyerol esters, caprylic triglycerides, capric triglycerides, isostearic triglyceride, adipic triglyceride, phenyl trimethicone, lanolin oil, polybutene, isopropyl palmitate, isopropyl isostearate, cetyl ricinoleate, octyl dodecanol, oleyl alcohol, hydrogenated vegetable oils, castor oil, modified lanolins, octyl palmitate, lanolin oil, maleated soybean oil, cetyl
- the oils used are selected such that the majority (at least about 75%, preferably at least about 80% and most preferably at least about 99%) of the types of oils used have solubility parameters that do not differ by more than from about 1 to about 0.1 , preferably from about 0.8 to about 0.1.
- a surfactant may also be added to compositions of the invention, in order to confer beneficial cosmetic or application properties.
- Surfactants suitable for use are those which can form emulsions and/or association structures.
- Surfactant emulsifier can be from 0% to about 20% of the formulation, preferably from 0% to about 15% and most preferably from about 1% to about 10%. Examples of suitable emulsifiers can be found in U.S. Pat. No. 5,085,856 to Dunphy et al.; and U.S. Pat. No. 5,688,831 to El-Nokaly et al. Examples of other suitable emulsifiers can be found in Cosmetic Bench Reference, pp. 1.22, 1.24-1.26 (1996), all of which are incorporated herein by reference.
- Ambient temperature/room temperature typically means about 20°C.
- Ambient temperature can range from about 18°C. to about 27°C, preferably from about 20°C. to about 25°C, depending on such variables as geographical location, i.e. sub-tropical vs. temperature regions.
- the surfactants suitable for use generally have a Krafft point at or below about ambient temperature about 20°C. or generally at or below about 18°C. to about 27°C, preferably at or below from about 20°C. to about 25°C.
- Krafft point is well known in the art and one of ordinary skill in the art can readily determine a surfactant's Krafft point.
- Krafft point is the melting point of the hydrocarbon chains of the surfactants. It can also be expressed as the temperature at which the solubility of an association colloid in water suddenly increases because critical micelle concentration is exceeded and micelles form.
- the surfactant In preparing a sample combination of surfactant and polar solvent to demonstrate the ability to form association structures, the surfactant needs to be sufficiently soluble in the polar solvent such that an association structure can form at ambient temperature.
- One of ordinary skill in the art is capable of determining compatible interactions.
- any surfactant which forms association structures at ambient temperature and is suitable for use in cosmetics is suitable for use herein.
- Surfactants suitable for use in cosmetics do not present dermatological or toxicological problems.
- Anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof are suitable for use.
- anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof having a Krafft point at or below about ambient temperature are used.
- nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof having a Krafft point at or below about ambient temperature are used.
- the surfactants can be used at levels from about 4% to about 97%, preferably from about 5% to about 95%, more preferably from about 20% to about 90% and most preferably from about 30% to about 70% of the association structure.
- the cosmetic compositions of this invention can contain one or more materials, herein singly or collectively referred to as a "solidifying agent", that are effective to solidify the particular liquid base materials to be used in a cosmetic composition.
- a solidifying agent refers to the physical and/or chemical alteration of the liquid base material so as to form a solid or semi-solid at ambient conditions, i.e., to form a final composition that has a stable physical structure and can be deposited on the skin under normal use conditions.
- the solidifying agent is preferably present at a concentration of from about 0 to about 90%, more preferably from about 1 to about 50%, even more preferably from about 5% to about 40%, most preferably from about 3% to about 20%.
- the wax cosmetic stick embodiments of this invention preferably contain from about 5% to about 50% (by weight) of a waxy solidifying agent.
- a waxy solidifying agent is meant a solidifying material having wax-like characteristics. Such waxy materials may also serve as emollients.
- the waxy materials useful herein are the high melting point waxes, i.e., having a melting point of from about 65° C. to about 125° C, such as beeswax, spermaceti, camauba, baysberry, candelilla, montan, ozokerite, ceresin, paraffin, synthetic waxes such as Fisher-Tropsch waxes, microcrystalline wax, and mixtures thereof.
- Such materials include fatty acids, fatty alcohols, fatty acid esters and fatty acid amides, having fatty chains of from about 8 to about 30 carbon atoms, and mixtures thereof.
- Preferred wax-like materials include cetyl alcohol, palmitic acid, stearyl alcohol, behenamide, sucrose esters of tallow fatty acids, mono and di-fatty acid esters of polyethylene glycol, and mixtures thereof. Stearyl alcohol, cetyl alcohol, and mixtures thereof, are particularly preferred. Additional fatty acids, fatty alcohols, and other wax-like materials useful in this invention are also well known in the art.
- NMR Nuclear Magnetic Resonance
- Example 1 Determination of Activity Utilizing-Neuronal Cell Stress Assay A. Isolation and Culture of Primary Hippocampal Neuronal Cells-
- Ne ⁇ robasal/B27i Neurobasal medium (Life Technologies, Rockville, MD) with 1x B27 supplement (Life Technologies), 0.5 ⁇ M L-glutamine, 25 ⁇ M L-glutamic acid, and 1 x Penicillin/Streptomycin.
- HSS Hank's Basic Salt Solution
- HEPES 10 mM, pH 7.3
- sodium bicarbonate 0.5%
- Penicillin/Streptomycin and 1 mM pyruvate.
- Plastic Culture Flasks T75 cm 2 or 12-well cell culture plates treated with Poly-D-Lysine (Sigma, St. Louis, MO).
- a pregnant female mouse (E18-E19) was euthanized with C0 2 prior to removal of the uterus, which was then placed in a sterile plastic petri dish.
- the embryos were removed from the sac, and the embryonic brains were removed and immersed in cold (4°C) Buffered Salt Solution (HBSS; Ca/Mg free; Life Technologies) in a small petri dish.
- HBSS cold (4°C) Buffered Salt Solution
- Hippocampi were then removed from the brains under a dissecting microscope and were placed on a paraffin-covered dish.
- the meninges were stripped away and the dissected hippocampi were collected in a small petri dish in HBSS.
- the hippocampi were transferred to a 15-ml centrifuge tube (normally 10-12 brains)filled with HBSS.
- the tube containing the brains was centrifuged at 1000 rpm for 2 min in a tabletop centrifuge. The supernatant was removed, 2 ml of HBSS was added to the hippocampi in the tube, and the resulting suspension was triturated 2 times each with long- tipped siliconized glass pipettes having progressively smaller apertures, starting with a pipette with a standard size opening (approximately 1.0 mm diameter), following with one having an aperture of half standard size (approximately 0.5 mm diameter), then with one having an aperture about one-half that size (0.25 mm diameter).
- the suspension was then centrifuged again at 1000 rpm for 2 min in a tabletop centrifuge, the supernatant was discarded, and 2 ml of Neurobasal/B27i (with antibiotics) was added to the tube. The trituration procedure described above was then repeated on this suspension.
- the density of cells was determined on a small aliquot of cells using standard counting procedures and correcting for cell viability by trypan blue stain exclusion. Using this procedure, the expected yield is 3 x 10 5 - 6 x 10 5 cells/brain. Cells were then added to PDL-coated 24-well plates, flasks or MetTek dishes in Neurobasal/B27l at a density of about 1.5 x 10 6 cells (T75 flask) or about 70,000 cells/well of a 24-well plate.
- This assay was used to induce ischemia by anoxia-reoxygenation in cultured hippocampal neuronal cells. Test compounds were added to assess potency and efficacy against ischemia-induced neuronal cell injury and cell death. Materials. • Neurobasal media, NoG neurobasal media, B27 supplement and B27 Supplement minus AO were obtained from Invitrogen Life Technologies.
- Neurobasal/B27 medium was prepared with 2X B27 minus AO supplement, 0.5 mM L-glutamine and 0.25X penicillin/streptomycin.
- LoG-Neurobasal contains NoG neurobasal medium plus 1 mM glucose, 0.5 mM L-glutamine, 0.25X Penicillin/Streptomycin, and 10mM Hepes (pH 7.4).
- Primary hippocampal neuronal cells were prepared according to the methods described above and were cultured in poly-D-lysine coated 24-well plates for 10-11 days prior to use.
- Deoxygenated LoG-Neurobasal medium 100 ml was prepared by pre-equilibrating the medium in a
- LoG- Neurobasal media was lightly bubbled with 100% N 2 for 30 min to completely deoxygenate the media.
- An additional 20 ml LoG-Neurobasal was pre-equilibrated in a T75 cm 2 flask and was incubated in a normal incubator (5% C0 2 ) overnight.
- Reoxygenated medium was prepared by placing Neurobasa/B27 media overnight in the culture incubator (5% C0 2 /95% 0 2 ).
- Plates containing cells with test compounds were placed in a hypoxic chamber for 4-5 hr with plate lids ajar.
- normoxia controls pre-equilibrated normoxic LoG-Neurobasal medium was added to each well of cells, and the plate was replaced in the normal culture incubator for4- 5 hr.
- the existing media was carefully aspirated off, and 400 ⁇ L of new, reoxygenated (pre-equilibrated) Neurobasal/B27 was added to each well.
- the same test compounds (in the same the concentrations) were added back into the corresponding wells. Plates were placed in the cell culture incubator (5% C0 2 /95% 0 2 ) and reoxygenated for 20-24 hr.
- Certain compounds of the present invention when tested as described above provided protection against stressor-induced cell death in at least about 20% of the cells tested, at concentrations ranging from about 1 to 1000 ⁇ M.
- 10X Heart Dissection Solution contains the following components (g/l) in tissue grade water: NaCI, 68; HEPES, 47.6; NaH 2 P0 4 , 2 ; Glucose, 10; KCI, 4; MgS0 4 , 1 , pH adjusted to 7.4. Prior to filter sterilization of diluted (1XHDS) solution, 10 mg phenol red was added to each 500 milliliters of medium.
- Transferrin and Bovine Insulin were obtained from Life Technologies, and resuspended at a concentration of 4 mg/ml in tissue culture grade water.
- DMEM-F12 - DMEM/F12, powder, 1 :1 containing glutamine and pyridoxine hydrochloride was purchased from Life Technologies. To one liter equivalent of the powder was added 2.43g of sodium bicarbonate and 10 ml of 100X Penicillin/Streptomycin in 950ml of tissue culture grade water with stirring. The pH was adjusted to 7.2 with 1 M HCI and volume was adjusted to 1 liter. The solution was filter sterilized then 2.5 ml of 4mg/ml Transferrin, 250 ⁇ l 4mg/ml Insulin and 30.7 mg of bromodeoxyuridine were added. • DMEM-F12 was also prepared 4% FBS for pre-coating the tissue culture plates and initial suspension of the cardiomyocyte pellet.
- Tissue culture ware was pre-coated with DMEM-F12-4%FBS by incubating 50 ⁇ l per well of a 96-well plate and 0.25ml per 12-well plate at 37°C.
- Two-day old rat pups were removed from their mothers and placed in a sterile container. Pups were dipped quickly into 70% alcohol, then decapitated and the body was placed in an empty sterile tissue culture dish. An incision was made starting at the neck and progressing towards the belly, cutting through the sternum. The heart was removed and placed in a tissue culture dishes containing 1x HDS. The atria were trimmed, and the remaining ventricles were placed into a separate tissue culture dish containing 1x HDS, where they were sectioned into 3-4 pieces each. Ventricles were then transferred to a sterile 250ml glass flask and the 1x HDS was removed.
- Percoll gradients were prepared by adding 2.5ml of 10x HDS to 22.5ml of Percoll (Life Technologies) with mixing (Percoll Stock). Top Gradient solution (11ml Percoll Stock and 14ml 1x HDS) and
- Bottom Gradient solution 13ml Percoll Stock and 7ml 1x HDS were prepared.
- Four milliliters of the Top Gradient solution were transferred into 6 x 15ml sterile Falcon tubes.
- Three milliliters of the Bottom Gradient solution were placed in each tube by inserting a serological pipette to the bottom of the tube and slowly adding the liquid. All the digests (5) were pooled in one 50ml Falcon tube and centrifuged on a tabletop centrifuge at
- the gradient tubes were then centrifuged at 3000 rpm for 30 minutes without braking in a Beckman Allegra 6 centrifuge (GH 3.8A rotor). Following centrifugation, the cells segregated into two sharp bands at the two interfaces. The lower band of the two bands was enriched for cardiomyocytes; there was also a cardiomyocyte pellet at the bottom of the tube. The upper band was enriched for fibroblasts and other non-cardiomyocytes. The upper portion of the gradient was aspirated down to just above the cardiomyocyte layer.
- the cardiomyocyte layer was then carefully removed along with the pellet, and the two fractions were pooled in a sterile 50ml Falcon tube, along with corresponding fractions from additional gradient tube; then 1x HDS was added to a total volume of about 50ml. The tube was centrifuged at 1000 rpm for 7 minutes. The supernatant was discarded and resuspended in 25ml 1x HDS. A further 25ml of 1x HDS was added and the centrifugation step was repeated. The cell pellet was resuspended carefully but thoroughly in 40-50 of DMEMF12-4% FBS.
- the DMEM/F12-FBS coating medium was aspirated from the tissue culture dishes.
- the cardiomyocytes were added to the dishes at a plating density of 7.5x10 4 / well per 96-well in 200 ⁇ L and 1.5 x 10 5 /well per 12-well in 3ml.
- the cultures were incubated at 37°C with 5% C0 2 overnight.
- the original medium was removed, and add fresh DMEM/F12-5% FBS was added to each culture, prior to incubation at 37°C with 5% C0 2 for a further 48 hours, before use.
- DMEM/F12 DMEM/F12, powder, 1 :1 containing glutamine and pyridoxine hydrochloride was purchased from Life Technologies (Invitrogen Life Technologies, Carlsbad, CA). Powder sufficient to prepare one liter of buffer and 2.43g of sodium bicarbonate was mixed into 950ml of tissue culture grade water. The pH was adjusted to 7.2 with 1M HCI and the remaining water was added to make 1 liter. Following filter sterilization, 10ml of 100X Penicillin/Streptomycin, 2.5ml of
- Neonatal cardiomyocytes were isolated as described above. The cardiomyocytes were plated in 96- well format (black clear-bottomed plates) at a density of 7.5 x 10 4 per well and grown for 2 days in the presence of 5% FBS prior to use in the assay.
- Physiological ischemia was simulated by placing the cardiomyocytes in an anaerobic chamber (0% 0 2 , 85% N 2 , 5% C0 2 & 10% H 2 ) in DMEM containing 1mM glucose. Positive control cells are treated with DMEM-F12 containing 25mM Glucose, which protects against the anoxia.
- test compounds were made up in DMEM-1mM glucose in 96 deep-well mother plates and appropriately diluted for use in the assay.
- the media was removed from the cells and replaced with 200 ⁇ l of either DMEM-F12 or 1mM DMEM with or without test compounds.
- the plates were then placed inside the 37°C incubator in the anaerobic chamber and incubated for 16 hours.
- the plates were then removed and reoxygenated by the addition of DMEM-F12.
- the DMEM with or without test compounds is carefully removed from the cells and replaced with pre-warmed DMEM-F12 containing 5% FBS.
- the cells were then placed in a normal incubator at 37°C and incubated for two hours to allow the cells to reoxygenate. A working solution of 20 ⁇ M Fluo-4 was added to pre-warmed IxHBSS. The cells were loaded with
- Fluo-4 by first removing media from the cells and replacing with 100 ⁇ l of 20 ⁇ M Fluo-4. Unloaded control cells were treated in parallel with IxHBSS alone. All cells were then incubated at 37°C for 30 minutes. Before fluorescence measurements were made, the cells were washed in indicator-free medium (HBSS) to remove any dye that is non-specifically associated with the cell surface. Cells were then incubated for an additional 20 minutes at room temperature. Basal Fluo-4 fluorescence was measured using the 485nm excitation and 538nm emission filter pair on a microplate flourometer (FluorskanTM, Thermo Labsystems Oy, Helsinki, Finland).
- mice Male Wistar rats (Harlan, IN) weighing 300-350g are commonly used in these experiments. Animals are allowed free access to water and commercial rodent diet under standard laboratory conditions. Room temperature is maintained at 20-23 °C and room illumination is on a 12/12-hour light/dark cycle. Animals are acclimatized to the laboratory environment 5 to 7 days prior to the study, and fasted (with free access to water) overnight before surgery.
- MCAO Middle Cerebral Artery Occlusion
- the body temperature may also be taken by inserting the temperature probe into the animal's rectum. Body temperature is recorded every hour for 6 hours post-occlusion; however, body temperatures were taken more frequently so that they could be maintained at the normothermic temperature. Animals were subjected to two hours MCAO using a modified intraluminal filament technique, as follows: A midline incision on the ventral part of the neck is made to expose external and internal carotid arteries. The right external and common carotid arteries are ligated by a suture (silk 5/0, Carlisle Laboratories, farmers Branch, TX) and the right internal artery is temporarily ligated using a microvascular clip (Fine Science Tool Inc., Foster City, CA). A small incision was made in the common carotid artery. A nylon filament, its tip rounded by heating, is prepared from a fishing line (Stren Fishing Lines, Wilmington,
- Test compounds may be administered by any of a number of routes, such as those described below. Compounds can be administered before, during or after occlusion, as appropriate to the protocol.
- ICV Intracerebroventricular
- the anesthetized animal is placed on a stereotaxic apparatus (Harvard Apparatus, S. Natick, MA). Anesthesia is maintained by inhalation of 3.0% isoflurane (Aerrane, Front Dodge, IA) in 0.8% oxygen throughout the entire procedure.
- the scalp is shaved and sterilized prior to surgery.
- a midline sagittal incision about 3 cm long is made slightly behind the eyes to expose the skull.
- the skull is scraped with a rounded end spatula to remove periosteal connective tissue.
- a bur hole is placed 1.5mm lateral, 1 mm posterior to the left of the bregma to mark the left lateral ventricle.
- a brain infusion cannula (ALZET Co., Palo Alto, CA) is inserted 4 mm deep into the hole. The desired depth is adjusted by attaching spacers to the cannula.
- the cannula attached to a 4-cm silastic catheter (Helix Medical Inc., Carpinteria, CA) fixed in place with dental cement (Ketac-cement, Norristown, PA).
- the catheter is either attached to a primed osmotic pump placed subcutaneously between the shoulder blades for permanent infusion or to a syringe for a short infusion.
- IV Intravenous
- Anesthesia is maintained by inhalation of 3.0% isoflurane (Aerrane, Front Dodge, IA) in 0.8% oxygen throughout the entire procedure.
- the animal's neck will be shaved and sterilized before operation.
- a midline incision is made on the ventral part of the neck to exposes the jugular vein.
- the vein is isolated and ligated with a suture (silk 5/0, Carlisle Laboratories, farmers Branch, TX) rostral to the point of the incision and a microvascular clip (Fine Science Tool Inc., Foster City, CA) close to the heart.
- a small incision is made between two ligations.
- a 2-cm silastic catheter (Helix Medical Inc.) attached to a PE-60 tube (Becton.
- Anesthesia is maintained by inhalation of 3.0% isoflurane (Aerrane, Front Dodge, IA) in 0.8% oxygen throughout the entire procedure.
- the exterior site of the right femoral vein is shaved and sterilized prior to surgery.
- a 3-cm incision is made in the right groin region and the femoral vein is isolated.
- a small incision is made on the femoral vein temporarily ligated with a microvascular clip to introduce and advance a polyethylene (PE-50) catheter (Becton Dickinson and Co. Sparks, MD).
- PE-50 polyethylene
- the catheter is secured in place with suture (silk 5/0, Carlisle Laboratories, farmers Branch, TX).
- IP Intraperitoneal
- each 2-mm slice is photographed with a TMC-7 camera (JH Technologies, Ca) which is directly connected to a desktop PC to capture and save the image of each brain slice.
- This image is used for the measurements of the regions of interest using a computer-based image processing system (Metamorph).
- the region of interest is selected using a freehand selection tool, the area is automatically computed by selecting the measure command.
- the measurements for primary regions of interest are right hemisphere, left hemisphere, total infarct, subcortical infarct, total penumbra and subcortical penumbra.
- edema volume is calculated and reported as the volumetric differences between the right and left hemispheres of each brain slice. Using the % of hemispheric swelling all the volumes will be corrected for the edema. The volume of the damage is determined using the calculations below for each rat's brain.
- Sample size is chosen to achieve a 90% probability of significant results.
- the measurements, which represented the same region of interest in seven slices of each rat's brain are added together to yield a single measurement for total infarct, subcortical infarct, cortical infarct, total penumbra, subcortical penumbra, cortical penumbra, total ischemic damage and edema in each animal.
- Group data are presented as means +/- SEM. Differences at the level of p ⁇ 0.05 are considered statistically significant. Between groups comparison of each region of interest are carried out by unpaired student t test (between two groups) or one way ANOVA followed by post hoc Bonferroni's multiple comparisons or by the nonparametric Dunnett's test (between control and the drug treated groups).
- Example 4 Model of Myocardial Infarction: Left Coronary Ligation (Rat) Male Sprague-Dawley weighing 250-320 g were allowed free access to water and commercial rodent diet under standard laboratory conditions. Room temperature was maintained at 20-23 °C and room illumination was on a 12/12-hour light/dark cycle. Animals were acclimatized to the laboratory environment 5 to 7 days prior to the study and were fasted overnight prior to surgery.
- Rats were anaesthetized with Urethane (1.2-1.5 gm/kg). Core body temperature was maintained at 37°C by using a heating blanket. The surgical area was shaved, and a ventral midline incision was made to expose the trachea and jugular area. A catheter (PE50) was placed in the jugular for administration of compound and maintenance anesthesia. The trachea was incised and a
- 14-16-gauge modified intravenous catheter was inserted and tied in place as an endotracheal tube.
- the animal was placed in right lateral recumbency and initially placed on a Harvard ventilator with a tidal volume of 5-10 ml/kg. 100% 0 2 was delivered to the animals by the ventilator.
- ECG electrodes were placed to record a standard Lead II ECG.
- the surgical site was cleaned with alcohol swab, and a skin incision was made over rib cage over the 4 th -5 th intercostal space.
- the underlying muscles were dissected with care to avoid the lateral thoracic vein, to expose the intercostal muscles.
- the chest cavity was entered through 4 th - 5 th intercostal space, and the incision expanded to allow visualization of the heart.
- the pericardium was opened to expose the heart.
- a 6-0 silk suture with a taper needle was passed around the left coronary artery near its origin, which lies in contact with the left margin of the pulmonary cone, at about 1 mm from the insertion of the left auricular appendage.
- a piece of tubing was placed over the suture to form an occluder.
- the coronary artery was occluded for 30 minutes by sliding the tube towards the heart until resistance is felt and holding it in place with a vascular clamp.
- the ECG was monitored for S-T changes indicative of ischemia. After 30 minutes, the occluder was removed, leaving the suture in place.
- the ECG was monitored for the first 10 minutes of reperfusion.
- the rat was transferred to the pressure control ventilator for the remainder of the protocol.
- the rats were ventilated by a small animal ventilator with a peak inspiratory pressure of 10-15 cm H 2 0 and respiratory rate 60-110 breaths/min.
- the heart was allowed to reperfuse for 90 minutes.
- Rats were anaesthetized with Ketamine/Xylazine IP (95 and 5 mg/kg) and intubated with a 14-16-gauge modified intravenous catheter. Anesthesia level was checked every 15 minutes by toe pinch. Core body temperature was maintained at 37°C by using a heating blanket. The surgical area was shaved and scrubbed. A ventral midline incision was made to expose the jugular vein. A catheter (PE50) was placed in the jugular for administration of compound and maintenance anesthesia.
- Ketamine/Xylazine IP 95 and 5 mg/kg
- the animal was placed in right lateral recumbency and initially placed on a ventilator with a tidal volume of 5- 10 ml/kg H 2 0 or a pressure controlled ventilator with a peak inspiratory pressure of 8-15 cm H 2 0 and respiratory rate 60-110 breaths/min. 100% 0 2 was delivered to the animals by the ventilator.
- ECG electrodes were placed to record a standard Lead II ECG.
- the surgical site was cleaned with surgical scrub and alcohol. A skin incision was made over rib cage over the 4 th -5th intercostal space. The underlying muscles were dissected with care to avoid the lateral thoracic vein, to expose the intercostal muscles.
- the chest cavity was entered through 4 th -5' intercostal space, and the incision expanded to allow visualization of the heart.
- the pericardium was opened to expose the heart.
- a 6-0 silk suture with a taper needle was passed around the left coronary artery near its origin, which lies in contact with the left margin of the pulmonary cone, at about 1 mm from the insertion of the left auricular appendage.
- a piece of tubing was placed over the suture to form an occluder.
- the coronary artery was occluded for 30 minutes by sliding the tube towards the heart until resistance is felt and holding it in place with a vascular clamp.
- the ECG was monitored for S-T changes indicative of ischemia. After 30 minutes, the occluder was removed, leaving the suture in place.
- the ECG was monitored for the first 10 minutes of reperfusion. The incision was closed in three layers. The IV catheter was removed or tunneled under the skin and exteriorized between the shoulder blades to allow for blood withdrawal or further drug therapy. The rat was ventilated until they are able to ventilate on their own. The rats were extubated and recovered on a heating pad. Once awake, they were returned to their cage(s). Animals may receive Buprenorphine (0.01-0.05 mg/kg SQ) for post-operative analgesia. After the designated reperfusion time (24 hours) the animals were anesthetized and the hearts removed under deep anesthesia. Treatment Protocols
- Rat weights were monitored during the study. Feed not consumed was weighed to estimate consumption rates.
- a ventral incision was made to expose the jugular area.
- a catheter (PE50) was placed in the jugular vein for administration of compound. Animals were dosed by bolus injection and/or continuous infusion. The time and duration of treatment varies with the protocol.
- each animal received 200 units of heparin IV under general anesthesia and the heart was removed and placed in cold saline. After removal the coronary artery was ligated with the suture that is already in place. The heart was placed on a perfusion apparatus and Evans Blue dyed was infused delineate the area at risk. The heart was then cut into five 2-mm thick transverse slices from apex to base.
- the slices were incubated in 1% triphenyltetrazolium chloride (TTC) in 0.9% saline for 20 minutes at 37°C. Tetrazolium reacts with NADH in the presence of dehydrogenase enzymes causing viable tissue to stain a deep red color and that is easily distinguished from the infarcted pale-unstained necrotic tissue.
- TTC triphenyltetrazolium chloride
- the slices were placed apex side down in the lid of a small petri dish for the staining procedure. The bottom of the dish was placed over the slices to keep them flat.
- the slices were photographed in order from apex to base, with the base side up.
- the areas of infarcted tissue, area at risk and the whole left ventricle were determined using a computerized image analysis system. The total area for each region was added together to give a total for the entire heart. Infarct size was expressed both as a percentage of the total ventricle and the area at risk.
- Group data is represented as means +/- SEM. Comparisons between treatment groups were made using ANOVA with p ⁇ 0.05 considered significant. Post hoc comparisons may be made using either Dunnett's test or Tukey's test .
- Example 5 The compounds of the present invention can be tested by this method.
- Example 5 The compounds of the present invention.
- Rota-Rod Treadmill for Rats (7750 Accelerating Model, from UGO BASILE, COMERIO- ITALY).
- the cylinder on the apparatus is set in motion before placing the rats in position.
- the motor is set at a constant selected speed in 7700 on RESET mode, and the rats are placed, one by one, in their sections. Testing is carried out on postoperative day 2 and repeated, in a blind-randomized fashion, twice weekly for a defined interval. Typically, three successive readings are taken for each animal with an intertrial interval long enough to record the data and zero both meters for the next trail.
- 225-275 g male Sprague-Dawley rats are anaesthetized with ketamine/xylazine (95 mg/kg and 5 mg/kg) and intubated with a 14-16-gauge modified intravenous catheter. Core body temperature is maintained at 37°C by using a heating blanket. The surgical area is clipped and scrubbed, and the animal is placed in right lateral recumbency and initially placed on a ventilator with a peak inspiratory pressure of 10-15 cm H 2 0 and respiratory rate 60-110 breaths/min. 100% 0 2 is delivered to the animals by the ventilator. ECG electrodes are positioned to record a standard Lead II ECG. An incision is made over rib cage over the 4th-5th intercostal space.
- the underlying muscles are dissected with care to avoid the lateral thoracic vein, to expose the intercostal muscles.
- the chest cavity is entered through 4th-5th intercostal space, and the incision expanded to allow visualization of the heart.
- the pericardium is opened to expose the heart.
- a 6-0 silk suture with a taper needle is passed around the left coronary artery near its origin, about 1 mm from the insertion of the left auricular appendage.
- the coronary artery is occluded by tying the suture around the artery.
- the ECG is monitored for S-T changes indicative of ischemia. If the animal develops ventricular fibrillation, gentle cardiac massage is used to convert the animal to a normal rhythm. Sham operated controls are subjected to the same procedure, but the suture is not tied off. The incision is closed in three layers. Infected or moribund animals are eliminated from the study.
- the animals are anesthetized, and a catheter is placed in the right carotid artery and advanced into the left ventricle for hemodynamic measurements. Pressure traces are recorded and analyzed for heart rate, left ventricular systolic and diastolic pressure, left ventricular developed pressure, and dP/dt max and min.. After measurements are taken, 2 ml blood is removed and placed in serum and plasma tubes. The heart is removed and placed on a Langendorff apparatus as follows:
- Buffer preparation Krebs-Henseleit (KH) buffer solution containing NaC1 118 mmol/L, KCI 4.7 mmol/L, MgS0 4 1.2 mmol/L, KHP0 4 1.2 mmol/L, Glucose 11 mmol/L, NaHC0 3 25 mmol/L and CaCI 2 2.5 mmol/L (Sigma) is made fresh daily using Nanopure pyrogen-free water.
- the animal receive 200 units of heparin, the thorax is opened and the heart is rapidly excised and placed in ice-cold KH buffer solution. After the contractile activity of the heart completely ceases, the heart is trimmed and the ascending aorta freed from the connective tissue.
- the heart is quickly weighed, then the aorta is cannulated, and the heart mounted on a non-recirculation Langendorff perfusion apparatus (Radnoti Glass Technology, Inc., Monrovia, CA).
- the heart is perfused in a retrograde fashion via the aorta with KH buffer solution oxygenated with 95% 0 2 and 5 % C0 2 to maintain pH 7.4 at 37°C.
- a latex balloon is inserted into the left ventricle through the mitral orifice and connected to a pressure transducer by rigid polyethylene tubing.
- the balloon is inflated with water to a left ventricular end- diastolic pressure (LVEDP) of 1 to 10 mm Hg.
- Flow is initiated at 12 ml/min and adjusted during the first 15 minutes of baseline to obtain a perfusion pressure between 65 and 75 mmHg.
- Target parameters for baseline are as follows:
- the heart is allowed to stabilize for 15 minutes. After this time functional measurements are taken, after which a pressure volume curve is generated by adjusting the volume in the balloon in 0.05 ml increments and recording ventricular pressures.
- the left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), first derivative of the rise and fall in the left ventricular pressure (dp/dt max, dp/dt min), perfusion pressure and heart rate are automatically recorded using a computerized data acquisition system.
- Other Measurements After removal the heart, lungs and liver are weighed. The lungs and liver are weighed and dried overnight for determination of wet to dry ratios.
- the heart is placed in cold saline to stop the beating, then cut into five 2-mm thick transverse slices from apex to base.
- Slice #3 will be incubated in 1 % triphenyltetrazolium chloride (TTC) in 0.9% saline for 20 minutes at 37°C.
- TTC triphenyltetrazolium chloride
- Tetrazolium reacts with NADH in the presence of dehydrogenase enzymes causing viable tissue to stain a deep red color and that is easily distinguished from the infarcted pale-unstained necrotic tissue.
- the slice is placed apex side down in the lid of a small petri dish for the staining procedure. The bottom of the dish is placed over the slice to keep it flat.
- infarcted tissue left and right ventricle are determined using a computerized image analysis system. Infarct size is expressed as a percentage of the total ventricle. Total areas of the left and right ventricle are measured. The remaining sections are divided into right and left ventricle and frozen for TBARS and glutathione assays.
- GPX Glutathione peroxidase
- TBARS thiobarbituric reactive substances
- GSH/GSSG glutathione ratio
- lung and liver wet to dry weight ratios serum isoprostane and interleukin-6 (IL-6).
- Certain compounds of the present invention can be tested by this method.
- Cytoprotective activity for skin can be evaluated in cell culture using the Epiderm Skin Model (EPI- 100) from the Mattek Corporation of Ashland, Mass.
- EPI- 100 Epiderm Skin Model
- Cell cultures of neonatal foreskin are cultured in accordance with the manufacturer's directions, and are assayed for percent cellular viability by measuring the amount of 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye taken up by the cells.
- MTT 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide
- Viable cells take up this dye and convert it to insoluble formazin crystals that resides in the mitochondria of the cells until extracted with alcohol.
- the amount of MTT converted to extractable formazin crystals is directly proportional to the viability of the cell culture. MTT is measured spectrophotometrically.
- MED Minimal Erythemal Dose
- the controls for this study are cell cultures without added test compound (positive control). All cell cultures are also compared to cultures that are not exposed to UV light and do not include the cytoprotective agents or blends in order to determine percent cellular viability (negative control). This latter measurement is assumed to be equal to 100% viability.
- Hair growth inhibition Reduction of hair growth is demonstrated when the frequency of hair removal is reduce, or the subject perceives less hair on the treated site, or quantitatively when the weight of hair removed by shaving (i.e., hair mass) is reduced.
- Male intact Golden Syrian hamsters are considered acceptable models for human beard growth in that they display oval shaped flank organs, one on each side, each about 8mm. in major diameter, which grow thick black and coarse hair similar to human beard hair. The organs produce hair in response to androgens in the hamster.
- flank organs of each of a group of hamster are depilated by applying a thioglycolate based chemical depilatory (Surgex).
- a thioglycolate based chemical depilatory Surgex
- Percent-reduction of hair growth is calculated by subtracting the hair mass (mg) value of the test compound treated side from the hair mass value of the vehicle treated side; the delta value obtained is then divided by the hair mass value of the vehicle treated side, and the resultant number is multiplied by 100.
- Example 9 In vitro cellular inflammation assay : A.. Human Hep3B Cells - CRP assay. Hep3B Cell Line is obtained from the American Type Culture
- the Hep3B cell line was derived from liver tissue of an 8-year-old Black male.
- the cells are epithelial in morphology and produce tumors in nude mice.
- the cells produce ⁇ - fetoprotein, hepatitis B surface antigen, albumin, ⁇ -2-macroglobulin, ⁇ -1-antitrypsin, transferrin, plasminogen, complement C3 and ⁇ -lipoprotein (Knowles BB, et al., Science, 1980, 209:497-499).
- This cell line has been widely used to study hepatocyte cytokine and acute phase protein release (e.g., Damtew B, et al.,1993, J Immunol 150:4001-4007).
- HEP3B cells are grown in Minimum Essential Medium (MEM; GIBCO) supplemented with 10% Fetal Bovine Serum (FBS; Hyclone), 1x Penicillin/StreRtomycin (GIBCO, Cat #. 15140-122) and 0.1mM non- essential amino acids (GIBCO, Catalog No. 11140-050). Cells are thawed and transferred to warm medium according to standard methods known in the art.
- MEM Minimum Essential Medium
- FBS Fetal Bovine Serum
- FBS Fetal Bovine Serum
- Penicillin/StreRtomycin GIBCO, Cat #. 15140-122
- 0.1mM non- essential amino acids GIBCO, Catalog No. 11140-050
- Cells are incubated in flasks at 37°C with 5% C0 2 in an air atmosphere incubator. HEP3B growth media is changed every 2 days until the cells reach 70-80% confluence (approx. 3-4 days).
- HEP3B growth media is changed every 2 days until the cells reach 70-80% confluence (approx. 3-4 days).
- the cells are transferred to 96-well plates, seeded at 5000 cells per well in culture media, and left to grow for 7 days in a 37°C incubator (air supplemented with 5% C0 2 ). Media is replaced daily until assay.
- Test compounds are diluted into "Stimulus Buffer” (MEM medium containing 0.1 mM non-essential amino acids, 1X penicillin/streptomycin, 10% FBS with 10 ng/ml IL-1 ⁇ , 20 ng/ml IL-6 and 1 ⁇ M dexamethasone. Media is removed from the cells and is replaced with 200 ⁇ l of test dilution. Cells are returned to the incubator for three days at 37°C. CRP ELISA is then performed on supernatant from the cells, as described below. Costar EIA/RIA plates are coated with rabbit anti-human CRP (DAKO) diluted 1 :4000 in carbonate buffer
- TMB 3,3',5,5'-Tetramethyl Benzidine
- CRP measured as above is normalized to cell count per well, using a cell viability assay, such as the Cell Tracker Green assay.
- a cell viability assay such as the Cell Tracker Green assay.
- the remainder of the medium is from the cell test plates, cells are washed with 200 ⁇ l of pre-warmed 1x Hanks Basic Salt Solution (HBSS; GIBCO), and 100 ⁇ L of 5 ⁇ M Cell Tracker Green (Molecular Probes, Eugene, OR) is added to each well. Plates are then incubated at 37°C for 30 minutes. Cells are then washed twice with prewarmed 1x HBSS. Plates are immediately read using a
- Fluoroskan® flourometer with a 485 excitation/538 emission filter pair.
- compounds such as: 6,7-Dimethyl-3-phenyl-benzofuran-5-ol; 1-(4-Bromo-5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone; 1-(5-Hydroxy-6,7-dimethyl-benzofuran-2-yl)-2-morpholin-4-yl-ethanone; Acetic acid 2-(6-hydroxy-3-methyl-[1 ,3]oxazinan-6-yl)-6,7-dimethyl-benzofuran-5-yl ester; 1-(5-Hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone; 3-(4-Methoxy-phenyl)-6,7-dimethyl-benzofuran-5-ol; 4,5-Dimethyl-1 ,8-diphenyl-benzo[1 ,2-b;4,3-b']difuran;and
- Endothelial-Leukocyte Adhesion Molecule also known as E-selectin
- LPS lipopolysaccharide
- IL-1 ⁇ are used to stimulate the expression of ELAM; test agents are tested for their abilities to reduce this expression, in accordance with studies showing that reduction of leukocyte adhesion to endothelial cell surface is associated with decreased cellular damage (e.g., Takada, M., Et al., Transplantation 64: 1520-25, 1997; Steinberg, J.B., et al., J. Heart Lung Trans. 13:306-313, 1994).
- Endothelial cells may be selected from any of a number of sources and cultured according to methods known in the art; including, for example, coronary artery endothelial cells, human brain microvascular endothelial cells (HBMEC; Hess, D.C., et al., Neurosci. Lett. 213(1): 37-40, 1996), or lung endothelial cells.
- HBMEC human brain microvascular endothelial cells
- HBMEC human brain microvascular endothelial cells
- et al. Neurosci. Lett. 213(1): 37-40, 1996)
- lung endothelial cells are conveniently cultured in 96-well plates. Cells are stimulated by adding a solution to each well containing 10 ⁇ g/ml LPS and 100 pg/ml IL-1 ⁇ for 6 hours in the presence of test agent (specific concentrations and time may be adjusted depending on the cell type).
- Treatment buffer is removed and replaced with pre-warmed Fixing Solution® (100 ⁇ l/well) for 25 minutes at room temperature. Cells are then washed 3X, then incubated with Blocking Buffer (PBS + 2% FBS) for 25 minutes at room temperature. Blocking Buffer containing Monoclonal E-Selectin Antibody (1 :750, Sigma Catalog #S-9555) is added to each well. Plates are sealed and stored at 4 ° overnight. Plates are washed 4X with 160 ⁇ L Blocking Buffer per well. Second Antibody-HRP diluted 1:5000 in Blocking Buffer is then added (100 ⁇ L/well), and plates are incubated at room temperature (protected from light) for two hours.
- Blocking Buffer PBS + 2% FBS
- HBSS buffer 950ml Pyrogen-free water, 2.44g/L MgCI2.6H20, 3.73g/L KCI, 59.58g/L Hepes, 58.44g/L NaCI, 1.36g/L KH2P04, 1.91 g/L CaCI2 .2H20 and pH to 4.5 with HCI
- Bovine Serum Albumin fraction V (BSA V) (Sigma Catalog # A4503)
- Reagent Diluent 500ml PBS + 5g BSA V (1%) pH 7.2 - 7.4 and filter sterilize through 0.2 ⁇ m.
- Stop Solution Make 2N sulfuric acid by adding 10ml 5N H 2 S0 4 to 15ml of dd H 2 0.
- the IL-1.beta, capture antibody was reconstituted in 1 ml of PBS to give a final concentration of 720 ⁇ g/ml, and the working concentration was 4 ⁇ g/ml.
- the IL-1.beta.standards were reconstituted in 0.5ml of Reagent Diluent (70ng/ml).
- 70ng/ml Reagent Diluent
- 7.1 ⁇ l of the 70ng/ml standard were diluted into 0.5ml of Reagent Diluent 3.
- the IL-1.beta, detection antibody was reconstituted in 1 ml of Reagent Diluent to give a final concentration of 18 ⁇ g/ml and the working concentration is 100ng/ml.
- Non-specific binding sites were blocked by adding 300 ⁇ l of Blocking Buffer to each well, and after sealing, incubating for at least 1hour at room temperature.
- the fresh Substrate Solution was prepared by mixing Color Reagent A (H 2 0 2 ) and Color Reagent B (Tetramethylbenzidine) in a 1 :1 ratio. 100 ⁇ l of this Substrate Solution mixture was added to each well and the plate was incubated in the dark for 20 minutes at room temperature.
- Example 10 In vivo cellular inflammation assays measure the ability of test compounds to prevent or reduce inflammation secondary to oxazolone or arachidonic acid.
- A. Arachidonic acid Albino male CD-1 mice, 7-9 weeks old were used in this test. A 20% (w/v) arachidonic acid solution in acetone is prepared. Twenty microliters of the arachidonic acid solution is applied to the dorsal left ear of the mouse. Immediately thereafter, test compounds (20 ⁇ L in 70% ethanol/30% propylene glycol) are applied to the left ear. The untreated right ears served as control. Mice are sacrificed by C0 2 inhalation, one hour after treatment. The left and right ears are removed and 7 mm punch biopsies taken from each. The punch biopsies are weighed, and the differences calculated.
- mice are induced by applying 3% oxazolone (Sigma) (30 mg/ml prepared in corn oihacetone) to the shaved abdomen. Five days later, the mice are challenged with 2% oxazolo ⁇ e (20 mg/ml) in acetone on the left ear (right ear was untreated control). One hour after challenge, test compounds are applied to the left ear in 70% ethanol/30% propylene glycol. Animals are sacrificed 24 hours later and 7 mm ear punches are removed. The ear punches are placed on a balance scale, and the difference between the untreated and treated ears is determined. Percent inhibition is calculated by comparing the means of each group to the vehicle group. (Hydrocortisone serves as a positive control in this test.). Compounds of the present invention can be tested for their ability to reduce inflammation in this model.
- Step 1 A mixture of 2,3-dimethyl-1 ,4-dihydroquinone (1.08 g, 7.826 mmol), 2-bromoacetophenone (1.45 g, 7.29 mmol), and potassium carbonate (1.78 g, 12.90 mmol) in acetone (30 mL) was stirred at room temperature for 3 h. The mixture was then poured into water resulting in the formation of a precipitate. The precipitate was washed with water and hexane, and dried to yield a mixture of mono and bis products.
- Step 1
- Step 2 A suspension of the diacetate from Step 1 (5.08 g) in boron trifluoride acetic acid complex (15 mL) was stirred at 110 °C for 1 h. After cooling, the mixture was poured into ice, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried. After evaporation, the residue was recrystallized from EtOAc-hexane to give 4.37 g of 1-(2-hydroxy-5-acetoxy-3,4-dimethyl-phenyl)- ethanone.
- Step 3 A suspension of the diacetate from Step 1 (5.08 g) in boron trifluoride acetic acid complex (15 mL) was stirred at 110 °C for 1 h. After cooling, the mixture was poured into ice, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried. After evaporation, the residue was recrystallized from EtOAc-hexane to give 4.37
- Step 1
- the tetrahydropyranyl ether was dissolved in methanol, p-toluenesulfonic acid monohydrate (20 mg) was added, and the solution was stirred at room temperature for an additional 30 min. After the addition of a small amount of NaHC0 3 , the methanol was evaporated. The residue was purified by silica gel column chromatography, eluting with hexane and ethyl acetate (7:3) to give 30 mg of 5-hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester.
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JP2003565991A JP2005517014A (en) | 2002-02-07 | 2003-02-06 | Cytoprotective benzofuran derivatives |
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EP03737697A EP1472241A4 (en) | 2002-02-07 | 2003-02-06 | Cytoprotective benzofuran derivatives |
MXPA04007550A MXPA04007550A (en) | 2002-02-07 | 2003-02-06 | Cytoprotective benzofuran derivatives. |
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WO2005011670A1 (en) | 2003-08-01 | 2005-02-10 | Chugai Seiyaku Kabushiki Kaisha | Heterocyclic compounds useful as malonyl-coa decarboxylase inhibitors |
WO2005020984A2 (en) * | 2003-08-29 | 2005-03-10 | Aaipharma Inc. | Method of reducing the risk of oxidative stress |
WO2014145118A1 (en) * | 2013-03-15 | 2014-09-18 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
CN106496168A (en) * | 2016-10-09 | 2017-03-15 | 湖北中烟工业有限责任公司 | Preparation method and applications of the cigarette with monomer perfume furancarboxylic acid Herba Pelargonii Graveolentiss alcohol ester |
US9670170B2 (en) | 2013-03-15 | 2017-06-06 | Bioelectron Technology Corporation | Resorufin derivatives for treatment of oxidative stress disorders |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
CN113173928A (en) * | 2021-04-25 | 2021-07-27 | 武汉国粹医药科技有限公司 | Terpenoid, preparation method and application thereof, and antibacterial agent |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ539727A (en) * | 2002-11-01 | 2008-01-31 | Viropharma Inc | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases |
US7642062B2 (en) * | 2006-12-29 | 2010-01-05 | Avon Products Inc. | Compositions and methods of their use for improving the condition and appearance of skin |
JP5564531B2 (en) * | 2012-06-01 | 2014-07-30 | 株式会社マンダム | Whitening agent evaluation method |
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US3331854A (en) * | 1964-12-14 | 1967-07-18 | American Cyanamid Co | Novel furan and thiophene compounds |
US5266711A (en) * | 1989-10-23 | 1993-11-30 | Sanofi | Process for the preparation of 3-benzoyl benzofuran derivatives |
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US5091533A (en) * | 1990-03-12 | 1992-02-25 | Merck Frosst Canada, Inc. | 5-hydroxy-2,3-dihydrobenzofuran analogs as leukotriene biosynthesis inhibitors |
US5674876A (en) * | 1995-01-20 | 1997-10-07 | Research Development Foundation | ρ-heteroatom-substituted phenols and uses thereof |
-
2003
- 2003-02-06 AU AU2003210904A patent/AU2003210904A1/en not_active Abandoned
- 2003-02-06 CA CA002474974A patent/CA2474974A1/en not_active Abandoned
- 2003-02-06 EP EP03737697A patent/EP1472241A4/en not_active Withdrawn
- 2003-02-06 JP JP2003565991A patent/JP2005517014A/en active Pending
- 2003-02-06 MX MXPA04007550A patent/MXPA04007550A/en not_active Application Discontinuation
- 2003-02-06 WO PCT/US2003/003709 patent/WO2003066618A1/en not_active Application Discontinuation
Patent Citations (2)
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US3331854A (en) * | 1964-12-14 | 1967-07-18 | American Cyanamid Co | Novel furan and thiophene compounds |
US5266711A (en) * | 1989-10-23 | 1993-11-30 | Sanofi | Process for the preparation of 3-benzoyl benzofuran derivatives |
Non-Patent Citations (1)
Title |
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See also references of EP1472241A4 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005011670A1 (en) | 2003-08-01 | 2005-02-10 | Chugai Seiyaku Kabushiki Kaisha | Heterocyclic compounds useful as malonyl-coa decarboxylase inhibitors |
WO2005020984A2 (en) * | 2003-08-29 | 2005-03-10 | Aaipharma Inc. | Method of reducing the risk of oxidative stress |
WO2005020984A3 (en) * | 2003-08-29 | 2005-09-09 | Aaipharma Inc | Method of reducing the risk of oxidative stress |
WO2014145118A1 (en) * | 2013-03-15 | 2014-09-18 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
US9296712B2 (en) | 2013-03-15 | 2016-03-29 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
US9670170B2 (en) | 2013-03-15 | 2017-06-06 | Bioelectron Technology Corporation | Resorufin derivatives for treatment of oxidative stress disorders |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
CN106496168A (en) * | 2016-10-09 | 2017-03-15 | 湖北中烟工业有限责任公司 | Preparation method and applications of the cigarette with monomer perfume furancarboxylic acid Herba Pelargonii Graveolentiss alcohol ester |
CN113173928A (en) * | 2021-04-25 | 2021-07-27 | 武汉国粹医药科技有限公司 | Terpenoid, preparation method and application thereof, and antibacterial agent |
CN113173928B (en) * | 2021-04-25 | 2022-05-27 | 武汉国粹医药科技有限公司 | Terpenoid, preparation method and application thereof and antibacterial agent |
Also Published As
Publication number | Publication date |
---|---|
AU2003210904A2 (en) | 2003-09-02 |
CA2474974A1 (en) | 2003-08-14 |
EP1472241A4 (en) | 2005-06-29 |
MXPA04007550A (en) | 2004-11-10 |
AU2003210904A1 (en) | 2003-09-02 |
JP2005517014A (en) | 2005-06-09 |
EP1472241A1 (en) | 2004-11-03 |
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