MXPA99007733A - Use of substituted (5,6)-dihydronaphthalenyl compounds having retinoid-like activity to prevent or reduce ischemic injury - Google Patents

Abstract

The present invention relates to methods of preventing, or reducing the severity of, an ischemic injury originating in an animal's dermal tissue by applying to the animal a composition comprising a compound of formula (I*) or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which X is -O-CO-, -NH-CO-, -CS-NH-, -CO-O-, -CO-NH-, -COS-, -SCO-, -SCH2-, -CH2-CH2-, -CH=CH-, -C=C-, -CH2-NH-, -COCH2-, -NHCS-, -CH2S-, -CH2O-, -OCH2-, -NHCH2- or -CR5=CR6-;n is 1 or 0;Rm and Rk are independently hydrogen, halogen, C1-6 alkyl, hydroxy, C1-6 alkyloxy or nitro;R4 is -(CH2)t-Yb, C1-6 alkyl, or C3-6 cycloalkyl;R1 is -CO2Z, C1-6 alkyl, CH2OH, -CONHRy, or CHO;Ra and Rb are independently hydrogen or C1-6 alkyl, or Ra and Rb together can form a radical of formula (II);Yb is naphtyl or phenyl, both radicals can be optionally substituted with one to three of C1-6 alkyl or halogen, which substituents can be the same or different;Z is hydrogen or (1-6 alkyl);R2, R3, R5, R6, and Ry are independently hydrogen or C1-6 alkyl;and t is zero to six.

Description

USE OF SUBSTITUTE (5,6) -DIHYDROACHETHYLENE SUBSTITUTE COMPOUNDS WHO HAVE ACTIVITY SIMILAR TO RETINOIDS TO PREVENT OR REDUCE ISCHEMIC INJURIES BACKGROUND OF THE INVENTION The present invention provides methods for preventing or reducing the severity of an ischemic injury to the dermal tissue of an animal using compounds having retinoid-like activity, primarily substituted (5,6) -dihydronaphthalenyl compounds. In accordance with the present invention, the compounds (5, 6) -dihydronaphthalenyl substituted can be used to prevent or reduce the damage that occurs to the dermal tissue when the flow of blood to the tissue is blocked, which can cause ischemic injuries. This Application is related to the North American Application 08 / 464,186 filed June 5, 1995, which is a continuation in part of the North American Application 08 / 306,092 filed on September 19, 1994, which is a continuation in part of US Application 08 / 216,740 filed on March 23, 1994, now abandoned, which in turn is a continuation in part of the North American Application 08 / 176,746 filed on January 3, 1994, now abandoned. These applications are incorporated in this REF .: 30990 as a reference in its entirety. Patients who are comatose, are diabetic, paraplegic or otherwise suffer from severe alterations of the neural and vascular systems, are at great risk of developing ischemic lesions such as pressure ulcers or ischemic ulcers. Such injuries tend to occur in parts of the body that are under compression such as heels, elbows, hips, back and buttocks. A number of risk factors that correlate with ischemic injuries have been gathered. The four main risk factors that cause ischemic injuries are (1) pressure, (2) shear forces, (3) friction and (4) humidity. Additional predisposing risk factors include incontinence, fecal contamination, acid accumulation, poor nutrition, advanced age, reduced mobility, and poor physical condition. The sustained pressure on a prominence with bone causes a high probability of ischemic injury, causing tissue necrosis. Short-term pressure-induced ischemia is followed by a reactive hyperemia (repercussion). After prolonged exposure to ischemia / reperfusion events, plasma is poured from the vessels into the interstitial tissues. Hemorrhage can occur and cause a non-pallid erythema. The accumulation of toxic metabolites and the lack of nutrients resulting from the occlusion of blood vessels and lymphatic channels, causes muscle necrosis, subcutaneous tissues and, finally, the dermis and epidermis. The cutting forces are the result of the sliding of a bony prominence against the subcutaneous tissue, for example. Such a slip can occur, for example, when a patient is not fully lifted from a stationary surface such as a bed when said patient moves or is moved. The effects of both pressure and shear forces generally start in the deeper tissues and eventually spread to the surface of the skin. Friction forces are generated, for example, by pulling a patient over the sheets of a bed. Friction can cause injuries such as intraepidermal blisters and ultimately surface erosions. Humidity can increase friction between two surfaces and can also cause maceration. Frictional forces and moisture can directly cause surface skin erosion. Combinations of any of these four major risk factors can cause more serious injuries. Some studies show that pressure induced ischemia, followed by repercussion, is the mechanism behind tissue necrosis. So that, ischemic injuries include damage caused by repercussions, such as neutrophil-mediated lesions. Ischemic lesions can also develop from other conditions that cause a cut or decrease in blood circulation to an area of dermal tissue, including traumas from blunt forces. In addition, ischemic lesions can cause peeling of the skin (removal of the outer epidermal layer) caused by the removal of pressure-sensitive adhesives. For example, ostomates use a set of devices that have a surface coated with pressure-sensitive adhesive to attach to the body around the surgically created stoma. Such devices are removed daily and in some cases several times a day to be discarded. This constant release of adhesive can cause the removal or peeling of the epidermal layer. Ischemic lesions are a major source of discomfort for the patient and of medical expenses, and the present invention provides methods for preventing or reducing the severity of ischemic injuries using certain compounds that have retinoid-like activity, such as binding to the receptors of the patient. Retinoic acid.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods that prevent or reduce the severity of an ischemic injury to the dermal tissue of an animal, which comprises administering to the animal a composition comprising a compound of Formula I *: or a non-toxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a solvate thereof, wherein X is -O-CO-, -NH-CO-, -CS-NH-, -CO-O-, -CO-NH -, -COS-, -SCO-, -SCH2-, -CH2-CH2-, -CH = CH-, -C = C-, -CH2 ~ NH-, -COCH2-, -NHCS-, -CH2S-, -CH20-, -OCH2 -, -NHCH2- or -CR5 = CR6-; n is 1 or 0; R and R are independently a hydrogen atom, a halogen radical, alkyl of 1 to 6 carbon atoms, hydroxy, alkyloxy of 1 to 6 carbon atoms or nitro; R is - (CH 2) t-, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R is -C02Z, alkyl of 1 to 6 carbon atoms, CH2OH, -CONHRy or CHO; Ra and R are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms, or Ra and R together can form a radical of the Formula: Y is a naphthyl or phenyl radical, both may be optionally substituted with one to three alkyl radicals of 1 to 6 carbon atoms or halogen, which substituents may be the same or different. Z is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; R, R, R, R and Ry are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; t is zero to six. Preferably, R 1 is a radical -C0 2 H; n is 1, R2 and R are independently a methyl radical or a hydrogen atom; and Ra and R are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms. In addition, preferably Rm and R are a hydrogen atom; R is a methyl radical; R is a methyl radical; Ra and Rb are hydrogen; X is a radical -CH = CH-; R is C02Z and Z is a hydrogen atom. In still more preferred embodiments, the compound is a compound of Formula I 4 which is presented below, in which R is a radical (CH2) t_Yb / an alkyl radical of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, and more preferably is 4 [[(E) - (5,6-dihydro-5,5-dimethyl) acid -8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid.

(Formula I11) In preferred methods of the present invention, the composition is applied to a surface area of dermal tissue using a bandage having an adhesive surface in contact with the skin. For example, the compound can be incorporated in an adhesive layer, coated on an adhesive surface in contact with the skin or it can be located on an adhesive surface in contact with the skin and in adjacent layers of a bandage. In certain preferred embodiments, the bandage comprises a hydrocolloid adhesive. Preferably, the compound is present in a topical application composition in an amount of about 0.01 to about 1% by weight of the composition. When the compound is applied in a bandage, preferably the compound is present in an amount of apt? Iihüdi-jiüe 0.5 to spxD? PBdanspbe 1.0 pg / in 2 (lQ? G / 6.45at? ^ Of the skin in contact with the adhesive surface of the dressing Preferably, the compound is administered before developing visually discernible damage in the "dermal ejido." In certain embodiments, the methods of the present invention are used to prevent or reduce the deleterious effects of an ischemic lesion resulting from the Removal of an adhesive from the animal In other embodiments, for example, the composition is administered to prevent or reduce the harmful effects of a resultant ischemic injury by exerting pressure on the dermal tissue covering a bony protrusion. The methods of the present invention can be determined, for example, by measuring microcirculatory blood flow or by histological examination of a sample. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods for preventing or reducing the severity of an ischemic lesion of the dermal tissue of an animal., which comprises administering a composition comprising a compound of Formula I (shown above) or a pharmaceutically acceptable non-toxic salt, a physiologically hydrolysable ester or a solvate thereof, with the substituents as described above. As mentioned above, those skilled in the art will recognize a number of circumstances in which the prophylactic administration of the present invention can be applied to prevent or reduce the severity of tissue damage caused by ischemic injury. For example, in a hospital or daycare center, a patient who has spent much of his or her time in bed will be at risk, particularly at sites of bony protuberances. Patients who must repeatedly remove adhesive bandages are also at risk. Based on intensive studies that have been and are being carried out to identify the risk factors in order to reduce the high fiscal and quality of life costs of these injuries, there are currently significant norms about when intervene to reduce this risk. The term "dermal tissue" is defined herein as tissue in any layer of the skin, including the epidermis, dermis and hypodermis. The injury to the dermal tissue includes lesions that originate in the dermal tissue that could optionally extend to other areas, including for example the muscle.

Preferred embodiments of the methods of the present invention include the use of compounds of the following Formulas, which are compounds of Formula I *, wherein the various substituents are as defined for Formula I * above.

- - For the description herein, the numbers in subscript after the symbol "C" define the number of carbon atoms that a particular group can contain. For example, C? -6 alkyl refers to straight or branched chain alkyl groups having from 1 to 6 carbon atoms and such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl radicals , n-pentyl, n-hexyl, 3-methylpentyl or the like; the term "C ^ - cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals; and the term "halogen radical" refers to fluorine, chlorine, bromine or iodine atom. In the present application, all symbols once defined retain the same meaning until they are redefined. The compounds of Formula I also form pharmaceutically acceptable salts with metals and amines, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. These salts are also part of the present invention. Suitable metal salts include the sodium, potassium, calcium, barium, zinc and aluminum salts. Sodium or potassium salts are preferred. Amines that are capable of forming stable salts include trialkylamines, such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-efhenamine, N, N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine. or similar pharmaceutically acceptable amines. When a compound of Formula I contains carboxy groups, these may be in the form of physiologically hydrolysable esters which serve as prodrugs to be hydrolyzed in the body to obtain the compounds of Formula I per se. These are preferably administered orally, since hydrolysis in many cases occurs mainly under the influence of digestive enzymes. Parenteral administration can be used when the ester per se is active or in those cases where hydrolysis occurs in the blood. Examples of physiologically hydrolysable esters of the compounds of Formula I include alkyl of 1 to 6 carbon atoms, benzyl, 4-methoxybenzyl, indanyl, phthalidyl, methoxymethyl; C- < RTI ID = 0.0 > C < / RTI > alkanoyloxy, for example acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl; alkoxycarbonyloxy-, C 1-6 alkyl, for example methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-l, 3-dioxolen-4-yl) -methyl and other known physiologically hydrolysable esters used, for example, in the field of penicillin and cephalosporins. Such esters are prepared by conventional techniques known in the art. Structural formulas such as those presented in the present application are thought to be the best representatives of the structures of the compounds used in the methods of the present invention. However, some compounds within the scope of the present invention may exist like other tautomeric forms, in which the hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules, consequently, rearrange . It should be understood that structural formulas represent all tautomeric forms, as long as they can exist.

The synthesis of a compound of Formula I can be achieved by a wide variety of methods, using raw materials and conventional processes. See, for example, European Patent EP 0,661,259 Al, which is hereby incorporated by reference in its entirety and US Application 08 / 464,186, filed June 5, 1995. Examples of chemical formulas encompassed by Formula I * include: in Formula D above, n is equal to 1, while in Formula E, n is equal to 0. In Formula F, Ra and R together form a fused ring structure. The compounds of Formula I can be used topically or systemically, in the treatment, palliation or prevention of ischemic lesions or repercussion. In this regard, they can be used for therapy in animals, including humans, for prophylaxis or for treatment. When used for treatment, they will usually be formulated with a liquid, semi-solid or solid pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is a material that is non-toxic and is generally inert and does not affect the functioning of the active ingredients. Such materials are known and include those materials sometimes referred to as diluents or carriers (excipients) in the field of pharmaceutical formulations. The vehicle can be of organic and inorganic nature. Examples of pharmaceutically acceptable carriers that can be used to formulate a compound of Formula I include water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, sorbitol, anitol, gum acacia, alginates, cellulose, talc , magnesium stearate, polyoxyethylene sorbitan monolaurate and other commonly used pharmaceutical vehicles. In addition to a compound of Formula I and a carrier, the formulation may contain minor amounts of additives such as flavoring agents, colorants, thickeners or gelling agents, emulsifiers, humectants, pH regulating solutions, stabilizing and preservative agents such as antioxidants. Dosages and dose regimens in which the compounds of Formula I are administered will vary in accordance with the dosage form, mode of administration, the disorder being treated or prevented and particular aspects of the patient being treated. The dose to be administered is not subject to defined bones, but will normally be an effective amount or the equivalent in a molar basis of the free pharmacologically active form produced from a formulation, after the metabolic release of the active ingredient to achieve its effects pharmacological and physiological Accordingly, the optimal therapeutic concentrations will be better determined at the time and place, through routine experimentation. In many embodiments, it is preferred to administer the drug topically and in other embodiments oral administration is preferred as the delivery mechanism. If the compounds according to the present invention are used topically, they will be found to exhibit good activity over a very wide range of dilution. For example, preferred compositions for topical application have a concentration of the active compound or active compounds of from about 0.0005 to about 10% w / v, preferably from about 0.01 to about 1%, still more preferably from about 0.05 to about 0.5% and still more preferably of about 0.1%. The doses for systemic administration preferably are from about 0.5 to about 50 mg / kg / day of the active compound or compounds and more preferably about 10 mg / kg. For topical administration, the compounds of the Formula I are conveniently provided in the form of ointments, gels, creams, powders, dyes, solutions, suspensions, emulsions, lotions, rubbers, adhesive plasters and impregnated pads. The compounds according to the present invention can be mixed with non-toxic inert materials, generally liquid or in paste, for topical application. The preparation of such topical formulations is well described in the field of pharmaceutical formulations, for example in Remington's Pharmaceutical Science, (17th edition, Mack Publishing Company, Easton, Pa). Other medications can be added to topical formulations for secondary purposes such as dry skin treatment, to provide protection against light; other medications for the treatment of dermatoses, to prevent infections, reduce irritation, inflammation and the like. The active compounds can be administered enterally. For oral administration, suitable pharmaceutical forms are, for example, tablets, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred administration method consists of pills. U.S. Patent No. 4,876,381 issued October 24, 1989 to Lang et al. , provides examples of formulations that constitute gel, ointment, powder, cream, etc., for a retinoid compound. The aforementioned US Patent can be used as a guideline for formulating a compound of Formula I is incorporated herein by reference in its entirety.

The compounds according to the present invention can also be administered parenterally in the form of solutions or suspensions for perfusion or intravenous or intramuscular injection. A preferred method of administration is to use solutions or suspensions containing about 0.01 to 1 mg of the active substance per ml. The present invention is more promising for application in humans, where the damaging effects of ulcers caused by ischemic injuries require, understandably, greater attention. However, situations arise in which it is possible to cause such injuries in animals. The preferred subjects for treatment are mammals, particularly humans. Some experiments have shown that the compounds of Formula I are at least retinoic acid antagonists in some systems, such as the induced activation of transcription mediated by retinoic acid receptors alpha, beta and gamma. These compounds also show some agonist activity. The present invention will be further described with the following Example, which is not limiting. EXAMPLE 1. Prevention of Ischemic Injuries Stanley male guinea pigs weighing 350 to 400 grams of body weight were independently housed and fed a diet of food and water ad libi tum.

The guinea pigs were housed in a controlled environment with a temperature ranging from 19 to 21 degrees Celsius, a light / dark cycle of twelve hours and 50% relative humidity. Of the guinea pigs, twenty-five were waxed four days before starting the experiment. The guinea pigs were randomly divided into five treatment groups, with five animals in each group. Group 1 was treated with 4- [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid in 0.01% ethanol w / v ("0.01% B.A."). The acid 4- [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid ("B.A.") has the following structure: Group 2 was treated with B.A. at 0.1% ethanol.

Group 3 was treated with 0.1% complete trans retinoic acid in 100% ethanol ("0.1% R.A."). Group 4 was a control group treated with ethanol before and after the ischemic lesion was induced surgically. Group 5 was treated with 0.1% B.A. in ethanol before and after the ischemic lesion was surgically induced. 100 μl of each treatment solution was applied to each of the animals in the treatment group, making contact in a 10 cm "area of skin with an icropipette containing the treatment solution, then the treatment site was covered with a transparent commercially available film bandage Tegaderm (Minnesota Mining and Manufacturing, St. Paul, MN) The treatment was repeated for a total of four consecutive days, with one treatment per day, a fifth application of each treatment solution was applied to each guinea pig in a group after the surgery described below, see Table I, below: TABLE I Group No. Pretreatment Solution Postrata Induction Treatment of Ischemia Treatment 0.01% BA Days 1-4 Day 5 None 0.1 * BA Days 1-4 Day 5 None 0.1% RA Days 1-4 Day 5 None Ethanol Days 1-4 Day 5 Posischemia days 1, 3, 7 and 10 Ischemic ulcers were induced in the guinea pigs in the following manner. The entire dorsal region of each guinea pig was prepared for surgery by washing the skin with an antiseptic, followed by a rinse with hot water.

The guinea pigs were anesthetized by injection Intraperitoneal dose of 100 mg / kg Cetamine (Ketase ™, Bristol-Myers Squib, Princeton, NJ, USA), followed by a TM intramuscular injection of 0.6 ml of Xylazine (Ro pun, Bayer AG, Leverkusen, Germany) at a concentration of 5 mg / kg. The combination provided approximately 45 minutes of surgical anesthesia, time during the which surgery was performed. A 5 cm transescapular incision was made with a number 10 scalpel. The skin was carefully undercut using blunt dissection until a narrow pouch was formed to accommodate a 10 ml rubber syringe plunger. An effort was made to minimize damage to the underlying tissue and focus only on the vertebral region where the plunger was placed. The rubber plunger was inserted over the vertebral region distant from the scapula. An orthodontic rubber band tourniquet was placed around the plunger to prevent blood flow to the five square centimeters of skin above the rubber plunger. The incision line was closed with staples (Ethicon, Somerville, NJ, USA, subsidiary of Johnson &Johnson Products). The rubber plunger was left in the incision for six hours after surgery. After this six-hour period, the guinea pigs were anesthetized again using an intraperitoneal injection of Cetamine-HCl. The incision was reopened, the rubber band was removed and the rubber plunger was removed by pulling an exposed suture attached to the rubber tip. After the release of the tourniquet, a fifth application of each treatment solution was applied to the surgical site of each guinea pig in a group. Afterwards, the site was occluded with a Tegaderm brand bandage and secured to the skin using an elastic band. The guinea pigs of groups 4 and 5 were treated on the first, third, seventh and tenth day after surgery using the relevant treatment solution. On the first, third, seventh, and tenth day after surgery, all guinea pigs were visually checked for tissue necrosis, which was subsequently recorded as a percentage of complete thickness damage, surface damage, or viable tissue. The full thickness damage was defined and involves both the epidermis and the dermis, extending down to the muscle. Surface damage was defined as the involvement of the epidermis and part of the dermis. Viable tissue was defined as pink, whitish skin. Photographs were taken throughout the study. The animals were subsequently slaughtered. On day 10, skin samples were taken including the epidermis, dermis and hypodermis of the adjacent site and the opposite site of the ischemic area for histological evaluation. Then, the skin samples were fixed in formalin with 10% buffer and processed for evaluation by light microscopy. Sections were prepared and stained with hematoxylin-eosin and Masson's trichrome technique for histological evaluation, which was carried out by a person who had no prior knowledge of the type of treatment received by each animal. The histological evaluation of the skin included a rating as normal, slight changes, moderate changes or remarkable changes. The epidermis was evaluated with respect to cell vaccinating, mitosis, inflammation and necrosis. The dermis was evaluated with respect to neovascularization, inflammation and necrosis. The hypodermis was evaluated with respect to the presence of tissue granulation, inflammation, angiogenesis and extravasation of blood cells. Changes in the collagen matrix or cell morphology were also recorded. In response to ischemic injury and treatments, a range of visual evaluations and histological evaluations were found. Response variations within a treatment group were not specific for a particular group. Visual test of skin damage: Group 1: animals treated with 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid at 0.01%. Three guinea pigs were observed, the other two died from anesthesia. One presented normal intact skin, while the other two showed full-thickness necrosis with various areas of viable tissue. Group 2: animals treated with 0.1% 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid. The guinea pigs in this group showed a marked reduction in the breakdown of the dermal tissue compared with the other groups. Group 3: animals treated with 0.1% completely trans retinoic acid. The damage of full thickness was avoided and more superficial damage was observed on days 7 and 10. Group 4: animals treated with 100% ethanol control (before and after the surgically induced lesion). This group presented the most extensive and highest degree of complete thickness damage. Group 5: animals treated with 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid both before and after induced injury surgically. The incidence and severity of the necrosis varied in this group. The data from the visual evaluation of the skin are summarized in Tables 2 and 3. Table 2 is a compilation of the data of the seven days after the induced ischemia and Table 3 is a compilation of the data of the tenth day after of induced ischemia.

TABLE 2 - Results after 7 days Solution Group of% Damage% of Damage% of Fabric) Treatment Treatment of Total Viable Surface Thickness 0.01% B.A. 64% 0% 36% 0.1% B.A. 20% 80% 0.1% R.A. 0% 100 ^ 0% Ethanol 82% 16% 2% 0.1% B.A. 20% 25 ^ 55% preischemia and posischemia TABLE 3 - Results after 10 days The results of group 5, where the agent in the vehicle was administered both before and after induced ischemia, are intermediate between the results obtained in group 2 and group 4, which agrees with the known harmful effect of the vehicle , ethanol, on the healing of wounds. Histological results: Group 1: animals treated with 0.01% 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid. The cutaneous reactions of the three treated guinea pigs were referred for microscopic examination. The skin of an animal seemed very normal and intact. The other two animals revealed a deeply affected skin. Its epidermis was markedly eroded and in some areas, particularly at the site of ischemia, skin was missing. In this site, the hair follicles have been eradicated. An intense inflammatory reaction was observed consisting mainly of macrophages, mast cells, histocytes and persistent eosinophils in the papillary dermis, just below the eroded stratum corneum as well as in the inferior region to the reticular dermis and the hypodermis. Massive extravasation of blood cells was observed in the reticular dermis and the presence of discrete hemorrhages was common. Distorted, broken and hyalinized collagen fibers were observed mostly in the reticular dermis near the hypodermis. Moderate fibroplasia confined to the hypodermis was observed. Group 2: animals treated with 0.1% 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid. Skin sections of four animals were available for histological evaluation. A guinea pig showed intact and normal epidermis and dermis slightly invaded by inflammatory cell infiltrates. The other three guinea pigs, despite showing an eroded stratum corneum, showed a mild inflammatory reaction in both the dermis and the hypodermis. The dermal collagen had a mostly normal appearance. The hypodermis showed very mild to moderate fibroplasia. Group 3: animals treated with 0.1% completely trans retinoic acid. The skin of four of the five guinea pigs showed a mild to moderate inflammatory reaction in both the papillary and reticular regions of the dermis. However, collagen fibers showed more damage in the lower region of the dermis than in the upper area. The hypodermis showed normal and intact muscle fibers. One animal responded differently to treatment and intense inflammatory cell infiltrates and particularly massive populations of eosinophils invading all regions of the skin were observed. Group 4: animals treated with a 100% ethanol control (before and after the surgically induced lesion). This group, in its entirety, manifested the deepest changes in the skin. A severe inflammatory reaction prevailed in the epidermis, dermis and hypodermis. Inflammatory cell infiltrates contained neutrophils, macrophages and a massive population of eosinophils. As a result of this extensive inflammatory reaction, the collagen fibers of the dermis appeared to be broken and hyalinized. Frequently hemorrhagic areas were found, particularly in the lower region of the hypodermis. Group 5: Animals treated with 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic acid 0.1% (before and after the surgically induced injury). The guinea pigs in this group showed a varied response to the treatment. Two of the five guinea pigs showed a negligible reaction, while the others showed moderate to severe changes. A guinea pig showed a severe inflammatory reaction involving all regions of the skin. Macrophages were observed, neutrophils and massive populations of eosinophils as main constituents of inflammatory cell infiltrates. A large part of the collagen fibers were disintegrated, hyalinized and some had already disappeared. The muscle fibers of the hypodermis were drastically affected and had a worn appearance and many were sarcolized. In general, the results of the test showed that the pretreatment of guinea pigs with 4 - [[(E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic 0.1% before the surgically induced lesion, reduced the incidence and severity of inflammation, damage to the collagen fibers and overall dermal necrosis. The guinea pigs in this treatment group showed an acceleration and improvement in the repair of the ischemic site superior to the other treatment groups. Since the present invention has been described with emphasis on the preferred embodiments, it will be obvious that those skilled in the art may use variations of the preferred devices and methods and that it is intended that the present invention may be practiced differently than specifically described here. Accordingly, the present invention includes all modifications encompassed within the spirit and scope thereof as defined by the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (21)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A method for preventing or reducing the severity of an ischemic lesion originating in the dermal tissue of an animal, characterized in that it comprises administering to the animal a composition comprising a compound of Formula I *: or a non-toxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a solvate thereof, wherein X is -O-CO-, -NH-CO-, -CS-NH-, -CO-O-, -CO-NH -, -COS-, -SCO-, -SCH2-, -CH2-CH2-, -CH = CH-, -C = C-, -CH2-NH-, -COCH2-, -NHCS-, -CH2S-, -CH20-, -OCH2-, -NHCH2- or -CR5 = CR6-; n is 1 or 0; R and R are independently a hydrogen atom, a halogen radical, alkyl of 1 to 6 carbon atoms, hydroxy, alkyloxy of 1 to 6 carbon atoms or nitro; R4 is - (CH2) t ~? / alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R is -CO2Z, alkyl of 1 to 6 carbon atoms, CH2OH, -CONHR? eight; Ra and Rb are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms, or Ra and R together can form a radical of the Formula: Y is a naphthyl or phenyl radical, both may be optionally substituted with one to three alkyl radicals of 1 to 6 carbon atoms or halogen, which substituents may be the same or different. Z is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; R, R, R, R and Ry are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; and t is zero to six.
2. 2. The method according to claim 1, characterized in that R is a -CO2H radical; n is 1, R 2 and R 3 are independently a methyl radical or a hydrogen atom; and Ra and R are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms.
3. 3. The method according to claim 1, characterized in that the compound is 4- [t (E) - (5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] -vinyl] -benzoic
4. 4. The method according to claim 2, characterized in that R is methyl.
5. 5. The method according to claim 4, characterized in that R is methyl.
6. 6. The method according to claim 1, characterized in that Rm and R are hydrogen.
7. The method according to claim 1, characterized in that Ra and R are hydrogen.
8. 8. The method according to claim 1, characterized in that X is -CH = CH-.
9. 9. The method according to claim 1, characterized in that R is CO2.
10. 10. The method according to claim 9, characterized in that Z is a hydrogen atom.
11. 11. The method according to claim 1, characterized in that the composition comprises a compound of Formula I: I11 in which R is a radical (CH2) t ~? , an alkyl radical of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.
12. The method according to claim 1, characterized in that the composition is administered in a bandage having a layer or adhesive surface to adhere to the skin of the animal.
13. The method according to claim 12, characterized in that the compound is incorporated in an adhesive layer or is coated on an adhesive layer or is located on an adhesive surface and in the adjacent layers of a bandage.
14. The method according to claim 12, characterized in that the bandage comprises a hydrocolloid adhesive.
15. The method according to claim 12, characterized in that the compound is present in an amount of about 0.5 to about 1.0 mg / in of the skin in contact with the adhesive surface of the bandage.
16. 16. The method according to claim 12, characterized in that the bandage is applied before developing visually discernible damage in the dermal tissue.
17. 17. The method according to claim 1, characterized in that the compound is present in a composition for topical application in an amount of about 0.01 to about 1% by weight of the composition.
18. 18. The method according to claim 1, characterized in that the reduction or prevention of damage is determined by measuring the microcirculatory blood flow.
19. 19. The method according to claim 1, characterized in that the reduction or prevention of damage is determined by histological examination of a sample of dermal tissue.
20. The method according to claim 1, characterized in that the composition is used to prevent or reduce the harmful effects of an ischemic injury resulting from the removal of an adhesive from the animal.
21. 21. The method according to claim 1, characterized in that the composition is applied to prevent or reduce the damaging effects of a resultant ischemic injury by exerting pressure on the dermal tissue covering a bony protuberance. SUMMARY OF THE INVENTION The present invention relates to methods for preventing or reducing the severity of an ischemic lesion originating in the dermal tissue of an animal, by applying to the animal a composition comprising a compound of Formula I * or a non-toxic pharmaceutically acceptable salt, a physiologically hydrolysable ester or a solvate thereof, wherein X is -0-C0-, < -NH-CO-, -CS-NH-, -C0-0-, -CO-NH-, -COS-, -SCO-, -SCH2-, -CH2-CH2-, -CH = CH-, -C = C-, -CH2-NH-, -COCH2- -NHCS-, -CH2S-, -CH20-, -OCH2-, -NHCH2- or -CR5 = CR6-; n is 1 or 0; Rm and Rk are independently a hydrogen atom, a halogen radical, alkyl of 1 to 6 carbon atoms, hydroxy, alkyloxy of 1 to 6 carbon atoms or nitro; R1 is - (CH2) t ~ Y1 alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R is -C02Z, alkyl of 1 to 6 carbon atoms, CH2OH, -CONHRy or CHO; Ra and R are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms, or Ra and R together can form a radical of Formula (II); Y is a naphthyl or phenyl radical, both may be optionally substituted with one to three alkyl radicals of 1 to 6 carbon atoms or halogen, which substituents may be the same or different; Z is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; R ", R, R, R and Ry are independently a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms, and t is zero to six.