MXPA99001774A - Method for inhibiting the expression of fas - Google Patents

Abstract

The present invention provides a method for inhibiting the expression of Fas which comprises administering to a mammal in need thereof an effective amount of a compound which is a dual non-selective&bgr;-adrenoceptor and&agr;1-adrenoceptor antagonist.

Description

METHOD TO INHIBIT THE EXPRESSION OF Fas FIELD OF THE INVENTION The present invention relates to a new method of treatment using compounds that are non-selective dual antagonists of β-adrenoceptors and alpha ^ -adrenoceptors, in particular the carbazolyl- (4) -oxypropanolamine compounds of the formula I, preferably carvedilol, for inhibit -.10 expression of Fas, a protein on the surface of the cell.

BACKGROUND OF THE INVENTION The proliferation, differentiation and survival of cells are often regulated by growth, differentiation and survival factors, respectively, which are collectively called cytosines. The Cytokines bind to their complementary receptors, which transduce the extracellular signal into a cascade of signals intracellular. The Fas ligand (FasL) is a cytosine. It is one of the few known cytokines that is a factor of death.

This ligand binds to its receptor, Fas, a protein on the surface of the cell, and induces apoptosis (death of the cell). Many tissues and cell lines weakly express Fas, but an abundant expression has been found in the heart, liver, lung, kidney, ovary and mouse thymus. (R. Watanabe-Fukunaga, et al., J. Immunol., 148, 1274, 1279 (1992)). In the immune system, Fas and FasL intervene in the sub-regulation of immune reactions as well as in T cell-mediated cytotoxicity. The malfunction of the Fas system causes lipoproliferative alterations and accelerates autoimmune diseases, while its exacerbation can cause tissue destruction ( S. Nagata, et al., Science, 267, 1449-1456 (1995)). Surprisingly, it has been found that carvedilol, a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor inhibits Fas expression. This inhibition may mean that carvedilol and related compounds of formula I are useful for diseases in which the inhibition of apoptosis mediated by Fas is indicated. Particularly, this inhibition may mean that carvedilol and the related compounds of formula I are useful for blocking ischemia-induced apoptosis in cardiac cells, to prevent or inhibit tissue remodeling, in particular in cardiac tissue and in blood vessels, for treat autoimmune diseases, and to inhibit tumor growth and metastasis.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a new treatment using compounds that are non-selective dual antagonists of β-adrenoceptor and alpha ^ -adrenoceptor, in particular the carbazolyl- (4) -oxypropanolamine compound of the formula I, preferably carvedilol, to inhibit the expression of Fas. The invention also relates to a method of treatment using compounds that are nonselective dual antagonists of β-adrenoceptor and alpha 1 -adrenoceptor, in particular the compound carbazoyl- (4) -oxypropanolamine of formula I, preferably carvedilol, to inhibit apoptosis. Additionally, this invention relates to a method of treatment using compounds that are non-selective dual antagonists of β-adrenoceptor and alpha ^ -adrenoceptor, in particular the carbazoyl- (4) -oxypropanolamine compounds of formula I, preferably carvedilol, for according to which the inhibition of Fas-mediated apoptosis is indicated. In particular, this invention is directed to the use of compounds of the formula I, preferably carvedilol, to specifically induce Fas-mediated apoptosis of undesirable cells, such as cancer cells or immune self-reactive cells. In addition, when control of aberrant forms of Fas activation is desired, compounds of formula I, preferably carvedilol, are used to prevent depletion of cells in AIDS or neurodegenerative diseases. This invention also relates to a method of treatment using compounds that are nonselective dual antagonists of β-adrenoceptor and alpha ^ -adrenoceptor, in particular the carbazoyl- (4) -oxypropanolamine compound of the formula I, preferably carvedilol, to prevent or inhibit the remodeling of tissues, in particular in cardiac tissue and blood vessels. The present method includes the use of compounds that are nonselective dual antagonists of β-adrenoceptor and alpha ^ -adrenoceptor, in particular the carbazoyl- (4) -oxypropanolamine compounds of the formula I, preferably carvedilol, to block apoptosis induced by ischemia in cardiac cells.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for inhibiting the expression of Fas using compounds that are non-selective dual antagonists of β-adrenoceptor and alpha ^ -adrenoceptor. Preferably, this invention provides a - a new method to inhibit the expression of Fas using compounds of the formula I: (I) according to which: R7"R13 are independently -H or -OH; and A is a portion of formula II according to which R_ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH-2-0-; X is a single bond, -CH2, oxygen or sulfur. Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R5 and Rg are selected individually from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group -CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. More preferably, the present invention provides a novel method for inhibiting the expression of Fas using compounds of formula III: (ID) whereby: R 1 is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R 4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4 together with R 5 can represent -CH 2 -; X is a single bond, -CH-2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a C0NH2 ~ group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms , lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. More preferably, the present invention provides a novel method for inhibiting the expression of Fas by using a compound of formula IV, better known as carvedilol or (1- (carbazol-4-yloxy-3- [[2- (o-methoxyphenoxy) ) ethyl] amino] -2-propanol): The compounds of the present invention are new multiple-action drugs used in the treatment of medium to moderate hypertension. Carvedilol is known to be a competitive non-selective antagonist of β-adrenoceptor and a vasodilator, and is also a calcium channel antagonist at higher concentrations. Vasodilatory actions of carvedilol result mainly from | alpha blocking] _- adrenoceptor, while the β-adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans. See Willette, R.N. , Sauermelch, C.F. and Ruffolo, R.R., Jr. (1990) Eur. J. Pharmacol. , 176, 237-1040; Nichols, A.J., Gellai, M. and Ruffolo, R.R., Jr. (1991) I w Fundam. Clin. Pharmacol., 5.25-38; Ruffolo, R.R. , Jr., Gellai, M., Hieble, J.P., Willette, R.N. and Nichols, A.J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88; Ruffolo, R.R., J., Boyle, D.A., Venuti, R.P. and Lukas, M.A. (1991) Drugs of Today, 27,465-492; Y Yue, T.-L., Cheng. H., Lysko, P.G., Mckenna, P.J .; Feuerstein, R., Gu, J., Lysko, K.A. , Davis, L.L. and Feuerstein, G. (1992) J.

Pharmacol. Exp. Ther. , 263.92-98. ß The antihypertensive action of carvedilol is mediated mainly by decreasing the total peripheral resistance vascular without causing concomitant reflex changes in cardiac rhythm commonly associated with other antihypertensive agents. Willette, R.N. , and others supra, Nichols, A.J., and others supra; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P .; Willette, R.N. and Nichols, A.J. (1990) Eur. J. Clin.

Pharmacol. , 38, S82-S88. Carvedilol also markedly reduces the size of the infarct in rats, dogs and porcine models of acute myocardial infarction, Ruffolo, R.R., Jr., and others, Drucs of Todav, supra, possibly as a consequence of its antioxidant action in the attenuation of > Lipid peroxidation initiated by free radicals. Yue, T.- 5 L., and others supra. Recently, it has been discovered that compounds that are nonselective dual antagonists of β-adrenoceptor and alpha ^ _-adrenoceptor, in particular compounds of formula I, preferably carvedilol, inhibit the expression of Fas inhibit Fas-mediated apoptosis. Based on this mechanism The compounds of the moment can be used to treat diseases according to which the inhibition or control of Fas-mediated apoptosis is indicated. In particular, the compounds of the present invention, Preferably, carvedilol can be used to block ischemia-induced apoptosis in cardiac cells, to prevent or inhibit tissue remodeling, particularly in cardiac tissue and blood vessels, to treat autoimmune diseases, and to inhibit the growth of tumors and metastases. Additionally, when control of aberrant forms of Fas activation is desired, compounds of formula I, preferably carvedilol, are used to prevent depletion of cells in AIDS or neurodegenerative diseases. Some of the compounds of formula I are known to be carvedilol metabolites. Certain preferred compounds of the present invention, ie, the compounds of formula I wherein A is the portion of formula II wherein R 1 is -H, R 2 is -H, R 3 is -H, R 4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and 1 of R7, Rg and Rio is -5 OH, are metabolites of carvedilol. The compounds of the formula I can be conveniently prepared as described in U.S. Pat. No. 4,503,067. reference should be made to that patent for its complete description, the full description of which is incorporated herein by reference. The pharmaceutical compositions of the compounds of the formula I, including carvedilol, can be administered to patients according to the present invention in any medically acceptable manner, preferably orally. For For parenteral administration, the pharmaceutical composition will be in the form of a sterile injectable liquid stored in a suitable container such as an ampule, or in the form of an aqueous or non-aqueous liquid suspension. The nature and composition of the pharmaceutical vehicle, diluent or excipient will, of course, be dependent on the designed route of administration, for example for intravenous or intramuscular injection. The pharmaceutical compositions of the compounds of the formula I to be used in accordance with the present The invention can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted by the addition of an acceptable diluent or other pharmaceutically acceptable carrier before use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solutions, 5% normal dextrose in water or sodium acetate or ammonium solution regulated in its pH. Such a formulation is especially suitable for parenteral administration, but can also be used for oral administration or contained in an inhaler. calculated dose or nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxycellulose, acasia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds can be encapsulated, tabletted or prepared in an emulsion or syrup for oral administration. Can pharmaceutically acceptable solid or liquid carriers be added to improve or? stabilize the composition, or to facilitate the preparation of the composition. Liquid vehicles include melase, oil peanut, olive oil, glycerin, saline, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, alba earth, magnesium stearate or stearic acid, talc, pectin, acasia, agar or gelatin. The vehicle can also include a material of Sustained release such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, it will be between 20 mg to almost 1 g per unit dose. The pharmaceutical preparations fc are made following conventional pharmacy techniques involving grinding, mixing, granulating and compressing, when necessary, for tablet forms; or grinding, mixing and filling for forms of hard gelatin capsules. When a liquid vehicle is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such liquid formulation can be administered directly p.o., or filled into a soft gel jelly capsule. The dosage in humans for the treatment of disease according to the present invention should not exceed a dosing scale of 3.125 to 50 mg of the compounds of the formula I, particularly carvedilol, preferably given twice a day. As one skilled in the art will readily understand, the patient should start with a low dosage regimen of the desired compound of formula I, particularly carvedilol, and supervised for well-known symptoms of intolerance, for example, fainting, to such a compound. Once it is found that the patient tolerates such a compound, the patient should be brought slowly and incrementally up to the maintenance dose. The choice of the most appropriate initial dose for the particular patient is determined by the physician using well-known medical principles, including, but not limited to, body weight. In the case in which the patient exhibits acceptable drug tolerance of the compound for two weeks, the dosage is doubled and at the end of the two weeks and the patient is kept in a new one, higher dosage for two more weeks, and observed for signs of intolerance. This method is followed until the patient is brought to a new maintenance dose. It will be appreciated that the present preferred dosages of the compounds being used in the compositions of this invention will vary according to the particular composition formulated, the mode of administration, the particular site of administration and the host being treated. Unacceptable toxicological effects are not expected when the compounds of the formula I are used according to the present invention. The following example is designed not to limit the scope of this invention in any way, but is provided to illustrate how to use the compounds of this invention.

Many other modalities will be readily apparent to those skilled in the art.

EXPERIMENTAL The effect of carvedilol on myocardial apoptosis was investigated in a rabbit model of cardiac ischemia and reperfusion (R. Gottlieb, et al., J. Clin. Invest., 94, 1621-1628 (1994) .In this model, ischemia and reperfusion arouses widespread apoptosis in cardiac myocytes Treatment with carvedilol before ischemic attack significantly reduced apoptotic myocytes from 14.7 cells per field to 4.5 cells per field (p <0.01).

Immunochemical detection of rabbit cardiomyocyte Fas expression Cardiac tissue was fixed in NBF for 24-48 hours at 4 ° C and cut lengthwise into pieces 2-3 mm thick. Following the standard histological procedure and embedding in paraffin, 5 μm thick sections were prepared for immunoperoxidase staining using the Vectastain equipment ABC (Bector Laboratories) according to the manufacturer's instructions. Briefly, the endogenous peroxidase was extinguished with 0.3% H2O2 in methanol for 30 minutes. The non-specific immunoglobulin binding sites were blocked with normal goat serum for 1 hour and then the sections were incubated with the primary antibody (mouse anti-FAS, 2 μg / ml, Upstate Biotechnology) for 1 hour at room temperature. The sections were then incubated for 30 minutes with a goat anti-mouse biotinylated IgM secondary antibody (1: 200, Vector Laboratories) followed by 30 minutes of incubation with the Vectastain ABC reagent solution. The immunoglobulin complexes were visualized under incubation with 3, 3'-diaminobenzidine (DAB, Vector Laboratories) at 0.5 mg / ml in 50 mM Tris-HCl, pH 7.4 and 3% H2O2. DAB staining was increased by treating the sections for 10 seconds with DAB increasing solution (Vector Laboratories). The sections were washed, stained with Gill's Hematoxilin, cleared, mounted with Aquamount (Polysciences) and then examined through an optical microscope. In summary, comparative studies were conducted according to which the basal levels of Fas were expressed in normal heart cardiomyocytes. In ischemic reperfusion injury, the expression of 'Fas in cardiomyocytes was stimulated. Through the treatment with carvedilol, this expression of Fas induced by reperfusion in cardiomyocytes was inhibited. The foregoing is illustrative of the use of the compounds of this invention. However, this invention is not limited to the precise embodiment described herein, but encompasses all modifications within the scope of the claims that follow.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a nonselective dual antagonist of β-adrenoceptor and α-α-adrenoceptor in the manufacture of a medicament to inhibit the expression of Fas.

2. The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor in accordance with claim 1 of formula I: wherein: R7-R13 are independently -H or -OH; and A is a portion of formula II: (ID wherein Ri is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a single bond, -CH, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R5 and Rg are selected individually from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group -CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof.

3. - The use of a nonselective dual antagonist of β-adrenoceptor and alpha] _-adrenoceptor according to claim 1 of formula III: a wherein: R ^ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R 4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4 together with R 5 can represent -CH 2"" 0-; X is a single bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group CONH2 ~, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms , lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof.

4. The use of a nonselective dual antagonist of β-adrenoceptor and alfat_-adrenoceptor according to claim 1 further characterized in that said antagonist is carvedilol.

5. - The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor in the manufacture of a drug to inhibit Fas-mediated apoptosis.

6. The use of a nonselective dual antagonist of β-adrenoceptor and alpha β-adrenoceptor according to claim 5 of formula I: (I) wherein: R7-R13 are independently -H or -OH; and A is a portion of formula II: (H) wherein R] _ is hydrogen, lower alkanoyl of up to 6 atoms 10 carbon or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 atoms 15 carbon, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a single link, -CH2. oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and --- tetrahydronaphthyl r; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl 20 to 6 carbon atoms, a -CO H2 ~ group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms carbon; or R5 and Rg together represent methylenedioxy; and sales 25 pharmaceutically acceptable thereof.

7. The use of a nonselective dual antagonist of β-adrenoceptor and alphax-adrenoceptor according to claim 5 of the formula III: sp) wherein: R ^ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from bensyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R 4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4 together with R 5 can represent -CH 2 -; X is a single bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Rg are selected individually from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group CONH2"", lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof.

8. The use of a nonselective dual antagonist of β-adrenoceptor and alf -adrenoceptor according to claim 5, further characterized in that said antagonist is carvedilol.

9. The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor in the manufacture of a medicament to treat diseases in which the inhibition of Fas-mediated apoptosis is indicated. 10.- The use of a nonselective dual antagonist of β-adrenoceptor and alfaj_-adrenoceptor in accordance with the 10 claim 9 of formula I: wherein: R -R13 are independently -H or -OH; and A is a portion of formula II: (ID wherein R] _ is hydrogen, lower alkanoyl of up to 6 atoms 25 carbon or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a single bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a -CONH2 ~ group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 11. The use of a nonselective dual antagonist of β-adrenoceptor and α alpha-adrenoceptor according to claim 9 of formula III: sp) wherein: R] _ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2_0-; X is a single bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Rg are selected individually from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms , lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 12. The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor according to claim 9 further characterized in that said antagonist is carvedilol. 13. - The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor in the manufacture of a drug to block apoptosis induced by ischemia in cardiac cells. 14. - The use of a nonselective dual antagonist of β-adrenoceptor and alpha? _-Adrenoceptor according to claim 13 of formula I: (D wherein: R? F -R ^ 2 are independently -H or - OH, and A is a portion of formula II: (ID wherein R] _ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-; X is a single bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a -CONH2 ~ group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 15. The use of a nonselective dual antagonist of β-adrenoceptor and alpha] _-adrenoceptor according to claim 13 of formula III: (IH) wherein: R] _ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R 4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4 together with R 5 can represent -CH 2 -; X is a single bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms , lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 16. The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor according to claim 13 further characterized in that said antagonist is carvedilol. 17.- The use of a nonselective dual antagonist of β-adrenoceptor and alpha] _-adsrenoceptor in the manufacture of a drug to prevent or inhibit tissue remodeling, to treat autoimmune diseases, or to inhibit the growth of tumors and metastases . 18. The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ _-adrenoceptor according to claim 17 of formula I: (D where: R7-R13 are independently -H or -OH; and A is a portion of formula II: (ID wherein R ^ _ is hydrogen, lower alsanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl, R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; is hydrogen or lower alkyl of up to 6 carbon atoms, R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-; X is a single bond, - CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and Tetrahydronaphthyl; R5 and Rg are selected individually from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group -CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms. carbon, lower alkylsulfinyl up to 6 15 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. jtffe 19. - The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor in accordance with the 20 claim 17 of formula III: sp) wherein: R ^ _ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R3 is hydrogen or lower alkyl of up to 6 carbon atoms; R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2 ~ 0-; X is a single bond, -CH2 / oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a group CONH2-, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms , lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 20. The use of a nonselective dual antagonist of β-adrenoceptor and alpha ^ -adrenoceptor according to claim 17 further characterized in that said antagonist is carvedilol.