MXPA00003770A - Method for treating alzheimer's disease - Google Patents

Abstract

A method of treatment using a compound of Formula (I):wherein R7-R13 are independently -H or -OH;and A is H, -OH, or a moiety of Formula (II), wherein R1 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 valency bond, -CH2, oxygen or sulfur;Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;R5 and R6 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, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms;or R5 and R6 together represent methylenedioxy;or a pharmaceutically acceptable salt, thereof for treating amyloid diseases, and, thus, having utility in the treatment of Alzheimer's disease.

Description

METHOD FOR TREATING ALZHEIMER'S DISEASE FIELD OF THE INVENTION The present invention relates to a novel method for treating amyloid diseases, in particular Alzheimer's disease, using carbazole compounds of the formula I, preferably carvedilol or hydroxylated derivatives of carvedilol.

BACKGROUND OF THE INVENTION Amyloid diseases are characterized by the presence of protein aggregates arranged extracellularly but not crystalline, comprising ß-cross-fibrils / β-antiparallel sheets formed by incorrect folding of the protein. Amyloid disease is usually pathogenic. The most common clinical amyloidoses are Alzheimer's disease, chronic inflammation, multiple myelomas, type II diabetes and Creutzfeldt-Jacob disease. Amyloid diseases can cause heart problems in familial amyloid polyneuropathy of old age, and may also create the need for dialysis for a long time. An inhibitor of general amyloidosis could be beneficial in the treatment of amyloid diseases, since the formation of systemic amyloid is reversible, and existing amyloid deposits can be reabsorbed, once the deposition rate decreases or stops. Alzheimer's disease (AD) is the most common cause in senile dementia, and they suffer from 5 to 10% of all people over 65 years of age. Characteristic changes in the brain include senile plaques, neurofibrillary tangles, and degeneration and loss of neurons. Senile plaques are located extracellularly and contain deposits of fibrillar β-amyloid, whose most important component is the ßA4 peptide. The aggregated forms of ßA4 are toxic to neurons cultured in vitro [L, Iverson et al., Biochem. J., 311, 1-16 (1995)], and the formation and aggregation of ßA4 in the brain is an essential early mediator of AD pathology. Surprisingly, it has been found that carvedilol and compounds related to formula I are useful for treating amyloid diseases. In particular these compounds are useful for inhibiting the formation of the oligomeric aggregate of neurotoxic ßA4, and, therefore, would be useful in the treatment of Alzheimer's disease.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a novel method for using compounds that are dual nonselective β-adrenoceptor and ai-adrenoceptor antagonists, in particular the carbazolyl- (4) -oxypropanolamine compounds of the formula I, preferably carvedilol, in the treatment of the amyloid diseases. The present invention also provides a novel method of treatment using compounds that are dual non-selective β-adrenoceptor antagonists and ai-adrenoceptor, in particular the carbazolyl- (4) -oxypropanolamine compounds of the formula I, preferably carvedilol, to inhibit the formation of the oligomeric aggregate of neurotoxic ßA4 in mammals, particularly in humans. In particular, the present invention provides a method that uses said compounds to treat Alzheimer's disease. This invention further provides a method for treating Alzheimer's disease comprising the stepwise administration or in physical combination of a compound of formula I and a cognition enhancer, such as Memric.

BRIEF DESCRIPTION OF THE DRAWING Figure 1 is a graph of absorbance versus concentration of peptides in the inhibition of toxic aggregate formation of Beta-Amiloid 1-40.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for using compounds that are dual nonselective β-adrenoceptor and ai-adrenoceptor antagonists, in particular the carbazolyl- (4) -oxypropanolamine compounds of the formula I, preferably carvedilol, in the treatment of Amyloid diseases. In particular, the present invention provides a novel method for inhibiting the formation of the oligomeric aggregate of neurotoxic ßA4 by using compounds that are dual non-selective dual-adrenoceptor and o.-1-adrenoceptor antagonists. Preferably, this invention provides a novel method for inhibiting the information of the oligomeric aggregate of neurotoxic ßA4, in particular in the treatment of Alzheimer's disease using compounds of the formula I: wherein: R7-R? 3 are independently -H or -OH; and A is H, -OH, or a portion of formula II: wherein: R-i 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 valence bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R5 and R6 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. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and R1 together represent methylenedioxy; or a pharmaceutically acceptable salt thereof.

Most preferably, the present invention provides a novel method for inhibiting the formation of the neurotoxic ßA4 oligomer aggregate using compounds of the formula III: wherein: R-i 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 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R together with R5 can represent -CH2-0-; X is a valence bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R and Rβ 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. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or s and T together represent methylenedioxy; or a pharmaceutically acceptable salt thereof. These compounds are useful in the treatment of Alzheimer's disease. Most preferably, the present invention provides a novel method for inhibiting the formation of the oligomeric aggregate of neurotoxic ßA4 using a compound of formula IV, better known as carvedilol or (1- (carbazol-4-yloxy-3 - [[2- ( o-methoxyphenoxy) ethyl] amino] -2-propanol): (IV) This compound is useful in the treatment of Alzheimer's Because the compounds of the formula I are inhibitors of amyloidosis, these compounds would be useful not only in the treatment of Alzheirmer's disease, but would also be useful in the treatment of chronic inflammation, multiple myelomas, type II diabetes and Creutzfeldt-Jacob. In addition, the compounds of the present invention may be useful for treating cardiac problems in familial amyloid polyneuropathy of old age, and may also avoid the need for long-term dialysis. The compounds of formula I, of which carvedilol is an example, are novel multi-action drugs useful in the treatment of mild or moderate hypertension. It is known that carvedilol is both a competitive nonselective β-adrenoceptor antagonist and a vasodilator, and it is also an antagonist of calcium channels at high concentrations. The vasodilatory actions of carvedilol result mainly from the blockade of a-i-adrenoceptor, while the blocking activity of the β-adrenoceptor of the drug avoids reflex tachycardia when it is 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. & Ruffolo, R.R., Jr. (1990) Eur. J. Pharmacol., 176, 237-240; Nichols, A.J., Gellai, M & Ruffolo, R.R, Jr. (1991) Fundam. Clin. Pharmacol., 5, 25-38; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88; Ruffolo, R.R., Jr., Boyle, D.A., Venuti, R.P. & Lukas, M.A. (1991) Drugs of Today, 27, 465-492; and Yue, T.-L, Cheng, H., Lysko, P.G., Mckenna, P.J., Feuerstein, R., Gu, J., Lysko, K.A., Davis, L.L. & Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263, 92-98. The antihypertensive action of carvedilol is mediated mainly by reducing the total peripheral vascular resistance without causing the concomitant reflex changes in heart rhythm commonly associated with other antihypertensive agents. Willette, R.N., et al. supra; Nichols, A.J., et al. supra; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88. Likewise, carvedilol significantly reduces the magnitude of the infarct in the models of rats, canines and porcine infarcts. acute myocardium, Ruffolo, R.R., Jr., et al., Drungs of Today, supra, possibly as a consequence of its antioxidant action by attenuating lipid peroxidation initiated by free oxygen radicals. Yue, T.-L., et al. supra. In accordance with the present invention, the compounds which are dual non-selective dual-adrenoceptor antagonists and a-i-adrenoceptor, in particular the compounds of the formula I, preferably carvedilol, treat amyloid diseases. These compounds inhibit the formation of the oligomeric aggregate of neurotoxic ßA4, and, therefore, said compounds are useful for treating Alzheimer's disease. It is known that some of the compounds of the formula I are metabolites of carvedilol. Certain preferred compounds of the present invention, ie, the compounds of the formula I wherein A is the portion of the formula II wherein R1 is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho-OH, and R6 is -H, and one of R7, Rg, or Rio is -OH, are metabolites of carvedilol. The compounds of the formula I can be conveniently prepared as described in the patent of E.U.A. number 4,503,067. Reference should be made to said patent for its full description, 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 parenteral administration, the pharmaceutical composition will be in the form of a sterile injectable liquid stored in an appropriate container such as an ampule, or in the form of an aqueous or non-aqueous liquid suspension. The nature and composition of the pharmaceutical carrier, diluent or excipient will, of course, be dependent on the desired route of administration, for example either by intravenous or intramuscular injection. The pharmaceutical compositions of the compounds of formula I for use in accordance with the present invention can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted by the addition of an appropriate diluent or other pharmaceutically acceptable carrier before use. The liquid formulation is generally an aqueous solution regulated at its pH and isotonic. Examples of suitable diluents are normal isotonic saline, 5% dextrose in standard water or sodium or ammonium acetate solution regulated in its pH. Said formulation is especially suitable for parenteral administration, but it can also be used for oral administration or it can be introduced into a metered dose inhaler or nebulizer for insufflation. It may be advisable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxycellulose, robinia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds can be made in capsule or tablet form, or prepared in an emulsion or syrup for oral administration. Liquid or solid pharmaceutically acceptable carriers can be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, alabaster, magnesium stearate or stearic acid, talc, pectin, robinia, agar or gelatin. The vehicle can also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carriers varies but, preferably, it will be between about 20 mg to about 1 g per unit dose. Pharmaceutical preparations are made following conventional pharmacy techniques involving milling, mixing, granulation and compression, when necessary, for tablet forms; or grinding, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly orally or a soft gelatin capsule can be filled with it.

Doses in humans for the treatment of the disease according to the present invention should not exceed a dose range of about 3.125 to about 50 mg of the compounds of the formula I, particularly carvedilol, preferably delivered twice a day. As will be readily understood by a person skilled in the art, the patient should be initiated on a low dose regimen of the desired compound of formula I, particularly carvedilol, and should be monitored for the well-known symptoms of intolerance, eg, fainting, said compound. Once it has been found that the patient tolerates said compound, it should be taken slowly and in increment 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 case the patient presents medically acceptable tolerance of the compound for two weeks, the dose is doubled at the end of the two weeks and the patient is kept at the new and higher dose, for two more weeks, and is observed for signs of intolerance. This course continues until the patient is taken to the maintenance dose. This invention further provides a method for treating Alzheimer's disease which comprises the gradual administration or in physical combination of a compound of formula I and a cognition enhancer, such as Memric. The compound known as Memric is [R- (Z)] - (methoxyimino) - (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride. Methods for their preparation are described in EP-A-0392803, WO95 / 31456 and W093 / 17018. The dose of Memric will vary in the usual way with the severity of the disorder, the weight of the patient and the relative efficiency of the compound. However, as a general guide, appropriate daily doses below 0.01 mg / kg more in particular 0.003 mg / kg and lower, for example 0.0001-0.003 mg / kg, such as 0.00035-0.003mg / kg, 0.0007-0.003mg / kg , 0.0001-0.0007mg / kg or 0.00035-0.002mg / kg. The appropriate unit doses to achieve these daily doses are 5, 12.5, 25, 50 or 75 g, administered twice a day and, in case of 50 g, once a day. It will be appreciated that the actual preferred doses of the compounds used in the compositions of this invention vary according to the particular formulated composition, the mode of administration, the particular site of administration and the subject being treated. Unacceptable toxicological effects are not expected when the compounds of formula I are used in accordance with the present invention. The following examples are not intended to limit the scope of this invention, but are 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 Section Determination of the inhibition of beta-amyloid peptide aggregation by immunosensing Bachem UK beta-amyloid peptide (1-40) was dissolved in 0.1% acetic acid at 2 mg / ml and further diluted to 55 μg / ml in phosphate buffered saline (Sigma P4417) containing 0.02% Tween 20 (PBS-Tween). The possible inhibitors were dissolved in DMSO at 10 mg / ml and further diluted in PBS-Tween. For each possible inhibitor 45ul of 55ug / ml of peptide solution were incubated with 5ul of the appropriately diluted inhibitor overnight at 37 ° C in plates with shallow cavities of Linbro Titertek EIA II (ICN, EIA II Microplates, No. of cat 76-181-04). The plates were sealed during all incubations with Dynatech Labs plate sealants, catalog # 001-010 3501. For the immunoassay, plates (flat bottom 96-well plate, from Gibco BRL, catalog # 1-67008-A ) were coated (overnight at 4 ° C) with capture antibody 2F12, produced for beta-amyloid peptide 1-16, at 1: 3000 in PBS. After the coating, the antibody solution was aspirated and the plates were blocked by incubation for 60 minutes at 37 ° C with 1% gelatin v / v (Amersham RPN416), 2.5% goat serum v / v (Sigma G9023) in buffer Test pH (50mM Tris HCl, 150mM NaCl, 0.5% bovine gammaglobulins, 0.05% Tween 20, pH 7.4, passed through a 0.2um filter before use). After blockade, the plates were washed 4 x 250ul with a saline solution. Experimental Section Determination of the inhibition of beta-amyloid peptide aggregation by immunosorbent Beta-amyloid peptide (1-40) of Bachem UK was dissolved in 0.1% of acetic acid at 2 mg / ml and further diluted to 55 ug / ml in phosphate buffered saline (Sigma P4417) containing 0.02% Tween 20 (PBS-Tween). The possible inhibitors were dissolved in DMSO at 10 mg / ml and further diluted in PBS-Tween. For each possible inhibitor 45ul of 55ug / ml of peptide solution were incubated with 5ul of the appropriately diluted inhibitor overnight at 37 ° C in plates with shallow cavities of Linbro Titertek EIA II (ICN, EIA II Microplates, No. of cat 76-181-04). The plates were sealed during all incubations with Dynatech Labs plate sealants, catalog # 001-010 3501. For the immunoassay, plates (flat bottom 96-well plate, from Gibco BRL, catalog # 1-67008-A ) were coated (overnight at 4 ° C) with capture antibody 2F12, produced for beta-amyloid peptide 1-16, at 1: 3000 in PBS. After coating, the antibody solution was aspirated and the plates were blocked by incubation for 60 minutes at 37 ° C with 1% gelatin v / v (Amersham RPN416), 2.5% goat serum v / v (Sigma G9023) in test pH regulator (50mM Tris HCl, 150mM NaCl, 0.5% bovine gammaglobulins, 0.05% Tween 20, pH 7.4, passed through a 0.2um filter before use). After blocking, the plates were washed 4 x 250ul with phosphate buffered saline with Tween 20 (Sigma No of Cat P3563). To carry out the assay of the added peptide content of samples incubated with possible inhibitors, the samples were diluted with assay pH regulator and 50ul of aliquots containing the equivalent of 20ng of beta amyloid 1-40, were added to the cavities of the plate coated with 2F12. The detection antibody was a fragment of 2F12 fab conjugated to dextran-biotin: that antibody was diluted 1: 3000 in a pH regulator assay. The plate coated with 2F12 containing beta-amyloid 1-40 and 150ul of detection antibody was incubated overnight at 4 ° C. Subsequently the plates were washed (4 x 250ul) with a saline solution of pH regulated with phosphate with Tween 20. The quantification of peptide-antibody complex was achieved by the union of strepatavidin-Europium. To each cavity were added 200ul of streptavidin-Europium (Wallac, catalog # 1244-360) diluted 1: 500 in 0.5% BSA, 0.05% of? Globulin 0.01% Tween 20, 20uM DTPA (Sigma D 6518) in pH saline regulated with Tris pH 7.4. The plates were incubated at room temperature for 60 minutes before washing them with phosphate buffered saline. Finally, 200ul of improving solution (Wallac, catalog # 1244-105) were added to each well and the plate was shaken for 5 minutes at room temperature before measuring the emission by time resolved fluorescence on a Wallac Fluorescence Meter 1234 Delfia Beta amyloid 1-40, which had been added as described above, produced fluorescence readings 30 to 50 times greater than the background. This increase in fluorescence was avoided when the appropriate inhibitors were included in the incubation. The peptide that had not been pre-incubated produced fluorescence readings of only 2 to 3 times the background. Therefore, the increase in incubation is attributed to the detection of the aggregated peptide.

Determination of the inhibition of formation of toxic aggregates of beta-amyloid peptide 1-40 The beta-amyloid peptide (1-40) of Bachem UK was dissolved in 0.1% acetic acid at 2 mg / ml and further diluted to 55ug / ml in a phosphate buffered saline solution (Sigma P4417) containing 0.02% Tween 20 (PBS-Twoseen). The possible inhibitors were dissolved in DMSO at 10 mg / ml and further diluted in PBS-Tween. For each possible inhibitor, 45ul of 55ug / ml of peptide solution was incubated with 5ul of inhibitor diluted appropriately overnight at 37 ° C in plates with shallow cavities of Linbro Titertek EIA II and (IC, Microplates EIA II , No. of cat 76-181-04). The plates were sealed with Dynatech Labs plate sealants (cat # 001-010 3501). Bromide of (3 (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium-Sigma) MTT is a metabolic dye absorbed by viable cell mitochondria and metabolized, producing a crystalline product of blue formazan.

This product can be solubilized and the optical density of the blue solution generated is proportional to the activity (viability) of the mitochondria of the cells. For the toxicity evaluation, IMR32 human nueroblastoma cells (ECACC, Porton Down, UK) were placed at 6 x 10 4 cells / cm 2 in a 96-well microtiter plate (Nunc) in a volume of 100ul growth medium (DMEM) : Hams F12 1: 1) per cavity and incubated for 2 hours (CO2 incubator, 37 ° C). The incubated beta-amyloid 1-40 solutions containing the possible inhibitors were diluted in a growth medium to produce final beta-amyloid 1-40 concentrations (in contact with cells) from 0.1 to 10 ng / ml, and were added to the IMR32 cells. Vehicles are included in each trial. The plates were incubated overnight (CO2 incubator, 37 ° C). Then 50μl of MTT solution and (5mg / ml in DMEM: F12 / 0.4% DMSO) added to each well were added to each well and the plates were incubated for a further 4 hours (CO2 incubator, 37 ° C). Then, the medium was aspirated and the formazan product was dissolved by the addition of 200 ul of DMSO and 25 ul of Sorensen's glycine pH regulator (0.1 M glycine, 0.1 M NaCl, pH 10.5 with 0.1 M NaOH). . The plates were read at 590 nm and the inhibition of toxicity was evaluated as the difference in the reading of OD between the cells in the presence and absence of the possible inhibitors.

Results 1) Results of the Beta-amyloid 1-40 immunoassay (50ug / ml) was incubated, as described, with carvedilol or the like. The aggregated peptide content of the incubated material was determined by immunoassay and the inhibition was determined as the decrease in fluorescence reading observed to the maximum.

Carvedilol C ^, 38 uM (n = 6) R = 4-OH; IC ^ g uM írplO) IC ^ 450 uM (n = 3) R = 6-OH; IC5042 uM (n = 9) 2) Inhibition of formation of toxic aggregates in IMR32 cells In the following example, 50ug / ml beta-amyloid 1-40 were incubated overnight with 50ug / ml carvedilol (or vehicle). The sample was then diluted in a growth medium and the cells were stimulated with 0 to 10 ng / ml of beta-amyloid 1-40. In the absence of carvedilol, beta-amyloid 1-40 produced a concentration-dependent decrease in MTT reduction in the peptide range tested. Inclusion of carvedilol during the aggregation step resulted in a noticeable shift to the right in the concentration response curve, so that there was no decrease in MTT reduction at 0.1 to 1 ng / ml of peptide. The results are given in Figure 1. The foregoing illustrates the use of the compounds of this invention. However, this invention is not limited to the precise embodiments described herein, but includes all modifications within the scope of the following claims.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a dual non-selective dual-adrenoceptor antagonist and ai-adrenoceptor in the manufacture of a medicament for treating amyloid diseases in a mammal.

2. The use of the β-adrenoceptor antagonist compound and a dual non-selective adrenoceptor as claimed in claim 1, wherein the compound is a compound of the formula I: wherein: R7-R.3 are independently -H or -OH; and A is a portion of formula II: (II) 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, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R and RT 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 Re together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 3.- The use of the β-adrenoceptor antagonist and a? dual non-selective adrenoceptor as claimed in claim 1, wherein the compound is a compound of formula III: (III) 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, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R and Re 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 R6 together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 4. The use of the β-adrenoceptor antagonist compound and dual non-selective adrenoceptor as claimed in claim 1, wherein said antagonist is carvedilol. 5. The use of a β-adrenoceptor antagonist compound and a dual non-selective adrenoceptor in the manufacture of a medicament for treating Alzheimer's disease in a mammal. 6. The use of the β-adrenoceptor antagonist compound and a dual non-selective adrenoceptor as claimed in claim 5, wherein the compound is a compound of the formula I: wherein: R7-R-13 are independently -H or -OH; and A is a portion of formula II: (II) wherein: R1 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 R6 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. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Re together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 7. The use of the ß-adrenoceptor antagonist compound and dual non-selective adrenoceptor as claimed in claim 5, wherein the compound is a compound of the formula III: (lll) wherein: R-i 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 Re 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. carbon, lower alkylsulfinyl of up to 6 carbon atoms, and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and Re together represent methylenedioxy; and pharmaceutically acceptable salts thereof. 8. The use of the ß-adrenoceptor antagonist compound and dual non-selective adrenoceptor according to claim 5, wherein said antagonist is carvedilol. 9. The use of a non-selective dual-adrenoceptor antagonist and ai-adrenoceptor compound in combination or together with a cognition enhancer in the manufacture of a medicament for the treatment of Alzheimer's disease in a mammal. 10. The use according to claim 9, wherein the non-selective dual β-adrenoceptor and ai-adrenoceptor antagonist compound is carvedilol. 11. The use according to claim 9, wherein the cognition enhancer is Memric. SUMMARY OF THE INVENTION A treatment method that uses a compound of the formula wherein: R -R? 3 are independently -H or -OH; and A is H, -OH, or a portion of formula II: 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 valence bond, -CH2, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl, and tetrahydronaphthyl; R5 and R6 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. carbon, lower alkylsulfinyl of up to 6 carbon atoms and lower alkylsulfonyl of up to 6 carbon atoms; or R5 and R6 together represent methylenedioxy; or a pharmaceutically acceptable salt thereof, for treating amyloid diseases, and, therefore, has utility in the treatment of Alzheimer's disease. P00 / 506F