Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-13
2002-03-19
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06358990
ABSTRACT:
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 Formula I, preferably carvedilol or hydroxylated derivatives of carvedilol.
BACKGROUND OF THE INVENTION
Amyloid diseases are characterized by the presence of extracellular ordered, but non-crystalline, protein aggregates comprised of cross-&bgr;-fibril/antiparallel &bgr;-sheets formed through incorrect protein folding. Amyloid 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 may cause cardiac problems in old age familial amyloid polyneuropathy, and may also create the need for long-term dialysis. A general amyloidosis inhibitor could be beneficial in treating amyloid diseases, since systemic amyloid formation is reversible, and existing amyloid deposits may be resorbed, once the rate of deposition is slowed or halted.
Alzheimer's disease (AD) is the most common cause of dementia in old age, and afflicts 5-10% of all individuals over the age of 65 years. Characteristic changes in the brain include senile plaques, neurofibrillary tangles, and the degeneration and loss of neurons. Senile plaques are located extracellularly and contain deposits of fibrillar &bgr;-amyloid, the most important component of which is the &bgr;A4 peptide. Aggregated forms of &bgr;A4 are toxic to cultured neurons in vitro [L. Iverson et al.,
Biochem. J
., 311, 1-16 (1995)], and the formation and aggregation of &bgr;A4 in the brain is an essential early mediator of the pathology of AD.
Surprisingly, it has been found that carvedilol and related Formula I compounds are useful for treating amyloid diseases. In particular these compounds are useful in inhibiting the formation of the neurotoxic &bgr;A4 oligomeric aggregate, and, thus, they would be useful in the treatment of Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention provides a new method of using compounds which are dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, in the treatment of amyloid diseases.
The present invention also provides a new method of treatment using compounds which are dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting the formation of the neurotoxic &bgr;A4 oligomeric aggregate, in mammals, particularly in humans. In particular, the present invention provides a method using said compounds for treating Alzheimer's disease.
This invention further provides a method for treating Alzheimer's disease which comprises administering stepwise or in physical combination a compound of Formula I and a cognition enhancer, such as Memric.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a new method of using compounds which are dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, in the treatment of amyloid diseases. In particular, the present invention provides a new method for inhibiting the formation of the neurotoxic &bgr;A4 oligomeric aggregate using compounds which are dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists. Preferably, this invention provides a new method for inhibiting the formation of the neurotoxic &bgr;A4 oligomeric aggregate, in particular in the treatment of Alzheimer's disease, using compounds of Formula I:
wherein:
R
7
-R
13
are independently —H or —OH; and
A is H, —OH, or a moiety of Formula II:
wherein:
R
1
is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
R
2
is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
R
3
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
—O—;
X is a valency bond, —CH
2
, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
R
5
and R
6
are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH
2
— 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
R
5
and R
6
together represent methylenedioxy;
or a pharmaceutically acceptable salt thereof.
More preferably, the present invention provides a new method for inhibiting the formation of the neurotoxic &bgr;A4 oligomeric aggregate using compounds of Formula III:
wherein:
R
1
is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
R
2
is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
R
3
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
—O—;
X is a valency bond, —CH
2
, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
R
5
and R
6
are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH
2
— 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
R
5
and R
6
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 new method for inhibiting the formation of the neurotoxic &bgr;A4 oligomeric aggregate using a compound of Formula IV, better known as carvedilol or (1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol):
This compound is useful in the treatment of Alzheimer's disease.
Since Formula I compounds are amyloidosis inhibitors, these compounds would be useful not only in the treatment of Alzheimer's disease, but they would also be useful in the treatment of chronic inflammation, multiple myelomas, Type II diabetes and Creutzfeldt-Jacob disease. Additionally, the compounds of the instant invention may be useful in treating cardiac problems in old age familial amyloid polyneuropathy, and they may also prevent the need for long-term dialysis.
Formula I compounds, of which carvedilol is exemplary, are novel multiple action drugs useful in the treatment of mild to moderate hypertension. Carvedilol is known to be both a competitive non-selective &bgr;-adrenoceptor antagonist and a vasodilator, and is also a calcium channel antagonist at higher concentrations. The vasodilatory actions of carvedilol result primarily from &agr;
1
-adrenoceptor blockade, whereas the &bgr;-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. & 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,
Howlett David Robert
Mitchell Davina Elizabeth
Boehringer Mannheim Pharmaceuticals Corp.
Criares Theodore J.
Kinzig Charles M
McCarthy Mary E.
Venetianer Stephen
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