Use of peptidic bradykinin antagonists for the treatment and...

Details Use of peptidic bradykinin antagonists for the treatment and... Use of peptidic bradykinin antagonists for the treatment and...

1997-10-14

2001-06-12

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S015800, C530S314000

Reexamination Certificate

active

06245736

ABSTRACT:

The present invention relates to the use of bradykinin antagonists for the treatment and/or prevention of Alzheimer's disease.
Bradykinin and related peptides are potent vasoactive, endogenous substances causing inflammation and pain. The use of bradykinin antagonists as agents for the control of conditions which are mediated, triggered and supported by bradykinin has been disclosed in EP-A-0 370 453, which is specifically incorporated by reference herein.
The importance of localized inflammation for the destructive changes in the brains of patients with Alzheimer's disease is increasingly recognized. Inflammatory changes lead to chronicity and to continuing destruction of the brain, and thus to severe dementia (J. Rogers, Inflammation as a pathogenic mechanism in Alzheimer's disease, Arzneimittelforschung 1995; 45 (3A),439-442). It was previously unknown that bradykinin, a strongly inflammatory mediator in the periphery, could play a part in Alzheimer's disease. This is to be attributed to the fact that there was no evidence of the release of bradykinin in the brains of patients with Alzheimer's disease. The inactive high molecular weight precursors from which bradykinin is released cannot pass directly into the brain (neuronal tissue), namely because of the low permeability of the blood-brain barrier.
Other investigations have shown that the Alzheimer's protein &bgr;/A4 can stimulate the release bradykinin from the endothelium of vascular walls. The essential pathological changes of Alzheimer's disease are ascribed to the Alzheimer protein&bgr;/A4. See, for example, C. L. Joachim and D. J. Selkoe, The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease, Alzheimer Dis. Assoc. Disord., 1992 Spring, vol. 6(1), pp. 7-34. If the release of the inflammatory bradykinin is shown to be due to a mechanism which is specific for Alzheimer's disease, bradykinin will become a pathophysiological factor of first rank, via which the Alzheimer's protein can mediate its destructive action. This applies especially to inflammation, whose importance for the destructive changes is increasingly recognized, since bradykinin is one of the most potent endogenous inflammatory substances.
Beside the inflammatory action, bradykinin additionally has two other properties through which it can contribute to the destructive changes in Alzheimer's disease. Bradykinin stimulates CNS neurons. In the case of severe stimulation, this leads to calcium overloading of the affected cells, with subsequent cell death. On moderate stimulation, bradykinin only becomes a false transmitter, which inadequately stimulates neurons. Such an inadequate stimulation of neurons, which actually should not be stimulated at all, can sensitively interfere with the process of information processing in the brain and contribute to the typical brain power disorders, the latter mechanism, induced by moderate stimulation, appearing to be reversible.
As a vasoactive mediator, bradykinin increases, as is known, the permeability of the blood-brain barrier. This leads to the fact that the precursors of bradykinin can first pass from the blood vessels into the brain, in order to display their destructive action there.
Surprisingly, it has now been found that bradykinin antagonists are suitable agents for the treatment and prevention of Alzheimer's disease. This relates both to the intention to prevent progress of the disease and to treat symptoms which have already appeared. Moreover, bradykinin antagonists can also be used preventively in order to prevent the origination of Alzheimer's disease if in the future it should become possible by means of suitable diagnostic measures to predict a later outbreak of the disease.
Suitable compounds are bradykinin antagonists which inhibit the effects of the Alzheimer's protein amyloid (&bgr;/A4) on isolated endothelial cells.
Preferred bradykinin antagonists are, inter alia, the peptides of the formula (I):
Z—P—A—B—C—E—F—K—(D)Q—G—M—F′—I  (I)
in which
Z is
a
1
) hydrogen, (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkanoyl, (C
1
-C
8
)-alkoxycarbonyl, (C
3
-C
8
)-cycloalkyl, (C
4
-C
9
)-cycloalkanoyl, or (C
1
-C
8
)-alkylsulfonyl,
(1) in which 1, 2 or 3 hydrogen atoms in each of (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkanoyl, (C
1
-C
8
)-alkoxycarbonyl, (C
3
-C
8
)-cycloalkyl, (C
4
-C
9
)-cycloalkanoyl or (C
1
-C
8
)-alkylsulfonyl are optionally replaced by 1, 2 or 3 identical or different radicals selected from carboxyl, (C
1
-C
4
)-alkyl, (C
1
-C
8
)-alkylamino, (C
6
-C
10
)-aryl-(C
1
-C
4
)-alkylamino, hydroxyl, (C
1
-C
4
)-alkoxy, halogen, Di-(C
1
-C
8
)-alkylamino, Di-{(C
6
-C
10
)-aryl-(C
1
-C
4
)}-alkylamino, carbamoyl, phthalimido, 1,8-naphthalimido, sulfamoyl, (C
1
-C
4
)-alkoxycarbonyl, (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryl-(C
1
-C
5
)-alkyl, NHR(1), {(C
1
-C
4
)-alkyl}NR(1) or {(C
6
-C
10
)-aryl-(C
1
-C
4
)-alkyl}NR(1), where R(1) is hydrogen or a urethane protective group, or
(2) 1 or 2 hydrogen atoms in each of (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkanoyl, (C
1
-C
8
)-alkoxycarbonyl, (C
3
-C
8
)-cycloalkyl, (C
4
-C
9
)-cycloalkanoyl or (C
1
-C
8
)-alkylsulfonyl are replaced by 1 or 2 identical or different radicals selected from carboxyl, amino, (C
1
-C
8
)-alkylamino, hydroxyl, (C
1
-C
4
)-alkoxy, halogen, di-(C
1
-C
8
)-alkylamino, carbamoyl, sulfamoyl, (C
1
-C
4
)-alkoxycarbonyl, (C
6
-C
14
)-aryl and (C
6
-C
14
)-aryl-(C
1
-C
5
)-alkyl, and 1 hydrogen atom in each of (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkanoyl, (C
1
-C
8
)-alkoxycarbonyl, (C
3
-C
8
)-cycloalkyl, (C
4
-C
9
)-cycloalkanoyl, or (C
1
-C
8
)-alkylsulfonyl is optionally replaced by a radical selected from (C
3
-C
8
)-cycloalkyl, (C
1
-C
6
)-alkylsulfonyl, (C
1
-C
6
)-alkylsulfinyl, (C
6
-C
14
)-aryl-(C
1
-C
4
)-alkylsulfonyl, (C
6
-C
14
)-aryl-(C
1
-C
4
)-alkylsulfinyl, (C
6
-C
14
)-aryl, (C
6
-C
14
)-aryloxy, (C
3
-C
13
)-heteroaryl and (C
3
-C
13
)-heteroaryloxy,
a
2
) (C
6
-C
14
)-aryl, (C
7
-C
15
)-aroyl, (C
6
-C
14
)-arylsulfonyl, (C
3
-C
13
)-heteroaryl, or (C
3
-C
13
)-heteroaroyl, or
a
3
) carbamoyl which can optionally be substituted on the nitrogen by (C
1
-C
8
)-alkyl, (C
6
-C
14
)-aryl or (C
6
-C
14
)-aryl-(C
1
-C
5
)-alkyl, where for the radicals defined under a
1
), a
2
) and a
3
) the aryl, heteroaryl, aroyl, arylsulfonyl and heteroaroyl groups are optionally substituted by 1, 2, 3 or 4 radicals selected from carboxyl, amino, nitro, (C
1
-C
8
)-alkylamino, hydroxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
6
-C
14
)-aryl, (C
7
-C
15
)-aroyl, halogen, cyano, di-(C
1
-C
8
)-alkylamino, carbamoyl, sulfamoyl and (C
1
-C
6
)-alkoxycarbonyl;
P is a direct bond or a radical of the formula (II),
—NR(2)—(U)—CO—  (II)
in which
R(2) is hydrogen, methyl or a urethane protective group,
U is (C
3
-C
8
)-cycloalkylidene, (C
6
-C
14
)-arylidene, (C
3
-C
1 3
)-heteroarylidene, (C
6
-C
14
)-aryl-(C
1
-C
6
)-alkylidene, each of which can optionally be substituted, or is {CHR(3)}
n
, where n is 1-8, preferably 1-6, and
R(3) independently of one another is hydrogen, (C
1
-C
6
)-alkyl, (C
3
-C
8
)-cycloalkyl, (C
6
-C
14
)-aryl or (C
3
-C
13
)-heteroaryl, which with the exception of the hydrogen are in each case optionally monosubstituted by amino, substituted amino, amidino, substituted amidino, hydroxyl, carboxyl, carbamoyl, guanidino, substituted guanidino, ureido, substituted ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 1,8-naphthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl,
where the substituted amino preferably is —N(A′)—Z, the substituted amidino preferably is —(NH)C—NH—Z, the substituted guanidino preferably is —N(A′)—C(N(A′))—NH—Z and the substituted ureido preferably is —C(O)—N(A′)—Z, in which A′ independently of one another is Z, Z being defined as under a
1
) or a
2
),
or in which
U is {CHR(3)}
n
, where n is 1-8, preferably 1-6, an

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