Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-19
2001-01-30
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S199000
Reexamination Certificate
active
06180649
ABSTRACT:
The present invention relates to certain neurotrophically active 1-(4-piperidyl)-benzimidazoles and their use in the treatment of neurodegenerative diseases and for the regeneration or prevention of degeneration of lesioned and damaged neurons.
BACKGROUND OF THE INVENTION
Growth (or neurotrophic) factors promote the differentiation, growth and survival of numerous peripheral and central nervous system neurons during development and adulthood. The molecular characteristics, regulation and signal transduction mechanism for a number of neurotrophic factors have been identified. The most therapeutically promising of these molecules are nerve growth factor (NGF), brain-derived neurotrophic factor (BNDF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and glial cell-line derived neurotrophic factor (GDNF).
Available data suggests that neurotrophic factors will be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Additionally neurotrophic factors have shown beneficial effects in animal models of peripheral nerve damage and toxin induced neuropathies (CNS Drugs, 2(6), 465-478 (1994)).
Various rat studies predict that compounds mimicking or enhancing the function of NGF can rescue septal colinergic neurons and alleviate benign forgetfulness and the memory impairment seen in senile dementia ( Science, Vol. 264, 772-774 (1994)).
Recent studies have shown that NGF has a neuroprotective effect on hippocampal neurons after cerebral ischaemia, which predicts a potential therapeutic role for NGF in the treatment of cerebral ischaemic neuronal damage (NeuroReport, vol. 6, No 4, 669-672 (1995)).
Growth factors initiate their biological action by binding to specific cell surface receptors. Binding of the growth factor to its receptor activates the intracellular signal transduction, leading to the generation of various second messengers and activation of enzyme cascades, involving tyrosine kinases and protein kinase C, and culminates in a biological effect. The intracellular signal transduction pathway is not yet fully understood.
NGF and related neurotrophins are large peptides, which makes them unlikely therapeutic candidates. Poor pharmacokinetic parameters (e.g. poor oral absorption and short in vivo half life), and administration to the target organs represent the major problems.
The identification of compounds with physicochemical properties different from the neurotrophins but capable of interaction with the neurotrophin-receptors is considered to be extremely important for the development of effective treatments of diseases and disorders responsive to neurotrophic factors.
The inventors of the present invention have found that the 1-(4-piperidyl)-benzimidazoles of formula (I) possess valuable neurotrophic activity. The neurotrophic activity found by the inventors of the present invention has not been ascribed to a specific step in the interaction between NGF and its receptor or in the NGF signal transduction pathway.
The neurotrophic activity of the compounds of formula (I), make them useful in the treatment of various nerve degenerative diseases, such as for example Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and in alleviating benign forgetfulness and the memory impairment seen in senile dementia or in connection with neurodegenerative diseases. Furthermore, the compounds are indicated to be useful in the treatment of neuropathy and especially peripheral neuropathy caused by e.g. genetic abnormalities and other conditions such as diabetes, polio, herpes and AIDS, and most especially neuropathy and peripheral neuropathy experienced by most cancer patients after or during chemotherapy.
The compounds of formula (I) are considered to be particularly useful in the treatment of traumatic lesions of peripheral nerves, the medulla, and/or the spinal cord, and in the treatment of cerebral ischaemia, e.g. ischaemic neuronal damage following cardiac arrest, stroke, or postasphyxial brain damage in newborns, or following near-drowning.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide a method for the treatment of disorders or diseases responsive to the activity of neurotrophic agents, such as traumatic lesions of peripheral nerves, the medulla, and/or the spinal cord, cerebral ischaemic neuronal damage, neuropathy and especially peripheral neuropathy, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or any other neurodegenerative disease, and memory impairment connected to dementia. Another object of the present invention is to provide a method for the prevention of the degenerative changes connected with the above diseases and disorders.
Still another object of the present invention is to provide novel 1-(4-piperidyl)-benzimidazoles, and novel pharmaceutical compositions containing these compounds which will be useful in the treatment of or prevention of the ailments mentioned above.
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following, alone or in combination:
A method of treating a disorder or disease of a living animal body, including a human, which is responsive to the activity of a neurotrophic agent, which comprises administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound selected from those having the formula:
wherein
the dotted bonds are optional extra bonds allowing any tautomeric isomers compatible with substituents X and R
3
;
R
3
is non-existing, hydrogen, or alkyl;
X is O, S, imino, alkoxy, alkylthio, or amino;
R
1
is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, acyl, acylalkyl, alkoxyalkyl, dialkoxyalkyl, or phenylalkyl which may be substituted with alkyl, halogen, amino, nitro or cyano; and
R
4
, R
5
, R
6
and R
7
independently of each other are hydrogen; halogen; amino; nitro; CN; CF
3
; COOH; COO-alkyl; alkyl; acyl; alkoxy; —(CH
2
)
n
,—OH wherein n is 0, 1, 2, or 3; —(CH
2
)
m
—O-alkyl wherein m is 0, 1,2, or 3; —(CH
2
)
p
—O-acyl wherein p is 0, 1,2, or 3; or a pharmaceutically acceptable addition salt thereof;
a method of treating a disorder or disease of a living animal body, including a human, which is responsive to the activation or potentiation of nerve growth factor(s), which comprises administering to such a living animal body, including a human, in need thereof a therapeutically-effective amount of a compound selected from those having the formula:
wherein
the dotted bonds are optional extra bonds allowing any tautomeric isomers compatible with substituents X and R
3
;
R
3
is non-existing, hydrogen, or alkyl;
X is O, S, imino, alkoxy, alkylthio, or amino;
R
1
is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, acyl, acylalkyl, alkoxyalkyl, dialkoxyalkyl, or phenylalkyl which may be substituted with alkyl, halogen, amino, nitro or cyano; and
R
4
, R
5
, R
6
and R
7
independently of each other are hydrogen; halogen; amino; nitro; CN; CF
3
; COOH; COO-alkyl; alkyl; acyl; alkoxy; —(CH
2
)
n
,—OH wherein n is 0, 1, 2, or 3; —(CH
2
)
m
—O-alkyl wherein m is 0, 1,2, or 3; —(CH
2
)
p
—O-acyl wherein p is 0, 1,2, or 3; or a pharmaceutically acceptable addition salt thereof;
a method of treating traumatic lesions of peripheral nerves, the medulla, and/or the spinal cord, cerebral ischaemic neuronal damage, neuropathy and especially peripheral neuropathy, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or any other neurodegenerative disease, of a living animal body, including a human, which comprises administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound selected from those having the formula:
wherein
the dotted bonds are optional extra bonds allowing any tautomeric isomers compati
Axelsson Oskar
Dahl Bjarne Hugo
Drejer Jorgen
Moldt Peter
Birch & Stewart Kolasch & Birch, LLP
Chang Ceila
NeroSearch A/S
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