Fused heterocyclic compounds and their use in the treatment...

Details Fused heterocyclic compounds and their use in the treatment... Fused heterocyclic compounds and their use in the treatment...

2001-06-07

2003-06-10

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S115000

Reexamination Certificate

active

06576641

ABSTRACT:

TECHNICAL FIELD
The present invention relates to certain fused heterocyclic compounds and their use in the treatment of neurodegenerative diseases and for the regeneration or prevention of degeneration of lesioned and damaged neurons.
BACKGROUND ART
Growth factors (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 neuropathy [
CNS Drugs
1994 2 (6) 465-478].
Various rat studies predict that compounds mimicking or enhancing the function of NGF can rescue septal cholinergic neurons and alleviate benign forgetfulness and the memory impairment seen in senile dementia [
Science
1994 264 772-774].
Recent studies have shown that NGF has a neuro protective effect on hippocampal neurons after cerebral ischaemia, which predicts a potential therapeutic role for NGF in the treatment of cerebral ischaemic neuronal damage [
NeuroReport
1995 6 (4) 669-672].
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.
There is a continued need for the development of new compounds capable of interacting with the neurotrophin-receptors, and which shows physicochemical properties different from the neurotrophins.
SUMMARY OF THE INVENTION
According to the present invention new neutrophically active compounds are provided. The neurotrophic activity 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 the invention makes them useful for the treatment or prevention of various degenerative diseases of the nerves, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), and for the alleviation of benign forgetfulness and the memory impairment seen in senile dementia or in connection with neurodegenerative diseases.
Moreover, the compounds of the invention have shown to be useful for the treatment of neuropathy and in particular 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 the present invention are considered to be particularly useful for 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.
In its first aspect the invention provides novel compounds characterized by the general formula (I)
wherein
n is 0 or 1;
m is 0 or 1;
A represents O, N—R′ or S—R′;
B represents O or N—R′ or S—R′ or CH—R′;
C represents O or N—R″ or S—R″ or CH—R″;
wherein R′ and R″ independently of each another represents hydrogen or a C
1-8
-alkyl group, a C
2-8
-alkenyl group, a C
2-8
-alkynyl group, a C
3-8
-cycloalkyl group, a C
3-8
-cycloalkyl-C
1-8
-alkyl group, which groups may be substituted one or more times with a substituent selected from the group consisting of hydroxy, C
1-8
-alkyl, C
1-8
-alkoxy, halogen, NO
2
, CN, NH
2
, NH(C
1-8
-alkyl), and N(C
1-8
-alkyl)
2
;
or C represents an aralkyl group, which aryl group is optionally substituted one or more times with a substituent selected from the group consisting of hydroxy, C
1-8
-alkyl, C
1-8
-alkoxy, halogen, NO
2
, CN, NH
2
, NH(C
1-8
-alkyl), and N(C
1-8
-alkyl)
2
;
R
1
and R
2
independently of each another represents hydrogen, a C
1-8
-alkyl group, or a group of the formula (CH
2
)
k
-aryl, wherein k is 0, 1 or 2, and which aryl group may optionally be substituted one or more times with a substituent selected from the group consisting of hydroxy, C
1-8
-alkyl C
1-8
-alkoxy, halogen, NO
2
, CN, NH
2
, NH(C
1-8
-alkyl), N(C
1-8
-alkyl)
2
, and SO
2
NR
3
R
4
;
or R
1
and R
2
independently of each another represents a group of the formula (CH
2
)
k
-heteroaryl, wherein k is 0, 1 or 2, and which heteroaryl group may optionally be substituted one or more times with a substituent selected from the group consisting of hydroxy, C
1-8
-alkyl C
1-8
-alkoxy, halogen, NO
2
, CN, NH
2
, NH(C
1-8
-alkyl), N(C
1-8
-alkyl)
2
, and SO
2
NR
3
R
4
:
wherein R
3
and R
4
independently of each another represents hydrogen or a C
1-8
-alkyl group, or R
3
and R
4
together form a 5- to 8-membered ring which is partially or completely saturated;
or a pharmaceutically acceptable addition salt thereof.
In another aspect the invention provides a pharmaceutical composition comprising a therapeutically-effective amount of the compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
In a third aspect the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or alleviation or prevention of a disease or a disorder or a condition of a living animal body, including a human, which disease or disorder or condition is responsive to the activity of a neurotrophic agent.
In a fourth aspect the invention provides a method for treatment or alleviation or prevention of a disease or a disorder or a condition of a living animal body, including a human, which disease or disorder or condition is responsive to the activity of a neurotrophic agent, and which method comprises administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound of the invention.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.
DETAILED DISCLOSURE OF THE INVENTION
Novel Neutrophic Compounds
In its first aspect the invention provides novel chemical compounds of the general formula (I)
wherein
n is 0 or 1;
m is 0 or 1;
A represents O, N—R′ or S—R′;
B represents O or N—R′ or S—R′ or CH—R′;
C represents O or N—R″ or S—R″ or CH—R″;
wherein R′ and R″ independently of each another represents hydrogen or a C
1-8
-alkyl group, a C
2-8
-alkenyl group, a C
2-8
-alkynyl group, a C
3-8
-cycloalkyl group, a C
3-8
-cycloalkyl-C
1-8
-alkyl group, which groups may be substituted one or more times with a substituent selected from the group consisting of hydroxy, C
1-8
-alkyl, C
1-8
-alkoxy, halogen, NO
2
, CN, NH
2
, NH(C
1-8
-alkyl), and N(C
1-8
-alkyl)
2
;
or C represents an aralkyl group,

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