Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-25
2004-01-20
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S211080, C514S253040, C514S249000, C514S256000, C540S575000, C544S362000, C544S235000, C544S333000, C544S353000, C546S124000, C546S125000, C546S126000, C546S130000
Reexamination Certificate
active
06680328
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel 8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives which are found to be cholinergic ligands at the nicotinic Acetyl Choline Receptors.
Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
BACKGROUND ART
The endogenous cholinergic neurotransmitter, acetylcholine, exert its biological effect via two types of cholinergic receptors, the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic Acetyl Choline Receptors (nAChR).
As it is well established that muscarinic ACh receptors dominate quantitatively over nicotinic ACh receptors in the brain area important to memory and cognition, and much research aimed at the development of agents for the treatment of memory related disorders have focused on the synthesis of muscarinic ACh receptor modulators.
Recently, however, an interest in the development of nicotinic ACh receptor modulators has emerged. Several diseases are associated with degeneration of the cholinergic system i.e. senile dementia of the Alzheimer type, vascular dementia and cognitive impairment due to the organic brain damage disease related directly to alcoholism. Indeed several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency.
The present invention is devoted to the provision novel nicotinic receptor modulators useful for therapy or diagnosis, which modulators are structurally close analogues of the compounds described in WO 98/54181 (NeuroSearch A/S).
SUMMARY OF THE INVENTION
The present invention is devoted to the provision novel nicotinic receptor modulators, which modulators are useful for the treatment of diseases or disorders related to the cholinergic receptors, and in particular the nicotinic ACh receptor (nAChR).
Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.
In its first aspect the invention provides chemical compounds having the general formula
in labelled or unlabelled form, or any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof;
wherein
represents a single or a double bond;
R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, a mono- or polycyclic aryl group, or aralkyl; and
R
1
represents a group of the formula
wherein
R
2
represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, amino or a fluorescent group; or
R
1
represents an mono- or polycyclic aryl group, which aryl group is substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, OCF
3
, CN, amino, carbamoyl, nitro, a mono- or polycyclic aryl group, a monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclic group, and a group of the formula —X—R′(—Y—R″)
n
; wherein X and Y independently of each another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independently of each another represent alkyl or cycloalkyl; or a fluorescent group; or
R
1
represents a monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclic group, which heterocyclic group may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF
3
, OCF
3
, CN, sulfanyl, nitro, a mono- or polycyclic aryl group, a monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclic group, and a group of the formula —X—R′(—Y—R″)
n
; wherein X and Y independently of each another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independently of each another represent alkyl or cycloalkyl; or a fluorescent group; or
R
1
represents a bi-cyclic heterocyclic group composed of a monocyclic 5- or 6-membered heterocyclic group with one heteroatom, fused to a benzene ring or fused to another monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclic group, all of which is substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF
3
, OCF
3
, CN, sulfanyl, amino, nitro, a mono- or polycyclic aryl group, a monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclic group, and a group of the formula —X—R′(—Y—R″)
n
; wherein X and Y independently of each another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independently of each another represent alkyl or cycloalkyl; or a fluorescent group.
In a second aspect the invention provides pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
In a third aspect the invention provides an assay kit comprising the composition according to the invention in a unit dosage form in a suitable container.
In a fourth aspect the invention relates to a use of the chemical compound of the invention for the manufacture of a medicament for the treatment or alleviation of a disease or disorder of a living animal body, including a human, which disease or disorder is responsive to the action of a nicotinic Acetyl Choline Receptor (nAChR) modulator.
A fifth aspect of the invention relates to the use of the chemical compound of the invention or any of its enantiomers or any mixture thereof, in labelled or unlabelled form, for the manufacture of a diagnostic agent for the diagnosis of a disorder or disease of a living animal body, including a human, which disease or disorder is responsive to the action of a nicotinic Acetyl Choline Receptor (nAChR) modulator, or a serotonin receptor modulator.
A sixth aspect of the invention provides a method for the preparation of the compounds according to the invention, which method comprises
A) the step of reacting a compound having the formula
wherein R is as defined herein, with a compound of the formula R
1
—Li,
wherein R
1
is as defined herein, followed by dehydration of the compound obtained; or
B) the step of reacting a compound having the formula
wherein R is as defined herein, with a compound of formula R
1
—X,
wherein R
1
is as defined herein,
and X represents halogen, boronic acid, or trialkylstannyl; or
C) the step of reducing a compound having the formula
wherein R
1
is as defined herein.
A seventh aspect of the invention provides a method of the treatment or alleviation of a disease or disorder of a living animal body, including a human, which diseas
Nielsen Elsebet Ostergaard
Nielsen Simon Feldbaek
Olsen Gunnar M.
Peters Dan
Birch Stewart Kolasch & Birch, LLP.
Huang Evelyn Mei
NeuroSearch A/S
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