Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-31
2003-05-27
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S018000
Reexamination Certificate
active
06569865
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel spiroazabicyclic heterocyclic amine or pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. A further object is to provide active compounds that are potent ligands for nicotinic acetylcholine receptors (nAChR's).
BACKGROUND OF THE INVENTION
The use of compounds which bind nicotinic acetylcholine receptors in the treatment of a range of disorders involving reduced cholinergic function such as Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, Tourette's syndrome, and Parkinson's disease has been discussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego, Calif.; and in Williams et al. (1994) “Neuronal Nicotinic Acetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.
U.S. Pat. No. 5,468,875 discloses N-alkylcarbamic acid 1-azabicyclo[2.2.1]hept-3-yl esters, which are centrally active muscarinic agents useful in the treatment of Alzheimer's disease and other disorders.
N-(2-Alkoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters are disclosed in Pharmazie, vol. 48, 465-466 (1993) along with their local anesthetic activity. N-Phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters substituted at the ortho position on the phenyl ring are described as local anaesthetics in
Acta Pharm. Suecica,
7, 239-246 (1970). Furopyridines useful in controlling synaptic transmission are disclosed in WO 97/05139.
Spiroquinuclidine furopyridines useful as acetylcholine agonists are disclosed in WO 99/03859.
SUMMARY OF THE INVENTION
The invention generally relates to a compound having the formula:
or a pharmaceutically-acceptable salt thereof, and their uses in therapy and compositions containing them.
DISCLOSURE OF THE INVENTION
One aspect of the invention is a compound having the formula:
and any pharmaceutically-acceptable salts thereof.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound as described above, and a pharmaceutically-acceptable diluent or carrier.
Another aspect of the invention relates to the above pharmaceutical composition for use in the treatment of prophylaxis of human diseases or conditions in which activation of the &agr;
7
nicotinic receptor beneficial.
Another aspect of the invention relates to the above pharmaceutical composition for use in the treatment or prophylaxis of psychotic disorders or intellectual impairment disorders.
Another aspect of the invention relates to the above pharmaceutical composition for use in the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, or mania or manic depression Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, craving, pain, and for ulcerative colitis.
Another aspect of the invention relates to a use of a compound as described above in the manufacture of a medicament for the treatment or prophylaxis of human diseases or conditions in which activation of the &agr;
7
nicotinic receptor is beneficial.
Another aspect of the invention relates to a use of a compound as described above in the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders or intellectual impairment disorders.
Another aspect of the invention relates to the above use, wherein the condition or disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder.
Another aspect of the invention relates to the above use, wherein the disorder is anxiety, schizophrenia, or mania or manic depression.
Another aspect of the invention relates to the above use, wherein the disorder is Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is loss of cholinergic synapses.
Another aspect of the invention relates to the use of a compound as described above in the manufacture of a medicament for the treatment or prophylaxis of jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, craving, pain, and for ulcerative colitis.
Another aspect of the invention relates to a method of treatment or prophylaxis of human diseases or conditions in which activation of the &agr;
7
nicotinic receptor is beneficial which comprises administering a therapeutically effective amount of a compound as described above.
Another aspect of the invention relates to a method of treatment or prophylaxis of psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a compound as described above.
Another aspect of the invention relates to the above method, wherein the disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, or Attention Deficit Hyperactivity Disorder.
Another aspect of the invention relates to the above method, wherein the disorder is Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is loss of cholinergic synapses.
Another aspect of the invention relates to the above method, wherein the disorder is anxiety, schizophrenia or mania or manic depression.
Another aspect of the invention relates to a method of treatment or prophylaxis of jetlag, cessation of smoking, nicotine addiction, craving, pain, and for ulcerative colitis, which comprises administering a therapeutically effective amount of a compound as described above.
Structurally related 5-aryl spirofuropyridines are described in WO 99/03859, for example the compounds of Example 3 and Example 21 (respectively, “Compound 1” and “Compound 2”). Relative to these compounds, the compounds of the present invention, and, in particular, the compound of Example 1 (“Compound 3”), possess surprisingly advantageous properties. In particular, as illustrated by the data in Table 1, the compound has the advantage of surprisingly enhanced potency in binding to the &agr;
7
nAChR, as well as enhanced selectivity versus the &agr;
4
receptor. The significantly greater potency and selectivity of Compound 3 result in advantageous properties that distinguish the compound's use as a pharmaceutical by lowering the efficacious dose, lengthening the duration of action, and improving side effect profile.
TABLE 1
&agr;
7
binding
nAChR Binding Selectivity
Compound
(&agr;
7
Ki
M)
(Ratio &agr;
4
Ki/&agr;
7
Ki)
Compound 1
0.14
14000
Compound 2
0.550
10000
Compound 3
0.033
88000
Pharmaceutical Compositions
A further aspect of the invention relates to a pharmaceutical composition for treating or preventing a condition or disorder as exemplified below arising from dysfunction of nicotinic acetylcholine receptor neurotransmission in a mammal, preferably a human, comprising an amount of a compound of formula I, an enantiomer thereof or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and an inert pharmaceutically acceptable carrier.
For the above-mentioned uses the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg to about 20 mg/kg of animal body weight, preferably given in divided doses 1 to 4 tim
Astrazeneca AB
Davis Zinna Northington
Mitchell Kenneth F.
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