Compositions and methods for treating CNS disorders
View Patent ↗The invention generally relates to thienopyridinone 5-HT 4 receptor modulators, and in particular the use of these compounds and their pharmaceutical compositions, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with serotonin action, such as in treating Alzheimer's disease, cognition disorders, depression, and anxiety.
1. A pharmaceutical composition comprising
a first compound of the formula
wherein R 1 is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (CH 2 ) p -aryl, where p is 1, 2, 3, or 4; R 2 and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof, the first compound being present in an amount which if administered alone does not substantially enhance memory; and
a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory.
2. The pharmaceutical composition of claim 1 , wherein R 1 is a (C 1 -C 8 ) alkyl selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, n-butyl or isobutyl; R 2 and R 3 taken together form a substituted or unsubstituted piperidine (N-containing six-membered cyclic ring); and n is 3.
3. The pharmaceutical composition of claim 1 , wherein the branched or unbranched haloalkyl group contains a halogen atom selected from the group consisting of F, Cl, Br, and I.
4. The pharmaceutical composition of claim 1 , wherein the first compound is 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt and/or ester thereof.
5. The pharmaceutical composition of claim 1 , wherein the amount of the first compound is sufficient to provide a dosage of less than about 0.25 mg/kg.
6. The pharmaceutical composition of claim 1 , wherein the amount of the first compound is sufficient to provide a dosage of between 0.01 and 0.25 mg/kg.
7. The pharmaceutical composition of claim 1 , wherein the second compound is selected from the group consisting of metrifonate, neostigmine, physostigmine, pyridostigmine, galantamine/galanthamine, donepezil, tacrine, ambenonium, demarcarium, edrophonium, rivastigmine, phenserine, mentane, and eptastigmine; or pharmaceutically acceptable salts and/or esters thereof.
8. The pharmaceutical composition of claim 1 , wherein the amount of the second compound is sufficient to provide a dosage of less than about 0.5 mg/kg.
9. The pharmaceutical composition of claim 1 , wherein the amount of the second compound is sufficient to provide a dosage of between 0.1 and 0.5 mg/kg.
10. A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to a patient in need thereof a therapy including a first compound having the formula
wherein R 1 is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (CH 2 ) p -aryl, where p is 1, 2, 3, or 4; R 2 and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof; and
a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory.
11. A method of enhancing memory in a patient in need thereof, administering to a patient in need thereof a therapy including a first compound having the formula
wherein R 1 is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (CH 2 ) p -aryl, where p is 1, 2, 3, or 4; R 2 and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof; and
a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory.
12. A method of treating Alzheimer's disease in a patient in need thereof, comprising diagnosing a patient in need of treatment and administering to a patient in need thereof a therapy including a first compound having the formula
wherein R 1 is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (CH 2 ) p , where p is 1, 2, 3, or 4; R 2 and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof, the first compound being present in an amount which if administered alone does not substantially enhance memory; and
a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory.
13. A method of enhancing memory in a patient in need thereof, comprising diagnosing a patient in need of treatment and administering to a patient in need thereof a therapy including a first compound having the formula
wherein R 1 is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (CH 2 ) p -aryl, where p is 1, 2, 3, or 4; R 2 and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof, the first compound being present in an amount which if administered alone does not substantially enhance memory; and
a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory.
14. The method of any one of claims 10 , 11 , 12 or 13 ; wherein the first and second compounds are administered together.
15. The method of any one of claims 10 , 11 , 12 or 13 , wherein the first and second compounds are administered separately.
16. The method of any one of claims 10 , 11 , 12 or 13 , wherein the amount of the first compound is sufficient to provide a dosage of less than about 0.25 mg/kg.
17. The method of any one of claims 10 , 11 , 12 or 13 , wherein the amount of the first compound is sufficient to provide a dosage of between 0.01 and 0.25 mg/kg.
18. The method of any one of claims 10 , 11 , 12 or 13 , wherein the amount of the second compound is sufficient to provide a dosage of less than about 0.5 mg/kg.
19. The method of any one of claims 10 , 11 , 12 or 13 , wherein the amount of the second compound is sufficient to provide a dosage of between 0.1 and 0.5 mg/kg.
20. A pharmaceutical composition comprising
a first compound of the formula
wherein R 1 is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (CH 2 ) p -aryl, where p is 1, 2, 3, or 4; R 2 and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof; and
a second compound which is a cholinesterase or acetylcholinesterase inhibitor, the first or second compound being present in an amount, which if administered alone, does not substantially enhance memory.
21. The pharmaceutical composition of claim 20 , wherein the first compound is 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt and/or ester thereof.
22. The pharmaceutical composition of claim 20 , wherein the amount of the first compound is sufficient to provide a dosage of less than about 0.25 mg/kg.
23. The pharmaceutical composition of claim 20 , wherein the second compound is selected from the group consisting of metrifonate, neostigmine, physostigmine, pyridostigmine, galantamine/galanthamine, donepezil, tacrine, ambenonium, demarcarium, edrophonium, rivastigmine, phenserine, mentane, and eptastigmine; or pharmaceutically acceptable salts and/or esters thereof.
24. The pharmaceutical composition of claim 20 , wherein the second compound is donepezil or pharmaceutically acceptable salt and/or ester thereof.
25. The pharmaceutical composition of claim 20 , wherein the amount of the second compound is sufficient to provide a dosage of less than about 0.5 mg/kg.