Treatment of Cognitive Disorders with Certain Alpha-7 Nicotinic Acid Receptor Agonists in Combination with Nicotine
A method for improving cognition comprising co-administering to a subject an alpha 7 agonist, or a pharmaceutically acceptable salt thereof and a tobacco-free nicotine dosage is described together with related compositions.
1 . A method for improving cognition and/or treating a cognitive disorder comprising co-administering to a subject a therapeutically effective amount of (1) a tobacco-free nicotine dosage; and (2) a compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 is hydrogen or (C 1 -C 6 )alkyl,
R 3 is hydrogen, halogen or (C 1 -C 6 )alkyl,
A is oxygen or sulfur, and
Z is halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino, heteroaryl-carbonylamino, arylcarbonylamino, (C 1 -C 4 )alkylsulfonylamino, di(arylsulfonyl)amino, (C 3 -C 6 )cycloalkylcarbonylmethyl or amino(hydroxyimino)methyl.
2 . The method according to claim 1 wherein R 2 is hydrogen, R 3 is hydrogen, A is sulfur, and Z is halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyoxy, (C 1 -C 6 )alkylthio, or (C 1 -C 6 )alkylamino.
3 . The method according to claim 1 wherein Z is heteroaryl-carbonylamino, arylcarbonylamino, (C 1 -C 4 )alkylsulfonylamino, di(arylsulfonyl)amino, (C 3 -C 6 )cycloalkylcarbonylmethyl or amino(hydroxyimino).
4 . The method according to claim 1 wherein Z is halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, or ethoxy.
5 . The method according to claim 1 wherein the compound of formula (I) is (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide.
6 . The method of claim 1 wherein the subject has been diagnosed with Alzheimer's disease or pre-Alzheimer's disease.
7 . The method of claim 1 wherein the subject has been diagnosed with mild to moderate Alzheimer's disease.
8 . The method of claim 1 wherein the subject has been diagnosed with moderate to severe Alzheimer's disease.
9 . The method of claim 1 wherein the subject has been diagnosed with schizophrenia or schizoaffective disorder.
10 . The method of claim 1 , wherein the method improves one or more of: learning, delayed memory, attention, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.
11 . The method of claim 1 wherein the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is administered at a dose that is therapeutically effective in the absence of a tobacco-free nicotine dosage.
12 . The method of claim 1 wherein one or both of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and a tobacco-free nicotine dosage is administered at a subclinical dose.
13 . The method of claim 1 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is administered at 0.03 to 1.0 mg/day.
14 . The method of claim 1 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at 0.03 to 0.5 mg/day.
15 . The method of claim 1 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at 0.03 to 0.3 mg/day.
16 . The method of claim 1 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at 0.03 to 0.1 mg/day.
17 . A pharmaceutical composition comprising (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and a tobacco-free nicotine dosage (TFN).
18 . A daily unit dosage pharmaceutical composition comprising 0.03 to 1.0 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, a TFN, and a pharmaceutically acceptable carrier.
19 . The daily unit dosage pharmaceutical composition of claim 18 comprising 0.03 to 0.5 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.
20 . The daily unit dosage pharmaceutical composition of claim 18 comprising 0.03 to 0.3 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.
21 . The pharmaceutical composition of claim 18 comprising 0.03 to 0.1 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.
22 . A packaged pharmaceutical comprising a package containing a unit dosage pharmaceutical composition comprising (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, and a transdermal patch comprising a tobacco-free nicotine dosage.