US2015313884A1PendingUtilityA1
Use of alpha 7 nicotinic acetylcholine receptor agonists
Est. expiryJan 15, 2033(~6.5 yrs left)· nominal 20-yr term from priority
Inventors:Markus FendtDominik FeuerbachSjoerd Johannes FinnemaBaltazar Gomez-MancillaChrister HalldinDonald JohnsCristina Lopez-LopezKevin Hall McallisterJudit SovagoMarkus Weiss
A61K 31/444A61K 31/135A61K 45/06A61K 47/02A61K 9/0019A61K 31/08
50
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Claims
Abstract
The invention concerns the use of certain alpha 7 nicotinic acetylcholine receptor agonist for the facilitation of emergence from general anesthesia.
Claims
exact text as granted — not AI-modified1 . An alpha 7 nicotinic acetylcholine receptor agonist for use in the facilitation of emergence from general anesthesia;
wherein said alpha 7 nicotinic acetylcholine receptor agonist is (i) a compound of formula (I)
wherein
L 1 is —CH 2 —; L 2 is —CH 2 —CH 2 —; and L 3 is —CH 2 — or —CH(CH 3 )—; or
L 1 is —CH 2 —CH 2 —; L 2 is —CH 2 —; and L 3 is —CH 2 —CH 2 —;
L 4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R 1 is methyl;
X 1 is —O— or —NH—;
A 2 is selected from
wherein the bond marked with the asterisk is attached to X 1 ;
A 1 is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R 2 , each R 2 independently is C 1-6 alkyl, C 1-6 halogenalkyl or halogen; or
(ii) a compound selected from the group consisting of
4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane;
(4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane;
4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane;
4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane;
N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide
N-(1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;
7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino-(2,3-h)(3)-benzazepine;
3-[1-(2,4-Dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3]bipyridinyl;
N-methyl-1-{5-[3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2S)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide;
5-{5-[(endo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-3-yl}-1H-indole;
(2′R)-spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];
1,4-Diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo-phenyl ester; and
5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;
in free base form or in acid addition salt form.
2 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 1 for use in the facilitation of emergence from general anesthesia in a subject treated with a general anesthetic agent,
wherein the general anesthetic agent is selected from an intravenous anesthetic and an inhalation anesthetic, or a combination thereof.
3 . (canceled)
4 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 2 , wherein the general anesthetic agent is selected from propofol; etomidate; a barbiturate; a benzodiazepine; ketamine, a halogenated ether, alone or combined with nitrous oxide; halothane; and xenon; or a combination thereof.
5 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 2 , wherein the general anesthetic agent is a combination of ketamine for the induction period and sevoflurane for the maintenance period.
6 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 2 , wherein the subject is a perioperative patient.
7 . (canceled)
8 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 2 , wherein the agonist is administered by intravenous administration, and wherein the intravenous administration of the agonist occurs when the subject is no longer being treated with the general anesthetic agent.
9 - 10 . (canceled)
11 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 8 , wherein the agonist administration is continuous intravenous infusion of 1 to 200 mg of the agonist within 10 to 60 minutes.
12 . An alpha 7 nicotinic acetylcholine receptor agonist according to claim 1 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form.
13 - 14 . (canceled)
15 . A pharmaceutical composition in the form of an aqueous solution for intravenous administration comprising
an alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 1 ; and at least one pharmaceutically acceptable excipient.
16 . An alpha 7 nicotinic acetylcholine receptor agonist for use in the treatment, amelioration, prevention or delay of progression of fatigue;
wherein said alpha 7 nicotinic acetylcholine receptor agonist is (i) a compound of formula (I)
wherein
L 1 is —CH 2 —; L 2 is —CH 2 —CH 2 —; and L 3 is —CH 2 — or —CH(CH 3 )—; or
L 1 is —CH 2 —CH 2 —; L 2 is —CH 2 —; and L 3 is —CH 2 —CH 2 —;
L 4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R 1 is methyl;
X 1 is —O— or —NH—;
A 2 is selected from
wherein the bond marked with the asterisk is attached to X 1 ;
A 1 is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R 2 , each R 2 independently is C 1-6 alkyl, C 1-6 halogenalkyl or halogen; or
(ii) a compound selected from the group consisting of
4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
(4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane;
4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide N-(1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;
7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino-(2,3-h)(3)-benzazepine;
3-[1-(2,4-Dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;
N-methyl-1-{5-[3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2S)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide;
5-{5-[(endo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-3-yl}-1H-indole;
(2′R)-spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];
1,4-Diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo-phenyl ester; and
5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;
in free base form or in acid addition salt form.
17 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 16 , wherein the fatigue is fatigue associated with multiple sclerosis, and is (i) caused by sleep deprivation, depression or general disabilities or (ii) lassitude.
18 . (canceled)
19 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 16 , wherein the fatigue is chronic fatigue syndrome.
20 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 16 , wherein the fatigue is fatigue associated with an infectious disease, and wherein the fatigue is associate with HIV infection.
21 . (canceled)
22 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 16 , wherein the daily dosage of said agonist is from 1 to 100 mg.
23 . (canceled)
24 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 16 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2,2,2]octane in free base form or in acid addition salt form and wherein the daily dosage of said agonist is from 1 to 100 mg.
25 - 27 . (canceled)
28 . A method of treatment amelioration, prevention or delay of progression of fatigue in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 16 .
29 - 30 . (canceled)
31 . An alpha 7 nicotinic acetylcholine receptor agonist for use in the treatment, amelioration, prevention or delay of progression of narcolepsy, excessive daytime sleepiness, nocturnal sleep disruption or cataplexy;
wherein said alpha 7 nicotinic acetylcholine receptor agonist is (i) a compound of formula (I)
wherein
L 1 is —CH 2 —; L 2 is —CH 2 —CH 2 —; and L 3 is —CH 2 — or —CH(CH 3 )—; or
L 1 is —CH 2 —CH 2 —; L 2 is —CH 2 —; and L 3 is —CH 2 —CH 2 —;
L 4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R 1 is methyl;
X 1 is —O— or —NH—;
A 2 is selected from
wherein the bond marked with the asterisk is attached to X 1 ;
A 1 is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R 2 , each R 2 independently is C 1-6 alkyl, C 1-6 halogenalkyl or halogen; or
(ii) a compound selected from the group consisting of
4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
(4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane;
4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1 azatricyclo[3.3.1.1 3,7 ]decane;
N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide
N-(1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;
N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;
(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;
7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino-(2,3-h)(3)-benzazepine;
3-[1-(2,4-Dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;
N-methyl-1-{5-[3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2S)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;
(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide;
5-{5-[(endo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole;
5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-3-yl}-1H-indole;
(2′R)-spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];
1,4-Diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo-phenyl ester; and
5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;
in free base form or in acid addition salt form.
32 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 31 for use in the treatment, amelioration, prevention or delay of progression of narcolepsy, wherein the narcolepsy is one of: narcolepsy with cataplexy, narcolepsy without cataplexy, or narcolepsy due to a medical condition.
33 - 35 . (canceled)
36 . An alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 31 for use in the treatment, amelioration, prevention or delay of progression of excessive daytime sleepiness, nocturnal sleep disruption, or cataplexy.
37 - 40 . (canceled)
41 . The alpha 7 nicotinic acetylcholine receptor agonist as defined in claim 31 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form and wherein the daily dosage of said agonist is from 1 to 100 mg.
42 - 48 . (canceled)Join the waitlist — get patent alerts
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