US2005222121A1PendingUtilityA1
Atypical antipsychotic agents having low affinity for the D2 receptor
Est. expiryJun 26, 2021(expired)· nominal 20-yr term from priority
A61P 25/18C07D 281/16C07D 267/20
44
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Claims
Abstract
The present invention provides novel compounds of Formula I: The invention further relates to pharmaceutical compositions comprising compounds of Formula I and to methods of using compounds of Formula I to treat neuropsychiatric disorders (e.g., psychosis, depression, schizophrenia).
Claims
exact text as granted — not AI-modified1 . A compound of Formula I or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said Formula I is represented by:
and wherein
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S; and
n is an integer selected from 2, 3, 4 and 5.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein X is O.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein X is S.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein R 2 is C 2-4 alkyl.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein R 2 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl and (CH 2 ) 2 OH.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein R 2 is selected from the group consisting of ethyl and (CH 2 ) 2 OH.
7 . The compound of claim 6 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein R 1 is selected from the group consisting of halo and CF 3 .
8 . The compound of claim 7 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein R 1 is selected from the group consisting of F, Cl, Br and I.
9 . The compound of claim 7 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein R 1 is selected from the group consisting of Cl and CF 3 .
10 . The compound of claim 1 , wherein said compound of Formula (I) is selected from the group consisting of:
(A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-2)=8-Trifluoromethyl-11-(4-(2′-hydroxyethyl)piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-3)=8-Trifluoromethyl-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-4)=8-Trifluoromethyl-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-5)=8-Trifluoromethyl-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-9)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-10)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-11)=8-Fluoro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine;
(A-14)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine;
(A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and
(A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value of at least 30 nM.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value from 30 nM to about 500 nM.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value of at least about 40 nM.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value from about 40 nM to about 500 nM.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value from about 40 nM to about 180 nM.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value from about 40 nM to about 80 nM.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value of at least about ½ times (K i for clozapine).
18 . The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said compound has a K i value from about ½ times (K i for clozapine) to about 2 times (K i for clozapine).
19 . (canceled)
20 . A method for the treatment of psychosis, said method comprising the step of administering, to a subject in need thereof, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, of Formula I:
wherein:
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S; and
n is an integer selected from 2, 3, 4, and 5.
21 . The method of claim 20 , wherein said compound, or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, of Formula I is selected from the group consisting of:
(A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-2)=8-Trifluoromethyl-11-(4-(2′-hydroxyethyl)piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-3)=8-Trifluoromethyl-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-4)=8-Trifluoromethyl-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-5)=8-Trifluoromethyl-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-9)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-10)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-11)=8-Fluoro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine;
(A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine;
(A-14)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine;
(A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and
(A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine.
22 . A pharmaceutical composition comprising a compound of Formula I, or its pharmaceutical salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, said Formula I represented by:
wherein:
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S; and
n is an integer selected from 2, 3, 4, and 5.
23 . The method of claim 20 , wherein said administering step comprises orally administering, for the treatment of schizophrenia, said compound, or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, of Formula I.
24 . A compound of Formula (A-12) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein said Formula (A-12) is represented by:
(A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine.
25 . A compound of Formula (A-15) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein said Formula (A-15) is represented by:
(A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine.
26 . A method for the treatment of psychosis, said method comprising the step of administering a therapeutically effective amount of a compound of Formula (A-12) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein said Formula (A-12) is represented by:
(A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine.
27 . A method for the treatment of psychosis, said method comprising the step of administering a therapeutically effective amount of a compound of Formula (A-15) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein said Formula (A-15) is represented by:
(A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine.
28 . A compound of Formula I or a pharmaceutically acceptable salt, or solvate thereof, wherein said Formula I is represented by:
and wherein
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S;
n is an integer selected from 2, 3, 4 and 5, and
wherein said Formula I has a K i of at least about 30 nM.
29 . A compound of Formula I or a pharmaceutically acceptable salt, or solvate thereof, wherein said Formula I is represented by:
and wherein
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S;
n is an integer selected from 2, 3, 4 and 5, and
wherein said Formula I has a K i of at least about 40 nM.
30 . A method for the treatment of psychosis, said method comprising the step of administering, to a subject in need thereof, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, of Formula I:
wherein:
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S;
n is an integer selected from 2, 3, 4, and 5, and
wherein said Formula I has a K i of at least about 30 nM.
31 . A method for the treatment of psychosis, said method comprising the step of administering, to a subject in need thereof, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, of Formula I:
wherein:
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-5 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S;
n is an integer selected from 2, 3, 4, and 5, and
wherein said Formula I has a K i of at least about 40 nM.
32 . The compound of claim 1 , wherein said Formula I represents an atypical antipsychotic drug.
33 . A method for the treatment of psychosis, said method comprising the step of administering to a human a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, of Formula I:
wherein:
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-4 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S;
n is an integer selected from 2, 3, 4, and 5, and
wherein said Formula I has a K i of at least about 30 nM.
34 . The method of claim 33 wherein said administering step further comprises administering said compound of Formula I by an administration route selected from the group consisting of a parenteral route, a nasal route, and an oral route.
35 . The method of claim 34 , wherein said parenteral route is selected from the group consisting of an intravenous route, an intramuscular route and a subcutaneous route.
36 . The method of claim 35 wherein said administration route is said subcutaneous route and said compound of Formula I is an atypical antipsychotic drug in humans.
37 . A method for the treatment of psychosis, said method comprising the step of administering to a human a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, of Formula I:
wherein:
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-4 alkyl and (CH 2 ) n OH;
X is selected from the group consisting of O and S;
n is an integer selected from 2, 3, 4, and 5, and
wherein said Formula I has a K i of at least about 40 nM.
38 . The method of claim 37 wherein said administering step further comprises administering said compound of Formula I by an administration route selected from the group consisting of a parenteral route, a nasal route, and an oral route.
39 . The method of claim 38 , wherein said parenteral route is selected from the group consisting of an intravenous route, an intramuscular route and a subcutaneous route.
40 . The method of claim 38 wherein said administration route is said subcutaneous route and said compound of Formula I is an atypical antipsychotic drug in humans.
41 . A compound of Formula I or a pharmaceutically acceptable salt, or solvate thereof, wherein said Formula I is represented by:
and wherein
R 1 is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3 and CH 3 O;
R 2 is selected from the group consisting of C 2-4 alkyl and (CH 2 ) n OH;
X is selected from the group consiting of O and S; and
n is an integer selected from 2, 3, 4 and 5.Join the waitlist — get patent alerts
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