US2003092912A1PendingUtilityA1
Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa Receptors
Assignee: NEUROGEN CORP A CORP OF THE STPriority: Apr 2, 1999Filed: Apr 3, 2002Published: May 15, 2003
Est. expiryApr 2, 2019(expired)· nominal 20-yr term from priority
C07D 471/04C07D 405/06C07D 409/12C07D 405/12C07D 401/06C07D 235/14
49
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Claims
Abstract
Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein the A, B, C, D, X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , are variables defined herein, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors, and are therefore useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, depression, overdose with benzodiazepine drugs, and enhancement of memory and alertness.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula:
or pharmaceutically acceptable non-toxic salts thereof wherein:
W represents
where
Z is O, or S;
R 1 represents phenyl, C 1 -C 6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
R 2 represents
hydroxyl;
C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each of which are optionally substituted with amino, mono or di(C 1 -C 6 ) alkylamino, a C 5 -C 7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH 2 ) n CO 2 R 8 where n=1,2,3,4, NR 8 COR 9 , COR 8 , CONR 8 R 9 or CO 2 R 8 where R 8 and R 9 are the same or different and represent hydrogen or C 1 -C 6 alkyl; or
NR 8 R 9 forms a 5-, 6-, or 7-membered heterocyclic ring;
or R 2 represents
hydrogen or
a group of the formula
where
R n and R k independently represent C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 cycloalkyl (C 1 -C 6 ) alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
a group of the formula IV-a
where
p, s, and t independently represent 1 or 2;
J is CH, N, O, or a carbon atom substituted with C 1 -C 6 alkyl; or
NR k R n represents
where s, t, and J are as defined above;
R 3 represents
C 1 -C 6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or
benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or hydroxy;
C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each of which is optionally substituted with amino, mono or di(C 1 -C 6 ) alkylamino, a C 5 -C 7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH 2 ) n CO 2 R 8 where n=1,2,3,4, NR 8 COR 9 , COR 8 , CONR 8 R 9 or CO 2 R 8 where R 8 and R 9 are the same or different and represent hydrogen or C 1 -C 6 alkyl;
NR 8 R 9 forms a 5-, 6-, 7-membered heterocyclic ring;
SO 2 R 8 , NHSO 2 R 8 , SO 2 NHR 8 , SO 2 NHCOR 8 , CONHSO2R 8 where R 8 is defined as above;
O(CH 2 ) n -G where n=1,2,3,4 and G is SO 2 R 8 , NHSO 2 R 8 , SO 2 NHR 8 , SO 2 NHCOR 8 , or CONHSO 2 R 8 , where R 8 is as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;
R 4 , R 5 and R 6 are the same or different and represent hydrogen; or
C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each of which is optionally substituted with amino, mono or di(C 1 -C 6 ) alkylamino, a C 5 -C 7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C 1 -C 6 alkylthiol, or halogen;
O(CH 2 ) n CO 2 R 8 where n=1,2,3,4, NR 8 COR 9 , COR 8 , CONR 8 R 9 or CO 2 R 8 where R 8 and R 9 are the same or different and represent hydrogen or C 1 -C 6 alkyl;
NR 8 R 9 forms a 5-, 6-, or 7-membered heterocyclic ring; or
R 4 and R 5 can form a 1,3-dioxolene ring;
X represents a bond, CH 2 , or CHCH; and
A, B, C, and D are the same or different and represent CH or N with the proviso that at least one, but not more than two of A,B,C, or D represent N.
2 . A compound according to claim 1 , which is N-((3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl)(3-fluorophenyl)-N-propylcarboxamide.
3 . A compound according to claim 1 , which is N-[(3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide.
4 . A compound according to claim 1 , which is N-((3-n-butyl-imidazolo[5,4-b]pyridin-2-yl)methyl](3-iodophenyl)-N-propylcarboxamide.
5 . A compound according to claim 1 for use in therapeutic treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor.
6 . A pharmaceutical composition comprising a compound according to claim 1 combined with at least one pharmaceutically acceptable carrier or excipient.
7 . A method for the treatment or prevention of a disease or disorder associated with pathogenic associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of claim 1 .
8 . The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor.
9 . The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of anxiety, depression, sleep disorders, or cognitive impairment.
10 . A method according to claim 7 wherein the disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor is anxiety, depression, a sleep disorder, or cognitive impairment.
11 . A method for localizing GABA A receptors in a tissue sample comprising: contacting the sample with a detectably-labeled compound of claim 1 under conditions that permit binding of the compound to GABA A receptors, washing the sample to remove unbound compound, and detecting the bound compound.
12 . A method for altering the signal-transducing activity of GABA A receptors, the method comprising exposing cells expressing GABA A receptors to a compound according to claim 1 at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABA A receptor in vitro.
13 . A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 6 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to agonism, inverse agonism or antagonism of the GABA A receptor.
14 . The packaged pharmaceutical composition of claim 13 , wherein the patient is suffering from anxiety, depression, a sleep disorder, or cognitive impairment.
15 . A compound according to claim 1 wherein the compound exhibits an IC 50 of 1 micromolar or less in a standard assay of GABA A receptor binding.
16 . A compound according to claim 1 wherein the compound exhibits an IC 50 of 100 nanomolar or less in a standard assay of GABA A receptor binding.
17 . A compound according to claim 1 wherein the compound exhibits an IC 50 of 10 nanomolar or less in a standard assay of GABA A receptor binding.
18 . A compound according to claim 1 which has the formula
where R 2 and R 3 are defined in the following table:
R 2
R 3
Methyl
3-Fluorophenyl
Allyl
3-Fluorophenyl
Propyl
3-Fluorophenyl
Allyl
3-Fluorophenyl
Propyl
3-Fluorophenyl
Propyl
3,4-Difluorophenyl
Allyl
2,5-Difluorophenyl
Propyl
2,5-Difluorophenyl
Propyl
1,3-Benzodioxol-5-yl
Allyl
3-Chloro-4-fluorophenyl
Propyl
3-Chloro-4-fluorophenyl
Methyl
5-Chloro-2-methoxyphenyl
3-Methylbutyl
3-{2-[(3-
Methoxypropyl)amino]ethoxy}phenyl
3-Methylbutyl
3-{2-[(3-Ethoxypropyl)amino]ethoxy}phenyl
3-Methylbutyl
3-{2-[(3-Ethoxypropyl)amino]ethoxy}phenyl
3-Methylbutyl
3-[2-(Benzylamino)ethoxy]phenyl
3-Methylbutyl
3-[2-(Benzylamino)ethoxy]phenyl
2-Methylpropyl
3-{2-[(3-i-
Propoxypropyl)amino]ethoxy}phenyl
3-Methylbutyl
3-{2-[(3-i-
Propoxypropyl)amino]ethoxy}phenyl
Benzyl
3-Chloro-2-thienyl
4-Fluorobenzyl
3-Chloro-2-thienyl
Benzyl
3-Chloro-4-methylphenyl
2-Fluorobenzyl
3-Chloro-4-methylphenyl
4-Fluorobenzyl
3-Chloro-4-methylphenyl
4-Fluorobenzyl
2-Fluoro-6-trifluoromethylphenyl
4-Fluorobenzyl
3,5-Dibromophenyl
Pentyl
3-Bromophenyl
3-Methylbutyl
3-Bromophenyl
2-Methylpropyl
4-Bromophenyl
3-Methylbutyl
4-Bromophenyl
Butyl
2-Bromophenyl
Pentyl
2-Bromophenyl
3-Methylbutyl
2-Bromophenyl
3-Methylbutyl
3-Methoxyphenyl
3-Methylbutyl
2-Methoxyphenyl
3-Methylbutyl
3-Chlorophenyl
3-Methylbutyl
2-Chlorophenyl
3-Methylbutyl
2-Chlorophenyl
Ethyl
5-Chloro-2-methoxyphenyl
Allyl
5-Chloro-2-methoxyphenyl
Propyl
5-Chloro-2-methoxyphenyl
Methyl
2,5-Dichlorophenyl
Allyl
2,5-Dichlorophenyl
Propyl
2,5-Dichlorophenyl
Propyl
5-Methyl-2-thienyl
Propyl
Phenyl
Propyl
3-Methylphenyl
Propyl
3-Fluoro-4-methylphenyl
Allyl
5-Fluoro-2-methylphenyl
Propyl
5-Fluoro-2-methylphenyl
Benzyl
2,3,5,6-Tetrafluorophenyl
4-Fluorobenzyl
2,3,5,6-Tetrafluorophenyl
Benzyl
2,4,6-Trifluorophenyl
Benzyl
2,3,6-Trifluorophenyl
4-Fluorobenzyl
2,3,6-Trifluorophenyl
4-Fluorobenzyl
2-Chloro-6-fluorophenyl
Benzyl
2-Fluoro-6-trifluoromethylphenyl
2-Methylpropyl
3-(2-{[(4-
Methylphenyl)methyl]amino}ethoxy)phenyl
3-Methylbutyl
3-{2-[(2-Cyclohex-1-
enylethyl)amino]ethoxy}phenyl
2-Methylpropyl
3-(2-{[(2-
Methylphenyl)methyl]amino}ethoxy)phenyl
2-Methylpropyl
3-(2-{[(3-
Methylphenyl)methyl]amino}ethoxy)phenyl
2-Methylpropyl
3-(2-{[(2-
Methoxyphenyl)methyl]amino}ethoxy)phenyl
2-Fluorobenzyl
3-Iodo-4-methylphenyl
4-Fluorobenzyl
3-Iodo-4-methylphenyl
4-Fluorobenzyl
2-Thienyl
Benzyl
2-Thienyl
4-Fluorobenzyl
2-Thienyl
Benzyl
3-Methyl-2-thienyl
4-Fluorobenzyl
3-Methyl-2-thienyl
Benzyl
5-Methyl-2-thienyl
2-Fluorobenzyl
5-Methyl-2-thienyl
4-Fluorobenzyl
5-Methyl-2-thienyl
4-Fluorobenzyl
4,5-Dimethyl-2-furyl
2-Methylpropyl
3,4-Dichlorophenyl
Pentyl
3,4-Dichlorophenyl
3-Methylbutyl
3,4-Dichlorophenyl
3-Methylbutyl
3,5-Dichlorophenyl
3-Methylbutyl
2,3-Dichlorophenyl
Butyl
2,5-Dichlorophenyl
2-Methylpropyl
2,5-Dichlorophenyl
Pentyl
2,5-Dichlorophenyl
3-Methylbutyl
2,5-Dichlorophenyl
Butyl
2,4-Dichlorophenyl
2-Methylpropyl
2,4-Dichlorophenyl
3-Methylbutyl
2,4-Dichlorophenyl
Allyl
3-Chlorophenyl
Propyl
3-Chlorophenyl
Propyl
2,3,6-Trifluorophenyl
Methyl
5-Chloro-2-methoxyphenyl
Ethyl
5-Chloro-2-methoxyphenyl
Allyl
5-Chloro-2-methoxyphenyl
Methyl
2,5-Dichlorophenyl
Methyl
3-Bromophenyl
Ethyl
3-Bromophenyl
Propyl
3-Bromophenyl
Methyl
3-Bromo-4-fluorophenyl
Methyl
3-Iodophenyl
3-Methylbutyl
3-(2-{[(2-
Methoxyphenyl)methyl]amino}ethoxy)phenyl
2-Methylpropyl
3-(2-{[(3-
Methoxyphenyl)methyl]amino}ethoxy)phenyl
2-Methylpropyl
3-(2-{[(4-
Methoxyphenyl)methyl]amino}ethoxy)phenyl
2-Methylpropyl
3-(2-{[(2-
Chlorophenyl)methyl]amino }ethoxy)phenyl
Benzyl
2,5-Dimethoxyphenyl
2-Fluorobenzyl
2,5-Dimethoxyphenyl
4-Fluorobenzyl
2,5-Dimethoxyphenyl
Butyl
4-Pentylphenyl
2-Methylpropyl
4-Pentylphenyl
3-Methylbutyl
4-Pentylphenyl
Butyl
3-Bromophenyl
2-Methylpropyl
3-Bromophenyl
Pentyl
3-Bromophenyl
3-Methylbutyl
3-Bromophenyl
2-Methylpropyl
4-Bromophenyl
3-Methylbutyl
4-Bromophenyl
Butyl
2-Bromophenyl
Pentyl
2-Bromophenyl
3-Methylbutyl
2-Bromophenyl
Ethyl
3-Iodophenyl
Allyl
3-Iodophenyl
Propyl
3-Chloro-4-methylphenyl
Propyl
5-Bromo-2-thienyl
Ethyl
Phenyl
Allyl
Phenyl
Propyl
Phenyl
Allyl
3-Methylphenyl
Propyl
3-Methylphenyl
Propyl
4-Methylphenyl
Methyl
3-Fluorophenyl
Propyl
3-Fluorophenyl
Butyl
3-Chloro-4-methoxyphenyl
2-Methylpropyl
3-Chloro-4-methoxyphenyl
3-Methylbutyl
3-Chloro-4-methoxyphenyl
Butyl
5-Chloro-2-methoxyphenyl
2-Methylpropyl
5-Chloro-2-methoxyphenyl
Pentyl
5-Chloro-2-methoxyphenyl
3-Methylbutyl
5-Chloro-2-methoxyphenyl
Butyl
3-Trifluoromethylphenyl
Pentyl
3-Trifluoromethylphenyl
3-Methylbutyl
3-Trifluoromethylphenyl
3-Methylbutyl
2-Trifluoromethylphenyl
Butyl
3,4-Dichlorophenyl
Propyl
4-Fluorophenyl
Methyl
2-Fluorophenyl
Allyl
2-Fluorophenyl
Propyl
2-Fluorophenyl
Propyl
3-Fluoro-4-methylphenyl
Methyl
5-Fluoro-2-methylphenyl
Propyl
5-Fluoro-2-methylphenyl
Methyl
3-Chlorophenyl
Allyl
3-Chlorophenyl
Propyl
3-Chlorophenyl
3-Methylbutyl
4-Hexylphenyl
3-Methylbutyl
2-Fluoro-3-trifluoromethylphenyl
Butyl
2,5-Dichlorophenyl
2-Methylpropyl
2,5-Dichlorophenyl
Pentyl
2,5-Dichlorophenyl
3-Methylbutyl
2,5-Dichlorophenyl
Butyl
2,4-Dichlorophenyl
2-Methylpropyl
2,4-Dichlorophenyl
3-Methylbutyl
2,4-Dichlorophenyl
Butyl
4-Pentylphenyl
2-Methylpropyl
4-Pentylphenyl
3-Methylbutyl
4-Pentylphenyl
Butyl
3-Bromophenyl
2-Methylpropyl
3-Bromophenyl
2-Methylpropyl
3-Bromo-4-methylphenyl
3-Methylbutyl
3-Bromo-4-methylphenyl
Butyl
3-Bromo-4-fluorophenyl
2-Methylpropyl
3-Bromo-4-fluorophenyl
3-Methylbutyl
3-Bromo-4-fluorophenyl
Butyl
3-Iodophenyl
2-Methylpropyl
3-Iodophenyl
Pentyl
3-Iodophenyl
3-Methylbutyl
3-Iodophenyl
2-Methylpropyl
4-Iodophenyl
3-Methylbutyl
3-Iodo-4-methylphenyl
Butyl
2-Thienyl
Pentyl
2-Thienyl
3-Methylbutyl
2-Thienyl
Butyl
3-Thienyl
Pentyl
3-Thienyl
3-Methylbutyl
3-Thienyl
3-Methylbutyl
Benzyl
Butyl
3-Methyl-2-thienyl
Pentyl
3-Methyl-2-thienyl
3-Methylbutyl
3-Methyl-2-thienyl
Pentyl
3-Methyl-5-thienyl
3-Methylbutyl
3-Methyl-5-thienyl
3-Methylbutyl
3-Methylphenyl
2-Methylpropyl
5-Chloro-2-methoxyphenyl
Pentyl
5-Chloro-2-methoxyphenyl
3-Methylbutyl
5-Chloro-2-methoxyphenyl
Butyl
3-Trifluoromethylphenyl
Pentyl
3-Trifluoromethylphenyl
3-Methylbutyl
3-Trifluoromethylphenyl
3-Methylbutyl
2-Trifluoromethylphenyl
Butyl
3,4-Dichlorophenyl
2-Methylpropyl
3,4-Dichlorophenyl
3-Methylbutyl
3,4-Dichlorophenyl
3-Methylbutyl
3,5-Dichlorophenyl
3-Methylbutyl
2,3-Dichlorophenyl
Butyl
Phenyl
Pentyl
Phenyl
3-Methylbutyl
Phenyl
Pentyl
3-Methylphenyl
3-Methylbutyl
3-Methylphenyl
2-Methylpropyl
4-Methylphenyl
3-Methylbutyl
4-Methylphenyl
Pentyl
2-Methylphenyl
3-Methylbutyl
2-Methylphenyl
Butyl
3-Fluorophenyl
2-Methylpropyl
3-Fluorophenyl
Pentyl
3-Fluorophenyl
3-Methylbutyl
3-Fluorophenyl
Pentyl
4-Fluorophenyl
3-Methylbutyl
4-Fluorophenyl
Pentyl
2-Fluorophenyl
3-Methylbutyl
2-Fluorophenyl
2-Methylpropyl
3,4-Dimethylphenyl
3-Methylbutyl
3,4-Dimethylphenyl
Pentyl
2,5-Dimethylphenyl
3-Methylbutyl
2,5-Dimethylphenyl
2-Methylpropyl
2,4-Dimethylphenyl
3-Methylbutyl
2,4-Dimethylphenyl
2-Methylpropyl
3-Methoxyphenyl
Pentyl
3-Methoxyphenyl
3-Methylbutyl
3-Methoxyphenyl
2-Methylpropyl
4-Methoxyphenyl
3-Methylbutyl
4-Methoxyphenyl
Pentyl
2-Methoxyphenyl
3-Methylbutyl
2-Methoxyphenyl
2-Methylpropyl
3-Fluoro-4-methylphenyl
Pentyl
3-Fluoro-4-methylphenyl
3-Methylbutyl
3-Fluoro-4-methylphenyl
3-Methylbutyl
3-Fluoro-2-methylphenyl
2-Methylpropyl
5-Fluoro-2-methylphenyl
Pentyl
5-Fluoro-2-methylphenyl
2-Methylpropyl
3-Chloro-4-fluorophenyl
Pentyl
3-Chloro-4-fluorophenyl
3-Methylbutyl
3-Chloro-4-fluorophenyl
3-Methylbutyl
3,4,5-Trifluorophenyl
3-Methylbutyl
4-Butylphenyl
Pentyl
4-i-propylphenyl
3-Methylbutyl
4-i-propylphenyl
Butyl
4-Ethylthiophenyl
2-Methylpropyl
4-Ethylthiophenyl
3-Methylbutyl
4-Ethylthiophenyl
3-Methylbutyl
3-Chloro-4-methoxyphenyl
Butyl
5-Chloro-2-methoxyphenyl
3-Methylbutyl
5-Fluoro-2-methylphenyl
2-Methylpropyl
2-Fluoro-3-methylphenyl
Pentyl
2-Fluoro-3-methylphenyl
3-Methylbutyl
2-Fluoro-3-methylphenyl
2-Methylpropyl
3-Chlorophenyl
Pentyl
3-Chlorophenyl
3-Methylbutyl
3-Chlorophenyl
2-Methylpropyl
4-Chlorophenyl
3-Methylbutyl
4-Chlorophenyl
3-Methylbutyl
2-Chlorophenyl
3-Methylbutyl
3,4-Difluorophenyl
3-Methylbutyl
1,2-Difluorophenyl
Pentyl
2,5-Difluorophenyl
3-Methylbutyl
2,5-Difluorophenyl
Pentyl
2,4-Difluorophenyl
3-Methylbutyl
2,4-Difluorophenyl
3-Methylbutyl
4-Propylphenyl
Pentyl
1,3-Benzodioxol-5-yl
3-Methylbutyl
1,3-Benzodioxol-5-yl
3-Methylbutyl
4-Methylthiophenyl
3-Methylbutyl
3-Fluoro-4-methoxyphenyl
2-Methylpropyl
4-Chloro-3-methylphenyl
3-Methylbutyl
4-Chloro-3-methylphenyl
Buty
3-Chloro-4-fluorophenyl
19 . A compound according to claim 1 which has the formula
where R 2 and R 3 are defined in the following table:
R 2
R 3
2-Methylpropyl
2,4,6-Trifluorophenyl
3-Methylbutyl
2,4,6-Trifluorophenyl
2-Methylpropyl
2,3,6-Trifluorophenyl
Pentyl
2,3,6-Trifluorophenyl
3-Methylbutyl
2,3,6-Trifluorophenyl
Pentyl
2-Chloro-6-fluorophenyl
3-Methylbutyl
2-Chloro-6-fluorophenyl
Pentyl
2-Fluoro-6-
trifluoromethylphenyl
3-Methylbutyl
2-Fluoro-6-
trifluoromethylphenyl
Pentyl
3-Bromo-4-fluorophenyl
2-Methylpropyl
4-Hexylphenyl
Butyl
4-Pentoxyphenyl
2-Methylpropyl
4-Pentoxyphenyl
Butyl
2-Fluoro-3-
trifluoromethylphenyl
2-Methylpropyl
2-Fluoro-3-
trifluoromethylphenyl
3-Methylbutyl
3-Bromo-4-fluorophenyl
2-Methylpropyl
4-heptylphenyl
Butyl
3-Iodophenyl
2-Methylpropyl
3-Iodophenyl
Pentyl
3-Iodophenyl
3-Methylbutyl
3-Iodophenyl
Butyl
4-Iodophenyl
2-Methylpropyl
4-Iodophenyl
2-Methylpropyl
4-Pentylphenyl
3-Methylbutyl
2-Fluoro-3-
trifluoromethylphenyl
Butyl
3-Bromo-4-methylphenyl
2-Methylpropyl
3-Bromo-4-methylphenyl
Pentyl
3-Bromo-4-methylphenyl
3-Methylbutyl
3-Bromo-4-methylphenyl
Butyl
3-Bromo-4-fluorophenyl
2-Methylpropyl
3-Bromo-4-fluorophenyl
3-Methylbutyl
3,4-Dichlorophenyl
Butyl
2,3-Dichlorophenyl
2-Methylpropyl
2,3-Dichlorophenyl
3-Methylbutyl
2,3-Dichlorophenyl
Butyl
2,5-Dichlorophenyl
Butyl
3-Bromophenyl
2-Methylpropyl
3-Bromophenyl
Pentyl
3-Bromophenyl
3-Methylbutyl
3-Bromophenyl
Butyl
4-Bromophenyl
2-Methylpropyl
4-Bromophenyl
3-Methylbutyl
4-Bromophenyl
Butyl
2-Bromophenyl
Pentyl
2-Bromophenyl
3-Methylbutyl
2-Bromophenyl
Pentyl
4-Hexylphenyl
2-Methylpropyl
4-Chloro-2-methoxyphenyl
2-Methylpropyl
2,5-Dichlorophenyl
Pentyl
2,5-Dichlorophenyl
3-Methylbutyl
2,5-Dichlorophenyl
Butyl
2,4-Dichlorophenyl
2-Methylpropyl
2,4-Dichlorophenyl
Pentyl
2,4-Dichlorophenyl
3-Methylbutyl
2,4-Dichlorophenyl
2-Methylpropyl
2,5-Dimethoxyphenyl
Pentyl
2,5-Dimethoxyphenyl
3-Methylbutyl
2,5-Dimethoxyphenyl
2-Methylpropyl
2,4-Dimethoxyphenyl
3-Methylbutyl
2,4-Dimethoxyphenyl
Pentyl
4-Chloro-2-methoxyphenyl
3-Methylbutyl
4-Chloro-2-methoxyphenyl
Butyl
3-Trifluoromethylphenyl
2-Methylpropyl
3-Trifluoromethylphenyl
Pentyl
3-Trifluoromethylphenyl
3-Methylbutyl
3-Trifluoromethylphenyl
2-Methylpropyl
4-Trifluoromethylphenyl
Butyl
2-Trifluoromethylphenyl
3-Methylbutyl
2-Trifluoromethylphenyl
Butyl
3,4-Dichlorophenyl
2-Methylpropyl
3,4-Dichlorophenyl
Butyl
4-Methylthiophenyl
Butyl
3-Chloro-4-methoxyphenyl
2-Methylpropyl
3-Chloro-4-methoxyphenyl
3-Methylbutyl
3-Chloro-4-methoxyphenyl
Butyl
5-Chloro-2-methoxyphenyl
2-Methylpropyl
5-Chloro-2-methoxyphenyl
Pentyl
5-Chloro-2-methoxyphenyl
3-Methylbutyl
5-Chloro-2-methoxyphenyl
Butyl
2,5-Difluorophenyl
2-Methylpropyl
2,5-Difluorophenyl
Pentyl
2,5-Difluorophenyl
3-Methylbutyl
2,5-Difluorophenyl
Butyl
2,4-Difluorophenyl
2-Methylpropyl
4-Methylthiophenyl
Butyl
3-Fluoro-4-methoxyphenyl
2-Methylpropyl
3-Fluoro-4-methoxyphenyl
3-Methylbutyl
3-Fluoro-4-methoxyphenyl
2-Methylpropyl
4-Chloro-3-methylphenyl
Butyl
3-Chloro-4-fluorophenyl
2-Methylpropyl
3-Chloro-4-fluorophenyl
Pentyl
3-Chloro-4-fluorophenyl
3-Methylbutyl
3-Chloro-4-fluorophenyl
2-Methylpropyl
4-Ethylthiophenyl
Butyl
2,5-Dimethoxyphenyl
Butyl
2-Chlorophenyl
2-Methylpropyl
2,4-Difluorophenyl
Pentyl
2,4-Difluorophenyl
3-Methylbutyl
2,4-Difluorophenyl
Butyl
1,3-Benzodioxol-5-yl
2-Methylpropyl
1,3-Benzodioxol-5-yl
Pentyl
1,3-Benzodioxol-5-yl
3-Methylbutyl
1,3-Benzodioxol-5-yl
3-Methylbutyl
3-Fluoro-2-methylphenyl
Butyl
5-Fluoro-2-methylphenyl
2-Methylpropyl
5-Fluoro-2-methylphenyl
Pentyl
5-Fluoro-2-methylphenyl
3-Methylbutyl
5-Fluoro-2-methylphenyl
2-Methylpropyl
2-Chlorophenyl
Pentyl
2-Chlorophenyl
3-Methylbutyl
2-Chlorophenyl
Butyl
3,4-Difluorophenyl
2-Methylpropyl
3,4-Difluorophenyl
Pentyl
3,4-Difluorophenyl
3-Methylbutyl
3,4-Difiluorophenyl
Butyl
2,3-Difluorophenyl
2-Methylpropyl
2,3-Difluorophenyl
Pentyl
2,3-Difluorophenyl
3-Methylbutyl
2,3-Difluorophenyl
2-Methylpropyl
4-Methoxyphenyl
Butyl
3-Chlorophenyl
2-Methylpropyl
3-Chlorophenyl
Pentyl
3-Chlorophenyl
3-Methylbutyl
3-Chlorophenyl
Butyl
4-Chlorophenyl
2-Methylpropyl
4-Chlorophenyl
3-Methylbutyl
4-Chlorophenyl
Butyl
2,5-Dimethylphenyl
2-Methylpropyl
2,5-Dimethylphenyl
Pentyl
2,5-Dimethylphenyl
3-Methylbutyl
2,5-Dimethylphenyl
Butyl
2,4-Dimethylphenyl
3-Methylbutyl
4-Methoxyphenyl
Butyl
2-Methoxyphenyl
2-Methylpropyl
2-Methoxyphenyl
Pentyl
2-Methoxyphenyl
3-Methylbutyl
2-Methoxyphenyl
Butyl
3-Fluoro-4-methylphenyl
2-Methylpropyl
3-Fluoro-4-methylphenyl
Pentyl
3-Fluoro-4-methylphenyl
3-Methylbutyl
3-Fluoro-4-methylphenyl
Butyl
3-Fluoro-2-methylphenyl
2-Methylpropyl
3-Fluoro-2-methylphenyl
Butyl
4-Fluorophenyl
2-Methylpropyl
2,4-Dimethylphenyl
3-Methylbutyl
2,4-Dimethylphenyl
Butyl
3-Methoxyphenyl
2-Methylpropyl
3-Methoxyphenyl
Pentyl
3-Methoxyphenyl
3-Methylbutyl
3-Methoxyphenyl
Butyl
4-Methoxyphenyl
3-Methylbutyl
3-Methylphenyl
Butyl
4-Methylphenyl
2-Methylpropyl
4-Methylphenyl
Pentyl
4-Methylphenyl
3-Methylbutyl
4-Methylphenyl
2-Methylpropyl
4-Fluorophenyl
Pentyl
4-Fluorophenyl
3-Methylbutyl
4-Fluorophenyl
Butyl
2-Fluorophenyl
2-Methylpropyl
2-Fluorophenyl
Pentyl
2-Fluorophenyl
3-Methylbutyl
2-Fluorophenyl
2-Methylpropyl
4-Ethylphenyl
Butyl
3,4-Dimethylphenyl
2-Methylpropyl
3,4-Dimethylphenyl
3-Methylbutyl
3,4-Dimethylphenyl
Butyl
2-Methylphenyl
Pentyl
2-Methylphenyl
3-Methylbutyl
2-Methylphenyl
Butyl
3-Fluorophenyl
2-Methylpropyl
3-Fluorophenyl
Pentyl
3-Fluorophenyl
3-Methylbutyl
3-Fluorophenyl
Butyl
Phenyl
2-Methylpropyl
Phenyl
Pentyl
Phenyl
3-Methylbutyl
Phenyl
Butyl
3-Methylphenyl
2-Methylpropyl
3-Methylphenyl
Pentyl
3-Methylphenyl
20 . A compound according to claim 1 which has the formula
where R 2 and R 3 are defined in the following table:
R 2
R 3
Allyl
2,5-Dichlorophenyl
Propyl
2,5-Dichlorophenyl
Propyl
2,4-Dichlorophenyl
Propyl
4-Pentylphenyl
Allyl
3-Bromophenyl
Propyl
3-Bromophenyl
Propyl
4-Bromophenyl
Propyl
2-Chlorophenyl
Methyl
Phenyl
Propyl
Phenyl
Methyl
3-Methylphenyl
Propyl
3-Methylphenyl
Propyl
2-Chlorophenyl
Propyl
3,4-Difluorophenyl
Methyl
2,3-Difluorophenyl
Propyl
2,3-Difluorophenyl
Methyl
2,5-Difluorophenyl
Allyl
2,5-Difluorophenyl
Propyl
2,5-Difluorophenyl
Propyl
2,4-Difluorophenyl
Allyl
1,3-Benzodioxol-5-yl
Propyl
1,3-Benzodioxol-5-yl
Propyl
4-Methylthiophenyl
Propyl
4-Chloro-3-methylphenyl
Propyl
4-Methylphenyl
Propyl
3-Fluorophenyl
Propyl
4-Fluorophenyl
Methyl
2-Fluorophenyl
Allyl
2-Fluorophenyl
Propyl
2-Fluorophenyl
Propyl
3,4-Dimethylphenyl
Propyl
3-Fluoro-4-methylphenyl
Propyl
2-Fluoro-3-methylphenyl
Allyl
3-Chlorophenyl
Propyl
3-Chlorophenyl
Propyl
4-Chlorophenyl
2-Methylpropyl
3-Chloro-2-thienyl
Pentyl
3-Chloro-2-thienyl
3-Methylbutyl
3-Chloro-2-thienyl
Butyl
3-Ethoxy-2-thienyl
Pentyl
3-Ethoxy-2-thienyl
3-Methylbutyl
2-Methoxybenzyl
3-Methylbutyl
2-(2-Fluorophenyl)ethenyl
2-Methylpropyl
2-(2-Chlorophenyl)ethenyl
3-Methylbutyl
2-(2-Chlorophenyl)ethenyl
Pentyl
2-Fluoro-6-trifluoromethylphenyl
3-Methylbutyl
3-Ethoxy-2-thienyl
Butyl
5-Methylthio-2-thienyl
2-Methylpropyl
5-Methylthio-2-thienyl
3-Methylbutyl
5-Methylthio-2-thienyl
3-Methylbutyl
4-Fluorophenyl
3-Methylbutyl
2-Fluorophenyl
3-Methylbutyl
3-Methoxyphenyl
3-Methylbutyl
2,3,5,6-Tetrafluoro phenyl
2-Methylpropyl
2,4,6-Trifluorophenyl
3-Methylbutyl
2,4,6-Trifluorophenyl
Butyl
2,3,6-Trifluorophenyl
2-Methylpropyl
2,3,6-Trifluorophenyl
3-Methylbutyl
2-Fluoro-6-trifluoromethylphenyl
2-Methylpropyl
2,4,6-Trichlorophenyl
Pentyl
2,5-Dimethyl-3-furyl
3-Methylbutyl
4,5-Dimethyl-2-furyl
Butyl
3,4-Dimethyl-2-furyl
2-Methylpropyl
3,4 -Dimethyl-2-furyl
Pentyl
3,4-Dimethyl-2-furyl
3-Methylbutyl
3,4-Dimethyl-2-furyl
Butyl
4-Methoxy-3-thienyl
3-Methylbutyl
4-Methoxy-3-thienyl
Butyl
3-Chloro-2-thienyl
Allyl
3-Bromo-4-fluorophenyl
Propyl
3-Bromo-4-fluorophenyl
Methyl
3-Iodophenyl
Ethyl
3-Iodophenyl
Allyl
3-Iodophenyl
Propyl
3-Iodophenyl
Propyl
3-Methyl-2-thienyl
Propyl
3-Fluorobenzyl
Pentyl
2,3,6-Trifluorophenyl
3-Methylbutyl
2,3,6-Trifluorophenyl
Butyl
2-Chloro-6-fluorophenyl
2-Methylpropyl
2-Chloro-6-fluorophenyl
Pentyl
2-Chloro-6-fluorophenyl
3-Methylbutyl
2-Chloro-6-fluorophenyl
Butyl
2-Fluoro-6-trifluoromethylphenyl
3-Methylbutyl
3-Chlorobenzyl
2-Methylpropyl
4-Chlorobenzyl
3-Methylbutyl
2-Chlorobenzyl
Butyl
2,3,5,6-Tetrafluoro phenyl
2-Methylpropyl
2,3,5,6-Tetrafluoro phenyl
Pentyl
2,3,5,6-Tetrafluoro phenyl
Allyl
3-Chloro-4-fluorophenyl
Propyl
3-Chloro-4-fluorophenyl
Propyl
4-Butylphenyl
Propyl
3-Chloro-4-methoxyphenyl
Allyl
5-Chloro-2-methoxyphenyl
Propyl
5-Chloro-2-methoxyphenyl
Propyl
3,4-Dichlorophenyl
Propyl
4-Hexylphenyl
Methyl
3-Bromo-4-methylphenyl
Allyl
3-Bromo-4-methylphenyl
Propyl
3-Bromo-4-methylphenyl
Methyl
3-Bromo-4-fluorophenyl
Butyl
2-Methoxybenzyl
21 . A compound according to claim 1 which has the formula
where R 2 and R 3 are defined in the following table:
R 2
R 3
Propyl
3-Chlorophenyl
Propyl
Phenyl
Allyl
2-Fluorophenyl
Propyl
2-Fluorophenyl
Propyl
3-Fluoro-4-methylphenyl
Methyl
2,5-Dichlorophenyl
Propyl
2,5-Dichlorophenyl
Propyl
4-Pentylphenyl
Propyl
3-Bromophenyl
Propyl
3-Methyl-2-thienyl
22 . A pharmaceutical composition comprising a compound according to claim 1 , together with at least one pharmaceutically acceptable carrier or excipient.
23 . A method for the treatment or prevention of physiological disorders associated with modulation of the GABAa receptor complex by selective interaction with the benzodiazepine receptor, the method comprising administering to a patient in need thereof a GABAa receptor complex agonist, antagonist or inverse agonist of a compound according to claim 1 .
24 . A method according to claim 23 for the treatment of enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
25 . The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment of enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
26 . A process for the preparation of a compound as claimed in claim 1.Join the waitlist — get patent alerts
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