US2002128274A1PendingUtilityA1
Benzylpiperazinyl-indolinylethanones
Est. expiryJun 14, 2019(expired)· nominal 20-yr term from priority
C07D 209/86C07D 209/42C07D 209/10C07D 209/12C07D 209/14C07D 209/08
46
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Claims
Abstract
Disclosed are benzylpiperazinyl-indolinylethanone compounds which are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. Pharmaceutical compositions, including packaged pharmaceutical compositions, are further provided. Compounds of the invention are also useful as probes for the localization of GABA A receptors in tissue samples.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
A represents a phenyl group optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C 1 -C 6 )hydrocarbylamino, aminosulfonyl, C 1 -C 6 hydrocarbylaminosulfonyl, di(C 1 -C 6 )hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C 1 -C 6 hydrocarbyl, trifluoromethoxy, C 3 -C 6 cyclohydrocarbyl, and C 1 -C 6 alkoxy;
R 1 represents hydrogen, halogen, hydroxy, amino, aminosulfonyl, C 1 -C 6 hydrocarbylaminosulfonyl, di(C 1 -C 6 )hydrocarbylaminosulfonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6 hydrocarbyl, cyclohydrocarbylhydrocarbyl, C 3 -C 7 cyclohydrocarbyl, and C 1 -C 6 alkoxy; and
R 2 is C 1 -C 6 hydrocarbyl and R 3 is hydrogen or C 1 -C 6 hydrocarbyl; or
R 2 is hydrogen and R 3 is mono, di, or trifluoromethyl, hydroxy(C 1 -C 3 )hydrocarbyl, C 1 -C 6 alkoxy(C 1 -C 3 )hydrocarbyl, mono or di(C 1 -C 6 )hydrocarbylamino(C 1 -C 3 )hydrocarbyl, carboxamido, mono or dihydrocarbylaminocarbonyl, aminohydrocarbyl, carboxy, C 1 -C 6 alkoxycarbonyl, carbamoyl, mono or di(C 1 -C 6 )hydrocarbylcarbamoyl, aryl(C 1 -C 6 )hydrocarbylcarbamoyl, or N,N-(aryl(C 1 -C 6 ) hydrocarbyl)((C 1 -C 6 )hydrocarbyl)carbamoyl; or
R 2 and R 3 taken together with the atoms to which they are attached form a saturated ring having from 5 to 7 carbon atoms; or
R 3 is hydrogen and R 2 is mono, di, or trifluoromethyl, hydroxy(C 1 -C 3 )hydrocarbyl, C 1 -C 6 alkoxy(C 1 -C 3 )hydrocarbyl, mono or di(C 1 -C 6 )hydrocarbylamino(C 1 -C 3 )hydrocarbyl, carboxamido, mono or dihydrocarbylaminocarbonyl, aminohydrocarbyl, carboxy, C 1 -C 6 alkoxycarbonyl, carbamoyl, mono or di(C 1 -C 6 )hydrocarbylcarbamoyl, aryl(C 1 -C 6 )hydrocarbylcarbamoyl, N,N-(aryl(C 1 -C 6 )hydrocarbyl)((C 1 -C 6 )hydrocarbyl)carbamoyl, or alkenyl.
2 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
A represents a phenyl group optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C 1 -C 6 )alkylamino, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1 -C 6 )alkyl, trifluoromethoxy, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkoxy;
R 1 represents hydrogen, halogen, hydroxy, amino, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, cycloalkylalkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkoxy; and
R 2 is (C 1 -C 6 )alkyl and R 3 is hydrogen or (C 1 -C 6 )alkyl; or
R 2 is hydrogen and R 3 is mono, di, or trifluoromethyl, hydroxy(C 1 -C 3 )alkyl, C 1 -C 6 alkoxy(C 1 -C 3 )alkyl, mono or di(C 1 -C 6 )alkylamino(C 1 -C 3 )alkyl, carboxamido, mono or dialkylaminocarbonyl, aminoalkyl, carboxy, C 1 -C 6 alkoxycarbonyl, carbamoyl, mono or di(C 1 -C 6 )alkylcarbamoyl, aryl(C 1 -C 6 )alkylcarbamoyl, N,N-(aryl(C 1 -C 6 )alkyl)((C 1 -C 6 )alkyl) carbamoyl, or alkenyl; or
R 2 and R 3 taken together with the atoms to which they are attached form a saturated ring having from 5 to 7 carbon atoms.
3 . A compound according to claim 1 , wherein A is a group of the formula:
where R 4 and R 5 independently represent hydrogen, halogen, hydroxy, amino, mono- or di(C 1 -C 6 )alkylamino, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, cyano, nitro, trifluoromethoxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
4 . A compound according to claim 3 , wherein R 3 is hydrogen and R 2 is C 1 -C 6 alkyl.
5 . A compound according to claim 4 , wherein R 4 and R 5 independently represent hydrogen, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
6 . A compound according to claim 3 , wherein both R 2 and R 3 are C 1 -C 6 alkyl.
7 . A compound according to claim 6 , wherein R 4 and R 5 independently represent hydrogen, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
8 . A compound according to claim 3 , wherein R 2 and R 3 together form a C 3 -C 5 -alkylene group.
9 . A compound according to claim 3 , wherein R 2 and R 3 together form a C 4 -alkylene group.
10 . A compound according to claim 9 , wherein R 4 and R 5 independently represent hydrogen, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
11 . A compound according to claim 3 , wherein R 2 is hydrogen and R 3 is mono, di, or trifluoromethyl, hydroxy(C 1 -C 3 )alkyl, C 1 -C 6 alkoxy(C 1 -C 3 )alkyl, mono or di(C l -C 6 )alkylamino(C 1 -C 3 )alkyl, aminoalkyl, carboxy, C 1 -C 6 alkoxycarbonyl, carbamoyl, mono or di(C 1 -C 6 )alkylcarbamoyl, aryl(C 1 -C 6 )alkylcarbamoyl, N,N-(aryl(C 1 -C 6 )alkyl) ((C 1 -C 6 )alkyl) carbamoyl, or alkenyl.
12 . A compound according to claim 11 , wherein R 4 and R 5 independently represent hydrogen, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
13 . A compound according to claim 1 , which is 2-{4-[(4-chlorophenyl)methyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
14 . A compound according to claim 1 , which is 2-{4-[(4-methylphenyl)methyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
15 . A compound according to claim 1 , which is 2-{4-[(4-ethylphenyl)methyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
16 . A compound according to claim 1 , which is 2-{4-[(4-isopropylphenyl)methyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
17 . A compound according to claim 1 , which is 1-((2R,3R)-2,3-dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl}ethan-1-one.
18 . A compound according to claim 1 , which is 1-((2S,3S)-2,3-dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl}ethan-1-one.
19 . A compound according to claim 1 , which is 1-(2,3-cis-dimethylindolinyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
20 . A compound according to claim 1 , which is 1-(2,3-cis-dimethylindolinyl)-2-{4-[(4-methoxyphenyl)methyl]piperazinyl}ethan-1-one.
21 . A compound according to claim 1 , which is 1-(2,3-cis-dimethylindolinyl)-2-{4-[(3-chloro-6-methoxyphenyl)methyl]piperazinyl}ethan-1-one.
22 . A compound according to claim 1 , which is 1-(2,3-cis-dimethylindolinyl)-2-{4-[(4-ethylphenyl)methyl]piperazinyl}ethan-1-one.
23 . A compound according to claim 1 , which is 1-(2,3-trans-dimethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
24 . A compound according to claim 1 , which is 1-(2,3-trans-dimethylindolinyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
25 . A compound according to claim 1 , which is 1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
26 . A compound according to claim 1 , which is 1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one (FIG. 1, 1 o ).
27 . A compound according to claim 1 , which is 1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-ethylphenyl)methyl]piperazinyl}ethan-1-one.
28 . A compound according to claim 1 , which is 1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-isopropylphenyl)methyl]piperazinyl}ethan-1-one.
29 . A compound according to claim 1 , which is methyl (2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indoline-2-carboxylate.
30 . A compound according to claim 1 , which is methyl (2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
31 . A compound according to claim 1 , which is methyl (2S)-1-(2-{4-[(4-ethylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
32 . A compound according to claim 1 , which is methyl (2S)-1-(2-{4-[(4-isopropylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
33 . A compound according to claim 1 , which is methyl (2R)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indoline-2-carboxylate.
34 . A compound according to claim 1 , which is methyl (2R)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
35 . A compound according to claim 1 , which is (2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}acetyl)indoline-2-carboxylic acid.
36 . A compound according to claim 1 , which is (2R)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetyl)indoline-2-carboxylic acid.
37 . A compound according to claim 1 , which is [(2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetyl)indoline-2-yl]-N-carboxamide.
38 . A compound according to claim 1 , which is [(2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}acetyl)indoline-2-yl]-N,N-dimethylcarboxamide.
39 . A compound according to claim 1 , which is 1-[(2S)-2-(hydroxymethyl)indolinyl]-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
40 . A compound according to claim 1 , which is 1-[(2S)-2-(hydroxymethyl)indolinyl]-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
41 . A compound according to claim 1 , which is 1-[(2S)-2-(hydroxymethyl)indolinyl]-2-{4-[(4-ethylphenyl)methyl]piperazinyl}ethan-1-one.
42 . A compound according to claim 1 , which is 1-[(2S)-2-(hydroxymethyl)indolinyl]-2-{4-[(4-isopropylphenyl)methyl]piperazinyl}ethan-1-one.
43 . A compound according to claim 1 , which is 1-[(2S)-2-(methoxymethyl)indolinyl]-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
44 . A compound according to claim 1 , which is 1-[(2S)-2-(methoxymethyl) indolinyl]-2-{4- [(4-methylphenyl) methyl]piperazinyl}ethan-1-one.
45 . A compound according to claim 1 , which is 1-((2S)-2-vinylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
46 . A compound according to claim 1 , which is 1-((2S)-2-vinylindolinyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
47 . A compound according to claim 1 , which is 1-((2S)-2-(fluoromethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
48 . A compound according to claim 1 , which is 1-((2S)-2-(fluoromethylindolinyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
49 . A compound according to claim 1 , which is 1-((2S)-2-(difluoromethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
50 . A compound according to claim 1 , which is 1-((2S)-2-(difluoromethylindolinyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
51 . A compound according to claim 1 , which is 1-{(2S)-2-[(dimethylamino)methyl]indolinyl}-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
52 . A compound according to claim 1 , which is 1-{(2S)-2-[(dimethylamino)methyl]indolinyl}-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
53 . A pharmaceutical composition comprising a compound according to claim 1 , together with at least one pharmaceutically acceptable carrier or excipient.
54 . A method for the treatment or prevention of a disease or disorder associated with pathogenic dopamine receptor activation, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of claim 1 .
55 . A method according to claim 54 wherein the disease or disorder is schizophrenia, psychotic depression, obsessive compulsive disorder, mania, Parkinson's disease, or tardive dyskinesia.
56 . A method according to claim 54 wherein the disease or disorder is attention deficit disorder or Alzheimer's disease.
57 . A method according to claim 54 wherein the disease or disorder is extrapyramidal side effects associated with the use of a neuroleptic agent.
58 . 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 dopamine receptor activation.
59 . A method for localizing dopamine receptors in a tissue sample comprising:
contacting with the sample a detectably-labeled compound of claim 1 under conditions that permit binding of the compound to dopamine receptors, washing the sample to remove unbound compound, and detecting the bound compound.
60 . The method of claim 59 wherein the dopamine receptor is a D4 receptor.
61 . A method of inhibiting the binding of a dopamine to a dopamine receptor, said method comprising contacting a compound of claim 1 with cells expressing such a receptor in the presence of a dopamine, wherein the compound is present at a concentration sufficient to inhibit dopamine binding to cells expressing a cloned human dopamine receptor in vitro.
62 . The method of claim 61 wherein the dopamine receptor is a dopamine D4 receptor.
63 . A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 53 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to dopamine receptor antagonism.
64 . The packaged pharmaceutical composition of claim 63 , wherein said patient is suffering from schizophrenia, psychotic depression, mania, Parkinson's disease, or tardive dyskinesia, attention deficit disorder, Alzheimer's disease, or the extrapyramidyl side effects associated with the use of a neuroleptic agent.
65 . A compound according to claim 1 wherein in an assay of dopamine receptor binding the compound exhibits a K i of 1 micromolar or less.
66 . A compound according to claim 1 wherein the compound exhibits a K i of 100 nanomolar or less.
66 - 1 . A compound according to claim 1 wherein the compound exhibits a K i of 10 nanomolar or less.
68 . A compound according to claim 1 wherein the compound exhibits a 20-fold greater affinity for the dopamine D4 receptor than or the dopamine D2 receptor in an assay of dopamine receptor binding.
69 . A compound according to claim 1 wherein the compound exhibits a 100-fold greater affinity for the dopamine D4 receptor than for the dopamine D2 receptor in an assay of dopamine receptor binding.Join the waitlist — get patent alerts
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