US 2002/0165251 A1Published application

Novel compounds, their use and preparation

AssigneeBiovitrum AB

InventorsPatrizia Caldirola, Bjorn M. Nilsson, Gary Johansson

Life of this patent

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Abstract

The invention provides 2, 3-, 4- or 5-substituted-N1-(arylsulfonyl)indole and (heteroaryl)indole compounds of the general formula (I): 1 in which Ar, R2, R3, R4 and R5 are as defined in the specification. The compounds bind to the 5-HT6 receptor and are useful for the treatment and prophylaxis of disorders mediated by the 5-HT6 receptor, such as obesity and CNS disorders.

Claims27

Dependent claims

A compound of formula (I):

181
wherein
Ar is
(1) phenyl,
(2) naphthyl,
(3) a 5- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, or
(4) —R9-phenyl;
wherein the phenyl, naphthyl, or heterocyclic ring is optionally substituted with halogen, C1-6 alkyl, CF3, hydroxyl, C1-6 alkoxyl, OCF3, COCF3, CN, NO2, phenyloxy, phenyl, C1-6 alkylsulfonyl, C2-6 alkenyl, —NR7R8, C1-6 alkylcarboxyl, formyl, —C16 alkyl-NH—CO-phenyl, —C1-6 alkyl-CO—NH-phenyl, —NH—CO—C1-6 alkyl, —CO—NR7R8, or SR7;
wherein each of R7 and R8 is independently H or C1-6 alkyl;
and R9 is C1-6 alkyl or C2-6 alkenyl, either of which is optionally substituted with phenyl or phenyloxy;
R2 is H, phenyl, I, or C1-6 alkyl;
R3 is H or 3-(1-azabicyclo[2.2.2]oct-2-en)yl;
R4 is H or is selected from the group consisting of:
182
wherein R6 is H, C1-6 alkyl, or benzyl;
and
R5 is H, hydroxy, C1-3 alkoxy, F, NO2, CF3, OCF3, or is selected from the group consisting of:
183
or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, with the proviso that when R2 is alkyl, R4 is not H.

16 more elements

A compound selected from the group consisting of:

1-phenylsulfonyl-4-piperazinylindole hydrochloride,
1-[(2,5-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-(mesitylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,
1-(1-naphthylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,
N,N-dimethyl-5-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}-1-naphthalenamine hydrochloride,
1-[(4-propoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(2,5-dichloro-3-thienyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(4-methoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(2,4-difluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(3,4-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
5-methyl-2-methoxyl-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenyl ether hydrochloride,
1-[(2,5-dichlorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(3-chloro-2-methylphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
2-chloro-5-(4-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenoxy)benzonitrile hydrochloride,
4-bromo-2-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenyl methyl ether hydrochloride,
4-(1-piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indole hydrochloride,
7-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride,
methyl 2-{[4-(1-piperazinyl)-1H-indol-1-yl]sulfonyl}phenyl sulfone hydrochloride,
1-[(4-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
4-(4-methyl-1-piperazinyl)-1-(4-methylbenzenesulfonyl)-1H-indole hydrochloride hydrochloride,
4-piperazino-N-(4-trifluoromethyl)phenylsulfonyl)indole hydrochloride,
4-(3-methylpiperazine)-(N-(4-trifluoromethyl)phenylsulfonyl)indole dihydrochloride,
4-(4-methyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(4-ethyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl) -1H-indole hydrochloride,
4-(1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(5-aza-indolizidinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(4-methyl-1-homopiperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(3-methyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(cis-3,5-dimethyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(4-isopropyl-1-piperazinyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptyl)-1-(2-methylbenzenesulfonyl)-1H-indole hydrochloride,
4-(4-methyl-1-homopiperazinyl)-1-(benzenesulfonyl)-1H-indole hydrochloride,
4-(cis 3,5-dimethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H-indole hydrochloride,
4-(4-ethyl-1-piperazinyl)-1-(benzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-nitro-benzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-bromo-benzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-chloro-benzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(E 2-phenyl-ethensulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-cyanobenzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-chloro-7-chloro-2,1,3-benzoxadiazole sulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(3-cyanobenzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-phenoxybenzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-chlorophenylmethanesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(4-methylphenylmethanesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(1,1-diphenylethanesulfonyl)-H-indole hydrochloride,
4-piperazinyl-1-(4-trifluoromethoxybenzenesulfonyl)-1H-indole hydrochloride,
4-piperazinyl-1-(5-[(benzoylamino)methyl]thiophene-2-sulfonyl)-1H-indole hydrochloride,
1-[(N-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1-piperazinyl)-1H-indole hydrochloride,
N-benzenesulfonyl-5-(4-methylpiperazin-1-yl)-indole,
N-(4-methylbenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole,
N-benzenesulfonyl-5-(4-isopropylpiperazin-1-yl)-indole,
N-(4-methylbenzenesulfonyl)-5-(4-isopropylpiperazin-1-yl)-indole,
N-(3,4-dimethoxybenzenesulfonyl)-5-(4-propylpiperazin-1-yl)-indole, hydrochloride,
N-(3-fluorobenzenesulfonyl)-5-(4-propylpiperazin-1-yl)-indole, hydrochloride,
N-(4-propylbenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole, hydrochloride,
N-(1-naphtalenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole, hydrochloride,
N-(biphenyl-4-sulfonyl)-5-(4-methylpiperazin-1-yl)-indole, hydrochloride,
N-(4-methoxybenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole, hydrochloride,
N-(3,4-dimethoxybenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole, hydrochloride,
N-(2,4-difluorobenzenesulfonyl)-5-(4-methylpiperazin-1-yl)-indole, hydrochloride,
N-(4-methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(2,4-difluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(4-butoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(3,4-dimethoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(biphenyl-4-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(napthalene-2-sulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(4-propylbenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(3-fluorobenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole, hydrochloride,
N-(4-methoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole, hydrochloride,
N-(2,4-difluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole, hydrochloride,
N-(4-butoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole, hydrochloride,
N-(3,4-dimethoxybenzenesulfonyl)-5-(piperazin-1-yl)-indole, dihydrochloride,
N-(biphenyl-4-sulfonyl)-5-(piperazin-1-yl)-indole, dihydrochloride,
N-(napthalene-2-sulfonyl)-5-(piperazin-1-yl)-indole, dihydrochloride,
N-(4-propylbenzenesulfonyl)-5-(iperazin-1-yl-indole, dihydrochloride,
N-(3-fluorobenzenesulfonyl)-5-(piperazin-1-yl)-indole, dihydrochloride,
N-benzenesulfonyl-5-(piperazin-1-yl)-indole, dihydrochloride,
3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1-[(4-fluorophenyl)sulfonyl]-1H-indole,
2-iodo-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,
2-phenyl-1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole hydrochloride,
4-piperazinyl-2-methyl-1-benzosulfonylindole trifluoroacetate, and
1-phenylsulfonyl-4-(homopiperazinyl)-indole hydrochloride.

83 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/037,110Filed 22 Oct 2001
Priority: SE 0003810-920 Oct 2000
Published: 7 Nov 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/24
Drugs for disorders of the nervous system: antidepressants
C07D 209/08
Indoles; Hydrogenated indoles: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms…

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Application60/243,115Us provisional application · filed 25 Oct 2000
US 7,087,750 B2Related patent
US 2002/0165251 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

10/037,110Filed 22 Oct 2001

Priority

SE 0003810-920 Oct 2000

Published

7 Nov 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/24
Drugs for disorders of the nervous system: antidepressants
C07D 209/08
Indoles; Hydrogenated indoles: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms…