Novel compounds, their use and preparation

• US 20050256106A1
• Filed: 02/11/2005
• Published: 11/17/2005
• Est. Priority Date: 10/20/2000
• Status: Active Grant

• Current Assignee: Proximagen Limited
• Original Assignee: Biovitrum AB (Swedish Orphan Biovitrum AB (publ))
• Inventors: Johansson, Gary, Nilsson, Bjorn M., Caldirola, Patrizia
• Granted Patent: US 7,524,839 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

The invention-provides 2, 3-, 4- or 5-substituted-N1-(arylsulfonyl)indole and (heteroaryl)indole compounds of the general formula (I):
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.

Claims

1-27. -27. (canceled)

28. A method for the treatment or prophylaxis of obesity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):

29. The method of claim 28, wherein

Ar is

(1) phenyl that is unsubstituted or optionally mono- or poly-substituted with halogen, C_1-6 alkyl, CF₃, hydroxyl, C_1-6 alkoxyl, OCF₃, CN, NO₂, phenyloxyl, phenyl, alkylsulfonyl, C_1-6 alkenyl, —

NH₂, —

NHR⁷, —

NR⁷R⁸, C_1-6 alkylcarboxyl, formyl, —

NH—

CO—

C_1-6 alkyl, —

CO—

NR⁷R⁸, or SR⁷ wherein each of R⁷ and R⁸ is independently H or C_1-6 alkyl;

(2) 1-naphthyl or 2-naphthyl that is unsubstituted or optionally mono- or poly-substituted with halogen, C_1-6 alkyl, CF₃, hydroxyl, C_1-6 alkoxyl, OCF₃, CN, NO₂, phenyloxyl, phenyl, alkylsulfonyl, C_2-6 alkenyl, —

NH₂, —

NHR⁷, —

NR⁷R⁸, C_1-6 alkylcarboxyl, formyl, —

NH—

CO—

C_1-6 alkyl, —

CO—

NR⁷R⁸, or SR⁷ wherein each of R⁷ and R⁸ is independently H or C_1-6 alkyl;

(3) cinnamoyl;

(4) benzyl;

(5) 1,1-diphenylethyl;

(6) a monocyclic or bicyclic heterocyclic ring selected from the group consisting of furyl, pyrrolyl, triazolyl, diazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, and benzoxadiazolyl, said heterocyclic ring being optionally mono- or di-substituted substituted with halogen or C_1-6 alkyl;

R⁴ is H or is selected from the group consisting of;

wherein R⁶ is H, C_1-6 alkyl, or benzyl; and

R⁵ is H, hydroxy, C_1-3 alkoxy, F, NO₂, CF₃, OCF₃ or is selected from the group consisting of;

30. The method of claim 28, wherein

Ar is

(1) phenyl,

(2) 1-naphthyl or 2-naphthyl,

(3) a 5- to 10-membered monocyclic or bicyclic heterocyclic ring having 1 to 4 hetero atoms 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 F, Cl, Br, C_1-6 alkyl, CF₃, hydroxyl, C_1-6 alkoxyl, OCF₃, phenyl, C_2-6 alkenyl, —

NR⁷R⁸, —

NH—

CO—

C_1-6 alkyl, or SR⁷, wherein each of R⁷ and R⁸ is independently H or C_1-6 alkyl; and

R⁹ is C_1-2 alkyl;

R² is H, phenyl, I, or C_1-6 alkyl;

R⁴ is selected from the group consisting of;

R⁵ is C_1-3 alkoxy or a heterocyclic ring selected from the group consisting of;

31. The method of claim 28, wherein Ar is phenyl, optionally substituted with F, Cl, Br, methyl, CF₃, C_1-4 alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl, methylsulfonyl, or —

NR⁷R⁸, where each of R⁷ and R⁸ is independently H or methyl.

32. The method of claim 28, wherein Ar is 1-naphthyl or 2-naphthyl, each of which is optionally substituted with F, Cl, Br, methyl, CF₃, C_1-4 alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl, methylsulfonyl, or —

NR⁷R⁸, where each of R⁷ and R⁸ is independently H or methyl.

33. The method of claim 28, wherein Ar is a heterocyclic ring selected from the group consisting of furyl, pyrrolyl, triazolyl, diazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, and benzoxadiazolyl, each of which is optionally substitiuted with halogen, C_1-6 alkyl, CF₃, hydroxyl, C_1-6 alkoxyl, OCF₃, CN, NO_2, phenyloxy, phenyl, C_1-6 alkylsulfonyl, C_2-6 alkenyl, —

NR⁷R⁸, C_1-6 alkylcarboxyl, formyl, —

NH—

CO—

C_1-6 alkyl, —

CO—

NR⁷R⁸, or SR⁷;

wherein each of R⁷ and R⁸ is independently H or C_1-6 alkyl.

34. The method of claim 28, wherein Ar is a heterocyclic ring selected from the group consisting of pyridinyl, thienyl, imidazolyl, pyrazolyl, benzothienyl, and benzoxadiazolyl, each of which is optionally substituted with halogen or C_1-6 alkyl.

35. The method of claim 28, wherein Ar is 2-pyridyl, 3-pyridyl, or 4-pyridyl.

36. The method of claim 28, wherein Ar is a 5- to 7-membered aromatic, partially saturated, or completely saturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of O, S, or NR¹⁰, where R¹⁰ is H, C_1-6 alkyl, —

CO—

CF₃, or absent.

37. The method of claim 28, wherein Ar is —

R⁹-phenyl, wherein R⁹ is C_1-3 alkyl or C_2-3 alkenyl, either of which is optionally substituted with phenyl or phenyloxy, each phenyl being optionally substituted with F, Cl, Br, methyl, CF₃, C_1-4 alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl, methylsulfonyl, or —

NR⁷R⁸; and

each of R⁷ and R⁸ being independently H or C_1-6 alkyl.

38. The method of claim 28, wherein each of R² and R³ is H.

39. The method of claim 28, wherein each of R⁴ and R⁵ is independently H or a heterocyclic ring selected from the group consisting of:

40. The method of claim 28, wherein Ar is phenyl, optionally substituted with F, Cl, Br, methyl, CF₃, C_1-4 alkoxyl, OCF₃, CN, NO_2, phenyloxy, phenyl, methylsulfonyl, or —

NR⁷R⁸ where each of R⁷ and R⁸ is independently H or methyl;

each of R² and R³ is H; and

each of R⁴ and R⁵ is independently H or a heterocyclic ring selected from the group consisting of;

41. The method of claim 28, wherein Ar is 1-naphthyl or 2-naphthyl, each of which is optionally substituted with F, Cl, Br, methyl, CF₃, C_1-4 alkoxyl, OCF₃, CN, NO₂, phenyloxy, phenyl, methylsulfonyl, or —

NR⁷R⁸, where each of R⁷ and R⁸ is independently H or methyl;

each of R² and R³ is H; and

each of R⁴ and R⁵ is independently H or a heterocyclic ring selected from the group consisting of;

42. The method of claim 28, wherein Ar is a heterocyclic ring selected from the group consisting of pyridinyl, thienyl, imidazolyl, pyrazolyl, benzothienyl, and benzoxadiazolyl, each being optionally substituted with halogen or C_1-6 alkyl;

each of R² and R³ is H; and

each of R⁴ and R⁵ is independently H or a heterocyclic ring selected from the group consisting of;

43. The method of claim 28, wherein Ar is 2-pyridyl, 3-pyridyl, or 4-pyridyl;

each of R² and R³ is H; and

each of R⁴ and R⁵ is independently H or a heterocyclic ring selected from the group consisting of;

44. The method of claim 28, wherein Ar is —

R⁹-phenyl;

each of R² and R³ is H; and

each of R⁴ and R⁵ is independently H or a heterocyclic ring selected from the group consisting of;

45. The method of claim 28, wherein the compound of formula (I) is 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)-1H-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-(piperazin-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.

46. The method of claim 28, wherein the compound of formula (I) is 1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indole.

47. The method of claim 28, wherein the compound of formula (1) is 1-[(2,5-dimethoxyphenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole.

48. The method of claim 28, wherein the compound of formula (I) is 4-(1-piperazinyl)-1-(3-pyridinylsulfonyl)-1H-indole hydrochloride.

49. A method for the treatment or prophylaxis of obesity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) in claim 28, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.