Compositions and methods for modulating gated ion channels
AssigneeAros Pharma ApS
InventorsRahul Vohra, Joachim Demnitz, Philip Ahring, Zhonghong Gan, Nachhattarpal Gill
Life of this patent
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Abstract
The present invention relates to compositions and methods to modulate the activity of gated ion channels.
Claims43
A method of modulating the activity of a gated ion channel, comprising contacting a cell expressing a gated ion channel with an effective amount of a compound represented by the Formula 1,
- and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof;
- wherein
- the dashed lines indicate a single or double bond;
- R1 is selected from the group consisting of hydrogen, alkyl, alkoxy-alkyl, hydroxy-alkyl, alkoxy-carbonyl-alkyl, alkyl-carbonyl-oxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, sulfonamide, amino, sulfonyl, sulfonic acid, urea, phenyl or benzyl, in which the phenyl or benzyl group is optionally substituted with halogen, CF3, nitro, amino, cyano, hydroxy-alkyl, alkoxy, sulfonamide, alkenyl, alkynyl, amino, sulfonyl, sulfonic acid and urea;
- R2 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, —(CH2)1-4S(O)3H, —C(O)C4alkyl and —S(O)2C1-4alkyl;
- R3 is selected from the group consisting of hydrogen, hydroxyl, alkyl, acyl, phenyl, benzyl, —COOH, —C(O)N(CH3)2, —O-phenyl, —OCF3, alkoxy, —O(CH2)0-4OCH3, —C(O)H, —C(O)CH3,
- and R4 and R5 are each, independently, selected from the group consisting of halogen, CF3, nitro, amino, cyano, hydroxyl, alkyl, alkoxy, phenoxy and phenyl, or a group of the formula —SO2NR′R″, wherein R′ and R″ independently of each another represents hydrogen or alkyl.
3-5. (canceled)
A method of modulating the activity of a gated ion channel, comprising contacting a cell expressing a gated ion channel with an effective amount of a compound selected from the group consisting of 5-phenyl-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 8-ethyl-5-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(2-ethoxy-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime.
22-33. (canceled)
37-56. (canceled)
A method of treating pain in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula 1, Formula 2, Formula 3 or Formula 4.
A method of treating pain in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from the group consisting of 5-phenyl-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 8-ethyl-5-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(2-ethoxy-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime.
60-63. (canceled)
A method of treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula 1, Formula 2, Formula 3 or Formula 4.
A method of treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from the group consisting of 5-phenyl-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 8-ethyl-5-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(2-ethoxy-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime.
67-69. (canceled)
A method of treating a neurological disorder in a subject in need thereof, comprising administering an effective amount of a compound of Formula 1, Formula 2, Formula 3 or Formula 4.
A method of treating a neurological disorder in a subject in need thereof, comprising administering an effective amount of a compound selected from the group consisting of 5-phenyl-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 8-ethyl-5-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(2-ethoxy-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime.
73-75. (canceled)
A method of treating a disease or disorder associated with the genitourinary and/or gastrointestinal systems of a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula 1, Formula 2, Formula 3 or Formula 4.
A method of treating a disease or disorder associated with the genitourinary and/or gastrointestinal systems of a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from the group consisting of 5-phenyl-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 8-ethyl-5-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(2-ethoxy-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime.
79-96. (canceled)
The compound of claim 99, wherein the compound is selected from the group consisting of 5-(5-fluoro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-methyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 5-(5-fluoro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 5-(5-chloro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-methyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 5-(3,5-dimethylphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-methyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 5-(3,5-dimethylphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 5-(2,5-dimethylphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 5-(2,3-dimethyl-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(5-chloro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one.
A compound selected from the group consisting of 5-phenyl-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one;
- 8-ethyl-5-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime;
- and 5-(2-ethoxy-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime.
A compound of the of Formula 1, Formula 2, Formula 3 or Formula 4, and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof.
Dependencies are inferred from the claim text.