Indolizine derivative and use thereof for medical purposes
Inventors
Shimizu, Kazuo • Iizuka, Masato • Takigawa, Yasushi
Assignees
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Publication Number
US-8748452-B2
Publication Date
2014-06-10
Expiration Date
Abstract
The present invention provides compounds useful as agents for the prevention or treatment of a disease associated with abnormal serum uric acid level and the like. That is, the present invention relates to indolizine derivatives represented by the following formula (I) having xanthine oxidase inhibitory activities and useful as agents for the prevention or treatment of a disease associated with abnormality of serum uric acid level, prodrugs thereof, salts thereof or the like. In the formula, ring U represents aryl or heteroaryl; R1 represents halogen, a hydroxy group or the like; R2 represents halogen, a hydroxy group, alkyl, alkoxy, alkyl substituted by fluorine, alkoxy substituted by fluorine or the like; m represents a number from 0 to 2; n represents a number from 0 to 3; and R3 represents hydrogen, fluorine or the like.
Core Innovation
The disclosed subject matter provides indolizine derivatives represented by formula (I), wherein ring U is aryl or heteroaryl, and the structure includes substituent variables R1, R2, R3, and substituent group a within specified selections of halogen, hydroxy, nitro, amino, cyano, carboxy, carbamoyl, and C1-6 alkyl or C1-6 alkoxy groups, including pharmaceutically acceptable salts thereof.
For the indolizine derivative of formula (I), R2 is selected from a detailed list of functional groups and related substituted groups, with optional ring formation when two neighboring R2 groups form a 5 to 8-membered ring together with binding atoms in the indolizine ring. The formula also constrains m and n as integral numbers within stated ranges, and substituent group a is limited to fluorine, chlorine, hydroxy, amino, carboxy, carbamoyl, cyano, C1-6 alkyl, C1-6 alkoxy, and mono(di)C1-6 alkylamino.
The disclosed content also explicitly recites individual embodiments of the indolizine derivative as benzoic acid derivatives, including 4-(1-Cyano-7-methylindolizine-3-yl) benzoic acid, 4-(1-Cyano-8-fluoro-7-methylindolizin-3-yl)-benzoic acid, 4-(1-Cyanoindolizine-3-yl)-2-hydroxybenzoic acid, 4-(1-Cyano-7-methylindolizine-3-yl)-2-hydroxybenzoic acid, and 4-(1-Cyano-8-fluoro-7-methylindolizine-3-yl)-2-hydroxybenzoic acid, each optionally as a pharmaceutically acceptable salt.
Claims Coverage
The claim coverage is centered on a broad formula (I) indolizine derivative with detailed substituent selections and optional ring-forming conditions, and is complemented by several specific indolizine benzoic acid embodiments as independent claims. Across the consolidated claims, there are six inventive features.
Indolizine derivative with formula (I) substituent selections
An indolizine derivative represented by formula (I), wherein ring U represents aryl or heteroaryl; R1 represents a halogen atom, a hydroxy group, nitro, amino or C1-6 alkyl which may be substituted by a fluorine atom; R2 represents specified options including halogen, hydroxy, amino, carbamoyl, cyano, carboxy, and various C1-6 alkyl, alkenyl, alkynyl, alkoxy, and related substituted groups; and R3 represents a hydrogen atom, a chlorine atom or a fluorine atom, with substituent group a consisting of fluorine, chlorine, hydroxy, amino, carboxy, carbamoyl, cyano, C1-6 alkyl, C1-6 alkoxy and mono(di)C1-6 alkylamino, or a pharmaceutically acceptable salt thereof.
Substituent-group constraints with m and n, and neighboring R2 ring formation
m and n are restricted integral numbers within stated ranges, with optional different groups when m is 2 and when n is 2 or 3, and two R2 bound to neighboring atoms optionally form a 5 to 8-membered ring together with the binding atoms in the indolizine ring.
4-(1-Cyano-7-methylindolizine-3-yl) benzoic acid
4-(1-Cyano-7-methylindolizine-3-yl) benzoic acid, or a pharmaceutically acceptable salt thereof.
4-(1-Cyano-8-fluoro-7-methylindolizin-3-yl)-benzoic acid
4-(1-Cyano-8-fluoro-7-methylindolizin-3-yl)-benzoic acid, or a pharmaceutically acceptable salt thereof.
4-(1-Cyanoindolizine-3-yl)-2-hydroxybenzoic acid
4-(1-Cyanoindolizine-3-yl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt thereof.
4-(1-Cyano-7-methylindolizine-3-yl)-2-hydroxybenzoic acid
4-(1-Cyano-7-methylindolizine-3-yl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt thereof.
4-(1-Cyano-8-fluoro-7-methylindolizine-3-yl)-2-hydroxybenzoic acid
4-(1-Cyano-8-fluoro-7-methylindolizine-3-yl)-2-hydroxybenzoic acid, or a pharmaceutically acceptable salt thereof.
Overall claim coverage spans a broad indolizine derivative definition by formula (I) with extensive substituent lists and optional ring-forming conditions, together with specific indolizine benzoic acid compounds as standalone claims, each including pharmaceutically acceptable salts.
Stated Advantages
Acts as xanthine oxidase inhibitors to reduce uric acid.
Inhibition includes URAT1-mediated uric acid transport inhibitory activity.
Demonstrates serum hypouricemic effect in rats for selected example compounds.
Useful for prevention or treatment of hyperuricemia and related conditions, including gouty tophus, gouty arthritis, renal disorder associated with hyperuricemia, and urinary calculi.
Prevents and/or treats diseases associated with abnormal serum uric acid levels.
Reduces serum uric acid levels.
Enhances uric acid excretion.
Provides pharmaceutical compositions for medical use.
Documented Applications
Compounds act as xanthine oxidase inhibitors to reduce uric acid for prevention or treatment of hyperuricemia and related conditions.
Related conditions explicitly listed include gouty tophus, gouty arthritis, renal disorder associated with hyperuricemia, and urinary calculi.
Treatment or prevention of hyperuricemia and related conditions including gouty tophus and gouty arthritis.
Treatment or prevention of renal disorder associated with hyperuricemia.
Treatment or prevention of urinary calculi.
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