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Sulfamoyl benzoic acid derivatives as trpm8 antagonists

An amino and receptor antagonism technology, which can be used in anti-inflammatory agents, drug combinations, anti-tumor drugs, etc., to solve the problems of sensory organ neurotoxicity in patients

Inactive Publication Date: 2012-04-25
RAQUALIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oxaliplatin, a third-generation platinum-based chemotherapy drug, induces severe sensory neurotoxicity in patients, which is exacerbated by low temperature exposure

Method used

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  • Sulfamoyl benzoic acid derivatives as trpm8 antagonists
  • Sulfamoyl benzoic acid derivatives as trpm8 antagonists
  • Sulfamoyl benzoic acid derivatives as trpm8 antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0447] 4-(N-Benzyl-N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)benzoic acid

[0448] Step-1: Methyl 4-(N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)benzoate salt

[0449] To a solution of 3-chloro-5-(trifluoromethyl)pyridin-2-amine (1.0 g, 5.1 mmol) in pyridine (5 mL) was added methyl 4-(chlorosulfonyl)benzoate (1.3 g, 5.6 mmol), and the mixture was refluxed for 14 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM. Next, with 2M aqueous HCl and saturated NaHCO 3 Wash the organic layer and make it in MgSO 4 Dry on top. Filtration was performed to make the solvent and MgSO 4 After the layers were separated, the solvent was removed under reduced pressure to obtain 550 mg (27% yield) of methyl 4-(N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl) as a dark solid Sulfamoyl) benzoate was used in the next step without further purification;

[0450] 1 H-NMR (300MHz, DMSO-d 6 )δ8.15-8.05 (2H, m), 8.05-7.95 (2H, m),...

Embodiment 2

[0461] 4-(N-Benzyl-N-(3-(trifluoromethyl)pyridin-2-yl)sulfamoyl)benzoic acid

[0462] Step-1: N-Benzyl-3-(trifluoromethyl)pyridin-2-amine

[0463] At room temperature, in 2-chloro-3-(trifluoromethyl)pyridine (500mg, 2.8mmol) and K 2 CO 3 (1.9g, 13.8mmol) in DMF (5mL) was added benzylamine (0.9g, 8.3mmol), and the mixture was stirred at 110°C for 16 hours. The reaction was quenched with water, and the product was extracted with (EtOAc / toluene=4 / 1). Next, the organic layer was washed with brine and placed in Na 2 SO 4 Dry on top. Filtration is performed to make the solvent and Na 2 SO 4 After separation, the solvent was removed under reduced pressure to obtain a residue, which was applied to an amino-silica gel chromatography column and eluted with hexane / EtOAc=19 / 1 to obtain 363 mg (52% yield) of the title compound as a white solid ;

[0464] 1 H-NMR (300MHz, CDCl 3 )δ8.28 (1H, d, J = 4.8Hz), 7.67 (1H, d, J = 7.3Hz), 7.40-7.30 (5H, m), 6.65 (1H, dd, J = 7.3, 4.8H...

Embodiment 3

[0469] N-Benzyl-N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)benzenesulfonamide

[0470] Step-1: N-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)benzenesulfonamide

[0471] As in step-1 of Example 1, it was prepared from benzenesulfonyl chloride;

[0472] 1 H-NMR (CDCl 3 , 300MHz) δ8.41 (1H, s), 8.18 (2H, d, J=7.3Hz), 8.00-7.80 (2H, m), 7.70-7.50 (3H, m);

[0473] LC-MS (Method A) m / z: M+1 obs 336.9, tR = 2.97 min.

[0474] Step-2: N-Benzyl-N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)benzenesulfonamide

[0475] As in step-2 of Example 1, it was prepared from N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)benzenesulfonamide (step-1 of Example 3);

[0476] 1 H-NMR (300MHz, CDCl 3 )δ8.52 (1H, d, J = 1.5Hz), 7.93 (1H, d, J = 2.2Hz), 7.90-7.80 (2H, m), 7.68 (1H, m), 7.60-7.52 (2H, m ), 7.37 (1H, m), 7.25-7.10 (4H, m), 4.69 (2H, s).

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Abstract

The present invention relates to sulfamoyl benzoic acid derivatives of formula (I) or a pharmaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders which are mediated via the TRPM8 receptor.

Description

technical field [0001] The present invention relates to sulfamoylbenzoic acid derivatives that function as modulators of the TRPM8 receptor. The present invention also relates to a process for the preparation of novel sulfamoylbenzoic acid derivatives and their use in the treatment of a wide range of diseases, syndromes and disorders, especially in the treatment of inflammation, pain and diseases or disorders of the urinary system. Background technique [0002] Transient receptor potential (TRP) channels are one of the largest groups of ion channels, subdivided into six subfamilies (TRPV, TRPM, TRPA, TRPC, TRPP and TRPML). TRP channels are cation-selective channels that are activated by various physical (eg, temperature, osmolarity, and mechanical) and chemical stimuli. TRPM8 is a member of the TRP channel family. The receptor was cloned in 2002 (McKemy, D.D., et al., Nature 416, 52-58, 2002; Peier, A.D., Cell 108, 705-715, 2002), showing sensitivity to low temperature and...

Claims

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Application Information

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IPC IPC(8): A61K31/18A61K31/196A61K31/44A61K31/443A61K31/4436A61K31/4439A61K31/444A61K31/4453A61K31/4709A61K31/495A61K31/5375A61K31/5377A61P1/04A61P9/10A61P11/06A61P13/00A61P13/02A61P13/08A61P13/10A61P13/12A61P19/08A61P25/00A61P25/04A61P25/22A61P25/24A61P29/00A61P43/00C07C311/21C07C311/29C07D211/16C07D213/42C07D213/76C07D295/12C07D295/18C07D401/12C07D401/14C07D405/04C07D405/12C07D409/04C07D409/12C07D413/12C07D417/12
CPCC07D295/185A61K31/5375A61K31/18A61K31/4453C07D405/12C07D213/75C07D409/12A61K31/4709C07D405/04A61K31/5377C07D413/12C07C311/21A61K31/44A61K45/06C07D401/14C07D213/42C07D401/12C07D409/04A61K31/4439A61K31/495A61K31/4436A61K31/444C07D417/12A61K31/443A61K31/196C07D295/13A61P1/00A61P1/04A61P9/10A61P9/12A61P11/00A61P11/06A61P13/00A61P13/02A61P13/08A61P13/10A61P13/12A61P17/04A61P19/00A61P19/02A61P19/08A61P21/00A61P25/00A61P25/04A61P25/06A61P25/22A61P25/24A61P29/00A61P35/00A61P43/00A61K2300/00C07D211/16
Inventor 井上义大见仁川村清安藤一男宍户祐二
Owner RAQUALIA PHARMA INC
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