Chemical Formula: C16H19N5O4S
Exact Mass: 377.1158
PHASE 2 , FOR EPILEPSY, TITINUS
Selurampanel (INN, code name BGG492) is a drug closely related to the quinoxalinedione series which acts as a competitive antagonist of the AMPA and kainate receptors and, as of 2015, is being investigated in clinical trials by Novartis for the treatment ofepilepsy. It has also been studied in the acute treatment of migraine, and was found to produce some pain relief, but with a relatively high rate of side effects.
Example 44: N-[7-IsopropyI-6-(l-methyl-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yl]-methanesulfonamide
2-Amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester
The 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester required for the coupling reaction described below was prepared according to the procedures described in WO 2004/033435 Al.
The l-methyl-5-tributylstannanyl-lH-pyrazole required for the coupling reaction was prepared according to the procedure described above.
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and l-methyl-5-tributylstannanyl-lH-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100 0C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H- pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 21 A [M+H]+, rt 5.20 min).
2-(4-Chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester
4-Chlorophenyl-chloroformate (88 μL, 1.1 equiv) was added to a solution of 2-amino-4-isopropyl-5-(2~ methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (156 mg, 0.57 mmol) in dioxane (1.5 mL). The mixture was stirred for 2 h (TLC control) at 80 0C. The mixture was evaporated to dryness. The obtained yellow solid was used in the next step without further purification, (rt 6.77 min)
N-[7-Isopropyl-6-(2-methyl-2H-pyrazol-3 -yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl] -methanesulfonamide
CH3SO2NHNH2 (79.5 mg, 1.1 equiv) and J-Pr2NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80 0C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH / DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3 ~yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]+, rt 4.20 min).
|Substituted 1H-quinazoline-2,4-diones useful as AMPA receptor ligands [US7655666]||2008-06-26||2010-02-02|
|2,4-DIOXO-1,4-DIHYDRO-2H-QUINAZOLIN-3-YL-SULFONAMIDE DERIVATIVES [US2013053381]||2011-05-18||2013-02-28|
|Use of 1H-quinazoline-2,4-diones [US2013090346]||2012-09-05||2013-04-11|
|Use of 1H-quinazoline-2,4-diones [US2013096145]||2011-06-24||2013-04-18|
|Use of 1H-quinazoline-2,4-diones [US2014163050]||2014-02-12||2014-06-12|
|FOMULATION COMPRISING 1 H-QUINAZOLINE-2, 4-DIONE AMPA RECEPTOR ANTAGONISTS, IN THE FORM OF IMMEDIATE RELEASE TABLETS AND PREPARATION THEREOF [US2012263791]||2010-12-21||2012-10-18|
|Use of 1H-Quinazoline-2,4-Diones [US2014018376]||2010-10-20||2014-01-16|
|1-H-QUINAZOLINE-2, 4-DIONES FOR USE IN THE TREATMENT OF NEURONAL CEROID LIPOFUSCINOSIS [US2012122903]||2010-07-23||2012-05-17|
- Faught, Edward (2014). “BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy”. Expert Opinion on Investigational Drugs 23 (1): 107–113.doi:10.1517/13543784.2014.848854. ISSN 1354-3784.
- Belcastro, Vincenzo; Verrotti, Alberto (2015). “Novel Molecular Targets for Drug-Treatment of Epilepsy”: 183–199.doi:10.1007/978-3-319-12283-0_10.
- Hanada, Takahisa (2014). “The AMPA receptor as a therapeutic target in epilepsy: preclinical and clinical evidence”. Journal of Receptor, Ligand and Channel Research: 39.doi:10.2147/JRLCR.S51475. ISSN 1178-699X.
- Gomez-Mancilla B, Brand R, Jürgens TP, et al. (February 2014). “Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks”. Cephalalgia 34 (2): 103–13.doi:10.1177/0333102413499648. PMID 23963355.
|Systematic (IUPAC) name|
|Molar mass||377.418 g/mol|
////Selurampanel, BGG492, 912574-69-7