2-aryloxycarbonylthiophene-3-sulfonamides highly potent and ET(A) selective endothelin receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 16, 1997, Pages 2093-2098

  Raju, B ^a,b   Wu, Chengde ^a,b   Castillo, Rosario ^a   Okun, Ilya ^a   Stavros, Fiona ^a,b   Chan, Ming Fai ^a  

^a ImmunoPharmaceutics Inc   (United States)

^b TEXAS BIOTECHNOLOGY CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 ARYLOXYCARBONYLTHIOPHENE 3 SULFONAMIDE DERIVATIVE; ENDOTHELIN RECEPTOR; ENDOTHELIN RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; DRUG ACTIVITY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; HUMAN; REACTION ANALYSIS;

EID: 0030842432     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00367-3     Document Type: Article

References (41)

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31. (a) To a stirred suspension of sodium hydride (8.0 g, 330 mmol, prewashed with hexane) in dry THF (400 mL) at 0 °C was added 5-amino-4-chloro-3-methylisoxazole (20 g, 150 mmol) in small portions. After complete addition the reaction mixture was stirred at room temperature for 30 min. (in the case of dimethyl isoxazole the reaction mixture was stirred at ambient temperature for 10 h). This slurry was cannulated slowly into a solution of 2-methoxycarbonylthiophene-3-sulfonyl chloride (36.2 g, 150 mmol) in dry THF at 0 °C. The resultant reaction mixture was stirred at ambient temperature for 1 h. The excess sodium hydride was decomposed by addition of methanol and then added to water (1000 mL). This mixture was extracted with ether (2 x 200 mL) to remove the neutral impurities. The aqueous layer was adjusted to pH 2-3 using concentrated hydrochloric acid and cooled to 10 °C with stirring. The resultant solid was filtered and dried under high vacuum and used in the next step without any further purification. For analytical purpose a small quantity of sample was purified by column chromatography; (b) The above esters were dissolved in sodium hydroxide (5%, 300 mL) and stirred at room temperature for 8 h. The reaction was monitored by TLC; (c) To a stirred solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (1 g, 3.2 mmol) in dry THF (5 mL) was added carbonyl diimidazole (0.533 g, 3.28 mmol), imidazole (225 mg, 3.2 mmol), and sesamol (884 mg, 6.4 mmol). The reaction mixture was heated under reflux for 4 h. THF was removed under reduced pressure and the residue was partitioned between 1 N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. Purification by HPLC using acetonitrile and water containing 0.1 % TFA (0 to 100% over 20 min, linear gradient) on a reverse phase C18 column gave the product; (d) To a stirred mixture of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (0.323 g, 1 mmol), phenol (188 g, 2 mmol) and triethylamine (0.834 ml, 6 mmol) in dry THF (3 mL) was added phosphonitrilic chloride trimer (0.381 g, 1.1 mmol) in one lot which resulted in a slightly exothermic reaction. The resultant reaction mixture stirred at ambient temperature for 30 min. This was diluted with water, the pH adjusted to 2-3 using 6 N HCl, extracted with ethyl acetate, and the combined organic layer was dried over magnesium sulfate. Removal of the solvent under reduced pressure and purification by flash chromatography gave N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenoxycarbonylthiophene-3-sulfonamide (256 mg, 65%).
32. Chan, M. F., Raju, B., Kois, A, Wu, C., Castillo, R.; Balaji, V. N. US Patent 5,464,853, Nov. 7, 1995.
33. Using carbonyldiimdazole as a coupling reagent under refluxing conditions in the presence of a phenol resulted in the formation of two products (9 and 10, as shown below) as determined by NMR of the mixture. This was explained by the formation of lactam 8 which was isolated and characterized. Therefore, phosphonitrilic chloroide trimer was identified as a coupling reagent for the formation of esters (6, Scheme I) which gave only the required ester 10. (equation presented)
34. All sulfonamides are characterized by high resolution FAB MS analysis, C, H, N analysis, PMR, IR and purities were further judged by analytical HPLC on a C18 reverse-phase chromatography.
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40. 2, 30 mM of HEPES buffer (pH 7.4) and 0.5 mg/mL bacitracin] to get 400 μM concentration. 50 μL of membrane (2 μg of protein) and 50 μL (20 nmol) of the stock solution of the compound were diluted to 0.2 mL with the buffer. After incubating for 24 h, an aliquot of this solution was analysed by analytical HPLC to get two peaks corresponding to the initial ester (6, Scheme I) and the respective acid (5, Scheme I), one of the cleaved product.
41. 11 Addition of 7r resulted in a parallel shift to the right of the ET-1 dose responce curve in the TE 671 cells indicating that 7r acts as functional antagonist of ET-1 in this system.