Novel Tetrahydronaphalene Antagonists to the Thromboxane A2 (TP) Receptor
a technology of thromboxane and tetrahydronaphalene, which is applied in the direction of peptide/protein ingredients, biocide, heterocyclic compound active ingredients, etc., can solve the problems of untreated mice with significant reduction of plaque load relative to untreated mice, sporadic ad deposition is still not fully understood, and trials of txa2 antagonists have not been successful, so as to improve brain penetration
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TP Receptor Antagonists
[0143]TP receptor antagonists have been sought by the pharmaceutical industry because TxA2 plays a role in platelet aggregation and lung inflammation (Narumiya et al., 2001, J Clin Invest 108:25-30; Chaer, et al., 2006, Vase Endovascular Surg. 40:261-267; Hata et al., 2004, Pharmacol Ther. 103:147-166). There are two splice isoforms of the human TP receptor (Raychowdhury, et al., 1994, Biol. Chem. 269:19256-19261), but there is no evidence of pharmacological differences between these two variants. A number of compounds have been identified that effectively antagonize the TP receptor and certain of these are being pursued clinically (Dogne, et al., 2006, Curr Pharm Des. 12:903-923). However, with few exceptions, existing TP antagonists (FIG. 1) contain a carboxylic acid moiety that greatly limits their ability to passively diffuse across the blood-brain barrier (BBB) and gain access to the brain, as carboxylate-containing molecules typically have poor brain exp...
example 2
Synthetic Chemistry
[0152]All solvents used for chemically modify existing TP receptor antagonists were reagent grade. All reagents were purchased from Aldrich or Acros and used as received. Thin layer chromatography (TLC) was performed with 0.25 mm E. Merck pre-coated silica gel plates. Unless otherwise stated, flash chromatography was performed with silica gel 60 (particle size 0.040-0.062 mm) supplied by Silicycle and Sorbent Technologies. TLC spots were detected by viewing under a UV light. Infrared (IR) spectra were recorded on a Jasco Model FT / IR-480 Plus spectrometer. Proton (1H) and carbon (13C) NMR spectra were recorded on a Bruker AMX-500 spectrometer. Chemical shifts were reported relative to solvents. High-resolution mass spectra were measured at the University of Pennsylvania Mass Spectrometry Center on either a VG Micromass 70 / 70H or VG ZAB-E spectrometer. Analytical reverse-phased (Sunfirelm C18; 4.6×50 mm, 5 mL) high-performance liquid chromatography (HPLC) was perfor...
example 3
Scheme 1
[0154]5-Bromo-3,4-dihydronaphthalen-2(1H)-one, designated as 2 in FIG. 5 was produced as follows (see e.g., Aroop, C.; Viswanathan, R.; Johnston, J. N. Org. Lett. 2007, 9, 5027). Oxalyl chloride (2.2 mL, 25.13 mmol) was added to a solution of 3-(2-bromophenyl)propanoic acid (2.86 g, 12.49 mmol) in dichloromethane (25 mL) at 0° C. After 30 min, the reaction was warmed to room temperature and stirring continued for 3 hr. The solvent was removed under reduced pressure and replaced with diethyl ether (25 mL). This solution was cooled to −40° C. and freshly prepared diazomethane (˜45 mmol) in diethyl ether (90 mL) was added dropwise over 1 hr. The reaction was warmed to room temperature over 1 hour and stirred at room temperature for a further 1 hour. The solvent was removed under a positive pressure of argon and the resultant yellow solid was purified by flash chromatography on silica gel (20% ethyl acetate in hexanes). The purified product was dissolved in dichloromethane (90 m...
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