801306-54-7Relevant articles and documents
1,2-Diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepines as TRPV1 antagonists with improved properties
Lebsack, Alec D.,Rech, Jason C.,Branstetter, Bryan J.,Hawryluk, Natalie A.,Merit, Jeffrey E.,Allison, Brett,Rynberg, Raymond,Buma, Johnathan,Rizzolio, Michele,Swanson, Nadia,Ao, Hong,Maher, Michael P.,Herrmann, Michelle,Freedman, Jamie,Scott, Brian P.,Luo, Lin,Bhattacharya, Anindya,Wang, Qi,Chaplan, Sandra R.,Wickenden, Alan D.,Breitenbucher, J. Guy
scheme or table, p. 7142 - 7146 (2011/01/03)
Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 = >237 μg/mL and SIF = 11 μg/mL) was significantly improved over compound 1 (pH 2 = 5 μg/mL and SIF = 0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL = 0.7 L/kg/h) compared to compound 1 (CL = 3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
AMIDE DERIVATIVE
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Page/Page column 26, (2008/06/13)
An amide derivative represented by the formula (I) wherein A is a cycloalkyl group, an aryl group or a heteroaryl group, X is a nitrogen atom or CR17, Y is NRa, -(CRbRb')m- and the like, m is 0-4, and R1-R17 may be the same or different and each is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, a formyl group, a hydroxyl group, an ammonium group, an alkyl group optionally having a substituent(s), ZR18 and the like, Z is -O-, -S(O)p-, -S(O)pO-, -NH-, -NR19- and the like, or R1 and R2 may in combination form a ring, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is applied to pharmaceutical use such as anti-inflammatory and analgesic action and the like.
