262298-02-2Relevant articles and documents
A 4-methoxy-2-methyl-benzyl cyanide synthesis method
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, (2019/02/02)
The invention relates to a synthesis method for 4-methoxy-2-methyl benzyl cyanide. The synthesis method takes 3, 4-dimethylphenol which is cheap and simple and easy to purchase as the raw material, and comprises six steps: methylation, oxidation, Witting reaction, alkene ether hydrolysis, oximation and dehydration. The synthesis method uses the simple and cheap raw material, is simple to operate, is easy for industrial production, has short production cycle, only needs purification in the last step of the six so as to obtain high-quality 4-methoxy-2-methyl benzyl cyanide, and avoids using extremely toxic substances like NaCN and KCN, thus filling the blank home and abroad.
8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: Selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists
Gilligan, Paul J.,He, Liqi,Clarke, Todd,Tivitmahaisoon, Parcharee,Lelas, Snjezana,Li, Yu-Wen,Heman, Karen,Fitzgerald, Lawrence,Miller, Keith,Zhang, Ge,Marshall, Anne,Krause, Carol,McElroy, John,Ward, Kathyrn,Shen, Helen,Wong, Harvey,Grossman, Scott,Nemeth, Gregory,Zaczek, Robert,Arneric, Stephen P.,Hartig, Paul,Robertson, David W.,Trainor, George
scheme or table, p. 3073 - 3083 (2010/01/16)
This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo-[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF1) receptor antagonists. CRF1 receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF1 antagonist (hCRF1 IC50 ) 4.7 ± 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.
TRICYCLIC AND HETEROCYCLIC DERIVATIVE COMPOUNDS AND DRUGS CONTAINING THESE COMPOUNDS AS THE ACTIVE INGREDIENT
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Page/Page column 25, (2008/06/13)
Tri- heterocyclic compound of formula (I) wherein each of W, X and Y is carbon or nitrogen; each of U and Z is CR2, NR13, nitrogen, oxygen, sulfur etc.; A ring is carbocyclic ring, heterocyclic ring; R1 is alkyl, alkenyl,
Estrogen receptor-β potency-selective ligands: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues
Meyers,Sun,Carlson,Marriner,Katzenellenbogen,Katzenellenbogen
, p. 4230 - 4251 (2007/10/03)
Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ERα) and beta (ERβ), we have found that 2,3-bis(hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ERβ than with ERα. To investigate the ERβ affinity- and potency-selective character of this DPN further, we prepared a series of DPN analogues in which both the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and nitrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity for ERβ (i.e., they are ERβ affinity-selective), and many, but not all of them, are also more potent in activating transcription through ERβ than through ERα (i.e., they are ERβ potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the highest ERβ affinity-selective ligands, and they have an ERβ potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogues have lower affinities, and only the fluorinated polar analogues have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ERβ selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group β to the nitrile in DPN or the addition of a methyl substitutent at an ortho position on the β-aromatic ring increases the affinity and selectivity of these compounds for ERβ. These ERβ-selective compounds may prove to be valuable tools in understanding the differences in structure and biological function of ERα and ERβ.
The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4- methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine: A corticotropin-releasing factor (hCRF1) antagonist
Gilligan, Paul J.,Baldauf, Caryn,Cocuzza, Anthony,Chidester, Dennis,Zaczek, Robert,Fitzgerald, Lawrence W.,McElroy, John,Smith, Mark A.,Shen,Saye, Jo Anne,Christ, David,Trainor, George,Robertson, David W.,Hartig, Paul
, p. 181 - 189 (2007/10/03)
Structure-activity relationship studies led to the discovery of 4-(3- pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]- pyrimidine 11-31 (DMP904), whose pharmacological profile strongly supports the hypothesis that hCRF1 antagonists may be potent anxiolytic drugs. Compound 11-31 (hCRF1 K(i) = 1.0 ± 0.2 nM (n = 8)) was a potent antagonist of hCRF1-coupled adenylate cyclase activity in HEK293 cells (IC50 = 10.0 ± 0.01 nM versus 10 nM r/hCRF, n = 8); α-helical CRF(9-41) had weaker potency (IC50 = 286 ± 63 nM, n = 3). Analogue 11-31 had good oral activity in the rat situational anxiety test; the minimum effective dose for 11-31 was 0.3 mg/kg (po). Maximal efficacy (approximately 57% reduction in latency time in the dark compartment) was observed at this dose. Chlordiazepoxide caused a 72% reduction in latency at 20 mg/kg (po). The literature compound 1 (CP154526-1, 30 mg/kg (po)) was inactive in this test. Compound 11-31 did not inhibit open-field locomotor activity at 10, 30, and 100 mg/kg (po) in rats. In beagle dogs, this compound (5 mg/kg, iv, po) afforded good plasma levels. The key iv pharmacokinetic parameters were t(1/2), CL and V(d,ss) values equal to 46.4 ± 7.6 h, 0.49 ± 0.08 L/kg/h and 23.0 ± 4.2 L/kg, respectively. After oral dosing, the mean C(max), T(max), t(1/2) and bioavailability values were equal to 1260 ± 290 nM, 0.75 ± 0.25 h, 45.1 ± 10.2 h and 33.1%, respectively. The overall rat behavioral profile of this compound suggests that it may be an anxiolytic drug with a low motor side effect liability. (C) 2000 Elsevier Science Ltd.
