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YANG Hongliang, XU Guoxing, BAO Meiying, ZHANG Dapeng, LI Zhiwei, PEI Yazhong
Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities

2014 Vol. 35 (12): 2584-2592 [Abstract] ( 781 ) [HTML 0KB] [PDF 2464KB] (116 )
doi: 10.7503/cjcu20140333

Chemical Journal of Chinese Universities 2014, Vol. 35 Issue (12): 2584-2592 DOI: 10.7503/cjcu20140333

Abstract Based on the X-ray co-crystal structures of reported allosteric kinase inhibitors bound to their corresponding protein kinases, a pharmacophore model was proposed. To examine the validity of this hypothesis, 21 new pyridinylisoxazole derivatives were designed and synthesized. Their structures were confirmed using 1H NMR, 13C NMR and MS data. Their inhibitory effects against human breast cancer cell(MCF-7) proliferation were evaluated. Preliminary results indicated that some of these pyridinylisoxazole derivatives possess potent anti-proliferative activities, with IC50 data in the micromolar range. The mechanism-of-action of these compounds is under investigation.

Cite this article:

Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities

YANG Hongliang¹, XU Guoxing¹, BAO Meiying², ZHANG Dapeng¹, LI Zhiwei¹, PEI Yazhong¹

1. The Center for Combinatorial Chemistry and Drug Discovery, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China;
2. Changchun Discovery Sciences Co. Ltd., Changchun 130012, China

YANG Hongliang,XU Guoxing,BAO Meiying et al. Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities[J]. Chemical Journal of Chinese Universities, 2014, 35(12): 2584-2592.

URL:

http://www.cjcu.jlu.edu.cn/EN/10.7503/cjcu20140333 OR http://www.cjcu.jlu.edu.cn/EN/Y2014/V35/I12/2584

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Venlafaxine

CAS : 93413-69-5

CAS Name: 1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

Additional Names: (±)-1-[a-[(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol; N,N-dimethyl-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethylamine; venlafexine

Molecular Formula: C17H27NO2

Molecular Weight: 277.40

Percent Composition: C 73.61%, H 9.81%, N 5.05%, O 11.54%

SEE

part 1………http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html / http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/

part 2……..http://newdrugapprovals.org/2015/04/09/venlafaxine-22/

PART 3…..http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html

Chemistry

The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride, and it has the empirical formula of C₁₇H₂₇NO₂. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesic tramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.^[66]

Venlafaxine
Systematic (IUPAC) name


(RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol
Clinical data
Trade names	Effexor XR, Effexor, Trevilor
AHFS/Drugs.com	monograph
Licence data	US Daily Med:link
Pregnancy category	AU: B2 US: C
Legal status	AU:Prescription Only (S4) CA: ℞-only UK:POM US:℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	42±15%^[1]
Protein binding	27±2% (parent compound), 30±12% (active metabolite,desvenlafaxine)^[2]
Metabolism	Hepatic (~50% of the parent compound is metabolised on first pass through the liver)^[1]^[2]
Half-life	5±2 h (parent compound for immediate release preparations), 15±6 h (parent compound for extended release preparations), 11±2 h (active metabolite)^[1]^[2]
Excretion	Renal (87%; 5% as unchanged drug; 29% asdesvenlafaxine and 53% as other metabolites)^[1]^[2]
Identifiers
CAS Registry Number	93413-69-5
ATC code	N06AX16
PubChem	CID 5656
DrugBank	DB00285
ChemSpider	5454
UNII	GRZ5RCB1QG
ChEBI	CHEBI:9943
ChEMBL	CHEMBL637
Chemical data
Formula	C₁₇H₂₇N O₂
Molecular mass	277.402 g/mol

Derivative Type: Hydrochloride

CAS : 99300-78-4

Manufacturers’ Codes: Wy-45030

Trademarks: Effexor (Wyeth)

Molecular Formula: C17H27NO2.HCl

Molecular Weight: 313.86

Percent Composition: C 65.06%, H 8.99%, N 4.46%, O 10.20%, Cl 11.30%

Properties: White to off-white crystalline solid from methanol/ethyl acetate, mp 215-217°. Soly (mg/ml): 572 water. Partition coefficient (octanol/water): 0.43.

Melting point: mp 215-217°

Log P: Partition coefficient (octanol/water): 0.43

Derivative Type: (+)-Form

Properties: Crystals from ethyl acetate, mp 102-104°. [a]D25 +27.6° (c = 1.07 in 95% ethanol).

Melting point: mp 102-104°

Optical Rotation: [a]D25 +27.6° (c = 1.07 in 95% ethanol)

Derivative Type: (+)-Form hydrochloride

Manufacturers’ Codes: Wy-45655

Properties: Crystals from methanol/ether, mp 240-240.5°. [a]D25 -4.7° (c = 0.945 in ethanol).

Melting point: mp 240-240.5°

Optical Rotation: [a]D25 -4.7° (c = 0.945 in ethanol)

Derivative Type: (-)-Form

Properties: Crystals from ethyl acetate, mp 102-104°. [a]D25 -27.1° (c = 1.04 in 95% ethanol).

Melting point: mp 102-104°

Optical Rotation: [a]D25 -27.1° (c = 1.04 in 95% ethanol)

Derivative Type: (-)-Form hydrochloride

Manufacturers’ Codes: Wy-45651

Properties: Crystals from methanol/ether, mp 240-240.5°. [a]D25 +4.6° (c = 1.0 in ethanol).

Melting point: mp 240-240.5°

Optical Rotation: [a]D25 +4.6° (c = 1.0 in ethanol)

Therap-Cat: Antidepressant.

Keywords: Antidepressant; Serotonin Noradrenaline Reuptake Inhibitor (SNRI).

1H NMR

HSQC

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1H NMR PREDICT OF HCL

Venlafaxine hydrochloride NMR spectra analysis, Chemical CAS NO. 99300-78-4 NMR spectral analysis, Venlafaxine hydrochloride H-NMR spectrum

13C NMR PREDICT OF HCL

Venlafaxine hydrochloride NMR spectra analysis, Chemical CAS NO. 99300-78-4 NMR spectral analysis, Venlafaxine hydrochloride C-NMR spectrum

Venlafaxine

BASE

Venlafaxine NMR spectra analysis, Chemical CAS NO. 93413-69-5 NMR spectral analysis, Venlafaxine H-NMR spectrum

Literature References:

Serotonin noradrenaline reuptake inhibitor (SNRI). Prepn: G. E. M. Husbands et al., EP 112669; US4535186 (1984, 1985 both to Am. Home Prods.);

and resolution of isomers: J. P. Yardley et al., J. Med. Chem. 33, 2899 (1990). Receptor binding studies: E. A. Muth et al., Biochem. Pharmacol. 35, 4493 (1986).

HPLC determn in biological fluids: D. R. Hickset al., Ther. Drug Monit. 16, 100 (1994).

Clinical pharmacokinetics: K. J. Klamerus et al., J. Clin. Pharmacol. 32, 716 (1992).

Clinical trial in major depression: E. Schweizer et al., J. Clin. Psychopharmacol. 11, 233 (1991).

Review of pharmacology and clinical efficacy in depression: S. A. Montgomery, J. Clin. Psychiatry 54, 119-126 (1993).

Clinical trial in generalized anxiety disorder: A. J. Gelenberg et al., J. Am. Med. Assoc. 283, 3082 (2000).