3D Mol Similar

Varenicline

: CAS No.: 249296-44-4; Molecular Weight：211.268; Modify Date.: 2022-11-05 04:28; Introduction: Varenicline, a partial agonist of the a4b2 nicotinic receptor, is a first-in-classdrug launched by Pfizer as an aid to smoking cessation treatment.Varenicline exhibits dual action by decreasing craving and withdrawal symptoms,and by decreasing the reinforcement associated with smoking. The addictiveproperties of nicotine are thought to be mediated in part through its action as an agonist at α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). Activationof α4β2 receptors by nicotine increases the release of dopamine in themesolimbic system, an effect that is shared by most drugs of abuse. As nicotinelevels decrease, dopamine levels decline, which in turn stimulates the urge tosmoke. Additionally, a reduced dopaminergic tone due to abstinence fromsmoking stimulates craving and the withdrawal syndrome. A partial agonist ofα4β2 receptors such as varenicline is expected to elicit a moderate and sustainedincrease in dopamine levels to relieve craving and withdrawal symptoms. Inaddition, by competitively binding to a4b2 receptors and inhibiting nicotineinduceddopaminergic activation, a partial agonist could attenuate the pharmacologicreward associated with smoking. View more+

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1. Names and Identifiers

: 1.1 Name; Varenicline; 1.2 Synonyms; (1R,12S)-5,8,14-triazatetracyclo[10.3.1.0^{2,11}.0^{4,9}]hexadeca-2,4(9),5,7,10-pentaene 10-Methano-6H-pyrazino[2 10-tetrahydro 10-tetrahydro- 3-h][3]benzazepine 5,8,14-triazatetracycIo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene 5,8,14-triazatetracyclo[10.3.1.0(2,11),0(4,9)]hexadeca-2(l11),3,5,7,9-pentaene 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene 7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine 7,8,9,10-tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline Chantix CS-861 Unii-W6hs99o8zo Vareniclene Varenicline Impurity; View all

1.3 CAS No.: 249296-44-4

1.4 CID: 53315056

1.5 Molecular Formula: C13H13N3 (isomer)

1.6 Inchi: InChI=1S/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2/t8-,9-/m0/s1

1.7 InChIkey: JQSHBVHOMNKWFT-IUCAKERBSA-N

1.8 Canonical Smiles: C1C2CNCC1C3=CC4=NC=CN=C4C=C23

1.9 Isomers Smiles: C1[C@H]2CNC[C@H]1C3=CC4=NC=CN=C4C=C23

2. Properties

2.1 Density: 1.247

2.1 Melting point: 138.5 °C

2.1 Boiling point: 400.6°Cat760mmHg

2.1 Refractive index: 1.667

2.1 Flash Point: 196.1°C

2.1 Precise Quality: 361.12700

2.1 PSA: 152.87000

2.1 logP: 0.01010

2.1 Solubility: In water, 5.1x10+4 mg/L at 25 deg C (est)

2.2 Decomposition: Hazardous decomposition products: Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx)

2.3 pKa: 9.60±0.20(Predicted)

2.4 Water Solubility: In water, 5.1x10+4 mg/L at 25 deg C (est)

2.5 Stability: Stable under recommended storage conditions.

2.6 Toxicity Summary: IDENTIFICATION AND USE: Varenicline; is used as an adjunct in the cessation of cigarette smoking. HUMAN EXPOSURE AND TOXICITY: Safety and efficacy of varenicline; as an adjunct for smoking cessation have been established in 6 placebo-controlled or active-comparator studies in 3659 patients (mean age: 43 years; 79-96% white; mean smoking history: about 25 years) who smoked at least 10 cigarettes daily (mean: about 21 cigarettes daily). Safety and efficacy of varenicline; also have been evaluated in a randomized, double-blind, placebo-controlled study in 703 patients with stable, documented cardiovascular disease (other than hypertension) who smoked at least 10 cigarettes daily; patients receiving varenicline; and placebo were comparable in baseline characteristics, including age (mean age 57 and 55.9 years, respectively), race (80.3 and 80.8% white, respectively), gender (75.2 and 82.2% male, respectively), and mean smoking history (40 and 39 years, and 22.1 and 22.9 cigarettes daily, respectively). Safety and efficacy of varenicline; also have been evaluated in a randomized, double-blind, placebo-controlled study in 460 patients (mean age 57 years, 82-84% white, approximately 62% male, mean smoking history of approximately 40 years) with mild to moderate chronic obstructive pulmonary disease (postbronchodilator FEV1/FVC below 70% and FEV1 at least 50% of predicted normal value) who smoked at least 10 cigarettes daily. Serious neuropsychiatric symptoms, including changes in mood (e.g., depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, and suicidality (e.g., suicidal ideation, attempted and completed suicides), have been reported during postmarketing experience in patients receiving varenicline;. Hypersensitivity reactions, including angioedema, have been reported during postmarketing experience in patients receiving varenicline;. Safety and efficacy of varenicline; have not been established in patients younger than 18 years of age and use of the drug in this age group is not recommended. Varenicline; was not genotoxic, with or without metabolic activation in vitro in human lymphocytes. ANIMAL STUDIES: Varenicline; is distributed into milk in animals. Rats were administered varenicline; (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n = 65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). There was no evidence of carcinogenicity in female rats. Varenicline; succinate; has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline; succinate; to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline; succinate; there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC). Varenicline; succinate; was not teratogenic in rats and rabbits at oral doses up to 15 and 30 mg/kg/day, respectively (36 and 50 times the maximum recommended human daily exposure based on AUC, respectively). Varenicline; was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow.; View all

3. Use and Manufacturing

3.1 Definition: ChEBI: An organic heterotetracyclic compound that acts as a partial agonist for nicotinic cholinergic receptors and is used (in the form of its tartate salt) as an aid to giving up smoking.

3.2 Methods of Manufacturing: Preparation: P. R. P. Brooks, J. W. Coe, World Intellectual Property Organization patent 0162736 (2001 to Pfizer).

3.3 Usage: Smoking cessation (selective nicotinic receptor modulator).

4. Safety and Handling

4.1 Exposure Standards and Regulations: The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl varenicline tartrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Varenicline tartrate/

4.2 Octanol/Water Partition Coefficient: log Kow = 1.03 (est)

4.3 DisposalMethods: SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

4.4 Formulations/Preparations: Chantix: 0.5 mg film-coated tablets
Oral: Kit: 11 Tablets, film-coated, Varenicline Tartrate 0.5 mg (of varenicline) (Chantix); 42 Tablets, film-coated, Varenicline Tartrate 1 mg (of varenicline) (Chantix). Chantix Pack (available as dose/cards for first month of therapy), (Pfizer). Tablets, film-coated: 0.5 mg (of varenicline) Chantix, (Pfizer), 1 mg (of varenicline) Chantix (available as 4 cards of 14 tablets and regular packaging), (Pfizer). /Tartrate salt/

4.5 Safety: Hazardous Substances Data: 249296-44-4(Hazardous Substances Data)

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

no data available

2.2 GHS label elements, including precautionary statements

Pictogram(s)	no data available
Signal word	no data available
Hazard statement(s)	no data available
Precautionary statement(s)
Prevention	no data available
Response	no data available
Storage	no data available
Disposal	no data available

2.3 Other hazards which do not result in classification

no data available

View all

6. NMR Spectrum

13C NMR : Predict

Predict 1H proton NMR

7. Synthesis Route

249296-44-4Total: 5 Synthesis Route

1197286-22-8

249296-44-4 87 Suppliers

Literatures:
TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC. Patent: WO2009/143347 A2, 2009 ; Location in patent: Page/Page column 25 ;
Yield: ~96%

1333145-92-8

249296-44-4 87 Suppliers

Literatures:
Teva Pharmaceutical Industries Ltd. Patent: US2010/324055 A1, 2010 ; Location in patent: Page/Page column 4-5 ;
Yield: ~83%

1333146-06-7

249296-44-4 87 Suppliers

Literatures:
Teva Pharmaceutical Industries Ltd. Patent: US2010/324055 A1, 2010 ; Location in patent: Page/Page column 5 ;
Yield: ~68%

View all

8. Precursor and Product

precursor:

1197286-22-8

1333145-92-8

1186072-37-6

1333146-06-7

1206484-38-9

product :

375815-87-5

9. Other Information

9.0 Description: Varenicline, a partial agonist of the a4b2 nicotinic receptor, is a first-in-class drug launched by Pfizer as an aid to smoking cessation treatment. Varenicline exhibits dual action by decreasing craving and withdrawal symptoms, and by decreasing the reinforcement associated with smoking. The addictive properties of nicotine are thought to be mediated in part through its action as an agonist at α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). Activation of α4β2 receptors by nicotine increases the release of dopamine in the mesolimbic system, an effect that is shared by most drugs of abuse. As nicotine levels decrease, dopamine levels decline, which in turn stimulates the urge to smoke. Additionally, a reduced dopaminergic tone due to abstinence from smoking stimulates craving and the withdrawal syndrome. A partial agonist of α4β2 receptors such as varenicline is expected to elicit a moderate and sustained increase in dopamine levels to relieve craving and withdrawal symptoms. In addition, by competitively binding to a4b2 receptors and inhibiting nicotineinduced dopaminergic activation, a partial agonist could attenuate the pharmacologic reward associated with smoking.; View all

9.1 Originator: Pfizer (US)

9.2 Uses: Smoking cessation (selective nicotinic receptor modulator).

9.3 Uses: Varenicline is a useful medication for smoking cessation.

9.4 Definition: ChEBI: An organic heterotetracyclic compound that acts as a partial agonist for nicotinic cholinergic receptors and is used (in the form of its tartate salt) as an aid to giving up smoking.

9.5 Brand name: Chantix (Pfizer).

9.6 Chemical Synthesis: Several modifications to the original synthesis have been reported in the literature, including an improved process scale synthesis of the last few steps.The Grignard reaction was initiated on a small scale by addition of 2-bromo fluorobenzene 113 to a slurry of Magnesium turnings and catalytic 1,2-dibromoethane in THF and heating the mixture until refluxing in maintained. To this refluxing mixture was added a mixture of the 2-bromo fluorobenzene 113 and cyclopentadiene 114 over a period of 1.5 h. After complete addition, the reaction was allowed to reflux for additional 1.5 h to give the Diels- Alder product 115 in 64% yield. Dihydroxylation of the olefin 115 by reacting with catalytic osmium tetraoxide in the presence of N-methylmorpholine N-oxide (NMO) in acetone: water mixture at room temperature provided the diol 116 in 89% yield. Oxidative cleavage of diol 116 with sodium periodate in biphasic mixture of water: DCE at 10oC provided di-aldehyde 117 which was immediately reacted with benzyl amine in the presence of sodium acetoxyborohydride to give benzyl amine 118 in 85.7% yield. The removal of the benzyl group was effected by hydrogenation of the HCl salt in 40-50 psi hydrogen pressure with 20% Pd(OH)2 in methanol to give amine hydrochloride 119 in 88% yield. Treatment of amine 119 with trifluoroacetic anhydride and pyridine in dichloromethane at 0oC gave trifluoroacetamide 120 in 94% yield. Dinitro compound 121 was prepared by addition of trifluoroacetamide 120 to a mixture of trifluoromethane sulfonic acid and nitric acid, which was premixed, in dichloromethane at 0oC. Reduction of the dinitro compound 121 by hydrogenation at 40-50 psi hydrogen in the presence of catalytic 5%Pd/C in isopropanol:water mixture provided the diamine intermediate 122 which was quickly reacted with glyoxal in water at room temperature for 18h to give compound 123 in 85% overall yield. The trifluoroacetamide 123 was then hydrolyzed with 2 M sodium hydroxide in toluene at 37-40oC for 2-3h followed by preparation of tartrate salt in methanol to furnish varenicline tartrate (XV).; View all

10. Computational chemical data

Molecular Weight: 211.268g/mol
Molecular Formula: C₁₃H₁₃N₃
Compound Is Canonicalized: True
XLogP3-AA: 0.8
Exact Mass: 211.110947427
Monoisotopic Mass: 211.110947427
Complexity: 254
Rotatable Bond Count: 0
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 3
Topological Polar Surface Area: 37.8
Heavy Atom Count: 16
Defined Atom Stereocenter Count: 2
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccBzAAAAAAAAAAAAAAAAAAAAAYAAAAA8WIAABYAAAGCx8AAAHAAQAAAADQjBHgQ8wLLIEACgAzRnRACCgCQxEiAI2KA4dJgIYOLAkZGUIAhgkADIyAcQgMAOiAAAQAAQACAQAACAACAAQQAACAAAAA==

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