128-62-1

Usage

Uses

Narcotine is used as an antitussive agent for its cough-suppressing effects. It is found in various pharmaceutical products under different brand names, such as Tusscapine, Bequitussin, Bisolvon compositum, and many others. The alkaloid's antitussive properties make it a valuable component in the development of medications aimed at treating cough and respiratory conditions.

World Health Organization (WHO)

Noscapine, a centrally-acting cough suppressant and one of several alkaloids present in papaveretum (opium concentrate) was introduced into medicine many years ago. Subsequently, it was shown to increase the number of chromosomes in mammalian cell lines maintained in vitro. Although the clinical significance of this finding is uncertain, restrictive action was taken in a few countries since the possibility of a genotoxic effect cannot be excluded. On 4 December 1992 the European Committee on Proprietary Medicinal Products concluded that the available evidence does not indicate that use of noscapine holds any significant hazard. The Swedish Medical Products Agency also concluded that there is no justification to restrict the use of noscapine in women of childbearing age.

Biological Functions

Noscapine is a naturally occurring product of the opium poppy. It is a benzylisoquinoline with no analgesic or other CNS effects. Its antitussive effects are weak, but it is used in combination with other agents in mixtures for cough relief.

Hazard

Narcotic, use legally restricted.

Safety Profile

Moderately toxic by ingestion andsubcutaneous routes. Mutation data reported. Anantitussive. When heated to decomposition it emits toxicfumes of NOx.

References

Robiquet., Ann. Chim. Phys., 5,275 (1817)Matthiessen, Foster.,!. Chern. Soc., 16,342 (1863)Perkin, Robinson., ibid, 99,775 (1911)Polonovski, Polonovski., Bull. Soc. Chim. Fr., 47, 361 (1930)Lovell., Acta Cryst., 6, 869 (1953)Barnes., Can. f. Chern., 33,444 (1955)Safe, Moir., ibid, 160 (1964)Stereochemistry: Battersby, Spenser., Tetrahedron Lett., 11 (1964)

InChI:InChI=1/C22H23NO7.ClH/c1-23-8-7-11-9-14-20(29-10-28-14)21(27-4)15(11)17(23)18-12-5-6-13(25-2)19(26-3)16(12)22(24)30-18;/h5-6,9,17-18H,7-8,10H2,1-4H3;1H/t17-,18-;/m1./s1

Upstream product

• 186581-53-3 diazomethane 
• 68353-55-9 (S)-7-hydroxy-6-methoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo-[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one 
• 488721-01-3 9-bromonoscapine 
• 98-80-6 phenylboronic acid 
• 35933-62-1 1S,9S β-narcotine 
• 3860-46-6 1R,9R-(-)-β-narcotine 
• 5780-07-4 3-methoxy-4,5-methylenedioxybenzaldehyde 
• 15896-78-3 (E)-4-methoxy-6-(2-nitrovinyl)benzo[d][1,3]dioxole 
• 23693-38-1 β-(3-methoxy-4,5-methylenedioxy)phenylethylamine 
• 121-33-5 vanillin 
• 1449378-31-7 tert-butyl [2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl]carbamate 
• 1521-38-6 2,3-dimethoxybenzoic acid 
• 569-31-3 meconin 
• 73563-23-2 3-bromo-6,7-dimethoxyphthalide 

Downstream Products

• 550-10-7 hydrocotarnine 
• 20377-62-2 6-[(S)-hydroxy-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-methyl]-2,3-dimethoxy-benzophenone 
• 569-31-3 meconin 
• 75-50-3 trimethylamine 
• 92621-03-9 (3S)-6,7-dimethoxy-3-((R)-4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one 
• 23942-99-6 (-)-α-narcotinediol 
• 82-54-2 4-methoxy-6-methyl-5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinolin-5-ol 
• 54383-36-7 α-narcotine N-oxide 
• 485319-76-4 (-)-narcotinehemiacetal 
• 2725-94-2 (-)-narcotinediol 
• 519-05-1 opianic acid 
• 518-90-1 3,4-dimethoxy-phthalic acid 
• 483-89-6 2,3-dimethoxy-6-{[4-methoxy-6-(2-methylamino-ethyl)-benzo[1,3]dioxol-5-yl]-acetyl}-benzoic acid 
• 15719-64-9 methylammonium carbonate 

Relevant academic research and scientific papers

New reactions of phthalidoisoquinoline alkaloids. Alkoxy exchange reactions and isomerisations of α- and β-narcotine

Substitution of the 7-methoxy group in α- and β-narcotine by other alkoxy groups occurs in an anhydrous ROH/RONa system. It is accompanied by isomerization in position 3 with preference for the α-configuration (5R, 3S). In an alkaline aqueous system (ROH/KOH or 1N KOH only isomerization in position 3 with preference for the β-configuration (5R, 3R) was observed. Some of the new 7-alkoxynarcotines were evaluated for their antitussive activity.

Synthesis and biological evaluation of novel biaryl type α-noscapine congeners

Natural α-noscapine, a known antitussive drug, is also now known to possess weak anticancer efficacy with relatively safe toxicity profile. In this study, we report synthesis and evaluation of novel biaryl type α-noscapine congeners designed by adding aryl unit to the tetrahydroisoquinoline part of natural α-noscapine core. Palladium catalyzed Suzuki cross coupling of 9-bromo α-noscapine with aryl boronic acids was employed using mild and inexpensive reagents to attain desired noscapinoids 5a-g in excellent yields. Screening anti-proliferative activity for new noscapinoids 5b-g, on human cancer cell lines resulted three compounds 5b, 5d and 5f as potent analogues, active against human breast epithelial (MCF-7), human cervix cancer (HeLa) and human lung adenocarcinoma epithelial (A549) cell lines.

An Acid-Catalyzed Epoxide Ring-Opening/Transesterification Cascade Cyclization to Diastereoselective Syntheses of (±)-β-Noscapine and (±)-β-Hydrastine

An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-β-Noscapine and (±)-β-Hydrastine were exploited.

Synthesis and click reaction of tubulin polymerization inhibitor 9-azido-α-noscapine

Abstract: An efficient protocol for the synthesis of tubulin polymerization inhibitor, 9-azido-α-noscapine 2h from 9-amino-α-noscapine 2g is developed using mild reaction conditions (t-butyl nitrite/trimethylsilyl azide in acetonitrile at room temperature). Operational simplicity, high product yield without formation of any side products are the advantages of this protocol. Further copper catalyzed click reactions of 9-azido-α-noscapine 2h with alkynes 6a–f resulted 9-triazolyl noscapinoids 7a–f resulted in excellent yields. Graphical Abstract: Developed an amicable protocol for the synthesis of 9-azido-α-noscapine from 9-amino-α-noscapineunder mild reaction conditions; was further derivatized to triazoles using click chemistry.[Figure not available: see fulltext.]

COMPOSITIONS AND METHODS FOR MAKING NOSCAPINE AND SYNTHESIS INTERMEDIATES THEREOF

Methods for the manufacture of the therapeutic chemical compound noscapine and noscapine synthesis intermediates comprising contacting a noscapine pathway precursor selected from a first canadine derivative, a first papaveroxine derivative and narcotine hemiacetal with at least one of the enzymes selected from the group CYP82Y1, CYP82X1, AT1, CYP82X2, OMT, CXE1 and NOS.

A new total synthesis of (±)-α-noscapine

A new, convergent total synthesis of (±)-α-noscapine was developed on a grams scale through the condensation of 3-trimethylsilyl-meconin derivative 9 and the iodized salt cotarnine derivative 20 as the key step. Staring from simple 2,3-dimethoxybenzoic acid, piperonal and 2,2-dimethoxyethanamine, through the traditional chemical processes to give the final product in 11.6% yield over 14 steps.

Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9-amino-α-noscapine from natural α-noscapine

Facile synthesis of natural α-noscapine analogue, 9-amino-α-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-noscapine (obtained by bromination of natural α-noscapine) with NaN3 in DMSO at 130 °C in the presence of l-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-α-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units.

Blocking group-directed diastereoselective total synthesis of (±)-α-noscapine

A new approach for the diastereoselective synthesis of (±)-α- noscapine, a phthalide tetrahydroisoquinoline alkaloid exhibiting several biological activities, is described. The strategy features a blocking group-directed Bischler-Napieralski reaction followed by diastereoselective reduction (α/β>23:1). One of the key intermediates, phthalide-3-carboxylic acid, could be efficiently prepared from simple benzoic acid derivative and glyoxylic acid in one-pot.

Combination of benzyl-4, 5-dihydro-1H-imidazole derivative and an opioid receptor ligand

The present invention refers to a combination of a Compound A, a benzyl-4,5-dihydro-1 H-imidazole derivative according to formula (I) and a Compound B, an opioid receptor ligand; especially of xylometazoline or oxymetazoline and a μ-opioid receptor agonist, most preferably of xylometazoline or oxymetazoline and morphine; a medicament comprising this combination; a pharmaceutical formulation for nasal application comprising this combination; or the use of this combination for the treatment of the symptoms of pain, or the prevention or the prophylaxis of the symptoms of pain, whereas pain particularily encompasses visceral pain, chronic pain, cancer pain, acute pain or neuropathic pain, specifically involving also breakthrough pain.

Delivery systems and methods for noscapine and noscapine derivatives, useful as anticancer agents

The present invention relates to methods useful for the treatment of neoplastic diseases, tumor cells, and the treatment of cancer delivering compounds of the formula The invention provides various methods of delivering such compounds, combinations of treatments, and altering such compounds to enhance their effectiveness.