134308-13-7

Basic information

• Product Name: Tolcapone
• Synonyms: 3,4-DIHYDROXYL-5-NITROBENZYL,4'-METHYLBENZENYL KETONE;TALCAPONE;TOLCAPONE;(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)-methanon;(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone;3,4-dihydroxy-4’-methyl-5-nitrobenzophenone;ro40-7592;TolcaponeTolcapone
• CAS NO: 134308-13-7
• Molecular Formula: C₁₄H₁₁NO₅
• Molecular Weight: 273.24
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;API;Inhibitor;Inhibitors
• Mol File: 134308-13-7.mol

Chemical Properties

• Melting Point: 126-1280C
• Boiling Point: 485.6 °C at 760 mmHg
• Flash Point: 205.8 °C
• Appearance: yellow/
• Density: 1.419 g/cm³
• Vapor Pressure: 4.72E-10mmHg at 25°C
• Refractive Index: 1.661
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: ≥15mg/mL
• PKA: 4.78±0.38(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 2 months.
• CAS DataBase Reference: Tolcapone(CAS DataBase Reference)
• NIST Chemistry Reference: Tolcapone(134308-13-7)
• EPA Substance Registry System: Tolcapone(134308-13-7)

Safety Data

• Hazard Codes: N
• Statements: 50
• Safety Statements: 61
• RIDADR: UN 3077 9 / PGIII
• RTECS: PC4952500
• Hazardous Substances Data: 134308-13-7(Hazardous Substances Data)

Usage

Uses

1. Used in Antiparkinsonian Applications:
Tolcapone is used as an adjunct to levodopa/carbidopa for the management of signs and symptoms of Parkinson's disease (PD). It acts as an inhibitor of both brain and peripheral catechol O-methyltransferase (COMT) enzymes, enhancing the effectiveness of levodopa therapy and reducing the occurrence of motor fluctuations in PD patients.
2. Used in COMT-Mediated Cell Signaling Studies:
Tolcapone is used as a potent inhibitor of alpha-synuclein and beta-amyloid oligomerization and fibrillogenesis, protecting against extracellular toxicity. It has been utilized in methyltransferase assays in human embryonic kidney 293 cells for studying COMT-mediated cell signaling pathways.
3. Used in Drug Delivery Systems:
Tolcapone is used as a high-affinity binder to transthyretin (TTR), inhibiting TTR aggregation in human plasma and preventing TTR-induced cytotoxicity in vitro. It also stabilizes TTR in mice and humans in vivo. This application is particularly relevant in the development of novel drug delivery systems to enhance the therapeutic outcomes of tolcapone.
4. Used in Inhibition of O-Methylation of Exogenous Polyphenols:
Tolcapone is used as an inhibitor of O-methylation of exogenous polyphenols such as EGCG (epigallocatechin gallate), which is an important aspect in the study of the bioavailability and biological effects of these compounds.
5. Used in Pharmaceutical Industry:
Tolcapone is used as a cell-permeable, orally bioavailable compound in the pharmaceutical industry for the development of drugs targeting COMT inhibition and related pathways, as well as for the treatment of Parkinson's disease and other neurodegenerative disorders.

Originator

Tasmar,Roche

Preparation

preparation by demethylation of 4-hydroxy-3-methoxy-4′-methyl-5-nitrobenzophenone with hydrobromic acid in refluxing aque-ous acetic acid.

Manufacturing Process

Condensation of 4-benzyloxy-3-methoxybenzaldehyde with 4-lithium-toluene (prepared from 4-bromotoluene and butyl lithium) leads to the corresponding benzhydrole. Oxidation of the new formed hydroxyl in benzhydrole gives the 4-benzyloxy-3-methoxyphenyl)-p-tolylmethanone. Treatment of this compound with hydrogen bromide selectively removes the benzyl ether that is additionally activated by the transannular carbonyl group. The intermediate is then nitrated under standart conditions to give the (4-hydroxy-3-methoxy-5- nitrophenyl)-p-tolylmethanone. A second treatment of the last compound with hydrogen bromide cleaves the ether group, which is now activated by the adjacent nitro group. This last step affords the (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone.

Therapeutic Function

Antiparkinsonian

Biochem/physiol Actions

Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor. It inhibits both central and peripheral COMT. Tolcapone crosses the blood-brain barrier, and has been used for L-DOPA adjunct therapy in the treatment of Parkinson′s Disease.

Clinical Use

Catechol-o-methyltransferase inhibitor: Treatment of Parkinson’s disease

Drug interactions

Potentially hazardous interactions with other drugs Antidepressants: avoid with MAOIs.

Metabolism

Extensively metabolised, mainly by conjugation to the inactive glucuronide, but methylation by catecholO-methyltransferase to 3-O-methyltolcapone and metabolism by cytochrome P450 isoenzymes CYP3A4 and CYP2A6 also occurs. Approximately 60% of a dose is excreted in the urine with the remainder appearing in the faeces.

References

1) Manisto?et al.?(1992),?Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat; Br, J. Pharmacol.,?105?569 2) Giovanni?et al.?(2010),?Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alpha-synuclein and beta-amyloid and protect against amyloid-induced toxicity;?J. Biol. Chem.,?285?14941 3) Sant’Anna?et al.?(2016),?Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity; Nat. Commun.,?7?10787 4) Forester and Lambert (2015),?The catechol-O-methyltransferase inhibitor, tolcapone, increases the bioavailability of unmethylated (-)-epigallocatechin-3-gallate in mice; Funct. Foods,?17?183

InChI:InChI=1/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3

Upstream product

• 134612-80-9 3-O-Methyltolcapone 
• 1391053-03-4 C₁₄H₁₂O₃ 

Related news

Right inferior frontal cortex activity correlates with Tolcapone (cas 134308-13-7) responsivity in problem and pathological gamblers07/26/2019

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impair...detailed

Comparison of the inhibitory effects of Tolcapone (cas 134308-13-7) and entacapone against human UDP-glucuronosyltransferases07/25/2019

Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited u...detailed

Relevant articles and documents

Convenient synthesis of tolcapone, a selective catechol-O-methyltransferase inhibitor

A convenient and efficient synthesis of tolcapone from commercial 4-benzyloxy-3-methoxybenzaldehyde is presented. Grignard reaction of 4-benzyloxy-3-methoxybenzaldehyde (1) with p-tolylmagnesium bromide followed by Oppenauer oxidation of the hydroxyl func

3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium cation: A green alternative to tert-butyl nitrite for synthesis of nitro-group-containing arenes and drugs at room temperature

Due to their remarkable properties, task-specific ionic liquids have turned out to be progressively popular over the last few years in the field of green organic synthesis. Herein, for the first time, we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL) derived from biodegradable ethyl nicotinate indeed acted as an efficient and eco-friendly reagent for the synthesis of highly valuable nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam. The bridging of an ionic liquid with nitrite group not only increases the yield and rate of direct C[sbnd]N bond formation reaction but also allows easy product separation and recyclability of a byproduct. Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are a portion of the extra focal points of TS-N-IL while contrasted with tert-butyl nitrite an outstanding and highly-flammable reagent utilized largely in organic synthesis.

Catechol derivatives

Catechol derivatives of the formula STR1 wherein Ra, Rb and Rc have the significance given herein, the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adensoylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuornal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure. Formula Ia above embraces not only compounds which form part of the invention, but also known compounds; the compounds which form part of the invention can be prepared according to known methods.