112887-68-0

Basic information

• Product Name: Raltitrexed
• Synonyms: RALTITREXED;(s)-2-[(1-{5-[methyl-(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-amino]-thiophen-2-yl}-methanoyl)-amino]-pentanedioic acid;ICI-D-1694;N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-L-glutamic Acid;Tomudex;ZD-1694;L-Glutamic acid, N-[[5-[[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-;(S)-2-(5-(METHYL((2-METHYL-4-OXO-3,4-DIHYDROQUINAZOLIN-6-YL)METHYL)AMINO)THIOPHENE-2-CARBOXAMIDO)PENTANEDIOIC ACID
• CAS NO: 112887-68-0
• Molecular Formula: C₂₁H₂₂N₄O₆S
• Molecular Weight: 458.49
• EINECS: 1533716-785-6
• Product Categories: Active Pharmaceutical Ingredients;Raltitrexed;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors
• Mol File: 112887-68-0.mol
• Article Data: 7

Chemical Properties

• Melting Point: 176-1800C
• Appearance: off-white to light yellow/
• Density: 1.49 g/cm³
• Refractive Index: 1.638
• Storage Temp.: Hygroscopic, -20°C Freezer, Under Inert Atmosphere
• Solubility: H2O: ≥10mg/mL
• PKA: 3.50±0.10(Predicted)
• CAS DataBase Reference: Raltitrexed(CAS DataBase Reference)
• NIST Chemistry Reference: Raltitrexed(112887-68-0)
• EPA Substance Registry System: Raltitrexed(112887-68-0)

Safety Data

• Hazard Codes: Xi,T
• Statements: 36/38-25-61
• Safety Statements: 26-37/39-45-53
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 2
• Hazardous Substances Data: 112887-68-0(Hazardous Substances Data)

Usage

Description

Tomudex was launched in Ireland, France, Luxembourg and the UK for advanced colorectal cancer and it was prepared in a convergent manner (6 steps) from diethyl L-glutamate and 6-bromomethyi-2-methyl-quinazolin4(3H)-one. Tomudex is a highly selective inhibitor of thymidylate synthase (TS), the key enzyme in the biochemical conversion of dUMP to dTMP. It enters the cell via the reduced folatefmethotrexate cell membrane carrier and is converted to the polyglutamate species by folylpolyglutamate synthase within 4h where it then binds to the folate substrate site of TS. Clinically, it had a 29% response rate in patients with advanced colorectal cancer. It is water soluble, can be administered as a single dose every three weeks and had no hepto- or nephrotoxicity.

Chemical Properties

Yellow Crystalline Powder

Uses

Folate-based inhibitor of thymidylate synthase; rapidly and extensively metabolized to its more potent polyglutamate derivatives. Antineoplastic

Brand name

Tomudex (Zeneca).

Biochem/physiol Actions

Raltitrexed is a folate-based inhibitor of thymidylate synthase (TS) that is rapidly and extensively metabolized to its more potent polyglutamate derivatives. By inhibiting the formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.

Clinical Use

Treatment of colorectal cancer when fluorouracil and folinic acid cannot be used

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. Folic and folinic acid: impairs cytotoxic action - avoid.

Metabolism

Raltitrexed is actively transported into cells and metabolised to active polyglutamate forms. The remainder of a dose is not metabolised and is excreted unchanged, about 50% of a dose appearing in the urine, and about 15% in the faeces.

InChI:InChI=1/C20H24N4O2S/c1-12-21-15-7-6-13(10-14(15)18(25)22-12)11-24(5)17-9-8-16(27-17)19(26)23-20(2,3)4/h6-10H,11H2,1-5H3,(H,23,26)(H,21,22,25)

Upstream product

• 67318-11-0 ethyl 2-amino-thiophene-5-carboxylate 
• 5751-84-8 5-nitro-2-thiophenecarboxylic acid ethyl ester 
• 6317-37-9 5-nitrothiophene-2-carboxylic acid 
• 527-72-0 2-thiophenylcarboxylic acid 
• 106585-64-2 N-(5-nitro-2-thiophenecarbonyl)-L-glutamic acid diethyl ester 
• 106585-63-1 N-(5-aminothiophene-2-carbonyl)-L-glutamic acid diethyl ester 
• 131052-68-1 5--2-thiophenecarboxylic acid 
• 132463-32-2 2-thiophene 
• 1118-89-4 diethyl-L-glutamate hydrochloride 
• 39978-57-9 5-nitrothiophene-2-carbonyl chloride 
• 651295-44-2 N-[5-[N-(tert-butoxycarbonyl)amino]-2-thiophenecarbonyl]-L-glutamic acid diethyl ester 
• 651295-42-0 diethyl N-(5-carboxy-2-thiophenecarbonyl)-L-glutamate 
• 132463-33-3 N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thiophenecarbonyl]-L-glutamic acid diethyl ester 
• 112889-02-8 N-(5-methylamino-2-thiophenecarbonyl)-L-glutamic acid diethyl ester 

Relevant articles and documents

New synthesis of thymidylate synthase inhibitor raltitrexed

The quinazoline-based inhibitor of thymidylate synthase, Raltitrexed, was synthesized from 2,5-thiophenedicarboxylic acid via monocoupling with diethyl L-glutamate, modified Curtius reaction, N-methylation, removal of Boc-protecting group, condensation with (bromomethyl)quinazolinone and saponification in 18.2% overall yield.

Raltitrexed pharmaceutical composition and preparation method thereof

The invention relates to a raltitrexed pharmaceutical composition which is high in safety and a preparation method thereof. The raltitrexed pharmaceutical composition comprises raltitrexed and thiophene related substances, wherein the content of the thiophene related substances is not higher than 0.3%. The raltitrexed pharmaceutical composition is good in safety, effectiveness and stability and can relieve the blood toxicity of the raltitrexed to a certain degree.

Anti-tumour agents

A quinazoline of the formula: STR1 wherein R1 is alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, aryloxy, arylalkyl, halogeno, hydroxy, mercapto, pyridylthio, pyrimidinylthio, or substituted alkyl or alkoxy; wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl or alkanoyl; wherein Ar is phenylene, naphthylene or heterocyclene which is unsubstituted or bears one or more substituents and wherein R3 is such that R3 --NH2 is an amino acid; or a pharmaceutically-acceptable salt or ester thereof. The compounds possess anti-tumour activity.