75507-68-5

Basic information

• Product Name: Flupirtine maleate
• Synonyms: 2-AMINO-6-[[(4-FLUOROPHENYL)METHYL]AMINO]-3-PYRIDINYL]-CARBAMIC ACID, ETHYL ESTER MALEATE;Flupirtinemaleatelupirtine;Ethyl-2-amino-6-[(4-fluorbenzyl)amino]pyridin-3-carbamat, Verbindung mit Maleinsure (1:1);Keiton;Ketadolon;N-[2-Amino-6-[[4-fluorophenyl)methyl]amino]-3-pyridinyl]carbamicacidethylestermaleate;Flupirtine Maleate Salt;2-AMino-6-[(p-fluorobenzyl)aMino]-3-pyridinecarbaMic Acid Ethyl Ester Maleate
• CAS NO: 75507-68-5
• Molecular Formula: C19H21FN4O6
• Molecular Weight: 420.3916432
• EINECS: 278-225-0
• Product Categories: Other Potassium channel modulators;APIS;Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Other APIs;Inhibitors;API
• Mol File: 75507-68-5.mol
• Article Data: 3

Chemical Properties

• Melting Point: 186-188°C
• Boiling Point: 434.9 °C at 760 mmHg
• Flash Point: 216.8 °C
• Appearance: white/
• Density: 1.35 g/cm3
• Vapor Pressure: 9.1E-08mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble >20mg/mL
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
• Merck: 14,4190
• CAS DataBase Reference: Flupirtine maleate(CAS DataBase Reference)
• NIST Chemistry Reference: Flupirtine maleate(75507-68-5)
• EPA Substance Registry System: Flupirtine maleate(75507-68-5)

Safety Data

• Safety Statements: 22-24/25-35-20
• WGK Germany: 3
• RTECS: EY8555800
• Hazardous Substances Data: 75507-68-5(Hazardous Substances Data)

Usage

Description

Flupirtine maleate is a centrally-acting, non-addicting analgesic agent that is more potent than aspirin, paracetamol, and pentazocine. It is a selective neuronal potassium channel opener (SNEPCO) with N-methyl-D-aspartate (NMDA) receptor antagonist properties, making it effective in managing body pain. Flupirtine maleate is a derivative of triaminopyridine and is available as the maleate salt due to its poor water solubility. It is an off-white solid and was first introduced in Europe in 1984 under the brand name Katadolon.

Uses

Used in Pain Management:
Flupirtine maleate is used as an analgesic for acute pain, particularly in moderate-to-severe cases. Its muscle relaxant properties make it popular for back pain and other orthopedic uses. It is also used for migraines, in oncology, postoperative care, and gynecology.
Used in Pulmonary Arterial Hypertension:
Flupirtine maleate is used as a treatment for pulmonary arterial hypertension. It has been shown to decrease mean right ventricular pressure and right ventricular hypertrophy in hypoxia-induced and serotonin transporter-overexpressing (SERT+) mouse models of the condition.
Used in Diabetic Neuropathy:
Flupirtine maleate is used as a treatment for streptozotocin-induced diabetic neuropathy in rats, increasing paw withdrawal threshold when administered at a dose of 10 mg/kg.
Used in Inflammation and Pain Management:
Flupirtine maleate is used in combination with morphine to increase paw withdrawal latency in a rat model of carrageenan-induced paw inflammation, providing additional pain relief and anti-inflammatory effects.
Used in Antagonizing NMDA Receptors:
Flupirtine maleate is used as an indirect antagonist of NMDA receptors through its effects on potassium channels, which can be beneficial in various neurological conditions and pain management.

Painkiller

At present, the pain medications, used in the clinical in China, are divided into two categories: a class is to morphine on behalf of narcotic analgesics, and the other is aspirin antipyretic analgesics as representative. While the former high pain intensity, but addiction is its Achilles heel, which greatly limits its application; but the latter, although with no addictive analgesic strength, but it is weak, and has serious gastrointestinal effects. Flupirtine Maleate, developed by Pliva,is subsidiary company German AWD, a new non-opioid analgesics central, listed in Germany in 1986 for the treatment of postoperative pain, dental pain, painful wounds and burns. Then in 1990, it was applied in the treatment of degenerative joint disease, neuropathic and cancer pain, migraine, headache and dysmenorrhea indications. After that, the flupirtine maleate list in Brazil and Portugal. China approved the company's German AWD flupirtine maleate capsules imports in September in 2006, trade name: Kodak DoLong (Katadolon (R)). Flupirtine maleate is a selective neuronal potassium channel opener, oral easily absorbed, which has three efficacy about analgesic, muscle relaxant and neuroprotective. It showed analgesic effects to pain caused by a variety of reasons. Flupirtine maleate has no affinity to Ah receptor, which do not inhibit prostaglandin synthesis. It is not antagonistic naloxone. Pain intensity (ED50) was weaker than methadone, buprenorphine and morphine, about 50% of morphine. Comparable to that of pentazocine, Flupirtine maleate is better than pethidine, codeine, phenacetin and paracetamol. Such as in the hot plate test, the effect of the strength of flupirtine (ED50 of 32mg/Kg, oral administration) is about half of morphine, codeine is 2 times, 10 times stronger than paracetamol and phenacetin. In the wake of dog dental pulp stimulation experiment, the analgesic intensity (ED50 of 3.5mg/ Kg, oral administration) is same with pentazocine. Oral absorption of this product is about 90%, and rectal administration of this product is about 70%. After oral administration of 20~30min. It showed the pharmacological effects, and the duration of action is 3~5h. Plasma half-life is 8~11h. The drug is in the body tissues, mainly in the liver metabolism, and about 70% of the drug is eliminated by the kidneys. Flupirtine maleate is inhibited to pain caused by various diseases. the analgesic effect is between methadone and paracetamol. Centrally acting, but it did not inhibit the respiratory cardiovascular systems, and has no pharmacological activity impact for cough center, nor constipation and urinary retention. Long-term use does not produce tolerance and dependence. It has no painkillers side effects like other medicines on the market, such as addiction, gastrointestinal symptoms. Long term use after a few years the efficacy is not reduced, but can reduce the amount of taking. In short, flupirtine maleate has good clinical application prospect.

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557425/ https://en.wikipedia.org/wiki/Flupirtine

References

1) Azad?et al. (2004), The potassium channel modulator flupirtine shifts the frequency-response function of hippocampal synapses to favour LTD in mice; Neuro. Sci. Lett.,?370?186 2) Klinger?et al.?(2012),?Concomitant facilitation of GABAA receptors and KV7 channels by the non-opioid analgesic flupirtine; Br. J. Pharmacol.,?166?1631 3) Osbourne?et al. (1998),?Flupirtine, a nonopioid centrally acting analgesic, acts as an NMDA antagonist; Gen. Pharmacol.,?30?255

Originator

Chemiewerk Homburg (Degussa) (W. Germany)

Biological Activity

Non-opioid analgesic with muscle relaxant properties. Activates K + channels and indirectly antagonizes NMDA receptors. Exhibits neuroprotective actions in a model of cerebral ischemia in mice and reduces apoptosis and necrosis induced by noxious stimuli.

InChI:InChI=1/C15H17FN4O2.C4H4O4/c1-2-22-15(21)19-12-7-8-13(20-14(12)17)18-9-10-3-5-11(16)6-4-10;5-3(6)1-2-4(7)8/h3-8H,2,9H2,1H3,(H,19,21)(H3,17,18,20);1-2H,(H,5,6)(H,7,8)/b;2-1-

Upstream product

• 33400-49-6 2-amino-3-nitro-6-(p-fluoro-benzylamino)-pyridine 

Downstream Products

• 366-79-0 p-fluorohippuric Acid 

Relevant articles and documents

Synthesis method for flupirtine maleate compound

The invention discloses a synthesis method for a flupirtine maleate compound. The method comprises the steps that 2-amino-3-nitro-6-chloropyridine (a first compound) is used as a starting material to react with fluorobenzylamine (a second compound) to generate 2-amino-3-nitro-6-p-fluorobenzylamine pyridine (a third compound), the third compound is processed through di-tert-butyl dicarbonate ester protection to obtain 2-amino-3-nitro-6-p-fluorobenzylamine pyridine-3-based-tert-butyl acetate (a fourth compound), the fourth compound is processed through hydrogenation reduction and then react with ethyl chloroformate, after reacting is finished, deprotection is performed to obtain flupirtine hydrochloride (a fifth compound), and the fifth compound is salified with maleic acid to obtain flupirtine maleate (the sixth compound). According to the synthesis method, the starting material is cheap and easy to obtain, byproduct generation is avoided through amino protection, therefore, the impurity content is decreased, and the product quality is improved; catalytic reduction is performed by adopting palladium chloride, the reaction condition is mild, the reaction process is easy to operate, and the method is suitable for industrial production.

2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate

There is prepared 2-amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate of the formula STR1 The compound has antiphlogistic and analgesic properties in the same manner as the known hydrochloride salt. In contrast to the hydrochloride 2-amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate can be produced without a disturbing blue coloration. This maleate generally is formed from a mixture of two crystal modifications A and B, whereby there is especial advantageous in regard to isolation as well as the galenical preparations a mixture entriched in modification A (60 to 90% modification A).