Preparation
1. Dissolve 2-bromo-4-pyridine in methanol in CH2Cl2, add C4H9)4NBr and benzenesulfonyl chloride, stir, and add a solution prepared with NaOH dropwise while stirring. Maintain the temperature at approximately 25 °C and stir vigorously for 1–2 h. Separate the solutions, concentrate, and pour the residue into diethyl ether while stirring. A light brown solid, benzenesulfonic acid-(2-bromo-4-pyridine methyl) ester, precipitates.
2. Add benzenesulfonic acid-(2-bromo-4-pyridine methyl) ester and K2CO3 to a three-necked flask, add butanone, and slowly add piperidine. Reflux for 2–3 h, filter while hot, wash the filter cake with butanone, combine the butanone, wash the butanone twice with water, concentrate, and obtain a brown oily substance, 4-(2-oxotetrahydropyranyl)-cis-2-buten-1-ol. 3. Take 4-(2-oxotetrahydropyranyl)-cis-2-buten-1-ol, 2-bromo-4-(piperidinylmethyl)pyridine (VI), NaOH, K2CO3, and (C4H9)4NBr, place them in a three-necked flask, heat to 105 °C and stir for 36 h. Pour the reaction solution into twice the volume of water, separate the layers, extract the aqueous layer with toluene 2-3 times, and wash once with water to obtain 2-[4-(2-oxotetrahydropyranyl)-cis-2-buten-1-oxo]-4-(1-piperidinyl)pyridine. 4. Add 2-[4-(2-oxotetrahydropyranyl)-cis-2-buten-1-oxo]-4-(1-piperidinyl)pyridine and toluene to concentrated HCl, stir at room temperature for 12 h, let stand, separate the layers, combine the aqueous layers, wash with chloroform and ethyl acetate respectively, adjust the pH to 10-11, extract with chloroform 3 times, filter the chloroform layer under vacuum with a 1.5 cm thick silica gel layer, evaporate the filtrate to dryness to obtain 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-2-buten-1-ol. 5. Add 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-2-buten-1-ol to a three-necked flask, dissolve it in CH2Cl2, and cool with ice water. Add K2CO3, then add thionyl chloride dropwise. After the addition is complete, raise the temperature to room temperature and continue stirring for 4-5 h. Filter, add saturated NaHCO3 aqueous solution to the filtrate, adjust to weak alkalinity, separate the organic phase, wash the organic phase once with water, separate the layers, filter, dry the filtrate, and distill under reduced pressure to obtain the product 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-2-buten-1-chloro. 6. 4-[4-(1-piperidinylmethyl)pyridine-2-oxy]-cis-2-butene-1-chloro, toluene, potassium phthalimide, (C4H9)4NBr were heated to 80 °C and stirred for 6 h. After cooling, the mixture was washed with 1 mol/L NaOH aqueous solution, washed once with water, filtered, and concentrated to obtain a yellow oily substance N-[4-[4-(1-piperidinylmethyl)pyridine-2-oxy]-cis-2-butene]phthalimide. 7. Dissolve maleate in 15% K2CO3, add 650 mL toluene and 50 mL ethanol, stir to dissolve, and separate the liquid. Add hydrazine hydrate to the organic phase, heat to reflux, the solid dissolves first, and then another solid precipitates. Reflux for 2-3 h, concentrate, and obtain a light yellow solid 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-butenyl-1-amine. 8. Add 4-[4-(1-piperidinylmethyl)pyridine-2-oxo]-cis-butenyl-1-amine and ethyl acetate to a three-necked flask. Add furanylmethylsulfinylacetic acid (p-nitrophenol) ester in batches and stir for 4-5 h. Add 15% acetic acid and stir for 0.5 h. Separate the liquid and extract the organic phase with 15% acetic acid. Separate the liquid and extract the aqueous phase. Extract the aqueous layer with ethyl acetate again and separate the aqueous phase. Adjust the pH to 9-10 with potassium carbonate and extract with ethyl acetate 2-3 times. Combine the ethyl acetate layers and wash with 1 mol/L NaOH until nearly colorless. Wash once with saturated NaCl, dry, filter, evaporate to dryness, add a small amount of petroleum ether and ethanol, stir, and precipitate a white solid, lafutidine.
Description
Lafutidine is a second generation of H2-receptor antagonist. H2-receptor antagonist can strongly inhibit gastric acid secretion compared with conventional drugs such as antacids. Unlike conventional H2-receptor antagonist, lafutidine inhibits gastric acid secretion during daytime as well as nighttime in clinical studies in humans. Lafutidine also has gastroprotective activity independent of its acid antisecretory efficacy, preventing noxious agent-induced gastric mucosal injury and accelerating the repair process following gastric mucosal damage. It also protects experimentally induced reflux esophagitis, indomethacin-induced intestinal, and dextran sulfate sodium-induced colonic inflammation.
Lafutidine is used for gastric and duodenal ulcers. It is also confirmed that lafutidine can be used as an empiric treatment and superior efficacy for primary care practice patients with dyspepsia.
References
[1] Tomohiko Shimatani, Masaki Inoue, Tomoko Kuroiwa, Jing Xu, Masuo Nakamura, Susumu Tazuma, Kazuro Ikawa, Norifumi Morikawa (2006) Lafutidine, a Newly Developed Antiulcer Drug, Elevates Postprandial Intragastric pH and Increases Plasma Calcitonin Gene-Related Peptide and Somatostatin Concentrations in Humans: Comparisons with Famotidine, Digestive Diseases and Sciences, 51, 114-120
[2] Bhupesh Dewan, Nisha Philipose (2011) Lafutidine 10 mg versus Rabeprazole 20 mg in the Treatment of Patients with Heartburn-Dominant Uninvestigated Dyspepsia: A Randomized, Multicentric Trial, Gastroenterology Research and Practice, 2011, Article ID 640685
[3] https://www.drugs.com
Description
Lafutidine is a histamine H
2 receptor antagonist with gastroprotective activity. It inhibits histamine-induced cAMP production in CHO cells expressing human histamine H
2 receptors when used at a concentration of 10 nM. Intragastric administration of lafutidine (3, 10, and 30 mg/kg) reduces hemorrhagic esophageal lesion size and gastric acid secretion in a rat model of pyloric ligation-induced reflux esophagitis. It prevents 5-fluorouracil-induced intestinal mucositis, diarrhea, and body weight loss in wild-type, but not
Trpv1-/- or sensory deafferented, mice when administered at doses ranging from 3 to 30 mg/kg. Lafutidine (10 mg/kg) also reduces indomethacin-induced antral ulcer size in wild-type, but not chemically-deafferented, rats.
Description
Lafutidine was launched in Japan for the treatment of gastritis, reflux oesophagitis and
peptic ulcers. It can be prepared in eight steps from 4-(2-tetrahydropyranyloxy)-2(Z)-butenl-
ol. Lafutidine is a potent and longer-acting H
2 antagonist compared to other marketed
compounds of its class such as cimetidine and famotidine. In contrast to other
commercially available H
2 antagonists, lafutidine also exerts a gastroprotective action
probably via capsaicin-sensitive afferent nerves. It was clinically effective in the treatment
of nonsteroidal antiinflammatory drug-induced ulcer in patients refractory to existing
antiulcer agents.
Originator
Fujirebio (Japan)
Uses
Lafutidine, a newly developed histamine H(2)-receptor antagonist, inhibits gastric acid secretion
Uses
(Z)-2-((Furan-2-ylmethyl)sulfinyl)-n-(4-((3-(piperidin-1-ylmethyl)pyridin-2-yl)oxy)but-2-en-1-yl)acetamide is a Histaminic H2 receptor antagonists in ulcer disease. Also, it is a model compound used to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA).
Uses
Second generation histamine H2-receptor antagonist. Antiulcerative
Definition
ChEBI: Lafutidine is an organic molecular entity.
brand name
Stogar, Protecadin
References
[1] Y. FUKUSHIMA. Potent and Long-Lasting Action of Lafutidine on the Human Histamine H2 Receptor[J]. Digestion, 2001, 64 1: 155-160. DOI:
10.1159/000048856[2] KENJI NAGAHAMA. Protective effect of lafutidine, a novel H2-receptor antagonist, on reflux esophagitis in rats through capsaicin-sensitive afferent neurons.[J]. Journal of pharmacological sciences, 2003, 93 1: 55-61. DOI:
10.1254/jphs.93.55[3] T SANO. Lafutidine, a histamine H2 receptor antagonist with mucosal protective properties, attenuates 5-fluorouracil-induced intestinal mucositis in mice through activation of extrinsic primary afferent neurons.[J]. Journal of Physiology and Pharmacology, 2017, 68 1: 79-90.
[4] S ONODERA. Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.[J]. Arzneimittel-Forschung-Drug Research, 1999, 49 6: 519-526. DOI:
10.1055/s-0031-1300454
