|Company Name:||J & K SCIENTIFIC LTD. |
|Rebamipide Chemical Properties|
|Rebamipide Usage And Synthesis|
|New anti-ulcer drug||Rebamipide, is a new anti-ulcer drug; in 1990, it first entered into market as acute and chronic gastritis drug and anti-gastric ulcer drug in Japan; rebamipide belongs to gastric mucosal protective agent, can increase gastric mucosal blood flow, the synthesis of prostaglandin E2 and the secretion of gastric mucus, promote the expression of epidermal growth factor and its receptor; therefore it is effective in prevention of ulcers and promoting ulcer healing. Studies have shown that it is effective against various experimental gastric ulcers and can promote gastric prostaglandin production, protect the gastric mucosa from the damage of various hazards ulcerogenic factors. It is suitable in the treatment of gastric ulcer, acute gastritis, the chronic gastritis in acute exacerbation stage, and stomach mucosal lesions. Therefore, it has relative high clinical value. |
Background: With the wild application of proton pump inhibitor (PPI), and the primary approach of treatment of gastric ulcer being the eradication of Helicobacter pylori infection, the clinical healing rate of peptic ulcer can be as high as 80% to 90%. However, the problem of the recurrence of ulcer recurrence still remains to be resolved. In recent years, the relationship between the quality of ulcer healing and ulcer recurrence has attracted more and more attention.
Figure 1 The molecular structure of Rebamipide
|Pharmacological effects||The chemical structure of rebamipide contains the para-amide groups in the benzyl group, the carbonyl group in 2’ position, and the double bond in 3’, 4’ position. It has a dose-dependent inhibitory effect on the reactive oxygen species produced by the activation of neutrophils and can further effectively scavenger free radicals, thereby preventing the damage of free radical on the gastric mucosa. This product can also promote gastric prostaglandin synthesis, enhance gastric mucosal barrier. In addition, by preventing the adhesion of Helicobacter pylori (Hp) adhesion to gastric epithelial cells, the product can reduce oxidative stress, reduce the concentration of cell factor produced by H. pylori and further inhibiting of HP’s injury on gastric mucosa.|
Animal experiment has already showed that rebamipide can remove free radicals within the epithelial cells, and have a significant inhibition on the O2- produced by neutrophils; it also has some effects on eliminating hydroxyl radical; it can also inhibit HP and its production of chemotaxis factors. It can also inhibit the injury of gastric mucosa caused by bile acid and increase the synthesis of prostaglandins.
The above information is edited by the chemicalbook of Dai Xiongfeng.
|Pharmacokinetics||Absorption and Metabolism: After oral administration of 0.6g, the time for reaching peak of plasma concentration is (1.95 ± 0.73) h, the peak plasma concentration is (510.3 ± 152.0) ng/ml, its elimination half-life is (1.75 ± 0.63) hours. According to reports, after oral administration of 0.1 g of rebamipide 0.1g, after about two hours, the plasma concentration reaches peak at 210ng/ml with the elimination half-life of about 2 hours; about 10% of the dose is excreted through the urine. Multiple dose study has showed that the drug did not accumulate in the human body.
Figure 2 The synthetic route of Rebamipide.
|Indications||1. Prevents and treatment of injury of gastric mucosal caused by NSAIDs |
Rebamipide has an obvious reversal effect on the side effects of NSAIDs drug-induced reduction of the synthesis of gastric mucosal prostaglandin and increased permeability of mucosa. Further study has found that patients taking NSAIDs had gotten high expression of gastric epithelial HIF-1, suggesting that the gastric mucosa of patients is within hypoxic-ischemic state; However, patients taking rebamipide has significantly reduced HIF-1 expression, demonstrating that rebamipide has a very good protective effect on the gastric mucosa of patients taking NSAIDs table. From this perspective, rebamipide may have a prevention and treatment effect on NSAIDs (especially non-selective NSAIDs) induced gastric mucosal damage.
2. HP-related gastritis treatment
Haruma et al have reported that: in the observation of clinical treatment of 86 HP-positive patients, 53 patients taking rebamipide had stomach antrum and stomach body monocytes with significant reduction on granulocytes cell infiltration and had the stomach inflammation much more be alleviated than those without medication, indicating that it has a high-quality effect on treating HP-associated gastritis.
Studies have reported that patients with gastric cancer who have taken rebamipide before surgeries had significant lower body temperature than the control group at 3 days after surgeries. Moreover, their serum IL-6 levels are also significantly lower than the control group, demonstrating that rebamipide has alleviated effect on the post-surgery systemic inflammatory response syndrome of gastric cancer patients; rebamipide may also become a new means of treatment for ulcerative colitis; may also become a new and effective approach for treating Meniere's disease.
|Safety||Rebamipide promotes the ulcer healing rate to be as high as 56% to 67%, higher than other gastric mucosal protective agent; it can increase the eradication frequency without the increase of antibiotics, preventing phenomenon of the increase of adverse reactions caused by increased dose of antibiotics.
|Adverse reactions||Adverse reactions include leukopenia, thrombocytopenia, dizziness, drowsiness, numbness, abnormal taste, bloating, constipation, thirst, nausea, vomiting, heartburn, belching, abdominal pain, diarrhea, throat foreign body sensation, increased blood urea nitrogen, swollen breasts galactorrhea, menstrual disorders and eczema. It may also cause male breast enlargement. It can also occasionally cause coughing, difficulty in breathing, palpitations, fever, swelling, rash, itching and liver dysfunction. During the medication, if allergic reactions such as itching, rashes or eczema occurs, stop taking drugs immediately. The incidence is about 2.2% with the symptoms disappearing after withdrawal. Disable it for people who are allergic to this drug. The elderly and pregnant women should take with caution. Lactating women should stop breastfeeding upon medication. Safety of children's medication safety is still unclear.
|Chemical Properties||obtain the white powder from dimethylformamide - water with its hemihydrate m.p. being 288-290°C (decomposition). |
(-) - Configuration: from dimethylformamide to give colorless needles, mp 305 ~ 306 °C (decomposition). [α] D20-116.7 ° (C = 1.0, dimethylformamide).
(+) - Configuration: from dimethylformamide to give colorless needles, mp 305 ~ 306 °C (decomposition). [α] D20 + 116.9 ° (C = 1.0, dimethylformamide).
|Application||It is used for treating stomach ulcers.|
It is a kind of novel anti-ulcer drugs.
|Production methods||1. Preparation of racemic rebamipide. Use 2 (1H)-quinolinone 4-carboxylate (I) as the raw material; it undergoes lithium borohydride reduction to obtain 2 (1H) - quinolin-4-methanol (II), and then further have reaction with hydrobromide to obtain 4-bromomethyl-brominated -2 (1H) - quinolinone (III). |
Dissolve acetamido malonate (12.0g, 55mmo1) and sodium metal (1.5g, 65mmo1) in 150ml of absolute ethanol, heat to boiling, add with stirring of compound (III) (12.0g, 50mmo1), reflux for another 2h; Concentrate under reduced pressure with the residue being poured into water. Filter and collect the resulted precipitate re-crystallize using ethanol to give 13.0g colorless prismatic crystals of compound (IV),with yield being 69%, and melting point 224 ~ 226 °C (decomposition).
Compound IV) (5.0g, 13mmo1) was first suspended in 150ml 20% hydrochloric acid, and refluxed for 9h. Evaporate to dryness under reduced pressure with the residue being recrystallized from ethanol-water to obtain 3.2g of colorless prismatic crystals of compound (V) with yield being 89%, mp 220 ~ 225°C (decomposition).
Compound (V) (2.7g, 10mmo1) and potassium carbonate (4.2g, 30mmo1) was dissolved in a mixed solution of acetone and 20 ml water 100rnl; upon ice-cooling and stirring, add p-chlorobenzoyl chloride (2.1g, 12mmo1) drop wise, and then stir for another 2h. Acetone was distilled off under reduced pressure with the remaining solution being acidified with dilute hydrochloric acid. The precipitate was collected by filtration, and further washed with methanol - water for recrystallization to obtain 1.8g of white powder-like rebamipide with the yields being 49% and melting point being 288 ~ 290 °C (decomposition).
2. Preparation of (-) - Configuration. It is derived from the racemic resolution. 21.6g of racemic rebamipide was suspended in 1100ml of methanol, add 23g (-) - dimethyl strychnine (brucine) to form a clear solution which was further stirred at room temperature for 4h, then cooled overnight. The precipitate was collected by filtration, washed with cold methanol. Recrystallized for four times to give 7.6g of pure salt, [α] D20 + 60.4 ° (C = 1.0, chloroform). The methanol solution of this salt was added into 10% hydrochloric acid; filter the precipitate and wash with water. Then use dimethylformamide - water for recrystallization of three times to give 1.6 g colorless needles (-) - configuration of rebamipide with the yield being 14.8% and mp being 305 ~ 306 °C, [α] D20 -116.7 ° (C = 1.0, dimethylformamide).
3. Preparation of (+) - Configuration. Dissolve the solid obtained from the first mother liquor obtained at the above (-) - configuration in methanol; further add 10% hydrochloric acid. Filter the precipitate, wash with water, suspend in methanol; further add (-) - dimethyl strychnine and stir at room temperature for 1h. Filter to remove the insoluble and add concentrated hydrochloric acid to the filtrate. The precipitate was collected by filtration, washed with water. Apply dimethylformamide-water and re-crystallize for four times to obtain 3 g of colorless needles-like (+) configured rebamipide with a yield of 27.8% and mp of 305 ~ 306 °C (decomposition), [α] D20 + 116.9 ° (C = 1.0, dimethylformamide).
|Chemical Properties||White Powder|
|Usage||Shows antiulcer activity in rats|
|Rebamipide Preparation Products And Raw materials|