Meloxicam
Molecular Formula: C14H13N3O4S2
Molecular Weight: 351.4
CAS No.: 71125-38-7
Names and Identifiers
Name
Meloxicam
Synonyms
Meloxicam
MeloxicaM API
MeloxicaM, BP
MeloxicamUsp27
MeloxicaM (Mobic)...
Category：Coating Additives
Introduction
Molecular Formula: C14H13N3O4S2
Molecular Weight: 351.4
CAS No.: 71125-38-7
Names and Identifiers
| Name | Meloxicam |
| Synonyms | Meloxicam MeloxicaM API MeloxicaM, BP MeloxicamUsp27 MeloxicaM (Mobic) Meloxicam (400 mg) 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-1,1-dioxide-2H-1,2-benzothiazine-3-carboxamide 4-HYDROXY-2-METHYL-N-(5-METHYL-2-THIAZOLYL)-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE 1,1-DIOXIDE 4-Hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazin-3-crboxamide 1,1-dioxide 4-Hydroxy-2-Methyl-N-(5-Methylthiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxaMide 1,1-dioxide 4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide Sodium 2-methyl-3-[(5-methyl-1,3-thiazol-2-yl)carbamoyl]-2H-1,2-benzothiazin-4-olate 1,1-dioxide |
| CAS | 71125-38-7 |
| EINECS | 615-253-8 |
| InChI | InChI=1/C14H13N3O4S2/c1-8-7-15-14(22-8)16-13(19)11-12(18)9-5-3-4-6-10(9)23(20,21)17(11)2/h3-7,18H,1-2H3,(H,15,16,19) |
| InChIKey | ZRVUJXDFFKFLMG-UHFFFAOYSA-N |
71125-38-7 – Physico-chemical Properties
| Molecular Formula | C14H13N3O4S2 |
| Molar Mass | 351.4 |
| Density | 1.613±0.06 g/cm3(Predicted) |
| Melting Point | 255 °C |
| Water Solubility | practically insoluble in water(0.154 mg/mL), with higher solubility observed in strong acids and bases. |
| Solubility | Soluble in water (22 mg/ml), DMSO (25 mg/ml), DMF, acetone(slightly soluble), ethanol(sli |
| Appearance | Bright yellow powder |
| Color | yellow |
| Merck | 14,5826 |
| pKa | 4.08 in water; 4.24 ± 0.01 in water/ethanol (1:1); 4.63 ± 0.03 in water/ethanol (1:4) |
| Storage Condition | 2-8°C |
| Stability | Stable. Incompatible with strong oxidizing agents. |
| Sensitive | Sensitive to heat |
| Refractive Index | 1.72 |
| MDL | MFCD00868752 |
| Physical and Chemical Properties | Crystallization from dichloromethane, melting point 254 °c (decomposition). pKa:4.08 water; 4.24±0.01 water-ethanol (1:1);4.63±0.03 water-ethanol (1:4). Acute toxicity LD50 mice (mg/kg):470 oral. |
| Use | For the treatment of rheumatoid arthritis, painful osteoarthritis |
71125-38-7 – Risk and Safety
| Risk Codes | R22 – Harmful if swallowed R36/37/38 – Irritating to eyes, respiratory system and skin. R25 – Toxic if swallowed |
| Safety Description | S26 – In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. S45 – In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.) S60 – This material and its container must be disposed of as hazardous waste. S36/37 – Wear suitable protective clothing and gloves. |
| UN IDs | UN 2811 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | DL0702000 |
| HS Code | 29349990 |
| Hazard Class | 6.1 |
| Packing Group | III |
| Toxicity | LD50 orally in mice: 470 mg/kg (Trummlitz, 1980) |
Reference Information
| analgesic anti-inflammatory drugs | meloxicam a non-steroidal antipyretic analgesic anti-inflammatory drugs, not hormonal drugs, with strong anti-inflammatory, analgesic and antipyretic effect, which selectively inhibits the activity of cyclooxygenase-2 (COX-2), thereby blocking the synthesis of prostaglandins, the inhibition of prostaglandin biosynthesis in inflammatory sites is stronger than that in gastric mucosa or kidney, and is safer than other NSAIDs. It is mainly used to relieve the symptoms of osteoarthritis, painful osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. |
| Overview | meloxicam (meloxicam), chemical name 4-hydroxy-2-methyl-n-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazine-3-carboxamide 1,1-dioxide, a non-steroidal anti-inflammatory drug. It was first launched in South Africa in 1996 by the German company Boehringer Ingelheim. It has analgesic, anti-inflammatory and antipyretic effects, and is clinically applicable to the symptomatic treatment of rheumatoid arthritis and painful osteoarthritis. The mechanism of action of non-steroidal anti-inflammatory drugs is to prevent the synthesis of inflammatory prostaglandins (PGs) and the like by inhibiting cyclooxygenase (COX). Cyclooxygenase (COX) is a membrane-bound serum protein and glycoprotein that catalyzes the oxidation of arachidonic acid (AA) to prostaglandin G2(PGG2) and the reduction from PGG2 to pgh2. There are two isoforms of COX: The cyclooxygenase-1 (COX-1)-structural enzyme and the cyclooxygenase-2 (COX-2)-PGG2-inducible enzyme. The inducible enzyme COX-2 is induced by inflammatory regulation and is involved in the regulation of the inflammatory response; Whereas the structural enzyme COX-1 is required for normal physiological processes and is present in most tissues, its function is to synthesize PG to regulate the normal physiological activity of cells, protect the digestive tract mucosa, support the microcirculation in the kidney and protect other organs from damage. Among the cyclooxygenase (COX) selective inhibitors of many different NSAIDs, meloxicam selectively inhibits COX-2, while diclofenac, piroxicam, indomethacin non-steroidal anti-inflammatory drugs or the same both inhibit COX, or inhibition of COX-1 than inhibition of COX-2. Meloxicam is safe in gastrointestinal tract and less toxic to kidney, which is due to its weak inhibition of COX-1. Fig.1 inflammatory reaction mechanism |
| pharmacological action | 1. Analgesic effect and other non-steroidal anti-inflammatory drugs, meloxicam is mainly used for mild to moderate chronic dull pain, such as neuralgia, Arthralgia. It has a strong and lasting analgesic effect on inflammatory pain in experimental rats. In male Lewis rats with experimental RA, the dose was 0.063 to 0 .5mg · kg-1, once a day, oral administration for 21 days, not only on the hind paw swelling and bone and cartilage damage, but also has a strong and lasting analgesic effect on inflammatory pain, oral doses up to 10mg · kg-1 had no effect on the central nervous system, similar to indomethacin, meloxicam had no analgesic effect on visceral pain. Antipyretic effect of meloxicam can reduce the body temperature of fever, but almost no effect on normal body temperature. For example, within the anti-inflammatory dose range, meloxicam had no effect on normal body temperature in rats, but reduced yeast-induced by Fever. Fever, respectively ip injection of meloxicam 0.1,0.3 or 0.5mg · kg-1, 2 times a week found that has obvious cooling effect, the best antipyretic dose was 0.3mg · kg-1. Twice a week. 3. Anti-inflammatory effects in animal models of inflammation (mainly including carrageenan, White Clay-induced edema in the hind paw of rats implanted cotton ball model of rat granuloma; carrageenan-induced pleurisy and liquid paraffin-adjuvant M. Tuberculosis-induced arthritis model), meloxicam showed strong anti-inflammatory activity. For carrageenan-induced pleurisy, unlike indomethacin, meloxicam reduces pleurisy secretion and inhibits leukocyte migration. In pleurisy in rats, the action of meloxicam is to inhibit the biosynthesis of prostaglandin E2(PGE2), which is 2 times that of piroxicam and 8 times that of diclofenac, respectively. In peritonitis in mice, meloxicam was 2 times more inhibitory than piroxicam and 10 times more inhibitory than diclofenac. Oral administration of meloxicam, piroxicam, diclofenac or tenidap once daily to male Lewis rats with experimental RA were observed for hind paw enlargement, bone and cartilage damage in hind paws, increase in spleen weight, erythrocyte sedimentation rate, and changes in serum protein components. It was found that the above drugs could inhibit the same inhibitory effect of the hind paw enlargement and the secondary reaction caused by the mouse hind paw enlargement, and the dose of the drug was twice as high as that of meloxicam, the doses of diclofenac and tenucleotide were 3.5 and 60 times higher than that of meloxicam, respectively. The daily dose of meloxicam required to inhibit bone and cartilage damage caused by RA is lower, and Piroxicam is four times that of meloxicam. Doses of diclofenac and tenidaph, which inhibit swelling of the hind paws in rats, had little effect on bone and cartilage damage. The dose of piroxicam was 3 to 4 times higher than that of meloxicam in the treatment of RA in rats. However, diclofenac and tenidaph did not produce comparable effects. |
| pharmacokinetics | The drug is well absorbed by oral and rectal administration, and the drug has no effect on absorption when eating. The bioavailability is 89%, the onset time after oral administration is 30 minutes, and the drug concentration of 7.5mg and 15mg orally is proportional to its dose. To achieve a steady-state blood concentration of 3 to 5 days, continuous treatment of more than 1 years in patients with drug concentration and the first time into a stable state of the patient. The concentration of its penetration into the inflammatory synovial membrane is about 50% of the blood concentration, and the plasma protein binding rate is> 99%, and its half-life is 20 hours. This product is metabolized in the liver, and the metabolites are inactive. 50% are excreted by the kidney, and the remaining 50% are excreted by the feces. |
| synthesis | There are many methods for the synthesis of meloxicam. With commercially available sodium saccharin (without purification and drying) as the starting material, by condensation with methyl chloroacetate in DMF to produce 2,2 in the refluxing solution of sodium methoxide in methanol to give 3, after N-methylation, the obtained 4 is reacted with 2-amino-5-methylthiazole to obtain crude product 1, and then recrystallized from 1, 2-dichloroethane to obtain a pure product with a content of ≥ 99%, the overall yield was 48.6%. 3-oxo-1, 2-benzisothiazole-2-acetic acid methyl ester 1, 1-dioxide (2)1000ml three-necked flask was added with DMF(410ml), sodium saccharin (1.0g, 162.8 mol, commercially available, containing water of crystallization) was added under magnetic stirring, and after being substantially dissolved, methyl chloroacetate (1.5g, mol) was added. The mixture was gradually heated to reflux (bath temperature 130-140°C) and reacted for 3H. After cooling to room temperature, the reaction mixture was added to cold water (820mL) with stirring, and a white solid was immediately precipitated. Suction filtration, water (100ml x 3). After vacuum drying (60°C) a white solid 2 was obtained. 4-hydroxy-2h-1, 2-benzothiazine-3-carboxylic acid methyl ester 1, 1-dioxide (3)250 ml three-necked flask was added with anhydrous methanol (60ml), sodium metal (6.5g,0.28mol) was then added portionwise, after complete dissolution of the sodium (which can be heated slightly), and the mixture was stirred electrically and heated to a bath temperature of 110-120°C. Powdered 2(18g,0.07mol) was immediately added quickly in one portion while stirring vigorously (care was taken to prevent flushing out), and the reaction was instantaneous to give a yellow-orange slurry. The oil bath was removed, and then ice (72g) -concentrated hydrochloric acid (28ml) mixture was added, stirred, and cooled to below 10°C in an ice water bath to precipitate a white solid, which was suction filtered and washed with water, vacuum drying (60°C) gave a white solid 3. 4-hydroxy-2-methyl-2h-1, 2-benzothiazine-3-carboxylic acid methyl ester 1, 1-dioxide (4)250ml three-necked flask was added with ethanol (72ml), with magnetic stirring, 3(14.4g,56.47mmol) was added followed by a solution of sodium hydroxide (3.16g) in water (72ml). After the reaction was exothermic and the solid was completely dissolved, the temperature was lowered to 20 ° C. Or lower, and then dimethyl sulfate (11.81g , 93.74mmol) was added dropwise (keeping the internal temperature not higher than 25 ° C.). After several minutes, a large amount of solid was precipitated and reacted at about 25 ° C. For 15 hours. It was cooled to below 10°C, suction filtered, and washed with 50% ethanol to obtain white solid 4. Fig.2 synthesis of meloxicam |
| Use | for rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, soft tissue injury pain, etc. (2015-11-23) Non-steroidal anti-inflammatory drugs. For the treatment of osteoarthritis, rheumatoid arthritis. drugs for arthritis and rheumatoid arthritis. for the treatment of rheumatoid arthritis, painful osteoarthritis cyclooxygenase-2 inhibitors for the symptomatic treatment of rheumatoid arthritis, painful osteoarthritis |
| adverse reactions | may occur dyspepsia, Abdominal Pain, Nausea, Diarrhea, elevated liver enzymes, dizziness, Head Pain, rash, anemia. There are occasional edema, elevated blood pressure, mild blood creatinine or urea nitrogen abnormalities, acute renal failure, gastric ulcer, gastric bleeding, gastric perforation, leukopenia and thrombocytopenia. |
| note | 1. Allergic to non-steroidal anti-inflammatory drugs, active peptic ulcer, severe liver dysfunction, pregnant and lactating women, under the age of 15 disabled. 2. History of upper digestive tract and is using anticoagulants, liver and kidney insufficiency in elderly patients with caution, if peptic ulcer or gastrointestinal bleeding should stop using this product. 3. Regular examination of liver and kidney function during medication, especially in elderly patients over 65 years of age. |
| drug interaction | 1. Concomitant use of oral anticoagulants, heparin and thrombolytic agents may increase the risk of bleeding. 2. The combination of this product and lithium salt can increase the plasma concentration of lithium, and the plasma lithium level should be monitored. 3. This product combined with methotrexate, can enhance the blood toxicity of the latter, should monitor the blood and liver function. 4. The combination of this product and cyclosporine can increase the renal toxicity of the latter through the indirect effect of renal prostaglandin, and the renal function should be determined regularly. 5. This product can reduce the effect of hypoglycemic drugs and antihypertensive drugs taken at the same time, so it is advisable to monitor and adjust the dosage of medication. No drug-drug interactions related to pharmacokinetics were observed with concomitant use of antacids, cimetidine, digoxin and furosemide. |
| production method | 4-hydroxy-2-methyl-2h-1, 2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 2-amino-5-methylthiazole were refluxed in xylene to give meloxicam in 74% yield. |
| category | toxic substances |
| toxicity grade | high toxicity |
| Acute toxicity | oral-rat LD50 84 mg/kg; Oral-mouse LD50: 470 mg/kg |
| flammability hazard characteristics | combustible, fire discharge of nitrogen oxides, sulfur oxides spicy stimulus smoke |
| storage and transportation characteristics | The warehouse is low temperature, ventilated and dry, and stored separately from food raw materials; custody of specialized institutions |
| extinguishing agent | water, carbon dioxide, dry powder, sand |
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