URAT1 (uric acid transporter 1) inhibitors, and preparation method and application thereof

Abstract

The invention provides carboxylic acid URAT1 inhibitors containing a naphthylmethyltriazole structure and represented by a general formula (I) which is described in the specification, a preparation method for the inhibitors, pharmaceutical compositions containing the inhibitors, and application of the inhibitors to preparation of drugs used for treating hyperuricemia and gout. The inhibitors as shown in the formula (I) have strong URAT1 inhibitory effect, normally have much stronger inhibitory effect compared with conventional URAT1 inhibitors with the structural characteristic that triazole and a naphthalene ring are directly linked by a covalent bond, and can be used as active ingredients for preparation of therapeutics used for treating gout and hyperuricemia. The inhibitors as shown inthe formula (I) are effective in wide dosage range; for example, the dosage of the inhibitors is about 1-1000 mg for each person each day.

Description

technical field [0001] The present invention relates to the field of drugs for the treatment of hyperuricemia and gout, in particular to a novel carboxylic acid URAT1 inhibitor containing a naphthalenemethyltriazole structure, a preparation method thereof, a pharmaceutical composition containing them and their application in the field of medicine use. Background technique [0002] Gout is a crystal-associated arthropathy caused by the deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by purine metabolism disorders and / or decreased uric acid excretion, specifically referring to acute characteristic arthritis and chronic Tophi diseases mainly include acute onset arthritis, tophi formation, tophi chronic arthritis, urate nephropathy and uric acid urolithiasis. In severe cases, joint disability and renal insufficiency may occur. Gout is often accompanied by abdominal obesity, hyperlipidemia, hypertension, type 2 diabetes and cardiovascular ...

AI Technical Summary

Problems solved by technology

The therapeutically effective dose of the drug is similar to the dose that causes gastrointestinal symptoms, and the incidence of side effects is extremely high (sometimes 100%). It was not approved by the FDA for use in the United States until 2009; It can control symptoms, but cannot relieve or treat gout itself; the clinical response rate of xanthine oxidase inhibitors is very low, and most of the effective rates are only 40-60%; in addition, allopurinol has severe allergic reactions, accompanied by systemic Allergic reactions can lead to toxic hepatitis and even severe liver cell necrosis

After administration of large doses of allopurinol, kidney damage can easily induce acute massive hepatic necrosis leading to death. Such cases are frequently reported; traditional uric acid excretion drugs probenecid, sulfazone, and benzbromarone also have many problems , the effect of probenecid is weak, the selectivity is not strong (URAT1, OAT1, OAT3, OAT4 inhibitory strength is similar), besulfazodone and benzbromarone have great side effects (the former inhibits platelets and bone marrow, and the latter is hepatotoxic), It is not sold in the United States, and benzbromarone was also withdrawn from the market in Europe in 2003, and is now only used in a few countries; the disadvantage of the newly approved lesinurad is its weak efficacy, large dosage (200mg), and the dosage is very close to the dosage of side effects (400mg has obvious kidney stones, and renal failure is significantly increased compared with 200mg); the disadvantage of uricase is that antibodies will be produced in the human body during use (about 25% of patients will produce antibodies), resulting in low efficiency (about 50%), long-term use decreases drug efficacy and causes infusion reactions, can also cause allergic reactions such as generalized urticaria-like itching, local redness after intramuscular injection, etc.

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