Uric acid is the final metabolite of diet and purine in human body. In vivo environment (pH 7.4, 37 degrees), uric acid is present in blood mainly in the form of sodium salt of uric acid, the serum uric acid value of normal people is generally lower than 6 mg/dL. When uric acid in serum exceeds 7 mg/dL (Shi, et al., Nature 2003, 425: 516-523), sodium salt of uric acid will crystallize out and precipitate on joints and other parts of the body, and result in disorders such as gout, urinary stones, kidney stones, etc. Patients with gout are often accompanied with other complications, including hypertension, diabetes, hyperlipidemia, dyslipidemia, atherosclerosis, obesity, metabolic disease, nephropathy, cardiovascular disease, and respiratory disease, etc. (Rock, Et al., Nature Reviews Rheumatology 2013, 9: 13-23). In 2002, Japanese scientists Endou group reported that anion transport channel protein URAT1 is a major protein responsible for reabsorption of uric acid in kidney, they also found that the blood uric acid in people with URAT1 gene mutation (causing the synthesis of such protein being interrupted, inducing nonfunctional proteins) is only one-tenth of that in normal people (Enomoto et. al., Nature 2002 417: 447-452). These findings in human genetics demonstrate that URAT1 anion transport protein in kidney plays very important role in concentration of uric acid in blood, and indicates that URAT1 is a very good and specific target of a drug for reducing blood uric acid.
The main objective in the treatment of gout and its complications caused by higher level of blood uric acid is to reduce blood uric acid to lower than 6 mg/dL, the main methods are as follows: 1) to inhibit the generation of uric acid, such as allopurinol, febuxostat, which are drugs for inhibiting Xanthine oxidase; 2) to inhibit the reabsorption of uric acid, such as benzbromarone and probenecid, and lesinurad which is currently in clinical research, all of which are drugs for inhibiting kidney URAT1 anion transport channel protein.
In addition to URAT1, there are other cation transport channel proteins in kidney, such as Glut9 and OAT1 etc., which are also found to be able to reabsorb uric acid back to blood from renal tubules. Kidney is a major excretion pathway of uric acid in human body (70%), intestinal system (via ABCG2 etc.,) is responsible for excreting approximate 30% of uric acid (Sakurai, et. al., Current Opinion in Nephology and Hypertension 2013, 22: 545-550).
Human urate anion transporter 1, hURAT1, a member of anion transporter family, is located at luminal surface side of epithelial cells of renal proximal convoluted tubules, mainly participates in the reabsorption of uric acid in renal proximal convoluted tubules. URAT1 accomplishes reabsorption of uric acid and excretion of small amount of uric acid by exchanging univalent anions within cells with uric acid in lumens. Anion transport channel proteins located in renal proximal convoluted tubules also comprise anion transport channel protein OAT4, which has 42% of similarity with URAT1 (amino acids of protein). Therefore, generally, a potent URAT1 inhibitor will also inhibit OAT4 and some other anion transport channel proteins.
At present, all the clinical drugs for reducing blood uric acid have some side effects, for example, allopurinol will cause life-threatening hypersensitivity in some populations, febuxostat has cardiovascular side effects, and benzbromarone has liver toxicity and has been taken back by Sanofi from some markets. Therefore, it is urgent to search for novel, efficient and low-toxic drugs for reducing blood uric acid, and this will have great clinical significance and application prospects.
Thioacetate compounds have been reported in the prior art, e.g., a class of phenylthioacetate compounds were reported in CN102939279A, a class of thioacetate compounds were reported in CN103068801A, wherein thioacetate compounds in CN103068801A are obtained from the compounds in CN102939279A by essentially replacing carbons of benzene groups in skeletons of the compounds in CN102939279A with 1 to 4 N atoms.
Step 1: Synthesis of 4-(4-chloropyridin-3-yl)benzonitrile (20-b)
3-bromo-4-chloropyridine (573 mg, 3 mmol), aqueous solution of sodium carbonate (6 mL, 12 mmol, 2 M), 4-cyanophenylboronic acid (441 mg, 3 mmol) and tetrakis(triphenylphosphine)palladium (0) (173 mg, 0.15 mmol) were added to dioxane (18 mL) in a single-necked flask (50 mL), and then purged with nitrogen 3 times, the mixture was heated to 80° C. and reacted for 5 hours. The reaction solution was cooled, added with ethyl acetate (100 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was dried, filtered, concentrated, and purified by preparative silica gel plate (ethyl acetate/petroleum ether: 1/4) to yield a yellow solid product.
Step 2: Synthesis of methyl 2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio) methyl)cyclopropyl)acetate (20-c)
Methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate (840 mg, 5.25 mmol), potassium carbonate (1.45 g, 10.5 mmol) and 4-(4-chloropyridin-3-yl) benzonitrile (450 mg, 2.1 mmol) were dissolved in dimethyl formamide (20 mL) in a single-necked flask (50 mL), the mixture was heated to 130° C. and reacted for 0.5 hour. The reaction solution was cooled, added with ethyl acetate (100 ml), and washed with water (100 ml) and brine (100×3 mL). The organic phase was dried, filtered, concentrated, and purified by preparative silica gel plate (ethyl acetate/petroleum ether: 1/2) to yield a yellow oily product.
Step 3: Synthesis of 2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl) cyclopropyl)acetic acid (20)
Methyl 2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl)cyclopropyl) acetate (67 mg, 0.2 mmol) and aqueous solution of sodium hydroxide (0.5 mL, 0.5 mmol, 1 M) were added to methanol (3 mL) in a single-necked flask (50 mL), and the mixture was reacted at room temperature for 5 hours. The reaction solution was adjusted to pH=3 with concentrated hydrochloric acid, concentrated and purified by preparative reverse-phase chromatography to yield a white solid product.
Kaufmann D, Chaiyakunapruk N, Schlesinger N (November 2024). “Optimizing gout treatment: A comprehensive review of current and emerging uricosurics”. Joint Bone Spine. 92 (2) 105826. doi:10.1016/j.jbspin.2024.105826. PMID39622367.
