Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout

An OR2, C1-C4 technology, applied in the field of uric acid transporter 1 inhibitors, can solve the problems of serious side effects, unsuitable long-term treatment, renal function damage, etc.

Inactive Publication Date: 2016-10-19
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs all have relatively serious side effects. For example, colchicine has common adverse reactions such as diarrhea, vomiting, and abdominal cramps, and is the first indication of its toxicity. The therapeutically effective dose and the dose that causes gastrointestinal symptoms Probenecid can cause renal colic and renal dysfunction; benzbromarone has the risk of causing fulminant hepatitis; allopurinol has adverse reactions such as liver and bone marrow toxicity and allergic reactions; uricase preparations are administered by injection, The patient's compliance is not as good as oral preparations, and it is only suitable for reducing blood uric acid during acute gout attacks, and it is not suitable for long-term treatment

Method used

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  • Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout
  • Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout
  • Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The synthesis of embodiment 1 compound I-1

[0036]

[0037] Step 1. Synthesis of compound IV-1

[0038]Compound II-1 (2.82g, 10mmol), Compound III (1.78g, 15mmol), KI (1.66g, 10mmol) and K 2 CO 3 (4.15g, 30mmol) was added to a dry 250mL round bottom flask and DMF (100mL) was added. The resulting reaction mixture was stirred at 80° C. under a nitrogen atmosphere until TLC indicated that the reaction was complete (typically around 6 h).

[0039] After the reaction mixture was cooled, it was poured into ice water (1000mL), stirred, the pH of the resulting mixture was >7, and the mixture was washed with CH 2 Cl 2 (200mL×3) extraction, the organic phase was discarded, and the aqueous phase was adjusted to pH = 3 with concentrated hydrochloric acid, and again with CH 2 Cl 2 (300 mL×5) extraction. Combine and extract the organic phases, wash with 5% brine, anhydrous Na 2 SO 4 dry. The dried organic phase was evaporated to remove the solvent on a rotary evaporato...

Embodiment 2-16

[0049] Synthesis of Example 2-16 Compounds I-2 to I-16

[0050] Referring to the method of Example 1, the following compounds with general formula I were synthesized.

[0051]

[0052]

[0053]

Embodiment 17

[0054] Example 17 Synthesis of sodium salt I-S-1 from compound I-1

[0055]

[0056] Compound I-1 (0.428g, 1mmol) was dissolved in methanol (5mL), stirred at room temperature, slowly added a solution prepared by NaOH (0.400g, 1mmol) and water (1mL), after the addition, the reaction mixture was at room temperature Stirring was continued for 10 minutes.

[0057] The reaction mixture was evaporated to dryness on a rotary evaporator, and the obtained residue was dissolved in methanol (20mL×2) and then evaporated to dryness to remove water in the residue, and the obtained residue was further dried in a water bath at 35°C on a vacuum oil pump After 12 hours, the sodium salt I-S-1 of I-1 was obtained as a white solid, 0.441 g, with a yield of 98%. 1 H NMR (DMSO-d 6 ,400MHz),δ8.55(d,1H,J=8.4Hz),7.71(t,1H,J=7.4Hz),7.62(t,1H,J=7.6Hz),7.56(d,1H,J= 7.6Hz), 7.40(d, 1H, J=7.6Hz), 7.12(d, 1H, J=8.4Hz), 4.47(d, 1H, J=14.0Hz), 4.43(d, 1H, J=14.4Hz ),2.51-2.56(m,1H),1.11-1.15(m,2H),0.8...

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Abstract

The invention relates to the medicine field of hyperuricemia and gout. Specifically, the present invention relates to a class of uric acid transporter 1 (URAT1) inhibitors containing a tetrazolium structure, their preparation methods, pharmaceutical compositions containing them, and their application in the preparation and treatment of hyperuricemia and gout . Wherein, each substituent is as shown in the description.

Description

technical field [0001] The invention relates to the medicine field of hyperuricemia and gout. Specifically, the present invention relates to a class of tetrazolium-containing uric acid transporter 1 (URAT1) inhibitors that have a therapeutic effect on the above diseases, their preparation methods, pharmaceutical compositions containing them and their use in medicine. Background technique [0002] Gout is a chronic metabolic disease characterized by hyperuricemia and pain caused by deposition of monosodium uric acid (MSU) in joints and other parts. The main reason is purine metabolism disorder and / or uric acid excretion disorder. There are tens of millions of gout patients worldwide. [0003] Current drugs for the treatment of hyperuricemia and gout mainly include: i) anti-inflammatory and analgesic drugs for the control of symptoms such as joint swelling and pain in acute attacks of gout, such as colchicine and non-steroidal anti-inflammatory drugs (NSAIDs); ii ) drugs use...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/4196A61P19/06
Inventor 赵桂龙蔡文卿商倩田禾刘巍刘钰强谢亚非张宪生辛晓徐为人汤立达邹美香
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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