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Triazole n-propionic acid urat1 inhibitor, preparation method and use thereof in the treatment of hyperuricemia and gout

A halogenated agent, XI-A technology, applied in the direction of bone diseases, drug combination, etc., can solve problems such as unsuitable for long-term treatment, serious side effects, patient compliance is not as good as oral preparations, etc.

Active Publication Date: 2018-06-22
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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  • Triazole n-propionic acid urat1 inhibitor, preparation method and use thereof in the treatment of hyperuricemia and gout
  • Triazole n-propionic acid urat1 inhibitor, preparation method and use thereof in the treatment of hyperuricemia and gout
  • Triazole n-propionic acid urat1 inhibitor, preparation method and use thereof in the treatment of hyperuricemia and gout

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The synthesis of embodiment 1 compound I-1

[0031]

[0032] Step 1. Synthesis of Compound VI-1

[0033] 4-Pentenylhydrazide II was synthesized according to literature method (Gilchrist, T.L.; et al. Synthesis, 1983, 153-154). 4-Pentenylhydrazide II (11.41g, 100mmol) and N,N-dimethylformamide dimethyl acetal III (11.92g, 100mmol) were dissolved in 230mL acetonitrile, heated and stirred at 50°C until TLC The reaction was found to be complete (usually around 0.5-1 hour).

[0034] After the reaction was completed, the reaction mixture was slightly cooled and concentrated to 1 / 3 of the original volume on a rotary evaporator, at this time a solution of IV was obtained. 4-cyclopropylnaphthylamine V-1 (18.32 g, 100 mmol) and 230 mL of glacial acetic acid were added thereto, and the reaction mixture was stirred overnight at 120° C. under nitrogen protection, and TLC inspection found that the reaction was complete.

[0035] After the reaction mixture was cooled, it was po...

Embodiment 2

[0054] The synthesis of embodiment 2 compound 1-2

[0055]

[0056] Step 1. Synthesis of Compound XI-A-2

[0057] Compound X-1 (0.96g, 3mmol) was dissolved in 10mL of acetonitrile, stirred at room temperature, and N-chlorosuccinimide (NCS, 0.48g, 3.6mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature until completion by TLC (typically 24 hours).

[0058] The reaction mixture was poured into 100mL ice water, stirred, and washed with 50mL×3CH 2 Cl 2 extraction. The combined and extracted organic phases were successively washed with Na 2 S 2 o 3 Solution, 100mL×5 saturated Na 2 CO 3 solution and 5% saline, anhydrous Na 2 SO 4 dry. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain the product XI-A-2 as a white solid, 0.82 g, with a yield of 77%. MS, m / z=356 ([M+H] + ).

[0059] Step 2. Synthesis of Compoun...

Embodiment 3

[0062] The synthesis of embodiment 3 compound 1-3

[0063]

[0064] Step 1. Synthesis of Compound XI-A-3

[0065] Compound X-1 (4.82g, 15mmol) was dissolved in 50mL of acetonitrile, stirred at room temperature, and N-iodosuccinimide (NIS, 4.05g, 18mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature until completion by TLC (typically 24 hours).

[0066] The reaction mixture was poured into 300mL ice water, stirred, and washed with 100mL×3CH 2 Cl 2 extraction. The combined and extracted organic phases were successively washed with Na 2 S 2 o 3 Solution, 100mL×5 saturated Na 2 CO 3 solution and 5% saline, anhydrous Na 2 SO 4 dry. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain the product XI-A-3, a white solid, 5.43 g, with a yield of 81%. MS, m / z=448 ([M+H] + ).

[0067] Step 2. Synthesis of Compound 1...

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Abstract

The invention relates to the field of medicine for treating hyperuricemia and gout. Concretely, the invention relates to an urate transporter 1(URAT1) inhibitor containing a triazole propionate structure, a preparation method thereof, and an application of a pharmaceutical composition containing the urate transporter 1 inhibitor in preparation of medicines for treating hyperuricemia and gout. Each substituent is shown in a specification.

Description

technical field [0001] 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 triazole-n-propionic acid structure that has a therapeutic effect on the above-mentioned diseases, its preparation method, and pharmaceutical compositions containing them, as well as in medicine the use of. 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 ant...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/10C07D249/14C07D249/12A61K31/4196A61P19/06
Inventor 赵桂龙田禾商倩于冰刘钰强谢亚非蔡文卿张宪生辛晓徐为人汤立达邹美香
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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