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Triazole propionate URAT1 inhibitor, preparation method thereof and purpose of triazole propionate URAT1 inhibitor for treating hyperuricemia and gout

A halogenated agent, XI-A technology, applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve serious side effects, unsuitable for long-term treatment, fulminant hepatitis and other problems

Active Publication Date: 2016-08-03
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 propionate URAT1 inhibitor, preparation method thereof and purpose of triazole propionate URAT1 inhibitor for treating hyperuricemia and gout
  • Triazole propionate URAT1 inhibitor, preparation method thereof and purpose of triazole propionate URAT1 inhibitor for treating hyperuricemia and gout
  • Triazole propionate URAT1 inhibitor, preparation method thereof and purpose of triazole propionate URAT1 inhibitor for treating hyperuricemia and gout

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Synthesis of Compound I-1

[0031]

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

[0033] 4-pentenoyl hydrazide II is synthesized according to literature methods (Gilchrist, T.L.; etal. Synthesis, 1983, 153-154). 4-pentenoyl hydrazide II (11.41 g, 100 mmol) and N,N-dimethylformamide dimethyl acetal III (11.92 g, 100 mmol) were dissolved in 230 mL of acetonitrile, and heated at 50°C with stirring until TLC The reaction was found to be complete (usually about 0.5-1 hour).

[0034] After the reaction was completed, the reaction mixture was slightly cooled and concentrated on a rotary evaporator to 1 / 3 of its original volume, at which time an IV solution 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 at 120° C. overnight under the protection of nitrogen. TLC inspection found that the reaction was complete.

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

Embodiment 2

[0054] Example 2 Synthesis of Compound I-2

[0055]

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

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

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

[0059] Step 2. Synthesis of Compound I-2

[0060] Compound XI-A-2 (0.71g, 2mmol)...

Embodiment 3

[0062] Example 3 Synthesis of Compound I-3

[0063]

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

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

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

[0067] Step 2. Synthesis of Compound I-3

[0068] Compound XI-A-3 (0.89g, 2mmol) was disso...

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PUM

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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 field of drugs for hyperuricemia and gout. Specifically, the present invention relates to a class of uric acid transporter 1 (URAT1) inhibitors containing triazole n-propionic acid structure that have therapeutic effects on the above-mentioned diseases, their preparation methods, and pharmaceutical compositions containing them, as well as in medicine the use of. Background technique [0002] Gout is a chronic metabolic disease characterized by pain and pain caused by hyperuricemia and monosodium uric acid (MSU) deposited on joints and other parts. The main reason is disorder of purine metabolism and / or uric acid excretion. There are currently tens of millions of gout patients worldwide. [0003] The current hyperuricemia and gout treatment drugs mainly include: i) Anti-inflammatory and analgesic drugs used for symptom control such as joint swelling and pain in acute attacks of gout, such as colchicine and non-steroidal anti-infl...

Claims

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Application Information

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Patent Type & Authority Applications(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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