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Spiro compound as well as preparation method, composition and application thereof

A technology of spiro compounds and oxides, applied in the field of spiro compounds, can solve problems such as itching and increase in low-density lipoprotein

Inactive Publication Date: 2018-06-29
宁波百纳西药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to provide a class of spiro compounds in order to overcome the shortcomings of the existing FXR agonists in the druggability and to avoid the side effects of OCA such as itching and low-density lipoprotein increase while maintaining the efficacy. , its preparation method, composition and use

Method used

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  • Spiro compound as well as preparation method, composition and application thereof
  • Spiro compound as well as preparation method, composition and application thereof
  • Spiro compound as well as preparation method, composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1. Preparation of 4-(7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-position)methoxy)-2-azaspiro[3.5 ]nonyl-2-position)benzoic acid (01)

[0126]

[0127] Intermediate 1-2:

[0128]

[0129] Dissolve ketone (0.990g, 0.0041mol, 1eq) in 10mL of methanol, add sodium borohydride (0.472g, 0.0124mol, 3eq) in batches under ice bath, and react for 30min under ice bath after addition, TLC shows that the conversion of raw materials is complete, concentrate It was dried, quenched with water and dilute hydrochloric acid, extracted three times with ethyl acetate, the organic layer was combined and washed with water, washed with saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 0.980 g of off-white solid.

[0130] Intermediates 1-3:

[0131]

[0132] Add 1-2 (0.980g, 0.0041mol, 1.5eq) to 10mL of anhydrous tetrahydrofuran, add 18-crown-6 (1.8g, 0.0069mol, 1.7eq) and potassium ter...

Embodiment 2

[0162] Example 2. Preparation of 3-(7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-position)methoxy)-2-azaspiro[3.5 ]nonyl-2-position)benzoic acid (02)

[0163]

[0164] Compound 02 was prepared by referring to the steps described in Example 1 (Compound 01), and only the reaction raw materials were replaced accordingly to obtain the target compound. 1 H NMR (400MHz, CDCl 3 )δ: 7.42-7.29 (m, 5H), 7.11 (s, 1H), 6.65-6.62 (m, 1H), 4.30 (s, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 3.25 -3.23(m, 1H), 2.16-2.12(m, 1H), 1.80-1.30(m, 8H), 1.15-1.10(m, 4H).ESI-MS m / z 525.8(M-H) - .

Embodiment 3

[0165] Example 3. Preparation of 6-(7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-position)methoxy)-2-azaspiro[3.5 ]Nonyl-2-Nicotinic acid (03)

[0166]

[0167] Intermediate 3-2

[0168]

[0169] Add intermediate 1-1 (0.150g, 0.368mmol, 1eq), methyl 2-bromonicotinate (0.111g, 0.516mmol, 1.4eq), cuprous iodide (0.029g, 0.147mmol , 0.4eq), L-proline (0.018g, 0.147mmol, 0.4eq) and 5ml DMSO, heated to 120 degrees and stirred overnight, TLC showed that the conversion of raw materials was complete, quenched with water, extracted three times with ethyl acetate, and the organic layer Combined, washed with water and brine in turn, dried and concentrated to dryness, silica gel column chromatography (PE / EA=10 / 1, 5 / 1) gave 140 mg of light yellow oil.

[0170] Compound 03

[0171]

[0172] Intermediate 3-2 (0.140mg, 0.258mmol, 1.0eq) was dissolved in 5ml THF and 5ml MeOH, potassium hydroxide (0.051mg, 0.774mmol, 3.0eq) was added, and 1ml of water was heated to 60°C and s...

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PUM

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Abstract

The invention discloses a spiro compound as well as a preparation method, a composition and application thereof. The spiro compound has a structure shown as a formula (I). The spiro compound disclosedby the invention can effectively treat Farnesol X receptor-mediated diseases and is more stable and long in half-life period.

Description

technical field [0001] The invention relates to a spiro compound as an FXR receptor agonist, its preparation method, composition and application. Background technique [0002] Recent studies have shown that farnesoid X receptor (FXR) agonists have anti-cholestasis and anti-fibrosis effects. FXR is a nuclear receptor and a sensor of bile acid, which can regulate the synthesis of bile acid and the flow of bile in the liver. effect. [0003] Research data show that 6-α-ethylchenodeoxycholic acid (6-ECDCA, OCA) has 100 times the activation effect on FXR than chenodeoxycholic acid. Clinical studies have shown that OCA can be used to treat primary bile Liver cirrhosis (PBC), portal hypertension (Portal hypertension), nonalcoholic steatohepatitis (NASH), bile acid diarrhea (Bile aciddiarrhea), alcoholic hepatitis, primary sclerosing cholangitis (PSC), etc. are related to bile secretion (Drug Discovery Today. Volume 17, Numbers 17 / 18, 2012). [0004] However, the cholic acid com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/14C07D417/14A61K31/422A61K31/428A61K31/455A61K31/438A61P1/16A61P1/12A61P9/10A61P9/12A61P31/14A61P31/20
CPCC07D413/12C07D413/14C07D417/14
Inventor 李小川
Owner 宁波百纳西药业有限公司
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