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Spiro compound and medicinal use thereof

A technology for compounds and drugs, applied in the field of spiro compounds and their pharmaceutical uses, can solve the problems of short half-life, toxicity, instability, etc.

Inactive Publication Date: 2017-05-10
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

[0007] Although these FXR agonists have shown some agonistic activity, each of these compounds has some disadvantages, such as the FXR agonist GW4064, which has low bioavailability and short half-life; trans-stilbene in its structure is a potential toxic group group (toxicology, 1981, 22(2), 149-160; Toxicol Appl.Pharmacol.2000, 167(1), 46-54); the ethylenic bond in trans-stilbene is unstable to ultraviolet light, so it also exists Potential Toxicity Concerns

Method used

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  • Spiro compound and medicinal use thereof
  • Spiro compound and medicinal use thereof
  • Spiro compound and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1. Preparation of 3-(5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-position)methoxy)hexahydrocyclopenta[c]pyrrole -2(1H)-position)benzoic acid (01)

[0073]

[0074] Compound 01 was prepared according to the following procedure:

[0075]

[0076] Dissolve ketone (1.000g, 0.0044mol, 1eq) in 10mL of methanol, add sodium borohydride (0.503g, 0.0133mol, 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 0.990 g of off-white solid.

[0077] Intermediates 1-3:

[0078]

[0079] Add 1-2 (0.990g, 0.0044mol, 1.5eq) to 10mL of anhydrous tetrahydrofuran, ...

Embodiment 2

[0110] Compounds 2-7 were prepared according to the steps described in Example 1, and only the reaction raw materials were replaced accordingly to obtain the target compounds. Compound numbers, compound structures and HNMR / MS details are listed in Table 1:

[0111] Table 1 Compound number, compound structure and HNMR / MS results

[0112]

[0113]

Embodiment 3

[0114] Example 3 Farnesoid X receptor (FXR) activation test

[0115] Adopt FXR reporter gene method to test the activation activity of compound of the present invention, method is as follows:

[0116] I. Cell Culture

[0117] a. Trypsinization, seed cells at appropriate density in 10ml of complete matrix.

[0118] b. Incubate the cells for 24 hours at 37°C, 5% CO2.

[0119] II. Cell Seeding and Transfection

[0120] FuGENE HD was used as transfection reagent.

[0121] a. Prepare the transfection mixture according to the table below.

[0122] pBIND-FXR (ng / well) 25 pG5Luc(ng / well) 25 FuGENE HD(ul / well) 0.15 No FBS media(ul / well) 1.85 Total mix(ul / well) 2.5

[0123] b. Tap the tube vigorously to mix and incubate at room temperature for 15 minutes.

[0124] c. Trypsinization to measure cell density.

[0125] d. Dilute the cell solution to the required volume at a density of 600,000 cells / ml.

[0126] e. Add the required volume of transf...

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Abstract

The invention relates to a spiro compound serving as a FXR receptor agonist, whose chemical structure is shown in type I, pharmaceutically acceptable salts of the spiro compound, or the enantiomers, diastereomers, tautomers, racemates, solvates, N-oxide or amino acid conjugates and the pharmaceutical compositions of the spiro compound, and the use in preparing drugs for treatment of diseases mediated by the FXR receptor.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a spiro compound and its medicinal use. 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 (DrrugDiscovery Today. Volume 17, Numbers 17 / 18, 2012). [0004] However, the ch...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14C07D417/14A61K31/422A61K31/4439A61K31/428A61P1/16A61P9/12A61P1/12A61P9/10
CPCC07D413/12C07D413/14C07D417/14
Inventor 李小川
Owner 宁波百纳西药业有限公司
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