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Benzo five-membered heterocyclic sulfonamide compound, and preparation method, pharmaceutical composition and application thereof

A compound and heterocycloalkyl technology, applied in the field of innovative drugs, can solve the problems of PPAR agonists with large toxic and side effects, and single structure of PPARα/γ/δ broad-spectrum agonists

Active Publication Date: 2020-10-20
瀚海新拓(杭州)生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved in the present invention is to overcome the defects of relatively large toxic and side effects of existing PPAR agonists and the single structure of PPARα / γ / δ broad-spectrum agonists, and provide a benzo five-membered heterocyclic sulfonamide compound, its Preparation method, pharmaceutical composition and application

Method used

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  • Benzo five-membered heterocyclic sulfonamide compound, and preparation method, pharmaceutical composition and application thereof
  • Benzo five-membered heterocyclic sulfonamide compound, and preparation method, pharmaceutical composition and application thereof
  • Benzo five-membered heterocyclic sulfonamide compound, and preparation method, pharmaceutical composition and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0232] Embodiment 1: the synthesis of compound S1

[0233]

[0234] Step 1: Synthesis of compound 3a

[0235] Compound 1a (5 g, 46.3 mmol), compound 2a (5.3 g, 46.3 mmol) and TEA (13 mL, 92.6 mmol) were dissolved in 1,4-dioxane and stirred at room temperature for 3 h. After the reaction of the raw materials is complete, the precipitated solid is suction-filtered, and the filter cake is washed three times with 1,4-dioxane. Dissolve the filter cake in 25mL of acetic acid, add 10mL of concentrated hydrochloric acid, and heat to reflux for 2h. The volatile substances were distilled off under reduced pressure, and then the resulting solid was suspended in 45 mL of acetone while it was hot, stirred, cooled to room temperature, filtered with suction, washed with acetone three times, and the filter cake was vacuum-dried to obtain compound 3a (5.6 g, 60%). 1 H NMR (500MHz, DMSO-d 6 )δ12.03(s,1H),7.54–7.48(m,1H),7.46–7.40(m,1H),7.19–7.08(m,2H),2.69(t,J=6.4Hz,2H),2.43 (t,J=7.0Hz,2...

Embodiment 2

[0239] Embodiment 2: the synthesis of compound S2

[0240]

[0241] 1 H NMR (500MHz, DMSO-d 6 )δ12.11(s,1H),8.36(s,1H),7.98(dd,J=8.3,2.3Hz,1H),7.95–7.86(m,2H),7.78(d,J=8.5Hz,1H ), 7.36(d, J=2.3Hz, 1H), 7.31–7.25(m, 1H), 2.99(t, J=6.4Hz, 2H), 2.82(s, 3H), 2.45(t, J=7.3Hz ,2H 2H),2.20–2.11(m,2H). 13 C NMR (125MHz, DMSO-d 6 )δ 177.32, 156.48, 152.08, 151.20, 144.62, 142.82, 135.98, 135.31, 134.81, 125.33, 122.94, 121.32, 120.60, 113.75, 110.75, 33.49, 30.51, 22.959, 2

Embodiment 3

[0242] Embodiment 3: the synthesis of compound S3

[0243]

[0244] 1 H NMR (500MHz, DMSO-d 6 )δ12.11(s,1H),8.35(s,1H),7.96–7.83(m,4H),7.36(dd,J=8.1,1.8Hz,1H),7.12(td,J=8.2,1.8Hz ,1H),3.06(t,J=6.4Hz,2H),2.40(t,J=7.1Hz,2H),2.23–2.14(m,2H). 13 C NMR (125MHz, DMSO-d 6 )δ177.30,161.24,159.22,157.02,152.08,151.18,144.60,142.92,142.86,135.20,135.17,134.83,122.94,121.32,114.94,114.88,113.65,113.49,110.72,105.67,105.51,33.48,30.49,22.99.

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PUM

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Abstract

The invention relates to a benzo five-membered heterocyclic sulfonamide compound, and a preparation method, a pharmaceutical composition and application thereof. The invention particularly discloses the compound shown as a formula I, a pharmaceutically acceptable salt, isomer, metabolite or prodrug thereof. The benzo five-membered heterocyclic sulfonamide disclosed by the invention has very good agonistic activity on PPARalpha / gamma / delta, and shows a very good treatment effect on non-alcoholic fatty liver disease (NASH). The invention further discloses a preparation method and application ofthe compound as shown in the formula I.

Description

technical field [0001] The invention belongs to the field of innovative drugs, and relates to a benzo five-membered heterocyclic sulfonamide compound, a preparation method, a pharmaceutical composition and an application thereof. Background technique [0002] Metabolic syndrome (MS for short) refers to the pathological state of metabolic disorders of protein, fat, carbohydrates and other substances in the human body. Metabolic syndrome includes many pathological factors, insulin resistance, hyperinsulinemia, abdominal obesity, impaired glucose tolerance, type 2 diabetes mellitus, microalbuminuria, high triglyceride levels, low HDL cholesterol levels, hypertension, high uric acid, High prevalence of fatty liver, proinflammatory and prothrombotic state. Peroxisome proliferator-activated receptors (PPARs for short) are a class of ligand-dependent nuclear hormone receptors that belong to the steroid receptor superfamily and can induce and inhibit the expression of various genes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D417/12A61K31/423A61K31/428A61P3/00A61P3/10A61P1/16
CPCC07D413/12C07D417/12A61P3/00A61P3/10A61P1/16
Inventor 张霁蒋晟
Owner 瀚海新拓(杭州)生物医药有限公司
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