Sulfonamide compound as well as preparation method and application thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problems of failure to reach the primary efficacy endpoint, high incidence of taste-related adverse events, high frequency of drug withdrawal in the 45mg group, and achieve good P2X3 receptor antagonism and good safety Sexuality, the effect of prolonging the time of antitussive action

Active Publication Date: 2021-12-10
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2 studies, the gefapixant 15 mg twice daily treatment group did not meet the primary efficacy endpoint; although the 45 mg group met the clinical endpoint, the 45 mg group had a higher frequency of discontinuation due to adverse events and a higher incidence of taste-related adverse events

Method used

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  • Sulfonamide compound as well as preparation method and application thereof
  • Sulfonamide compound as well as preparation method and application thereof
  • Sulfonamide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048]Example 1: (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6 - Preparation of dihydro-1,3,5-triazin-1(2H)-yl)-2-methyl-N-(methylsulfonyl)propanamide (compound 1):

[0049] Step 1: Preparation of 4-(pyridine-2-oxyl)aniline (compound b-1)

[0050]

[0051] 2-fluoropyridine (97.1g, 1.0mol) and p-aminophenol (108.1g, 0.99mol) were dissolved in dimethyl sulfoxide (600ml), cesium carbonate (620g, 1.96mol) was added to obtain a reaction mixture, and mechanically stirred The reaction mixture was stirred evenly. Then the internal temperature of the reaction system was raised to 80° C. for 3 h. Thin-layer chromatography tracked the reaction progress. After the reaction was complete, the reaction mixture was added to 2L of water and kept stirring. Then extract the product three times with ethyl acetate, combine and dry the ethyl acetate and then concentrate to obtain the crude product. The crude product is slurried with 500ml of water for 1h and filt...

Embodiment 2

[0075] Example 2: (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6 Preparation of -dihydro-1,3,5-triazin-1(2H)-yl)-N-(ethylsulfonyl)-2-methylpropanamide (compound 2)

[0076] Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar ethylsulfonamide, and the rest of the conditions are the same. (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)-yl)-N-(ethylsulfonyl)-2-methylpropanamide (compound 2), yield: 77.0%, purity is 99.13%.

[0077] ESI-MS:m / z=599.2(M+H) + .

[0078] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),8.60(s,1H),8.15(dd,J=5.0,2.0Hz,1H),7.90–7.79(m,1H),7.45– 7.37(m,2H),7.30(d,J=8.4Hz,2H),7.15(m,4H),7.14–7.09(m,1H),7.03(d,J=8.3Hz,1H),5.42–5.15 (m,2H), 3.88(m,2H), 3.33(m,2H), 2.69(m,1H), 1.27(m,3H), 0.98(m,3H).

Embodiment 3

[0079] Example 3: (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6 Preparation of -dihydro-1,3,5-triazin-1(2H)-yl)-N-(N,N-dimethylaminosulfonyl)-2-methylpropionamide (compound 3)

[0080] Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar N,N-dimethylaminosulfonamide, and the rest of the conditions are the same. (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)-yl)-N-(N,N-dimethylaminosulfonyl)-2-methylpropanamide (compound 3), yield: 78.6% with a purity of 98.12%.

[0081] ESI-MS:m / z=614.2(M+H) + .

[0082] 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.60(s,1H),8.15(dd,J=5.0,2.0Hz,1H),7.90–7.79(m,1H),7.45– 7.37(m,2H),7.30(d,J=8.4Hz,2H),7.15(m,4H),7.14–7.09(m,1H),7.03(d,J=8.3Hz,1H),5.42–5.15 (m,2H), 3.88(m,2H), 2.79(s,6H), 2.69(m,1H), 0.98(m,3H).

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Abstract

The invention discloses a sulfonamide compound as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The structure of the sulfonamide compound is shown as a formula I in the specification. The invention also discloses a preparation method of the compound as shown in the formula I. The invention provides application of a compound as shown in the formula I or a salt, a solvate, an allomer, a metabolite, nitrogen oxide and a prodrug of the compound in preparation of drugs for treating or preventing P2X3 and / or / P2X2 / 3 receptor related diseases. The sulfonamide compound provided by the invention has almost no influence on the taste of mice, and has a significant statistical difference from a positive control drug gefapixant. The antitussive effect strong positive drug has an antitussive effect time obviously prolonged compared with that of a contrast 1 compound, and the inhibitory activity of the antitussive drug pair on P2X3 is superior to that of the contrast 1 compound and the positive control drug gefapixant.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to sulfonamide compounds, their preparation method and application. Background technique [0002] The incidence of chronic cough is high, with 5%-10% of adults worldwide suffering from chronic cough, chronic cough lasting > 8 weeks accounts for more than 1 / 3 of respiratory outpatient clinics, and the incidence rate is 2-10%. There are many factors that lead to chronic cough, such as genetic factors, long-term smoking, eating habits, environmental pollution, cold air, etc. Chronic cough not only aggravates the burden of medical resources, but also seriously affects the quality of life of patients and creates a serious psychological burden. The treatment of chronic cough in the prior art generally adopts: glucocorticoids, β2 receptor agonists, antihistamines, anti-reflux drugs, antibiotics and the like. Currently, there is no clinically approved drug specif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/53A61P11/14A61P11/06A61P29/00A61P11/00
CPCC07D401/12A61P11/14A61P11/06A61P29/00A61P11/00
Inventor 曾燕群朱绪成黄龙朱涛牟霞付海霞
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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