Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline

A technology of tetrahydroisoquinoline and benzothiazole, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of lack of in vivo activity and low efficacy, and achieve the effect of easy-to-obtain raw materials and simple and easy preparation methods

Inactive Publication Date: 2020-04-03
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although more than 10 PRMT5 inhibitors have been reported, most exhibit low potency or lack activity in vivo

Method used

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  • Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline
  • Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline
  • Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Rational design of compounds A_1~A_10 and B_1~B_2.

[0026] Since GSK3326595 and EPZ015666 were the best two of the previously reported substrate binding site inhibitors, we selected them as template compounds for further structural optimization; analysis of the crystal structure data revealed that the N-(3-(3 , 4-dihydroisoquinoline-2(1H))-2-hydroxypropyl) amino fragment interacts with many residues (L319, T323, F327, E435, L437, E444, W579), hydroxyl in PZ015666 It forms stable hydrogen bonds with L437, E444, and W579, indicating that it is a pharmacophore, and this hydroxyl group is retained in the subsequent molecular design. Therefore, N-(3-(3,4-dihydroisoquinoline -2(1H))-2-hydroxypropyl)amino, replace the left part of EPZ015666 with a group that can form a hydrophobic interaction with PRMT5; according to this design strategy, using traditional structure optimization methods, compounds A_1~A_10 and B_1~B_2, the structure is designed as Image 6 shown....

Embodiment 2

[0027] Embodiment 2: the preparation of compound A_1~A_10.

[0028] 1,2,3,4-Tetrahydroisoquinoline (compound 1) reacts with 2-(chloromethyl)oxirane under basic conditions to obtain the intermediate 2-(oxocyclo-2-ethylmethyl )-1,2,3,4-tetrahydroisoquinoline (compound 2); benzenesulfonyl chloride derivative (compound 3) was treated with ammonium hydroxide to obtain benzenesulfonamide derivative (compound 4); in solid-liquid phase transfer Under catalytic conditions, compound 2 reacts with compound 4 to obtain A_1~A_10 through ring opening; the preparation route is as follows Figure 4 as shown, Figure 4 Middle (a): 2-(chloromethyl)oxirane, potassium carbonate, methanol, room temperature; (b): ammonium hydroxide, acetonitrile, 0°C; (c) potassium carbonate, benzyltriethyl chloride Ammonium chloride, 1,4-dioxane, 90°C.

[0029] N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzenesulfonamide (A_1): yellow oil (130mg, 75%); 1 H-NMR (600 MHz, CDCl 3 ) δ 7.89-7.83 (m, 2...

Embodiment 3

[0039] Embodiment 3: Preparation of compounds B_1~B_2.

[0040] Treatment of 2-chloro-6-nitrobenzimidazole (compound 5) with tetrahydro-2H-pyran-4-amine gave 6-nitro-N-(tetrahydro-2H-pyran-4-yl)benzene And[d]thiazol-2-amine (compound 6) or 1-(3,4-dihydroisoquinolin-2(1H)-yl-3-((6-nitrobenzimidazol-2-yl) Amino) propan-2-alcohol (compound 7), reducing compound 6 to obtain an amine intermediate, and the amine intermediate reacts with compound 2 to obtain compound B_1; after reducing compound 7, reductive amination obtains B_2. The preparation route is as follows Figure 5 as shown, Figure 5 Middle (a): Tetrahydro-2H-pyran-4-amine or 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol, potassium carbonate, N,N-Dimethylformamide, 115 °C; (b): i) palladium / carbon, hydrogen, methanol, ii) 2, ethanol, 120 °C, sealed; (c) i) palladium / carbon, hydrogen , methanol, ii) sodium cyanoborohydride, dihydro-2H-pyran-4(3H)-one, methanol.

[0041] 1-(3,4-Dihydroisoquinolin-2(1H)-yl)-3-((...

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PUM

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Abstract

The invention discloses a sulfanilamide compound, containing tetrahydroisoquinoline, shown as figure 1, and a benzothiazole compound, containing tetrahydroisoquinoline, shown as figure 2, and application of the sulfanilamide compound and the benzothiazole compound as novel protein arginine methyltransferase 5 inhibitors.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a preparation method and application of tetrahydroisoquinoline-containing sulfonamide and benzothiazole compounds. Background technique [0002] Protein arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is an important post-translational modification, which uses S-adenosyl-methionine as a methyl donor, methylation Modifies the nitrogen atom of the arginine side chain of the protein. The substrates of protein arginine methyltransferases are glycine- and arginine-rich proteins. The nine identified human PRMTs (PRMTs 1–9) were further subdivided into type I, type II, and type III according to the status of methylated arginine. Type I PRMTs catalyze the formation of monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA): including PRMT1, PRMT3, PRMT4, PRMT6 and PRTM8; type II PRMTs catalyze the formation of monomethyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04C07D417/14A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D217/04C07D417/14
Inventor 张华刘凯璐闫薛朱孔凯
Owner UNIV OF JINAN
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