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New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma

A compound, -R8 technology, applied in the field of new compound inhibitors, can solve problems such as unreported inhibitory activity

Inactive Publication Date: 2020-01-17
INVENTIVA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Two hydrogenated benzothiazole derivatives are disclosed that are different from the compounds disclosed in this application, but no YAP / TAZ-TEAD interaction inhibitory activity, let alone specific anticancer activity is reported

Method used

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  • New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
  • New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
  • New compounds inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0352] Example 1: N-[(E)-(4-fluorophenyl)methyleneamino]-N-methyl-1,1-dioxo-1,2-benzothiazol-3-amine

[0353] Step A: 3-Chloro-1,2-benzothiazole 1,1-dioxide

[0354] A mixture of saccharin (70.00 g; 382.13 mmol; 1.00 equiv), thionyl chloride (41.58 ml; 573.19 mmol; 1.50 equiv) and a catalytic amount of DMF (2.10 ml) in 1,4-dioxane (350 ml) Heat at reflux for 24 hours. The reaction mixture was concentrated, co-evaporated 4 times with toluene (200ml) and dried to give 3-chloro-1,2-benzothiazole 1,1-dioxide (77.00g; 99%) which was used without further purification . 1 H NMR (DMSO-d 6 ,300MHz): δ8.19(dd, J=1.0Hz, J=7.0Hz, 1H); 7.99(m,3H).

[0355] Step B: 1-(1,1-dioxo-1,2-benzothiazol-3-yl)-1-methyl-hydrazine

[0356] 3-Chloro-1,2-benzothiazole 1,1-dioxide (7.00g; 0.03mol; 1.00eq) was dissolved in anhydrous THF (56ml), then added dropwise to methylhydrazine (2.22ml; 0.04mol; 1.20 equivalent) in THF (56ml) solution. The reaction was then stirred at reflux for 1 hour and the ...

Embodiment 2

[0359] Example 2: 2-[3-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]phenoxy ] Ethanol

[0360] From 1-(1,1-dioxo-1,2-benzothiazol-3-yl)-1-methyl-hydrazine (Example 1, Step B, 70.0 mg; 0.33 mmol; 1.00 equiv) and 3-(2-hydroxyethoxy)benzaldehyde (82.6 mg, 0.5 mmol, 1.5 equiv) started the preparation of the compound to give 2-[3-[( E)-[(1,1-Dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]phenoxy]ethanol (24.0 mg; 20%). 1 H NMR (DMSO-d 6 ,400MHz):δ8.87(m,1H); 8.46(s,1H); 8.09(m,1H); 7.92(m,2H); 7.48(m,2H); 7.42(m,1H); 7.11( m, 1H); 4.92 (t, J = 5.4Hz, 1H); 4.10 (t, J = 5.0Hz, 2H); 3.80 (s, 3H); 3.77 (q, J = 5.3Hz, 2H).

Embodiment 3

[0361] Example 3: N-methyl-N-[(E)-(4-morpholinophenyl)methyleneamino]-1,1-dioxo-1,2-benzothiazol-3-amine

[0362] From 1-(1,1-dioxo-1,2-benzothiazol-3-yl)-1-methyl-hydrazine (Example 1, Step B, 50.0 mg; 0.24 mmol; 1.00 equiv) and 4-(4-morpholinyl)benzaldehyde (49.8 mg, 0.26 mmol, 1.10 equiv) started the preparation of the compound to give N-methyl-N-[ (E)-(4-Morpholinophenyl)methyleneamino]-1,1-dioxo-1,2-benzothiazol-3-amine (60.0 mg; 66%). 1 H NMR (DMSO-d 6 ,400MHz):δ8.90(d,J=7.1Hz,1H); 8.37(s,1H); 8.07(d,J=7.1Hz,1H); 7.89(m,2H);7.75(d,J= 8.5Hz, 2H); 7.09 (d, J = 8.5Hz, 2H); 3.79 (s, 3H); 3.75 (t, J = 4.9Hz, 4H); 3.27 (t, J = 4.9Hz, 4H). Melting point: 258°C-261°C.

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Abstract

The invention relates to compounds of formula: wherein R1 to R7 are as defined in the description. These compounds are useful as inhibitors of the YAP / TAZ-TEAD interaction.

Description

technical field [0001] The present invention relates to novel compound inhibitors of the YAP / TAZ-TEAD interaction and their use in therapy, especially in the treatment of malignant mesothelioma. Background technique [0002] The Hippo pathway regulates cell proliferation, cell death and cell differentiation in multicellular organisms to ensure normal tissue development (Tumaneng K et al., Curr. Biol., 2013, 22, R368-379; Yu Fx et al., Genes Dev, 2013 , 27, 355-371). Over the past few years, various genetic and biochemical studies in Drosophila and mammals have identified a highly conserved core hippo signaling module (Huang et al., Cell, 2005, 122, 421-434; Zeng et al., Cancer Cell, 208, 13, 188-192; Badouel et al., Curr. Opin. Cell. Biol., 2009, 21, 837-843). [0003] Essentially, the core hippo signaling module consists of the following members: Ste20-like kinase (MST1 / 2) and large tumor suppressor 1 / 2 (LATS1 / 2), and MOB activator 1A (MOB1A) and MOB1B and AGC (protein K...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D275/06C07F5/02A61P35/00A61K31/425
CPCC07D417/12C07D275/06C07F5/025A61P35/00A61K31/425A61K31/501A61K31/69C07F5/027C07D417/04
Inventor 马丁·巴斯西尔维·孔塔尔让-路易斯·朱丽亚克里斯蒂安·玛萨蒂克里斯蒂安·蒙塔尔贝蒂安妮·苏德
Owner INVENTIVA