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Benzimidazole derivatives as pi3 kinase inhibitors

A technology of benzimidazole and compounds, applied in the field of benzimidazole derivatives, can solve problems such as unidentified somatic mutations

Active Publication Date: 2016-03-30
GLAXOSMITHKLINE LC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unlike PIK3CA, somatic mutations have not been identified in the β isoform

Method used

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  • Benzimidazole derivatives as pi3 kinase inhibitors
  • Benzimidazole derivatives as pi3 kinase inhibitors
  • Benzimidazole derivatives as pi3 kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0344]

[0345] Preparation of 5-bromo-2-methyl-7-nitro-1H-benzimidazole

[0346] a) 4-bromo-2,6-dinitroaniline

[0347]

[0348] Bromine (1.5 mL, 30 mmol) was added dropwise to a stirred suspension of 2,6-dinitroaniline (5 g, 27.3 mmol) in glacial acetic acid (50 mL) and heated at 120 °C for 2 h. After cooling to ambient temperature, the resulting mixture was poured into water (50 mL). The precipitated solid was collected by filtration, washed with water, and dried in vacuo. The solid was redissolved in EtOAC, washed with water and saturated brine. The organic layer was collected and concentrated in vacuo to give the desired product (6.88 g, 95%). 1 HNMR (300MHz, DMSO-d 6 ) δppm 8.37 (brs, 2H), 8.58 (s, 2H).

[0349] b) 5-bromo-3-nitrobenzene-1,2-diamine

[0350]

[0351] 4-Bromo-2,6-dinitroaniline was dissolved in EtOH (50 mL), and (NH 4 ) 2 S (2.2 mL) was added to the mixture. The reaction mixture was heated to 90 °C for 1 h. Thin layer chromatography (...

Embodiment 2

[0355] Example 2 (R=H) and Example 3 (R=Ac)

[0356]

[0357] 2-Methyl-6-(4-morpholinyl)-1-(1-naphthylmethyl)-1H-benzimidazol-4-amine and N-(2-methyl-6-morpholinyl-4 Preparation of -yl-1-naphthalen-1-ylmethyl-1H-benzimidazol-4-yl)-acetamide

[0358] a) 6-bromo-2-methyl-1-(naphthalene-1-ylmethyl)-4-nitro-1H-benzo[d]imidazole

[0359]

[0360] 6-bromo-2-methyl-4-nitro-1H-benzo[d]imidazole (prepared according to the same operation as in Example 1) (3g), 1-(bromomethyl)naphthalene (2.85g ) and K 2 CO 3 (3.23 g) in DMF (100 mL) was stirred overnight at 80°C. It was cooled to room temperature and filtered. Then pour the filtrate into water. It was then filtered to give a solid which was washed with water and dried in vacuo to give the desired product (4.63 g, 100%). 1 HNMR (300MHz, DMSO-d 6 )δppm2.54(s,3H),6.16(s,2H),6.32(d,1H, J =7.5Hz),7.33(t,1H, J =7.5Hz),7.61-7.72(m,2H),7.87(d,1H, J =7.5Hz),8.01(d,1H, J =7.5Hz),8.14(d,1H, J =1.8Hz),8.19(d,1H, J =7.5Hz),8.28...

Embodiment 4

[0367]

[0368] Preparation of N-[2-methyl-6-(4-morpholinyl)-1-(1-naphthylmethyl)-1H-benzimidazol-4-yl]methanesulfonamide

[0369] a) 2-methyl-6-morpholino-1-(naphthalene-1-ylmethyl)-1H-benzo[d]imidazol-4-amine

[0370]

[0371] 4-(2-Methyl-3-(naphthalen-1-ylmethyl)-7-nitro-3H-benzo[d]imidazol-5-yl)mol, prepared as described in Example 2 morphine (804mg), iron powder (168mg) and FeSO 4 (84mg) in ethanol (30mL) and H 2 The mixture in O (30 mL) was stirred overnight at reflux temperature. The mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in DCM and filtered. Then the filtrate was washed with brine, washed with anhydrous Na 2 SO 4 Drying, filtering, and concentration in vacuo afforded the desired product as a solid (720 mg, 97%). 1 HNMR (300MHz, DMSO-d 6 )δppm2.33(s,3H),2.91(t,4HJ=4.8Hz),3.64(t,4HJ=4.8Hz),5.15(brs,2H),5.83(s,2H),6.10(d,1H, J=2.1Hz),6.12(d,1H,J=2.1Hz),6.38(d,1H,J=7.5Hz),7.34(t,1H,J=7.5Hz),7...

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Abstract

The present invention relates to the use of benzimidazole derivatives for modulating, in particular inhibiting, the activity or function of the phosphoinositide 3'OH kinase family (hereinafter referred to as PI3 kinases), suitably PI3Kα, PI3Kδ, PI3Kβ and / or PI3K gamma. Suitably, the present invention relates to the use of benzimidazole compounds in the treatment of one or more disease states selected from the group consisting of: autoimmune disease, inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, asthma , pancreatitis, multiorgan failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury. More suitably, the present invention relates to PI3Kβ-selective benzimidazoles for the treatment of cancer.

Description

technical field [0001] The present invention relates to the use of benzimidazole derivatives for modulating, in particular inhibiting, the activity or function of the phosphoinositide 3'OH kinase family (hereinafter referred to as PI3 kinases), suitably PI3Kα, PI3Kδ, PI3Kβ and / or PI3K gamma. Suitably, the present invention relates to the use of benzimidazole compounds in the treatment of one or more disease states selected from the group consisting of: autoimmune disease, inflammatory disease, cardiovascular disease, neurodegenerative disease, allergy, asthma , pancreatitis, multiorgan failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury. More suitably, the present invention relates to PI3Kβ-selective benzimidazoles for the treatment of cancer. Background technique [0002] The phosphoinositide 3-kinase (PI3K) pathway is most commonly activated in human cancers and its importance in carcinogenesis is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/04A61K31/4164A61P35/00
CPCC07D235/10C07D235/24C07D403/04C07D405/04C07D413/04C07D417/04A61K31/5377C07D235/08A61K31/337C07D401/10C07D403/10C07D405/10C07D409/10C07D413/10C07D417/10A61P29/00A61P35/00A61P35/02A61P37/00
Inventor J.屈R.里韦罗R.桑切斯R.特德斯科
Owner GLAXOSMITHKLINE LC
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