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Phenyl ring-aromatic ring cascaded compound, and preparation method and medical application thereof

A compound and aryl technology, applied in the field of medical technology, can solve problems such as poor cell permeability, low bioavailability, and difficulty in making medicines

Active Publication Date: 2015-07-22
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

1) For relatively mature drug targets such as PTP1B, it is necessary to solve the problems of poor cell permeability, low bioavailability, and difficulty in making drugs in existing inhibitors; in-depth understanding of the relationship between inhibitors, enzymes, and diseases relationship between the two; a closer look at why anti-diabetic drug candidates (e.g. Ertiprotafib) did not go out of the clinic and were successfully brought to market

Method used

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  • Phenyl ring-aromatic ring cascaded compound, and preparation method and medical application thereof
  • Phenyl ring-aromatic ring cascaded compound, and preparation method and medical application thereof
  • Phenyl ring-aromatic ring cascaded compound, and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119]

[0120] Reagents and conditions: a) Benzoyl chloride, pyridine, DCM

[0121] Compound 1-1 (552 mg, 3 mmol) and pyridine (4.5 mL, 18 mmol) were dissolved in DCM (10 mL), and benzoyl chloride (833 μL, 7.2 mmol) was added under ice-cooling conditions. After the reaction was detected by TLC, the reaction solution was filtered, and the solid was washed with methanol and water, and dried to obtain compound 3-2 (3-HC-392) (700 mg, 60%). 1 H NMR(400MHz,DMSO-d6)δ7.57(t,J=7.4Hz,4H),7.63(t,J=7.0Hz,2H),7.70(d,J=8.8Hz,4H),7.90(d ,J=8.4Hz,4H),7.99(d,J=7.6Hz,4H),10.35(s,2H).

[0122] Except that benzoyl chloride is appropriately replaced by the corresponding reaction compound, the preparation of the following compounds can refer to the preparation method in Example 1.

[0123]

Embodiment 2

[0125]

[0126] Reagents and conditions: a) piperidine, 57% perchloric acid; b) fuming nitric acid, acetic anhydride, 0°C; c) p-nitroacetophenone, triethylamine, acetic acid, ammonium acetate, acetonitrile, 0°C, room temperature; d) hydrazine hydrate, palladium carbon, THF; e) benzoyl chloride, triethylamine, THF

[0127] Compound 4 (98mL, 595mmol) and 57% perchloric acid (56mL) were stirred at room temperature for 1.5h, then a solution of piperidine (117.6mL, 1190mmol) was added dropwise under ice-cooling conditions, and after the addition was completed, it was stirred at 0°C for 40min , and then add 57% perchloric acid 70mL. After the reaction was completed, the reaction solution was placed in a refrigerator at 4 °C for 3 h, and the precipitated solid was filtered, washed with ether, and dried to obtain compound 5 (52.48 g, 29%). 1 H NMR (400MHz, DMSO-d 6 )δ1.50-1.70(m,12H),3.45-3.70(m,8H),5.82(t,J=11.8Hz,1H),7.69(d,J=12.0Hz,2H).

[0128] Compound 5 (50g, 163mmol) was ...

Embodiment 3

[0136]

[0137] Reagents and conditions: a) Boc anhydride, K 2 CO 3 ,THF,H 2 O; b) Et 3 N, HATU, DCM, 40°C; c) trifluoroacetic acid, CH 2 Cl 2 ,40℃; d) Benzoyl chloride, triethylamine, DCM

[0138] Compound 10 (10 g, 77.5 mmol) and potassium carbonate (21.4 g, 155 mmol) were dissolved in water (150 mL), and a solution of Boc anhydride (16.9 g, 77.5 mmol) in THF (50 mL) was slowly added dropwise under ice cooling. After the dropwise addition, it was reacted at room temperature for 12 hours. After the reaction was completed, THF was removed by rotary evaporation, and the pH was adjusted to 1 with 1N hydrochloric acid. A large amount of solid precipitated, filtered, and the obtained solid was washed once with water, and dried to obtain compound 11 (30.4 g, 86%). 1 H NMR (400MHz, CDCl 3 )δ1.45(s,9H),1.59-1.69(m,2H),1.89-1.92(m,2H),2.45-2.52(m,1H),2.82-2.88(m,2H),3.95-4.10( m,2H).

[0139] Compound 11 (11g, 48mmol) was added to DCM (100mL), benzidine (3.68g, 20mmol), tri...

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Abstract

The invention relates to a phenyl ring-aromatic ring cascaded micro-molecular organic compound which can be used as a protein-tyrosine-phosphatase subtype inhibitor and is shown in a general formula I as described in the specification. The compound can be used as a tool compound for research on the biological functions of a variety of subtypes of a protein-tyrosine-phosphatase family in cell signal transduction, so novel means is provided for prevention and treatment of cancers, metabolism and immunological diseases, cardiovascular diseases and nervous diseases. The invention also relates to a preparation method and medicinal application of the compound.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a class of benzene-aromatic ring series small molecular organic compounds that can be used as subtype inhibitors of protein tyrosine phosphatases. These compounds can be used as tool compounds to study each protein tyrosine phosphatase family The biological functions of the isoforms in the process of cell signal transduction provide new means for the prevention and treatment of cancer, metabolic and immune diseases, cardiovascular diseases and neurological diseases. The invention also relates to the preparation method and medical use of the compound. Background technique [0002] The dynamic balance of phosphorylation and dephosphorylation of protein tyrosine plays an important role in cell growth, differentiation, metabolism, motility and apoptosis. Once there is a slight imbalance in the biological function balance between protein tyrosine kinases that regulate pho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/68C07D333/38C07C233/65C07C235/56C07C233/58C07C233/66C07C233/04C07C231/02C07D211/62C07D405/14C07D213/75C07D207/34C07D277/56A61K31/341A61K31/381A61K31/165A61K31/4545A61K31/4418A61K31/443A61K31/40A61K31/426A61P35/00A61P3/00A61P37/00A61P9/00A61P25/00A61P3/10A61P3/04A61P9/10A61P25/28
Inventor 李佳王文龙冯柏年沈佳汇黄超高立信陈立杨天训李亚楠苗冉冉
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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