CN104725307A - A kind of PTP1B inhibitor containing nicotinic acid amide structure, preparation method and use thereof - Google Patents

Abstract

The present invention relates to the field of medicaments associated with type II diabetes. Specifically, the invention relates to a PTP1B inhibitor containing a nicotinic acid amide structure, a preparation method thereof and application thereof in preparing medicaments for treating type II diabetesApplication is carried out.

Description

A kind of PTP1B inhibitor containing nicotinic acid amide structure, preparation method and use thereof

technical field

The invention relates to the field of drugs for the treatment of type II diabetes. More specifically, the present invention relates to a PTP1B inhibitor containing a nicotinamide structure that has a therapeutic effect on type II diabetes, its preparation method, and its use in pharmacy.

Background technique

Type II diabetes mellitus is a common metabolic disorder characterized by peripheral insulin resistance, and at the molecular level, it is manifested as a loss of signal transduction after insulin binds to insulin receptors. The phosphorylation level of protease tyrosine is an important regulator of intracellular signal transduction, which is regulated by protein tyrosine kinase (PTK) and protein tyrosine phosphatase (protein tyrosine phosphatase, PTP). Recent studies have found that protease amino acid phosphatase 1B can dephosphorylate protease amino acid, which plays an important negative regulatory role in the insulin signal transduction pathway. Knocking out the PTPIB gene, or using antisense nucleotides (ASO) to inhibit the expression of PTP1B protein and mRNA in vivo can not only significantly improve the sensitivity of the tested mice to insulin, but also significantly reduce the incidence of obesity. These studies suggest that PTP1B may become a new target for the treatment of type II diabetes.

The invention discloses a PTP1B inhibitor containing a nicotinic acid amide structure with a novel structure, and these compounds can be used to prepare drugs for treating type II diabetes.

Contents of the invention

An object of the present invention is to provide a PTP1B inhibitor with good activity of formula I.

Another object of the present invention is to provide a process for the preparation of compounds of formula I.

Another object of the present invention is to provide the application of the compound of formula I as an active ingredient in the treatment of type II diabetes.

The content of the present invention will now be specifically described in conjunction with the purpose of the present invention.

Compounds of the present invention having formula I have the following structural formula:

Formula I compound of the present invention is synthesized by following route:

Compound II undergoes a substitution reaction with compound III in the presence of a base to obtain compound IV; compound IV reacts with compound V in the presence of DCC (N,N'-dicyclohexylcarbodiimide) to obtain VI; compound VI is oxidized by an oxidant , to obtain compound I. Compound II can be prepared according to literature methods (Leon Katz; et al, Journal of Organic Chemistry, 1954, 19, 711).

The compound of formula I in the present invention has the inhibitory effect on PTP1B, and can be used as an active ingredient in the preparation of drugs for treating type II diabetes. The activity of the compound of formula I in the present invention is verified by receptor binding assay.

The compounds of formula I according to the invention are effective over a fairly wide dosage range. For example, the daily dose is about in the range of 1 mg-1000 mg/person, divided into one or several administrations. The actual dose of the compound of formula I of the present invention can be determined by a doctor according to the relevant conditions.

Detailed ways

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

The synthesis of embodiment 1 compound I

A. Synthesis of Compound IV-1

Compound II (1.55g, 10mmol), Compound III-1 (1.96g, 10mmol) and solid K ₂ CO ₃ (5.53g, 40mmol) were added to 30mL of dry DMF, stirred overnight at room temperature, and TLC traced that the reaction was complete. The reaction mixture was poured into 200 mL of ice water, stirred, adjusted to pH=4-5 with concentrated hydrochloric acid, extracted with CH ₂ Cl ₂ (60 mL×3), the extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV-1 as a white solid. ESI-MS, m/z=269 ([MH] ⁻ ).

B. Synthesis of Compound VI-1

Compound IV-1 (1.35g, 5mmol), Compound V-1 (0.43g, 5mmol), DCC (1.24g, 6mmol) and 4-dimethylaminopyridine (DMAP, 0.3g) were dissolved in dry 20mL THF, After stirring overnight at room temperature, TLC traced that the reaction was complete. The reaction mixture was poured into 200 mL of ice water, stirred, extracted with CH ₂ Cl ₂ (60 mL×3), the combined extracts were washed with 2% dilute hydrochloric acid and brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound VI-1 as a white solid. ESI-MS, m/z=338 ([M+H] ⁺ ).

C. Synthesis of Compound I

Compound VI-1 (0.67g, 2mmol) was dissolved in 10mL CH ₂ Cl ₂ , stirred at room temperature, m-chloroperoxybenzoic acid (mCPBA, 1.72g, 10mmol) was added, the reaction mixture was stirred at room temperature for 1 hour, and then heated Refluxed for 3 hours, TLC detected that the reaction was complete. The reaction mixture was poured into 200 mL of ice water, stirred, extracted with CH ₂ Cl ₂ (60 mL×3), the combined extracts were washed successively with saturated NaHCO ₃ solution and brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain Compound I as a white solid. ESI-MS, m/z=386 ([M+H] ⁺ ).

The synthesis of embodiment 2 reference compound R-1

In order to further compare the pharmacological effects of the present invention, the applicant has recorded in this application the unknown compound R-1 (not yet published) invented by the same applicant.

A. Synthesis of Compound IV-2

Compound II (1.55g, 10mmol), compound III-2 (1.71g, 10mmol) and solid K ₂ CO ₃ (5.53g, 40mmol) were added to 30mL of dry DMF, stirred at room temperature overnight, TLC tracking found that the reaction was complete. The reaction mixture was poured into 200 mL of ice water, stirred, adjusted to pH=4-5 with concentrated hydrochloric acid, extracted with CH ₂ Cl ₂ (60 mL×3), the extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV-2 as a white solid. ESI-MS, m/z=244 ([MH] ⁻ ).

B. Synthesis of Compound VI-2

Compound IV-2 (1.23g, 5mmol), compound V-1 (0.43g, 5mmol), DCC (1.24g, 6mmol) and 4-dimethylaminopyridine (DMAP, 0.3g) were dissolved in dry 20mL THF, After stirring overnight at room temperature, TLC traced that the reaction was complete. The reaction mixture was poured into 200 mL of ice water, stirred, extracted with CH ₂ Cl ₂ (60 mL×3), the combined extracts were washed with 2% dilute hydrochloric acid and brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound VI-2 as a white solid. ESI-MS, m/z = 313 ([M+H] ⁺ ).

C. Synthesis of Compound R-1

Compound VI-2 (0.62g, 2mmol) was dissolved in 10mL CH ₂ Cl ₂ , stirred at room temperature, m-chloroperoxybenzoic acid (mCPBA, 1.72g, 10mmol) was added, the reaction mixture was stirred at room temperature for 1 hour, and then heated Refluxed for 3 hours, TLC detected that the reaction was complete. The reaction mixture was poured into 200 mL of ice water, stirred, extracted with CH ₂ Cl ₂ (60 mL×3), the combined extracts were washed successively with saturated NaHCO ₃ solution and brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound R-1 as a white solid. ESI-MS, m/z=361 ([M+H] ⁺ ).

Inhibitory test of the compound of Example 3 on PTP1B in vitro

The compound solution with an original concentration of 50 mM was diluted with 1/2 gradient with 95% DMSO, and a total of 11 concentration gradients were diluted. The enzyme activity reaction system was 102 μL in total, and the compound addition volume was 2 μL. First, 50 μL of PTP1B protein and 2 μL of test compounds of different concentrations were sequentially added to a 96-well plate, shaken for 1 min, incubated at 30°C for 30 min, and then 50 μL of pNPP (p-nitrophenyl phosphate) was added and shaken for 10 s. Measure the change of absorbance at 405nm wavelength with the reaction time, measure once in 6 seconds, measure 60 points, measure in parallel three times, and draw the reaction process curve, so as to calculate the inhibitory activity of each compound on the enzyme at different concentrations, using the software GraphPad Prism 5 The software performs nonlinear fitting analysis, draws a curve with the residual activity value as the ordinate and the logarithm of the compound concentration as the abscissa, and calculates the IC ₅₀ value of the compound.

The test results are shown in the table below.

compound IC ₅₀ (nM) Reference compound R-1 18.6 Compound I of the present invention 9.5

It can be seen from the results in the above table that the compound of the present invention has a strong inhibitory effect on PTP1B and can be used as a drug for the treatment of type II diabetes.

Claims (2)

1. A compound of formula I structure, 2. The use of the compound of formula I according to claim 1 in the preparation of medicaments for treating type 2 diabetes.