CN106008421A - Human body urate transporter-1 inhibitor capable of promoting uric acid excretion and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of medicine, and specifically discloses a human urate transporter-1 inhibitor capable of promoting uric acid excretion and a preparation method thereof. The inhibitor is a compound or a salt or a prodrug represented by 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid. The inhibitor of the present invention has better hURAT1 inhibitory ability and selectivity, and at the same time has less toxic and side effects, and is expected to become a uric acid excretion drug with less adverse reactions.

Description

A human urate transporter-1 inhibitor capable of promoting uric acid excretion and its preparation method

technical field

The invention relates to the technical field of medicine, in particular to a human urate transporter-1 inhibitor capable of promoting uric acid excretion and a preparation method thereof. The inhibitor is used for treating hyperuricemia, gout and tophi deposition.

Background technique

Gout is more common in middle-aged and elderly people over 40 years old, and the incidence rate of adults in developed countries is 1-2%, and its prevalence rate increases with age. And with the improvement of living standards and the increase of intake of high purine substances, the incidence of gout is increasing year by year. According to epidemiological statistics in 2008, the prevalence of gout in my country has reached 1.14%. In recent years, the global incidence of gout has increased significantly and the trend of younger people has made people pay more and more attention to the treatment of gout. There are few types of drugs used in the clinical treatment of gout and most of the adverse reactions are serious. hURAT1-specific inhibitors can effectively reduce the occurrence of side effects. Therefore, hURAT1 inhibitors have become the focus of research by world pharmaceutical companies in recent years.

The hURAT1 transporter was reported in 2002 to be related to congenital renal hyperuricemia. It is mainly expressed in the luminal side membrane of renal proximal tubule epithelial cells, mediates the transport of extracellular uric acid into the cell, and completes the first step of uric acid reabsorption. In the first step, the mutation of the receptor gene can accelerate the excretion of uric acid, resulting in hypouricemia. Therefore, hURAT1 inhibitors can be used as new urate-lowering drugs, mainly for the treatment of hyperuricemia, gout and ventilation-related symptoms. The specific hURAT1 inhibitor just approved by the FDA in 2016 is Lesinurad. Combining it with drugs that reduce uric acid production (such as allopurinol and febuxostat) can increase the response of gout patients who do not respond well to the above drugs Rate. However, its single drug still has kidney-related risks and poor curative effect. How to maximize the efficacy of hURAT1 inhibitors and overcome its side effects as much as possible has become a research hotspot.

There are many different transporters located in renal tubular epithelial cells, such as hOAT1, etc. The low specific binding ability to hURAT1 may be one of the reasons for the side effects of drugs. Drugs with high specificity can relatively reduce the side effects caused by them.

Contents of the invention

The technical problem to be solved by the present invention is to provide a hURAT1 inhibitor with high specificity, which is 3.5 times stronger than the marketed drug Lesinurad, and has better selectivity.

In order to solve the problems of the technologies described above, the technical solution of the present invention is:

A human urate transporter-1 inhibitor (i.e. hURAT1 inhibitor) that can promote uric acid excretion, the inhibitor is represented by 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid compounds or salts or prodrugs of

Wherein, the chemical formula of the 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid is:

The present invention also provides a preparation method of the above human urate transporter-1 inhibitor, comprising the following steps:

Step 1: Take monomethyl terephthalate and place it in thionyl chloride, reflux and stir for 4 to 8 hours, distill off thionyl chloride under reduced pressure, add 2-ethylbenzofuran and aluminum trichloride, and stir at room temperature 20-30h; add ice water to the reaction solution, stir and stand still, separate the organic layer; add dilute HCl, stir; add distilled water, stir and stand still, separate the organic layer; add saturated NaCl solution, stir and stand still, separate the organic layer, reduce Remove the organic solvent by steaming under pressure; separate and purify by silica gel column chromatography to obtain 4-(2-ethyl-benzofuran-3-carbonyl)-methyl benzoate;

Step 2, take the 4-(2-ethyl-benzofuran-3-carbonyl)-methyl benzoate obtained in step 1 and place it in a mixed solvent of water, methanol and tetrahydrofuran, add sodium hydroxide, and stir at room temperature for 10 ~14h, evaporate the solvent under reduced pressure; add distilled water to dissolve it completely, slowly add dilute hydrochloric acid dropwise until the pH is weakly acidic; add chloroform for extraction, separate, and evaporate chloroform; separate and purify by silica gel column chromatography to obtain 4-(2-ethane -benzofuran-3-carbonyl)-benzoic acid.

As a preferred scheme, every 1 mmol of monomethyl terephthalate corresponds to 1.3 mmol of 2-ethylbenzofuran.

As a preferred solution, the mass ratio of each component in the mixed solvent of water, methanol and tetrahydrofuran is 1:1:1.

Compared with the prior art, the present invention has the following beneficial effects: [14]C uric acid uptake experiment and MTT experiment prove that 4-( 2-Ethyl-benzofuran-3-carbonyl)-benzoic acid has better hURAT1 inhibitory ability and selectivity, and at the same time has less toxic and side effects, and is expected to become a uricosuric drug with less adverse reactions.

It should be noted that the essence or improvement of the present invention lies in preparing by selecting the above-mentioned components or using the above-mentioned components. What can be determined in the prior art or through simple experiments can be realized by those skilled in the art by simple derivation or experiments based on the above technical solutions, so the relevant components are not clearly defined in the above description.

Description of drawings

The following drawings are only intended to illustrate and explain the present invention schematically, and do not limit the scope of the present invention. in:

Fig. 1 is the inhibitory ability graph of inhibitor (B-1) of the present invention compared with inhibitor (Lesinurad) in the prior art to hURAT1;

Fig. 2 is a selectivity diagram of hURAT1 for the inhibitor (B-1) of the present invention compared with the inhibitor (Lesinurad) in the prior art.

detailed description

Below in conjunction with accompanying drawing and embodiment, further elaborate the present invention. In the following detailed description, certain exemplary embodiments of the invention are described by way of illustration only. Needless to say, those skilled in the art would realize that the described embodiments can be modified in various different ways, all without departing from the spirit and scope of the present invention. Accordingly, the drawings and description are illustrative in nature and not intended to limit the scope of the claims.

A human urate transporter-1 inhibitor (i.e. hURAT1 inhibitor) that can promote uric acid excretion, the inhibitor is represented by 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid compound of;

Wherein, the chemical formula of the 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid is:

The preparation method of above-mentioned inhibitor, comprises the following steps:

Step 1. Take 500 mg of monomethyl terephthalate and place it in 6 ml of thionyl chloride, stir under reflux for 6 hours, distill off the thionyl chloride under reduced pressure, add 535 mg of 2-ethylbenzofuran and 630 mg of aluminum trichloride, Stir at room temperature for 24 hours; add 10ml of ice water to the reaction solution, stir and let it stand, and separate the organic layer; add 10ml of dilute HCl, stir; add distilled water, stir and let it stand, and separate the organic layer; add 20ml of saturated NaCl solution, stir and let it stand, and separate the organic layer , the organic solvent was evaporated under reduced pressure; separation and purification by silica gel column chromatography gave 4-(2-ethyl-benzofuran-3-carbonyl)-methyl benzoate; the yield was 26%;

Spectral data: MS: m/z 309 ([M+H] ⁺ ). ¹ H-NMR (400MHz, CDCl3) δ8.18–8.14(m,2H),7.89–7.83(m,2H),7.49(d,J=8.4Hz,1H),7.34–7.27(m,2H), 7.22–7.15(m,1H),3.97(s,3H),2.91(q,J=7.6Hz,2H),1.34(t,J=7.6Hz,3H);

Step 2. Take the 4-(2-ethyl-benzofuran-3-carbonyl)-methyl benzoate prepared in step 1 and place it in a mixed solvent of water, methanol and tetrahydrofuran (mass ratio 1:1:1) , add 80 mg of sodium hydroxide, stir at room temperature for 12 hours, evaporate the solvent under reduced pressure; add 10 ml of distilled water to dissolve it completely, slowly add dilute hydrochloric acid until the pH is weakly acidic; add 20 ml of chloroform for extraction and separation, and evaporate the chloroform; silica gel column layer Analysis, separation and purification gave 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid; the yield was 72%;

Spectral data: MS: m/z 293 ([MH] ^- ). ¹ H-NMR (400MHz,MeOD)δ8.10(s,2H),7.79(s,2H),7.54(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),7.33 (t,J=8.0,7.6Hz,1H),7.22(t,J=7.6Hz,1H),2.87(q,J=7.6Hz,2H),1.33(t,J=7.6Hz,3H). ¹³ C-NMR (101MHz, CDCl3) δ191.19, 167.46, 153.65, 143.89, 143.84, 130.32, 129.64, 128.87, 126.42, 124.58, 123.72, 122.10, 121.22, 115.75, 115.1.99, 1211.07,

Among them, 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid, English chemical name: 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid, abbreviation: B-1, synthesized The route is as follows:

Referring to Figure 1 and Figure 2, through the [14]C uric acid uptake test and MTT test, the hURAT1 inhibitor (B-1) of the present invention compared with the control drug (Lesinurad) has the ability to inhibit hURAT1, as shown in Table 1:

Table 1. Comparison of Inhibition Capabilities

drug name B-1 (10μM) Lesinurad (10μM) Inhibition rate 53% 28%

It can be seen that the hURAT1 inhibitor B-1 of the present invention has a higher inhibitory intensity on hURAT1 than the marketed drug Lesinurad, and has better hURAT1 inhibitory ability.

The selectivity of the hURAT1 inhibitor (B-1) of the present invention to hURAT1 compared with the control drug (Lesinurad), as shown in Table 2:

Table 2. Selectivity Comparison

drug name B-1 Lesinurad hURAT1 inhibition rate (10μM) 53% 28% hOAT1 inhibition rate (20μM) 40% 31%

It can be seen that the ratio of hURAT1 inhibitor B-1 of the present invention to hURAT1 inhibition rate to hOAT1 inhibition rate is higher than that of the marketed drug Lesinurad, indicating that B-1 has better selectivity for hURAT1.

The above descriptions are only illustrative specific implementations of the present invention, and are not intended to limit the scope of the present invention. Any equivalent changes and modifications made by those skilled in the art without departing from the concepts and principles of the present invention shall fall within the protection scope of the present invention.

Claims (4)

1. Human Urine hydrochlorate transporter-1 inhibitor that can promote urate excretion, it is characterised in that: described inhibitor is 4- (2-Ethyl-benzofuran-3-carbonyl)-benzoic compound or salt or prodrug；

Wherein, described 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic chemical formula is:

2. the method preparing Human Urine hydrochlorate transporter-1 inhibitor as claimed in claim 1, it is characterised in that include following step Rapid:

Step one, take terephthalic acid monomethyl ester and be placed in thionyl chloride, return stirring 4～8h, remove thionyl chloride under reduced pressure, add Enter 2-ethyl benzofuran and aluminum chloride, be stirred at room temperature 20～30h；Adding frozen water in reactant liquor, stirring stands, separates organic Layer；Add dilute HCl, stirring；Adding distilled water, stirring stands, and separates organic layer；Adding saturated NaCl solution, stirring stands, point From organic layer, remove organic solvent under reduced pressure；Silica gel column chromatography separating-purifying obtains 4-(2-Ethyl-benzofuran-3-carbonyl)-benzene first Acid methyl ester；

Step 2, take step one prepare 4-(2-Ethyl-benzofuran-3-carbonyl)-essence of Niobe be placed in water, methanol, four In the mixed solvent of hydrogen furan, add sodium hydroxide, stirring at normal temperature 10～14h, remove solvent under reduced pressure；Adding distilled water makes it complete CL, being slowly added dropwise dilute hydrochloric acid to pH is faintly acid；Add chloroform extraction, separate, chloroform is evaporated off；Silica gel column chromatography separates and carries Pure 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid.

3. the preparation method of Human Urine hydrochlorate transporter-1 inhibitor as claimed in claim 2, it is characterised in that: every 1mmol's The 2-ethyl benzofuran of terephthalic acid monomethyl ester's correspondence 1.3mmol.

4. the preparation method of Human Urine hydrochlorate transporter-1 inhibitor as described in Claims 2 or 3, it is characterised in that: described water, Methanol, oxolane mixed solvent in the mass ratio of each component be 1:1:1.