CN104311441B - Succinamide derivative, the Preparation Method And The Use of one class chloro naphthalene nucleus - Google Patents

Abstract

The invention relates to the field of medicines related to hyperuricemia and gout. Specifically, the present invention relates to a class of uric acid transporter 1 inhibitors with chloronaphthalene cyclosuccinic acid amide structure, a preparation method thereof, a pharmaceutical composition containing them and their application in the preparation of diabetes medicines. <b>(I)</b> wherein, R ¹ is selected from H, halogen substituents.

Description

A class of succinic acid amide derivatives of chloronaphthalene ring, its preparation method and use

technical field

The invention relates to the field of drugs related to the treatment of hyperuricemia and gout. Specifically, the present invention relates to a class of uric acid transporter 1 (uratetransporter1, URAT1) inhibitors containing chlorinated naphthalene ring-containing succinic acid amide derivatives that have a therapeutic effect on hyperuricemia and gout, a preparation method, and a method containing them. The pharmaceutical composition and its application in medicine.

Background technique

Gout is a chronic metabolic disease characterized by hyperuricemia and pain caused by deposition of monosodium uric acid (MSU) in joints and other parts. The main reason is purine metabolism disorder and/or uric acid excretion disorder. It is estimated that there are more than 20 million gout patients worldwide. Drugs currently used to treat gout include anti-inflammatory drugs for pain relief (such as colchicine, etc.), drugs that inhibit uric acid production (xanthine oxidase inhibitors represented by allopurinol and febuxostat), crude uric acid Excretion drugs (uric acid excretion drugs represented by probenecid, besulfazone, benzbromarone, and losartan) and uricase (represented by pegloticase). These drugs have different degrees of toxic and side effects, such as benzbromarone has the risk of causing fulminant hepatitis, allopurinol has adverse reactions such as liver and bone marrow toxicity and allergic reactions, and so on.

Lesinurad (RDEA594) is an oral drug developed by Ardea that can inhibit the uric acid transporter (uratetransporter1, URAT1) in the kidney and excrete uric acid in the blood through the urine. It is currently in phase III clinical stage. Lesinurad was first developed from the antiviral drug RDEA806 developed by Valeant. The ownership of Lesinurad is currently owned by AstraZeneca due to the acquisition of the Ardea company.

The invention discloses a class of URAT1 inhibitors of succinic acid amide derivatives of chlorinated naphthalene rings, and these compounds can be used for preparing medicines for treating hyperuricemia and gout.

Contents of the invention

One object of the present invention is to provide a class of compounds having general formula I with good activity.

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

Another object of the present invention is to provide a pharmaceutical composition containing a compound of general formula I as an active ingredient, and one or more pharmaceutically acceptable carriers, excipients or diluents, and its effect in the treatment of gout application.

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

The present invention has the compound of general formula I and pharmaceutically acceptable prodrug ester thereof with following structural formula:

(I)

Wherein, R ¹ is selected from H, halogen substituents.

Preferably : R ¹ is selected from H, F, Cl, Br substituents.

Preferred compounds of general formula I have the following structure,

.

Further, it is preferred that the compound of general formula I has the following structure,

.

The compound of general formula I of the present invention is synthesized by the following route:

.

Compound II is condensed with monomethyl succinate III in the presence of a condensing agent to obtain compound IV ; compound IV is hydrolyzed in the presence of a base to obtain compound V ; compound V is condensed with compound R ² NH ( VI ) in the presence of a condensing agent, Product I is obtained. The condensing agent is selected from DCC, EDC, TBTU and HATU and the like. ^The definition of R1 is as described above.

The compound of the general formula I of the present invention has the inhibitory effect on URAT1, and can be used as an active ingredient for the preparation of therapeutic drugs for hyperuricemia and gout. The activity of the compound of general formula I in the present invention is verified by receptor binding assay.

The compounds of general 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 1mg-500mg/person, divided into one or several administrations. The actual dosage of the compound of general formula I of the present invention can be determined by a doctor according to relevant conditions.

detailed description

Below in conjunction with embodiment the present invention will be further described. 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 should be within the scope of protection required by the claims of the present application.

Example 1

.

A. Synthesis of Compound IV-1

3.54g (20mmol) of compound II-1 and 2.64g (20mmol) of compound III were dissolved in 50mL of dry THF, stirred under cooling in an ice-water bath, and 4.13g (20mmol) of dicyclohexylcarbodiimide (DCC) and 4- Dimethylaminopyridine (DMAP) 0.61 g (5 mmol), then stirred at room temperature until the reaction was detected by TLC (within 12 h). The reaction mixture was poured into 300 mL of ice water, stirred, extracted with 100 mL×3 CH ₂ Cl ₂ , the combined extracts were washed with 100 mL of 1% dilute hydrochloric acid and 100 mL of 5% 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 , a white solid, ESI-MS, m/z =314 ([M+Na] ⁺ ).

B. Synthesis of Compound V-1

Compound IV-1 4.36g (15mmol) was dissolved in 30mL of anhydrous methanol, stirred at room temperature, added 3mL of 10% LiOH solution, and then continued to stir at room temperature until the reaction was detected by TLC (within 5h).

The reaction mixture was poured into 200 mL of ice water, stirred, and adjusted to pH=2-3 with concentrated hydrochloric acid. Extract with 100 mL×3 CH ₂ Cl ₂ , combine the extract phases, wash with 100 mL of 5% brine, and dry 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 (short column) to obtain compound V-1 , a white solid, ESI-MS, m/z =276 ([MH ] ^- ).

C. Synthesis of Compound I-1

2.77g (10mmol) of compound V-1 and 1.27g (10mmol) of compound VI-1 were dissolved in 30mL of dry THF, stirred under cooling in an ice-water bath, and 2.06g (10mmol) of dicyclohexylcarbodiimide (DCC) was added and 0.61 g (5 mmol) of 4-dimethylaminopyridine (DMAP), then stirred at room temperature until the reaction was detected by TLC (within 12 h). The reaction mixture was poured into 200 mL of ice water, stirred, extracted with 70 mL×3 CH ₂ Cl ₂ , the combined extracts were washed with 100 mL of 1% dilute hydrochloric acid and 100 mL of 5% 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-1 as a pale yellow solid. ESI-MS, m/z = 405 ([M+NH ₄ ] ⁺ ).

Example 2-9

Referring to the operation steps of Example 1, the compounds listed in the following table were prepared.

Example 10

The IC ₅₀ values of the compounds of the present invention and related compounds for URAT1 inhibition were determined by similar methods described in the literature (Example 12 in US2014/0005136). The results are listed below.

Construction of a cell line stably expressing the humanized URAT1 transporter: The humanized URAT1 gene (SLC22A112) was subcloned from the plasmid pCMV6-XL-5 (Origene) into the eukaryotic expression plasmid pCMV6/neo (Origene). Gene sequencing confirmed that the humanized URAT1 was consistent with the information recorded in the gene bank (NM_144585.2). HEK293 human embryonic kidney cells (ATCC #CRL-1573) were cultured in EMEM tissue culture medium in an atmosphere of 5% CO ₂ and 95% air. pCMV6/Neo/URAT1 was transfected onto HEK293 cells using L2000 type transfection agent (Invitrogene). After 24 hours, the transfected cells were divided into tissue culture dishes with a diameter of 10 cm, continued to grow for one day, and then the medium was replaced with fresh medium containing 0.5 mg/mL G418 (Gibco). Eight days later, drug-resistant colonies were selected and collected, and tested for transport activity towards ¹⁴ C-labeled uric acid. HEK293/URAT1 cells were seeded on poly-D-lysine-coated 96-well plates at a density of 75,000/well.

These cells were grown overnight at 37°C in an incubator, then cooled to room temperature, and the culture medium was washed once with 250 μL/well of washing solution (125 mM sodium gluconate, 10 mM HEPES pH=7.3). Add the compound to be tested or the blank control to a buffer containing 40 μM ¹⁴ C-labeled uric acid (54 mCi/mmol), which contains 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.2 mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 1.3mM calcium gluconate, 5.6mM glucose, 25mM HEPES, final pH=7.3. The 96-well plate was incubated at room temperature for 10 minutes, and then washed three times with 50μL/well and 250μL/well of the above cleaning solution. Add Microscint20 liquid flash agent to the 96-well plate, culture the plate at 45°C overnight, and then read it on TopCountPlateReader, and calculate the IC ₅₀ accordingly. The results are listed below:

.

The above _IC50 measurement results show that the compounds of the present invention are good URAT1 inhibitors and can be used to prepare medicines for treating hyperuricemia and gout.

Claims (6)

1. there is the compound of general formula I,

Wherein, R ¹be selected from H, halogenic substituent.

2. the compound with general formula I that claim 1 defines,

Wherein, R ¹be selected from H, F, Cl, Br substituting group.

3. the compound of Formula I that defines of claim 2, is selected from:

4. the compound of Formula I that defines of claim 3, is selected from:

5. synthesize the method for the compound of the general formula I that any one of claim 1-4 defines:

Compound II per and monomethyl succinate III condensation under condensing agent exists, obtain compound IV; Compound IV hydrolysis under LiOH exists obtains compound V; Compound V and compound VI condensation under condensing agent exists, obtain product I; Described condensing agent is selected from DCC, EDC, TBTU and HATU; Described R ¹definition as described in any one of claim 1-4.

6. the compound of Formula I that any one of claim 1-4 defines is preparing the application in treatment hyperuricemia and gout medicine.