CN104311441A

CN104311441A - Chloronaphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives

Info

Publication number: CN104311441A
Application number: CN201410501864.1A
Authority: CN
Inventors: 不公告发明人
Original assignee: Individual
Current assignee: Mao Tingting
Priority date: 2014-09-27
Filing date: 2014-09-27
Publication date: 2015-01-28
Anticipated expiration: 2034-09-27
Also published as: CN104311441B

Abstract

The invention relates to the field of medicines related to hyperuricemia and gout, and particularly relates to urate transporter 1 inhibitors having structures of chloronaphthalene-ring-containing butanedioic acid amides, a preparing method thereof, pharmaceutical compositions containing the inhibitors and applications of the inhibitors in preparation of medicines for diabetes. A formula (I) is shown in the specification, wherein R1 is selected from H and a halogen substituent group.

Description

Succinamide derivative, the Preparation Method And The Use of one class chloro naphthalene nucleus

Technical field

The present invention relates to the pharmaceutical field that treatment hyperuricemia is relevant with gout.Specifically, the present invention relates to hyperuricemia and the medicative class of gout containing uric acid transporter body 1 (urate transporter 1, the URAT1) inhibitor of the succinamide derivative of chloro naphthalene nucleus, preparation method, containing they pharmaceutical composition and in purposes pharmaceutically.

Background technology

Gout is a kind of chronic metabolic disease, and the pain being deposited on the positions such as joint with hyperuricemia and monosodium urate salt (MSU) and causing is for principal character, and major cause is purine metabolic disturbance and/or uric acid excretion disorder.According to estimates, current global patient with gout has more than 2,000 ten thousand.The medicine being used for the treatment of gout at present comprises for lenitive anti-inflammatory drug (as colchicine etc.), suppresses uricogenesis medicine (xanthine oxidase inhibitor being representative with allopurinol and Febuxostat), thick uric acid excretion medicine (the uric acid excretion medicine being representative with probenecid, sulfinpyrazone, benzbromarone and losartan) and uriKoxidase (with pegloticase for representative).There is the toxic side effect of different degree in these medicines, as benzbromarone has the danger causing explosive hepatitis, allopurinol has liver and the untoward reaction such as bone marrow toxicity and transformation reactions, etc.

Lesinurad (RDEA 594) be a kind of developed by Ardea company can suppress uric acid transporter body (urate transporter 1 in kidney, URAT1) discharged the oral pharmaceutical of uric acid in blood by the approach of urine, be in III phase clinical stage at present.The antiviral RDEA806 that Lesinurad is researched and developed by Valeant company the earliest develops.The right of ownership of present Lesinurad is at present because Ardea company is belonged to Astra Zeneca by purchasing.

The invention discloses the URAT1 inhibitor of the succinamide derivative of a class chloro naphthalene nucleus, these compounds can be used for the medicine preparing treatment hyperuricemia and gout.

Summary of the invention

An object of the present invention is to provide one and there is excellent activity, there is a compounds of general formula I.

Another object of the present invention is to provide the method that preparation has the compound of general formula I.

Another object of the present invention is to provide compound containing general formula I as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment gout.

Now in conjunction with object of the present invention, content of the present invention is specifically described.

The present invention have general formula I compound and pharmaceutically acceptable prodrug ester there is following structural formula:

( I )

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

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

The compound of preferred formula I has following structure,

。

Further, the compound of preferred formula I has following structure,

。

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

。

Compound II per with monomethyl succinate III condensation under condensing agent exists, obtain compound IV; Compound IV is hydrolyzed in the presence of a base and obtains compound V; Compound V and compound R ²nH (VI) condensation under condensing agent exists, obtains product I.Described condensing agent is selected from DCC, EDC, TBTU and HATU etc.Described R ¹definition as previously mentioned.

Compound of Formula I of the present invention has the restraining effect of URAT1, can be used as the medicine of effective constituent for the preparation of hyperuricemia and gout.The activity of compound of Formula I of the present invention is verified by receptor binding assays.

Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage taken such as every day, within the scope of 1 mg-500 mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.

Embodiment

Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.

embodiment 1

。

A. the synthesis of compound IV-1

3.54g (20 mmol) Compound II per-1 and 2.64 g (20 mmol) compound III are dissolved in the THF of 50 mL dryings, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 4.13 g (20 mmol) and DMAP (DMAP) 0.61 g (5 mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 300 mL frozen water, stirs, uses the CH of 100 mL × 3 ₂cl ₂extraction, merges extraction phase, uses the dilute hydrochloric acid of 100 mL 1% and the salt water washing of 100 mL 5% successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=314 ([M+Na] ⁺).

B. the synthesis of compound V-1

Compound IV-1 4.36 g (15 mmol) is dissolved in 30 mL anhydrous methanols, and stirred at ambient temperature adds the LiOH solution of 3 mL 10%, then continues under room temperature to stir, until TLC detection reaction completes (within 5h).

Reaction mixture is poured in 200 mL frozen water, stirs, regulates pH=2-3 with concentrated hydrochloric acid.Use the CH of 100 mL × 3 ₂cl ₂extraction, merges extraction phase, uses the salt water washing of 100 mL 5%, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification (short column), obtains compound V-1, white solid, ESI-MS, m/z=276 ([M-H] ^-).

C. the synthesis of Compound I-1

2.77g (10 mmol) compound V-1 and 1.27 g (10 mmol) compound VI-1 is dissolved in the THF of 30 mL dryings, ice-water bath cooling is lower stirs, add dicyclohexyl carbodiimide (DCC) 2.06 g (10 mmol) and DMAP (DMAP) 0.61 g (5 mmol), then stirred at ambient temperature, until TLC detection reaction completes (within 12h).Reaction mixture is poured in 200 mL frozen water, stirs, uses the CH of 70 mL × 3 ₂cl ₂extraction, merges extraction phase, uses the dilute hydrochloric acid of 100 mL 1% and the salt water washing of 100 mL 5% successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I-1, faint yellow solid.ESI-MS, m/z = 405([M+NH ₄] ⁺)。

embodiment 2-9

With reference to the operation steps of embodiment 1, prepare compound listed in Table.

embodiment 10

The IC that compound of the present invention and related compound suppress URAT1 ₅₀be worth the similar method recorded according to document and measure (in US2014/0005136 embodiment 12).Shown in the following list of result.

Build the cell strain of stably express humanization URAT1 transporter: be subcloned into the plasmid pCMV6/neo (Origene) of eukaryotic expression from plasmid pCMV6-XL-5 (Origene) by humanization URAT1 gene (SLC22A112).Gene sequencing confirms humanization URAT1 consistent with the information recorded in gene pool (NM_144585.2).HEK293 human embryonic kidney cell (ATCC# CRL-1573) in EMEM tissue culture medium at the CO of 5% ₂cultivate with in the air atmosphere of 95%.L2000 type transfection agents (Invitrogene) is used to be transfected on HEK293 cell by pCMV6/Neo/URAT1.After 24 hours, transfected cell being assigned to diameter is in the tissue culture dishes of 10cm, continued growth one day, then substratum is replaced by the fresh substratum containing 0.5 mg/mL G418 (Gibco).After 8 days, select and collect resistance bacterium colony, and right with its test ¹⁴the transport activity of the uric acid of C-mark.By HEK293/URAT1 cell with 75, the density in 000/ hole is planted on 96 orifice plates that cover in poly-D-Lys.

These cells grow overnight under 37 ° of C in incubator, then under cool to room temperature, nutrient solution wherein uses the scavenging solution washing in 250 μ L/ holes once (10 m MHEPES of 125 mM Sunmorl N 60Ss, pH=7.3).Testing compound or blank be added to containing 40 μMs ¹⁴c-marks in the damping fluid of uric acid (54mCi/mmol), described damping fluid contains 125 mM Sunmorl N 60Ss, 4.8 mM Potassium Gluconates, 1.2 mM potassium primary phosphates, 1.2 mM magnesium sulfate, 1.3 mM calglucons, 5.6 mM glucose, 25 mM HEPES, final pH=7.3.96 orifice plates at room temperature cultivate 10 minutes, then respectively clean three times with the above-mentioned scavenging solution in 50 μ L/ holes and 250 μ L/ holes successively.96 orifice plates add Microscint 20 type liquid and dodges agent, plank is overnight incubation under 45 ° of C, then reading on TopCount Plate Reader, and calculates IC accordingly ₅₀.Shown in the following list of result:

。

Above-mentioned IC ₅₀measurement result show, compound of the present invention all shows good URAT1 inhibitor, can be used for preparing treatment hyperuricemia and the medicine of gout.

Claims

1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,

( I )

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

2. the compound with general formula I that claim 1 defines and pharmaceutically acceptable prodrug ester,

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 claim 1-4 defines:

Compound II per with monomethyl succinate III condensation under condensing agent exists, obtain compound IV; Compound IV is hydrolyzed in the presence of a base and obtains compound V; Compound V and compound R ²nH (VI) condensation under condensing agent exists, obtains product I; Described condensing agent is selected from DCC, EDC, TBTU and HATU; Described R ¹definition as arbitrary in claim 1-4 as described in.

6. the compound of Formula I that defines of claim 1-4 and the pharmaceutically application of acceptable prodrug ester in preparation treatment hyperuricemia and gout medicine thereof.