CN115772117A - 2-hydroxysuccinic acid compound and pharmaceutical composition and application thereof - Google Patents
2-hydroxysuccinic acid compound and pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN115772117A CN115772117A CN202211630879.9A CN202211630879A CN115772117A CN 115772117 A CN115772117 A CN 115772117A CN 202211630879 A CN202211630879 A CN 202211630879A CN 115772117 A CN115772117 A CN 115772117A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- pharmaceutical composition
- nmr
- esi
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a 2-hydroxysuccinic acid compound, a pharmaceutical composition and an application thereof, wherein the compound is a compound with a structure shown in formula I or II or an isomer, a pharmaceutically acceptable salt or a mixture thereof. The compound and the pharmaceutical composition thereof can effectively inhibit the citric acid transport activity of HEK293 cells, are used for treating metabolic diseases and/or cardiovascular diseases, can exert the drug effect at the molecular level, and have better treatment effectExcellent, and can optimally reach the nanomolar concentration level. In addition, the preparation method of the compound is simple and convenient and is easy to operate.
Description
Technical Field
The invention relates to a compound, a pharmaceutical composition and application thereof, in particular to a 2-hydroxysuccinic acid compound, a pharmaceutical composition and application thereof.
Background
Cardiovascular diseases are currently the first leading cause of death worldwide, and dyslipidemia due to high cholesterol is one of the major risks of death from cardiovascular diseases. Statins are first-line therapeutic drugs for hyperlipidemia, but 15% of patients have clinical defects such as statin intolerance or poor lipid-lowering effect of statins. Therefore, the development of efficient and safe hyperlipemia therapeutic drugs has important research significance.
Cytosolic citrate is a key precursor and regulator of de novo fatty acid synthesis and is considered to be an important intermediate linking glucose metabolism and lipid metabolism. The concentration of citrate in the cytoplasm directly affects the fat synthesis rate. There are three major sources of cytoplasmic citric acid: (1) The cytoplasmic citrate transporter (NaCT), encoded by the SLC13A5 gene, takes up plasma citrate into the cytoplasm. (2) The mitochondrial inner membrane citrate transporter (PMCT) encoded by the SLC25A1 gene transports excess citrate from the tricarboxylic acid cycle into the cytosol. (3) Alpha-ketoglutaric acid (alpha-KG) is formed by glutamine metabolism and enters tricarboxylic acid cycle metabolism to form citric acid. All three sources of citric acid require the production of acetyl-coa and oxaloacetate by cytosolic ATP-citrate lyase (ACLY), followed by a lipid de novo synthesis pathway (DNL) starting from acetyl-coa. Therefore, key transporters inhibiting the uptake of citrate and joint enzymes of citrate catabolism are important targets for the treatment of lipid metabolism diseases.
The citrate transporter encoded by the SLC13A5 gene, also known as the plasma membrane citrate transporter/sodium ion dependent citrate transporter (NaCT), is localized to the cell membrane and is responsible for the uptake of plasma citrate into the cytosol. SLC13A5 gene is highly expressed in the liver of mammal, and has certain distribution in kidney, testis, and brain. The SLC13A5 gene expression level is obviously up-regulated in patients with obesity, non-alcoholic steatohepatitis, diabetes and the like. The mice with the SLC13A5 gene knocked out can avoid the occurrence and development of related metabolic diseases induced by high-fat diet, and NaCT becomes an ideal target point for regulating energy metabolism and lipid metabolism.
Currently, no NaCT inhibitor for treating hyperlipidemia is successfully marketed, only the pfeiffe company reports PF-06649298 and PF-06761281, and the behmere noble company reports BI-01383298 and PF-06761281 can increase the concentration of citric acid in blood plasma and urine, so that the safety needs to be further studied, and the patent medicine property needs to be further improved.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a 2-hydroxysuccinic acid compound for inhibiting NaCT, which can effectively solve the problems of insufficient NaCT inhibition activity, poor pharmacy and the like of the existing compound; another object of the present invention is to provide a pharmaceutical composition comprising the 2-hydroxysuccinic acid-based compound as an active ingredient; the invention also aims to provide a method for preparing Na by using the 2-hydroxysuccinic acid compound + Use in the manufacture of a medicament for the treatment of a disease associated with a dependent citrate transporter. Extracellular citrate uptake inhibitors
The technical scheme is as follows: the 2-hydroxysuccinic acid compound is a compound with a structure shown in formula I or II or an isomer, a pharmaceutically acceptable salt or a mixture thereof:
R 1 is hydrogen, halogen, cyano, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, pyrazolyl or phenyl;
R 2 is 1-4 hydrogens by R 2a Substitution6-10 membered aryl, 5-10 membered heteroaryl or tetrahydroquinolinyl, benzothiazolyl, benzoxazolyl;
R 2a is hydrogen, halogen, cyano, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group;
l and M are selected from-CH 2 -, -NH-or-O-;
the heteroatom in the 5-10 membered heteroaryl is N, O or S, and the number of the heteroatoms is 1-4.
Preferably, in the structure:
R 1 is hydrogen, fluoro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, isopropyl, methoxy, ethoxy, isopropoxy, pyrazolyl or phenyl;
R 2 is 1-4 hydrogen R 2a Substituted phenyl, pyrazolyl, pyridyl or tetrahydroquinolinyl, benzothiazolyl, benzoxazolyl;
R 2a is hydrogen, fluorine, cyano, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, dioxanone, methoxy, ethoxy or isopropoxy.
Preferably, the 2-hydroxysuccinic compound is selected from any one of the following compounds:
preferably, the pharmaceutically acceptable salt is a salt of the above compound with an acid or a base, the acid being hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, and the base being an inorganic base containing a basic metal cation, an alkaline earth metal cation or an ammonium cation salt.
The inhibitor and pharmaceutically acceptable carrier form pharmaceutical composition, and can be made into common pharmaceutical preparations, such as tablet, capsule, syrup, suspension or injection, and optionally flavoring agent, sweetener, liquid/solid filler, diluent, etc.
The inhibitor and its pharmaceutical composition can be prepared into the forms of medicine for treating and preventing Na + A medicament for the treatment of diseases associated with dependent citrate transporters, in particular hyperlipidemia, diabetes, non-alcoholic steatohepatitis or cancer.
Has the beneficial effects that: compared with the prior art, the invention has the following remarkable advantages: (1) The compound and the pharmaceutical composition thereof can effectively inhibit the NaCT activity of SLC13A5 gene code, effectively inhibit the citric acid uptake of HEK293T cells, and optimally inhibit the IC50 value of the cell level to be less than 60nM; (2) The compound and the pharmaceutical composition thereof have wide application, can be prepared into medicines for treating metabolic diseases such as hyperlipemia and the like, can exert the drug effect at the molecular level, have more excellent treatment effect and optimally reach the nanomolar concentration level; and (3) the preparation method of the compound is simple and convenient and is easy to operate.
Drawings
FIG. 1 is a graph of the effect of compound LA-33 on lipid accumulation in AML12 cells;
FIG. 2 is a graph of the effect of compound LA-33 on SLC13A5, ACLY in AML12 cells;
FIG. 3 is a graph of the effect of compound LA-33 on lipid accumulation in mouse primary hepatocytes;
FIG. 4 is a graph of the effect of compound LA-33 on primary mouse hepatocyte SLC13A5, ACLY;
FIG. 5 is a graph of the effect of compound LA-33 on plasma lipid levels in starvation-induced mice;
FIG. 6 is a graph of the effect of compound LA-33 on starvation-induced liver lipid accumulation in mice;
FIG. 7 is a graph showing the effect of LA-33 on mRNA associated with lipid accumulation in the liver of starvation-induced mice.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Example 1
Synthesis of LA-1:
step 1: cuprous iodide (0.2g, 1.05mmol) was added to 60ml of THF, triethylamine (1.13g, 44.32mmol) was added, the reaction liquid turned from off-white turbidity to light gray slightly clear, nitrogen gas was replaced three times, p-bromophenylacetylene (4 g, 22.09mmol) and oxalyl chloride monoethyl ester (6 g, 43.94mmol) were slowly added dropwise under ice bath, and the reaction liquid turned to light yellow turbidity and then turned to yellowish turbidity. The reaction mixture was reacted at room temperature for 16 hours and then stopped. To the reaction solution was added 60ml of saturated sodium bicarbonate solution, the organic layer was separated, the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, using PE: EA =60 column chromatography 1 gave 4g of a pale yellow oil. 1 H NMR(300MHz,DMSO-d 6 )δ7.62–7.53(m,4H),4.37(s,2H),1.34(s,3H).HR-MS(ESI):Calculated for C 12 H 10 BrO 3 [M+H] + :280.9813,found280.9803.
Step 2: ethyl acetate (5.01g, 56.9mmol) is dissolved in THF, the temperature is reduced to-78 ℃, lithium bis (trimethylsilyl) amide (56.9ml, 56.9mmol) reaction liquid is added dropwise, the reaction liquid is kept at-78 ℃ for reaction for 30min, and then 1-1 is dissolved in THF and added dropwise into the reaction liquid. The reaction was kept at-78 ℃ for 1.5h and monitored by TLC for completion. The reaction was stopped, quenched with saturated ammonium chloride, extracted with EA, and the organic layers were combined and dried over anhydrous sodium sulfate. Column chromatography using PE: EA = 15. 1 H NMR(300MHz,Chloroform-d)δ7.52–7.42(m,2H),7.37–7.27(m,2H),4.39(qd,J＝7.1,1.3Hz,2H),4.22–4.15(m,2H),3.28(d,J＝16.5Hz,1H),3.14(d,J＝16.5Hz,1H),1.38(t,J＝7.1Hz,3H),1.29(t,J＝7.1Hz,3H).HR-MS(ESI):Calculated for C 16 H 18 BrO 5 [M+H] + :369.0338,found 369.0366.
And step 3: 1-2 (0.50g, 1.35mmol) and 2-methoxypyridine-4-boronic acid pinacol ester (0.36g, 1.62mmol) were dissolved in 7ml of solvent (dioxane: water =6 1), anhydrous sodium carbonate (0.43g, 4.06mmol) was added, and after nitrogen substitution three times, pd (dppf) Cl was added 2 (0.10g, 0.14mmol), and the reaction was completed by TLC after reacting at 95 ℃ for 5 hours after nitrogen substitution three times. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated, ethyl acetate was added, washed twice with water, once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography was performed using PE: EA = 10.
1 H NMR(300MHz,DMSO-d 6 )δ8.23(d,J＝5.0Hz,1H),7.80–7.70(m,2H),7.61–7.51(m,2H),7.51(dd,J＝5.1,1.0Hz,1H),7.08(d,J＝1.0Hz,1H),4.31(s,2H),4.10(s,2H),3.89(s,3H),2.82(d,J＝0.4Hz,2H),1.25(d,J＝15.6Hz,6H).HR-MS(ESI):Calculated for C 22 H 24 NO 6 [M+H] + :398.1604,found 398.1600.
And 4, step 4: dissolving the intermediate 1-3 in 30ml of absolute ethanol, adding 5ml of Raney nickel catalyst, replacing with hydrogen for three times, and reacting overnight. After the reaction was completed by TLC, the reaction mixture was filtered, the filtrate was concentrated, and the mixture was purified by silica gel column to obtain 120mg of a colorless oil. 1 H NMR(300MHz,DMSO-d 6 )δ8.23(d,J＝5.0Hz,1H),7.58–7.47(m,3H),7.27–7.16(m,2H),7.08(d,J＝1.0Hz,1H),4.17(d,J＝0.5Hz,2H),4.09(s,2H),3.88(s,3H),2.83–2.67(m,2H),2.53(dt,J＝3.1,1.0Hz,2H),2.13(d,J＝0.8Hz,2H),1.22(s,3H),1.14(s,3H).C 22 H 28 NO 6 [M+H] + :402.1917,found 402.1933.
And 5: dissolving the intermediate 1-4 in 5ml of absolute ethyl alcohol, adding 1.5ml of 1N NaOH solution, reacting overnight at room temperature, evaporating the solvent under reduced pressure after the HPLC detection shows that the reaction is complete, and adjusting the PH to 2-3 by using 1mol/L hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3X 5 ml), the organic phases were combined, dried over anhydrous sodium sulfate and filtered under suction, and the filtrate was evaporated under reduced pressure to remove the solvent to give 70mg of a white solid. 1 H NMR(300MHz,DMSO-d 6 )δ8.23(d,J＝5.0Hz,1H),7.58–7.47(m,3H),7.27–7.16(m,2H),7.08(d,J＝1.0Hz,1H),5.14(s,1H),3.88(s,3H),2.82–2.66(m,2H),2.59–2.41(m,2H),2.20–2.02(m,2H).HR-MS(ESI):Calculated for C 18 H 20 NO 6 [M+H] + :346.1291,found 346.1308.
In a similar procedure to example 1, the following compounds were prepared:
1 H NMR(300MHz,DMSO-d 6 )δ7.59(d,J＝8.1Hz,2H),7.37(t,J＝7.9Hz,1H),7.31–7.04(m,4H),6.93(ddd,J＝8.1,2.6,1.0Hz,1H),3.83(s,3H),2.79(t,J＝12.1Hz,2H),2.57(d,J＝15.7Hz,1H),2.45(dd,J＝13.5,5.3Hz,1H),2.01–1.83(m,2H).HR-MS(ESI):Calculated for C 19 H 21 O 6 [M+H] + :345.1338,found 345.1372.
1 H NMR(300MHz,DMSO-d 6 )δ7.60–7.50(m,2H),7.40(dt,J＝7.4,2.0Hz,1H),7.35–7.16(m,4H),6.96(dt,J＝7.4,2.0Hz,1H),5.14(s,1H),4.08(s,2H),2.82–2.66(m,2H),2.59–2.41(m,2H),2.20–2.02(m,2H),1.40(s,3H).HR-MS(ESI):Calculated for C 20 H 23 O 6 [M+H] + :359.1495,found 359.1507
1 H NMR(300 MHz,DMSO-d 6 )δ7.26(q,J＝8.2 Hz,4H),6.86(dd,J＝7.4,1.6 Hz,1H),6.76(dd,J＝7.5,1.7 Hz,1H),6.52(t,J＝7.4 Hz,1H),3.16(t,J＝5.5 Hz,2H),2.85–2.69(m,4H),2.58(d,J＝15.6 Hz,1H),2.45(dd,J＝13.3,5.4 Hz,1H),2.04–1.74(m,4H).HR-MS(ESI):Calculated for C 21 H 24 NO 5 [M+H] + :370.1654,found 370.1660.
1 H NMR(300 MHz,DMSO-d 6 )δ7.50–7.41(m,3H),7.30(d,J＝7.9 Hz,2H),6.37(d,J＝1.9 Hz,1H),3.85(s,3H),2.87–2.75(m,2H),2.61(s,1H),1.94(qt,J＝14.0,6.3 Hz,2H).HR-MS(ESI):Calculated for C 16 H 19 N 2 O 5 [M+H] + :319.1294,found 319.1300.
1 H NMR(300 MHz,DMSO-d 6 )δ8.14(s,1H),7.82(s,1H),7.48(d,J＝7.9 Hz,2H),7.15(d,J＝7.9 Hz,2H),4.15(q,J＝7.3 Hz,2H),2.80(d,J＝15.7 Hz,1H),2.73–2.64(m,1H),2.59(s,1H),2.40(dd,J＝13.5,5.5 Hz,1H),2.01–1.77(m,2H),1.41(t,J＝7.3 Hz,3H).HR-MS(ESI):Calculated for C 17 H 22 N 2 O 5 [M+H] + :333.1450,found 333.1455.
1 H NMR(300 MHz,DMSO-d 6 )δ7.70(dd,J＝6.5,1.0 Hz,3H),7.23–7.13(m,2H),6.82(s,1H),5.14(s,1H),2.71(d,J＝12.4 Hz,1H),2.59–2.41(m,2H),2.20–2.02(m,2H).HR-MS(ESI):Calculated for C 15 H 17 N 2 O 5 [M+H] + :305.1137,found 305.1144.
1 H NMR(300 MHz,DMSO-d 6 )δ7.80–7.70(m,2H),7.63(s,1H),7.28–7.18(m,2H),6.80(s,1H),5.14(s,1H),4.52(s,1H),2.71(d,J＝12.4 Hz,1H),2.59–2.41(m,2H),2.20–2.02(m,2H),1.44(d,J＝15.1 Hz,5H).HR-MS(ESI):Calculated for C 18 H 23 N 2 O 5 [M+H] + :347.1607,found 347.1618.
1 H NMR(300 MHz,Methanol-d 4 )δ7.98(s,1H),7.58(s,1H),7.50(d,J＝8.6 Hz,1H),7.28(dd,J＝8.7,1.6 Hz,1H),3.10–2.86(m,2H),2.81–2.56(m,2H),2.09(dtd,J＝26.0,13.5,6.7 Hz,2H).HR-MS(ESI):Calculated for C 13 H 15 N 2 O 5 [M+H] + :279.0981,found279.0996.
1 H NMR(300 MHz,DMSO-d 6 )δ7.60–7.50(m,2H),7.42–7.30(m,2H),7.27–7.16(m,2H),6.89(d,J＝7.5 Hz,1H),6.04(d,J＝0.7 Hz,2H),5.14(s,1H),2.59–2.41(m,2H),2.20–2.02(m,2H).HR-MS(ESI):Calculated for C 19 H 19 O 7 [M+H] + :359.1131,found359.1144.
1 H NMR(300 MHz,DMSO-d 6 )δ7.50(h,J＝4.6,3.8 Hz,4H),7.39(d,J＝7.8 Hz,2H),7.28(d,J＝7.8 Hz,2H),2.81(d,J＝15.6 Hz,2H),2.60(s,1H),2.44(d,J＝5.1 Hz,1H),1.94(dq,J＝12.4,6.9,6.0 Hz,2H).HR-MS(ESI):Calculated for C 19 H 19 O 7 [M+H] + :399.1055,found 399.1068.
1 H NMR(300 MHz,DMSO-d 6 )δ7.39(d,J＝8.0 Hz,2H),7.30(dd,J＝15.3,7.6 Hz,2H),7.20(d,J＝7.8 Hz,2H),7.15–6.97(m,2H),3.76(s,3H),2.87(d,J＝19.9 Hz,1H),2.81–2.69(m,2H),2.60(s,1H),1.93(qd,J＝14.0,13.0,5.9 Hz,2H).HR-MS(ESI):Calculated for C 19 H 21 O 6 [M+H] + :345.1338,found 345.1372.
1 H NMR(300 MHz,Chloroform-d)δ7.54(d,J＝7.8 Hz,2H),7.37(d,J＝7.9 Hz,1H),7.28(d,J＝7.8 Hz,2H),7.22–7.10(m,2H),6.91(dd,J＝8.2,2.5 Hz,1H),4.12(q,J＝6.9Hz,2H),3.16(d,J＝17.0 Hz,1H),2.93(q,J＝11.1 Hz,2H),2.68(t,J＝12.3 Hz,1H),2.15(t,J＝12.0 Hz,2H),1.48(d,J＝13.9 Hz,3H).HR-MS(ESI):Calculated for C 20 H 23 O 6 [M+H] + :359.1495,found 359.1508.
1 H NMR(300 MHz,DMSO-d 6 )δ7.61(dd,J＝7.5,2.0 Hz,1H),7.54–7.45(m,2H),7.40(td,J＝7.5,2.0 Hz,1H),7.25–7.16(m,2H),7.11(td,J＝7.5,2.0 Hz,1H),6.95(dd,J＝7.5,2.0 Hz,1H),5.14(s,1H),4.68(s,1H),2.82–2.66(m,2H),2.59–2.41(m,2H),2.20–2.02(m,2H),1.35(d,J＝14.9 Hz,5H).HR-MS(ESI):Calculated for C 21 H 25 O 6 [M+H] + :373.1651,found 373.1673.
1 H NMR(300 MHz,DMSO-d 6 )δ7.58(d,J＝8.2 Hz,2H),7.35(t,J＝7.9 Hz,1H),7.29–7.11(m,4H),6.91(dd,J＝8.2,2.4 Hz,1H),4.00(t,J＝6.5 Hz,2H),2.84–2.68(m,2H),2.60(s,1H),2.01–1.81(m,2H),1.75(p,J＝7.1 Hz,2H),1.01(t,J＝7.4 Hz,3H).HR-MS(ESI):Calculated for C 21 H 25 O 6 [M+H] + :373.1651,found 373.1679.
1 H NMR(300 MHz,DMSO-d 6 )δ7.84(dd,J＝7.5,2.0 Hz,1H),7.69(td,J＝7.3,2.0 Hz,1H),7.63(dd,J＝7.5,2.4 Hz,1H),7.58–7.45(m,3H),7.25–7.14(m,2H),5.14(s,1H),2.82–2.66(m,2H),2.59–2.41(m,2H),2.20–2.02(m,2H).HR-MS(ESI):Calculated forC 19 H 18 F 3 O 5 [M+H] + :383.1106,found 383.1116.
1 H NMR(300MHz,DMSO-d 6 )δ7.84(dd,J＝7.5,2.0Hz,1H),7.69(td,J＝7.3,2.0Hz,1H),7.63(dd,J＝7.5,2.4Hz,1H),7.58–7.45(m,3H),7.25–7.14(m,2H),5.14(s,1H),2.82–2.66(m,2H),2.59–2.41(m,2H),2.20–2.02(m,2H).HR-MS(ESI):Calculated for C 19 H 18 F 3 O 5 [M+H] + :383.1106,found 383.1119.
example 2
Synthesis of LA-18:
synthesis of intermediate 2-2:
adding cuprous iodide (0.34g, 3.57mmol) into 60ml THF, adding triethylamine (7.22g, 0.071mol), changing the reaction solution from grey-white turbidity to light grey slightly clear, replacing with nitrogen for three times, and adding dropwise (triethylsilyl) acetylene (5 g,0.036 mol) and oxalyl chloride under ice bathEthyl ester (9.7g, 0.076 mol), the reaction mixture became pale yellow and turbid, and the reaction mixture was reacted at room temperature for 16 hours and then stopped. To the reaction solution was added 60ml of a saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the sand was prepared using PE: EA =60 column chromatography 1 gave 9g of a pale yellow oil. The yield thereof was found to be 76%. 1 H NMR(300MHz,DMSO-d 6 )δ4.34(s,2H),1.32(s,3H),1.03(s,9H),0.94(s,6H).HR-MS(ESI):Calculated for C 12 H 20 NaO 3 Si[M+Na] + :263.1079,found 263.1088.
Synthesis of intermediates 2 to 3:
ethyl acetate (1.12g, 12.69mmol) was dissolved in THF, cooled to-78 deg.C, liHMDS (12.69ml, 12.69mmol) was added dropwise to the reaction mixture, the reaction mixture was maintained at-78 deg.C and reacted for 30min, then intermediate 2b (2.70g, 7.93mmol) was dissolved in THF and added dropwise to the reaction mixture. The reaction was kept at-78 ℃ for 1.5h and monitored by TLC for completion. The reaction was stopped, quenched with saturated ammonium chloride, extracted with EA, the organic layers combined and dried over anhydrous sodium sulfate. Column chromatography using PE: EA =15 gave 1.3g of yellow oil. The yield thereof was found to be 34%. 1 H NMR(300MHz,DMSO-d 6 )δ4.10(s,2H),3.69–3.53(m,2H),2.65(s,2H),1.22(s,3H),1.14(s,3H),1.03(s,9H),0.87(s,6H).HR-MS(ESI):Calculated for C 16 H 30 NaO 4 Si[M+Na] + :337.1811,found 337.1816.
Synthesis of intermediates 2 to 4:
intermediate 2c (1.3g, 3.95mmol) was dissolved in 15ml of anhydrous ether and tetrabutylammonium fluoride (5.94ml, 5.94mmol) was added dropwise under ice-bath and the reaction was monitored by TLC for 1.5h for completion. Quenching the reaction by using 10ml of saturated ammonium chloride solution, demixing the reaction solution, extracting an aqueous layer by using diethyl ether for three times, combining organic layers, drying the organic layers by using anhydrous sodium sulfate, filtering, removing the solvent by reducing pressure, and carrying out column chromatography on a crude product to obtain 0.63g of light yellow oily matter with the yield of 74%. 1 H NMR(300MHz,DMSO-d 6 )δ6.66(s,1H),4.31(s,2H),4.10(s,2H),3.65(s,1H),2.76(d,J＝0.3Hz,3H),1.25(d,J＝15.6Hz,6H).HR-MS(ESI):Calculated for C 10 H 14 NaO 5 [M+Na] + :237.0739,found 237.0749.
Synthesis of intermediates 2 to 5:
4- (4-iodophenyl) morpholine (0.50g, 1.73mmol) was dissolved in 5ml of tetrahydrofuran, cuprous iodide (33mg, 0.17mmol) and 0.7ml of triethylamine were added, pd (PPh 3) 4 (200mg, 0.17mmol) was added after three nitrogen replacements, nitrogen replacement was performed again, intermediate 2d (440mg, 2.07mmol) was added dropwise to the reaction solution after the temperature of the reaction solution had risen to 60 ℃, and completion of the reaction was monitored by TLC after 1.5 hours. The reaction solution was cooled to room temperature and then filtered, the filtrate was added with water and separated, the aqueous layer was extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate and filtered, the solvent was removed under reduced pressure, and the crude product was subjected to column chromatography to give 0.64g of a pale yellow solid. 1 H NMR(300MHz,DMSO-d 6 )δ7.52–7.42(m,2H),7.04–6.94(m,2H),4.31(s,2H),4.10(s,2H),3.74(d,J＝3.6Hz,4H),3.18(d,J＝1.1Hz,4H),2.82(d,J＝0.4Hz,2H),1.25(d,J＝15.6Hz,6H).HR-MS(ESI):Calculated for C 20 H 26 NO 6 [M+H] + :376.1760,found 376.1772.
Synthesis of intermediates 2 to 6:
intermediate 2-5 (0.60g, 1.60mmol) was dissolved in 30ml of a solvent (methanol: tetrahydrofuran =6 1), 3ml of raney nickel was added, hydrogen gas was substituted three times, reaction was carried out overnight at room temperature, the reaction solution was suction filtered after completion of the TLC monitoring reaction, and the solvent was removed under reduced pressure to obtain 0.6g of an off-white solid. 1 H NMR(300MHz,DMSO-d 6 )δ7.16–7.05(m,2H),6.87–6.77(m,2H),4.17(d,J＝0.6Hz,2H),4.09(s,2H),3.74(d,J＝3.6Hz,4H),3.19(d,J＝1.7Hz,4H),2.83–2.67(m,2H),2.59–2.40(m,2H),2.13(d,J＝0.8Hz,2H),1.22(s,3H),1.14(s,3H).HR-MS(ESI):Calculated for C 20 H 30 NO 6 [M+H] + :380.2073,found 380.2079.
Synthesis of LA-18:
intermediate 2-6 (0.50g, 1.32, mmol) was dissolved in 8ml of anhydrous ethanol, and was added with 5ml of 1mol/L NaOH solution, stirred at room temperature for 16h and then monitored by TLC for completion of the reaction. Evaporating under reduced pressure to remove solvent, adding 1mol/L HCl solution to adjust pH to 2-3, extracting with ethyl acetate three times (3 × 5 ml), combining organic layers, washing with water twice, washing with saturated salt water once, drying with anhydrous sodium sulfate, and reducingThe solvent was evaporated under pressure to give 300mg of a white solid. 1 H NMR(300MHz,Deuterium Oxide)δ7.15(d,J＝8.3Hz,2H),7.00–6.91(m,2H),3.79(dd,J＝6.2,3.4Hz,4H),3.07–2.98(m,4H),2.68–2.52(m,2H),2.41–2.21(m,2H),1.76(dtd,J＝41.7,13.3,4.8Hz,2H).HR-MS(ESI):Calculated for C 16 H 22 NO 6 [M+H] + :324.1447,found 324.1459.
In a similar procedure to example 2, the following compound was prepared:
1 H NMR(300MHz,DMSO-d 6 )δ7.10(t,J＝0.5Hz,4H),5.14(s,1H),2.82–2.63(m,4H),2.55–2.46(m,2H),2.20–2.02(m,2H),1.23(s,3H).HR-MS(ESI):Calculated for C 14 H 19 O 5 [M+H] + :267.1232,found 267.1246.
1 H NMR(300MHz,DMSO-d 6 )δ7.10(tdt,J＝7.7,6.9,0.9Hz,4H),5.14(s,1H),2.90(t,J＝0.9Hz,1H),2.74(d,J＝5.5Hz,2H),2.59–2.42(m,2H),2.20–2.02(m,2H),1.25(d,J＝15.1Hz,6H).HR-MS(ESI):Calculated for C 15 H 21 O 5 [M+H] + :281.1389,found 281.1366.
1 H NMR(300MHz,DMSO-d 6 )δ7.70–7.60(m,2H),7.49–7.39(m,2H),5.14(s,1H),2.82–2.66(m,2H),2.59–2.41(m,2H),2.20–2.02(m,2H).HR-MS(ESI):Calculated for C 13 H 14 F 3 O 5 [M+H] + :307.0793,found 307.0801.
1 H NMR(300 MHz,DMSO-d 6 )δ7.26–7.09(m,4H),5.14(s,1H),2.77(d,J＝12.4 Hz,1H),2.71(d,J＝12.4 Hz,1H),2.59–2.46(m,2H),2.46(dt,J＝7.7,1.0 Hz,1H),2.20–2.02(m,2H),1.73(dd,J＝16.9,13.0 Hz,4H),1.59(dd,J＝13.0,10.1 Hz,4H).HR-MS(ESI):Calculated for C 17 H 23 O 5 [M+H] + :307.1575,found 307.1554.
1 H NMR(300 MHz,Chloroform-d)δ7.16–7.06(m,2H),6.84–6.74(m,2H),3.43–3.29(m,4H),2.89–2.71(m,2H),2.59(dt,J＝12.4,1.0 Hz,1H),2.51(dt,J＝12.4,1.0 Hz,1H),2.16(d,J＝12.4 Hz,1H),2.08–1.98(m,3H).HR-MS(ESI):Calculated for C 16 H 22 NO 5 [M+H] + :308.1498,found 308.1495.
1 H NMR(300 MHz,Chloroform-d)δ7.26–7.09(m,4H),2.89–2.71(m,2H),2.61–2.42(m,3H),2.19(d,J＝12.3 Hz,1H),2.08(s,1H),1.80(d,J＝13.1 Hz,2H),1.70(d,J＝13.0 Hz,2H),1.61–1.31(m,6H).HR-MS(ESI):Calculated for C 18 H 25 O 5 [M+H] + :321.1702,found 321.1718.
1 H NMR(300 MHz,Chloroform-d)δ7.16–7.06(m,2H),6.84–6.74(m,2H),3.22(d,J＝4.8 Hz,4H),2.98(d,J＝9.7 Hz,4H),2.89–2.71(m,2H),2.55(qt,J＝12.4,1.0 Hz,2H),2.16(d,J＝12.4 Hz,1H),2.03(d,J＝12.4 Hz,1H).HR-MS(ESI):Calculated for C 16 H 23 N 2 O 5 [M+H] + :323.1607,found 323.1608.
1 H NMR(300 MHz,Chloroform-d)δ7.17–7.06(m,2H),6.84–6.74(m,2H),3.19(d,J＝13.0 Hz,4H),2.84(d,J＝12.4 Hz,1H),2.76(d,J＝12.4 Hz,1H),2.56(dd,J＝12.0,3.8Hz,7H),2.29(s,3H),2.16(d,J＝12.4 Hz,1H),2.03(d,J＝12.4 Hz,1H).HR-MS(ESI):Calculated for C 17 H 25 N 2 O 5 [M+H] + :337.1763,found 337.1766.
1 H NMR(300 MHz,Chloroform-d)δ7.15–7.05(m,2H),6.86–6.76(m,2H),3.78(s,3H),2.89–2.71(m,2H),2.55(qt,J＝12.4,1.0 Hz,2H),2.16(d,J＝12.4 Hz,1H),2.03(d,J＝12.4 Hz,1H).HR-MS(ESI):Calculated for C 13 H 17 O 6 [M+H] + :269.1025,found 269.1033.
1 H NMR(300 MHz,Chloroform-d)δ7.17–7.06(m,2H),6.85–6.74(m,2H),4.08(s,2H),2.84(d,J＝12.4 Hz,1H),2.76(d,J＝12.4 Hz,1H),2.55(qt,J＝12.4,1.0 Hz,2H),2.16(d,J＝12.4 Hz,1H),2.03(d,J＝12.4 Hz,1H),1.42(s,3H).HR-MS(ESI):Calculated forC 14 H 19 O 6 [M+H] + :283.1182,found 283.1189.
1 H NMR(300 MHz,Chloroform-d)δ7.15(d,J＝7.4 Hz,1H),6.94(dtt,J＝7.5,2.0,1.0Hz,1H),6.88–6.76(m,2H),3.81(s,3H),2.89–2.71(m,2H),2.57(dt,J＝12.4,1.0 Hz,1H),2.47(dt,J＝12.4,1.0 Hz,1H),2.16(d,J＝12.4 Hz,1H),2.04(d,J＝12.4 Hz,1H).HR-MS(ESI):Calculated for C 13 H 17 O 6 [M+H] + :269.1025,found 269.1033.
1 H NMR(300 MHz,DMSO-d 6 )δ7.18(t,J＝7.4 Hz,1H),6.95(dtt,J＝7.6,2.0,1.0 Hz,1H),6.88–6.75(m,2H),4.07(s,2H),2.82–2.66(m,2H),2.56(dt,J＝12.4,1.0 Hz,1H),2.47(dt,J＝12.3,1.0 Hz,1H),2.10(d,J＝12.4 Hz,1H),2.00(d,J＝12.4 Hz,1H),1.39(s,3H).HR-MS(ESI):Calculated for C 14 H 19 O 6 [M+H] + :283.1182,found 283.1185.
1 H NMR(300 MHz,DMSO-d 6 )δ8.14(d,J＝7.9 Hz,1H),8.03(dd,J＝11.4,8.0 Hz,3H),7.55(t,J＝7.6 Hz,1H),7.46(t,J＝7.5 Hz,1H),7.38(d,J＝7.9 Hz,2H),2.81(s,1H),2.76(s,1H),2.58(d,J＝15.5 Hz,2H),1.95(dq,J＝12.4,7.0,6.2 Hz,2H).HR-MS(ESI):Calculated for C 19 H 18 NO 5 S[M+H] + :372.0906,found 372.0916.
1 H NMR(300MHz,DMSO-d 6 )δ8.14(d,J＝7.9Hz,1H),8.01(dd,J＝11.4,8.0Hz,3H),7.55(t,J＝7.6Hz,1H),7.48(t,J＝7.5Hz,1H),7.38(d,J＝7.9Hz,2H),2.81(s,1H),2.76(s,1H),2.58(d,J＝15.5Hz,2H),1.95(dq,J＝12.4,7.0,6.2Hz,2H).HR-MS(ESI):Calculated for C 19 H 18 NO 6 [M+H] + :356.1134,found 356.1155.
1 H NMR(300MHz,DMSO-d 6 )δ7.69–7.54(m,4H),7.46(t,J＝7.6Hz,2H),7.36(dd,J＝8.4,6.2Hz,1H),7.27(d,J＝8.1Hz,2H),2.82(d,J＝15.7Hz,2H),2.61(s,1H),2.51–2.40(m,1H),2.05–1.81(m,2H)..HR-MS(ESI):Calculated for C 18 H 19 O 5 [M+H] + :315.1232,found 315.1239.
1 H NMR(300MHz,DMSO-d 6 )δ7.89(d,J＝5.1Hz,3H),7.50(d,J＝5.1Hz,3H),7.28(d,J＝0.6Hz,1H),2.78–2.54(m,5H),2.11(d,J＝12.4Hz,1H),2.00(d,J＝12.3Hz,1H).HR-MS(ESI):Calculated for C 16 H 17 O 5 [M+H] + :289.1076,found 289.1077.
example 3
The experiment of inhibiting the uptake of HEK-293T extracellular D4-citric acid with high expression of SLC13A5 by partial compounds of the invention comprises the following steps:
1. experimental methods
(1) Cell recovery and culture: the HEK293T cells taken out of liquid nitrogen are quickly placed into a 37 ℃ water bath to be thawed for about 1min, then transferred into a centrifuge tube containing 5mL of culture medium, centrifuged at 1100rpm for 3min, the supernatant is discarded, 2mL of 10-percent FBS DMEM high-sugar medium is added for resuspension, 1mL of the culture medium is taken to be inoculated into a cell culture dish containing 7mL of culture medium, and the cell culture dish is placed into a cell culture box which is 5 percent CO2 and 37 ℃, and the cells grow in a monolayer adherent manner. When the cells fused to about 90%, the medium was discarded, washed with 37 ℃ preheated PBS 2 times, and digested with 2mL of 0.25% trypsin at room temperatureGently shaking for 30s, discarding trypsin, adding 2mL of fresh medium to terminate the reaction, gently and repeatedly blowing and beating by a pipette, transferring the medium containing the cells into a sterilized Ep tube, centrifuging at 800rpm for 3min, discarding the supernatant after the centrifugation is completed, adding 2mL of 10% FBS DMEM high-sugar medium for resuspension, inoculating into a cell culture dish, and adding 5% CO 2 And culturing in a cell culture box at 37 ℃.
(2) Transfection: discarding the original culture medium, replacing with DMEM medium without double antibody and serum and high sugar, and sequentially diluting SLC13A5 overexpression plasmid and Lipofectamine with Opti-MEM serum-free culture medium TM 2000 transfection reagents. The overexpression plasmid and Lipofectamine were used TM 2000 adding the mixture into a 24-hole cell culture plate, slightly shaking and uniformly mixing the mixture, and placing the mixture in a cell culture box for culture;
(3) Taking: after transfection is successful for 24h, sucking out the original culture medium in a 24-well plate, adding 1mL of sodium buffer into each well, washing for three times, adding 250 mu L of sodium buffer containing compounds with different concentrations, putting the mixture into a shaking incubator, and carrying out pre-incubation for 30min at the uptake temperature of 37 ℃; sucking out the sodium buffer containing the compound, and adding 1mL of the sodium buffer for washing three times; adding 250 μ L of sodium buffer containing the above compounds at different concentrations and 200 μ M D4-citric acid into each well, and taking at 37 deg.C for 30min; discarding the sodium buffer containing D4-citric acid, adding 1mL of choline buffer into each hole, washing for three times to terminate the intake; after the reaction is finished, adding 200 mu L of double distilled water into each hole, placing the double distilled water at the temperature of minus 80 ℃ for freezing for 30min, unfreezing at room temperature, repeatedly freezing and thawing for 3 times, carrying out ultrasonic treatment for 10min, fully crushing cells, transferring the solution containing the crushed cells into an Ep tube, adding acetonitrile containing an internal standard at 12000rpm, centrifuging for 10min, taking the supernatant, detecting the intracellular D4-citric acid concentration by using LC-MS/MS, and simultaneously subtracting the intracellular D4-citrate concentration of an HEK-293T-vector group to calculate the net content.
2. Data processing
(1) Formula for calculating citric acid intake experiment
％Inhibition＝[1-(A_sample/A_max)]
Wherein A _ sample represents the content of D4-citrate in the sample, and A _ max represents the content of D4-citrate in the blank.
(2) Fitting dose-response curves as log values of concentrationsAs the X-axis, percent inhibition was the Y-axis, and the log (inhibitor) vs. response-Variable slope of the software GraphPad Prism5 was used to fit the dose-response curves to obtain the IC of each compound for citric acid uptake activity 50 The value is obtained.
Calculating the formula:
Y＝Bottom+(Top-Bottom)/(1+10^((Log IC 50 -X)×Hill Slope))。
IC 50 the data are shown in Table 1.
TABLE 1 citric acid uptake inhibitory Activity of Compounds on HEK293 cells
| Number of | Citric acid uptake inhibitory Activity | Numbering | Citric acid uptake inhibitory Activity |
| LA-1 | A | LA-2 | A |
| LA-3 | A | LA-4 | A |
| LA-5 | A | LA-6 | A |
| LA-7 | A | LA-8 | A |
| LA-9 | B | LA-10 | C |
| LA-11 | A | LA-12 | B |
| LA-13 | A | LA-14 | A |
| LA-15 | A | LA-16 | A |
| LA-17 | A | LA-18 | A |
| LA-19 | B | LA-20 | A |
| LA-21 | B | LA-22 | A |
| LA-23 | C | LA-24 | A |
| LA-25 | A | LA-26 | A |
| LA-27 | B | LA-28 | C |
| LA-29 | A | LA-30 | B |
| LA-31 | B | LA-32 | C |
| LA-33 | C | LA-34 | C |
Note: a: < 1. Mu.M, B: 1-5. Mu.M, C: > 5. Mu.M.
As shown in Table 1, all the tested compounds have better inhibition effect on citrate transporters of HEK293 cells, and all the compounds have micromolar inhibition rate on NaCT, wherein the compound LA-33 has optimal inhibition rate on citrate uptake of HEK293T cells, and IC (integrated Circuit) is 50 ＝60nM。
Example 4
In vitro efficacy experiment of representative compound LA-33 of the invention on AML12 cells
The experimental steps are as follows:
AML12 cells were cultured in 10-% FBS-containing DMEM/F12 high-glucose medium and placed at 37 ℃ with 5% CO 2 In a cell culture incubator. The liver cells were first pre-protected for 30min with serum-free medium containing different concentrations of compounds, followed by stimulation with a mixture of PA and OA (designated OPA, PA/OA, 1. To mimic the endogenous extracellular matrix of the physiological state, an aliquot of 200 μ M citrate was supplemented into the culture medium. AML12 cells were incubated with OPA for 24 hours and lipid accumulation and mRNA expression were assessed after adding compounds LA-33 with different concentrations to the medium for 24 hours, respectively.
As shown in FIG. 1, compound LA-33 was effective in reducing TC, TG levels in OPA-stimulated AML cells at a concentration of 10. Mu.M. Figure 2 shows that ACLY is significantly down-regulated and that compound LA-33 only inhibits SLC13A5 function without affecting its expression.
Example 5
In vitro efficacy experiment of representative compound LA-33 of the invention on primary mouse hepatocytes
The experimental steps are as follows:
mouse liver primary cells were cultured in 10-percent FBS-containing DMEM high-glucose medium and placed at 37 ℃ with 5% CO 2 In a cell culture incubator. The liver cells were first pre-protected with serum-free medium containing different concentrations of the compound for 30min, and then stimulated with a mixture of PA and OA (designated OPA, PA/OA, 1. To mimic the physiological state of the endogenous extracellular matrix, an aliquot of 200 μ M citrate was supplemented into the culture medium. AML12 cells were incubated with OPA for 24 hours and lipid accumulation and mRNA expression were assessed after adding compounds LA-33 with different concentrations to the medium for 24 hours, respectively.
As shown in fig. 3, compound LA-33 was effective in reducing TC, TG content in OPA-stimulated AML cells. Figure 4 shows that ACLY is significantly down-regulated, and compound LA-33 only inhibits SLC13A5 function without affecting its expression, showing the same results as AML12 cell line.
Example 6
In vivo efficacy test of representative Compound LA-33 of the present invention
1. Experimental procedure
C57BL/6J mice were purchased from Equisetum biotechnologies, jiangsu, and were randomly divided into four groups after 1 week of adaptive feeding. The blank group was fed normally and the remaining three groups were fasted for 48h. After fasting was terminated, the low dose group and the high dose group were intraperitoneally injected at a dose of 10mg/kg and a dose of 30mg/kg, respectively. 1.5h later the animals were anesthetized with sodium pentobarbital intraperitoneally (50 mg/kg) to collect blood samples or liver tissue. Measuring fatty acids (NEFA) in plasma and liver using the free fatty acid kit; measuring Triglyceride (TG) content in plasma and liver using a triglyceride test kit; measuring Triglyceride (TC) content in plasma and liver using a total cholesterol test kit; HDL-c and LDL-c in plasma were measured using a low density lipoprotein cholesterol test kit and a high density lipoprotein cholesterol test kit, respectively. Plasma samples were assayed directly and tissue samples were homogenized with 9 volumes of saline.
2. Data processing:
plasma sample calculation formula:
cholesterol (TC) content (mmol/L) = (a) Sample(s) -A Blank space )/(A Standard of reference -A Blank space )×C Standard of merit
Triglyceride (TG) content (mmol/L) = (a) Sample(s) -A Blank space )/(A Standard of merit -A Blank space )×C Standard of reference
NEFA content (mmol/L) = (Δ A) Sample(s) -ΔA Blank space )/(ΔA Standard of merit -ΔA Blank space )×C Sample(s) ；
LDL-C and HDL-C contents (mmol/L) = (Δ a sample- Δ a blank)/(Δ a standard- Δ a blank) × C sample;
as shown in fig. 5, compound LA-33 significantly reduced total cholesterol, total triglycerides and free fatty acid levels in plasma of mice with significant dose dependence, while significantly reduced starvation-induced low density lipoprotein levels in plasma of mice at a dose of 30 mg/kg.
As shown in fig. 6, compound LA-33 significantly reduced the total cholesterol, total triglycerides and free fatty acid content in the mouse liver with significant dose dependence.
As shown in fig. 7, compound LA-33 can significantly reduce the mRNA expression level of ACLY and the mRNA expression levels of DNL pathway ACC1 and FASN in the liver of mice, but the mRNA expression level of the TC synthesis pathway key enzyme HMGCR has no significant change, which is consistent with the determination results of liver TC and TG.
Claims (7)
1. A 2-hydroxysuccinic compound, which is a compound having a structure represented by formula i or ii or an isomer, a pharmaceutically acceptable salt or a mixture thereof:
R 1 is hydrogen, halogen, cyano, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkoxy, pyrazolyl or phenyl;
R 2 is 1-4 hydrogens by R 2a Substituted 6-10 membered aryl, 5-10 membered heteroaryl, tetrahydroquinolinyl, benzothiazolyl, or benzoxazolyl;
R 2a is hydrogen, halogen, cyano, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group;
l and M are selected from-CH 2 -, -NH-or-O-;
the heteroatom in the 5-10 membered heteroaryl is N, O or S, and the number of the heteroatoms is 1-4.
2. The compound of claim 1, wherein in the structure:
R 1 is hydrogen,Fluoro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, isopropyl, methoxy, ethoxy, isopropoxy, pyrazolyl or phenyl;
R 2 is 1-4 hydrogen R 2a Substituted phenyl, pyrazolyl, pyridyl or tetrahydroquinolinyl, benzothiazolyl, benzoxazolyl;
R 2a is hydrogen, fluorine, cyano, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, dioxacene, methoxy, ethoxy or isopropoxy.
3. The compound of claim 1, selected from any one of the following:
LA-1
LA-18
LA-2
LA-19
LA-3
LA-20
LA-4
LA-21
LA-5
LA-22
LA-6
LA-23
LA-7
LA-24
LA-8
LA-25
LA-9
LA-26
LA-10
LA-27
LA-11
LA-28
LA-12
LA-29
LA-13
LA-30
LA-14
LA-31
LA-15
LA-32
LA-16
LA-33
LA-17
LA-34
4. the compound of claim 1, wherein the pharmaceutically acceptable salt is a salt of the compound with an acid or a base, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid, and the base is an inorganic base comprising an alkali metal cation, an alkaline earth metal cation, or an ammonium cation salt.
5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 as an active ingredient, said pharmaceutical composition comprising a pharmaceutically acceptable carrier.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the preparation of Na + Use in the manufacture of a medicament for the treatment of a disease associated with a dependent citrate transporter.
7. Use according to claim 6, wherein said Na + The dependent citrate transporter-related disease is a metabolic disease or cancer, and specifically is hyperlipidemia or non-alcoholic fatty liver disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211630879.9A CN115772117A (en) | 2022-12-19 | 2022-12-19 | 2-hydroxysuccinic acid compound and pharmaceutical composition and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211630879.9A CN115772117A (en) | 2022-12-19 | 2022-12-19 | 2-hydroxysuccinic acid compound and pharmaceutical composition and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115772117A true CN115772117A (en) | 2023-03-10 |
Family
ID=85392490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211630879.9A Pending CN115772117A (en) | 2022-12-19 | 2022-12-19 | 2-hydroxysuccinic acid compound and pharmaceutical composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115772117A (en) |
-
2022
- 2022-12-19 CN CN202211630879.9A patent/CN115772117A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113194958B (en) | THR beta receptor agonist compound, preparation method and application thereof | |
| CA3000483C (en) | Compounds, compositions, and methods for modulating cftr | |
| US10227312B2 (en) | Glucosylceramide synthase inhibitors for the treatment of diseases | |
| CN102131778A (en) | Heterocyclic gpcr agonists | |
| WO2007015744A1 (en) | Disubstituted thienyl compounds and their use as pharmaceuticals | |
| US20140315949A1 (en) | Modulators of methyl modifying enzymes, compositions and uses thereof | |
| HUE027149T2 (en) | Pyrrolidinones as metap2 inhibitors | |
| KR20150061644A (en) | Hydropyrrolopyrrole derivatives for use as fatty acid synthase inhibitors | |
| EP3686196A1 (en) | Polycyclic compound acting as ido inhibitor and/or ido-hdac dual inhibitor | |
| US11911353B2 (en) | Fatty acid synthase inhibitor and application thereof | |
| TW201904974A (en) | Heteroarylpyrimidinone derivative, preparation method thereof and use thereof in medicine | |
| US11034663B2 (en) | Tetrahydronaphtho[1,2-b]furan-2(3H)-one derivatives and preparation and uses thereof | |
| CN103917526B (en) | Pyrimidine carboxamide derivatives | |
| EP3398942B1 (en) | Substituted oxadiazole chemical compound and composition containing said chemical compound and use thereof | |
| CN104125960A (en) | Derivatives of aza adamantane and uses thereof | |
| US4997848A (en) | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition | |
| US20240174635A1 (en) | Tlr 9 inhibitors | |
| CN115772117A (en) | 2-hydroxysuccinic acid compound and pharmaceutical composition and application thereof | |
| KR20150085045A (en) | 3-aminocyclopentane carboxamide derivatives | |
| JP2016540812A (en) | Imidazolin-5-one derivatives useful as FASN inhibitors for the treatment of cancer | |
| EP3327010B1 (en) | Thiazideamide derivative and use thereof | |
| WO2021110138A1 (en) | Crystal form of thieno[2,3-c]pyridazine-4(1h)-one compound, preparation method therefor and use thereof | |
| WO2021110135A1 (en) | Crystal form as inhibitor of acc1 and acc2, and preparation method therefor and use thereof | |
| WO2019056375A1 (en) | Acid-sensitive gefitinib axially substituted silicon phthalocyanine complex and preparation method therefor and medical use thereof | |
| CN108047132A (en) | Diphenylamines yl pyridines anti-tumor compounds and preparation method thereof and purposes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |