WO2023045985A1 - 长链类化合物及其用途 - Google Patents

长链类化合物及其用途 Download PDF

Info

Publication number
WO2023045985A1
WO2023045985A1 PCT/CN2022/120315 CN2022120315W WO2023045985A1 WO 2023045985 A1 WO2023045985 A1 WO 2023045985A1 CN 2022120315 W CN2022120315 W CN 2022120315W WO 2023045985 A1 WO2023045985 A1 WO 2023045985A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
cycloalkyl
group
cycloalkenyl
carbon atoms
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.)
Ceased
Application number
PCT/CN2022/120315
Other languages
English (en)
French (fr)
Inventor
南发俊
李静雅
张梅
谢治富
张仰明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Burgeon Therapeutics Co Ltd
Original Assignee
Burgeon Therapeutics Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Burgeon Therapeutics Co Ltd filed Critical Burgeon Therapeutics Co Ltd
Priority to US18/694,947 priority Critical patent/US20250144127A1/en
Priority to JP2024518781A priority patent/JP7808892B2/ja
Priority to EP22872030.6A priority patent/EP4406537A4/en
Publication of WO2023045985A1 publication Critical patent/WO2023045985A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/26—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings
    • C07C55/28—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a class of novel long-chain fatty acid ACLY inhibitors, pharmaceutically acceptable salts, pharmaceutically acceptable esters, crystalline hydrates, solvates or mixtures thereof, and pharmaceutical compositions containing such inhibitors.
  • Use in the preparation of drugs for treating metabolic diseases such as hypercholesterolemia, non-alcoholic steatohepatitis (NASH), and liver fibrosis.
  • metabolic diseases such as hypercholesterolemia, non-alcoholic steatohepatitis (NASH), and liver fibrosis.
  • Acetyl-CoA produced by the mitochondrial tricarboxylic acid cycle is the source substrate for the de novo synthesis of endogenous cholesterol and triglycerides.
  • Acetyl-CoA produced by the tricarboxylic acid cycle usually cannot directly pass through the mitochondrial membrane and enter the cytoplasm, but generates citric acid through the catalysis of citrate synthase in the mitochondria; citric acid enters through the mitochondrial membrane through the tricarboxylic acid transporter The cytoplasm is then cleaved into acetyl-CoA and oxaloacetate by ATP-dependent citrate lyase (ACLY) distributed on the endoplasmic reticulum.
  • ACLY ATP-dependent citrate lyase
  • oxaloacetate generates malate with the help of NADH, and the latter further generates pyruvate with the help of NAPDH.
  • Malate and pyruvate can be transported back to the mitochondria through their respective transporters; acetyl-CoA can be directly involved in triglyceride and cholesterol as a substrate.
  • de novo synthesis Various metabolic diseases, such as non-alcoholic steatohepatitis (NASH), hypercholesterolemia, and atherosclerosis, are associated with abnormally elevated levels of hepatic lipid synthesis. Therefore, inhibiting the activity of ACLY can significantly reduce the de novo synthesis of hepatocyte lipids, and the ACLY inhibitor can be used to prepare therapeutic drugs for metabolic diseases.
  • NASH non-alcoholic steatohepatitis
  • hypercholesterolemia hypercholesterolemia
  • atherosclerosis are associated with abnormally elevated levels of hepatic lipid synthesis. Therefore, inhibiting the activity of ACLY can significantly reduce the de novo
  • Bempedoic acid (ETC-1002) is the first small molecule inhibitor of ACLY listed in the world, and it is mainly used for the treatment of statin-intolerant heterozygous familial hypercholesterolemia; in addition, benzenesulfonamides and other ACLY inhibitors The drug has also been verified to have lipid-lowering pharmacological activity at the cellular level and the preclinical animal level.
  • the object of the present invention is to provide the use of a long-chain compound for treating diseases such as cholesterolemia, non-alcoholic steatohepatitis (NASH), liver fibrosis, and atherosclerosis.
  • diseases such as cholesterolemia, non-alcoholic steatohepatitis (NASH), liver fibrosis, and atherosclerosis.
  • NASH non-alcoholic steatohepatitis
  • liver fibrosis liver fibrosis
  • atherosclerosis atherosclerosis
  • the first aspect of the present invention provides a compound represented by general formula (I), or its deuterated compound, stereoisomer, enantiomer, diastereomer, racemate or its
  • a pharmaceutically acceptable salt or a mixture of two or more compounds in the compound represented by general formula (I) for the preparation of a drug for the treatment of metabolic diseases; or for the preparation of a drug for the treatment of atherosclerosis hardened drugs,
  • n and n are each independently 1, 2, 3, 4, 5 or 6;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C3- C7 cycloalkenyl, phenyl or benzyl;
  • R and R form C3-C7 cycloalkyl or C3-C7 cycloalkenyl together with their adjacent carbon atoms;
  • R 5 and R 6 form C3-C7 cycloalkyl or C3-C7 cycloalkenyl together with their adjacent carbon atoms;
  • R 3 and R 4 form a C3-C7 cycloalkyl group or a C3-C7 cycloalkenyl group together with adjacent carbon atoms;
  • Y 1 and Y 2 are each independently selected from: -OH, -COOH, -COCoA, -COOR 7 ; wherein, R 7 is methyl, ethyl or The CoA structure looks like this:
  • the compound has the structure shown in the general formula II:
  • the compound has a structure represented by general formula III:
  • the compound has the structure shown in the general formula IV
  • p 0, 1, 2 or 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, C1-C4 alkyl, deuterated C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, deuterated C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl or benzyl;
  • R and R together with their adjacent carbon atoms form deuterated C3-C7 cycloalkyl, C3-C7 cycloalkyl or C3-C7 cycloalkenyl;
  • R 5 and R 6 form deuterated C3-C7 cycloalkyl, C3-C7 cycloalkyl or C3-C7 cycloalkenyl together with their adjacent carbon atoms;
  • R 3 and R 4 together with their adjacent carbon atoms form a deuterated C3-C7 cycloalkyl, C3-C7 cycloalkyl or C3-C7 cycloalkenyl.
  • R 1 and R 2 are each independently H, methyl, ethyl, deuterated methyl, deuterated ethyl, deuterated propyl or propyl, preferably R 1 and R 2 are both H is either methyl at the same time; or R 1 and R 2 together with their adjacent carbon atoms form a C3-C6 cycloalkyl, C3-C5 cycloalkyl or C3-C4 cycloalkyl.
  • R 3 and R 4 are each independently H, methyl, ethyl, deuterated methyl, deuterated ethyl, deuterated propyl or propyl, preferably R 3 and R 4 are both H is either methyl at the same time; or R3 and R4 together with their adjacent carbon atoms form a C3-C6 cycloalkyl group, a C3-C5 cycloalkyl group or a C3-C4 cycloalkyl group.
  • R 5 and R 6 are each independently H, methyl, ethyl, deuterated methyl, deuterated ethyl, deuterated propyl or propyl, preferably R 5 and R 6 are both H is either methyl at the same time; or R 5 and R 6 form C3-C6 cycloalkyl, C3-C5 cycloalkyl or C3-C4 cycloalkyl together with their adjacent carbon atoms.
  • Y 1 and Y 2 are each independently -COOH, -COCoA or -COOR 7 ; wherein, R 7 is methyl, ethyl or The CoA structure looks like this:
  • the compound is selected from the following group:
  • the compound is also selected from the following group:
  • the metabolic disease is selected from hypercholesterolemia, non-alcoholic steatohepatitis (NASH), and liver fibrosis.
  • NASH non-alcoholic steatohepatitis
  • the atherosclerosis is caused by hypercholesterolemia.
  • the second aspect of the present invention provides a compound represented by general formula (I), or its deuterated compound, stereoisomer, enantiomer, diastereoisomer, racemate or its A pharmaceutically acceptable salt or a mixture of two or more compounds of the compounds represented by general formula (I),
  • n and n are each independently 1, 2, 3, 4, 5 or 6;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C3- C7 cycloalkenyl, phenyl or benzyl;
  • R and R form C3-C7 cycloalkyl or C3-C7 cycloalkenyl together with their adjacent carbon atoms;
  • R 5 and R 6 form C3-C7 cycloalkyl or C3-C7 cycloalkenyl together with their adjacent carbon atoms;
  • R 3 and R 4 form a C3-C7 cycloalkyl group or a C3-C7 cycloalkenyl group together with adjacent carbon atoms;
  • Y 1 and Y 2 are each independently selected from: -OH, -COOH, -COCoA, -COOR 7 ; wherein, R 7 is methyl, ethyl or The CoA structure looks like this:
  • the compound has a structure represented by general formula II, III or IV:
  • p 0, 1, 2 or 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, C1-C4 alkyl, deuterated C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl or benzyl;
  • R and R together with their adjacent carbon atoms form deuterated C3-C7 cycloalkyl, C3-C7 cycloalkyl or C3-C7 cycloalkenyl;
  • R 5 and R 6 form deuterated C3-C7 cycloalkyl, C3-C7 cycloalkyl or C3-C7 cycloalkenyl together with their adjacent carbon atoms;
  • R 3 and R 4 together with their adjacent carbon atoms form a deuterated C3-C7 cycloalkyl, C3-C7 cycloalkyl or C3-C7 cycloalkenyl.
  • the compound is selected from the following group:
  • the compound is also selected from the following group:
  • the third aspect of the present invention provides a pharmaceutical composition, comprising the compound described in the first aspect, or its deuterated compound, stereoisomer, enantiomer, diastereoisomer, racemic or a pharmaceutically acceptable salt thereof or a mixture of two or more compounds of the compound represented by general formula (I); and
  • the dosage form of the pharmaceutical combination of the present invention can be various, including but not limited to: tablet, capsule, granule, syrup, solution, suspension or aerosol.
  • the fourth aspect of the present invention provides a method for treating metabolic diseases, comprising administering the compound described in the second aspect, or its deuterated compound, stereoisomer, enantiomer, non- An enantiomer, a racemate or a pharmaceutically acceptable salt thereof, or a mixture of two or more compounds of the compound represented by general formula (I), or the pharmaceutical combination described in the third aspect things.
  • the metabolic disease is selected from hypercholesterolemia, non-alcoholic steatohepatitis (NASH), and liver fibrosis.
  • NASH non-alcoholic steatohepatitis
  • the fifth aspect of the present invention provides a method for treating atherosclerosis, comprising administering the compound described in the second aspect, or its stereoisomers, enantiomers, diastereoisomers to a subject in need isomer, racemate or a pharmaceutically acceptable salt thereof, or a mixture of two or more compounds of the compound represented by general formula (I), or the pharmaceutical composition described in the third aspect.
  • the atherosclerosis is caused by hypercholesterolemia.
  • Chinese patent application No. 201610105067 discloses a class of fatty acid compounds, their preparation methods and their uses. This type of compound has the ability to activate APMK activity and inhibit the glucose output of primary hepatocytes in mice. It can be used to prepare and treat obesity or diabetes medications.
  • the inventors unexpectedly found that this type of compound has the activity of inhibiting ACLY. Further in vivo and in vitro pharmacological activity evaluations found that the representative compound A3 could inhibit de novo lipid synthesis in primary hepatocytes, improve hyperlipidemia and hypercholesterolemia in golden hamsters and ApoE -/- mice, and significantly improve hyperlipidemia and hypercholesterolemia. NASH symptoms in ob/ob mice and cynomolgus monkeys induced by a sugar-high cholesterol diet.
  • this application discloses that the series of compounds have good ACLY inhibitory activity, can inhibit the de novo synthesis of triglyceride and cholesterol in primary hepatocytes, and significantly improve hyperlipidemia in golden hamsters and spontaneous aged rhesus monkeys. Prominent therapeutic effects have been shown in both rodent and non-human primate NASH models.
  • this class As a new small molecule inhibitor of ACLY, this class has a significant therapeutic effect on metabolic diseases represented by hypercholesterolemia and non-alcoholic steatohepatitis, and can be used to develop hypercholesterolemia and non-alcoholic steatohepatitis, etc. Drugs for the treatment of metabolic diseases.
  • Figure 1 shows the evaluation of the inhibitory effect of compound A3 on the de novo synthesis of lipids in primary hepatocytes; wherein, A: the inhibitory effect of compound A3 on the de novo synthesis of triglycerides was investigated in hepatocytes of WT mice and ACLY knockout mice; B: The inhibitory effect of compound A3 on de novo triglyceride synthesis was investigated in hepatocytes of WT mice and ACLY knockout mice. Compared with the control group, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, compared with the corresponding dose group, # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001.
  • Figure 2 shows the evaluation of compound A3 and A4 multiple administrations on the reduction effect of golden hamster serum total cholesterol and low-density lipoprotein cholesterol content, wherein *, compared with the model control group, P ⁇ 0.05; **, compared with the model Compared with the control group, P ⁇ 0.01; ***, compared with the model control group, P ⁇ 0.001.
  • Figure 3 shows the impact of long-term administration of test substance compound A3 on the formation of ApoE -/- mice aortic plaques, wherein, *, compared with the model control group, P ⁇ 0.05; **, compared with the model control group Compared with the model control group, P ⁇ 0.01; ***, compared with the model control group, P ⁇ 0.001.
  • Figure 5 shows the change of liver NAS score after long-term administration of compound A3, wherein, *, compared with the model control group, P ⁇ 0.05; **, compared with the model control group, P ⁇ 0.01; ***, compared with the model control group, P ⁇ 0.01; ***, compared with the model control group, P ⁇ 0.01; Compared with the model control group, P ⁇ 0.001.
  • the inventors of the present application found that the compound of the present application has ACLY inhibitory activity, and this type of compound can inhibit the de novo synthesis of lipids in primary hepatocytes, and has shown therapeutic effect on various animal models of metabolic diseases. As a result, it can be further developed into therapeutic drugs for metabolic diseases such as hypercholesterolemia and non-alcoholic steatohepatitis, and can also be used for the treatment of atherosclerosis. On this basis, the present invention has been accomplished.
  • C 1 -C 6 means having 1, 2, 3 or 4 carbon atoms.
  • C3 - C7 means having 3, 4, 5, 6 or 7 carbon atoms. and so on.
  • alkyl means a saturated linear or branched chain hydrocarbon moiety
  • C1-C4 alkyl means a straight chain or branched chain alkyl group with 1 to 4 carbon atoms, without limitation Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • alkenyl means a straight or branched chain hydrocarbon moiety containing at least one double bond
  • C 2 -C 4 alkenyl means a moiety having 2 to 4 carbon atoms containing a double bond straight chain or branched alkenyl, including, but not limited to, ethenyl, propenyl, butenyl, isobutenyl.
  • alkynyl refers to a straight chain or branched alkynyl group containing a triple bond, including non-limitingly ethynyl, propynyl, butynyl, isobutynyl and the like.
  • cycloalkyl means a saturated cyclic hydrocarbon moiety
  • C 3 -C 7 cycloalkyl means a cyclic alkyl group having 3 to 7 carbon atoms in the ring, not Limitations include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkenyl means a cyclic hydrocarbon moiety containing at least one double bond
  • C 3 -C 7 cycloalkenyl means a cyclic hydrocarbon moiety having 3 to 7 carbon atoms in the ring Alkyl includes, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
  • the pharmaceutically acceptable salt of the present invention may be a salt formed by an anion and a positively charged group on the compound of formula I.
  • Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate Acid, glutamate, glucuronate, lactate, glutarate or maleate.
  • salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium, such as tetramethylammonium.
  • diethylzinc reagent (1mL, 1mmol) was cooled to -40°C in 1mL DCM, after 5min, 0.5mL DCM solution of diiodomethane (0.54g, 2mmol) was added dropwise, and reacted at -40°C After 1h, add trichloroacetic acid (16mg, 0.1mmol) and DME (45mg, 0.5mmol), rise to -15°C for 1h after addition, add B7 (193mg, 0.5mmol) in 0.5mL DCM solution, after addition, room temperature Stir overnight.
  • the above imidazole intermediate was dissolved in dry THF (8.5 mL), and a NaHCO 3 (0.1 M, 3 mL) solution of trilithium salt of coenzyme A (20 mg, 0.026 mmol) was added dropwise.
  • the reaction solution was stirred at room temperature for 24 h.
  • the reaction solution was extracted with ethyl acetate (2 ⁇ 3 mL).
  • the aqueous layer was adjusted to pH 2 by adding 1M HCl.
  • the aqueous layer ( ⁇ 1mL) was directly passed through the column (SPE, Agilent HF Bond Elur C18 column, size: 5gm/20mL, USA), and the concentration of the eluent was 0%, 5%, 10%, 20%, 30%, 40%, 50%, and 100% MeCN (10 mL each). A13 was obtained, and its structure was confirmed by 1 H NMR spectroscopy LR-ESI-MS.
  • Compound A13 Solvent systems on Zorbax-SB C18 column, 4.6*50mm, 3.5 ⁇ : Gradient, A: 10mM NH 4 COOH in H 2 O, B: CH 3 OH, 0min: 50% A and 50% B; 0- 30min: A 50% ⁇ 0%, B 50% ⁇ 100%, 0.5mL/min.
  • Embodiment 2 biological activity evaluation in vitro
  • ACLY catalyzed citrate cracking process needs to consume a molecule of ATP to activate citric acid.
  • the inventors used the ADP-Glo detection kit to detect the amount of ATP converted into ADP to reflect the catalytic activity of ACLY. After the establishment of the assay system and the optimization of the reaction conditions, the inventors evaluated the inhibitory activity of ACLY on the obtained new small molecule inhibitor of ACLY.
  • Bioassay protocol Human ACLY protein was purchased from Beijing Yiqiao Shenzhou Technology Co., Ltd. (Cat. No.: 11769-H07B), and the ADP-Glo detection kit was purchased from Promega (Cat. No.: V9102).
  • the final reaction system is shown in Table 1.
  • the total reaction volume is 5 ⁇ L, which is composed of three parts: 1 ⁇ L 2% DMSO, 2 ⁇ L substrate mixture, and 2 ⁇ L enzyme (final concentration: 25 nM). Then add 1 ⁇ L of different concentrations of compounds for incubation. Reaction conditions: 30min, 37°C.
  • Test results first calculate the cumulative amount of fluorescence intensity RFU/min of the enzyme in the 30min reaction time, which represents the initial velocity of the enzyme, and then calculate the ratio of the enzyme velocity (vsample) after adding the compound to the enzyme velocity (vDMSO) without adding the compound
  • the logarithm value of the concentration was plotted against the activity percentage, and then the fitting curve was calculated by nonlinear regression, and the curve was fitted using the software GraphPad Prism 8.0 formula log(inhibitor) vs. response--Variable slope, and the IC 50 value was calculated, and the result As shown in the following table:
  • ACLY is responsible for cleaving mitochondrial-derived citric acid to generate acetyl-CoA, which is a key raw material for cellular lipid synthesis. Inhibiting the activity of ACLY can significantly reduce the de novo synthesis of lipids (triglycerides and cholesterol).
  • the inventors isolated mouse primary hepatocytes and used [1,2- 14 C]-sodium acetate as a substrate tracer to evaluate the ability of de novo lipid synthesis. At the same time, the compound ETC-1002 was used as a positive control.
  • mice liver was perfused with calcium-free perfusate, the mouse liver was digested with collagenase, and primary mouse liver cells were obtained by density gradient centrifugation. In a 6-well plate (0.2% gelatin was spread before the plate), the cells were adhered to the wall for 6 hours after the plate was plated, and replaced with serum-free LG-DMEM (containing 2x double antibody) to starve overnight.
  • LG-DMEM containing 2x double antibody
  • Isotope tracer the next day, change to serum-free LG-DMEM containing 10nM insulin, and the corresponding concentration of compound (1950 ⁇ L, 4 replicate wells per group); add 0.1 ⁇ Ci of [1,2- 14 C]-B to each well salt serum-free medium and incubated in an incubator for 4 hours.
  • Lipid saponification add 1.6mL ice-cold PBS to each well to wash 3 times, dry the plate and add 600 ⁇ L 0.5M KOH to each well for lysis, and the lysis time is 1h. Pipette 480 ⁇ L into a glass test tube pre-added with 400 ⁇ L 20% KOH (methanol as a solvent), oscillate and mix well, and place in a 95-degree water bath for saponification for 3 hours; the remaining lysate is used for protein concentration determination.
  • KOH methanol as a solvent
  • Quantification of isotope incorporation Add 1700 ⁇ L of scintillation fluid to each tube and read.
  • Example 3 The efficacy of compounds A3 and A4 in improving hypercholesterolemia
  • Dosing regimen the golden hamster hyperlipidemia model is recognized as one of the ideal animal models for the study of hyperlipidemia drug treatment (pharmacodynamic evaluation).
  • pharmacodynamic evaluation In order to preliminarily investigate the potential regulatory effect of candidate compounds on the balance of liver lipid metabolism, a preliminary pharmacodynamic evaluation was carried out using the hyperlipidemia model of golden hamsters induced by a high-fat and high-cholesterol diet.
  • the specific plan is to model 56 golden hamsters, male, with high-fat and high-cholesterol diet (Research diet, product number C11953) for two weeks, and reserve 8 as the blank control group.
  • group administration (7 groups, n 8), i.e.
  • model control group positive control ETC-1002 30mg/kg group, compound A3 10mg/kg and 30mg/kg group, compound A4 10mg/kg and 30mg/kg group ,Blank control group.
  • the compounds in each group were prepared with physiological saline (0.9% NaCl), the administration frequency was 1 time/day, and the administration cycle was 7 days.
  • Hypercholesterolemia is an important cause of atherosclerosis.
  • compound A3 can significantly improve hyperlipidemia and hypercholesterolemia, the inventors further found that compound A3 can significantly slow down the occurrence of atherosclerosis in ApoE -/- mice.
  • long-term drug treatment was carried out, that is, the model control group, the positive control ETC-1002 30mg/kg group, the compound A3 15mg/kg, 30mg/kg and 60mg/kg groups, and the blank control group.
  • the compounds in each group were formulated with physiological saline (0.9% NaCl), the administration frequency was once/day, and the administration cycle was 24 weeks.
  • Test results show that, compared with the control group, after compound administration for 24 weeks, the three dose groups of compound A3 can significantly reduce the aortic valve plaque area of ApoE -/- mice (the right figure is Statistical diagram of the left figure), indicating that compound A3 has the effect of significantly improving the occurrence of atherosclerosis induced by hypercholesterolemia.
  • Example 4 Compound A3 improves diet-induced non-alcoholic steatohepatitis efficacy evaluation
  • NASH non-alcoholic steatohepatitis
  • Test results ob/ob mice appear whitish and grainy due to excessive lipid accumulation, and the above phenomenon can be significantly reversed after administration of compound A3 (A in Figure 4); further, the inventors carried out pathological analysis of the liver: Compared with the model control group, the H&E staining study found that the fatty degeneration and ballooning of the liver in the compound A3 administration group were significantly reduced (fatty liver, A in Figure 4); the macrophage CD68 staining study found that the liver inflammatory cells in the compound A3 administration group The infiltration was significantly reduced (inflammation, A in Figure 4, B in Figure 4); Sirius red staining showed that the collagen deposition in the liver of the compound A3 administration group was significantly reduced (fibrosis, A in Figure 4, C in Figure 4). The above results indicate that compound A3 has the pharmacological activity of significantly improving diet-induced NASH in ob/ob mice.
  • the inventors further evaluated the therapeutic effect of long-term administration of compound A3 on non-alcoholic steatohepatitis in cynomolgus monkeys in a non-human primate model.
  • the high-fat, high-sugar, high-cholesterol, and high-food diet was fed for 14 weeks and administered simultaneously (20 mg/kg), the administration frequency was 1 time/day, and the administration cycle was 14 weeks.
  • Test results The results of liver puncture showed that long-term administration of compound A3 can significantly reduce the liver lipid accumulation in cynomolgus monkeys, and reduce the occurrence of inflammation and fibrosis, and the non-alcoholic fatty liver disease activity (NAS) score after administration Significantly lower ( Figure 5).
  • NAS non-alcoholic fatty liver disease activity
  • Embodiment 5 Compound A3 Oral Pharmacokinetic Animal Parameters Investigation
  • Test results by detecting the plasma drug concentration at different times, and calculating the pharmacokinetic parameters of the two compounds (Table 4). The investigation found that the plasma exposure of the test compound A3 was significantly higher than that of the positive control drug ETC-1002 (C max : 13.4 ⁇ g/mL vs 3.81 ⁇ g/mL; AUC 0-t : 63.7h* ⁇ g/mL vs 14.4h* ⁇ g/mL, the former is compound A3).
  • the series of compounds of this application have good ACLY inhibitory activity, and have shown good therapeutic effects on various metabolic disease drug models, and can be further developed into metabolic diseases such as hypercholesterolemia and nonalcoholic steatohepatitis. Drugs for the treatment of diseases.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)

Abstract

一种长链类化合物及其用途，长链类化合物结构如式(I)所示。所述化合物能够直接抑制ACLY，对以高胆固醇血症和非酒精性脂肪肝炎为代表的代谢性疾病具有显著的治疗效果，可用于开发制成高胆固醇血症和非酒精性脂肪肝炎等代谢性疾病的治疗药物。

Description

长链类化合物及其用途 技术领域
本发明涉及一类新型长链脂肪酸类ACLY抑制剂、其药学上可接受的盐、药用酯、结晶水合物、溶剂合物或它们中的混合物，以及包含该类抑制剂的药物组合物，在制备高胆固醇血症、非酒精性脂肪肝炎(NASH)、肝纤维化等代谢性疾病治疗药物中的用途。
背景技术
线粒体三羧酸循环(TCA cycle)产生的乙酰辅酶A是内源性胆固醇和甘油三酯从头合成的源头底物。三羧酸循环生成的乙酰辅酶A通常不能直接穿过线粒体膜进入细胞浆，而是在线粒体中通过柠檬酸合成酶的催化作用生成柠檬酸；柠檬酸借助三羧酸转运体透过线粒体膜进入胞浆，随后被分布于内质网上的ATP依赖的柠檬酸裂解酶(adenosine triphosphate citrate lyase,ACLY)裂解为乙酰辅酶A和草酰乙酸。其中，草酰乙酸借助NADH生成苹果酸，后者借助NAPDH进一步生成丙酮酸，苹果酸和丙酮酸可通过各自转运体被运回线粒体；乙酰辅酶A则可以作为底物直接参与甘油三酯和胆固醇的从头合成。非酒精脂肪肝炎(NASH)、高胆固醇血症以及动脉粥样硬化等多种代谢性疾病都与肝脏脂质合成水平的异常升高有关。因此，抑制ACLY的活性可以显著减少肝细胞脂质从头合成，ACLY抑制剂可被用于制备代谢性疾病的治疗药物。已知，Bempedoic acid(ETC-1002)是全球首个上市的ACLY小分子抑制剂，主要用于他汀不耐受的杂合子家族性高胆固醇血症的治疗；此外，苯磺酰胺类等ACLY抑制剂在细胞水平和临床前动物水平也被分别验证具有降脂的药理学活性。
因此为治疗高胆固醇血症、非酒精性脂肪肝炎(NASH)、肝纤维化等代谢性疾病，需要研究ACLY抑制剂。
发明内容
本发明的目的在于提供一种长链类化合物的用途，用于治疗胆固醇血症、非酒精性脂肪肝炎(NASH)、肝纤维化、动脉粥样硬化等疾病。
本发明的第一方面，提供一种通式(I)所示的化合物，或其氘代化合物、立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或通式(I)所示的化合物中的两种或两种以上的化合物组成的混合物的用途，用于制备治疗代谢性疾病的药物；或者用于制备治疗动脉粥样硬化的药物，
Figure PCTCN2022120315-appb-000001
其中，
Figure PCTCN2022120315-appb-000002
表示双键或单键；
m、n各自独立地为1、2、3、4、5或6；
R 1、R 2、R 3、R 4、R 5、R 6各自独立地为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、苯基或苄基；
或者，R 1和R 2与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
或者，R 5和R 6与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
或者，R 3和R 4与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
Y 1和Y 2各自独立地选自：-OH、-COOH、-COCoA、-COOR 7；其中，R 7为甲基、乙基或
Figure PCTCN2022120315-appb-000003
CoA结构如下所示：
Figure PCTCN2022120315-appb-000004
在另一优选例中，
Figure PCTCN2022120315-appb-000005
表示双键，双键构型为顺式或反式。
在另一优选例中，所述化合物具有通式II所示的结构：
Figure PCTCN2022120315-appb-000006
在另一优选例中，所述化合物具有通式III所示的结构：
Figure PCTCN2022120315-appb-000007
在另一优选例中，所述化合物具有通式IV所示的结构
Figure PCTCN2022120315-appb-000008
式中，p为0、1、2或3。
在另一优选例中，R 1、R 2、R 3、R 4、R 5、R 6各自独立地为H、C1-C4烷基、氘代C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、氘代C3-C7环烷基、C3-C7环烯基、苯基或苄基；
或者，R 1和R 2与其相邻的碳原子一起形成氘代C3-C7环烷基、C3-C7环烷基或C3-C7环烯基；
或者，R 5和R 6与其相邻的碳原子一起形成氘代C3-C7环烷基、C3-C7环烷基或C3-C7环烯基；
或者，R 3和R 4与其相邻的碳原子一起形成氘代C3-C7环烷基、C3-C7环烷基或C3-C7环烯基。
在另一优选例中，R 1、R 2各自独立地为H、甲基、乙基、氘代甲基、氘代乙基、氘代丙基或丙基，优选R 1和R 2同时为H或同时为甲基；或者R 1和R 2与其相邻的碳原子一起形成C3-C6环烷基、C3-C5环烷基或C3-C4环烷基。
在另一优选例中，R 3、R 4各自独立地为H、甲基、乙基、氘代甲基、氘代乙基、氘代丙基或丙基，优选R 3和R 4同时为H或同时为甲基；或者R 3和R 4与其相邻的碳原子一起形成C3-C6环烷基、C3-C5环烷基或C3-C4环烷基。
在另一优选例中，R 5、R 6各自独立地为H、甲基、乙基、氘代甲基、氘代乙基、氘代丙基或丙基，优选R 5和R 6同时为H或同时为甲基；或者R 5和R 6与其相邻的碳原子一起形成C3-C6环烷基、C3-C5环烷基或C3-C4环烷基。
在另一优选例中，Y 1和Y 2各自独立地为-COOH、-COCoA或-COOR 7；其中，R 7为甲基、乙基或
Figure PCTCN2022120315-appb-000009
CoA结构如下所示：
Figure PCTCN2022120315-appb-000010
在另一优选例中，所述化合物选自下组：
Figure PCTCN2022120315-appb-000011
在另一优选例中，所述化合物还选自下组：
Figure PCTCN2022120315-appb-000012
Figure PCTCN2022120315-appb-000013
在另一优选例中，所述代谢性疾病选自：高胆固醇血症、非酒精性脂肪肝炎(NASH)、肝纤维化。
在另一优选例中，所述动脉粥样硬化由高胆固醇血症引起。
本发明的第二方面，提供一种通式(I)所示的化合物，或其氘代化合物、立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或通式(I)所示的化合物中的两种或两种以上的化合物组成的混合物，
Figure PCTCN2022120315-appb-000014
其中，
Figure PCTCN2022120315-appb-000015
表示双键或单键；
m、n各自独立地为1、2、3、4、5或6；
R 1、R 2、R 3、R 4、R 5、R 6各自独立地为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、苯基或苄基；
或者，R 1和R 2与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
或者，R 5和R 6与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
或者，R 3和R 4与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
Y 1和Y 2各自独立地选自：-OH、-COOH、-COCoA、-COOR 7；其中，R 7为甲基、乙基或
Figure PCTCN2022120315-appb-000016
CoA结构如下所示：
Figure PCTCN2022120315-appb-000017
在另一优选例中，所述化合物具有通式II、III或IV所示的结构：
Figure PCTCN2022120315-appb-000018
式中，p为0、1、2或3。
在另一优选例中，R 1、R 2、R 3、R 4、R 5、R 6各自独立地为H、C1-C4烷基、氘代C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、苯基或苄基；
或者，R 1和R 2与其相邻的碳原子一起形成氘代C3-C7环烷基、C3-C7环烷基或C3-C7环烯基；
或者，R 5和R 6与其相邻的碳原子一起形成氘代C3-C7环烷基、C3-C7环烷基或C3-C7环烯基；
或者，R 3和R 4与其相邻的碳原子一起形成氘代C3-C7环烷基、C3-C7环烷基或C3-C7环烯基。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2022120315-appb-000019
Figure PCTCN2022120315-appb-000020
在另一优选例中，所述化合物还选自下组：
Figure PCTCN2022120315-appb-000021
本发明的第三方面，提供一种药物组合物，包含第一方面所述的化合物，或其氘代化合物、立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或通式(I)所示的化合物中的两种或两种以上的化合物组成的混合物；和
药学上可接受的盐。
本发明所述的药物组合的剂型可以是多样的，包括但不限于：片剂、胶囊、颗粒、糖浆、溶液、悬浮液或气雾剂。
本发明的第四方面，提供一种治疗代谢性疾病的方法，包括向有需要的对象施用第二方面所述的化合物，或其氘代化合物、立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或通式(I)所示的化合物中的两种或两种以上的化合物组成的混合物或第三方面所述的药物组合物。
在另一优选例中，所述代谢性疾病选自：高胆固醇血症、非酒精性脂肪肝炎(NASH)、肝纤维化。
本发明的第五方面，提供一种治疗动脉粥样硬化的方法，包括向有需要的对象施用第二方面所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或通式(I)所示的化合物中的两种或两种以上的化合物组成的混合物或第三方面所述的药物组合物。
在另一优选例中，所述动脉粥样硬化由高胆固醇血症引起。
有益效果
中国专利申请第201610105067号(CN107118098)公开了一类脂肪酸类化合物、其制备方法及其用途，该类化合物具有激活APMK活性，具有抑制小鼠原代肝细胞葡萄糖输出的能力，可用于制备治疗肥胖或糖尿病的药物。
发明人意外发现该类化合物具有抑制ACLY的活性。进一步的体内外药理学活性评价发现，代表性化合物A3在原代肝细胞中可以抑制脂质的从头合成，改善金黄地鼠和ApoE -/-小鼠高脂高胆固醇血症，显著改善高脂高糖高胆固醇饮食诱导的ob/ob小鼠和食蟹猴的NASH症状。研究结果还提示，双键为反式构型的化合物的体内活性要优于双键为顺式构型的化合物；而且，同等口服剂量下化合物A3比Bempedoic acid的血浆暴露量高出4倍多，提示化合物A3具有更好的治疗效果。
综上，本申请公开该系列化合物具有良好的ACLY抑制活性，可在原代肝细胞中抑制甘油三酯和胆固醇的从头合成，显著改善金黄地鼠及自发性老年恒河猴高脂血症，在啮齿类动物及非人灵长类动物的NASH模型上都显示出突出的治疗效果。
该类作为新型ACLY小分子抑制剂，对以高胆固醇血症和非酒精性脂肪肝炎为代表的代谢性疾病具有显著的治疗效果，可用于开发制成高胆固醇血症和非酒精性脂肪肝炎等代谢性疾病的治疗药物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。
附图说明
图1示出化合物A3对原代肝细胞脂质从头合成的抑制作用评价；其中，A：在WT小鼠和ACLY敲除小鼠的肝细胞考察化合物A3对甘油三酯从头合成的抑制作用；B：在WT小鼠和ACLY敲除小鼠的肝细胞考察化合物A3对甘油三酯从头合成的抑制作用。与对照组相比，*P<0.05,**P<0.01,***P<0.001，与对应剂量组相比， #P<0.05， ##P<0.01, ###P<0.001。
图2示出化合物A3和A4多次给药对金黄地鼠血清总胆固醇和低密度脂蛋白胆固醇含量的降低作用评价，其中*，与模型对照组相比，P<0.05；**，与模型对照组相比，P<0.01；***，与模型对照组相比，P<0.001。
图3示出受试物化合物A3长期给药对ApoE -/-小鼠主动脉斑块形成的影响，其中，*，与模型对照组相比，P<0.05；**，与模型对照组相比，P<0.01；***，与模型对照组相比，P<0.001。
图4示出化合物A3对ob/ob小鼠NASH的治疗作用评价，其中，A.ob/ob小鼠肝脏外观及化合物长期给药后肝脏病理分析结果(n＝8)；B.CD68免疫组化病理分析统计图；C：天狼星红染色病理分析统计图。其中，*，与模型对照组相比，P<0.05；**，与模型对照组相比，P<0.01；***，与模型对照组相比，P<0.001。
图5示出化合物A3长期给药后肝脏NAS评分的变化，其中，*，与模型对照组相比，P<0.05；**，与模型对照组相比，P<0.01；***，与模型对照组相比，P<0.001。
具体实施方式
本申请的发明人经过广泛而深入的研究，发现本申请化合物具有ACLY抑制活性，该类化合物在原代肝细胞中能抑制脂质的从头合成，并在多种代谢性疾病动物模型上显示出治疗效果，可进一步开发成为高胆固醇血症、非酒精性脂肪肝炎等代谢性疾病的治疗药物，还能用于治疗动脉粥样硬化。在此基础上，完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C 1-C 6”是指具有1、2、3或4个碳原子。术语“C 3-C 7”是指具有3、4、5、6或7个碳原子。以此类推。
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C4烷基”是指具有1至4个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
在本发明中，术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如术语“C 2-C 4烯基”是指具有2至4个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基。
在本发明中，术语“炔基”是指含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基等。
在本发明中，术语“环烷基”表示饱和的环状烃基部分，例如术语“C 3-C 7环烷基”是指在环上具有3至7个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基等。
在本发明中，术语“环烯基”表示包含至少一个双键的环状烃基部分，例如术语“C 3-C 7环烯基”是指在环上具有3至7个碳原子的环状烷基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基等。
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地，可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例一：化合物合成及表征
化合物A4合成
Figure PCTCN2022120315-appb-000022
1.化合物5-炔-1-己醇(9g,91mmol)和对甲苯磺酸吡啶盐(25.1g,100mmol)溶解于100mL DCM中，加入四氢吡喃(12.5mL,126mmol)，室温搅拌过夜。TLC监测反应完全。除去大部分DCM，约剩余30mL，加入约100mL乙醚搅拌0.5h，滤除固体，固体加乙醚洗一次，浓缩滤液，过柱，PE/EA(体积比)＝50/1,得产物B1油状物18g，收率>100％.
2.化合物5-溴-1-戊醇(15.1g,91mmol)和对甲苯磺酸吡啶盐(25.1g,100mmol)溶解于100mL DCM中，加入四氢吡喃(12.5mL,126mmol)，室温搅拌过夜。TLC监测反应完全。除去大部分DCM，约剩余30mL，加入约100mL乙醚搅拌0.5h，滤除固体，固体加乙醚洗一次，浓缩滤液，过柱，PE/EA(体积比)＝50/1,得化合物B2，18g，收率79％。
3.化合物B2(5.4g,30mmol)溶于40mL无水THF中，冷却至-40℃，滴加正丁基锂(19mL,30.4mmol)(约0.5h加完)，再加入10mL HMPA，此温度搅拌1h后，加入化合物B2(7.78g,31mmol)的10mL THF溶液。此温度1h后，缓慢升至室温搅拌过夜。加入饱和氯化铵溶液猝灭反应，分层，水相再用乙酸乙酯萃取1次，合并有机相，加水和饱和食盐水洗涤。干燥浓缩过柱，PE/EA(体积比)＝20/1→10/1→5/1，得产物B3，8.5g，收率80％。
4.化合物B3(3g,8.5mmol)溶解于100mL甲醇和10mL中，加入对甲苯磺酸(300mg)，室温搅拌过夜。TLC监测反应完全。浓缩除去大部分的甲醇，加水稀释，用乙醚萃取2次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩过柱，PE/EA(体积比)＝2/1→1/1→1/2，得产物B4，1.1g，收率70％。
5.化合物B4(1.1g,5.9mmol)和四溴化碳(5.95g,17.9mmol)溶于30mL无水DCM中，冷却至0℃，滴加三苯基膦(4.7g,17.9mmol)的10mLDCM溶液，室温搅拌1h后，反应完全。浓缩至约15mL，加入50mL乙醚搅拌0.5h，滤除固体，滤液浓缩，过柱PE/EA＝30/1，得溴代物B5,1.84g，收率100％。
6.化合物B5(1.84g,5.9mmol)和异丁酸乙酯(2.73g,23.6mmol)溶于50mL无水THF中，冷却至0℃，滴加LDA(15.7mL,23.6mmol),(约0.5h加完)，保持此温度1h后，升至室温搅拌过夜。TLC监测反应完全。加饱和氯化铵溶液猝灭反应，分层，水相加EA萃取2次，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝50/1→20/1，得产物B6，1.8g，收率80％。
7.一个大气压H 2下，醋酸镍(749mg,3mmol)悬浮于20mL无水乙醇，快速加入硼氢化钠(114mg,3mmol)，氢气再置换2次，溶液变黑。室温搅拌15分钟后，加入乙二胺(0.45mL,6mmol)后加入化合物B6(1.8g,4.7mmol)的10mL无水乙醇溶液。室温搅拌2h后，TLC监测反应完全。加入50mL乙醚稀释，垫硅藻土过滤，滤液浓缩过柱，过柱PE/EA(体积比)＝50/1，得产物B7，1.7g，收率95％。
8.化合物B7(1.7g,4.45mmol)溶于50ml乙醇，加入KOH(2g,35mmol)的10mL水溶液，加热回流6h，TLC监测反应完全。冷却后旋转蒸发除去大部分乙醇，加水(40ml)稀释，加乙醚萃取2次除杂质。水层加2N HCl调至酸性，加DCM萃取4次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩。过柱DCM/MeOH(体积比)＝100/1，得A4 1.1g。
A4  1H NMR(600MHz,DMSO)δ5.31-5.32(m,2H),1.96-1.98(m,4H),1.40-1.44(m,4H),1.22-1.30(m,4H),1.18-1.22(m,6H),1.06(s,12H).
替换不同底物，采用与A4相类似的合成路线，得到下列化合物
A2  1H NMR(300MHz,CD3Cl)δ5.31-5.32(m,2H),1.96-1.98(m,4H),1.40-1.44(m,4H),1.18-1.22(m,8H),1.06(s,12H)
A6  1H NMR(300MHz,CD3Cl)δ5.30-5.32(m,2H),1.96-1.98(m,4H),1.40-1.45(m,4H),1.18-1.22(m,12H),1.06(s,12H)
A8  1H NMR(400MHz,CDCl3)δ5.40–5.29(m,2H),2.05–1.93(m,4H),1.57–1.48(m,4H),1.39–1.22(m,14H),1.19(s,6H),1.18(s,6H).
A10  1H NMR(300MHz,CD3Cl)δ5.30-5.32(m,2H),1.98-2.02(m,4H),1.48-1.53(m,4H),1.18-1.22(m,16H),1.06(s,12H)
化合物A3的合成
Figure PCTCN2022120315-appb-000023
1.氮气保护下，将350mg四氢铝锂(9.1mmol)溶于10ml二乙二醇二甲醚，将410mg B2(1.1mmol)溶于2ml二乙二醇二甲醚，140℃反应18小时，TLC监测反应完全，加30ml乙醚稀释，冰水浴冷却条件下，分批次加入十水硫酸钠至不冒泡为止，硅藻土过滤除去固体，无水乙醚洗涤，无水硫酸钠干燥，浓缩，PE：EA＝20：1过柱，得产物B8 250mg，无色液体，产率62％。
2.化合物B8(250mg，0.71mmol)溶解于10mL甲醇和11mL中，加入对甲苯磺酸(25mg)，室温搅拌过夜。TLC监测反应完全。浓缩除去大部分的甲醇，加水稀释，用乙醚萃取2次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩过柱，PE/EA(体积比)＝4/1，得产物B9，100g，收率75％。
3.化合物B9(100mg，0.53mmol)和四溴化碳(360mg，1.1mmol)溶于10mL无水DCM中，冷却至0℃，滴加三苯基膦(256g，0.98mmol)的2mLDCM溶液，室温搅拌1h后，反应完全。浓缩过柱，PE/EA(体积比)＝20/1，得溴代物B10，142mg，收率87％。
4.化合物B10(142mg，0.46mmol)和异丁酸乙酯(320mg，2.76mmol)溶于10mL无水THF中，冷却至0℃，滴加LDA(1.84mL，2.76mmol)，(约0.5h加完)，保持此温度1h后，升至室温搅拌过夜。TLC监测反应完全。加饱和氯化铵溶液猝灭反应，分层，水相加EA萃取2次，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝50/1，得产物B11，140mg，收率80％.
5.化合物B11(107mg，0.28mmol)溶于10ml乙醇，加入KOH(200mg，3.5mmol)的2mL水溶液，加热回流6h，TLC监测反应完全。冷却后旋转蒸发除去大部分乙醇，加水(10ml)稀释，加乙醚萃取2次除杂质。水层加2N HCl调至酸性，加DCM萃取4次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩。过柱DCM/MeOH(体积比)＝100/1，得化合物A3 70mg。
A3  1H NMR(600MHz，DMSO)δ5.35-5.36(m,2H),1.92-1.94(m,4H),1.40-1.43(m,4H),1.27-1.29(m,4H),1.17-1.19(m,6H),1.18ppm(s,12H).
替换不同底物，采用与A3相类似的合成路线，得到下列化合物
A1  1H NMR(400MHz,CDCl3)δ5.37–5.23(m,2H),2.07–1.90(m,4H),1.60–1.44(m,4H),1.34–1.21(m,8H),1.16(s,12H).
A5  1H NMR(400MHz,CDCl3)δ5.41–5.30(m,2H),2.09–1.87(m,4H),1.60–1.46(m,4H),1.41–1.32(m,4H),1.31–1.23(m,8H),1.22–1.07(s,12H).
A7  1H NMR(400MHz,CDCl3)δ5.40–5.28(m,2H),2.06–1.88(m,4H),1.57–1.48(m,4H),1.40–1.20(m,14H),1.18(s,12H).
A9  1H NMR(400MHz,CDCl3)δ5.33–5.24(m,2H),2.00–1.92(m,4H),1.54–1.47(m,4H),1.31–1.17(m,28H).
化合物A11
Figure PCTCN2022120315-appb-000024
1.频哪醇联硼酸酯(483mg，1.9mmol)和四三苯基磷铂(70mg)置于25mL圆底烧瓶中，氩气置换3次后，滴加B6(660mg,1.74mmol)的10mL DMF溶液中，80℃反应过夜。加水稀释，乙醚萃取，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝10/1，得产物B12，1g，收率90％.
2.化合物B12(150mg,0.23mmol)，碘甲烷(0.1mL)和三苯基膦(10mg)溶于1mL二氧六环中，氩气置换3次后，加入醋酸钯(20mg),KOH(40mg)的0.2mL水溶液，90℃反应12h，加水和乙酸乙酯稀释，乙酸乙酯萃取3次，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA＝50/1，得产物B13，30mg，收率31％.
3.化合物B13(30mg，0.07mmol)溶于5ml乙醇，加入KOH(50mg,0.89mmol)的1mL水溶液，加热回流6h，TLC监测反应完全。冷却后旋转蒸发除去大部分乙醇，加水(4ml)稀释，加乙醚萃取2次除杂质。水层加2N HCl调至酸性，加DCM萃取4次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩。过柱DCM/MeOH(体积比)＝100/1，得A11 15mg.
A11  1H NMR(300MHz,CDCl 3)δ1.94-1.96(m,4H),1.58(s,6H),1.48-1.50(m,4H),1.25-1.33(m,12H),1.13ppm(s,12H)
化合物A12合成
Figure PCTCN2022120315-appb-000025
1.氮气保护下，二乙基锌试剂(1mL,1mmol)在1mL DCM，冷却至-40℃，5min后，滴加二碘甲烷(0.54g，2mmol)的0.5mL DCM溶液，-40℃反应1h后，加入三氯乙酸(16mg，0.1mmol)和DME(45mg，0.5mmol),加完升至-15℃反应1h，加入B7(193mg，0.5mmol)的0.5mL DCM溶液，加完，室温搅拌过夜。加饱和氯化铵溶液淬灭反应，乙酸乙酯萃取3次，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝50/1，得产物B14，120mg，收率60％.
2.化合物B14(100mg，0.25mmol)溶于5ml乙醇，加入KOH(10mg,0.18mmol)的1mL水溶液，加热回流6h，TLC监测反应完全。冷却后旋转蒸发除去大部分乙醇，加水(4ml)稀释，加乙醚萃取2次除杂质。水层加2NHCl调至酸性，加DCM萃取4次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩。过柱DCM/MeOH(体积比)＝100/1，得A12 65mg.
A12  1H NMR(300MHz,CDCl 3)δ1.1.45-1.52(m,4H),1.21-1.43(m,16H),1.18(s,12H),0.65-0.70ppm(m,2H)
化合物A13合成
Figure PCTCN2022120315-appb-000026
1.化合物A3(30mg)溶于CH 2Cl 2(5.0mL),加入1,1’-羰基二咪唑(50mg,30mmol)室温搅拌2h.加入5.0mL CH 2Cl 2稀释,加入水(10mL每次,两次)洗涤。无水硫酸镁干燥后直接进行下步反应。
2.氩气保护下，上述咪唑中间体溶于干燥的THF(8.5mL),滴加辅酶A三锂盐(20mg,0.026mmol)的NaHCO 3(0.1M,3mL)溶液。反应液室温搅拌24h。反应液加乙酸乙酯萃取(2×3mL).水层加1M HCl调至pH 2。水层(～1mL)直接过柱(SPE,Agilent HF Bond Elur C18柱,size:5gm/20mL,USA)，洗脱液的浓度依次为0％,5％,10％,20％,30％,40％,50％,和100％MeCN(10mL每次)。得到A13，结构用 1H NMR spectroscopy LR-ESI-MS确证。
化合物A13:Solvent systems on Zorbax-SB C18柱,4.6*50mm,3.5μ:Gradient,A:10mM NH 4COOH in H 2O,B:CH 3OH,0min:50％A和50％B；0-30min:A 50％→0％,B 50％→100％,0.5mL/min.HPLC分析:tr＝14.777min和16.074min；白色固体(13mg,42％)； 1H NMR(400MHz,D 2O)δ8.65(s,1H),8.58(s,1H),8.30(s,1H),6.01(d,J＝5.4Hz,1H),5.45-5.42(m,2H),4.75-4.74(m,2H),4.48(bs,1H),4.28(bs,2H),3.98(s,1H),3.82-3.80(m,1H),3.56-3.52(m,1H),3.40-3.38(m,2H),3.20-3.18(m,2H),2.25-2.22(m,2H),2.33-2.30(m,2H),1.78-1.74(m,4H),1.42-1.35(m,4H),1.29-1.20(m,10H),1.06(s,12H),0.80(s,3H),0.65(s,3H)ppm；LR-ESI-MS m/z calcd for C 40H 68N 7O 19P 3S[M–H] –:1074.3,found 1074.3
化合物A14合成
Figure PCTCN2022120315-appb-000027
以A4为底物，参照化合物A13合成方法，得到A14： 1H NMR(400MHz,D 2O)δ8.65(s,1H),8.57(s,1H),8.30(s,1H),6.02(d,J＝5.4Hz,1H),5.47-5.42(m,2H),4.75-4.73(m,2H),4.49(bs,1H),4.27(bs,2H),3.98(s,1H),3.82-3.81(m,1H),3.56-3.52(m,1H),3.40-3.38(m,2H),3.20-3.18(m,2H),2.25-2.20(m,2H),2.33-2.29(m,2H),1.78-1.75(m,4H),1.42-1.35(m,4H),1.29-1.19(m,10H),1.06(s,12H),0.80(s,3H),0.65(s,3H)ppm；LR-ESI-MS m/z calcd for C 40H 68N 7O 19P 3S[M–H] –:1074.3,found 1074.3
化合物A15合成
Figure PCTCN2022120315-appb-000028
Figure PCTCN2022120315-appb-000029
1.化合物A3(326mg,1mmol)和(2S,3R,4S,5S,6S)-2-溴-6-(甲氧基羰基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(476mg,1.20mmol)溶解在10ml甲苯，冷却至0℃，加入氧化银(925mg,4mmol)和吡啶(0.35ml,4mmol),室温搅拌过夜。垫硅藻土过滤，甲苯洗涤，浓缩后，过柱，二氯甲烷/甲基叔丁基醚(体积比)＝10/1，得B15 350mg.
2.B15(350mg,0.54mmol)溶解于5ml甲醇中，冷却至0℃，加入二异丙基乙基胺(0.3ml),室温搅拌2天，浓缩后过柱，石油醚/乙酸乙酯/异丙醇(体积比)＝50/50/6，得到化合物B16 100mg.
3.B16(60mg,0.17mmol)在异丙醇(0.5ml)，加入PH＝7磷酸的缓冲溶液(5ml),加入CAL-B(100mg),室温搅拌3小时，除去少量异丙醇，过滤水洗，乙酸乙酯萃取2次，合并有机相，饱和食盐水洗涤后，干燥浓缩，过反相柱，甲醇/水(体积比)＝90/10，得到A15，15mg.
化合物A15  1H NMR(400MHz,CD3OD)δ5.46(d,J＝7.9Hz,1H),5.40–5.35(m,2H),3.80(d,J＝9.5Hz,1H),3.57–3.34(m,3H),2.01–1.94(m,4H),1.60–1.47(m,4H),1.39–1.23(m,10H),1.22–1.17(m,6H),1.17–1.11(m,6H)ppm.LR-ESI-MS m/z calcd for C 25H 42O 10[M–H] –:501.2,found 501.2
化合物A16合成
Figure PCTCN2022120315-appb-000030
1.NaH(672mg,16.8mmol)悬浮于10mL THF中，冷却至0℃，滴加甲基丙二酸二甲酯(2.35g，16mmol)(约0.5h加完)，升至室温搅拌0.5h后，再缓慢滴加化合物B10(730mg，2.3mmol)/10mLTHF溶液。加完，60℃搅拌7h，TLC监测反应完全。加饱和氯化铵溶液猝灭反应，分层，水相加EA萃取2次，合并有机相， 加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝50/1，得产物B17，510mg，收率50％.
2.化合物B17(300mg，0.68mmol)溶于5mL DMSO，加入LiCl((286mg，6.8mmol),H 2O(0.12mL)，微波加热180℃反应5分钟，TLC监测反应完全。冷却后加水稀释，水相加EA萃取4次，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝50/1，得产物B18，166mg，收率75％。
3.化合物B17(140mg，0.43mmol)溶于5mL无水THF中，冷却至-78℃，滴加LDA(1.84mL，2.76mmol)，HMPA(0.4mL)，保持此温度1h后，滴加CD 3I(0.16mL,2.58mmol),升至室温搅拌过夜。TLC监测反应完全。加饱和氯化铵溶液猝灭反应，分层，水相加EA萃取2次，合并有机相，加水，饱和食盐水洗涤，干燥浓缩。过柱PE/EA(体积比)＝50/1，得产物B19，77mg，收率49％
4.化合物B19(77mg，0.21mmol)溶于乙醇(2mL)，加入NaOH(120mg，3mmol)的2mL水溶液，加热回流6h，TLC监测反应完全。冷却后旋转蒸发除去大部分乙醇，加水(10ml)稀释，加乙醚萃取2次除杂质。水层加2N HCl调至酸性，加DCM萃取4次，合并有机相，加水和饱和食盐水洗涤，干燥浓缩。过柱DCM/MeOH(体积比)＝50/1，得化合物A16 50mg。
A16  1H NMR(400MHz，CD 3Cl)δ5.33-5.34(m,2H),1.96-1.99(m,4H),1.51-1.55(m,4H),1.35-1.42(m,4H),1.22-1.28(m,6H),1.18(s,3H),1.17ppm(s,3H).
以化合物A16为原料，采用与化合物A15相类似的合成路线，得到下列化合物A17。
Figure PCTCN2022120315-appb-000031
化合物A17  1H NMR(400MHz,CD 3OD)δ5.48(d,J＝7.9Hz,1H),5.37–5.41(m,2H),3.82(d,J＝9.4Hz,1H),3.58–3.55(t,1H),3.48–3.44(t,1H),3.42–3.38(m,1H),2.01–1.94(m,4H),1.60–1.44(m,4H),1.39–1.21(m,10H),1.19(s,3H),1.15(s,3H)ppm.LR-ESI-MS m/z calcd for C 25H 36D 6O 10[M–H] –:507.2,found 507.2
实施例二：生物学体外活性评价
(1)化合物抑制ACLY柠檬酸裂解酶的活性
ACLY催化柠檬酸裂解过程需要消耗一分子ATP来活化柠檬酸。基于该反应原理，发明人利用ADP-Glo检测试剂盒，检测ATP转化为ADP的量来反应 ACLY的催化活性。经过测活体系的建立、反应条件的优化后，发明人对获得的新型ACLY小分子抑制剂进行ACLY的抑制活性评价。
测活方案：人源ACLY蛋白购北京义翘神州科技有限公司(货号：11769-H07B)，ADP-Glo检测试剂盒购自Promega(货号：V9102)。反应最终体系见表1，反应总体积5μL，由三部分混合而成：1μL 2％的DMSO，底物混合液2μL，2μL酶(终浓度为25nM)。再加入1μL不同浓度的化合物进行孵育。反应条件：30min，37℃。再使用ADP-Glo Kit中的ADP Reagent 2.5μL，混匀后反应2h，加入ADP Detection 5μL，离心混匀后，用Envision多功能读板仪读取全波长数值。
表1.酶促反应体系
Figure PCTCN2022120315-appb-000032
试验结果：首先计算酶在30min反应时间内荧光强度的累积量RFU/min，以此代表酶的初速度，然后计算添加化合物后酶的速度(vsample)与不添加化合物的酶速度(vDMSO)的比值，为样品各浓度组的活性百分数(Activity rate％)，公式如下：％Activity＝(V(sample))/(v(DMSO))×100％。以浓度的对数值对活性百分数作图，然后采用非线性回归算出拟和曲线，利用软件GraphPad Prism 8.0公式log(inhibitor)vs.response--Variable slope拟合曲线，并计算得到IC 50值，结果如下表：
表2.部分化合物对ACLY酶活抑制的IC 50值(mean±SD)
化合物名称 IC 50(μM)
A1 42.3±6.5
A2 104.5±7.1
A3 85.4±9.8
A4 53.9±13.8
A5 16.7±1.8
A6 25.5±6.8
A7 12.0±2.2
A8 21.3±9.7
A9 25.8±9.2
A10 9.6±5.1
A11 40.19±2.9
A12 56.90±4.7
A13 5.31±1.2
A14 5.63±1.2
A15 36.7±0.8
ETC-1002-CoA 10.56±2.9
Figure PCTCN2022120315-appb-000033
以上为阳性对照ETC-1002-CoA的结构式。
(2)化合物抑制原代肝细胞脂质从头合成活性评价
ACLY是负责将线粒体来源的柠檬酸裂解生成乙酰辅酶A，后者作为细胞脂质合成的关键原料，抑制ACLY的活性可以显著降低脂质(甘油三酯和胆固醇)的从头合成。为了进一步评价受试物抑制ACLY的引起的功能变化，发明人分离了小鼠原代肝细胞并以[1,2- 14C]-乙酸钠为底物示踪进行脂质从头合成能力评价，同时以化合物ETC-1002为阳性对照。
试验方案：
肝原代细胞分离及贴壁：无钙灌流液灌洗小鼠肝脏后，利用胶原酶消化小鼠肝脏，并通过密度梯度离心获得小鼠原代肝细胞，以3x 10 5/ml密度接于6孔板中(接板前先铺0.2％明胶)，接板后细胞贴壁6h，换成无血清LG-DMEM(含2x双抗)饥饿过夜。
同位素示踪：第二天换为含有10nM胰岛素的无血清LG-DMEM，以及对应浓度的化合物(1950μL，每组4复孔)；每孔加入0.1μCi的[1,2- 14C]-乙酸盐无血清培养基，置于培养箱孵育4小时。
脂质皂化：每孔加入1.6mL冰PBS洗3次，甩干板子每孔加入600μL 0.5M KOH裂解，裂解时间为1h。吸取480μL至预先加入400μL 20％KOH(甲醇作为溶剂)玻璃试管中，震荡混匀后置于95度水浴皂化3h；剩余裂解液用于蛋白质浓度测定。每管加入400μL石油醚，移液器吹吸5-6次后2500rpm离心5min，取350μL上层清液至EP管，再加入400μL石油醚重复抽提2次(一共为3次)。将上层清液完全转移后，每管加入200μL水和400μL 5N硫酸酸化，震荡混匀。每管加入400μL石油醚，移液器吹吸5-6次后2500rpm离心5min，取350μL上层清液至EP管，再加入400μL石油醚重复抽提2次(一共为3次)。放置于通风橱中，过夜挥干石油醚。
同位素参入定量：每管加入1700μL闪烁液，读数。
数据处理及分析：首先计算未处理组小鼠原代肝细胞Control组在4小时内的游离脂肪酸和胆固醇的同位素参入量(R control,单位：CCPM/mg protein)，以此代表基础合成量。然后计算样品各浓度组的脂质合成抑制百分数。
部分化合物(12.5μM)处理原代肝细胞后，对甘油三酯和胆固醇从头合成的抑制率如下表所示：
表3.部分化合物对原代肝细胞的脂质合成抑制率(mean±SD)
化合物名称 脂质合成抑制率(％)
Control 0±19.1
A2 80.9±5.9
A3 71.2±4.3
A4 78.2±4.3
A5 56.6±7.6
A6 68.7±20.9
A8 21.6±1.3
A9 30.9±4.2
A10 21.1±11.7
A12 38.7±11.4
A15* 58.2±7.4
ETC-1002 46.3±15.3
*表示化合物的使用浓度为8μM
Figure PCTCN2022120315-appb-000034
以上为阳性对照ETC-1002的结构式。
(3)化合物A3抑制脂合成的活性对ACLY的依赖性
试验方案：为了进一步考察系列化合物抑制脂质从头合成作用对ACLY的依赖性，发明人选用了ACLY敲除的原代肝细胞进行进一步的脂质从头合成评价，同时以化合物ETC-1002为阳性对照。具体是试验方案如前，采用0.1μCi/孔[ 14C]-柠檬酸进行示踪。
试验结果：在WT小鼠原代肝细胞中，ACLY小分子抑制剂ETC-1002及化合物A3均可以显著抑制细胞以[ 14C]-柠檬酸为底物的甘油三脂(图1中A)和胆固醇(图1中B)的从头合成。但是，在ACLY敲除的肝细胞中，上述两个化合物抑制甘油三酯和胆固醇从头合成的作用效果显著减弱甚至未体现出抑制作用(图1)。
实施例三：化合物A3和A4改善高胆固醇血症的药效
(1)化合物A3和A4对金黄地鼠高脂高胆固醇血症的改善作用
给药方案：金黄地鼠高脂血症模型是公认的研究高脂血症药物治疗(药效学评价)理想动物模型之一。为了初步考察候选化合物对肝脏脂质代谢平衡存在潜在的调节作用，利用高脂高胆固醇饮食诱导的金黄地鼠高脂血症模型进行初步的药效学评价。具体方案为金黄地鼠56只，雄性，高脂高胆固醇饲料(Research diet，货号C11953)造模两周，预留8只为空白对照组。随后进行分组给药(7组，n＝8)，即模型对照组、阳性对照ETC-1002 30mg/kg组、化合物A3 10mg/kg和30mg/kg组、化合物A4 10mg/kg和30mg/kg组、空白对照组。各组化合物用生理盐水配置(0.9％NaCl)，给药频次为1次/天，给药周期为7天。
指标检测：给药期间密切监测金黄地鼠体重及摄食变化。各组化合物给药7天，分别眼眶取血(饥饿过夜，约16小时)，离心取血清，低温冷冻保存，检测血清中总胆固醇、低密度脂蛋白胆固醇含量。相关指标的相对两计算方法为：相对量(100％)＝给药组的含量/模型对照组的含量*100％。
试验结果：和对照组相比，化合物给药1周后：1)化合物A3两个剂量组均可以显著降低金黄地鼠血清总胆固醇和低密度脂蛋白胆固醇，高剂量组降低幅度与阳性对照ETC-1002 30mg/kg剂量组效果相当；2)化合物A4 10mg/kg给药组的血清总胆固醇和低密度脂蛋白胆固醇无显著改变，30mg/kg给药组可以显著降低血清总胆固醇和低密度脂蛋白胆固醇含量(图2)。此外，研究发现化合物A4在给药过程中出现体重显著降低，摄食明显减少，并伴随活动减慢等不耐受现象。综合上述结果，表明认为化合物A3改善高胆固醇血症的有效性和安全性优于化合物A4，也进一步提示双键为反式构型对高胆固醇血症治疗效果很重要。
(2)化合物A3对ApoE -/-小鼠动脉粥样硬化的改善作用
给药方案：高胆固醇血症是动脉粥样硬化发生的重要诱因。在看到化合物A3对高脂高胆固醇血症具有显著改善的前提下，发明人进一步发现化合物A3可以显著减缓ApoE -/-小鼠动脉粥样硬化的发生。具体方案为ApoE -/-小鼠60只，雄性，平均分为6组(n＝10)，其中5组高胆固醇饲料(Research diet，货号D12079B)造模喂养，预留1组为空白对照组，同时进行长期给药治疗，即模型对照组、阳性对照ETC-1002 30mg/kg组、化合物A3 15mg/kg和30mg/kg及60mg/kg组、空白对照组。各组化合物用生理盐水配置(0.9％NaCl)，给药频次为1次/天，给药周期为24周。
指标检测：给药期间密切监测ApoE -/-小鼠体重及摄食变化。各组化合物给药24周，剥离小鼠主动脉血管，进行主动脉斑块苏丹IV染色，并用Image-Pro Plus软件统计斑块面积。
试验结果：图3结果表明，和对照组相比，化合物给药24周后，化合物A3三个剂量组均可显著性减少ApoE -/-小鼠主动脉主动脉瓣斑块面积(右图为左图的统计图)，说明化合物A3具有显著改善高胆固醇血症诱导的动脉粥样硬化的发生的作用。
实施例四：化合物A3改善饮食诱导的非酒精性脂肪肝炎药效评价
非酒精性脂肪肝炎(NASH)的发病机制研究众多，概括来讲“脂质沉积是基础，炎症是核心，纤维化是病情恶化或者难以控制的关键因素”。一方面，抑制肝细胞ACLY的活性可以有效减少肝脏脂质从头合成，减少驱动NASH发生的重要因素；另一方面，ACLY介导组蛋白表观遗传修饰(乙酰化、琥珀酰化等)，由此引发免疫细胞代谢重编程、对炎性刺激的响应以及ROS的产生等；此外，抑制肝星状细胞的脂质从头合成，可以有效减少研究肝星状细胞(HSC)的活化。基于NASH发生的三大特征(脂质累积、炎症、纤维化)的潜在干预，发明人进一步评价了化合物A3对NASH改善的可行性。
(1)化合物A3对高脂高糖高胆固醇饮食诱导的ob/ob小鼠NASH的改善作用
给药方案：7-8周ob/ob小鼠16只，雄性，平均分为2组(n＝8)，高脂高糖高胆固醇饲料(Research diet，货号D09100310)造模喂养8周，另设一组同窝野生型小鼠为空白对照组。造模8周后开始进行长期给药治疗，各组分别为模型对照组、化合物A3 30mg/kg组、空白对照组。各组化合物用生理盐水配置(0.9％NaCl)，给药频次为1次/天，给药周期为10周。
指标检测：给药期间密切监测ob/ob小鼠和空白对照小鼠的体重及摄食变化。各组化合物给药10周，摘取肝脏，进行NASH相应指标的检测(HE染色、天狼星红染色、炎症信号的免疫组化等)。
试验结果：ob/ob小鼠由于过量的脂质累积而出现发白及颗粒感，化合物A3给药后可以显著逆转上述现象(图4中A)；进一步地，发明人将肝脏进行病理分析：和模型对照组相比，H&E染色研究发现化合物A3给药组肝脏脂肪变性和气球样变显著减少(脂肪肝，图4中A)；巨噬细胞CD68染色研究发现化合物A3给药组肝脏炎症细胞浸润显著变少(炎症，图4中A，4中B)；天狼猩红染色研究发现化合物A3给药组肝脏胶原沉积程度显著减少(纤维化，图4中A，4中C)。以上结果表明化合物A3具有显著改善饮食诱导的ob/ob小鼠NASH的药理学活性。
(2)化合物A3对高脂高糖高胆固醇饮食诱导的食蟹猴NASH的改善作用
进一步地，发明人在非人灵长类动物模型进一步评价化合物A3长期给药可对食蟹猴的非酒精性脂肪肝炎的治疗作用。
给药方案：18只非酒精性脂肪肝炎食蟹猴，雄性，分为2组(n＝8-10)，一组设为模型对照组，一组设为给药组。高脂高糖高胆固醇高饮食喂养14周的同时进行给药治疗(20mg/kg)，给药频次为1次/天，给药周期为14周。
指标检测：给药期间密切监测食蟹猴的体重及摄食变化。化合物给药14周，肝脏穿刺进行NASH相应指标的病理分析检测。
试验结果：肝脏穿刺结果显示，化合物A3长期给药可以显著减少食蟹猴的肝脏脂质累积，并减少炎症和纤维化的发生，非酒精性脂肪性肝病活动性(NAS)评分在给药之后显著降低(图5)。以上结果表明化合物A3具有显著改善食蟹猴非酒精性脂肪肝炎的药理学活性。
实施例五：化合物A3口服药代动物参数考察
前期的研究发现，化合物A3改善动脉粥样硬化的效果显著优于ETC-1002，本部分研究将比较两类化合物的口服药物暴露量及相关药代动力学参数。
给药方案：6只正常ICR小鼠，雄性，分为2组(n＝3)，一组口服给予阳性对照ETC-1002，一组口服给予受试物化合物A3，给药剂量均为30mg/kg；给药前后不同时间点眼眶取血，检测血浆药物浓度。
试验结果：通过检测不同时间的血浆药物浓度，并计算两个化合物的药代动力学参数(表4)。考察发现，受试物化合物A3的血浆暴露量显著高于阳性对照药物ETC-1002(C max:13.4μg/mL vs 3.81μg/mL；AUC 0-t：63.7h*μg/mL vs 14.4h*μg/mL，前者为化合物A3)。
表4.化合物A3和对照物ETC-1002的口服药代动力学参数
Figure PCTCN2022120315-appb-000035
上述试验结果表明，本发明化合物具有抑制ACLY的活性。进一步的体内外药理学活性评价发现，代表性化合物A3在原代肝细胞中可以抑制脂质的从头合成，改善金黄地鼠和ApoE -/-小鼠高脂高胆固醇血症，显著改善高脂高糖高胆固醇饮食诱导的ob/ob小鼠和食蟹猴的NASH症状。研究结果还提示，双键为反式构型的化合物的体内活性要优于双键为顺式构型的化合物；而且，同等口服剂量下化合物A3比Bempedoic acid的血浆暴露量高出4倍多，提示化合物A3具有更好的治疗效果。
综上，本申请的系列化合物具有良好的ACLY抑制活性，并在多种代谢性疾病药效模型上显示出良好的治疗效果，可进一步开发成为高胆固醇血症、非酒精性脂肪肝炎等代谢性疾病的治疗药物。

Claims (12)

  1. 一种通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐的用途，用于制备治疗代谢性疾病的药物；或者用于制备治疗动脉粥样硬化的药物，
    Figure PCTCN2022120315-appb-100001
    其中，
    Figure PCTCN2022120315-appb-100002
    表示双键或单键；
    m、n各自独立地为1、2、3、4、5或6；
    R 1、R 2、R 3、R 4、R 5、R 6各自独立地为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、苯基或苄基；
    或者，R 1和R 2与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
    或者，R 5和R 6与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
    或者，R 3和R 4与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
    Y 1和Y 2各自独立地选自：-OH、-COOH、-COCoA、-COOR 7；其中，R 7为甲基、乙基或
    Figure PCTCN2022120315-appb-100003
    CoA结构如下所示：
    Figure PCTCN2022120315-appb-100004
  2. 如权利要求1所述的用途，其特征在于，所述化合物具有通式II所示的结构：
    Figure PCTCN2022120315-appb-100005
  3. 如权利要求1所述的用途，其特征在于，所述化合物具有通式III所示的结构：
    Figure PCTCN2022120315-appb-100006
  4. 如权利要求1所述的用途，其特征在于，所述化合物具有通式IV所示的结构
    Figure PCTCN2022120315-appb-100007
    式中，p为0、1、2或3。
  5. 如权利要求1-4任一项所述的用途，其特征在于，所述化合物为氘代化合物。
  6. 如权利要求1-5任一项所述的用途，其特征在于，所述化合物选自下组：
    Figure PCTCN2022120315-appb-100008
    Figure PCTCN2022120315-appb-100009
  7. 如权利要求1所述的用途，其特征在于，所述代谢性疾病选自：高胆固醇血症、非酒精性脂肪肝炎(NASH)、肝纤维化。
  8. 一种通式(I)所示的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，
    Figure PCTCN2022120315-appb-100010
    其中，
    Figure PCTCN2022120315-appb-100011
    表示双键或单键；
    m、n各自独立地为1、2、3、4、5或6；
    R 1、R 2、R 3、R 4、R 5、R 6各自独立地为H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C3-C7环烯基、苯基或苄基；
    或者，R 1和R 2与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
    或者，R 5和R 6与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
    或者，R 3和R 4与其相邻的碳原子一起形成C3-C7环烷基或C3-C7环烯基；
    Y 1和Y 2各自独立地选自：-OH、-COOH、-COCoA、-COOR 7；其中，R 7为甲基、乙基或
    Figure PCTCN2022120315-appb-100012
    CoA结构如下所示：
    Figure PCTCN2022120315-appb-100013
  9. 如权利要求8所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物具有通式II、III或IV所示的结构：
    Figure PCTCN2022120315-appb-100014
    式中，p为0、1、2或3。
  10. 如权利要求8或9所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物为氘代化合物。
  11. 如权利要求8-10任一项所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其特征在于，所述化合物选自下组：
    Figure PCTCN2022120315-appb-100015
    Figure PCTCN2022120315-appb-100016
  12. 一种药物组合物，包含权利要求8-11任一项所述的化合物，或其立体异构体、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐；和
    药学上可接受的盐。
PCT/CN2022/120315 2021-09-23 2022-09-21 长链类化合物及其用途 Ceased WO2023045985A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US18/694,947 US20250144127A1 (en) 2021-09-23 2022-09-21 Long-chain compound and use thereof
JP2024518781A JP7808892B2 (ja) 2021-09-23 2022-09-21 長鎖化合物およびその使用
EP22872030.6A EP4406537A4 (en) 2021-09-23 2022-09-21 LONG CHAIN COMPOUND AND ITS USAGE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111116447.1A CN115887435A (zh) 2021-09-23 2021-09-23 长链类化合物及其用途
CN202111116447.1 2021-09-23

Publications (1)

Publication Number Publication Date
WO2023045985A1 true WO2023045985A1 (zh) 2023-03-30

Family

ID=85720070

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/120315 Ceased WO2023045985A1 (zh) 2021-09-23 2022-09-21 长链类化合物及其用途

Country Status (5)

Country Link
US (1) US20250144127A1 (zh)
EP (1) EP4406537A4 (zh)
JP (1) JP7808892B2 (zh)
CN (1) CN115887435A (zh)
WO (1) WO2023045985A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894220A (zh) * 2021-09-23 2023-04-04 中国科学院上海药物研究所 一类作用于acly的长链类化合物、其制备方法及其用途
CN116746550A (zh) * 2023-08-08 2023-09-15 厦门大学附属翔安医院 一种构建小鼠非酒精性脂肪性肝炎模型的方法
WO2025223509A1 (zh) * 2024-04-25 2025-10-30 博骥源（上海）生物医药有限公司 一类作用于acly的双烯基长链类化合物及其制备方法和用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4634795A (en) * 1981-12-15 1987-01-06 Epis S.A. Long-chain α,ω-di-carboxylic acids and derivatives thereof and pharmaceutical compositions containing them
US4711896A (en) * 1984-06-22 1987-12-08 Epis S.A. α, ω-dicarboxylic acids and medicaments which contain these compounds
CN101677982A (zh) * 2007-02-26 2010-03-24 塞多麦克斯有限公司 治疗心血管病症的组合疗法、组合物和方法
CN107118098A (zh) 2016-02-25 2017-09-01 中国科学院上海药物研究所 一类脂肪酸类化合物、其制备方法及其用途
CN110054562A (zh) * 2018-03-23 2019-07-26 深圳市塔吉瑞生物医药有限公司 取代的十五烷二酸化合物及药物组合物及其用途
WO2021021563A1 (en) * 2019-07-26 2021-02-04 Espervita Therapeutics, Inc. Functionalized long-chain hydrocarbon mono- and di-carboxylic acids useful for the prevention or treatment of disease

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4436578A1 (de) * 1994-10-13 1996-04-18 Boehringer Mannheim Gmbh Neue alpha,alpha,alpha',alpha'-Tetrachlordicarbonsäuren, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4634795A (en) * 1981-12-15 1987-01-06 Epis S.A. Long-chain α,ω-di-carboxylic acids and derivatives thereof and pharmaceutical compositions containing them
US4711896A (en) * 1984-06-22 1987-12-08 Epis S.A. α, ω-dicarboxylic acids and medicaments which contain these compounds
CN101677982A (zh) * 2007-02-26 2010-03-24 塞多麦克斯有限公司 治疗心血管病症的组合疗法、组合物和方法
CN107118098A (zh) 2016-02-25 2017-09-01 中国科学院上海药物研究所 一类脂肪酸类化合物、其制备方法及其用途
CN110054562A (zh) * 2018-03-23 2019-07-26 深圳市塔吉瑞生物医药有限公司 取代的十五烷二酸化合物及药物组合物及其用途
WO2021021563A1 (en) * 2019-07-26 2021-02-04 Espervita Therapeutics, Inc. Functionalized long-chain hydrocarbon mono- and di-carboxylic acids useful for the prevention or treatment of disease

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY ANONYMOUS : "INDEX NAME NOT YET ASSIGNED", XP093053595, retrieved from STN *
JOSHUA P. SAMSOONDAR, AMY C. BURKE, BRIAN G. SUTHERLAND, DAWN E. TELFORD, CYNTHIA G. SAWYEZ, JANE Y. EDWARDS, STEPHEN L. PINKOSKY,: "Prevention of Diet-Induced Metabolic Dysregulation, Inflammation, and Atherosclerosis in Ldlr −/− Mice by Treatment With the ATP-Citrate Lyase Inhibitor Bempedoic AcidHighlights", TRANSLATIONAL SCIENCES, LIPPINCOTT, WILLIAMS & WILKINS, vol. 37, no. 4, 1 April 2017 (2017-04-01), pages 647 - 656, XP055413415, ISSN: 1079-5642, DOI: 10.1161/ATVBAHA.116.308963 *
PINKOSKY STEPHEN L., NEWTON ROGER S., DAY EMILY A., FORD REBECCA J., LHOTAK SARKA, AUSTIN RICHARD C., BIRCH CAROLYN M., SMITH BREN: "Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis", NATURE COMMUNICATIONS, vol. 7, no. 1, 28 November 2016 (2016-11-28), XP093053582, DOI: 10.1038/ncomms13457 *
SAMBROOK ET AL.: "Molecular Cloning: Laboratory Manual", 1989, COLD SPRING HARBOR LABORATORY PRESS
See also references of EP4406537A4
SONG GAO‐LEI, CAO LEI, ZHANG MEI, YANG YU‐ROU, MA JIE, XIE ZHI‐FU, LI JING‐YA, NAN FA‐JUN: "Discovery of Novel Long-Chain Alkenyl Diacid Derivatives as ACLY Inhibitors", CHINESE JOURNAL OF CHEMISTRY, ZHONGGUO KEXUEYUAN, CN, vol. 40, no. 22, 1 August 2022 (2022-08-01), CN , pages 2663 - 2670, XP093053592, ISSN: 1001-604X, DOI: 10.1002/cjoc.202200362 *
XIE ZHIFU, ZHANG MEI, SONG QIAN, CHENG LONG, ZHANG XINWEN, SONG GAOLEI, SUN XINYU, GU MIN, ZHOU CHENDONG, ZHANG YANGMING, ZHU KEXI: "Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia", ACTA PHARMACEUTICA SINICA B, vol. 13, no. 2, 1 February 2023 (2023-02-01), pages 739 - 753, XP093053588, ISSN: 2211-3835, DOI: 10.1016/j.apsb.2022.06.011 *
YANG, WEILI ET AL.,: "A distinct type of glycerol-3-phosphate acyltransferase with sn-2 preference and phosphatase activity producing 2-monoacylglycerol,", PNAS, vol. 107, no. 26, 29 June 2010 (2010-06-29), XP055581252, DOI: 10.1073/pnas.0914149107 *

Also Published As

Publication number Publication date
JP2024536860A (ja) 2024-10-08
CN115887435A (zh) 2023-04-04
EP4406537A1 (en) 2024-07-31
EP4406537A4 (en) 2025-12-03
US20250144127A1 (en) 2025-05-08
JP7808892B2 (ja) 2026-01-30

Similar Documents

Publication Publication Date Title
AU2021218228B2 (en) Oxysterols and methods of use thereof
AU2021218230B2 (en) Oxysterols and methods of use thereof
CN121568944A (zh) 用作shp2抑制剂的杂环化合物、包含其的药物组合物及其制备方法和用途
EP4406537A1 (en) Long-chain compound and use thereof
JP2022511469A (ja) 環状パンテテイン誘導体及びその使用
WO2022228544A1 (zh) 异喹啉酮类化合物及其用途
UA75660C2 (en) Triamide-substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein (mtp) and/or apolipoprotein b (apo b) secretion
US20190359646A1 (en) Oxysterols and methods of use thereof
JP2001511172A (ja) 特に神経興奮薬性アミノ酸に感受性をもつ中枢神経系受容体のエフェクターを構成する化合物、その製造およびその生物学的利用
JP7744689B2 (ja) 脂質代謝関連疾患の予防又は治療用化合物
JP2016512227A (ja) ピリジン−４−イル誘導体
JP2019523245A (ja) オーファン核内受容体Ｎｕｒ７７のリガンド及びその使用
BR112021016457A2 (pt) Composto, medicamento e método para tratar dor ou um distúrbio do sistema nervoso central em um paciente que precisa do mesmo
WO2019109415A1 (zh) 一种靶向降解hmgcr的化合物及其应用
KR20140113692A (ko) 전압-게이팅 나트륨 채널 조절제로서의 2-(피리딘-2-일)-1,7-디아자-스피로[4.4]노난-6-온 화합물
AU2022209835B2 (en) Functionalized long-chain carboxylic acids, and their use for treatment of disease
JP2025508025A (ja) Ｄｈｃｒ２４阻害化合物
CN101115709A (zh) 氨基羧酸衍生物及其医药用途
JP2004083465A (ja) Ｓｍアーゼインヒビターとしてのシホスタチンアナログ
JP2003335680A (ja) Ａｃａｔ−１阻害剤
FR3067028B1 (fr) Modulateurs de recepteurs nmda, compositions les comprenant et utilisation de ces composes dans le traitement de maladies impliquant le systeme nerveux central
TW202411231A (zh) 用作泛素-特異性蛋白酶抑制劑的取代嘌呤酮衍生物
WO2024213088A1 (zh) 嘧啶三并环衍生物的结晶及用途
TW202600128A (zh) 一種包括tdg抑制劑和免疫檢查點抑制劑的藥物組合及其用途
JPH0368844B2 (zh)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22872030

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 18694947

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2024518781

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2022872030

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022872030

Country of ref document: EP

Effective date: 20240423

WWP Wipo information: published in national office

Ref document number: 18694947

Country of ref document: US