WO2006069466A1 - Serie d’inhibiteurs de ptp1b triterpenoides et leur procede de preparation et utilisation - Google Patents

Serie d’inhibiteurs de ptp1b triterpenoides et leur procede de preparation et utilisation Download PDF

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Publication number
WO2006069466A1
WO2006069466A1 PCT/CN2004/001525 CN2004001525W WO2006069466A1 WO 2006069466 A1 WO2006069466 A1 WO 2006069466A1 CN 2004001525 W CN2004001525 W CN 2004001525W WO 2006069466 A1 WO2006069466 A1 WO 2006069466A1
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WIPO (PCT)
Prior art keywords
group
substituted
ptp1b
triterpenoid
insulin
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PCT/CN2004/001525
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English (en)
Chinese (zh)
Inventor
Lihong Hu
Jia Li
Di Hong
Liqiang Zhang
Qizhuang Ye
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
The National Center For Drug Screening
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Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences, The National Center For Drug Screening filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority to PCT/CN2004/001525 priority Critical patent/WO2006069466A1/fr
Priority to PCT/CN2005/000172 priority patent/WO2006069499A1/fr
Publication of WO2006069466A1 publication Critical patent/WO2006069466A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to a class of triterpenoids which exhibit high inhibitory activity against protein tyrosine phosphatase ⁇ ( ⁇ ⁇ ). These compounds are useful as PTP1B inhibitors and insulin sensitizers for the treatment of diabetes, obesity and its complications caused by insulin resistance.
  • the invention also relates to a process for the preparation of such compounds. ⁇ . technical background:
  • Diabetes mellitus is a group of clinical syndromes caused by the interaction of genetic and environmental factors, due to absolute or relative deficiency of insulin secretion and decreased sensitivity of target tissue cells to insulin, causing sugar, protein, fat, water, and electrolytes.
  • a series of metabolic disorders Clinically, hyperglycemia is the main common marker. Long-term illness can cause multiple system damage. Acute metabolic disorders such as ketoacidosis can occur when the condition is severe and stress. Serious complications such as coronary heart disease, iron deficiency or hemorrhagic cerebrovascular disease, blindness, and gangrene in the diabetic population were significantly higher than those in the non-diabetic population. Therefore, diabetes and its complications have become a worldwide public health problem that seriously threatens human health.
  • type I diabetes insulin-dependent diabetes mellitus
  • type II diabetes non-insulin-dependent diabetes mellitus
  • More than 90% of diabetes is type 2 diabetes.
  • the WHO expects that due to an aging population, obesity, unhealthy diet and a lack of exercise, the number of diabetic patients will increase from 135 million in 1995 to 300 million in 2025.
  • Type I diabetes patients have genetic susceptibility due to HLA-D gene on the short arm of chromosome 6 and abnormal response to environmental factors, especially viral infection or chemical toxic substances, directly or indirectly through autoimmune reactions, causing islets Beta cells are destroyed, resulting in insufficient insulin.
  • the clinical features are acute onset, more common symptoms such as polyphagia, polyuria, polydipsia, and weight loss. There is a tendency to develop ketoacidosis, and insulin therapy must be relied upon to maintain life.
  • Type 2 diabetes also has strong hereditary and environmental factors, and it is significantly heterogeneous.
  • the pathogenesis is diverse and complex, and there are large differences among patients. In general, it can be summarized as the relative deficiency of insulin secretion and insulin resistance.
  • a series of studies on people with type 2 diabetes, especially obese diabetics, have confirmed that insulin resistance is a key factor in the development and progression of U-type diabetes.
  • Based on the study of insulin signaling pathways in adipocytes and muscle cells, the development of insulin sensitizers to improve insulin resistance is the focus of new drug research for type II diabetes and one of its main directions. '
  • Type II diabetes is characterized by resistance to insulin action by insulin-sensitive tissues such as skeletal muscle, liver, and adipose tissue. Although the specific mechanism is still unclear, the attenuation or even blockade of insulin signaling in its conduction pathway must be a direct factor. Insulin binds to its receptor extracellular alpha subunit to activate the intrinsic tyrosine kinase activity of the receptor intracellular beta subunit, resulting in autophosphorylation of key tyrosine residues in the regulatory domain, thereby fully activating insulin receptor tyrosine The kinase activity of the insulin receptor, the insulin receptor tyrosine kinase, then transmits the signal by phosphorylating its substrate.
  • insulin-sensitive tissues such as skeletal muscle, liver, and adipose tissue.
  • PTPases protein tyrosine phosphatase
  • TTPases may act on multiple pathways in the pathway, such as dephosphorylation of autophosphorylation-activated insulin receptor (1R), thereby reducing receptor kinase activity; Or dephosphorylation of a protein tyrosine residue in a substrate such as insulin receptor substrate 1 (IRS-1), insulin receptor substrate 2 (IRS-2), She, etc., thereby negatively regulating insulin Acting on the receptor pathway.
  • An imbalance in enzyme activity between tyrosine kinases in specific PTPases and insulin pathways may be responsible for insulin resistance in type 2 diabetes. Therefore, it is becoming more and more important to treat type 2 diabetes by finding inhibitors of PTPases that selectively act on this pathway to inhibit its activity, and to enhance and prolong insulin signaling.
  • PTPases include a large family of transmembrane (receptor) and intracellular (non-receptor) enzymes involved in the regulation of a range of important life processes. Although a variety of PTPases are expressed in insulin-sensitive tissues, such as transmembrane CD45 and LAR-PTPase; intracellular SHPTP-1, SHPTP-2, PTP1B, PTP1C, etc., only a few PTPases may be in the insulin pathway. The receptor or receptor pathway affects normal insulin action. Current research focuses on LAR-PTPase, SHPTP-2 and PTP1B. '
  • PTP1B is the first PTPase to be purified and characterized biologically, with a total length of approximately 50 KD.
  • PTP1B derived from human placenta into Xenopus oocytes will reduce insulin-induced oocyte maturation and S6 peptide phosphorylation .
  • PTP1B was highly expressed in all insulin-sensitive tissues; after administration of PTP1B antibody by osmotic shock, DNA synthesis and PI3 kinase activity levels were significantly increased in mouse KRC-7 hepatocytes stimulated by insulin, IR autophosphorylation level, 1R The level of kinase activity and the level of IRS-1 tyrosine phosphorylation were also significantly elevated.
  • PTP1 B interacts directly with the active IR; it also shows the highest selective activity against IRS-1 in vitro; high expression of PTP1B in rat fibroblasts can significantly reduce ligand-induced IR Phosphorylation level: Adenovirus-mediated gene transfection, high expression of PTP1 B in insulin-targeted skeletal and liver model cells L6 muscle cells and Fao cells, significantly inhibiting insulin-induced IR and IRS-1 Tyrosine phosphorylation, and thus significantly inhibits the formation of IRS-1 and PI3 kinase P85 subunit complexes and phosphorylation of Akt, MAPK, and insulin-induced glycogen synthesis is also inhibited [Egawa. et al. J. Biol. Chem.
  • PTP1B knockout mice demonstrate that PTP1B is capable of negatively regulating the insulin signaling pathway and acting primarily on the insulin receptor. More important experimental evidence comes from PTP1 B knockout mice. Elchebly et al. reported that PTP1B knockout mice produced by homologous recombination have normal growth, fertility, and significant sensitivity to insulin, and this enhancement is associated with insulin receptors and insulin in the liver and skeletal muscle. Enhancement of phosphorylation levels in human substrate 1 [Elchebly M., et al. Science, 283, 1544-1548.] Surprisingly, PTP1B knockout mice also have food-induced weight gain and insulin resistance. Resistance.
  • the object of the present invention is to provide a class of triterpenoids which are useful as protein tyrosine phosphatase PTP1B inhibitors and insulin sensitizers for the treatment of various diabetes, obesity and complications thereof.
  • Another object of the present invention is to provide a method for synthesizing such compounds by using oleanolic acid or ursolic acid as a raw material. ⁇ .
  • the triterpenoid PTP1B inhibitor of the present invention has the following structure:
  • R 2 is hydrogen or methyl
  • R4 is a fluorenyl group, a substituted alkyl group, an unsaturated fluorenyl group, an aryl group, a substituted aryl group;
  • R 5 is an indenyl group, a substituted indenyl group, an unsaturated indenyl group, an aromatic group, or a substituted aromatic group.
  • a preferred compound of the invention is a triterpenoid PTP1B inhibitor of formula I and a physiologically acceptable salt thereof, wherein Ri is hydrogen;
  • R 2 is a methyl group
  • R 3 is a hydroxyl group, an amino group, a halogen, a fluorenyl group
  • ⁇ - ⁇ . ⁇ group CONH(CH 2 )nCH(R4) , CONH(CH 2 )nCONH(CH 2 )mCH(R 5 ), wherein n is 1 -20, m is 1-20;
  • R 5 is an indenyl group, an aromatic group, or a substituted aromatic group.
  • Another preferred compound of the invention is a triterpenoid PTP1B inhibitor of structural formula I and is physiologically acceptable
  • ⁇ is methyl
  • R 2 is hydrogen
  • X is a substituted fluorenyl group of d-Czo, an unsaturated fluorenyl group; CONH(CH 2 )nCH(R4) , CONH(CH 2 )nCONH(CH 2 )mCH(R 5 ), wherein n is 1 -20, m is 20;
  • R4 is a substituted alkyl group, an unsaturated alkyl group, an aromatic group, or a substituted aromatic group
  • the invention is implemented by the following steps:
  • the invention uses oleanolic acid or ursolic acid as raw material to synthesize 28-long-chain fatty acid derivatives by Wittig or Wittig-Homer reaction, and obtains 3 other substituted 28-long-chain fatty acid derivatives by substituting 3-hydroxyl groups; Or by condensing with various amino acids, a 28-peptide chain derivative is synthesized, and 3 other substituted 28-peptide chain derivatives are obtained by substituting the 3-position hydroxyl group.
  • Synthesis route of 28-peptide chain triterpene derivatives Compound A is reacted with a mixed solution of acetic anhydride and pyridine (1:1, V/V) to give acetylated product I of compound A.
  • Compound I is treated with a certain amount of oxalyl chloride to give compound J.
  • Compound J is reacted with the methyl ester of the amino acid and the methyl ester of the dipeptide in an anhydrous aprotic solvent (eg, dichloromethane, trichloromethane, 1, 4-dioxane), and some organic base is required to be added.
  • an anhydrous aprotic solvent eg, dichloromethane, trichloromethane, 1, 4-dioxane
  • Catalyst eg triethylamine, pyridine, diisopropylethylamine, N, N-dimethylpiperidine, etc.
  • the reaction temperature is generally carried out at room temperature, and the reaction time is usually from 1 to 3 h, and TLC is usually used to detect the degree of completion of the reaction.
  • the product was directly subjected to removal of the solvent under reduced pressure, and the concentrate was subjected to column chromatography to obtain the final products 1 and 1 .
  • the reaction yield is generally from 75% to 90%.
  • the compound L or K gives a 3-keto derivative under the action of IBX, and the 3-keto derivative is reacted with benzylamine to obtain a compound S by sodium borohydride treatment and hydrogenation reduction.
  • Compound G is reacted with hydrogen sulfide and trialuminate to give a 3-mercapto derivative T.
  • Compound G is subjected to hydrazine treatment to give a 3-halo derivative U.
  • the product obtained was confirmed by NMR.
  • Figure 1 shows the effect of compound L-5 on the Km value of PTP1B on the substrate pNPP.
  • Figure 2 shows the effect of compound L-5 on the kcat value of PTP1B versus bottom pNPP.
  • Figure 3 shows the effect of compound L-5 on the level of tyrosine phosphorylation of ⁇ in CHO/IR cells. . 'Benefit effect
  • the present invention demonstrates that a series of compounds synthesized are a novel class of protein tyrosine gluconate 1B inhibitors which are derived from natural products compared to the now known PTP1B inhibitors; such compounds
  • the parent ursolic acid and oleanolic acid are the drugs used in the bed. They are very toxic and very safe.
  • the raw materials for synthesizing these compounds are ursolic acid and oleanolic acid. detailed description
  • A-1 (500 mg, 1.093 mmol) was dissolved in dry tetrahydrofuran (25 mL) then EtOAc. Unreacted lithium aluminum hydride was quenched with a small amount of ethyl acetate, then iced water and chloroform (50 mL). The mixture was transferred to a sep. funnel, chloroform layer was dried, dried over anhydrous sodium sulfate, and evaporated to give a white solid B-1 (460 mg, 1.016 mmol).
  • Oxalyl chloride (0.4 mL, 4.4 mmol) was dissolved in dichloromethane (10 mL), cooled to -60 °C, and DMSO (0.68 mL, 8.8 mmol) in dichloromethane (10 mL) , stir 5 niin at -60 °C.
  • a solution of B-l (1.824 g, 4 mmol) in dichloromethane (20 mL) was slowly added dropwise and stirred at -60 °C for 15 min, then triethylamine (2.8 mL, 20 mmol). The temperature was slowly raised to room temperature and stirred for 48 h.
  • the reaction mixture was cooled with EtOAc EtOAc (EtOAc m. , the yield is 90%. .
  • Methyl oleate (470 mg, 1 mmol) was dissolved in 10 mL of anhydrous DMF and added with imidazole (98 mg, 1.2 Methyl), TBDMSCl (180 mg, 1.2 mmol). Diluted with 100 mL of distilled water, suction filtered, washed with EtOAc (EtOAc)EtOAc.
  • Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dichloromethane (5 mL), cooled to -60 V, DMSO (0.17 mL, 2.2 mmol) in dichloromethane (5 mL) Add and stir at -60 °C for 5 min.
  • a solution of the above white solid product in dichloromethane (5 mL) was slowly added dropwise and stirred at -60 °C for 15 min, then triethylamine (0.7 mL, 5 mmol). The temperature was slowly raised to room temperature and stirred.
  • the methylene chloride solution was washed three times with water (10 mL), dried over sodium sulfate and evaporated under reduced pressure to give a pale yellow solid.
  • Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dichloromethane (5 mL), cooled to -60 °C, then EtOAc (0.17 mL, 2.2 mmol) Stirring 5 min at -60 °C The solution of the above white solid product in dichloromethane (5 mL) was slowly added dropwise. After stirring at -60 °C for 15 min, triethylamine (0.7 mL, 5 mmol) ) Join. The temperature was slowly raised to room temperature and stirred for 48 h. The solution of methylene chloride was washed three times with water (10 mL), dried over sodium sulfate and evaporated.
  • Acetyl chloride of acetylated oleanolic acid (103.3 mg, 0.2 mmol) was dissolved in (10 mL) anhydrous dichloromethane.
  • (87 mg, 0.4 mmol) of the hydrochloride salt of L-phenylalanine methyl ester was dissolved in (10 mL) anhydrous dichloromethane, and (0.5 mL) triethylamine was added to give L-phenylalanine methyl ester.
  • the hydrochloride salt is completely dissolved.
  • SZST00/f00ZM3/X3d 99t690/900Z OAV The product of PT/CN2004/001525 has a strong light absorption at 410 nm , so it is possible to directly observe the change in light absorption at 410 nm to observe changes in enzyme activity and compound-inhibition of enzyme activity.
  • the standard assay system is as follows: 50 mM Mops, ra 7.0, 1 mM EDTA, 2 mM DTT, 2 mM PNPP, 2% DMSO, 40 nM hPTPlB.
  • pNPP 410 nm II Observation index: The optical absorption at 410 nm is measured dynamically for 3 min, and the slope of the first-order reaction of the kinetic curve is used as the activity index of the enzyme.
  • Sample test 1. Dissolve the l mg sample in 200 L DMSO. 20 L was added to the A2-H11 sample well of a %-well polypropylene plate, and then 80 L of DMSO was added as a mother plate. 2. Use the Biomek 2000 Automated Loading System to take 2 samples into the corresponding sample wells of the %-well polystyrene plate for use as a daughter plate for screening. 3. Sample wells 2 DMSO was added to Al-DK E12-H12 as a 100% enzyme activity control. 4. Add 2 L of different concentrations of positive control (four concentrations diluted by 10 g/mL) to sample wells A12-D12 and E1-H1. 5.
  • Sample wells A1-H12 are added to the 88 ⁇ Assay mix. 6. Sample wells A1-H12 are added to 10 ⁇ 1 ⁇ 1 ⁇ . 7. Measure the light absorption at 410 nm on a SpectraMAX 340 for 3 minutes. 8. Output the data as a text file and open it in Excel. The Vmax values of sample wells A1-D1 and E12-H12 are averaged as 100% enzyme activity. The inhibition rate of the compound to PTP1B was obtained by the following formula:
  • % inhibition rate (1 - Vmax value for each screening well I blank control Vmax average) ⁇ 100%
  • the screening result is the percent inhibition of enzyme activity when the concentration of the compound is 20 g/mL.
  • the IC 5 o is obtained by routine screening, and the positive control 4-[4 - (4-oxalyl - phenoxymethyl) - phenylmethoxy] - phenylethyl acid (4- [4- (4-oxalyl -phenoxymethyl) -benzyloxy] -phenyl-oxo-acetic acid) of the IC 50 It is 5.4 ⁇ [Christopher T. Seto, et al. J. Med. Chem., 2002, 45, 3946-3952].
  • the IC50 values of each test compound for inhibiting hPTP- ⁇ are shown in Table 1.
  • test method 1, in the 96-well polystyrene plate sample hole A1 - HI; A3-H3; A5-H5; A7-H7; A9-H9; A1 1 - H11 respectively added 625nM start with DMSO two Double dilutions of 6 L of L-5 in DMSO solution. 2.
  • sample wells A1-A12; B1-B12; C1-C12; D1-D12; E1-E12; F1-F12; G1-G12; H1-H12, add eight dilutions of 40 mM starting with DMSO Concentration of substrate pNPP in DMSO solution 10 ⁇ . 3.
  • sample wells A1-H12 were added to the 88 L Assay mix. 6. Sample well A H12 is added with 10 ⁇ ⁇ 1 ⁇ . 7. Measure the light absorption at 410 nm on a SpectraMAX 340 for 3 minutes.
  • Test methods 1. Cell seeding: Cells with good growth state were connected to a 6-well plate at a density of 3-4 X 105 cells/well, and 2 mL of medium F12 + 10% NCS per well. 2. Hunger: After 24 hours, serum-free F12 medium, 2 mL, overnight for 12 h. 3. Administration: Remove the old medium, add fresh F12, lmL, and incubate for 20 minutes. The compound 1 ⁇ ⁇ 1 mL F12 serum-free medium was diluted and added to each well for 2 to 4 hours. Positive and negative controls were made with 1 mM Na 3 V0 4 and 0.1% DMSO, respectively. 4. Insulin stimulation: Insdin with a final concentration of 10 nM was added to each well for 10 minutes. Or no insulin stimulation. 5, take the sample: Discard 'to the medium, add 100 ⁇ L X 1 per well to the buffer to lyse the cells.

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Abstract

L’invention décrit une série d’inhibiteurs de PTP1B triterpenoïdes de formule (I) suivante. Les études pharmacologiques suggèrent que de tels composés ou leurs sels acceptables d’un point de vue physiologique présentent l’activité d’inhibition de PTP1B. Ainsi, ces composés peuvent être des agents euglycémiques et peuvent être utilisés pour préparer le médicament pour le traitement des troubles causés par la résistance à l’insuline. L’invention concerne également un procédé pour préparer de tels composés.
PCT/CN2004/001525 2004-12-27 2004-12-27 Serie d’inhibiteurs de ptp1b triterpenoides et leur procede de preparation et utilisation WO2006069466A1 (fr)

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PCT/CN2004/001525 WO2006069466A1 (fr) 2004-12-27 2004-12-27 Serie d’inhibiteurs de ptp1b triterpenoides et leur procede de preparation et utilisation
PCT/CN2005/000172 WO2006069499A1 (fr) 2004-12-27 2005-02-06 Inhibiteurs de la proteine tyrosine phosphatase 1b de type triterpenes et procede de preparation et utilisation

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CN103509079A (zh) * 2013-10-22 2014-01-15 中国人民解放军第三军医大学 一种熊果酸衍生物及其制备方法
CN104098645A (zh) * 2014-07-14 2014-10-15 南京林业大学 一类熊果酸吲哚衍生物、制备方法及其用途
CN112047993A (zh) * 2020-07-02 2020-12-08 济南大学 一种α-葡萄糖苷酶抑制剂及其用途
CN115677815A (zh) * 2022-10-28 2023-02-03 江西中医药大学 一种靶向降解ptp1b的protac化合物及其制备方法与应用

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CN101928321B (zh) * 2010-03-02 2012-09-05 福州大学 具抗癌活性的经酸性氨基酸化学修饰的熊果酸衍生物
CN109232708A (zh) * 2018-10-24 2019-01-18 江西农业大学 水溶性山楂酸衍生物及其制备方法和应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103509079A (zh) * 2013-10-22 2014-01-15 中国人民解放军第三军医大学 一种熊果酸衍生物及其制备方法
CN104098645A (zh) * 2014-07-14 2014-10-15 南京林业大学 一类熊果酸吲哚衍生物、制备方法及其用途
CN112047993A (zh) * 2020-07-02 2020-12-08 济南大学 一种α-葡萄糖苷酶抑制剂及其用途
CN115677815A (zh) * 2022-10-28 2023-02-03 江西中医药大学 一种靶向降解ptp1b的protac化合物及其制备方法与应用
CN115677815B (zh) * 2022-10-28 2024-06-14 江西中医药大学 一种靶向降解ptp1b的protac化合物及其制备方法与应用

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