WO2023030470A1 - 一种内皮素a(eta)受体拮抗剂化合物及其制备方法和医药用途 - Google Patents

一种内皮素a(eta)受体拮抗剂化合物及其制备方法和医药用途 Download PDF

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WO2023030470A1
WO2023030470A1 PCT/CN2022/116652 CN2022116652W WO2023030470A1 WO 2023030470 A1 WO2023030470 A1 WO 2023030470A1 CN 2022116652 W CN2022116652 W CN 2022116652W WO 2023030470 A1 WO2023030470 A1 WO 2023030470A1
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pharmaceutically acceptable
enantiomer
racemate
tautomer
mesomer
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PCT/CN2022/116652
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English (en)
French (fr)
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吴俊军
陆银锁
邢伟
胡浩
肖瑛
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深圳信立泰药业股份有限公司
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Priority to CN202410840418.7A priority Critical patent/CN118772120A/zh
Priority to CN202280006429.4A priority patent/CN116194449B/zh
Publication of WO2023030470A1 publication Critical patent/WO2023030470A1/zh

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of chemical medicine, and provides an endothelin A (ETA) receptor antagonist compound, a preparation method and a medical application thereof.
  • ETA endothelin A
  • Atrasentan (CAS: 173937-91-2) is a potent and selective endothelin A (ETA) receptor antagonist with the following structural formula:
  • Atrasentan hydrochloride (CAS: 195733-43-8) is clinically used, and its structure is as follows:
  • the present invention provides a novel endothelin A (ETA) receptor antagonist compound, its preparation method and its application in medicine.
  • ETA endothelin A
  • the present invention provides a compound represented by general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its A mixture form or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
  • the present invention is realized through the following technical schemes, the compound shown in general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 is hydrogen or C 1-6 alkyl, or R 1 , C 3-6 cycloalkyl composed of R 2
  • L is selected from substituted or Unsubstituted C 1-6 -alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, substituted or unsubstituted -(CH 2 )n-heterocycle, n is 0-3
  • a natural number selected from 0, 1, 2 and 3.
  • the substituents of substituted C 1-6 -alkyl include hydroxyl, phosphoric acid, amino, C 1-6 -alkyl substituted amino; substituted -(CH 2 )n-
  • the substituents of the heterocyclic ring include C 1-6 alkyl, hydroxyl, carbonyl, the heterocyclic ring is selected from the C 3-6 saturated or unsaturated heterocyclic ring, and more than one C atom in the heterocyclic ring is replaced by O, N or S .
  • R1 and R2 are not hydrogen at the same time.
  • the C 1-6 alkyl group includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • the C 3-6 cycloalkyl group includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • the C1-6 alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Butoxy, tert-butoxy; substituted or unsubstituted heterocycles are selected from
  • R 1 and R 2 are independently selected from hydrogen, methyl, and R 1 and R 2 are not hydrogen at the same time;
  • L is selected from methyl, ethyl, isopropyl, Cyclopropyl,
  • the pharmaceutically acceptable salt of the compound refers to the preparation of the compound, or its isomer, or its racemate, with a pharmaceutically acceptable acid or base.
  • the compound represented by the general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereomer contains an unnatural proportion of atomic isotopes, and the isotopes are selected from deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C), etc. wait.
  • the present invention further provides the compounds of the present invention, or tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof or pharmaceutically acceptable
  • the use of the salt used in the preparation of medicines specifically, preferably the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating and/or pre-endothelin A (ETA) receptor antagonism-related diseases .
  • ETA pre-endothelin A
  • the diseases include treatment of diseases such as chronic kidney disease, IgA, FSGS and hypertension.
  • the present invention further provides a pharmaceutical composition, which contains the aforementioned compound, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, and more than one pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable salt” as used herein belongs to the derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.
  • the atoms of the compound molecules of the present invention are isotopes, and the isotope derivatization can generally prolong the half-life, reduce the clearance rate, enhance metabolic stability, and improve in vivo activity. Also, an embodiment is included wherein at least one atom is replaced by an atom having the same atomic number (proton number) and different mass number (sum of protons and neutrons).
  • isotopes included in the compound of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl.
  • radioisotopes such as3H or14C, which emit radiation as they decay, are useful in the topographical examination of pharmaceutical preparations or compounds in vivo.
  • Stable isotopes neither decay nor change with their amount, nor are they radioactive, so they are safe to use.
  • the isotopes can be converted according to general methods by substituting reagents used in the synthesis with reagents containing the corresponding isotopes.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • one or more hydrogen atoms of the compound of the present invention are substituted by the isotope deuterium ( 2 H). After the compound of the present invention is deuterated, it has the effects of prolonging the half-life, reducing the clearance rate, enhancing metabolic stability and improving activity in vivo.
  • the preparation method of the isotopic derivative generally includes: a phase transfer catalytic method.
  • a preferred deuteration method employs a phase transfer catalyst (eg, tetraalkylammonium salt, NBu4HSO4 ).
  • a phase transfer catalyst eg, tetraalkylammonium salt, NBu4HSO4 .
  • the use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher rate than that with a deuterated silane (e.g. triethyldeuterosilane) or with a Lewis acid such as trichlorosilane in the presence of an acid (e.g. methanesulfonic acid).
  • Aluminum is reduced with sodium deuterated borate to introduce higher deuterium.
  • pharmaceutically acceptable carrier refers to any preparation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil , vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization.
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • Keto-enol tautomerization Another example of tautomerization is phenol-keto tautomerization. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the compound of the present invention is an endothelin A (ETA) receptor antagonist compound, the prodrug can be completely converted into atrasentan in human liver microsomes, and has a technical effect comparable to that of Atrasentan in pharmacokinetic studies .
  • ETA endothelin A
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
  • HPLC High-performance liquid chromatography
  • the CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
  • the thin-layer chromatography silica gel plate uses Yantai Yinlong HSGF 254 or GF 254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.17mm to 0.23mm.
  • the specification of the thin-layer chromatography separation and purification product is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
  • Step A Synthesis of 1-[(ethoxycarbonyl)oxy]methyl(2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)- 1-[2-(Dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino) -2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
  • chloromethyl ethyl carbonate 270 mg, 1.96 mmol
  • cesium carbonate 640 mg, 1.96 mmol
  • potassium iodide 325 mg, 1.96 mmol
  • reaction solution was cooled to room temperature, poured into 40 ml of ice-water solution, extracted with dichloromethane (100 ml ⁇ 3), combined the organic phases, washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate.
  • Step A Synthesis of 1-[(ethoxycarbonyl)oxy]ethyl(2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)- 1-[2-(Dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino) -2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
  • 1-chloroethyl ethyl carbonate 298 mg, 1.96 mmol
  • cesium carbonate 640 mg, 1.96 mmol
  • potassium iodide 325 mg, 1.96 mmol
  • reaction solution was cooled to room temperature, poured into 40 ml of ice-water solution, extracted with dichloromethane (100 ml ⁇ 3), combined the organic phases, washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate.
  • Step A Synthesis of 1-[(isopropoxycarbonyl)oxy]ethyl-(2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl )-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino) -2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
  • 1-chloroethyl isopropyl carbonate 325 mg, 1.96 mmol
  • cesium carbonate 640 mg, 1.96 mmol
  • potassium iodide 325 mg, 1.96 mmol
  • Step A Synthesis of 1-[(methoxycarbonyl)oxy]ethyl-(2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl) -1-[2-(Dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino) -2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
  • 1-chloroethyl methyl carbonate 270 mg, 1.96 mmol
  • cesium carbonate 640 mg, 1.96 mmol
  • potassium iodide 325 mg, 1.96 mmol
  • Step A Synthesis of tert-butyl (2-(((1-chloroethoxy)carbonyl)oxy)ethyl)(methyl)carbamate
  • Step B Synthesis of 2,2,5-trimethyl-4,9-dioxo-3,8,10-trioxa-5-aza-11-ethyl-(2R,3R,4S)-4 -(Benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methyl Oxyphenyl)pyrrolidine-3-carboxylate
  • Step C Synthesis of 1-(((2-(methylamino)ethoxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzo[d][1,3]di Oxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • Step A 1-Chloroethyl(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)carbonate
  • Step B Synthesis of 1-(((((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)carbonyl)oxy)ethyl-(2R, 3R,4S)-4-(Benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]- 2-(4-Methoxyphenyl)pyrrolidine-3-carboxylate
  • Step C Synthesis of 1-((((S)-2,3-dihydroxypropoxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzo[d][1, 3] Dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3- Carboxylate
  • Step A Synthesis of 1-[(cyclopropoxycarbonyl)oxy]ethyl-(2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl )-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • atrasentan (2R,3R,4S)-4-(benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino) -2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
  • 1-chloroethyl cyclopropyl carbonate 240 mg, 1.96 mmol
  • cesium carbonate 640 mg, 1.96 mmol
  • potassium iodide 325 mg, 1.96 mmol
  • Step A Synthesis of 2-((tert-butyldimethylsilyl)oxy)ethyl(1-chloroethyl)carbonate
  • Step B Synthesis of 2,2,3,3-tetramethyl-8-oxo-4,7,9-trioxa-3-sila-10-ethyl-(2R,3R,4S)-4 -(Benzo[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methyl Oxyphenyl)pyrrolidine-3-carboxylate
  • Step C Synthesis of 1-(((2-hydroxyethoxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzo[d][1,3]dioxolane Alkyl-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
  • Step A ((R)-1,4-dioxan-2-yl)methyl(1-chloroethyl)carbonate
  • Step B Synthesis of 1-(((((R)-1,4-dioxan-2-yl)methoxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzene And[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxybenzene base) pyrrolidine-3-carboxylate
  • oxetan-3-ol 176 mg, 2.38 mmol
  • pyridine 225 mg, 2.85 mmol
  • 1- Chloroethyl chloroformate 408 mg, 2.85 mmol
  • Step B Synthesis of 1-((((oxetan-3-yl)oxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzo[d][1, 3] Dioxolane-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3- Carboxylate
  • Step A ((S)-1,4-dioxan-2-yl)methyl(1-chloroethyl)carbonate
  • Step B Synthesis of 1-(((((S)-1,4-dioxan-2-yl)methoxy)carbonyl)oxy)ethyl-(2R,3R,4S)-4-(benzene And[d][1,3]dioxolan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxybenzene base) pyrrolidine-3-carboxylate
  • DMSO dimethyl sulfoxide
  • acetonitrile formic acid
  • propranolol internal standard
  • Preparation at point 0 Take 15 ⁇ L of the above liver microsomal suspension, add 6 mM NADPH solution, immediately add 150 ⁇ L propranolol acetonitrile solution to precipitate, then add 15 ⁇ L of the above administration solution and mix well for use.
  • Sample preparation at 20 min and 60 min Take 15 ⁇ L of the administration solution, add 15 ⁇ L of liver microsome suspension and 15 ⁇ L of 6 mM NADPH solution, mix well, and incubate at 37°C for 20 min and 60 min, respectively. The above sample preparations were performed in parallel with duplicate wells. When the above samples were incubated to relevant time points, 150 ⁇ L of propranolol acetonitrile solution was added to terminate the reaction. All the above samples were centrifuged at 4000rpm for 5min, 100 ⁇ L of supernatant was added to 100 ⁇ L of ultrapure water and mixed for LC-MS/MS analysis.
  • LC-MS/MS detection conditions are as follows:
  • Example compounds are converted into the amount of atrasentan in microsomes
  • Example 3 The results show that the compound of Example 3 can be rapidly metabolized in human microsomes and can be completely converted into atrasentan.
  • SD rats male, 200-300 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • DMSO dimethyl sulfoxide
  • PEG-400 polyethylene glycol 400
  • normal saline normal saline
  • heparin normal saline
  • acetonitrile formic acid
  • propranolol internal standard
  • the compound was weighed and dissolved in DMSO-PEG-400-normal saline (5:60:35, v/v/v) system. After oral administration to rats, 15min, 30min, 1h, 2h, 5h , 7h, and 24h collected 200 ⁇ L of venous blood into heparinized EP tubes added with sodium fluoride, centrifuged at 12,000 rpm for 2 minutes, and took plasma to be frozen at -80°C for testing. Accurately weigh a certain amount of the test product and dissolve it in DMSO to 2 mg/mL as the stock solution. Accurately draw an appropriate amount of compound stock solution, add acetonitrile to dilute to make a standard series solution.
  • the exposure of the compounds of Examples 3 and 4 in rats is higher than that of atrasentan at the same dose, and the absorption after intragastric administration is better than that of atrasentan.
  • SD rats male, 200-300 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • DMSO dimethyl sulfoxide
  • PEG-400 polyethylene glycol 400
  • normal saline normal saline
  • heparin normal saline
  • acetonitrile formic acid
  • propranolol internal standard
  • the compound was weighed and dissolved in DMSO-PEG-400-normal saline (5:60:35, v/v/v) system. After oral administration to rats, 15min, 30min, 1h, 2h, 5h , 7h, and 24h collected 200 ⁇ L of venous blood into heparinized EP tubes added with sodium fluoride, centrifuged at 12,000 rpm for 2 minutes, and took plasma to be frozen at -80°C for testing. Accurately weigh a certain amount of the test product and dissolve it in DMSO to 2 mg/mL as the stock solution. Accurately draw an appropriate amount of compound stock solution, add acetonitrile to dilute to make a standard series solution.
  • the exposure of the compound of Example 7 in rats is significantly lower than that of atrasentan with the same dose, and the absorption after intragastric administration is not as good as that of atrasentan.
  • Example 3 can be rapidly converted into atrasentan both in vivo and in vitro, and the exposure at an equimolar dose is higher than that of atrasentan.
  • mice Male Dahl/SS rats were used in the experiment, all of which were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. After the adaptation period, the animals were randomly divided into 5 groups according to their basic blood pressure and body weight. The specific grouping and dosing regimen are shown in Table 5:
  • Measurement indicators are expressed as mean ⁇ standard deviation. When the number of samples is less than 3, the data of this group will not be included in the statistical comparison. The data were input and statistically analyzed by Excel 2010, GraphPad Prism 7, SPSS 22.0 and Stata 15.0 software. The LEVENE variance homogeneity test was first used for measurement indicators. When the variances were homogeneous (P>0.05), the results of the variance analysis could be directly quoted to determine whether the overall difference was statistically significant. When the overall difference was statistically significant (P ⁇ 0.05), use Dunnett-t test was used to compare the differences between groups.

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Abstract

属于化学药物技术领域，提供了一种内皮素A(ETA)受体拮抗剂化合物及其制备方法和医药用途。

Description

一种内皮素A(ETA)受体拮抗剂化合物及其制备方法和医药用途 技术领域
本发明属于化学药物技术领域，提供了一种内皮素A(ETA)受体拮抗剂化合物及其制备方法和医药用途。
背景技术
阿曲生坦(CAS：173937-91-2)是一种有效且选择性的内皮素A(ETA)受体拮抗剂，结构式如下：
Figure PCTCN2022116652-appb-000001
在临床上应用的是盐酸阿曲生坦(CAS：195733-43-8)，结构如下：
Figure PCTCN2022116652-appb-000002
先前在临床试验中评估其用于治疗前列腺癌，现在在临床试验中评估其用于治疗与II型糖尿病相关的慢性肾脏疾病。同时已被证明能够降低糖尿病肾病患者的白蛋白尿，目前暂未有上市产品。
发明内容
鉴于现有技术存在的问题，本发明提供了一种结构新颖的内皮素A(ETA)受体拮抗剂化合物、其制备方法及其在医药上的应用。
具体而言，本发明提供通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所有变量如本文所定义。
本发明通过以下技术方案来实现，通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2022116652-appb-000003
其中：R 1为氢或C 1-6的烷基，R 2为氢或C 1-6的烷基，或者R 1，R 2组成的C 3-6的环烷基；L选自取代或者未取代的C 1-6-烷基、C 3-6的环烷基、C 1-6的烷氧基、取代或者未取代的-(CH 2)n-杂环，n为0-3的自然数，选自0、1、2和3。
作为本发明的一种优选技术方案，取代的C 1-6-烷基的取代基包括羟基、磷酸基、胺基、C 1-6-烷基取代氨基；取代的-(CH 2)n-杂环的取代基包括C 1-6的烷基、羟基、羰基，杂环选自C 3-6的饱和或者不饱和杂环，杂环中一个以上的C原子被O、N或S所替换。
作为本发明的一种优选技术方案，R 1和R 2不同时为氢。
作为本发明的一种优选技术方案，所述C 1-6的烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
作为本发明的一种优选技术方案，C 3-6的环烷基包括环丙烷、环丁烷、环戊烷、环己烷。
作为本发明的一种优选技术方案，所述C 1-6的烷氧基，包括甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基；取代或者未取代的杂环选自
Figure PCTCN2022116652-appb-000004
Figure PCTCN2022116652-appb-000005
作为本发明的一种优选技术方案，其中R 1和R 2独自的选自氢、甲基，且R 1和R 2不同时为氢；L选自甲基、乙基、异丙基、
Figure PCTCN2022116652-appb-000006
环丙基、
Figure PCTCN2022116652-appb-000007
Figure PCTCN2022116652-appb-000008
作为本发明的一种优选技术方案，选自以下化合物：
Figure PCTCN2022116652-appb-000009
Figure PCTCN2022116652-appb-000010
作为本发明的一种优选技术方案，所述化合物的可药用的盐是指化合物，或其异构体、或其消旋体与药学上可接受的酸或碱制备。
作为本发明的一种优选技术方案，所述通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的原子上包含非天然比例的原子同位素，同位素选自氘( 2H)，碘-125( 125I)或C-14( 14C)等等。
本发明进一步提供了本发明所述化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐在制备药物中的用途，具体地，优选所述化合物或其药学上可接受的盐在制备用于治疗和/或预内皮素A(ETA)受体拮抗相关疾病的药物方面的用途。
进一步地，所述疾病包括治疗慢性肾病、IgA、FSGS和高血压等疾病。
本发明进一步提供了一种药物组合物，所述药物组合物含有前述化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，和一种以上药学上可接受的载体。
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品 名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。
本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明化合物分子的原子是同位素，通过同位素衍生化通常可以延长半衰期、降低清除率、增强代谢稳定和提高体内活性等效果。并且，包括一个实施方案，其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子，其分别包括 2H、 3H、 13C、 14C、 15N、 17O、 18O、 31P、 32P、 35S、 18F、 36Cl。特别的是，随其衰退而发射辐射的放射性同位素例如3H或14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化，也不具有放射性，因此其可以安全使用。当构成本发明化合物分子的原子是同位素时，通过用包含相应同位素的试剂替代合成中所用的试剂，可以根据通用方法转化同位素。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。进一步地，本发明的化合物一个或多个氢原子上被同位素氘( 2H)取代，本发明化合物氘代后，具有延长半衰期、降低清除率、增强代谢稳定和提高体内活性等效果。所述同位素衍生物的制备方法通常包括：相转移催化方法。例如，优选的氘化方法采用相转移催化剂(例如，四烷基铵盐，NBu 4HSO 4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子，导致比在酸(例如，甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“互变异构体”变或“互变异构形式”变是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构。互变异构的另一个实例是酚-酮互变异构。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括 在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明相对于现有技术的有益效果包括：
本发明化合物一种内皮素A(ETA)受体拮抗剂化合物，该前药在人肝微粒体中能完全转化为阿曲生坦，且在药代动力学研究表面具有与Atrasentan相当的技术效果。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-III核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
MS的测定用ISQ EC质谱仪(生产商:Thermo,型号:ISQ EC)。
高效液相色谱法(HPLC)分析使用Thermo U3000 HPLC DAD高效液相色谱仪。
CombiFlash快速制备仪使用CombiFlash Rf+LUMEN(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台银龙HSGF 254或GF 254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.17mm～0.23mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用乳山上邦硅胶100～200目硅胶为载体。
DMF N,N-二甲基甲酰胺、氯甲基乙基碳酸酯、碘化钾、碳酸铯、DCM二氯甲烷、正己烷、乙酸乙酯。
实施例1
1-[(乙氧羰基)氧基]甲基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁胺)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000011
步骤A:合成1-[(乙氧羰基)氧基]甲基(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000012
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(500毫克，0.98毫摩尔)、氯甲基乙基碳酸酯(270毫克，1.96毫摩尔)、碳酸铯(640毫克，1.96毫摩尔)和碘化钾(325毫克，1.96毫摩尔)加入到10毫升干燥的DMF中，升温至65摄氏度反应2小时。
反应结束后，将反应液冷却至室温，倒入40毫升的冰水溶液中，二氯甲烷(100毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩蒸干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到480毫克无色油状产物[(乙氧羰基)氧基]甲基(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：79.9％)。
LC-MS：RT＝2.20min，[M+H] +＝613.42。
1H NMR(400MHz,DMSO)δ7.23(d,J＝8.6Hz,2H),7.04(d,J＝1.2Hz,1H),6.89(d,J＝8.7Hz,2H),6.84–6.76(m,2H),5.98(d,J＝4.6Hz,2H),5.58(q,J＝6.2Hz,2H),4.12(q,J＝7.1Hz,2H),3.78–3.72(m,1H),3.72(s,3H),3.49(dd,J＝11.2,5.3Hz,1H),3.26–3.20(m,3H),3.16(s,1H),3.02–2.90(m,3H),2.86–2.80(m,1H),2.71(d,J＝13.8Hz,1H),1.33(dd,J＝14.6,7.0Hz,2H),1.27–1.09(m,7H),0.96(dd,J＝14.7,7.3Hz,2H),0.81(t,J＝7.3Hz,3H),0.71(t,J＝7.3Hz,3H).
实施例2
1-[(乙氧羰基)氧基]乙基(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000013
步骤A:合成1-[(乙氧羰基)氧基]乙基(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000014
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(500毫克，0.98毫摩尔)、1-氯乙基乙基碳酸酯(298毫克，1.96毫摩尔)、 碳酸铯(640毫克，1.96毫摩尔)和碘化钾(325毫克，1.96毫摩尔)加入到10毫升干燥的DMF中，升温至65摄氏度反应2小时。
反应结束后，将反应液冷却至室温，倒入40毫升的冰水溶液中，二氯甲烷(100毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩蒸干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到442毫克无色油状产物1-[(乙氧羰基)氧基]甲基(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：66.5％)。
LC-MS：RT＝2.21min，[M+H] +＝627.40。 1H NMR(400MHz,DMSO)δ7.27–7.17(m,2H),7.09–6.98(m,1H),6.92–6.85(m,2H),6.85–6.74(m,2H),6.60–6.52(m,1H),5.98(d,J＝5.3Hz,2H),4.11(dq,J＝11.1,7.1Hz,2H),3.67-3.73(m,4H),3.57–3.44(m,1H),3.30–3.20(m,3H),3.19–3.10(m,1H),3.01–2.85(m,3H),2.77(ddd,J＝9.4,6.9,2.6Hz,1H),2.70(d,J＝13.9Hz,1H),1.39–1.22(m,6H),1.21–1.04(m,6H),1.01–0.89(m,2H),0.81(t,J＝7.3Hz,3H),0.71(t,J＝7.3Hz,3H)
实施例3
1-[(异丙氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000015
步骤A:合成1-[(异丙氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000016
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(500毫克，0.98毫摩尔)、1-氯乙基异丙基碳酸酯(325毫克，1.96毫摩尔)、碳酸铯(640毫克，1.96毫摩尔)和碘化钾(325毫克，1.96毫摩尔)加入到10毫升干燥的DMF中，升温至65摄氏度反应2小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到482毫克无色油状产物1-[(异丙氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：76.9％)。
LC-MS：RT＝2.29min，[M+H] +＝641.48。 1H NMR(400MHz,DMSO)δ7.25(t,J＝9.0Hz,2H),7.07–7.04(m,1H),6.93–6.89(m,2H),6.85–6.78(m,2H),6.59–6.54(m,1H),5.99(d,J＝6.2Hz,2H),4.79–4.69(m,1H),3.76–3.70(m,4H),3.55–3.44(m,1H),3.33–3.23(m,4H),3.21–3.13(m,1H),3.02–2.90 (m,3H),2.80–2.75(m,1H)2.71(d,J＝13.9Hz,1H),1.39–1.33(m,1H),1.32(d,J＝5.4Hz,2H),1.26(d,J＝5.4Hz,2H),1.22–1.14(m,9H),1.00–0.94(m,2H),0.82(t,J＝7.3Hz,3H),0.72(t,J＝7.3Hz,3H)。
实施例4
1-[(甲氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000017
步骤A:合成1-[(甲氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000018
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(500毫克，0.98毫摩尔)、1-氯乙基甲基碳酸酯(270毫克，1.96毫摩尔)、碳酸铯(640毫克，1.96毫摩尔)和碘化钾(325毫克，1.96毫摩尔)加入到10毫升干燥的DMF中，升温至65摄氏度反应2小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到428毫克无色油状产物1-[(甲氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：71.3％)。
LC-MS：RT＝2.20min，[M+H] +＝613.42。 1H NMR(400MHz,DMSO)δ7.25(dd,J＝10.3,8.7Hz,2H),7.08–7.04(m,1H),6.91(dd,J＝8.7,2.9Hz,2H),6.86–6.78(m,2H),6.60–6.55(m,1H),5.99(d,J＝5.1Hz,2H),3.76–3.69(m,6H),3.56–3.44(m,1H),3.33–3.16(m,5H),3.00–2.94(m,3H),2.81–2.76(m,1H),2.71(d,J＝13.7Hz,1H),1.39–1.14(m,9H),1.02–0.93(m,2H),0.82(t,J＝7.3Hz,3H),0.72(t,J＝7.3Hz,3H)。
实施例5
1-(((2-(甲基氨基)乙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000019
步骤A:合成(2-(((1-氯乙氧基)羰基)氧基)乙基)(甲基)氨基甲酸叔丁酯
Figure PCTCN2022116652-appb-000020
冰浴下，将2-(N-Boc-N-甲基氨基)乙醇(500毫克，2.85毫摩尔)和吡啶(248毫克，3.14毫摩尔)加入到10毫升干燥的二氯甲烷中，冰浴下滴入1-氯乙基氯甲酸酯(248毫克，3.14毫摩尔)，滴毕，升至室温反应1小时。
反应结束后，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，1M/L盐酸(20毫升)洗涤有机层2次，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干得到725毫克无色油状产物(2-(((1-氯乙氧基)羰基)氧基)乙基)(甲基)氨基甲酸叔丁酯(收率：90.6％)。
步骤B:合成2,2,5-三甲基-4,9-二氧代-3,8,10-三噁-5-氮杂-11-乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000021
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(500毫克，0.98毫摩尔)、(2-(((1-氯乙氧基)羰基)氧基)乙基)(甲基)氨基甲酸叔丁酯(550毫克，1.96毫摩尔)、碳酸铯(640毫克，1.96毫摩尔)和碘化钾(325毫克，1.96毫摩尔)加入到10毫升干燥的DMF中，升温至65摄氏度反应4小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到625毫克无色油状产物2,2,5-三甲基-4,9-二氧代-3,8,10-三噁-5-氮杂-11-乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：84.4)。LC-MS：RT＝2.34min，[M+H] +＝756.49。
步骤C:合成1-(((2-(甲基氨基)乙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000022
室温下，将2,2,5-三甲基-4,9-二氧代-3,8,10-三噁-5-氮杂-11-乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(300毫克，0.39毫摩尔)溶于10毫升乙酸乙酯溶剂中，冰浴下加入2毫升4M/L的盐酸二氧六环溶液，室温反应2小时。
反应结束后，浓缩得260毫克黄色固体1-(((2-(甲基氨基)乙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：101.6％)。
LC-MS：RT＝1.82min，[M+H] +＝656.45。 1H NMR(400MHz,DMSO)δ7.60(m,2H),7.21(m,1H),7.01(d,J＝8.1Hz,2H),6.90(d,J＝15.8Hz,2H),6.50(m,1H),6.04(s,2H),3.77(s,3H),3.17(d,J＝6.4Hz,3H),3.08–2.90(m,4H),2.52(d,J＝5.6Hz,3H),2.06(d,J＝4.1Hz,3H),1.90(s,6H),1.33(d,J＝34.4Hz,4H),1.23–1.10(m,7H),0.83(t,J＝7.0Hz,6H).
实施例6
1-((((S)-2,3-二羟基丙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000023
步骤A:1-氯乙基(((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲基)碳酸酯
Figure PCTCN2022116652-appb-000024
冰浴下，将(S)-(+)-1,2-异亚丙基甘油(315毫克，2.38毫摩尔)和吡啶(225毫克，2.85毫摩尔)加入到10毫升干燥的二氯甲烷中，冰浴下滴入1-氯乙基氯甲酸酯(408毫克，2.85毫摩尔)，滴毕，升至室温反应2小时。
反应结束后，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)得到250毫克无色油状产物1-氯乙基(((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲基)碳酸酯(收率：44.2％)。
步骤B:合成1-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000025
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(100毫克，0.20毫摩尔)、1-氯乙基(((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲基)碳酸酯(72毫克，0.3毫摩尔)、碳酸铯(130毫克，0.4毫摩尔)和碘化钾(66.4毫克，0.4毫摩尔)加入到5毫升干燥的DMF中，升温至65摄氏度反应4小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)得到85毫克无色油状产物1-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：59.9％)。LC-MS：RT＝2.21min，[M+H] +＝713.46。
步骤C:合成1-((((S)-2,3-二羟基丙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000026
室温下，将1-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(80毫克，0.11毫摩尔)溶于10毫升二氯甲烷溶剂中，加入2毫升三氟乙酸溶液，室温反应0.5小时。
反应结束后，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)得56毫克黄色固体1-((((S)-2,3-二羟基丙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：74.1％)。
LC-MS：RT＝2.06min，[M+H] +＝673.39。 1H NMR(400MHz,DMSO)δ7.32–7.17(m,2H),7.12–7.04(m,1H),6.93(s,2H),6.84(s,2H),6.55(s,1H),6.00(d,J＝5.2Hz,2H),4.18–4.06(m,2H),3.90(s,1H),3.73(s,3H),3.64(s,2H),3.55–3.42(m,2H),3.18–3.07(m,3H),3.00(s,4H),2.66(s,1H),2.44–2.35(m,2H),2.32(s,1H),1.31(s,3H),1.18(s,3H),0.99(s,3H),0.81(t,J＝7.4Hz,3H),0.74(s,3H).
实施例7
1-[(环丙氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000027
步骤A:合成1-[(环丙氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000028
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(500毫克，0.98毫摩尔)、1-氯乙基环丙基碳酸酯(240毫克，1.96毫摩尔)、碳酸铯(640毫克，1.96毫摩尔)和碘化钾(325毫克，1.96毫摩尔)加入到10毫升干燥的DMF中，升温至65摄氏度反应2小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(100毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到412毫克无色油状产物1-[(环丙氧羰基)氧基]乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：65.8)。LC-MS：RT＝2.29min，[M+H] +＝639.40。 1H NMR(400MHz,DMSO)δ7.25(s,2H),7.06(d,J＝10.4Hz,1H),6.90(m,2H),6.83(m,2H),6.57(m,1H),5.98(s,2H),4.09(s,2H),3.73(m,4H),3.53–3.42(m,2H),2.95(m,5H),2.71(d,J＝13.2Hz,3H),1.98(s,1H),1.38–1.02(m,9H),0.99–0.87(m,2H),0.81(s,2H),0.71(d,J＝7.0Hz,6H).
实施例8
1-(((2-羟基乙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000029
步骤A:合成2-((叔丁基二甲基硅烷基)氧基)乙基(1-氯乙基)碳酸酯
Figure PCTCN2022116652-appb-000030
冰浴下，将2-叔丁基二甲基硅烷基氧基乙醇(1000毫克，5.67毫摩尔)和吡啶(739毫克，9.36毫摩尔)加入到10毫升干燥的二氯甲烷中，冰浴下滴入1-氯乙基氯甲酸酯(900毫克，6.24毫摩尔)，滴毕，升至室温反应1小时。
反应结束后，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)得到245毫克无色油状产物2-((叔丁基二甲基硅基)氧代)乙基(1-氯乙基)碳酸酯(收率：15.4％)。
步骤B:合成2,2,3,3-四甲基-8-氧代-4,7,9-三氧杂-3-硅杂-10-乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000031
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(100毫克，0.20毫摩尔)、2-((叔丁基二甲基硅烷基)氧基)乙基(1-氯乙基)碳酸酯(85毫克，0.3毫摩尔)、碳酸铯(130毫克，0.4毫摩尔)和碘化钾(66.4毫克，0.4毫摩尔)加入到5毫升干燥的DMF中，升温至65摄氏度反应4小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)得到62毫克无色油状产物2,2,3,3-四甲基-8-氧代-4,7,9-三氧杂-3-硅杂-10-乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：41.0％)。LC-MS：RT＝2.75min，[M+H] +＝757.50。
步骤C:合成1-(((2-羟基乙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000032
室温下，将2,2,3,3-四甲基-8-氧代-4,7,9-三氧杂-3-硅杂-10-乙基-(2R,3R,4SS)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(62毫克，0.08毫摩尔)溶于10毫升二氯甲烷溶剂中，冰浴下加入2毫升4M/L的盐酸二氧六环溶液，室温反应2小时。
反应结束后，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)得40毫克黄色固体1-(((2-羟基乙氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：77.9％)。
LC-MS：RT＝2.07min，[M+H] +＝643.44。 1H NMR(400MHz,DMSO)δ7.71–7.38(m,2H),7.19(d,J＝12.2Hz,1H),7.00(d,J＝6.8Hz,2H),6.93–6.79(m,2H),6.48(s,1H),6.03(s,2H),4.02(d,J＝7.1Hz,3H),3.76(m,4H),3.57–3.48(m,3H),3.20–3.09(m,1H),3.08–2.90(m,3H),1.45–1.02(m,14H),0.91– 0.68(m,8H).
实施例9
1-(((((R)-1,4-二噁烷-2-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000033
步骤A:((R)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯
Figure PCTCN2022116652-appb-000034
冰浴下，将(R)-(1,4-二噁烷-2-基)甲醇(280毫克，2.38毫摩尔)和吡啶(225毫克，2.85毫摩尔)加入到10毫升干燥的二氯甲烷中，冰浴下滴入1-氯乙基氯甲酸酯(408毫克，2.85毫摩尔)，滴毕，升至室温反应2小时。
反应结束后，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)得到212毫克无色油状产物((R)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯(收率：39.8％)。
步骤B:合成1-(((((R)-1,4-二噁烷-2-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000035
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(100毫克，0.20毫摩尔)、((R)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯(67.2毫克，0.3毫摩尔)、碳酸铯(130毫克，0.4毫摩尔)和碘化钾(66.4毫克，0.4毫摩尔)加入到5毫升干燥的DMF中，升温至65摄氏度反应4小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)得到80毫克无色油状产物1-(((((R)-1,4-二噁烷-2-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：59.9％)。
LC-MS：RT＝2.16min，[M+H] +＝699.42。 1H NMR(400MHz,DMSO)δ7.24(dd,J＝11.6,8.6Hz,2H), 7.06(d,J＝11.4Hz,1H),6.91(dd,J＝8.6,2.7Hz,2H),6.85–6.75(m,2H),6.59–6.53(m,1H),5.99(d,J＝6.0Hz,2H),4.06(dd,J＝9.5,4.7Hz,2H),3.75–3.56(m,8H),3.53(d,J＝9.9Hz,1H),3.50–3.41(m,2H),3.29–3.21(m,5H),2.95(dd,J＝18.3,10.6Hz,3H),2.79–2.73(m,1H),2.69(d,J＝14.1Hz,1H),1.33(t,J＝8.5Hz,3H),1.29–1.21(m,3H),1.17(dd,J＝14.8,7.4Hz,3H),0.96(d,J＝4.7Hz,2H),0.81(t,J＝7.3Hz,3H),0.71(t,J＝7.3Hz,3H).
实施例10
1-((((氧杂环丁烷-3-基)氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000036
步骤A:1-氯乙基氧杂环丁烷-3-基碳酸酯
Figure PCTCN2022116652-appb-000037
冰浴下，将氧杂环丁烷-3-醇(176毫克，2.38毫摩尔)和吡啶(225毫克，2.85毫摩尔)加入到10毫升干燥的二氯甲烷中，冰浴下滴入1-氯乙基氯甲酸酯(408毫克，2.85毫摩尔)，滴毕，升至室温反应2小时。
反应结束后，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩蒸至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)得到200毫克无色油状产物1-氯乙基氧杂环丁烷-3-基碳酸酯(收率：46.7％)。
步骤B:合成1-((((氧杂环丁烷-3-基)氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000038
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(100毫克，0.2毫摩尔)、1-氯乙基氧杂环丁烷-3-基碳酸酯(54毫克，0.3毫摩尔)、碳酸铯(130毫克，0.4毫摩尔)和碘化钾(66.4毫克，0.4毫摩尔)加入到5毫升干燥的DMF中，升温至65摄氏度反应4小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)得到76毫克无色油状产物1-((((氧杂环丁烷-3-基)氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷 -3-羧酸酯(收率：58.0％)。
LC-MS：RT＝2.18min，[M+H] +＝655.39。 1H NMR(400MHz,DMSO)δ7.24(t,J＝8.4Hz,2H),7.05(d,J＝12.1Hz,1H),6.94–6.86(m,2H),6.85–6.71(m,2H),6.61–6.50(m,1H),5.99(d,J＝5.7Hz,2H),5.41–5.26(m,1H),4.82–4.63(m,2H),4.53–4.32(m,2H),3.80–3.60(m,4H),3.57–3.41(m,1H),3.27–3.11(m,4H),2.98(dd,J＝14.1,6.6Hz,3H),2.82–2.74(m,1H),2.68(s,1H),1.32(t,J＝7.1Hz,3H),1.26(dd,J＝18.2,7.3Hz,3H),1.17(dd,J＝14.8,7.1Hz,3H),0.96(d,J＝6.6Hz,2H),0.81(t,J＝7.3Hz,3H),0.71(t,J＝7.3Hz,3H).
实施例11
1-(((((S)-1,4-二噁烷-2-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000039
步骤A:((S)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯
Figure PCTCN2022116652-appb-000040
冰浴下，将(S)-(1,4-二噁烷-2-基)甲醇(280毫克，2.38毫摩尔)和吡啶(225毫克，2.85毫摩尔)加入到10毫升干燥的二氯甲烷中，冰浴下滴入1-氯乙基氯甲酸酯(408毫克，2.85毫摩尔)，滴毕，升至室温反应2小时。
反应结束后，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)得到219毫克无色油状产物((S)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯(收率：41.0％)。
步骤B:合成1-(((((S)-1,4-二噁烷-2-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯
Figure PCTCN2022116652-appb-000041
室温下，将阿曲生坦(2R,3R,4S)-4-(苯并[d][1,3]二氧戊环-5-基)-1-[2-(二丁氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸(100毫克，0.20毫摩尔)、((S)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯(44.8毫克，0.3毫摩尔)、碳酸铯(130毫克，0.4毫摩尔)和碘化钾(66.4毫克，0.4毫摩尔)加入到5毫升干燥的DMF中，升温至65摄氏度反应4小时。
反应结束后，降至室温，倒入40毫升的冰水溶液中，二氯甲烷(20毫升×3)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸镁干燥，过滤，减压浓缩至干，粗品化合物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)得到92毫克无色油状产物1-(((((S)-1,4-二噁烷-2-基)甲氧基)羰基)氧基)乙基-(2R,3R,4S)-4-(苯并[d][1,3]二氧杂环戊烷-5-基)-1-[2-(二丁基氨基)-2-氧代乙基]-2-(4-甲氧基苯基)吡咯烷-3-羧酸酯(收率：65.8％)。
LC-MS：RT＝2.14min，[M+H] +＝699.43。 1H NMR(400MHz,DMSO)δ7.24(dd,J＝11.6,8.7Hz,2H),7.06(d,J＝10.7Hz,1H),6.91(dd,J＝8.6,2.7Hz,2H),6.85–6.70(m,2H),6.59–6.53(m,1H),5.99(d,J＝6.2Hz,2H),4.09–3.97(m,2H),3.75–3.65(m,6H),3.56(dd,J＝22.9,9.5Hz,3H),3.47–3.38(m,2H),3.23(dd,J＝31.0,20.1Hz,5H),2.96(dt,J＝16.3,8.0Hz,3H),2.84–2.62(m,2H),1.33(t,J＝8.2Hz,3H),1.29–1.20(m,3H),1.19–1.07(m,3H),0.96(d,J＝7.4Hz,2H),0.81(t,J＝7.3Hz,3H),0.71(t,J＝7.3Hz,3H).
实施例12
化合物微粒体研究
(1)实验材料
人肝微粒体均购自瑞德肝脏疾病研究(上海)有限公司。
试剂：DMSO(二甲亚砜)，乙腈，甲酸，普萘洛尔(内标)均为市售可得。
仪器：赛默飞LC-MS(U300UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。
(2)实验方法
精密称取一定量的化合物溶于DMSO中配成10mM的储备液，用稀释剂(ACN:H 2O＝1:1)将储备液稀释至100μM的工作液，之后用0.1M磷酸钾缓冲溶液稀释成3μM的给药溶液备用。取75μL肝微粒体加入到925μL的0.1M磷酸钾缓冲溶液中混匀得1.5mg/mL的肝微粒体混悬液于37℃预孵10min。0点的制备：取上述肝微粒体混悬液15μL加入6mM的NADPH溶液立即加入150μL的普萘洛尔乙腈溶液沉淀，再加入15μL上述给药溶液混匀待用。20min和60min样品制备：取15μL给药溶液加入15μL肝微粒体混悬液和15μL 6mM的NADPH溶液混匀于37℃分别孵育20min和60min。上述样品制备均为双复孔平行操作。待上述样品孵育到相关时间点时均加入150μL的普萘洛尔乙腈溶液终止反应。将上述所有样品于4000rpm离心5min，取100μL上清加入100μL超纯水混匀后进行LC-MS/MS分析。LC-MS/MS检测条件如下：
色谱柱：Waters ACQUITYTM PREMIER HSS T3，50*2.1mm，1.8μm。
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱
Figure PCTCN2022116652-appb-000042
(3)数据处理
将初始0点作为100％，计算出各时间点药物的相对剩余含量，以阿曲生坦各个时间点作为100％，计算实施例化合物转化为阿曲生坦相对量。结果见表2和表3.
表2.各药物在微粒体中原型变化
Figure PCTCN2022116652-appb-000043
Figure PCTCN2022116652-appb-000044
表3.实施例化合物在微粒体中转化为阿曲生坦量
Figure PCTCN2022116652-appb-000045
Figure PCTCN2022116652-appb-000046
结果显示，实施例3化合物在人微粒体中能快速代谢，能完全转化为阿曲生坦。
实施例13
化合物大鼠药代动力学研究
(1)实验材料
SD大鼠：雄性，200-300g，购于北京维通利华实验动物技术有限公司。
试剂：DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，生理盐水，肝素，乙腈，甲酸，普萘洛尔(内标)均为市售可得。
仪器：赛默飞LC-MS/MS(U300UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。
(2)实验方法
称取化合物溶于DMSO-PEG-400-生理盐水(5：60：35，v/v/v)体系中，大鼠灌胃给药后，于给药后15min、30min、1h、2h、5h、7h、24h采集静脉血200μL于加氟化钠肝素化EP管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入 空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为1、3、5、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆，加入内标普萘洛尔(50ng/mL)的乙腈溶液200μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清LC-MS/MS分析。LC-MS/MS检测条件如下：
色谱柱：Waters ACQUITYTM PREMIER HSS T3，50*2.1mm，1.8μm。
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱
时间(min) 水(含0.1％甲酸) 乙腈
0 85％ 15％
0.6 85％ 15％
1 20％ 80％
2.3 20％ 80％
2.31 85％ 15％
3 85％ 15％
(3)数据处理
LC-MS/MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数,结果见表4
表4阿曲生坦、实施例3和实施例4 SD大鼠灌胃给药后阿曲生坦药代参数
Figure PCTCN2022116652-appb-000047
注：给药剂量折算为阿曲生坦量
实施例3和4化合物在大鼠体内暴露量比同剂量的阿曲生坦暴露量偏高，灌胃给药后吸收优于阿曲生坦。
实施例14
化合物大鼠药代动力学研究
(1)实验材料
SD大鼠：雄性，200-300g，购于北京维通利华实验动物技术有限公司。
试剂：DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，生理盐水，肝素，乙腈，甲酸，普萘洛尔(内标)均为市售可得。
仪器：赛默飞LC-MS/MS(U300UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。
(2)实验方法
称取化合物溶于DMSO-PEG-400-生理盐水(5：60：35，v/v/v)体系中，大鼠灌胃给药后，于给药后15min、30min、1h、2h、5h、7h、24h采集静脉血200μL于加氟化钠肝素化EP管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为1、3、5、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆，加入内标普萘洛尔(50ng/mL)的乙腈溶液200μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清 LC-MS/MS分析。LC-MS/MS检测条件如下：
色谱柱：Waters ACQUITYTM PREMIER HSS T3，50*2.1mm，1.8μm。
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱
时间(min) 水(含0.1％甲酸) 乙腈
0 85％ 15％
0.6 85％ 15％
1 20％ 80％
2.3 20％ 80％
2.31 85％ 15％
3 85％ 15％
(3)数据处理
LC-MS/MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数,结果见表4
表4阿曲生坦、实施例7 SD大鼠灌胃给药后阿曲生坦药代参数
Figure PCTCN2022116652-appb-000048
实施例7化合物在大鼠体内暴露量比同给药量的阿曲生坦暴露量明显要低，灌胃给药后吸收不及阿曲生坦。
综合实施例12和13、14，总体上，实施例3化合物在体内外均可以快速转化为阿曲生坦，并且口服等摩尔剂量下暴露量相比阿曲生坦更高。
实施例15受试化合物对Dahl/SS大鼠高血压模型的降压作用和肾功能评价
1.实验动物及实验分组
实验采用雄性Dahl/SS大鼠，均购自北京维通利华实验动物技术有限公司，适应期结束后根据动物基础血压和体重随机分为5组。具体分组及给药方案如下表5：
表5实验动物及实验分组
Figure PCTCN2022116652-appb-000049
2.实验方法及实验结果
所有动物饲喂0.3％盐浓度饲料并适应无创血压仪一周后，依据血压值和体重将动物随机分为正常对照组、模型组和三个给药组。正常对照组继续饲喂0.3％盐浓度饲料，模型组和三个给药组改换8％盐浓度饲料，持续饲喂6周。造模时同步给药，每日经口灌胃给药，连续给药6周。血压检测时间：给药后1、3、7、24h检测血压，计算曲线下面积(AUC)；血清肌酐检测时间：分组前检测1次、实验终点检测一次。实验终点大鼠肾脏取材后进行组织病理学检查。
计量指标采用均数±标准差表示。样本数小于3时，该组数据不纳入统计比较。数据经Excel 2010、GraphPad Prism 7、SPSS 22.0和Stata 15.0软件进行录入与统计分析。计量指标先采用LEVENE方差齐性检验，当方差齐时(P＞0.05)，可直接引用方差分析的结果判断总体差异是否有统计学意义，总体差异有统计学意义时(P≤0.05)，用Dunnett-t检验对组间差异进行比较，总体差异无统计学意义时(P＞0.05)，统计分析结束；当LEVENE方差齐性检验显示方差不齐 时(P≤0.05)，则采用非参数检验(Kruskal-Wallis H检验)，Kruskal-Wallis H检验显示总体差异有统计学意义时(P≤0.05)，用Mann-Whitney U检验进行组间差异的比较，当Kruskal-Wallis H检验显示总体差异无统计学意义时(P＞0.05)，统计分析结束。
表6收缩压曲线下面积统计分析汇总结果(Mean±SD)
Figure PCTCN2022116652-appb-000050
备注：*P≤0.05表示与正常对照组相比差异具有统计学意义， &P≤0.05表示与模型对照组相比差异具有统计学意义。
表7血清肌酐统计分析结果(Mean±SD)
Figure PCTCN2022116652-appb-000051
备注：*P≤0.05表示与正常对照组相比差异具有统计学意义， &P≤0.05表示与模型对照组相比差异具有统计学意义。
表8动物肾肾小球硬化评分统计分析汇总结果(Mean±SD)
Figure PCTCN2022116652-appb-000052
备注：*P≤0.05表示与正常对照组相比差异具有统计学意义， &P≤0.05表示与模型对照组相比差异具有统计学意义。
综合以上结果，在本试验条件下在剂量为10mg/kg～40mg/kg时，于造模同时给予每天1次的实施例3化合物干预具有显著的降血压效果。
同时，在本试验条件下，高盐饲料饲养2周后Dahl盐敏感性大鼠肾脏的滤过功能和排泄功能受到严重损伤，高盐饲料饲养的同时每天给予10～40mg/kg实施例3化合物干预对肾脏滤过功能和排泄功能损伤具有显著改善，此外实施例3化合物具有显著改善肾脏组织病理变化的效果。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (12)

  1. 通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，
    Figure PCTCN2022116652-appb-100001
    其中：R 1为氢或C 1-6的烷基，R 2为氢或C 1-6的烷基，或者R 1，R 2组成的C 3-6的环烷基；L选自取代或者未取代的C 1-6-烷基、C 3-6的环烷基、C 1-6的烷氧基、取代或者未取代的-(CH 2)n-杂环，n为0-3的自然数。
  2. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，取代的C 1-6-烷基的取代基包括羟基、磷酸基、胺基、C 1-6-烷基取代氨基；取代的-(CH 2)n-杂环的取代基包括C 1-6的烷基、羟基、羰基，杂环选自C 3-6的饱和或者不饱和杂环，杂环中一个以上的C原子被O、N或S所替换。
  3. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，R 1和R 2不同时为氢。
  4. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，所述C 1-6的烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
  5. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，C 3-6的环烷基包括环丙烷、环丁烷、环戊烷、环己烷。
  6. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，所述C 1-6的烷氧基，包括甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基；取代或者未取代的杂环选自
    Figure PCTCN2022116652-appb-100002
    Figure PCTCN2022116652-appb-100003
  7. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，其中R 1和R 2独自的选自氢、甲基，且R 1和R 2不同时为氢；L选自甲基、乙基、异丙基、
    Figure PCTCN2022116652-appb-100004
    环丙基、
    Figure PCTCN2022116652-appb-100005
    Figure PCTCN2022116652-appb-100006
  8. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，选自以下化合物：
    Figure PCTCN2022116652-appb-100007
    Figure PCTCN2022116652-appb-100008
  9. 根据权利要求1所述的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其特征在于，所述化合物的可药用的盐是指化合物，或其异构体、或其消旋体与药学上可接受的酸或碱制备。
  10. 根据权利要求1-9任一项所述化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐在制备用于治疗和/或预防内皮素A(ETA)受体拮抗相关疾病的药物方面的用途。
  11. 根据权利要求10所述的用途，其特征在于，所述疾病包括慢性肾病、IgA、FSGS和高血压的疾病。
  12. 一种药物组合物，所述药物组合物含有前述权利要求1-11任一项所述化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，和一种以上药学上可接受的载体。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622971A (en) * 1994-08-19 1997-04-22 Abbott Laboratories Endothelin antagonists
US6162927A (en) * 1994-08-19 2000-12-19 Abbott Laboratories Endothelin antagonists
CN1384100A (zh) * 1996-02-13 2002-12-11 艾博特公司 苯并－1,3－间二氧杂环戊烯基和苯并呋喃基取代的吡咯烷衍生物
US7208517B1 (en) * 1994-08-19 2007-04-24 Abbott Labortories Endothelin antagonists
CN101454283A (zh) * 2006-05-29 2009-06-10 尼科克斯公司 作为内皮素受体拮抗剂的硝化的杂环化合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1301264A (zh) * 1997-08-04 2001-06-27 艾博特公司 内皮素拮抗剂
WO2024022262A1 (zh) * 2022-07-25 2024-02-01 深圳信立泰药业股份有限公司 一种内皮素a(eta)受体拮抗剂化合物的盐及其制备方法和医药用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622971A (en) * 1994-08-19 1997-04-22 Abbott Laboratories Endothelin antagonists
US6162927A (en) * 1994-08-19 2000-12-19 Abbott Laboratories Endothelin antagonists
US7208517B1 (en) * 1994-08-19 2007-04-24 Abbott Labortories Endothelin antagonists
CN1384100A (zh) * 1996-02-13 2002-12-11 艾博特公司 苯并－1,3－间二氧杂环戊烯基和苯并呋喃基取代的吡咯烷衍生物
CN101454283A (zh) * 2006-05-29 2009-06-10 尼科克斯公司 作为内皮素受体拮抗剂的硝化的杂环化合物

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