WO2024022262A1 - 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 - Google Patents
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 Download PDFInfo
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- WO2024022262A1 WO2024022262A1 PCT/CN2023/108780 CN2023108780W WO2024022262A1 WO 2024022262 A1 WO2024022262 A1 WO 2024022262A1 CN 2023108780 W CN2023108780 W CN 2023108780W WO 2024022262 A1 WO2024022262 A1 WO 2024022262A1
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Classifications
-
- 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
Definitions
- the invention belongs to the technical field of chemical drugs and provides a salt of an endothelin A (ETA) receptor antagonist compound and its preparation method and application.
- 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 used clinically, with the following structure:
- salt formation can improve some undesirable physical, chemical or biological properties of drugs. Therefore, it is of great significance to develop a salt of an endothelin A (ETA) receptor antagonist compound with more excellent properties in terms of physical, chemical or pharmaceutical properties.
- ETA endothelin A
- the present invention provides a salt of an endothelin A (ETA) receptor antagonist compound with a novel structure and its preparation method and application.
- ETA endothelin A
- the present invention provides a salt of the compound represented by formula (I), whose structural formula is shown in Figure 1, as follows:
- the inorganic acid is selected from sulfuric acid, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, carbonic acid or nitric acid;
- the organic acid is selected from benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, oxalic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, caproic acid, adipic acid, Benzenesulfonic acid, 4-chlorobenzenesulfonic acid, caprylic acid, capric acid, cinnamic acid, citric acid, aspartic acid, gluconic acid, glutamic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, Succinic acid, formic acid, fumaric acid, gentisic acid, glutaric acid, valeric acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, nicotinic acid, propionic acid, salicylic acid, 4-Aminosalicylic acid, sebacic acid,
- the inorganic acid is selected from phosphoric acid.
- the organic acid is selected from oxalic acid.
- the present invention further provides a pharmaceutical composition, which contains the salt of the compound represented by formula (I) and one or more pharmaceutically acceptable carriers.
- the present invention further provides the use of the salt of the compound represented by formula (I) in preparing drugs for treating and/or preventing diseases related to endothelin A (ETA) receptor antagonism.
- ETA endothelin A
- the diseases include chronic kidney disease, IgA, FSGS, Alport and hypertension.
- the present invention further provides a method for preparing a salt of the compound represented by formula (I), wherein the compound A is
- the molar ratio of the compound to the acid molecule is 1:1-2.
- step 2 Weigh an appropriate amount of ionic acid and add it to step 1 to react to form a salt;
- the acid is selected from the group consisting of M, which is an inorganic acid or an organic acid, and the inorganic acid is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, carbonic acid or nitric acid.
- the organic acid is selected from benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, oxalic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, caproic acid, adipic acid, Benzenesulfonic acid, 4-chlorobenzenesulfonic acid, caprylic acid, capric acid, cinnamic acid, citric acid, aspartic acid, gluconic acid, glutamic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, Succinic acid, formic acid, fumaric acid, gentisic acid, glutaric acid, valeric acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, nicotinic acid, propionic acid, salicylic acid, 4-Aminosalicylic acid, sebacic acid,
- the solvent used to form the salt of the present disclosure is selected from the group consisting of ethyl acetate, methanol, n-propanol, isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tert-butyl ether, acetonitrile, ethanol, 1,4- At least one of dioxane, n-hexane and isopropyl ether.
- the method for preparing the aforementioned pharmaceutically acceptable salts also includes steps such as evaporating the solvent or stirring for crystallization, filtration, and drying.
- “Pharmaceutically acceptable salts” as used herein belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by salt formation with an acid or salt with a base.
- Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
- prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
- Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
- solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
- the atoms of the compound molecules of the present invention are isotopes, and isotope derivatization can usually extend the half-life, reduce the clearance rate, enhance metabolic stability, and improve in vivo activity. Also included is an embodiment in which at least one atom is replaced by an atom with the same atomic number (number of protons) and a different mass number (sum of protons and neutrons).
- isotopes included in the compound of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H, 3 H, 13 C, 14 C, and 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl.
- radioactive isotopes that emit radiation as they decay such as 3H or 14C, may be used in pharmaceutical preparations or in the anatomical examination of compounds in the body. Stable isotopes do not decay or change with their amount, nor are they radioactive, making them safe to use.
- the isotope can be converted according to general methods by substituting reagents containing the corresponding isotope for the reagents used in the synthesis.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- compounds can be labeled with radioactive isotopes such as deuterium ( 2H ), iodine-125 ( 125I ) or C-14 ( 14C ). All variations in the 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 replaced by the isotope deuterium ( 2H ).
- the compound of the present invention is deuterated. Afterwards, it has the effects of extending half-life, reducing clearance rate, enhancing metabolic stability and improving in vivo activity.
- the preparation method of the isotope derivative usually includes: phase transfer catalysis method.
- phase transfer catalysts eg, tetraalkylammonium salts, NBu 4 HSO 4 .
- the use of a phase transfer catalyst to exchange the methylene proton of the diphenylmethane compound results in a lower ratio of the methylene protons with a deuterated silane (e.g. triethyldeuterated silane) in the presence of an acid (e.g. methanesulfonic acid) or with a Lewis acid such as trichloro Aluminum is reduced by deuterated sodium borate to introduce higher deuterium.
- a deuterated silane e.g. triethyldeuterated silane
- an acid e.g. methanesulfonic acid
- Lewis acid such as trichloro Aluminum
- 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 matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on vectors, please refer to 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 for formulating an effective pharmaceutical composition.
- the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
- the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
- the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
- active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
- tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
- protontautomers also known as prototropic tautomers
- prototropic tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
- Valence tautomers involve interconversions through the reorganization of some bonding electrons.
- Keto-enol tautomerism Another example of tautomerism is phenol-ketone tautomerism. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- the compounds of the present invention may exist in specific 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 racemic mixtures thereof and other mixtures, such as enantiomeric 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 such 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 auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods 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 combined with chemical derivatization methods (e.g., generation of amino groups from amines). 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, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments 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 equivalent to that of Atrasentan in pharmacokinetic studies. .
- the salt of the compound represented by formula (I) provided by the present invention has improved physical and chemical properties compared with the free compound represented by (I), and is more convenient for pharmaceutical applications.
- Figure 1 is a schematic structural formula diagram of the salt of compound A of the present invention.
- Figure 2 is the nuclear magnetic spectrum of the hydrochloride obtained in Example 18 of the present invention.
- Figure 3 is the nuclear magnetic spectrum of the sulfate obtained in Example 19 of the present invention.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- MS was measured using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
- HPLC High performance liquid chromatography
- CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
- Thin layer chromatography silica gel plates use Yantai Yinlong HSGF 254 or GF 254 silica gel plates.
- the specifications of the silica gel plates used in thin layer chromatography (TLC) are 0.17mm ⁇ 0.23mm.
- the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
- Silica gel column chromatography generally uses Rushan Bangbang silica gel 100-200 mesh silica gel as the carrier.
- the invention relates to the following reagents: DMF (N,N-dimethylformamide), KI (potassium iodide), Cs 2 CO 3 (cesium carbonate), DCM (dichloromethane), n-hexane, EA (ethyl acetate), Py (pyridine), CF 3 COOH (trifluoroacetic acid), IPA (isopropyl alcohol), isopropyl ether, acetone.
- DMF N,N-dimethylformamide
- KI potassium iodide
- Cs 2 CO 3 cesium carbonate
- DCM diichloromethane
- n-hexane n-hexane
- EA ethyl acetate
- Py pyridine
- CF 3 COOH trifluoroacetic acid
- IPA isopropyl alcohol
- isopropyl ether acetone.
- 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]dioxolane-5-yl)-1-[2-(dibutylamino) -2-Oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
- chloromethylethyl carbonate 270 mg, 1.96 mmol
- cesium carbonate 640 mg, 1.96 mmol
- potassium iodide 325 mg, 1.96 mmol
- reaction solution After the reaction is completed, cool the reaction solution to room temperature, pour it into 40 ml of ice-water solution, extract with dichloromethane (100 ml ⁇ 3), combine the organic phases, wash with saturated brine (50 ml), and dry 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]dioxolane-5-yl)-1-[2-(dibutylamino) -2-Oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
- 1-chloroethylethyl carbonate 298 mg, 1.96 mmol
- cesium carbonate 640 mg, 1.96 mmol
- potassium iodide 325 mg, 1.96 mmol
- reaction solution After the reaction is completed, cool the reaction solution to room temperature, pour it into 40 ml of ice-water solution, extract with dichloromethane (100 ml ⁇ 3), combine the organic phases, wash with saturated brine (50 ml), and dry 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]dioxolane-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]dioxolane-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 (2-(((1-chloroethoxy)carbonyl)oxy)ethyl)(methyl)carbamic acid tert-butyl ester
- 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 Oxolan-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
- Step A 1-Chloroethyl (((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methyl)carbonate
- Step B Synthesis of 1-(((((S)-2,2-dimethyl-1,3-dioxolane-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]dioxolan-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]dioxolane-5-yl)-1-[2-(dibutylamino) -2-Oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid 500 mg, 0.98 mmol
- 1-chloroethylcyclopropyl 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]dioxola Alk-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 pyrrolidine-3-carboxylate
- Step B Synthesis of 1-(((oxetan-3-yl)oxy)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 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 pyrrolidine-3-carboxylate
- Human liver microsomes were purchased from Red Liver Disease Research (Shanghai) Co., Ltd.
- DMSO dimethyl sulfoxide
- acetonitrile formic acid
- propranolol internal standard
- 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, 200-300g, purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.
- DMSO dimethyl sulfoxide
- PEG-400 polyethylene glycol 400
- physiological saline physiological saline
- heparin acetonitrile
- formic acid formic acid
- propranolol internal standard
- the compound was weighed and dissolved in the DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system. After intragastric administration to the rats, 15min, 30min, 1h, 2h, and 5h after administration Collect 200 ⁇ L of venous blood into heparinized EP tubes with sodium fluoride at 7 and 24 hours, centrifuge at 12,000 rpm for 2 min, and freeze the plasma at -80°C for testing. Precisely weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg/mL as a stock solution. Accurately draw an appropriate amount of compound stock solution and add acetonitrile to dilute it to prepare a standard series of solutions.
- SD rats male, 200-300g, purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.
- DMSO dimethyl sulfoxide
- PEG-400 polyethylene glycol 400
- physiological saline physiological saline
- heparin acetonitrile
- formic acid formic acid
- propranolol internal standard
- the compound was weighed and dissolved in the DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system. After intragastric administration to the rats, 15min, 30min, 1h, 2h, and 5h after administration Collect 200 ⁇ L of venous blood into heparinized EP tubes with sodium fluoride at 7 and 24 hours, centrifuge at 12,000 rpm for 2 min, and freeze the plasma at -80°C for testing. Precisely weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg/mL as a stock solution. Accurately draw an appropriate amount of compound stock solution and add acetonitrile to dilute it to prepare a standard series of solutions.
- Example 3 can be rapidly converted into atrasentan both in vivo and in vitro, and the oral exposure is higher than that of atrasentan in equimolar doses.
- Dissolve compound A in different solvents such as isopropyl alcohol, acetone, ethyl acetate, etc., and add acids with the same molar ratio (as shown in the table below, a total of 17 acids). After a certain reaction time, the solution becomes clear. By adding anti-solvent and lowering the temperature Wait for the solid to precipitate.
- Compound A is an oily substance that can only form a salt with a few acids before precipitating as a solid. As can be seen from the above table, it is quite difficult to form a salt of compound A. Only a few acids: sulfuric acid, phosphoric acid, oxalic acid and hydrochloric acid can form a salt.
- ⁇ 0.93 is the methyl hydrogen on C atoms 34 and 37, with a proton number of 6 and two sets of triplet peaks;
- the number of protons is 12, for three groups of multiple peaks;
- ⁇ 4.39 is the methine hydrogen on C atom No. 7, with a proton number of 1, and is two sets of doublets;
- ⁇ 2.78, 2.99, 3.19, 3.31, and 3.50 are respectively the methylene hydrogen on C atoms 30, 31, 26, 11, 9, and 10, with a proton number of 12, and are three sets of multiplets;
- ⁇ 6.57 and 6.84 are the methine hydrogens on C atoms 18, 15 and 14 respectively, with a proton number of 3, and are three sets of doublets;
- ⁇ 6.92 is the methine hydrogen on the C atom of the benzene ring No. 4 and No. 6, with a proton number of 2 and two sets of triplet peaks;
- ⁇ 7.06
- 7.27 is the methine hydrogen on C atoms of No. 1 and 3 benzene ring, and is the methine hydrogen on C atom of No. 38.
- the number of protons is 3, which are two sets of triplet peaks.
- the oxalate and phosphate obtained by the present invention have lower hygroscopicity and are better than hydrochloride and sulfate.
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Abstract
本发明属于化学药物技术领域,提供了一种内皮素A(ETA)受体拮抗剂化合物的盐及其制备方法和应用。
Description
本发明属于化学药物技术领域,提供了一种内皮素A(ETA)受体拮抗剂化合物的盐及其制备方法和应用。
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:
在临床上应用的是盐酸阿曲生坦(CAS:195733-43-8),结构如下:
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。
近一半药物分子都是以盐的形式存在,同时,成盐可改善药物某一些不理想的物理化学或生物学性质。因此,开发出一种在理化性质或药学性质方面具有更优异的性质内皮素A(ETA)受体拮抗剂化合物的盐是具有重要意义的。
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)受体拮抗剂化合物的盐及其制备方法和应用。
具体而言,本发明提供了一种式(I)所示的化合物的盐,其结构式如图1所示,如下:
M为无机酸或有机酸,其中n:x=1:1-2。
作为本发明的一种优选技术方案,所述无机酸选自硫酸、盐酸、氢氟酸、氢溴酸、氢碘酸、磷酸、碳酸或硝酸;
所述有机酸选自苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、草酸、醋酸、二氯醋酸、三氯醋酸、己酸、己二酸、苯磺酸、4-氯苯磺酸、辛酸、癸酸、肉桂酸、柠檬酸、天冬门氨酸、葡萄糖酸、谷氨酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、琥珀酸、蚁酸、富马酸、龙胆酸、戊二酸、戊酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、烟酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、棕榈酸、双羟萘酸、三氟乙酸、硫氰酸、对甲基苯磺酸和L-苹果酸。
作为本发明的一种优选技术方案,所述无机酸选自磷酸。
作为本发明的一种优选技术方案,所述无机酸选自磷酸,其中n=3,x=3-6。
作为本发明的一种优选技术方案,所述无机酸选自磷酸,其中n=3,x=3;或者n=3,x=4,或者n=3,x=5,或者n=3,x=6。
作为本发明的一种优选技术方案,所述有机酸选自草酸。
作为本发明的一种优选技术方案,所述有机酸选自草酸,其中n=1,x=1。
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所述式(I)所示化合物的盐,和一种以上药学上可接受的载体。
本发明进一步提供了所述式(I)所示化合物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。
作为本发明的一种优选技术方案,所述疾病包括慢性肾病、IgA、FSGS、Alport和高血压的疾病。
本发明进一步提供了所述式(I)所示化合物的盐的制备方法,将所述化合物A
与酸混合,制备得到。
作为本发明的一种优选技术方案,所述化合物与酸分子的摩尔比为1:1-2。
作为本发明的一种优选技术方案,包括如下步骤:
1)称取适量的游离碱,用良性溶剂溶解;
2)称取适量的离子酸加入步骤1中反应成盐;
3)将步骤2的反应液反滴到不良溶剂中搅拌析出;
4)快速离心或静置得到化合物的盐。
所述酸选自M为无机酸或有机酸,所述无机酸选自硫酸、盐酸、氢氟酸、氢溴酸、氢碘酸、磷酸、碳酸或硝酸。所述有机酸选自苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、草酸、醋酸、二氯醋酸、三氯醋酸、己酸、己二酸、苯磺酸、4-氯苯磺酸、辛酸、癸酸、肉桂酸、柠檬酸、天冬门氨酸、葡萄糖酸、谷氨酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、琥珀酸、蚁酸、富马酸、龙胆酸、戊二酸、戊酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、烟酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、棕榈酸、双羟萘酸、三氟乙酸、硫氰酸、对甲基苯磺酸和L-苹果酸。
本公开成盐所用溶剂选自乙酸乙酯、甲醇、正丙醇、异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、正己烷、异丙醚中的至少一种。
进一步地,在可选实施方案中,制备前述可药用盐的方法还包括挥发溶剂或搅拌析晶,过滤、干燥等步骤。
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,NBu4HSO4)。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。
本发明所提供的式(I)所示化合物的盐较游离的(I)所示化合物理化性质有所改善,更利于药学应用使用。
图1是本发明化合物A的盐的结构式示意图
图2是本发明实施例18所得盐酸盐的核磁图谱
图3是本发明实施例19所得硫酸酸盐的核磁图谱
下面结合实施例和附图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-d6),氘代氯仿(CDCl3),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HSGF254或GF254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。
本发明涉及如下试剂:DMF(N,N-二甲基甲酰胺)、KI(碘化钾)、Cs2CO3(碳酸铯)、DCM(二氯甲烷)、正己烷、EA(乙酸乙酯)、Py(吡啶)、CF3COOH(三氟乙酸)、IPA(异丙醇)、异丙醚、丙酮。
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
步骤A:((R)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯
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
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
步骤A:1-氯乙基氧杂环丁烷-3-基碳酸酯
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
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
步骤A:((S)-1,4-二噁烷-2-基)甲基(1-氯乙基)碳酸酯
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
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:H2O=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
(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1和表2。
表1.各药物在微粒体中原型变化
表2.实施例化合物在微粒体中转化为阿曲生坦量
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
(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3
表3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
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
(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
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盐的筛选实施例
将化合物A溶解在异丙醇、丙酮、乙酸乙酯等不同溶剂中,加入相同摩尔比的酸(如下表,共17种酸),反应一定时间后,溶液澄清,通过添加反溶剂以及降低温度等将固体析出。
表5 17种酸配体的筛选
化合物A为油状物,只能与少数酸成盐后才会以固体析出。由上表可知,化合物A成盐具有相当的难度,只有少数的酸:硫酸、磷酸、草酸和盐酸可以成盐。
实施例16草酸盐的制备
将化合物A游离碱(3.5g)溶于异丙醇(10ml)中,加入草酸二水合物(689mg),室温搅拌反应1h,浓缩,得到油状物,冰浴下加入异丙醚(50ml)搅拌析出固体,冰浴搅拌1天,过滤,得草酸盐固体。
将化合物A游离碱(2.4g)与草酸二水合物(46mg)在乙酸乙酯(1w/w)中反应成盐,于-5℃下滴加至异丙醚(15w/w)中,
搅拌1天,过滤,干燥,得到固体。
将化合物A游离碱(2.2g)与草酸(70mg)在异丙醇(2ml)中反应,浓缩,加乙酸异丙酯(0.5ml),于-15℃下加入异丙醚(15ml),搅拌4h,过滤得到固体。
草酸盐的核磁数据:
归属:
解析:
δ=0.93的为34,37号C原子上的甲基氢,质子数为6,为两组三重峰;
δ=1.28的为45号C原子上的甲基氢,质子数为3,为一组双重峰;
δ=1.34的为46号C原子上的甲基氢,33,36号C原子上的亚甲基氢,质子数为7,分别为一组三重峰和两组双重峰;
δ=1.52的为32,35号C原子上的亚甲基氢,质子数为4,为两组三重峰;
δ=1.59的为39号C原子上的甲基氢,质子数为3,为一组双重峰;
δ=3.24,3.29,3.31,3.35,3.41,3.59,3.68的分别为30,31,26,11,9,10号C原子上的亚甲基氢,质子数为
12,为三组多重峰;
δ=3.78的为25号C原子上的甲基氢,质子数为3,为一组单峰;
δ=4.39的为7号C原子上的次甲基氢,质子数为1,为两组双重峰;
δ=5.08的为44号C原子上的次甲基氢,质子数为1,为一组多重峰;
δ=5.93的为20号C原子上的亚甲基氢,质子数为2,为一组三重峰;
δ=6.63,6.72,6.82的分别为18,15,14号C原子上的次甲基氢,质子数为3,为三组双重峰;
δ=6.91的为4,6号苯环C原子上的次甲基氢,质子数为2,为两组三重峰;
δ=7.20的为1,3号苯环C原子上的次甲基氢,质子数为2,为两组三重峰;
δ=7.51的为38号C原子上的次甲基氢,质子数为1,为一组多重峰;
δ=11.05的为草酸上的C原子上的羧基氢,质子数为2,为一组单峰。
实施例17磷酸盐的制备
将化合物A游离碱(4.1g)溶于异丙醇(12ml)中,加入磷酸(800mg)反应1h,冰浴下加入异丙醚(80ml)搅拌4h,得到磷酸盐固体。
磷酸盐的核磁数据:
归属:
解析:
δ=0.73,0.83的为34,37号C原子上的甲基氢,质子数为6,为两组三重峰;
δ=1.25的为45,46,39号C原子上的甲基氢,33,36号C原子上的亚甲基氢,32,35号C原子上的亚甲基氢,质子数为14,为多重峰;
δ=2.78,2.99,3.19,3.31,3.50的分别为30,31,26,11,9,10号C原子上的亚甲基氢,质子数为12,为三组多重峰;
δ=4.75的为7号C原子上的次甲基氢,质子数为1,为两组双重峰;
δ=6.00的为20号C原子上的亚甲基氢,质子数为2,为一组三重峰;
δ=6.57,6.84的分别为18,15,14号C原子上的次甲基氢,质子数为3,为三组双重峰;
δ=6.92的为4,6号苯环C原子上的次甲基氢,质子数为2,为两组三重峰;
δ=7.06,7.27的为1,3号苯环C原子上的次甲基氢,为38号C原子上的次甲基氢,质子数为3,为两组三重峰。
元素分析,P元素含量(%)=6.46,相对标准偏差(%)=0.2。
检测仪器:全谱直读等离子体原子法射光谱仪,iCAP6500Duo(美国Thermo);
检测条件:入射功率:1150W等离子体气流量:14L/min雾化器流量:0.5L/min。
实施例18盐酸盐的制备
称取化合物A游离碱(202.5mg)于5mL小瓶中,加入MeOH(1.0mL),等摩尔比盐酸甲醇溶液。-20℃悬浮搅拌1天,旋蒸除去甲醇,样品呈胶状,转至真空干燥仍呈胶状。加入异丙醚(2.0mL),于-20℃悬浮搅拌1天,析出固体,离心并转至真空干燥得到固体。
核磁谱图如图2所示。
实施例19硫酸盐的制备
称取化合物A游离碱(203.1mg)于5mL小瓶中,加入IPA(1.0mL)溶剂,等摩尔比硫酸,-20℃悬浮搅拌1天,转至真空干燥除去IPA,样品成胶状。加入异丙醚(2.0mL),于-20℃悬浮搅拌1天,析出固体,离心并真空干燥得到固体。
核磁谱图如图3所示。
实施例20稳定性研究
将硫酸盐、磷酸盐、盐酸盐和草酸盐分别在25℃/60%RH和40℃/75%RH条件下放置1周,通过HPLC检测样品的化学稳定性。
从上表可知,本发明得到的草酸盐和磷酸盐稳定性好,且优于盐酸盐和硫酸盐。
实施例21引湿性研究
将硫酸盐、磷酸盐、盐酸盐和草酸盐通过动态水分吸附仪(DVS)进行引湿性评估。测试收集了25℃恒温条件下,随湿度变化时,样品的质量变化百分比。DVS测试结果如下:
从上表可知,本发明得到的草酸盐和磷酸盐引湿性较低,且优于盐酸盐和硫酸盐。
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 (13)
- 一种式(I)所示的化合物的盐,其特征在于,
M为无机酸或有机酸,其中n:x=1:1-2。 - 根据权利要求1所述的式(I)所示化合物的盐,其特征在于,所述无机酸选自硫酸、盐酸、氢氟酸、氢溴酸、氢碘酸、磷酸、碳酸或硝酸;所述有机酸选自苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、草酸、醋酸、二氯醋酸、三氯醋酸、己酸、己二酸、苯磺酸、4-氯苯磺酸、辛酸、癸酸、肉桂酸、柠檬酸、天冬门氨酸、葡萄糖酸、谷氨酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、琥珀酸、蚁酸、富马酸、龙胆酸、戊二酸、戊酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、烟酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、棕榈酸、双羟萘酸、三氟乙酸、硫氰酸、对甲基苯磺酸和L-苹果酸。
- 根据权利要求1所述的式(I)所示化合物的盐,其特征在于,所述无机酸选自磷酸。
- 根据权利要求1所述的式(I)所示化合物的盐,其特征在于,所述无机酸选自磷酸,其中n=3,x=3-6。
- 根据权利要求1所述的式(I)所示化合物的盐,其特征在于,所述无机酸选自磷酸,其中n=3,x=3,n=3,x=4;或者n=3,x=5,或者n=3,x=6。
- 根据权利要求1所述的式(I)所示化合物的盐,其特征在于,所述有机酸选自草酸。
- 根据权利要求1所述的式(I)所示化合物的盐,其特征在于,所述有机酸选自草酸,其中n=1,x=1。
- 根据权利要求1-7任一权利要求所述化合物的盐的制备方法,其特征在于,所述化合物A与酸混合,制备得到。
- 根据权利要求8所述的制备方法,其特征在于,所述化合物与酸分子的摩尔比为1:1-2。
- 根据权利要求8所述的制备方法,包括如下步骤:1)称取适量的游离碱,用良性溶剂溶解;2)称取适量的离子酸加入步骤1中反应成盐;3)将步骤2的反应液反滴到不良溶剂中搅拌析出;4)快速离心或静置得到化合物的盐。
- 一种药物组合物,所述药物组合物含有前述权利要求1-7任一项所述式(I)所示化合物的盐,和一种以上药学上可接受的载体。
- 根据权利要求1-7任一项所述式(I)所示化合物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。
- 根据权利要求12所述的用途,其特征在于,所述疾病包括慢性肾病、IgA、FSGS、Alport和高血压的疾病。
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