WO2024088307A1 - Nouveau composé peptidylnitrile et son utilisation - Google Patents

Nouveau composé peptidylnitrile et son utilisation Download PDF

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WO2024088307A1
WO2024088307A1 PCT/CN2023/126526 CN2023126526W WO2024088307A1 WO 2024088307 A1 WO2024088307 A1 WO 2024088307A1 CN 2023126526 W CN2023126526 W CN 2023126526W WO 2024088307 A1 WO2024088307 A1 WO 2024088307A1
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mmol
compound
formula
room temperature
pharmaceutically acceptable
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PCT/CN2023/126526
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叶斌
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上海壹迪生物技术有限公司
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Publication of WO2024088307A1 publication Critical patent/WO2024088307A1/fr

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  • the present invention relates to the field of medical technology, in particular to a novel peptide-based nitrile compound and application thereof.
  • Inflammatory diseases are currently an important area of drug research and development. Although interleukin antibody drugs and small molecule drugs such as JAK inhibitors have been used clinically, they all have defects to varying degrees. For example, antibody drugs can only be administered by injection and have low clinical compliance. JAK inhibitors are used for inflammatory diseases and have potential adverse cardiovascular reactions due to their target mechanism (Norman P, Expert Opinion on Investigational Drugs. 2014, 23(8):1067–77). Therefore, it is still necessary to explore new anti-inflammatory drugs.
  • Cathepsin C also known as dipeptidyl peptidase I (DPP-1), is a lysosomal cysteine protease belonging to the papain family with a molecular weight of 200 KDa.
  • Cathepsin C acts as a key enzyme that activates neutrophil and mast cell granule serine peptidases in inflammatory cells (such as four neutrophil proteases, elastase (NE), cathepsin G (CatG), proteinase 3 (PR3) and neutrophil serine protease (NSP4), as well as mast cell-related chymase, tryptase and serine protease, etc.) (Guay, D. et al, Curr.
  • cathepsin C can be used as potential therapeutic drugs for the treatment of neutrophil-dominated inflammatory diseases, including chronic obstructive pulmonary disease (COPD), emphysema, asthma, multiple sclerosis, idiopathic pneumonia, cystic fibrosis, etc. (Laine et al, Expert Opin. Ther. Patents 2010, 20, 497).
  • COPD chronic obstructive pulmonary disease
  • emphysema asthma
  • multiple sclerosis multiple sclerosis
  • idiopathic pneumonia cystic fibrosis
  • cathepsin downstream serine protease elastase plays a very important role in the occurrence and metastasis of cancer, as well as cardiovascular and cerebrovascular diseases such as myocardial infarction. Therefore, theoretically, inhibiting cathepsin also has the same pharmacological effect as inhibiting elastase. Therefore, theoretically, cathepsin inhibitors can also be used for the treatment of cancer diseases and cardiovascular and cerebrovascular diseases.
  • cathepsin C inhibitors There is still a large unmet demand for cathepsin C inhibitors.
  • Existing compounds are difficult to inhibit the activity of cathepsin C and downstream serine proteases, so it is necessary to provide new peptide-based nitrile compounds and their applications.
  • One object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • X, Y are each independently selected from O, -NH, -NMe, -CH 2 -, -C(O)-;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, cyano, fluorine, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
  • R 4 and R 5 are each independently selected from H and cyano.
  • R 1 , R 2 , and R 3 are each independently selected from H, fluorine, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy.
  • R 1 and R 2 are linked to form a cycloalkyl group.
  • R 4 and R 5 are connected to form the following structure:
  • R 6 is selected from H, methyl, ethyl, cyclopropyl, propyl, isopropyl, deuterated methyl.
  • the compound of formula (I) when R 4 and R 5 are connected to form a five-membered ring, the compound of formula (I) has a structure of formula (II), formula (III), or formula (IV):
  • Z is O or S;
  • R 3 is selected from H, cyano, fluorine, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds:
  • the beneficial effects of the present invention relate to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and preventing diseases of cathepsin C and its downstream serine proteases NE, PR3, CaTG, and NSP4.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in the treatment of patients with respiratory diseases, metabolic diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, cancers, infectious diseases and other inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, non-cystic fibrosis, cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, allergic diseases, immune inflammatory bowel disease, rheumatoid arthritis, nephrotic syndrome, Use of the present invention in a drug for treating glomerulonephritis, eosinophilic diseases, neutrophilic diseases, ANCA-related inflammation, anti-neutrophil cytoplasmic antibody-related necrotizing crescentic glomerulonep
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition contains one or more compounds of formula (I) and a pharmaceutically active compound selected from a group consisting of other compounds, wherein the other compounds include but are not limited to: b mimetics, anticholinergic drugs, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, NE inhibitors, MMP9 inhibitors, MMP12 inhibitors and a combination of two or three active substances.
  • a pharmaceutically active compound selected from a group consisting of other compounds, wherein the other compounds include but are not limited to: b mimetics, anticholinergic drugs, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, NE inhibitors, MMP9 inhibitors, MMP12 inhibitors and a combination of
  • the pharmaceutical composition also includes combined use with small molecule compounds and/or macromolecular antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases
  • the small molecule compounds and/or macromolecular antibodies include but are not limited to glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophylline drugs, antioxidants, elastase inhibitors, metalloproteinase inhibitors, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, chemokine receptor inhibitors, interleukin antibodies such as IL-6 antibodies, IL-23 antibodies, targeted anti-thymic stromal lymphopoietin (TSLP) antibodies such as tezepelumab, and complement inhibitors.
  • glucocorticoids include but are not limited to glucocorticoids, adrenergic agonists,
  • the beneficial effects of the present invention relate to the use of a composition of the compound of formula (I) in a drug for treating and preventing diseases caused by cathepsin C and its downstream serine proteases NE, PR3, CaTG, and NSP4, wherein the disease is selected from respiratory diseases, metabolic diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, cancer, infectious diseases, or inflammatory infectious diseases.
  • the compounds of the present invention may be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers, for example, enantiomers and diastereomers. Containing asymmetrically substituted carbon atoms.
  • the compounds of the present invention may be isolated into optically pure or racemic forms. Optically pure forms may be prepared by resolution of racemates, or by using chiral synthons or chiral reagents.
  • the compounds of the present invention may also include tautomeric forms.
  • Tautomeric forms are generated by the interchange of a single bond with an adjacent double bond accompanied by the migration of a proton.
  • the compounds of the present invention may also include all isotopic forms of atoms present in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the present invention also includes pharmaceutically acceptable salts of compounds of formula (I).
  • Pharmaceutically acceptable salts refer to derivatives of compounds of formula (I) wherein the parent compound is modified by conversion of the base moiety present into its salt form, or derivatives of compounds of formula (I) wherein the parent compound is modified by conversion of the acid moiety present into its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids of basic groups (such as amines), or salts of inorganic or organic bases of acidic groups (such as carboxylic acids).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds of formula (I) by reacting the free base forms of these compounds with 1-4 equivalents of an appropriate acid in a solvent system. Suitable salts are listed in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • solvate forms or hydrate forms are equivalent to non-solvate forms or non-hydrate forms, and are all included within the scope of the present invention.
  • Some compounds of the present invention may exist in multiple crystal forms or amorphous forms. Generally speaking, all physical forms of compounds are included within the scope of the present invention.
  • the present invention also includes prodrugs of compounds of formula (I).
  • a prodrug is a pharmacological substance (i.e., a drug) derived from a parent drug. Once administered, the prodrug is metabolized in vivo to become the parent drug.
  • Prodrugs can be prepared by substituting one or more functional groups present in a compound, wherein the substituents in the prodrug are removed in vivo in such a way as to be converted into the parent compound. The preparation and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" Vol. 14 of the A.C.S. Symposium Series and Bioreversible.
  • alkyl used in the present invention refers to a straight or branched saturated hydrocarbon group containing 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 6 carbon atoms, and such as 1 to 4 carbon atoms.
  • C1-C6 alkyl is within the scope of “alkyl” and represents the alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), isopropyl (“i-Pr”), n-butyl (“n-Bu”), isobutyl (“i-Bu”), sec-butyl (“sBu”), and tert-butyl (“t-Bu”).
  • halo refers to fluoro, chloro, bromo and iodo
  • halogen refers to fluorine, chlorine, bromine and iodine
  • cycloalkyl used in the present invention refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3-12 ring carbon atoms, for example 3-8 ring carbon atoms, and for example 3-6 ring carbon atoms, which may have one or more rings, for example 1 or 2 rings.
  • C3-8 cycloalkyl represents the cycloalkyl group with 3-8 ring carbon atoms.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and similar groups.
  • cycloalkoxy refers to the group -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, including their isomers.
  • group and “radical” are synonymous and are used to indicate a functional group or a molecular fragment that can be connected to other molecular fragments.
  • the compound represented by the structural formula is a chiral compound, that is, the compound is in R-configuration or S-configuration.
  • the configuration of the compound can be determined by a person skilled in the art using a variety of analytical techniques, such as single crystal X-ray crystallography and/or optical polarimetry and according to conventional protocols.
  • substitution pattern, event or situation described herein may occur once or multiple times, or may not occur, and the description includes situations where the substitution pattern occurs and situations where the substitution pattern does not occur.
  • “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined herein. It should be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable substitution pattern.
  • substituted or “substituted by" as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given substituent group, provided that the normal valence of the given atom is not exceeded.
  • two hydrogen atoms on a single atom are replaced by oxygen.
  • a chemically correct and stable compound means that the compound is stable enough to be isolated from a reaction mixture and the chemical structure of the compound can be determined, and then can be formulated into a formulation that at least has practical utility.
  • some compounds of formula (I) may contain one or more chiral centers, and therefore there are two or more stereoisomers. Racemic mixtures of these isomers, single isomers and mixtures enriched in one enantiomer, and diastereomers and mixtures partially enriched in specific diastereomers when there are two chiral centers are within the scope of the present invention. It will also be appreciated by those skilled in the art that the present invention includes all single stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.
  • the present invention provides compounds having various degrees of stereoisomeric purity, i.e., diastereomeric or enantiomeric purity expressed as different "ee” or “de” values.
  • the compounds of formula (I) e.g., as described herein
  • have an enantiomeric purity of at least 60% ee e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these recited values).
  • the compounds of formula (I) have an enantiomeric purity of greater than 99.9% ee, up to 100% ee.
  • the compound of formula (I) e.g., as described herein
  • has a diastereomeric purity of at least 60% de e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between these recited values).
  • the compound of formula (I) e.g., as described herein
  • enantiomeric excess refers to the amount of one enantiomer relative to the other.
  • the percentage of enantiomeric excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the enantiomeric mixture and [a]max is the optical rotation of the pure enantiomer.
  • Determination of diastereomers and/or enantiomeric excess may be accomplished using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography, and/or optical polarimetry, and according to conventional protocols familiar to those skilled in the art.
  • the racemic mixture can be used as such or resolved into the individual isomers.
  • the method of separating isomers is well known, including physical methods, such as chromatography using chiral adsorbents.
  • a single isomer in chiral form can be prepared from a chiral precursor.
  • a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, ⁇ -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salt, and then freeing one or two of the resolved bases, optionally repeating this process, thereby obtaining one or two isomers that are substantially free of another isomer, that is, an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight of the desired stereoisomer.
  • a chiral acid e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, ⁇ -bromocamphor
  • the racemate can be covalently linked to a chiral compound (auxiliary) to provide diastereomers which can be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary to provide the pure enantiomers.
  • auxiliary chiral compound
  • pharmaceutically acceptable salt refers to a non-toxic, biologically tolerable or other biologically suitable salt of a free acid or base of a compound of formula (I) for administration to a subject for treatment.
  • “Pharmaceutically acceptable salts” include, but are not limited to, acid addition salts formed by compounds of formula (I) with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH 2 )n-COOH (wherein n is 0-4), etc.
  • inorganic acids such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates,
  • “Pharmaceutically acceptable salts” also include base addition salts formed by compounds of formula (I) with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.
  • the molar ratio of the compound of formula (I) to the acid or cation in the resulting pharmaceutically acceptable salts includes, but is not limited to, 1:1, 1:2, 1:3 and 1:4.
  • the "prodrug” of the present invention refers to a pharmacological substance (i.e., drug) derived from a parent drug. Once administered, the prodrug is metabolized into the parent drug in the body.
  • the prodrug can be prepared by replacing one or more functional groups present in the compound, wherein the substituent in the prodrug is removed in the body in such a way as to be converted into the parent compound.
  • the preparation and use of prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series and Bioreversible.
  • “Prodrugs” include, but are not limited to: esters of compounds of formula (I) such as phosphates, formates, and carbamates; amides such as formamide and acetamide.
  • the compounds of the present invention are obtained in the form of acid addition salts, their free base forms can be obtained by alkalizing a solution of the acid addition salt.
  • the product is in the form of a free base, its acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds.
  • Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts without undue experimentation.
  • solvate means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to entrain a fixed molar ratio of solvent molecules in the solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance, wherein the water retains its molecular state of H 2 O, and such a combination can form one or more hydrates, such as hemihydrates, monohydrates and dihydrates, as well as variable hydrates.
  • group and “radical” used in the present invention are synonymous and are used to indicate a functional group or a molecular fragment that can be connected to other molecular fragments.
  • active ingredient is used to refer to a chemical substance with biological activity.
  • an "active ingredient” is a chemical substance with pharmaceutical use.
  • actual drug activity can be determined by appropriate preclinical tests, whether in vitro or in vivo.
  • drug activity that is sufficient to be accepted by regulatory agencies (such as the FDA in the United States) must have higher standards than preclinical tests. Whether such a higher standard of drug activity can be successfully obtained generally cannot be reasonably expected from preclinical test results, but can be established through appropriate and effective randomized, double-blind, controlled clinical trials conducted in humans.
  • the term "effective amount” as used herein refers to an amount or dosage of a cathepsin C inhibitor that is generally sufficient to produce a beneficial therapeutic effect in patients who need treatment for a disease or disorder mediated by cathepsin C and downstream serine protease activity.
  • the effective amount or dosage of the active ingredient in the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., the mode or route of administration or administration, the pharmacokinetics of the drug ingredient, the severity and course of the disease or disorder, the individual's previous or ongoing treatment, the individual's health status and response to the drug, and the judgment of the attending physician).
  • the determination of an effective dose is generally difficult to predict from preclinical trials. In fact, the dose is completely unpredictable, and new and unpredictable dosage regimens will develop after the dose is originally used in randomized, double-blind, controlled clinical trials.
  • Typical dosage range is from about 0.0001 to about 200 mg of active ingredient per kg of individual body weight per day, for example, from about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg, once a day or in divided dose units (for example, twice a day, three times a day, four times a day).
  • a suitable dosage range can be about 0.05 to about 7 grams/day, or about 0.2 to about 5 grams/day.
  • subject refers to mammals and non-mammals.
  • subject is not limited to a specific age or gender. In some embodiments, the subject is a human.
  • Trimethylsilyl chloride (2.57 g, 23.7 mmol) was slowly added dropwise to DMF (40 mL) containing zinc powder (3.59 g, 55.3 mmol) at room temperature. After stirring for 1.5 hours, iodine (468 mg, 1.8 mmol) was added and stirring was continued for 15 minutes. Then, a DMF solution (8 mL) of methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate ((R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate, 2.6 g, 7.9 mmol) was slowly added dropwise over 20 minutes.
  • reaction solution was cooled to room temperature, and a DMF solution (25 mL) of 1-i (800 mg, 2.6 mmol) was added dropwise over 20 minutes. Then, Pd 2 (dba) 3 (722 mg, 0.79 mmol) and S-Phos (647 mg, 1.58 mmol) were added in sequence. The reaction mixture was stirred at 50°C overnight. After cooling to room temperature, the solid was removed by filtration.
  • n-buthyl lithium 2.5M in hexane (3.6mL containing 2.5M n-butyl lithium) was added dropwise to a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (2-m, 1.66g, 9.0mmol) in THF (50ml).
  • the reaction solution was stirred at -78°C for 2 hours, and then 2-l (1.7g, 6.0mmol) was added all at once.
  • the reaction was allowed to slowly warm to room temperature and stirred overnight.
  • Saturated NH 4 Cl (30mL) was added, and ethyl acetate was extracted (3x50mL).
  • n-buthyl lithium 2.5M in hexane 2.5M hexane solution of n-butyl lithium, 1.34mL was added dropwise to a solution of 2-n (1.2g, 2.8mmol, 1.0eq.) in THF (30mL).
  • the reaction solution was stirred at -78°C for 30 minutes, and B(OiPr) 3 (1.3mL, 5.6mmol, 2.0eq.) was added.
  • the reaction was allowed to slowly warm to room temperature and stirred overnight.
  • Saturated NH 4 Cl (30mL) solution was added, and the mixture was extracted with ethyl acetate (3x50mL).
  • TMSCl 8 mL, 67.1 mmol
  • a DMF 150 mL
  • I 2 1.2 g, 4.7 mmol
  • a DMF 30 mL
  • methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate ((R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate, 8.9 g, 27 mmol) was added dropwise over 20 minutes.
  • NBS 10.8 g, 60.7 mmol
  • AIBN 1.00 g, 8.1 mmol
  • 4-h 10 g, 40.5 mmol
  • CCl 4 100 mL
  • the mixture was heated under reflux for 6 hours, cooled to room temperature, and water was added.
  • the mixture was extracted with ethyl acetate, dried over Na 2 SO 4 , concentrated, and purified by column chromatography to obtain a white solid product 4-h (2.9 g, 22%).
  • BH 3 ⁇ THF (1M THF solution, 62.2 mL) was added dropwise to a solution of 4-bromo-3-hydroxybenzoic acid (22-a, 15 g, 81.9 mmol) in anhydrous THF (100 mL) at 0°C, then the mixture was warmed to room temperature and stirred overnight. After the reaction was completed by LCMS, methanol (50 mL) was added to quench the reaction, and the mixture was concentrated to obtain a colorless oily product (22-b, 5.1 g, 100%).
  • n-butyllithium solution 2.5M n-butyllithium in hexane, 6mL, 15mmol
  • n-butyllithium solution 2.5M n-butyllithium in hexane, 6mL, 15mmol
  • THF 50mL
  • 22-d 2.6g, 10mmol
  • LiOH H 2 O (5.1 g, 120.7 mmol) was added to a solution of 22-h (17.6 g, 60.36 mmol) in THF/H 2 O (200 mL/200 mL). After stirring at room temperature for 2 hours, EtOAc/H 2 O (200 mL/200 mL) was added. The aqueous phase was washed with ethyl acetate twice, and then treated with 4N HCl until pH ⁇ 3.
  • TMSCl (2.7 mL, 21.3 mmol) was added dropwise to a suspension of Zn (2.7 g, 41.5 mmol) in DMF (50 mL). After stirring for 1.5 hours, I 2 (370 mg, 1.46 mmol) was added and stirred for another 15 minutes.
  • the intracellular enzyme activity assay was performed in a 384-well plate, with cell culture medium: 1640, 10% FBS, 1*PS.
  • 30 ⁇ L of cell culture medium cell suspension containing U937 cells was added to the 384-well plate, so that each well contained 2 ⁇ 10 4 cells;
  • 30 nL of AZD7986, vehicle control (100% DMSO) or serial dilutions of the test compound were added to the wells by Echo, and after incubation at 37°C for 1 hour, h-Gly-phe-AFC (10 ⁇ L) was added to each well and the reaction was started, and further incubated at 37°C for 1 hour, and then the fluorescence absorption was read by EX ⁇ 400nm and EM ⁇ 505nm.
  • the above test results were calculated using Graphpad 8.0 for IC 50 values, and the results are listed in Table 1.
  • Recombinant human cathepsin rhCathepsin C/DPP1 purchased from R&D systems
  • AZD7986 purchased from MCE
  • Gly-Arg-AMC (hydrochloride) was purchased from Cayman Chemical
  • DMSO was purchased from Sigma-Aldrich

Abstract

L'invention concerne un nouveau composé peptidylnitrile et son utilisation, et spécifiquement un composé de formule (I) et/ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique comprenant le composé et/ou le sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation du composé et une utilisation du composé pour le traitement de maladies provoquées par la cathepsine C et une sérine protéase issue de celle-ci.
PCT/CN2023/126526 2022-10-26 2023-10-25 Nouveau composé peptidylnitrile et son utilisation WO2024088307A1 (fr)

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CN202211316580.6 2022-10-26
CN202211316580.6A CN117964637A (zh) 2022-10-26 2022-10-26 一种新型肽基腈类化合物及其应用
CN202310320160 2023-03-29
CN202310320160.3 2023-03-29

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CN114106005A (zh) * 2020-08-26 2022-03-01 四川海思科制药有限公司 一种作为二肽基肽酶1抑制剂的腈衍生物及其用途
WO2022117059A1 (fr) * 2020-12-04 2022-06-09 瑞石生物医药有限公司 Inhibiteur à petites molécules de la cathepsine c et son utilisation médicinale

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CN110483492A (zh) * 2014-01-24 2019-11-22 阿斯利康(瑞典)有限公司 二肽基肽酶i抑制剂
CN107074870A (zh) * 2014-09-12 2017-08-18 勃林格殷格翰国际有限公司 组织蛋白酶c的螺环化合物抑制剂
CN114106005A (zh) * 2020-08-26 2022-03-01 四川海思科制药有限公司 一种作为二肽基肽酶1抑制剂的腈衍生物及其用途
WO2022117059A1 (fr) * 2020-12-04 2022-06-09 瑞石生物医药有限公司 Inhibiteur à petites molécules de la cathepsine c et son utilisation médicinale

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