WO2023046150A1 - 磺酰胺类化合物及其制备方法和用途 - Google Patents

磺酰胺类化合物及其制备方法和用途 Download PDF

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WO2023046150A1
WO2023046150A1 PCT/CN2022/121271 CN2022121271W WO2023046150A1 WO 2023046150 A1 WO2023046150 A1 WO 2023046150A1 CN 2022121271 W CN2022121271 W CN 2022121271W WO 2023046150 A1 WO2023046150 A1 WO 2023046150A1
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compound
preparation
unsubstituted
substituted
pharmaceutically acceptable
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French (fr)
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曾燕群
朱绪成
黄龙
朱涛
牟霞
付海霞
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成都施贝康生物医药科技有限公司
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Priority to EP22872194.0A priority Critical patent/EP4410786A1/en
Publication of WO2023046150A1 publication Critical patent/WO2023046150A1/zh
Priority to US18/618,590 priority patent/US20240287029A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to sulfonamide compounds, their preparation method and application.
  • chronic cough The incidence of chronic cough is high, with 5% to 10% of adults worldwide suffering from chronic cough, chronic cough lasting more than 8 weeks accounts for more than 1/3 of respiratory outpatient clinics, and the incidence rate is 2 to 10%.
  • factors that lead to chronic cough such as genetic factors, long-term smoking, eating habits, environmental pollution, cold air, etc.
  • Chronic cough not only aggravates the burden of medical resources, but also seriously affects the quality of life of patients and creates a serious psychological burden.
  • the treatment of chronic cough in the prior art generally adopts: glucocorticoids, ⁇ 2 receptor agonists, antihistamines, anti-reflux drugs, antibiotics and the like.
  • glucocorticoids glucocorticoids
  • ⁇ 2 receptor agonists antihistamines
  • anti-reflux drugs antibiotics and the like.
  • P2X3 receptors are related to various diseases including chronic cough.
  • P2X3 receptor is a member of the purinergic receptor family, is a non-selective ligand-gated ion channel, and plays an important role in the generation and transmission of harmful information.
  • cough reflex hypersensitivity may be mediated specifically through P2X3 receptors. Excessive, persistent, and frequent coughing can be caused by airway and pulmonary neuronal hypersensitivity from injury or infection.
  • Gefapixant (MK-7264) is an oral, selective P2X3 receptor antagonist developed by Merck & Co for the treatment of refractory chronic cough (RCC) or unexplained chronic cough (UCC) ).
  • RCC refractory chronic cough
  • UCC unexplained chronic cough
  • NDA New Drug Application
  • One of the objectives of the present invention is to provide a sulfonamide compound with better P2X3 receptor antagonism and better safety.
  • the second object of the present invention is to provide a preparation method of the compound.
  • the third object of the present invention is to provide the application of the compound.
  • the present invention provides a compound with a structure as shown in formula I, or a pharmaceutically acceptable salt, solvate, isomer, metabolite, nitrogen oxide and prodrug thereof,
  • R is selected from substituted or unsubstituted C1 ⁇ C12 alkyl, substituted or unsubstituted C1 ⁇ C12 cycloalkyl, substituted or unsubstituted C6 ⁇ C10 aryl, substituted or unsubstituted C1 ⁇ C12 alkane Amino group, or substituted or unsubstituted ring C4 ⁇ C8 alkylamino group;
  • R 2 and R 3 are independently selected from hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, or substituted or unsubstituted C1-C12 cycloalkyl; or R 2 and R 3 are connected to form a substituted or unsubstituted A 3- to 15-membered cycloalkyl group;
  • R 4 is selected from hydrogen or 1 to 2 halogens, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.
  • R 2 and R 3 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl;
  • R 2 and R 3 are connected to form cyclopropyl, cyclohexyl or cyclopentyl;
  • R 1 is selected from substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C6 ⁇ C10 aryl, or substituted or unsubstituted C1 ⁇ C6 alkylamino; wherein the substituent of R 1 is selected from One or more of deuterium, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, amido, NO 2 , CN or CF 3 .
  • R 2 and R 3 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl;
  • R 2 and R 3 are connected to form a cyclopropyl group
  • And/or R is selected from methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, tetrahydropyrrolyl, diethylamino, methyl, ethyl, propyl, isopropyl, Trifluoromethyl, difluoromethyl, phenyl, halophenyl, tolyl, halotolyl or halomethoxyphenyl.
  • R 2 and R 3 are independently selected from hydrogen, methyl or cyclopropyl; or R 2 and R 3 are connected to form a cyclopropyl;
  • R1 is selected from methyl, ethyl, methylamino, dimethylamino, isopropylamino, tetrahydropyrrolyl, diethylamino, trifluoromethyl, phenyl, tolyl or fluorophenyl .
  • the hydrogens in the above compounds are replaced by one or more deuteriums.
  • the present invention also provides the preparation method of the above-mentioned compound of formula I, or its salt, solvate, isomer, metabolite, nitrogen oxide and prodrug, comprising the following steps:
  • Step 1 compound a and compound k undergo a substitution reaction under basic conditions to generate compound b;
  • Step 2 intermediate compounds c and d undergo a substitution reaction under basic conditions to obtain compound e;
  • Step 3 Mitsunobu reacts intermediate compound e and f to obtain compound g;
  • Step 4 intermediate compound g and compound b undergo a coupling reaction in the presence of a catalyst to obtain compound h;
  • Step 5 Compound h is hydrolyzed under inorganic base catalysis or acid catalysis to obtain compound j;
  • Step 6 Compound j and compound m undergo a condensation reaction to obtain a compound of formula I;
  • R 1 , R 2 , R 3 , and R 4 are the same as those defined above, and X is halogen.
  • the present invention provides a pharmaceutical preparation, comprising the compound of formula I and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above-mentioned compound of formula I or its salt, solvate, isomer, metabolite, nitrogen oxide and prodrug in the preparation of medicines for treating or preventing P2X3 and/or P2X2/3 receptor-related diseases.
  • the above-mentioned uses include the use of the above-mentioned compound of formula I or its salts, solvates, isomers, metabolites, nitrogen oxides and prodrugs in the preparation of drugs for the treatment or prevention of respiratory diseases, preferably, Use in the preparation of medicines for treating or preventing cough, asthma, pain or sleep apnea.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with humans and/or or other animal tissues without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • halogen used in the present invention refers to: fluorine, chlorine, bromine, iodine.
  • the present invention has the following beneficial effects:
  • the sulfonamide compound provided by the invention has good P2X3 receptor antagonism and safety. Tests show that the sulfonamide compound of the present invention has almost no effect on the sense of taste of mice under 10mg/kg intravenous administration, and there is a significant statistical difference with the positive control drug gefapixant, indicating that the compound of the present invention has better safety sex.
  • the compound of the present invention After the compound of the present invention was administered for 30 minutes, the number of coughs induced by ammonia water in mice was significantly less than that of the positive control, and the antitussive action time was significantly longer than that of the compound of Comparative Example 1, and its inhibitory activity on P2X3 was better than that of the compound of Comparative Example 1 and the positive control drug gefapixant, indicating that the present invention The compounds have better P2X3 receptor antagonism.
  • the preparation method of the compound of formula I provided by the invention is simple and convenient to operate, and the raw materials are easy to obtain and easy to be industrialized.
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).
  • Liquid-mass spectrometry is Agilent G6120B (matched with liquid phase Agilent 1260); nuclear magnetic resonance ( 1 H NMR) is Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance ( 1 H NMR) shift ( ⁇ ) is given in parts per million (ppm), the measurement solvent is DMSO, the internal standard is tetramethylsilane (TMS), and the chemical shifts are given in units of 10 ⁇ 6 (ppm).
  • room temperature in the present invention means that the temperature is 10-25°C.
  • Step 2 Preparation of 6-chloro-1-(4-chlorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (compound e)
  • 6-chloro-1,3,5-triazine-2,4(1H,3H)-dione (147.5g, 1.0mol) and 4-chlorobenzyl bromide (226.5g, 1.1mol) were mixed with 300ml DMF After dissolving, add DIPEA (387.6g, 3.0mol) dropwise and keep it at 30°C for 5h.
  • DIPEA 387.6g, 3.0mol
  • reaction mixture After the reaction is complete, add the reaction mixture to 1000ml of water, wash out the solid and filter, dry the filter cake with 1000ml Slurry with ethyl acetate, filter to obtain a solid, and dry in a blast dryer to obtain 6-chloro-1-(4-chlorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (Compound e) (212.5 g, white solid), yield 78.1%, purity 99.52%.
  • Step 3 3-(4-Chloro-3-(4-chlorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl) -Preparation of methyl 2-methylpropionate (compound g-1)
  • Step 4 3-(3-(4-Chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6-dihydro-1 , Preparation of 3,5-triazin-1(2h)-yl)-2-methylpropionic acid methyl ester (compound h-1)
  • reaction mixture was heated to 80°C in an oil bath for 1-2h, and the reaction was detected by thin layer chromatography until the compound g -1 is completely consumed, the reaction mixture is distilled under reduced pressure to remove dioxane, and then extracted three times with 100ml ethyl acetate and 100ml water solution, the ethyl acetate phase is dried and concentrated, and purified by column chromatography to obtain 3-(3-(4-chlorobenzyl Base)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6-dihydro-1,3,5-triazine-1(2h)- base)-methyl 2-methylpropionate (4.60g, yellow-brown foamy solid), yield 88.1%, purity 97.34%.
  • Step 5 (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6- Dihydro-1,3,5-triazin-1(2H)-yl)-2-methylpropionic acid (compound j-1)
  • Step 6 (S)-3-(3-(4-Chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6- Preparation of Dihydro-1,3,5-triazin-1(2H)-yl)-2-methyl-N-(methylsulfonyl)propanamide (compound 1)
  • Example 2 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar ethylsulfonamide, and the rest of the conditions are the same.
  • (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)-yl)-N-(ethylsulfonyl)-2-methylpropanamide (compound 2), yield: 77.0%, purity is 99.13%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar N,N-dimethylaminosulfonamide, and the rest of the conditions are the same.
  • (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)-yl)-N-(N,N-dimethylaminosulfonyl)-2-methylpropanamide (compound 3), yield: 78.6% with a purity of 98.12%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar trifluoromethylsulfonamide, and the rest of the conditions are the same.
  • (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)yl)-2-methyl-N-((trifluoromethyl)sulfonyl)propanamide (compound 4), yield: 76.5% , with a purity of 99.71%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar pyrrolylsulfonamide, and the rest of the conditions are the same.
  • (S)-3-(3-(4-Chlorobenzyl)-2,6-dioxa-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid ,6-dihydro-1,3,5-triazin-1(2H)-yl)-2-methyl-N-(pyrrolidin-1-ylsulfonyl)propanamide (compound 5), yield: 78.2% with a purity of 99.12%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar N-isopropylaminosulfonamide, and the rest of the conditions are the same.
  • (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)-yl)-N-(N-isopropylsulfonyl)-2-methylpropanamide (compound 6), yield: 76.6% , with a purity of 97.64%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methanesulfonamide is replaced by equimolar benzenesulfonamide to obtain (S)-3-(3 -(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6-dihydro-1,3,5-triazine -1(2H)-yl)-2-methyl-N-(benzenesulfonyl)propionamide (compound 7), yield: 74.2%, purity: 99.68%.
  • methanesulfonamide is replaced by equimolar benzenesulfonamide to obtain (S)-3-(3 -(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6-dihydro
  • Example 8 (S)-3-(3-(4-chlorobenzyl)-4-(4-(5-(5-(difluoromethoxy)pyridin-2-yl)oxyphenyl)amino )-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)yl)-N-(4-(4-fluorophenyl)sulfonyl)-2- Preparation of methylpropionamide (compound 8)
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the a-1 in step 1: 2-fluoropyridine is replaced by equimolar 2-fluoro-5-difluoromethoxypyridine, and the a-1 in step 6 Compound m-1: methanesulfonamide was replaced by equimolar 4-fluorobenzenesulfonamide, and the rest of the conditions were the same to obtain (S)-3-(3-(4-chlorobenzyl)-4- (4-(5-(5-(difluoromethoxy)pyridin-2-yl)oxyphenyl)amino)-2,6-dioxo-3,6-dihydro-1,3,5-tri Azin-1(2H)yl)-N-(4-(4-fluorophenyl)sulfonyl)-2-methylpropanamide (compound 8), yield: 78.2%, purity: 98.98%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the compound m-1 in step 6: methylsulfonamide is replaced by equimolar 4-methylphenylsulfonamide, and the rest of the conditions are the same.
  • (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3 was obtained as a white solid, 6-dihydro-1,3,5-triazin-1(2H)-yl)-2-methyl-N-(4-methylphenyl)sulfonyl)propanamide (compound 9) Yield: 75.2 %, the purity is 99.11%.
  • Example 1 Compared with Example 1, the preparation method of this example is different in that the a-1 in step 1: 2-fluoropyridine is replaced by equimolar 2-fluoro-5-chloropyridine, and the compound m- 1: Methylsulfonamide was replaced by equimolar methylaminosulfonamide, and the rest of the conditions were the same.
  • step 3 (S)-3-hydroxyl-2-methylpropionic acid methyl ester is replaced by equimolar 3-hydroxyl-2, Methyl 2-dimethylpropionate, all the other conditions are the same.
  • 3-(3-(4-Chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6-dihydro was obtained as a white solid -1,3,5-triazin-1(2H)-yl)-2,2-dimethyl-N-(methylsulfonyl)propionamide (compound 11), yield: 75.9%, purity: 97.28% .
  • Example 12 1-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxyl)phenyl)amino)-3,6-dihydro- Preparation of 1,3,5-triazin-1(2H)methyl)-N-(methylsulfonyl)cyclopropane-1-carboxamide (compound 12)
  • Example 1 Compared with Example 1, the preparation method of this example is different in that f-1 in step 3: (S)-3-hydroxyl-2-methyl propionate is replaced by equimolar 1-(hydroxymethyl ) methyl cyclopropane-1-carboxylate, all the other conditions are the same.
  • 1-(3-(4-Chlorobenzyl)-2,6-dioxo-4-(4-(pyridine-2-oxy)phenyl)amino)-3,6-dihydro was obtained as a white solid -1,3,5-Triazin-1(2H)yl)methyl)-N-(methylsulfonyl)cyclopropane-1-carboxamide (compound 12), yield: 71.8%, purity: 99.11%.
  • This comparative example 1 is an intermediate produced during the synthesis of the example: compound j-1. Its preparation method is the same as that of compound j-1 in Example 1.
  • mice Healthy adult KM mice, half male and half male, 6 mice in each group, weighing about 28-30 g.
  • the preparation method of 50% ammonia solution measure 2.5ml of ammonia solution and dissolve it in 5ml of 0.9% sodium chloride injection, and mix well.
  • Positive control medicine and comparative example 1 compound solution preparation method respectively take 9mg positive control medicine, the compound of comparative example 1 and dissolve in 3ml 0.5% CMC-Na solution, fully mix, be configured into the solution of 3mg/ml.
  • Example compound solution preparation method Weigh 9 mg of the example compound and dissolve it in 3 ml of 0.5% CMC-Na solution, mix well, and configure a 3 mg/ml solution.
  • Grouping comparative example 1 group, positive control group, embodiment group, model group. Get 6 KM mice in each group, and the KM mice in each group were given the compound of Comparative Example 1 (30 mg/kg), the positive control drug (gefapixant, purchased, 30 mg/kg), and the compound of Example (30 mg/kg) by intragastric administration respectively. , the model group was given an equal volume of 0.5% CMC-Na solution. After administration for 30 min, 60 min or 120 min, the mice were placed in a 500 ml beaker respectively, and a cotton ball (100 ⁇ 5 mg in weight) was placed in the beaker, which contained 0.3 ml of 50% ammonia water. Observe the number of typical coughs in the mice within 3 minutes (typical cough action: abdominal muscle contraction or chest shrinkage, while opening the mouth wide, accompanied by coughing sound).
  • the symptoms of coughing are: contraction of abdominal muscles or shrinking of chest, opening mouth wide at the same time, accompanied by coughing sound.
  • Test Example 2 In Vitro Biological Activity Evaluation
  • the reagents, consumables and instruments used in this example are all commercially available.
  • HEK 293 cell line stably transfected with human P2X3 receptor was used.
  • Cell lines are usually diluted and passaged at a ratio of 1:3 to 1:4, and passaged twice a week (the passage ratio of 1:3 is more commonly used). After passage, the cells need 2 to 3 days to grow to reach 85% confluence;
  • Step 1 Preparation of cell assay plate
  • HPE high efficacy control: a single dose of positive control compound; FAC (final effect concentration): 40 ⁇ M; ZPE (zero effect control): 100% DMSO;
  • Step 3 Perform a screening test
  • the IC50 of the inhibitory effect of the compounds of the examples on the P2X3 receptor is shown in the table below, wherein A means less than 10 nM, and B means 10.1-100 nM.
  • 0.3mM quinine solution preparation method weigh 119.20mg of quinine hydrochloride and dissolve it in 1000ml of tap water, and mix well.
  • test sample solution Preparation method of test sample solution: Weigh 40mg of test sample, add appropriate amount of DMSO to dissolve it, then add solubilizer HS-15 solution, mix well, add 16ml of normal saline, and prepare a 2.5mg/ml solution.
  • Animals and grouping 160-180g male SD rats, 10 in each group, with similar average body weights in each group, housed in a single cage.
  • Water drinking habit training Animals in each group were given normal drinking water for 30 minutes at 8:30 am and 16:30 pm every day, and water was abstained for the rest of the time, lasting for 5 days, and the placement of two bottles of water was changed every day.
  • test group was given 4 mL/kg (10 mg/kg) of the test sample by tail vein injection at the following dose, and the model group was given 0.5% of 4 mL/kg (10 mg/kg) by intravenous injection.
  • HS-15 the night before the experiment, deprivation of water, the next morning, the test group was given 4 mL/kg (10 mg/kg) of the test sample by tail vein injection at the following dose, and the model group was given 0.5% of 4 mL/kg (10 mg/kg) by intravenous injection.
  • 1Measurement of drinking water put the animals back into the original cage after injection, and the measurement time of each group is in the Tmax range of each drug (the measurement time is 0min ⁇ 15min after administration), and put a bottle of normal drinking water in each cage at the same time , a bottle of drinking water containing 0.3mM quinine hydrochloride (Quinie), and the left and right positions of the two bottles of water in all animal breeding cages are consistent.
  • the animals were allowed to drink water freely for 15 minutes, and the drinking water volumes of the two bottles of water were respectively measured to an accuracy of 0.1 ml.
  • the ratio of mice drinking quinine/tap water has a statistical difference (P ⁇ 0.01), indicating that the compound gefapixant in the positive control group has a significant impact on the taste of the mice .
  • the test result of embodiment 1 group, 3 groups, 6 groups, 11 groups and 12 groups is compared with vehicle group respectively, and the ratio of mice drinking quinine/tap water does not possess statistical significance, shows that compound of the present invention is in 10mg/kg Intravenous administration has almost no effect on the sense of taste of the mice; in addition, compared with the positive control group in Example 1, Group 3, Group 6, Group 11 and Group 12, the ratio of mice drinking quinine/tap water has a significant statistical difference.

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Abstract

本发明公开了磺酰胺类化合物、其制备方法及用途，属于药物化学技术领域。本发明的磺酰胺类化合物结构如式I所示。本发明还提供了式I所示化合物或其盐、溶剂化物、异体构、代谢物、氮氧化物及前药在制备治疗或预防P2X3和/或/P2X2/3受体相关疾病的药物中的应用。本发明的磺酰胺类化合物的止咳作用强且药效持续时间明显延长，对P2X3的抑制活性优于对比例1化合物及阳性对照药gefapixant。

Description

磺酰胺类化合物及其制备方法和用途
本申请要求于2021年09月27日提交中国专利局、申请号为202111135636.3、申请名称为磺酰胺类化合物、其制备方法及用途的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物化学技术领域，具体涉及磺酰胺类化合物、其制备方法及用途。
背景技术
慢性咳嗽发病率高，全球有5％～10％的成年人患有慢性咳嗽，持续时间＞8周的慢性咳嗽占呼吸科门诊1/3以上，发病率为2～10％。导致慢性咳嗽的因数较多，如遗传因素、长期吸烟、饮食习惯、环境污染、冷空气等。慢性咳嗽不仅加剧了医疗资源的负担，而且严重影响患者生存质量，产生严重的心理负担。现有技术中慢性咳嗽治疗一般采用：糖皮质激素、β2受体激动药、抗组胺药、抗反流药、抗生素类等。目前临床上还没有专门针对慢性咳嗽的批准用药。
近来年研究发现P2X3受体与包括慢性咳嗽在内的多种疾病有关。P2X3受体是嘌呤类受体家族中的一员，是非选择性的配体门控离子通道，在伤害性信息的产生、传递中起着重要的作用。研究表明，咳嗽反射超敏反应可能是通过P2X3受体特异性介导的。损伤或感染引发的气道和肺部神经元超敏反应可引起过度、持续和频繁地咳嗽。
gefapixant(MK-7264)是由默沙东公司(Merck&Co)研发的一种口服、选择性P2X3受体拮抗剂，其用于治疗成从患者的难治性慢性咳嗽(RCC)或不明原因慢性咳嗽(UCC)。该药目前已向FDA递交新药申请(NDA)。该药物的两项临床III期试验表明，与安慰剂组相比，每天2次45mg剂量gefapixant治疗组在第12周(COUGH-1研究)和第24周(COUGH-2研究)的24小时咳嗽频率(采用24小时录音客观地测量每小时的咳嗽次数)显著降低，具有统计学意义的。2项研究中，每天2次15mg剂量gefapixant治疗组没有达到主要疗效终点；45mg组虽然达到临床终点，但45mg组因不良事件而停药的频率更高、味觉相关不良事件发生率更高。因此提代一种更加安全、有效的P2X3受体拮抗剂成为了本领域技术人员亟待解决的问题。
发明内容
本发明的目的之一在于，提供一种磺酰胺类化合物，其具有更好的P2X3受体拮抗作用和更好的安全性。
本发明的目的之二在于，提供该化合物的制备方法。
本发明的目的之三在于，提供该化合物的用途。
为实现上述目的，本发明采用的技术方案如下：
本发明提供一种结构如式I所示的化合物，或其药学上可接受的盐、溶剂化物、异体构、代谢物、氮氧化物及前药，
Figure PCTCN2022121271-appb-000001
其中，R 1选自取代或未取代的C1～C12烷基、取代或未取代的C1～C12的环烷基、取代或未取代的C6～C10芳基、取代或未取代的C1～C12烷胺基、或取代或未取代的环C4～C8烷胺基；
R 2、R 3独立地选自氢、卤素、取代或未取代的C1～C12烷基、或取代或未取代的C1～C12的环烷基；或者R 2、R 3连接形成取代或未取代的3元至15元环烷基基团；
R 4选自氢或1～2个卤素、甲基、二氟甲基、三氟甲基、二氟甲氧基或三氟甲氧基。
本发明的部分实施方案中，上述R 2、R 3独立地选自氢、甲基、乙基、丙基、异丙基或环丙基；
或R 2、R 3连接形成环丙基、环已基或环戊基；
和/或R 1选自取代或未取代的C1～C6烷基、取代或未取代的C6～C10芳基、或取代或未取代的C1～C6烷胺基；其中R 1的取代基选自一个或多个的氘、卤素、羟基、烷基、烯基、炔基、烷氧基、烷胺基、烷硫基、酰胺基、NO 2、CN 或CF 3。
本发明的部分实施方案中，上述R 2、R 3独立地选自氢、甲基、乙基、丙基、异丙基或环丙基；
或R 2、R 3连接形成环丙基；
和/或R 1选自甲胺基、乙胺基、丙胺基、异丙胺基、二甲胺基、四氢吡咯基、二乙胺基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、苯基、卤代苯基、甲苯基、卤代甲苯基或卤代甲氧苯基。
本发明的部分实施方案中，上述R 2、R 3独立地选自氢、甲基或环丙基；或R 2、R 3连接形成环丙基；
或/和R 1选自甲基、乙基、甲胺基、二甲胺基、异丙胺基、四氢吡咯基、二乙胺基、三氟甲基、苯基、甲苯基或氟苯基。
本发明的部分实施方案中，选自下列表1所示的化合物或其药学上可接受的盐。
表1
Figure PCTCN2022121271-appb-000002
Figure PCTCN2022121271-appb-000003
Figure PCTCN2022121271-appb-000004
本发明的部分实施方案中，上述化合物中的氢被一个或多个氘所取代。
本发明还提供上述式I化合物，或其盐、溶剂化物、异体构、代谢物、氮氧化物及前药的制备方法，包括以下步骤：
步骤1：化合物a及化合物k在碱性条件下进行取代反应，生成化合物b；
步骤2：中间体化合物c与d在碱性条件下下发生取代反应得到化合物e；
步骤3：中间体化合物e与f发生光延反应得到化合物g；
步骤4：中间体化合物g与化合物b在催化剂存在下，发生偶联反应得到化合物h；
步骤5：体化合物h在无机碱催化或者酸催化发生水解反应得到化合物j；
步骤6：化合物j和化合物m发生缩合反应得到式I化合物；
Figure PCTCN2022121271-appb-000005
其中，R 1、R 2、R 3、R 4的定义同上述任一项相应定义，X为卤素。
本发明提供一种药物制剂，包括上述式I化合物以及药学上可接受的载体。
本发明还提供上述式I化合物或其盐、溶剂化物、异体构、代谢物、氮氧化物及前药在制备治疗或预防P2X3和/或P2X2/3受体相关疾病的药物中的用途。
本发明的部分实施方案中，上述用途包括上述式I化合物或其盐、溶剂化物、异体构、代谢物、氮氧化物及前药在制备治疗或预防呼吸系统疾病药物中的用途，优选地，在制备治疗或预防咳嗽、哮喘、疼痛或睡眠呼吸暂停药物中的用途。
本发明使用术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或 其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
本发明使用术语“卤素”指：氟、氯、溴、碘。
与现有技术相比，本发明具有以下有益效果：
本发明提供的磺酰胺类化合物其具有良好的P2X3受体拮抗作用和安全性。试验表明，本发明的磺酰胺类化合物在10mg/kg静脉给药下对小鼠的味觉几乎没有影响，与阳性对照药gefapixant有显著性的统计性差异，表明本发明的化合物具有更好的安全性。
本发明化合物给药30min后氨水诱导小鼠咳嗽的次数明显小于阳性对照，止咳作用时间较对比例1化合物明显延长，对P2X3的抑制活性优于对比例1化合物及阳性对照药gefapixant，表明本发明化合物具有更好的P2X3受体拮抗作用。
本发明提供的式I化合物的制备方法操作简便，原料易得，易于工业化。
具体实施方式
以下将结合实施例和试验例对本发明作进一步的详细描述，本发明的实施例和试验例仅用于说明本发明的技术方案，并非对本发明的限制，凡依照本发明公开的内容所作的任何本领域的等同置换，均属于本发明的保护范围。
化合物的结构是核磁共振( 1H NMR)或液质联用(LC-MS)来确定的。
液质联用仪(LC-MS)为安捷伦G6120B(与液相Agilent 1260配用)；核磁共振仪( 1H NMR)为Bruker AVANCE-400或Bruker AVANCE-800，核磁共振( 1H NMR)位移(δ)以百万分之一(ppm)的单位给出，测定溶剂为DMSO，内标为四甲基硅烷(TMS)，化学位移是以10 -6(ppm)作为单位给出。
本发明的术语“室温”是指温度为10～25℃。
实施例1：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(甲磺酰基)丙酰胺(化合物1)的制备：
步骤1：4-(吡啶-2-氧基)苯胺(化合物b-1)的制备
Figure PCTCN2022121271-appb-000006
将2-氟吡啶(97.1g，1.0mol)和对氨基苯酚(108.1g，0.99mol)溶解入二 甲亚砜(600ml)中，加入碳酸铯(620g，1.96mol)得到反应混合物，并用机械搅拌匀速搅拌反应混合物。随后升温反应体系内温到80℃反应3h。薄层色谱跟踪反应进程，反应完全后，将反应混合物加入2L水中，并保持搅拌。之后用乙酸乙酯三次萃取产物，合并干燥乙酸乙酯后浓缩得到粗品，粗品以500ml水打浆1h后过滤，鼓风干燥箱干燥得到4-(吡啶-2-氧基)苯胺(179.7g，褐色颗粒状固体)，收率97.8％。
ESI-MS:m/z＝187.1(M+H) +。
步骤2：6-氯-1-(4-氯苄基)-1,3,5-三嗪-2,4(1H，3H)-二酮(化合物e)的制备
Figure PCTCN2022121271-appb-000007
将6-氯-1,3,5-三嗪-2,4(1H,3H)-二酮(147.5g，1.0mol)和4-氯苄溴(226.5g，1.1mol)混合后用300ml DMF溶解后滴加DIPEA(387.6g，3.0mol)后保持30℃反应5h，薄层色谱跟踪反应进程，反应完全后，将反应混合物加入1000ml的水中，洗出固体过滤，干燥后将滤饼用1000ml乙酸乙酯打浆，过滤得到固体，鼓风干燥机干燥后得到6-氯-1-(4-氯苄基)-1,3,5-三嗪-2,4(1H，3H)-二酮(化合物e)(212.5g，白色固体)，收率78.1％，纯度为99.52％。
ESI-MS:m/z＝272.0(M+H) +。
步骤3：3-(4-氯-3-(4-氯苄基)-2,6-二氧-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸甲酯(化合物g-1)的制备
Figure PCTCN2022121271-appb-000008
将化合物e(27.2g，0.1mol)，(S)-(+)-3-羟基-2-甲基丙酸甲酯(11.8g，0.1mol)以及三苯基膦(52.4g，0.2mol)，用300ml无水四氢呋喃溶解澄清，用氩气置换反应体系内空气后，冰水浴冷却反应体系，保持搅拌下缓慢匀速滴加偶氮二甲酸 二异丙酯(40.4g，0.2mol)，30min内滴加完毕后，保持室温反应，薄层色谱跟踪反应进程，反应完全后，反应液用500ml水淬灭后，用30ml乙酸乙酯萃取三次，有机溶液干燥后浓缩的到油状物粗品。用100ml乙酸乙酯和500ml石油醚的混合溶剂分散油状物粗品，析出大量三苯基氧膦固体，过滤除去三苯基氧膦，母液浓缩后这层析提纯得到3-(4-氯-3-(4-氯苄基)-2,6-二氧-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸甲酯(30.9g，白色固体)，收率83.1％，纯度99.11％。
ESI-MS:m/z＝372.1(M+H) +。
步骤4：3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2h)-基)-2-甲基丙酸甲酯(化合物h-1)的制备
Figure PCTCN2022121271-appb-000009
将化合物g-1(3.72g，0.01mol)，化合物b-1(1.87g，0.01mol)，xant-phos(868mg，1.5mmol)，醋酸钯(337mg，1.5mmol)，磷酸钾(4.24g，0.02mol)混合后用30ml二氧六环溶解，氩气置换反应瓶内空气，并且氩气保护反应，反应混合物在油浴中升温到80℃反应1-2h，薄层色谱检测反应至化合物g-1消耗完全，反应混合物减压蒸馏除去二氧六环后用100ml乙酸乙酯和100ml水分液萃取三次，乙酸乙酯相干燥浓缩后柱层析提纯得到3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2h)-基)-2-甲基丙酸甲酯(4.60g，黄褐色泡沫状固体)，收率88.1％，纯度97.34％。
ESI-MS:m/z＝522.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.20～8.11(m,1H),7.90～7.79(m,1H),7.48～7.38(m,2H),7.29(d,J＝8.3Hz,2H),7.21～7.14(m,4H),7.14～7.10(m,1H),7.03(d,J＝8.3Hz,1H),5.28(s,2H),3.89(m,2H),3.47(s,3H),2.77(m,1H),1.00(m,3H)。
步骤5：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸(化合物j-1)
Figure PCTCN2022121271-appb-000010
将化合物h-1(522mg，1.0mmol)溶于甲醇(3ml)和四氢呋喃(3ml)的混合溶剂中，保持温度在10℃左右，加入氢氧化锂(168mg，4mmol)的水(3ml)溶液，以得到反应混合物，使所述反应混合物在室温下反应过夜。薄层色谱跟踪反应进程，反应完全后，经柱层析纯化得到(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸(409mg，类白色固体)，收率：80.5％，纯度为99.69％。
ESI-MS:m/z＝508.1(M+H) +。
1H NMR(400MHz,DMSO-d6)δ8.16(dd,J＝5.1,2.0Hz,1H),7.94～7.80(m,1H),7.48～7.39(m,2H),7.35～7.26(m,2H),7.16(m,4H),7.14～7.11(m,1H),7.04(d,J＝8.3Hz,1H),5.30(s,2H),4.06～3.79(m,2H),2.75(m,1H),0.98(m,3H)。
步骤6：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(甲磺酰基)丙酰胺(化合物1)的制备
Figure PCTCN2022121271-appb-000011
将化合物j-1(254mg，0.5mmol)，和N,N'甲基二咪啶(CDI)(89mg，0.55mmol)溶于5mL无水THF加热回流lh，冷却后加入甲磺酰胺(47.5mg，0.5mmol)，搅拌lh后，滴加DBU(0.125mL，0.5mmol)，在室温下反应过夜，将反应液倒入IN HCl中并用乙酸乙酯萃取，有机混合相用水、饱和盐水冼涤后，MgSO 4干燥、过滤、减压去溶剂、再经层析硅胶柱纯化、减压收集，真空干燥，得到(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(甲磺酰基)丙酰胺(197.7mg，)收率67.6％，纯度99.85％。
ESI-MS:m/z＝585.1(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.45～7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),3.01(s,3H),2.69(m,1H),0.98(m,3H)。
实施例2：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-N-(乙基磺酰基)-2-甲基丙酰胺(化合物2)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的乙基磺酰胺，其余条件均相同。得到白色固体状的(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-N-(乙基磺酰基)-2-甲基丙酰胺(化合物2)，收率：77.0％，纯度为99.13％。
ESI-MS:m/z＝599.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.45～7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),3.33(m,2H),2.69(m,1H),1.27(m,3H),0.98(m,3H)。
实施例3：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-N-(N，N-二甲氨基磺酰基)-2-甲基丙酰胺(化合物3)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的N,N-二甲氨基磺酰胺，其余条件均相同。得到白色固体状的(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-N-(N，N-二甲氨基磺酰基)-2-甲基丙酰胺(化合物3)，收率：78.6％，纯度为98.12％。
ESI-MS:m/z＝614.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.45～7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),2.79(s,6H),2.69(m,1H),0.98(m,3H)。
实施例4：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)基)-2-甲基-N-((三氟甲基)磺酰基)丙酰胺(化合物4)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的三氟甲基基磺酰胺，其余条件均相同。得到白色固体状的(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)基)-2-甲基-N-((三氟甲基)磺酰基)丙酰胺(化合物4)，收率：76.5％，纯度为99.71％。
ESI-MS:m/z＝639.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.45～7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),2.69(m,1H),0.98(m,3H)。
实施例5：(S)-3-(3-(4-氯苄基)-2,6-二氧杂-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(吡咯烷-1-基磺酰基)丙酰胺(化合物5)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的吡咯基磺酰胺，其余条件均相同。得到白色固体状的(S)-3-(3-(4-氯苄基)-2,6-二氧杂-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(吡咯烷-1-基磺酰基)丙酰胺(化合物5)，收率：78.2％，纯度为99.12％。
ESI-MS:m/z＝640.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.45～7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),3.37-3.60(m,4H),2.69(m,1H),1.76-1.74(m,4H),0.98(m,3H)。
实施例6：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-N-(N-异丙基磺酰基)-2-甲基丙酰胺(化合物6)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的N-异丙胺基磺酰胺，其余条件均相同。得到白色固体 状的(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-N-(N-异丙基磺酰基)-2-甲基丙酰胺(化合物6)，收率：76.6％，纯度为97.64％。
ESI-MS:m/z＝628.1(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.45～7.37(m,3H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),2.83(m,1H),2.69(m,1H),1.22-1.22(d,J＝6.6Hz,6H)，0.98(m,3H)。
实施例7：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(苯磺酰基)丙酰胺(化合物7)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的苯磺酰胺，得到白色固体状的(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(苯磺酰基)丙酰胺(化合物7)，收率：74.2％，纯度为99.68％。
ESI-MS:m/z＝647.1(M+H) +。
1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.96～7.90(m,2H),7.90～7.79(m,1H),7.74～7.58(m,3H),7.45～7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),2.69(m,1H),0.98(m,3H)。
实施例8：(S)-3-(3-(4-氯苄基)-4-(4-(5-(5-(二氟甲氧基)吡啶-2-基)氧苯基)氨基)-2,6-二氧-3,6-二氢-1,3,5-三嗪-1(2H)基)-N-(4-(4-氟苯基)磺酰基)-2-甲基丙酰胺(化合物8)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤一中的a-1：2-氟吡啶替换为等摩尔的2-氟-5-二氟甲氧基吡啶，将步骤6中的化合物m-1：甲磺酰胺替换为等摩尔的4-氟苯磺酰胺，其余条件均相同，得到白色固体状的(S)-3-(3-(4-氯苄基)-4-(4-(5-(5-(二氟甲氧基)吡啶-2-基)氧苯基)氨基)-2,6-二氧-3,6-二氢-1,3,5-三嗪-1(2H)基)-N-(4-(4-氟苯基)磺酰基)-2-甲基丙酰胺(化合物8)，收率：78.2％，纯度为98.98％。
ESI-MS:m/z＝731.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.59(s,1H),8.02(s,1H),7.98～7.93(m,2H),7.82～7.73(m,1H),7.52(s,1H)，7.45～7.37(m,4H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.11～7.06(m,1H),5.42～5.15(m,2H),3.86(m,2H),2.68m,1H),0.98(m,3H)。
实施例9：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(4-甲基苯基)磺酰基)丙酰胺(化合物9)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤6中的化合物m-1：甲基磺酰胺替换为等摩尔的4-甲基苯基磺酰胺，其余条件均相同。得到白色固体状的(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(4-甲基苯基)磺酰基)丙酰胺(化合物9)收率：75.2％，纯度为99.11％。
ESI-MS:m/z＝661.1(M+H) +。 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.60(s,1H),8.15(dd,J＝5.0,2.0Hz,1H),7.90～7.79(m,1H),7.81(d,J＝8.3Hz,2H),7.45～7.37(m,4H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.42～5.15(m,2H),3.88(m,2H),2.37(s,3H),2.69(m,1H),0.98(m,3H)。
实施例10：(S)-3-(3-(4-氯苄基)-4-(4-(5-氯吡啶-2-氧基)苯基)氨基)-2,6-二氧杂-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(N-甲基氨基磺酰基)丙酰胺(化合物10)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤一中的a-1：2-氟吡啶替换为等摩尔的2-氟-5-氯吡啶，将步骤6中的化合物m-1：甲基磺酰胺替换为等摩尔的甲胺基磺酰胺，其余条件均相同。得到白色固体状的(S)-3-(3-(4-氯苄基)-4-(4-(5-氯吡啶-2-氧基)苯基)氨基)-2,6-二氧杂-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基-N-(N-甲基氨基磺酰基)丙酰胺(化合物10)，收率：73.8％，纯度为98.99％。
ESI-MS:m/z＝521.2(M+H) +。 1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.58(s,1H),8.18(s,1H),7.90～7.79(m,1H),7.45～7.37(m,3H),7.30(d,J＝8.4Hz,2H),7.22(d,J＝8.3Hz,1H),7.13(m,4H),5.42～5.15(s,2H),3.88(m,2H), 2.80(s,3H),2.69(m,1H),0.98(m,3H)。
实施例11：3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2,2-二甲基-N-(甲磺酰基)丙酰胺(化合物11)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤三中f-1：(S)-3-羟基-2-甲基丙酸甲酯替换为等摩尔的3-羟基-2,2-二甲基丙酸甲酯，其余条件均相同。得到白色固体状的3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2,2-二甲基-N-(甲磺酰基)丙酰胺(化合物11)，收率：75.9％，纯度为97.28％。
ESI-MS:m/z＝599.2(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.64(s,1H),8.20～8.09(m,1H),7.84(m,1H),7.42(d,J＝8.6Hz,2H),7.31～7.25(m,2H),7.20～7.13(m,4H),7.13～7.09(m,1H),7.03(d,J＝8.3Hz,1H),5.25(s,2H),4.03(s,2H),3.02(s,3H),1.05(s,6H)。
实施例12：1-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)基)甲基)-N-(甲磺酰基)环丙烷-1-羧酰胺(化合物12)的制备
本实施例的制备方法与实施例1相比，区别在于将步骤三中f-1：(S)-3-羟基-2-甲基丙酸甲酯替换为等摩尔的1-(羟甲基)环丙烷-1-羧酸甲酯，其余条件均相同。得到白色固体状的1-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)基)甲基)-N-(甲磺酰基)环丙烷-1-羧酰胺(化合物12)，收率：71.8％，纯度为99.11％。
ESI-MS:m/z＝597.1(M+H) +。
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.64(s,1H),8.15(dd,J＝5.2,2.0Hz,1H),7.85(m,1H),7.46～7.38(m,2H),7.31(d,J＝8.4Hz,2H),7.23～7.15(m,4H),7.15～7.09(m,1H),7.04(d,J＝8.3Hz,1H),5.28(s,2H),4.13(s,2H),3.12(s,3H),1.07～0.91(m,4H)。
对比例1：(S)-3-(3-(4-氯苄基)-2,6-二氧-4-(4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸(对比例1化合物)的制备
Figure PCTCN2022121271-appb-000012
本对比例1为实施例合成过程中产生的中间体：化合物j-1。其制备方法同实施例1中化合物j-1的制备方法。
试验例1：小鼠咳嗽试验
1试验材料
1.1供试品基本信息
实施例1～12合成的化合物1～12(本发明人实验室合成)、阳性对照药(gefapixant，批号：01030-210326-2-1，掌心医药购买获得)、对比例1化合物(本发明人实验室合成)。
1.2试验试剂
生理盐水，氨水。
2实验动物
健康成年KM小鼠，雌雄各半，每组6只，体重28～30g左右。
3试验方法
3.1剂量设计及供试品使用量
目前文献报道的动物咳嗽模型多采用机械、化学和电刺激等方法刺激动物的神经和感受器，引发咳嗽。根据候选化合物的特点和已有相似靶点化合物为参考，初步选择浓氨水诱导的方法建立小鼠咳嗽造模试验。
3.2供试品的配制方法
50％氨水溶液的配制方法：量取2.5ml氨水溶于5ml的0.9％的氯化钠注射液中，充分混匀即可。
阳性对照药和对比例1化合物溶液配制方法：分别称取9mg阳性对照药、对比例1的化合物溶于3ml 0.5％CMC-Na溶液，充分混匀，配置成3mg/ml的溶液。
实施例化合物溶液配制方法：称取9mg实施例化合物溶于3ml 0.5％CMC-Na溶液，充分混匀，配置成3mg/ml的溶液。
3.3实验操作方法
分组：对比例1组、阳性对照组、实施例组、模型组。每组取6只KM小鼠，各组KM小鼠分别灌胃给予对比例1化合物(30mg/kg)、阳性对照药(gefapixant，购买获得，30mg/kg)、实施例化合物(30mg/kg)，模型组给予等体积的0.5％CMC-Na溶液。给药30min、60min或120min后，分别将小鼠置于500ml烧杯，烧杯中放入1枚棉球(重量为100±5mg)，棉球内含有50％氨水0.3ml。观察小鼠3min内出现典型咳嗽的次数(典型咳嗽动作：腹肌收缩或缩胸，同时张大嘴，伴有咳声)。
4结果与讨论
4.1结果判断标准
①咳嗽判定标准：
咳嗽的表现为：腹肌收缩或缩胸，同时张大嘴，伴有咳声。
②用秒表计时，记录小鼠3min内咳嗽次数(次)，用软件进行统计学分析，各组数据采用均数±标准差统计描述，进行多组间单因素方差分析，P<0.05为差异有统计学意义。
4.2结果讨论
4.2.1实施例化合物30mg/kg给药30min后小鼠咳嗽的咳嗽次数
表2
组别 咳嗽次数(次) 组别 咳嗽次数(次)
模型组 51.30 实施例6组 20.60**
阳性对照组 20.51** 实施例7组 28.66*
对比例1组 15.61** 实施例8组 29.83*
实施例1组 13.33** 实施例9组 25.11*
实施例2组 17.12** 实施例10组 20.27**
实施例3组 15.34** 实施例11组 17.62**
实施例4组 28.61* 实施例12组 19.39**
实施例5组 12.85** / /
备注：与模型组比较：**P<0.01，*P<0.05。
由表2可以看出：给药30min后氨水诱导小鼠咳嗽，阳性对照组与模型组比较，咳嗽次数明显减少，具有统计学差异(P<0.01)，说明造模成功；多个实施 例化合物组与模型组比较，咳嗽次数明显减少，具有显著的统计学差异(P<0.01)。
4.2.2试验样品30mg/kg给药60、120min后咳嗽次数
表3
Figure PCTCN2022121271-appb-000013
备注：与模型组比较：**P<0.01，*P<0.05。与对比例1化合物比较： △P<0.05。
从表3可知，与模型组相比，对比例1组给药60min后咳嗽次数明显减少，具有统计学差异(P<0.01)；给药120min后咳嗽次数与模型组比较则不具备统计学差异，说明对比例1组化合物给药120min后不具备明显的止咳作用。
实施例1组、3组、5组、6组、10组、11组、12组分别与模型组比较，不仅在给药60min后咳嗽次数明显减少，给药120min后咳嗽次数也明显减少，且均具有统计学差异(P<0.05)。表明本发明的化合物1、3、5、6、10、11、12的止咳作用时间与对比例1化合物相比明显延长。
试验例2：体外生物活性评价
本实施例所用试剂、耗材和仪器均为市售。
1.细胞系
使用稳定转染人源P2X3受体的HEK 293细胞系。
2.细胞培养
生长培养基：DMEM high glucose；
10％FBS；
1％PenStrep。
3.细胞培养过程：
a)复苏细胞
1)将细胞冻存管浸入37℃水浴中，并持续晃动使其尽快溶解；
2)用1mL移液枪上下缓慢地吹打细胞使其至悬浮，滴加到含有10mL新鲜预温生长培养基的15mL离心管中，然后以1000rpm/min，离心5分钟；
3)弃去上清液，用5mL新鲜生长培养基重悬细胞。将细胞悬液转移到培养皿中，放于5％CO 2的培养箱中37℃静置培养；
4)24小时后，缓慢去除培养基(注意不要破坏细胞单层)，用新鲜生长培养基培养。
b)传代培养
细胞系通常以1：3到1：4的比例稀释传代，每周传代两次(1：3的传代比例更常用)，传代后的细胞需要2～3天才能生长达到85％的汇合度；
1)当细胞在10cm培养皿中达到>85％饱和后，用0.25％Trypsin-EDTA溶液消化约1min，将培养皿中的细胞吸出；
2)根据稀释比将细胞转移到含有完全生长培养液的培养皿中。注意：为保持细胞的对数生长，应该维持细胞单层培养；
3)根据细胞系细胞倍增时间(HEK293-P2X3：24小时)，使用0.25％胰蛋白酶溶液对细胞进行传代。
c)冻存细胞
1)将培养皿从培养箱中取出，置于超净工作台中，用0.25％Trypsin-EDTA溶液消化约1min，收集细胞并计数，再以1000rpm/min，离心5min；
2)吸出上清液，将细胞重新悬浮于冻存液(90％FBS和10％DMSO)中，密度为2×10 6cells/mL，每支冻存管中加入1mL细胞悬液；
3)将细胞冻存管放入冻存盒中，然后将其转移到-80℃过夜；
4)把冻存管转移到液氮罐中(-196℃)。
4.实验过程
步骤1：细胞实验板的准备
1)当15cm培养皿中的细胞长至80％融合时，去除上清液，加入5mLDPBS清洗细胞并吸出，再加入2.5mL 0.25％Trypsin-EDTA溶液至培养皿中，将培养皿放入培养箱1～3分钟，或直到细胞消化下来，再加入3mL完全培养基终止消化，用细胞计数仪检测细胞密度；
2)1000rpm/min离心5min后，用生长培养基重悬细胞并调节悬浮液体积，使细胞密度达到4×10 5cells/mL(1×10 4cells/25μL)；
3)黑色微孔板中加入10μL 5×Matrigel，将微孔板置于培养箱中15分钟后，取出微孔板，倒置300g/min离心30s，除去5×Matrigel。然后将配好的细胞悬浮液加入384黑色微孔板中，每孔25μL；
4)将微孔板放入5％CO 2的培养箱中37℃培养过夜，直到第二天细胞生长至融合状态。
步骤2：化合物的准备
拮抗剂模式
1)测试化合物母液浓度：20mM；
2)384-LDV板上的化合物运用Bravo进行12点稀释，化合物起始浓度10μM，稀释倍数为3倍稀释；
3)HPE(高效药效对照)：阳性对照化合物单剂量；FAC(终效浓度)：40μM；ZPE(零效对照)：100％DMSO；
4)使用ECHO将384-LDV板上的化合物及HPE、ZPE转移至384孔板(PE6008590)作为化合物板；
5)将化合物板保存在-20℃。
步骤3：进行筛选试验
1)将生长至融合状态的细胞板从培养箱中取出；
2)准备检测缓冲液：30mL缓冲液含0.3mL 250mM probenecid、0.6mL 1M HEPES和29.1mLHBSS，实际的检测缓冲液量将根据细胞板数而定；
3)准备C6dye，C6dye原液为10×，用缓冲液将C6dye稀释至1×；
4)使用Bluewasher的gentle spin模式进行倒置离心弃去培养基。
5)用移液排枪在细胞板上加入C6dye，20μL/孔；
6)将细胞板300rpm/min离心30s后，在培养箱中孵育1.5h；
7)在预先准备好的化合物板上使用Dragonfly自动加样仪在每孔加入20μL的实验缓冲液，根据实验板布局用Bravo将10μL的化合物转移到细胞板中，测试化合物最终检测浓度最高剂量FAC：10μM，3倍稀释，12个浓度点。
8)细胞板300rpm/min离心30s，放入培养箱中孵育30min；
9)在激动剂板(PE 6008590)上准备25μL 4×BZATP(终浓度3.5uM)激动剂作用于P2X3细胞。
10)将细胞板、FLIPR枪头和激动剂板置于室温15min；
11)用FLIPR转移10μL的BZATP激动剂到细胞板中并读数。
步骤4：实验结果与分析
实施例化合物对P2X3受体的抑制作用IC50如下表所示，其中A表示小于10nM，B表示10.1～100nM。
表4
Figure PCTCN2022121271-appb-000014
结果显示：本发明实施例化合物中，多个实施例化合物的对P2X3受体的体外抑制作用优于阳性对照药。
试验例3：味觉障碍试验
1试验材料
1.1供试品基本信息
实施例1、3、6、11、12化合物(本发明人实验室合成)、阳性对照药(gefapixant，批号：01030-210326-2-1，掌心医药购买获得)。
1.2试验试剂
0.9％氯化钠注射液、盐酸奎宁(Quinie，批号：C12476271)。
2实验动物
健康成年SD大鼠，全雄，体重280～300g左右。
3试验方法
3.1供试品的配制方法
0.3mM的奎宁溶液配制方法：称取119.20mg盐酸奎宁溶于1000ml的自来水中，充分混匀即可。
试验样品溶液配制方法：称取40mg试验样品先加入适量DMSO溶解后再加入增溶剂HS-15溶液，充分混匀，加入16ml生理盐水，配置成2.5mg/ml的溶液。
3.2实验操作方法
动物及分组：160～180g/只左右的雄性SD大鼠，每组10只，各组平均体重相近，单笼饲养。
饮水习惯训练：各组动物每天上午8:30和下午16:30分别给正常饮水30分钟，其余时间禁水，持续5天，每天更换两瓶水左右摆放位置。
给药：实验前一天晚上禁水，次日上午试验组按以下剂量尾静脉注射给予4mL/kg(10mg/kg)的试验样品，模型组静脉注射给予4mL/kg(10mg/kg)的0.5％HS-15。
4结果与讨论
4.1结果判断标准
①饮水量测量：注射后将动物放回原来的笼子，各组的测量时间分别在各种药物Tmax区间(测量时间为给药后0min～15min)，每个笼子同时放入一瓶正常饮用水，一瓶含有0.3mM盐酸奎宁(Quinie)的饮水，所有动物饲养笼中两瓶水放置的左右位置一致。让动物自由饮水15min，分别测量两瓶水的饮水量，精确到0.1ml。
②数据统计分析：分别统计奎宁苦味水、自来水的饮用量，以及奎宁水占自来水量的百分比，用方差分析比较各组之间的差异有无显著性。
4.2结果讨论
表5
试验样品 奎宁/自来水(％)
溶媒组 38.16％
阳性对照组 79.01％**
实施例1组 37.01％ △
实施例3组 38.11％ △
实施例6组 41.54％ △
实施例11组 37.12％ △
实施例12组 39.39％ △
备注：与溶媒组比较：**P<0.01；与阳性对照组比较： △P<0.01。
由表5可以看出，阳性对照组与溶媒组相比，小鼠饮用奎宁/自来水的比例 具有统计学差异(P<0.01)，说明阳性对照组化合物gefapixant对小鼠的味觉有显著的影响。而实施例1组、3组、6组、11组和12组的试验结果分别与溶媒组相比，小鼠饮用奎宁/自来水的比例不具备统计学意义，表明本发明化合物在10mg/kg静脉给药下对小鼠的味觉几乎没有影响；此外，实施例1组、3组、6组、11组和12组与阳性对照组相比，小鼠饮用奎宁/自来水的比例有显著性的统计性差异。
上述实施例仅为本发明的优选实施方式之一，不应当用于限制本发明的保护范围，但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色，其所解决的技术问题仍然与本发明一致的，均应当包含在本发明的保护范围之内。

Claims (10)

  1. 一种结构如式I所示的化合物，或其药学上可接受的盐、异体构：
    Figure PCTCN2022121271-appb-100001
    其中，R 1选自取代或未取代的C1～C12烷基、取代或未取代的C1～C12的环烷基、取代或未取代的C6～C10芳基、取代或未取代的C1～C12烷胺基、或取代或未取代的环C4～C8烷胺基；
    R 2、R 3独立地选自氢、卤素、取代或未取代的C1～C12烷基、或取代或未取代的C1～C12的环烷基；或者R 2、R 3连接形成取代或未取代的3元至15元环烷基基团；
    R 4选自氢或1～2个卤素、甲基、二氟甲基、三氟甲基、二氟甲氧基或三氟甲氧基。
  2. 根据权利要求1所述的化合物，或其药学上可接受的盐、异体构，其特征在于，
    R 2、R 3独立地选自氢、甲基、乙基、丙基、异丙基或环丙基；
    或R 2、R 3连接形成环丙基、环戊基或环己基；
    和/或R 1选自取代或未取代的C1～C6烷基、取代或未取代的C6～C10芳基、或取代或未取代的C1～C6烷胺基；
    其中R 1的取代基选自一个或多个的氘、卤素、羟基、烷基、烯基、炔基、烷氧基、烷胺基、烷硫基、酰胺基、NO 2、CN或CF 3。
  3. 根据权利要求1所述的化合物，或其药学上可接受的盐、异体构，其特征在于，
    R 2、R 3独立地选自氢、甲基、乙基、丙基、异丙基或环丙基；
    或R 2、R 3连接形成环丙基；
    和/或R 1选自甲胺基、乙胺基、丙胺基、异丙胺基、二甲胺基、四氢吡咯基、 二乙胺基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、苯基、卤代苯基、甲苯基、卤代甲苯基或卤代甲氧苯基。
  4. 根据权利要求1所述的化合物，或其药学上可接受的盐、异体构，其特征在于，
    R 2、R 3独立地选自氢、甲基或环丙基；
    或R 2、R 3连接形成环丙基；
    或/和R 1选自甲基、乙基、甲胺基、二甲胺基、四氢吡咯基、二乙胺基、三氟甲基、异丙胺基、苯基、甲苯基或氟苯基。
  5. 根据权利要求1所述的化合物，或其药学上可接受的盐、异体构，其特征在于，选自下列化合物或其药学上可接受的盐：
    Figure PCTCN2022121271-appb-100002
    Figure PCTCN2022121271-appb-100003
  6. 根据权利要求1～5任意一项所述的化合物，或其药学上可接受的盐、异体构，其特征在于，所述化合物中的氢被一个或多个氘所取代。
  7. 根据权利要求1～6任意一项所述的化合物，或其药学上可接受的盐、异体构的制备方法，其特征在于，包括以下步骤：
    步骤1：化合物a及化合物k在碱性条件下进行取代反应，生成化合物b；
    步骤2：中间体化合物c与d在碱性条件下发生取代反应，得到化合物e；
    步骤3：中间体化合物e与f发生光延反应，得到化合物g；
    步骤4：中间体化合物g与b发生偶联反应，得到化合物h；
    步骤5：体化合物h在无机碱催化或者酸催化下发生水解反应，得到化合物j；
    步骤6：化合物j和化合物m发生缩合反应，得到式I化合物；
    Figure PCTCN2022121271-appb-100004
    其中，R 1、R 2、R 3、R 4的定义同权利要求1，X为卤素。
  8. 一种药物制剂，其特征在于，包括权利要求1～6任意一项所述的化合物以及药学上可接受的载体。
  9. 权利要求1～6中任意一项所述的化合物，或其药学上可接受的盐、异体构在制备治疗或预防P2X3和/或P2X2/3受体相关疾病的药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于，所述用途为在制备治疗或预防呼吸系统疾病药物中的用途，优选地，所述用途为在制备治疗或预防咳嗽、哮喘、疼痛或睡眠呼吸暂停药物中的用途。
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