WO2022001331A1 - 一类三环化合物、制备方法及其医药用途 - Google Patents

一类三环化合物、制备方法及其医药用途 Download PDF

Info

Publication number
WO2022001331A1
WO2022001331A1 PCT/CN2021/090073 CN2021090073W WO2022001331A1 WO 2022001331 A1 WO2022001331 A1 WO 2022001331A1 CN 2021090073 W CN2021090073 W CN 2021090073W WO 2022001331 A1 WO2022001331 A1 WO 2022001331A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
arh
acid
formula
reaction
Prior art date
Application number
PCT/CN2021/090073
Other languages
English (en)
French (fr)
Inventor
何广卫
储昭兴
许勤龙
莫佳佳
林高峰
赵炎
邵莉
Original Assignee
合肥医工医药股份有限公司
合肥恩瑞特药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 合肥医工医药股份有限公司, 合肥恩瑞特药业有限公司 filed Critical 合肥医工医药股份有限公司
Priority to EP21833899.4A priority Critical patent/EP4177248A4/en
Priority to CN202180028913.2A priority patent/CN115427405B/zh
Priority to JP2022532071A priority patent/JP2023531338A/ja
Priority to US17/800,361 priority patent/US20230140276A1/en
Publication of WO2022001331A1 publication Critical patent/WO2022001331A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a class of tricyclic compounds, a preparation method and medical use thereof.
  • the compound of the present invention has significant antihistamine activity, extremely low inhibition of choline and extremely low The effect of hERG toxicity, the present invention also provides its use in the preparation of drugs for preventing and treating allergic diseases.
  • Allergic diseases such as acute urticaria, chronic idiopathic urticaria, allergic rhinitis, allergic ophthalmia, allergic skin diseases (including eczema, pityriasis rosea, drug eruption, summer dermatitis, contact dermatitis, atopic dermatitis) , allergic purpura, pollen allergy, bronchial asthma, etc., greatly reducing people's quality of life.
  • antihistamines and immunosuppressants are mainly used for clinical treatment of these diseases.
  • H 1 receptor antagonists competitively block the histamine H 1 receptors in the H1 receptor, thereby inhibiting histamine play a biological It has anti-allergic effect [Zolaly MA.Histamine H 1 antagonists and clinical characteristics of febrile seizures[J].Int J Gen Med.2012,5:277-281].
  • histamine H1 receptor antagonists are mainly divided into two generations.
  • the first-generation antihistamines include chlorpheniramine, diphenhydramine, hydroxyzine, etc., all of which have significant central system side effects and easily lead to drowsiness. ,Unconcious.
  • Second-generation antihistamines such as terfenadine, loratadine, desloratadine, astemizole, etc., although the central system side effects of first-generation antihistamines have been improved, some compounds have serious side effects. Cardiotoxicity, such as terfenadine and astemizole, can cause arrhythmias, prolongation of the QT interval on the electrocardiogram, and even cardiac arrest and sudden death. Other drugs such as loratadine, desloratadine, etc., although there is no obvious cardiotoxicity, but there are obvious side effects of inhibiting choline, such as dry mouth, dry eyes, and serious motor dysfunction.
  • the Chinese patent CN107602534B applied by the present inventor discloses a series of desloratadine derivatives with antihistamine and anti-inflammatory dual activities, among which the compound LHC-7 has the best activity,
  • the Chinese patent CN109096251A filed by the present inventor discloses a class of multi-target desloratadine derivatives, including compound LP-2.
  • World patent WO9200293A1 also discloses a series of antihistamine compounds, including compound 1 with the following structure:
  • the present invention researches and develops a series of new compounds on the basis of the prior art, and finds that these compounds show excellent effects and functions.
  • the compound of the present invention not only retains significant antihistamine activity, but also has lower anticholinergic activity and lower hERG toxicity than desloratadine, LHC-7, LP-2, and compound 1. Has higher security.
  • the present invention provides a novel tricyclic compound through structural modification.
  • Pharmacodynamic experiments show that the compound of the present invention significantly antagonizes the activity of histamine H 1 receptor, and significantly reduces or basically eliminates the current
  • the anticholinergic activity of the compound disclosed in the prior art reduces the inhibitory activity of the prior art compound hERG potassium channel.
  • the present invention provides a tricyclic compound having the structure of the following formula (I), or its pharmacy acceptable salts, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers above,
  • X is H, OH
  • n is an integer from 0 to 6;
  • a ring is benzene ring, pyridine ring, thiophene ring;
  • R 1 and R 4 are H, halogen
  • R 5 is H
  • R 6 is H, any mono- or poly-substituted C 1 -C 6 alkyl, halogen, hydroxyl, trifluoromethyl, cyano, oxytrifluoromethyl, methoxy, amino, nitro, and carboxyl.
  • the alkyl group is substituted, it is preferably a halogen substituent.
  • n is an integer of 0-4;
  • R 1 is H, Cl;
  • R 5 is H;
  • R 6 is H, methyl, F, Cl, Br, hydroxyl, trifluoromethyl, Cyano, oxytrifluoromethyl, methoxy, amino, nitro.
  • the above-mentioned compound of the present invention is a compound of the following formula:
  • n is an integer of 0-6;
  • X is H, OH;
  • R 5 is H;
  • R 6 is H, any mono- or poly-substituted C 1 -C 6 alkane group, halogen, hydroxyl, trifluoromethyl, cyano, oxytrifluoromethyl, methoxy, amino, nitro, carboxyl.
  • the substituent is halogen.
  • the above-mentioned compound of the present invention is a compound of the following formula
  • the pharmaceutically acceptable salts of the present invention are salts formed by the compound of formula (I) and alkali metal or alkaline earth metal, amino acid or basic compound containing amino group, or the compound of formula (I) and inorganic acid or organic acid. , or a compound salt of a polybasic acid alkali metal or alkaline earth metal salt of the compound of formula (I).
  • the pharmaceutically acceptable salts described in the present invention include potassium salts, sodium salts, and ammonium salts of compounds of formula (I); compounds of formula (I) with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid or acetic acid; the compound of formula (I) polybasic acid alkali metal or alkaline earth metal salt complex salt, wherein the polybasic acid , selected from citric acid, succinic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, oxalic acid, sulfuric acid, phosphoric acid, sulfurous acid, malic acid, wherein the alkali metal or alkaline earth metal is selected from sodium, potassium ,Ca, Mg, Zn.
  • the compounds described in the present invention are selected from the following compounds 1-42:
  • the compounds of the present invention also include crystalline forms or solvates and the like of the above-mentioned compounds.
  • the present invention also provides a pharmaceutical composition, which contains the above-mentioned compound and pharmaceutically acceptable excipients; preferably, the pharmaceutical composition is a tablet, a capsule, a granule, an oral liquid, an oral spray, Suppositories, transdermal formulations, injections, nasal drops, eye drops, or nasal spray.
  • the present invention also provides the use of the above-mentioned compound in the preparation of antihistamine drugs; preferably, the drug is a drug for preventing or treating allergic diseases; preferably, the allergic diseases are selected from: allergic rhinitis, urticaria Measles, chronic urticaria, allergic purpura, asthma, atopic dermatitis, eczema, allergic conjunctivitis, atopic dermatitis, sinusitis, chronic sinusitis.
  • allergic diseases are selected from: allergic rhinitis, urticaria Measles, chronic urticaria, allergic purpura, asthma, atopic dermatitis, eczema, allergic conjunctivitis, atopic dermatitis, sinusitis, chronic sinusitis.
  • R 5 is a C 1 -C 6 alkyl group.
  • R 1 , R 2 , R 3 , R 4 and R 6 are as defined above, and R 5 is a C 1 -C 6 alkyl group;
  • the compound of formula (II) is a compound of the following structure:
  • n is an integer of 0-6;
  • X is H, OH;
  • R 5 is an alkyl group of C 1 -C 6 ;
  • R 6 is H, optionally mono- or poly-substituted C 1 -C 6 alkyl, halogen, hydroxyl, trifluoromethyl, cyano, oxytrifluoromethyl, methoxy, amino, nitro, and carboxyl.
  • the alkyl group is substituted, it is preferably substituted by halogen.
  • the compound of formula (II) is a compound of the following structure:
  • n is an integer of 0-6;
  • X is H, OH;
  • R 5 is a C 1 -C 6 alkyl group.
  • mice Take ICR mice, weighing 18-22g, adaptively reared for 7 days, randomly divided into groups, 10 mice in each group, namely model group, compound group of the present invention, positive drug desloratadine group, LHC-7 control group, LP- 2.
  • Control group compound 1 (referring to the compound disclosed in WO9200293A1; the same below) control group. 1 hour before modeling, the control group was given the corresponding vehicle, the compound group was given 5 mg/kg of the corresponding compound, and the desloratadine group was given 5 mg/kg of the corresponding drug respectively.
  • Mice were depilated with 10% sodium sulfide (3cm ⁇ 3cm) on the back of the mice.
  • Example number Dosage (mg/kg) Inhibition rate(%) Example number Dosage (mg/kg) Inhibition rate(%) 1 5 52.22 19 5 53.26 2 5 53.98 20 5 57.95 3 5 41.66 twenty one 5 42.65 4 5 65.37 twenty two 5 63.28 5 5 47.93 twenty three 5 66.73 6 5 53.21 twenty four 5 47.65 7 5 42.56 25 5 66.82 8 5 34.87 26 5 68.15 9 5 50.60 27 5 48.76 10 5 41.21 28 5 43.76 11 5 36.86 29 5 64.26 12 5 44.65 30 5 52.22 13 5 51.02 31 5 47.95 14 5 42.76 LHC-7 5 53.20 15 5 52.76 Compound 1 5 36.10 16 5 50.76 LP-2 5 54.10 17 5 49.24 desloratadine 5 58.46 18 5 46.58
  • Wistar male rats, 180-220 g were divided into blank group, model group, desloratadine group, compound group of the present invention, LHC-7 control group, LP-2 control group, compound 1 control group, 10 rats in each group .
  • Rats in each group were given corresponding drugs by gavage, and 15 minutes later, pilocarpine (1 mg/kg, dissolved in normal saline) was injected intraperitoneally to induce saliva secretion.
  • the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate immediately. After the rats were anesthetized, the residual saliva in the oral cavity was taken out with cotton balls, and then the weighed (M1) cotton balls were placed in the oral cavity (two under the tongue, on both sides). One of each), and the cotton ball weight (M2) was measured immediately after taking it out after 10 minutes.
  • Inhibition rate saliva secretion in the administration group / saliva secretion in the model group ⁇ 100%
  • the experimental results are shown in Table 2 below.
  • the model group was injected intraperitoneally with 1 mg/kg of pilocarpine, and the secretion of saliva was significantly increased, and the model was successful.
  • Oral administration of desloratadine (10mg/kg), LP-2 (10mg/kg), LHC-7 (10mg/kg) and compound 1 (10mg/kg) decreased salivary secretion (P ⁇ 0.01), It shows that desloratadine, LP-2, LHC-7 and compound 1 have obvious inhibitory effect on choline.
  • the saliva secretion of the compound of the present invention (10 mg/kg) by gavage had no statistical difference compared with the model group (P>0.05), but had a significant difference compared with the control group (P ⁇ 0.05). It shows that compared with compounds LHC-7, LP-2, compound 1 and desloratadine, the compounds of the present invention have extremely low activity of inhibiting choline.
  • Example number Dosage (mg/kg) Inhibition rate(%) Example number Dosage (mg/kg) Inhibition rate(%) 1 10 18.53 19 10 11.83 2 10 7.64 20 10 7.65 3 10 7.02 twenty one 10 16.54 4 10 8.72 twenty two 10 18.43 5 10 11.60 twenty three 10 8.54 6 10 6.34 twenty four 10 10.32 7 10 4.65 25 10 9.68 8 10 8.23 26 10 13.28 9 10 12.01 27 10 5.48 10 10 5.13 28 10 19.65 11 10 5.20 29 10 11.28 12 10 7.48 30 10 6.74 13 10 5.77 31 10 13.25 14 10 3.78 32 10 18.93
  • the compounds of the present invention significantly reduce the activity of inhibiting hERG potassium channel, especially compounds 1-4, 7, 8, 11, 21 , 26, 29, 32 inhibit hERG with IC 50 >30 ⁇ m, less risk of cardiotoxicity, and higher safety.
  • tautomers may exist, and the present invention embraces these compounds, including all possible isomers and mixtures thereof.
  • the compound of the present invention may be obtained in the form of a salt, and it may be directly purified, and if the compound of the present invention is obtained in a free form, it may be dissolved or suspended In a suitable organic solvent, an acid or base is added and the salt is formed using conventional methods.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof sometimes exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also included in the present invention.
  • Methyl 2-(4-iodophenyl)-2-methylpropanoate (1, 5.00 g, 16.44 mmol) was dissolved in acetonitrile 50 mL, followed by CuI (313 mg, 1.64 mmol) and Pd(PPh 3 ) 2 Cl 2 (577mg, 0.82mmol), under nitrogen protection, cooled to -10°C, triethylamine (7.50g, 73.98mmol) was added dropwise, and after the addition was continued stirring for 10min, propargyl alcohol (1.30mg, 19.73mmol) was added dropwise After adding and stirring for 10 min, the reaction was moved to room temperature for 4 h.
  • Example 26 Referring to the preparation method of Example 25, using methyl 2-(4-cyano-3-iodophenyl)acetate instead of methyl 2-(3-iodophenyl)acetate as a raw material, 260 mg of the compound of Example 26 was obtained , white solid, yield 63.2%.
  • Step 3 Ethyl 2-(4-(4-(4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]]cyclohepta[1,2-b]pyridine-11- Alkenyl)piperidin-1-yl)-1-hydroxybutyl)phenyl)-2-methylpropionate (4)
  • Step 7 2-(3-(4-(4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-enyl) Piperidin-1-yl)-1-hydroxybutyl)phenyl)-2-methylpropionic acid (Example 30)
  • Example 29 Referring to the synthesis method of Example 29, substituting propargyl alcohol for 3-butyn-1-ol, 380 mg of the compound of Example 31 was obtained as an off-white solid with a yield of 44%.
  • Example 33 Referring to the preparation method of Example 31, replacing NaOH with KOH, the compound of Example 33 (173 mg, 86.6% yield) was obtained as an off-white solid. HPLC: 98.433%.
  • Example 31 Referring to the preparation method of Example 31, replacing the starting material from Example 2 with Example 25, the compound of Example 34 (152 mg, 83.3% yield) was obtained as an off-white solid. HPLC: 98.433%.
  • Example 25 500 mg, 0.97 mmol
  • dioxane hydrochloride 3 mL, 2.7 M
  • the reaction solution was directly concentrated to obtain a residue, DCM (10 mL) was added to it, the solution was stirred, concentrated, and n-heptane (6 mL) was added to beat overnight. After filtration, the solid filter cake was collected and dried at -0.1 MPa, 49° C. and 8 hours to obtain the compound of Example 41 (380 mg, 66.46% yield) as an off-white solid.
  • Example 25 The compound of Example 25 (153 mg, 0.3 mmol), 90% ethanol (3 mL), water (0.5 mL) and L-lysine (44 mg, 0.3 mmol) were added to a 25 mL single-neck flask, and the reaction was carried out at 60° C. for 1.5 h under nitrogen atmosphere. . The reaction solution was concentrated to dryness to form a viscous oil. Diethyl ether (20 mL) was added to make slurry for 1 h, filtered, and the solid was dried under vacuum at room temperature for 2 h to obtain Example 42 (167 mg, 84% yield) as an off-white solid.
  • composition examples of the present invention taking the compound of Example 34 as an example, include but are not limited to the adjuvants and formulation ratios used in the following examples.
  • Preparation method The compound of Example 34 and magnesium stearate are passed through a 120-mesh sieve, and the microcrystalline cellulose, calcium hydrogen phosphate, and pregelatinized starch are passed through a 100-mesh sieve, for subsequent use; Crystalline cellulose, calcium hydrogen phosphate, and pregelatinized starch, pass through an 80-mesh sieve and mix uniformly according to the equal increment method, use 30% ethanol solution as a wetting agent to make a soft material, granulate with a 20-mesh sieve, and dry at 50-60°C 3-4 hours, 20-mesh sieve for granulation, adding the prescribed amount of magnesium stearate, mixing evenly, and pressing to obtain the tablet.
  • Preparation method The compound of Example 34, magnesium stearate are passed through a 120-mesh sieve, and the microcrystalline cellulose, sodium carboxymethyl starch, and lactose are passed through an 80-mesh sieve, and are for later use; Cellulose, sodium carboxymethyl starch and lactose, pass through an 80-mesh sieve and mix well according to the equal increment method, use 30% ethanol solution as a wetting agent to make soft material, granulate with a 30-mesh sieve, and dry at 50-60°C for 3- 4 hours, 30-mesh sieve to granulate, add the prescribed amount of magnesium stearate, mix well, and press to obtain the tablet.
  • Preparation method The compound of Example 34, magnesium stearate were passed through a 120-mesh sieve, and the low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and lactose were passed through an 80-mesh sieve, for subsequent use; the compound of Example 34 in the formulation proportion was weighed , low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and lactose, pass through an 80-mesh sieve and mix well according to the equal increment method, use 30% ethanol solution as a wetting agent to make soft materials, granulate with a 30-mesh sieve, 50 Dry at ⁇ 60°C for 3 to 4 hours, sieve with 30 meshes for granulation, add magnesium stearate in the prescribed amount, mix well, and then fill the capsules.
  • Preparation method the compound of Example 34, microcrystalline cellulose, sucrose powder, sodium carboxymethyl starch, lactose, aspartame were passed through a 100-mesh sieve, and orange essence and sodium lauryl sulfate were passed through an 80-mesh sieve, for use; Take the compound of Example 34, microcrystalline cellulose, sucrose powder, sodium carboxymethyl starch, lactose, and aspartame in the proportion of the prescription and mix by the equal increment method, and use 30% ethanol solution of 3% povidone.
  • Soft material is prepared, granulated by a 20-mesh sieve, dried at 50-60°C for 3-4 hours, granulated by a 18-mesh sieve, added with the prescribed amount of orange essence and sodium lauryl sulfate, mixed well, bagged and sealed.
  • Preparation method aspartame, orange essence and sodium citrate are dissolved in ready-made water for injection, filtered, the compound of Example 34 in the recipe quantity is added at room temperature, dissolved, filtered and filled.
  • Preparation method add sucrose to 900ml of water for injection, heat and boil, dissolve, filter while hot, and cool to room temperature for later use; dissolve the compound of Example 34, aspartame, orange essence, and sodium citrate in 60mL for injection.
  • filter add to the above syrup, add water for injection to 1000mL, mix well, and fill to prepare.
  • Preparation method completely dissolve polysorbate 80, citric acid, sodium chloride, the compound of Example 34 and benzalkonium chloride in 70 ml of sterile water for injection, adjust the pH to 7.8 with borax, and then use sterile injection Add water to a volume of 100 mL, filter, sterilize the filtrate, and store it in a container suitable for eye drops.
  • Preparation method dissolve citric acid, disodium hydrogen phosphate and disodium EDTA in 1600mL water for injection, add the compound of Example 34 and sodium chloride in the recipe quantity and stir until completely dissolved, adjust with 0.1mol/L dilute hydrochloric acid. pH to 7.0-7.8, add the prescribed amount of activated carbon, stir and adsorb, decarbonize and filter, add water for injection to 2000mL, then filter with a 0.22 ⁇ m filter, and fill in a 2mL ampoule. The ampoule was sealed and sterilized at 115°C for 30 minutes.
  • the preparation process is as follows: take a buffer solution of about 60% of the recipe amount in a preparation container, add a bioadhesive to fully swell until completely dissolved; add a bacteriostatic agent, an isotonicity regulator, and a metal ion chelating agent to stir Dissolve; add cyclodextrin in stages, after stirring and dissolving, add the compound of Example 34, stir for 1-2 hours, and after complete dissolution, add buffer to the full amount, and mix evenly.
  • the medicinal solution is filtered through a 0.45 ⁇ m microporous membrane until it becomes clear, and then filtered through a 0.22 ⁇ m microporous membrane to sterilize, and then dispensed into sterilized nasal spray bottles with a quantitative spray pump. cap, and store tightly closed at low temperature.
  • Preparation method mannitol/polyoxyethylene 40 hydrogenated castor oil, vitamin E, and the compound of Example 34 are added to water for injection to 10 mL, slowly heated at 60 ° C, after adding glyceride, high-speed shearing dispersing emulsifier dispersion, citric acid adjusting After the pH reaches 6.0, it is filtered, autoclaved and placed in a container.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Ophthalmology & Optometry (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明提供一类三环化合物、其制备方法和医药用途，所述三环化合物是具有下列式(I)结构的化合物或其药学上可接受的盐、前药、互变异构体、立体异构体或者立体异构体的混合物。本发明化合物具有显著的拮抗组胺H 1受体的活性，且抗M-胆碱副作用更低，hERG毒性更低。其中，基团如说明书中所述定义。

Description

一类三环化合物、制备方法及其医药用途 技术领域
本发明涉及药物化学领域，具体涉及一类三环化合物、制备方法及其医药用途，本发明的化合物与现有技术相比，具有显著的抗组胺活性、极低的抑制胆碱和极低的hERG毒性的作用，本发明还提供了其在制备预防和治疗过敏性疾病药物中的用途。
背景技术
过敏性疾病如急性荨麻疹、慢性特发性荨麻疹、过敏性鼻炎、过敏性眼炎、过敏性皮肤病(包括湿疹、玫瑰糠疹、药疹、夏季皮炎、接触性皮炎、特应性皮炎)、过敏性紫癜、花粉过敏、支气管哮喘等，极大的降低了人们的生活质量。目前，用于临床上治疗这类疾病主要是以抗组胺药和免疫抑制剂为主。
其中抗组胺药物以H 1受体拮抗剂为主，H 1受体拮抗剂可竞争性地与H1受体结合而阻断组胺与H 1受体的作用，进而抑制组胺发挥生物学效应，起到抗过敏的作用[Zolaly MA.Histamine H 1antagonists and clinical characteristics of febrile seizures[J].Int J Gen Med.2012,5:277-281]。目前临床常用的组胺H1受体拮抗剂主要分为两代，第一代抗组胺药包括氯苯那敏、苯海拉明、羟嗪等，都具有显著的中枢系统副作用，容易导致嗜睡、精神恍惚。第二代抗组胺药如特非那定、氯雷他定、地氯雷他定、阿司咪唑等，虽然改善了第一代抗组胺药物的中枢系统副作用，但是部分化合物存在严重的心脏毒性如特非那定和阿司咪唑，会引起心律失常、心电图出现Q-T间期延长，甚至出现心跳骤停及猝死。其他药物如氯雷他定、地氯雷他定等，虽然未见明显的心脏毒性，但是存在明显的抑制胆碱的副作用，如口干，眼睛干涩，严重会引起运动功能障碍。
因此，开发新的具有更高安全性的H 1受体阻断剂，改善现有治疗药物的不足，降低中枢、心脏毒性和胆碱抑制活性，具有重要的价值。
本发明人申请的中国专利CN107602534B中公开了一系列具有抗组胺和抗炎双重活性的地氯雷他定衍生物，其中化合物LHC-7活性最佳，
Figure PCTCN2021090073-appb-000001
但是在随后的研究中发现其具有很强的hERG毒性(hERG钾离子通道的抑制强，具有心脏毒性风险)。
本发明人申请的中国专利CN109096251A中公开了一类多靶点地氯雷他定衍生物，包括化合物LP-2。
Figure PCTCN2021090073-appb-000002
Figure PCTCN2021090073-appb-000003
世界专利WO9200293A1中也公开了一系列的抗组胺化合物，其中包括以下结构的化合物1：
Figure PCTCN2021090073-appb-000004
但该世界专利中未公开化合物1的实施方法、活性数据等。
本发明在现有技术的基础上研究开发了一系列新的化合物，并发现这些化合物表现出优异的效果和作用。尤其是本发明化合物既保留了显著的抗组胺的活性，同时比地氯雷他定、LHC-7、LP-2、化合物1的抗胆碱活性更低，hERG毒性更低，本发明化合物具有更高的安全性。
发明内容
本发明针对现有技术的不足，通过结构改造，提供一种新型三环化合物，药效学实验表明本发明的化合物显著的拮抗组胺H 1受体活性，极显著的降低或者基本消除了现有技术中公开的化合物的抗胆碱活性，降低了现有技术的化合物hERG钾通道的抑制活性，具体而言，本发明提供一种具有下列式(I)结构的三环化合物，或其药学上可接受的盐、前药、互变异构体、立体异构体或者立体异构体的混合物，
Figure PCTCN2021090073-appb-000005
式(I)中
X为H、OH；
n为0-6的整数；
A环为苯环、吡啶环、噻吩环；
R 1、R 4为H、卤素；
R 2、R 3选自H、羟基、＝O；
R 5为H；
R 6为H，任意单取代或多取代的C 1～C 6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。优选的，当所述烷基被取代时，优选为卤素取代基。
优选的，式(I)中，n为0-4的整数；R 1为H、Cl；R 5为H；R 6为H、甲基、F、Cl、Br、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基。
优选的，本发明上述所述的化合物，为下式结构的化合物：
Figure PCTCN2021090073-appb-000006
其中，n为0-6的整数；X为H、OH；R 3为H、羟基、＝O；R 5为H；R 6为H，任意单取代或多取代的C 1～C 6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。优选的，当所述烷基被取代时，所述取代基为卤素。
优选的，本发明上述所述的化合物，为下式结构的化合物
Figure PCTCN2021090073-appb-000007
其中，n为0-6的整数；X为H、OH；R 5为H。
本发明所述的药学上可接受的盐为式(I)化合物和碱金属或者碱土金属，氨基酸或者含有氨基的碱性化合物形成的盐，或者为式(I)化合物与无机酸或者有机酸形成的盐，或者为式(I)化合物多元酸碱金属或者碱土金属盐复合盐。
具体的，本发明所述的所述药学上可接受的盐包括式(I)化合物的钾盐，钠盐，铵盐；式(I)化合物与盐酸、硫酸、磷酸、氢溴酸、马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸或醋酸形成的盐；所述式(I)化合物多元酸碱金属或者碱土金属盐复合盐，其中所述的多元酸，选自枸橼酸、丁二酸、酒石酸、琥珀酸、富马酸、马来酸、草酸、硫酸、磷酸、亚硫酸、苹果酸，其中所述的碱金属或碱土金属选自钠、钾、钙、镁、锌。
优选的，本发明所述的化合物选自以下化合物1-化合物42：
Figure PCTCN2021090073-appb-000008
Figure PCTCN2021090073-appb-000009
Figure PCTCN2021090073-appb-000010
本发明化合物也包括上述所述化合物的结晶形态或溶剂化物等。
本发明还提供一种药物组合物，其含有上述所述化合物和药学上可接受辅料；优选地，所述的药物组合物，其为片剂，胶囊、颗粒剂、口服液、口喷剂、栓剂、透皮制剂、注射剂、滴鼻剂、滴眼液或鼻喷剂。
本发明还提供上述所述的化合物在制备抗组胺药物中用途；优选地，所述药物为预防或治疗过敏性疾病的药物；优选的，所述过敏性疾病选自：过敏性鼻炎、荨麻疹、慢性荨麻疹、过敏性紫癜、哮喘、过敏性皮炎、湿疹、过敏性结膜炎、特应性皮炎、鼻窦炎、慢性鼻窦炎。
作为本发明另一目的，还提供上述所述式(I)化合物的制备方法，包括由如下式(II)化合物反应生成所述式(I)化合物的步骤：
Figure PCTCN2021090073-appb-000011
Figure PCTCN2021090073-appb-000012
其中，X、n、A、R 1、R 2、R 3、R 4和R 6如上所述定义，R 5为C 1～C 6的烷基。
优选的，提供了如下所示结构的式(II)的化合物，
Figure PCTCN2021090073-appb-000013
其中，X、n、A、R 1、R 2、R 3、R 4和R 6如上所述定义，R 5为C 1～C 6的烷基；
优选地，所述的式(II)化合物为如下结构的化合物：
Figure PCTCN2021090073-appb-000014
其中，n为0-6的整数；X为H、OH；R 3为H、羟基、＝O；R 5为C 1～C 6的烷基；R 6为H，任意单取代或多取代的C 1～C 6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。优选的，当所述烷基被取代时，优选被卤素所取代。
或，所述的式(II)化合物为如下结构的化合物：
Figure PCTCN2021090073-appb-000015
其中，n为0-6的整数；X为H、OH；R 5为C 1～C 6的烷基。
生物活性
1.本发明化合物对组胺诱导的小鼠血管通透性的抑制作用
取ICR小鼠，体重18-22g，适应性饲养7天，随机分组，每组10只，即模型组、本发明化合物组、阳性药地氯雷他定组、LHC-7对照组、LP-2对照组，化合物1(指WO9200293A1中公开的化合物；下同)对照组。于造模前1h灌胃给药，对照组给予相应溶媒，化合物组给予5mg/kg相应化合物，地氯雷他定组分别给予5mg/kg相应药物。小鼠用10％硫化钠将小鼠背部脱毛(3cm×3cm)，给药1h后于脱毛处皮内注射磷酸组胺生理盐水溶液1ug/0.1mL，注射后立即由尾静脉注射0.25％伊文思蓝溶液4ml/kg，30min后脱臼处死，取下蓝染部分的皮肤打孔(直径15mm)，剪碎后浸泡于丙酮-生理盐水(7:3)溶液1ml中，24h后离心(3000r/min，10min)，取上清液，用紫外分光光度计在波长610nm处，以丙酮-生理盐水溶液空白校零，测定所取样本的吸光度值。
结果见表1，与模型组比较，各化合物组及地氯雷他定组均具有显著的抑制组胺诱导小鼠皮肤血管通透性(P<0.01)；与对照组比较，本发明化合物抑制率与地氯雷他定、LHC-7、 LP-2化合物抑制率相当，优于化合物1(P<0.05)。说明本发明化合物具有较强的抗组胺活性。
表1本发明化合物对组胺诱导的小鼠血管通透性的抑制作用
实施例编号 剂量(mg/kg) 抑制率(％) 实施例编号 剂量(mg/kg) 抑制率(％)
1 5 52.22 19 5 53.26
2 5 53.98 20 5 57.95
3 5 41.66 21 5 42.65
4 5 65.37 22 5 63.28
5 5 47.93 23 5 66.73
6 5 53.21 24 5 47.65
7 5 42.56 25 5 66.82
8 5 34.87 26 5 68.15
9 5 50.60 27 5 48.76
10 5 41.21 28 5 43.76
11 5 36.86 29 5 64.26
12 5 44.65 30 5 52.22
13 5 51.02 31 5 47.95
14 5 42.76 LHC-7 5 53.20
15 5 52.76 化合物1 5 36.10
16 5 50.76 LP-2 5 54.10
17 5 49.24 地氯雷他定 5 58.46
18 5 46.58      
2.本发明化合物对毛果芸香碱诱导的大鼠流涎的试验结果
Wistar雄性大鼠，180-220g，分为空白组、模型组、地氯雷他定组、本发明化合物组，LHC-7对照组、LP-2对照组、化合物1对照组、每组10只。各组大鼠灌胃给予相应药物，15min后腹腔注射毛果芸香碱(1mg/kg，生理盐水溶解)诱导唾液分泌。立即腹腔注射10％水合氯醛麻醉大鼠，大鼠麻醉后，口腔内残留的唾液用棉球取出，然后将称重过(M1)的棉球放入口腔内(舌下两个，两侧各一个)，10分钟后取出立即测量棉球重量(M2)。
唾液分泌量＝M2-M1
抑制率＝给药组唾液分泌量/模型组唾液分泌量×100％
实验结果如下表2所示，模型组腹腔注射毛果芸香碱1mg/kg，唾液分泌量显著增加，模型成功。灌胃给药地氯雷他定(10mg/kg)、LP-2(10mg/kg)、LHC-7(10mg/kg)和化合物1(10mg/kg)唾液分泌量减少(P<0.01)，说明地氯雷他定、LP-2、LHC-7和化合物1有明显的抑制胆碱的作用。灌胃给药本发明化合物(10mg/kg)唾液分泌量与模型组比较无统计学差异(P>0.05)，与对照组比较具有显著性差异(P＜0.05)。说明与化合物LHC-7、LP-2、化合物1及地氯雷他定相比，本发明化合物抑制胆碱的活性极低。
表2本发明化合物对毛果芸香碱诱导的大鼠流涎的抑制作用
实施例编号 剂量(mg/kg) 抑制率(％) 实施例编号 剂量(mg/kg) 抑制率(％)
1 10 18.53 19 10 11.83
2 10 7.64 20 10 7.65
3 10 7.02 21 10 16.54
4 10 8.72 22 10 18.43
5 10 11.60 23 10 8.54
6 10 6.34 24 10 10.32
7 10 4.65 25 10 9.68
8 10 8.23 26 10 13.28
9 10 12.01 27 10 5.48
10 10 5.13 28 10 19.65
11 10 5.20 29 10 11.28
12 10 7.48 30 10 6.74
13 10 5.77 31 10 13.25
14 10 3.78 32 10 18.93
15 10 8.42 LHC-7 10 95.60
16 10 10.76 化合物1 10 84.30
17 10 6.54 LP-2 10 98.40
18 10 12.50 地氯雷他定 10 92.02
3.本发明化合物hERG钾通道活性测试
本发明化合物与对比专利化合物LHC-7、LP-2、化合物1及地氯雷他定相比，化合物抑制hERG钾通道的活性明显降低，特别是化合物1～4、7、8、11、21、26、29、32抑制hERG的IC 50>30μm，心脏毒性风险小，具有更高的安全性。
实施例编号 hERG IC 50(μm)
1 >30
2 >30
3 >30
4 >30
7 >30
8 >30
11 >30
21 >30
26 >30
29 >30
32 >30
LHC-7 0.248
化合物1 2.033
LP-2 4.032
地氯雷他定 1.214
具体实施方式
以下列举本发明化合物的一般制造方法。另外，萃取、纯化等只要进行通常有机化学的实验中进行的处理即可。
本发明化合物的合成可以一边参考本领域中公知的步骤一边进行实施。
原料化合物可以使用市售的化合物、本说明书中记载的化合物、本说明书中引用的文献中记载的化合物、和其它公知化合物。
在本发明的化合物中，可以存在互变异构体，本发明含有这些化合物，包含所有可能的异构体和它们的混合物。
当欲获得本发明化合物的盐时，对于本发明的化合物以盐的形式得到的情况，只要直接纯化即可，另外，对于本发明的化合物以游离的形式得到的情况，可以使其溶解或悬浮在合适的有机溶剂中，加入酸或碱，利用常规的方法形成盐。
另外，本发明的化合物和其药学上可接受的盐有时也以与水或各种溶剂的加成物(水合物或溶剂化物)的形式存在，这些加成物也包含在本发明中。
实施例1
Figure PCTCN2021090073-appb-000016
步骤1 2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯(2)
Figure PCTCN2021090073-appb-000017
将2-(4-甲基苯基)-2-甲基丙酸甲酯(200mg，1.04mmol)溶于CCl 4(15mL)，依次加入NBS(194mg，1.09mmol)和AIBN(17mg，0.10mmol)。氮气保护下，80℃反应2.5h。TLC(V石油醚：V乙酸乙酯＝20：1)监测反应完全。反应液浓缩干经快速制备色谱纯化(20g，V石油醚：V乙酸乙酯＝50：1)得到242mg中间体2，收率85.8％。
步骤2 2-(4-((4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)甲基)苯基)-2-甲基丙酸甲酯(3)
Figure PCTCN2021090073-appb-000018
将地氯雷他定(240mg，0.77mmol)溶于DMF(6mL)，再依次加入中间体2(230mg，0.85mmol)和K 2CO 3(267mg，1.93mmol)。氮气保护下，60℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完全。冷却至室温，加入H 2O(30mL)，乙酸乙酯(20mL×3)萃取。合并有机相，饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩经快速制备色谱纯化(20g，V二氯甲烷：V甲醇＝30：1)得到300mg浅红色油状中间体3，收率77.5％。
1H NMR(400MHz,CDCl 3)δ(ppm)8.39-8.37(m,1H,ArH),7.42(d,J＝6.55Hz,1H,ArH),7.24-7.26(m,4H,ArH),7.01-7.17(m,4H,ArH),3.64(s,3H,O-CH 3),3.47(s,2H,ArH-CH 2),3.42-3.32(m,2H,ArH-CH 2),2.87-2.69(m,4H,N(CH 2) 2),2.52(br,1H,ArH-CH),2.46-2.37(m,1H,ArH-CH 2),2.36-2.29(m,2H,N(CH 2) 2),2.17-2.12(m,1H,ArH-CH),1.92-1.82(m,1H,ArH-CH),1.76-1.69(m,1H,ArH-CH 2),1.56(s,6H,(CH 3) 2)。
2-(4-((4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)甲基)苯基)-2-甲基丙酸(实施例1)
Figure PCTCN2021090073-appb-000019
将中间体3(295mg，0.59mmol)溶于MeOH(8mL)，然后加入NaOH(94mg，2.35mmol)的H 2O(2mL)溶液。60℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完全，加入水(15mL)，减压除去甲醇，用2N HCl溶液调节pH至4-5，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩并快速制备色谱纯化(20g，V二氯甲烷：V甲醇＝12.5：1)得到实施例1化合物120mg，类白色固体，收率41.9％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.22-8.21(m,1H,ArH),7.55(d,J＝7.81Hz,1H,ArH),7.35-7.29(m,2H,ArH),7.27-7.22(m,2H,ArH),7.18-7.12(m,2H,ArH),7.10-7.05(m,1H,ArH),7.03-6.98(m,1H,ArH),3.80(br,2H,ArH-CH 2),3.37-3.25(m,2H,ArH-CH 2),3.03-2.96(m,2H,N(CH 2) 2),2.81-2.72(m,2H,N(CH 2) 2),2.65-2.58(m,2H,N(CH 2) 2),2.50-2.44(m,2H,N(CH 2) 2),2.40-2.30(m,1H,ArH-CH 2),2.28-2.18(m,1H,ArH-CH 2),1.42(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):181.08,156.39,147.76,145.75,139.88,138.38,136.77,134.48,134.16,133.06,130.19,130.07,128.98,126.11,125.80,122.92,60.29,53.40,52.72,31.12,30.63,28.17,28.05,26.28.
实施例2
Figure PCTCN2021090073-appb-000020
步骤1 2-(4-(2-溴乙酰基)苯基)-2-甲基丙酸乙酯的合成(2)
Figure PCTCN2021090073-appb-000021
将三氯化铝(6.93g，52.0mmol)加入二氯甲烷(35mL)中，氮气保护，降温至-20℃，依次滴加1(5.00g，26.0mmol)和溴乙酰氯(60,8.18g，52.0mmol)。加毕升温至0℃，反应6h。TLC(V石油醚：V乙酸乙酯＝10：1)显示反应已完成。加入饱和碳酸氢钠溶液，调节pH至7。过滤，滤液分液，水层用二氯甲烷萃取(50mL)，合并有机相，用饱和食盐水洗涤(30mL×4)，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝40：1)纯化得到4.01g淡黄色油状物2，收率49.2％。
步骤2 2-(4-(2-溴乙基)苯基)-2-甲基丙酸乙酯的合成(3)
Figure PCTCN2021090073-appb-000022
将2(1.00g，3.2mmol)溶于三氟乙酸(2.0mL，26.8mmol)中，氮气保护，降温至0℃，滴加三乙基硅烷(1.0ml，3.2mmol)，搅拌30min后升温至60℃，反应过夜。TLC(V石油醚：V乙酸乙酯＝20：1)显示反应已完成。冰水浴冷却，滴加饱和碳酸氢钠溶液，调节pH至7。乙酸乙酯萃取(30mL×3)，合并有机相，用饱和食盐水洗涤(40mL×3)，无水硫酸钠干燥。过滤浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝100：1)纯化得到520mg无色油状物3，收率54.4％。
步骤3 2-(4-(2-(4-(8-氯-5,6-二氢-11H-苯并[5,6]]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)乙基)苯基)-2-甲基丙酸乙酯(4)
Figure PCTCN2021090073-appb-000023
将3(375mg，1.25mmol)溶于DMF(6mL)，再依次加入地氯雷他定(324mg，1.04mmol)和二异丙基乙胺(269mg，2.08mmol)。置换氮气，70℃反应过夜。TLC(V二氯甲烷：V甲醇:MeOH＝20：1)检测反应已完成。冰水浴冷却，加入水(15mL)淬灭反应，乙酸乙酯萃取(20mL×3)，合并有机相，饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，过滤，浓缩并经制备板分离(V二氯甲烷：V甲醇＝20：1)纯化得到307mg黄色固体4，收率55.7％。
步骤4 2-(4-(2-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)乙基)苯基)-2-甲基丙酸(实施例2)
Figure PCTCN2021090073-appb-000024
将4(307mg，0.58mmol)溶于EtOH(4mL)，再加入H 2O(2mL)和氢氧化钠(70mg，1.74mmol)，70℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完全。滴加3N稀盐酸，调节pH至3，减压浓缩，加入二氯甲烷(10mL)溶解，过滤，滤除无机盐。滤液浓缩并经制备板分离(V二氯甲烷：V甲醇＝10：1)纯化得到实施例2化合物105mg，淡黄色固体，收率36.1％。
1H NMR(400MHz,CDCl 3)δ(ppm):8.44(dd,J 1＝1.6Hz,J 2＝4.8Hz,1H,ArH),7.49(dd,J 1＝1.2Hz,J 2＝4.4Hz,1H,ArH),7.38(d,J＝8.4Hz,2H,ArH),7.17-7.12(m,3H,ArH),7.08-7.06(m,1H,ArH),6.92(d,J＝8.4Hz,2H,ArH),3.39-3.29(m,2H,ArH-CH 2),2.69-2.57(m,14H,ArH-CH 2,N(CH 2) 4),1.57(s,6H,(CH 3) 2)；
实施例3
Figure PCTCN2021090073-appb-000025
步骤1 2-(4-(3-羟丙基-1-炔-1-基)苯基)-2-甲基丙酸甲酯(2)
Figure PCTCN2021090073-appb-000026
将2-(4-碘苯基)-2-甲基丙酸甲酯(1，5.00g，16.44mmol)溶于乙腈50mL，再依次加入CuI(313mg，1.64mmol)和Pd(PPh 3) 2Cl 2(577mg，0.82mmol)，氮气保护，降温至-10℃，滴加三乙胺(7.50g，73.98mmol)，加完继续搅拌10min后再滴加炔丙醇(1.30mg，19.73mmol)，加完搅拌10min后移至室温反应4h。TLC(V石油醚：V乙酸乙酯＝3：1)检测原料反应完全。加水(50mL)淬灭，用乙酸乙酯(50mL×2)萃取，合并有机相，饱和食盐水洗涤(50mL×4)，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝5：1)纯化得到3.50g黄色固体中间体2，收率91.6％。
步骤2 2-(4-(3-羟丙基)苯基)-2-甲基丙酸甲酯(3)
Figure PCTCN2021090073-appb-000027
将中间体2(3.50g，15.1mmol)溶于乙醇(35mL)，加入10％Pd/C(1.05g，10％wt)，在氢气氛围(15psi)下RT反应过夜。TLC(V石油醚：V乙酸乙酯＝2：1)检测原料反应完全。加硅藻土过滤，滤液浓缩并经柱层析(V石油醚：V乙酸乙酯＝10：1)纯化得到1.80g无色油状物中间体3，收率50.5％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.26-7.23(m,2H,ArH),7.17-7.14(m,2H,ArH),3.69-3.67(m,2H,ArHCH 2),3.65(s,3H,OCH 3),2.70-2.66(m,2H,(CH 2) 2),1.92-1.85(m,2H,(CH 2) 2),1.56(s,6H,(CH 3) 2).
步骤3 2-(4-(3-溴丙基)苯基)-2-甲基丙酸甲酯(4)
Figure PCTCN2021090073-appb-000028
将中间体3(1.80g，7.6mmol)溶于二氯甲烷(30mL)，加入CBr 4(3.78g，11.4mmol)，氮气保护，降温至0℃，滴加PPh 3(3.09g，11.8mmol)的二氯甲烷(5mL)溶液，加完RT反应过夜。TLC(V石油醚：V乙酸乙酯＝2：1)检测原料反应完全。直接浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝40：1)纯化得到1.98g无色油状物中间体4，收率86.9％。
ESI-Mass m/z:299.09(M ++H).
步骤4 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸甲酯(5)
Figure PCTCN2021090073-appb-000029
将中间体4(1.98g，6.62mmol)溶于DMF(30mL)，在依次加入地氯雷他定(2.47g，7.94mmol)和二异丙基乙胺(1.71g，13.23mmol)，氮气保护，70℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完全。冷却至室温，加水(30mL)淬灭，乙酸乙酯(40 mL×2)萃取，合并有机相，用饱和食盐水洗涤(40mL×3)，无水硫酸钠干燥，过滤，浓缩并经快速制备色谱(80g，V二氯甲烷：V甲醇＝50：1)纯化得到0.97g粉红色固体中间体5，收率79.4％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.30-8.32(m,1H,ArH),7.65-7.63(m,1H,ArH),7.26-7.21(m,4H,ArH),7.18-7.11(m,4H,ArH),3.63(s,3H,O-CH 3),3.44-3.35(m,2H,ArH-CH 2),2.87-2.80(m,4H,ArH-CH 2),2.63-2.59(m,2H ArH-CH 2),2.48-2.23(m,8H,N(CH 2) 4),1.88-1.82(m,2H,N(CH 2)),1.53(s,6H,(CH 3) 2).
步骤5 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸(实施例3)
Figure PCTCN2021090073-appb-000030
将中间体5(500mg，0.94mmol)溶于甲醇(12mL)，加入水(4mL)和NaOH(151mg，3.78mmol)，60℃反应过夜。TLC(V二氯甲烷：V甲醇＝10：1)检测反应完全。浓缩除去甲醇，加入水(5mL)，乙酸乙酯(5mL×3)洗涤，水相用1N稀盐酸溶液调节pH至5，有粘稠固体析出，过滤，滤饼溶于甲醇(5mL)中，无水硫酸钠干燥，过滤，浓缩，经制备板经制备板(V二氯甲烷：V甲醇＝6：1)纯化得到实施例3化合物115mg，白色固体，收率23.6％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.24(dd,J 1＝1.2Hz,J 2＝4.8Hz,1H,ArH),7.56-7.54(m,1H,ArH),7.22-7.13(m,4H,ArH),7.09-6.96(m,4H,ArH),3.34-3.24(m,2H,ArH-CH 2),3.09-3.02(m,2H,ArH-CH 2),2.82-2.35(m,6H,N(CH 2) 3),2.56-2.47(m,4H,ArH-CH 2),2.41-2.25(m,2H,N(CH 2)),1.86-1.76(m,2H,ArH-CH 2),1.38(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):182.24,155.80,145.30,144.88,139.44,137.91,137.63,136.23,134.00,133.81,133.74,132.60,129.58,128.50,127.21,125.33,125.19,122.46,55.88,52.26,31.64,30.61,30.14,27.51,27.37,26.22,26.18,25.65.
实施例4 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-亚基)哌啶-1-基)丙基)-3-氰基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-氰基4-碘苯基)-2-甲基丙酸甲酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例4化合物175mg，白色固体，收率80.0％。
1H NMR(400MHz,CDCl 3)δ(ppm):8.42(d,J＝4.4Hz,1H,ArH),7.68(d,J＝1.6Hz,1H,ArH),7.57-7.60(m,1H,ArH),7.47-7.46(m,1H,ArH),7.16-7.12(m,4H,ArH),7.04(d,J＝8.0Hz,1H,ArH),3.40-3.27(m,2H,ArH-CH 2),2.99(br,2H,ArH-CH 2),2.99-2.49(m,10H,ArH-CH 2,N(CH 2) 4),2.33(s,2H,ArH-CH 2),1.96-1.93(m,2H,ArH-CH 2),1.58-1.56(m,6H,(CH 3) 2).
13C NMR(100MHz,DMSO-d 6)δ(ppm):181.50,156.26,147.01,145.79,142.01,139.94,138.41,134.50,134.11,133.11,131.23,130.06,129.99,129.01,129.00,125.84,122.96,117.83,111.42,56.02,52.81,21.10,30.69,30.64,28.03,27.89,26.26,25.59.
实施例5 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-甲氧基苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-甲氧基-4-碘苯基)-2-甲基丙酸甲酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例5化合物104mg，淡黄色固体，收率30.8％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.35(dd,J 1＝4.9Hz,J 2＝1.5Hz,1H,ArH),7.67(dd,J 1＝7.8Hz,J 2＝1.4Hz,1H,ArH),7.31–7.25(m,2H,ArH),7.20(dd,J 1＝8.1Hz,J 2＝2.1Hz,1H,ArH),7.1(d,J＝8.2Hz,1H,ArH),7.07(d,J＝7.8Hz,1H,ArH),6.95(d,J＝1.6Hz,1H,ArH),6.91(dd,J 1＝7.8Hz,J 2＝1.8Hz,1H,ArH),3.81(s,3H,O-CH 3),3.48–3.35(m,4H,ArH-CH 2),3.15–3.00(m,4H,N(CH 2) 2),2.94–2.81(m,2H,ArH-CH 2),2.72–2.61(m,4H,N(CH 2) 2),2.59–2.42(m,2H,(CH 2)),2.05–1.94(m,2H,(CH 2)),1.52(s,6H,(CH 3) 2).
13C NMR(400MHz,CD 3OD)δ(ppm):180.16,157.20,155.81,145.83,140.05,138.62,136.49,135.37,134.59,133.32,132.23,129.85,129.33,129.03,126.26,125.89,123.12,117.60,108.17,56.30,54.37,52.60,46.49,30.98,30.62,27.48,27.31,26.55,26.00,24.30.
实施例6 2-(3-氨基-4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-氨基4-碘苯基)-2-甲基丙酸甲酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例6化合物240mg，收率85％。
1H NMR 400MHz(CD 3OD)δ(ppm):8.31(dd,J 1＝1.6Hz,J 2＝5.2Hz,1H,ArH),7.63(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H,ArH),7.27-7.22(m,2H,ArH),7.18-7.16(m,1H,ArH),7.10(d,J＝3.6Hz,1H,ArH),6.71-6.88(m,3H,ArH),3.44-3.31(m,2H,ArH-CH 2),3.00-2.96(m,2H,ArH-CH 2),2.87-2.83(m,2H,ArH-CH 2),2.61(m,2H,ArH-CH 2),2.54-2.40(m,7H,ArH-CH 2,N(CH 2) 2),2.37-2.28(m,1H,ArH-CH 2),1.86-1.80(m,2H,N(CH 2) 2),1.45(s,6H,(CH 3) 2).
13C NMR 100MHz(CD 3OD)δ(ppm):156.70,146.37,145.73,144.21,139.83,138.29,136.84,135.83,134.51,133.46,132.94,130.24,128.96,128.88,125.72,123.47,122.85,116.25,114.00,99.97,56.40,53.22,31.19,30.61,28.84,28.74,27.83,26.73,26.71,24.92.
实施例7 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-(三氟甲氧基)苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-氧三氟甲基4-碘苯基)-2-甲基丙酸甲酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例7化合物54mg，白色固体，收率18.7％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.32(dd,J 1＝5.2Hz,J 2＝1.6Hz,1H,ArH),7.55(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H,ArH),7.33-7.16(m,6H,ArH),7.11(d,J＝8.0Hz,1H,ArH),3.44-3.34(m,2H,ArH-CH 2),3.20-3.11(m,2H,ArH-CH 2),2.91-2.74(m,6H,N(CH 2) 3),2.69-2.57(m,4H,ArH-CH 2,N(CH 2) 4),2.50-2.44(m,1H,ArH-CH 2),2.40-2.34(m,1H,ArH-CH 2),1.94-1.87(m,2H,(CH 2)),1.49(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):181.64,156.26,148.09,147.04,145.79,139.94,138.43,136.69,F(134.53,134.43),134.04,133.14,130.55,130.05,129.82,129.00,125.83,124.95,122.98,118.20,56.22,52.77,31.09,30.63,27.98,27.84,26.42,26.39,26.11,24.79.
实施例8 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-氟苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-氟-4-碘苯基)-2-甲基丙酸甲酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例8化合物60mg，收率19.4％。
1H NMR 400MHz(CD 3OD)δ(ppm):8.32(dd,J 1＝1.6Hz,J 2＝4.8Hz,1H,ArH),7.65(d,J＝8.0Hz,1H,ArH),7.28-7.06(m,7H,ArH),3.45-3.35(m,2H,ArH-CH 2),3.17(s,2H,ArH-CH 2),2.92-2.75(m,6H,N(CH 2) 3),2.67-2.56(m,4H,ArH-CH 2),2.52-2.35(m,2H,ArH-CH 2),1.97-1.89(m,2H,(CH 2)),1.48(s,6H,(CH 3) 2).
13C NMR 100MHz(CD 3OD)δ(ppm):161.96,159.55,156.25,C-F(148.35,148.28),145.79,139.94,138.41,136.70,(134.51,134.43),134.01,133.13,130.04,(129.78,129.73),128.99,125.82,124,65,124.49,122.96,(121.67,121.63),112.63,112.39,70.17,56.27,52.79,31.09,30.63,27.99,27.85,26.44,26.41,25.39,24.96.
实施例9 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-2-氟苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(2-氟-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例9化合物231mg，类白色固体，收率75.3％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.33(d,J＝4.28Hz,1H,ArH),7.77(br,1H,ArH),7.35(br,1H,ArH),7.27-7.18(m,2H,ArH),7.15-7.11(m,1H,ArH),7.07(br,1H,ArH),6.95(d,J＝7.05Hz,1H,ArH),6.88(d,J＝12.09Hz,1H,ArH),3.59-3.27(m,4H,ArH-CH 2),3.03(br,2H,ArH-CH 2),2.95-2.16(m,10H,ArH-CH 2,N(CH 2) 4),2.00(br,2H,(CH 2)),1.42(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):178.56,161.58,159.14,(140.79,140.71),139.57,135.49,133.21,130.33,129.38,128.63,126.12,125.64,(123.35,123.32),114.68,114.45,55.46,51.93,42.95,30.89,30.14,31.10,26.90,24.75,24.40.
实施例10 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-甲基苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-甲基-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例10化合物150mg，收率32.8％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.23(dd,J 1＝1.2Hz,J 2＝4.4Hz,1H,ArH),7.56(d,J＝7.2Hz,1H,ArH),7.18-7.14(m,2H,ArH),7.10-7.01(m,4H,ArH),6.88(s,1H,ArH),3.34-3.25(m,2H,ArH-CH 2),2.99(s,1H,ArH-CH 2),2.82-2.49(m,10H,ArH-CH 2,N(CH 2) 4),2.39-2.35(m,1H,ArH-CH 2),2.28-2.25(m,1H,ArH-CH 2),2.17-2.14(m,3H,(CH 3)),1.79-1.71(m,2H,ArH-CH 2),1.37(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):156.49,145.74,145.17,139.89,138.33,136.79,136.41,134.98,134.50,133.93,133.03,130.12,128.96,128.06,127.39,125.76,123.27,122.88,56.75,53.06,46.86,31.31,30.62,29.57,28.44,28.31,26.58,26.57,25.45,18.23.
实施例11 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-2-甲基苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(2-甲基-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例11化合物177mg，棕色固体，收率46.9％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.34(d,J＝4.28Hz,1H,ArH),7.67(d,J＝7.55Hz,1H,ArH),7.33-7.24(m,3H,ArH),7.22-7.17(m,1H,ArH),7.15-7.10(m,1H,ArH),7.01-6.94(m,2H,ArH),3.47-3.36(m,2H,ArH-CH 2),3.15-3.13(m,2H,ArH-CH 2),2.96-2.68(m,6H,N(CH 2) 3),2.65-2.55(m,4H,ArH-CH 2,N(CH 2)),2.50-2.46(m,1H,ArH-CH 2),2.40-2.36(m,1H,ArH-CH 2),2.31(s,3H,(CH 3)),2.02-1.87(m,2H,ArH-CH 2),1.51(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):184.87,157.69,147.21,144.56,141.36,139.86,139.45,138.13,137.77,135.93,135.75,135.60,134.53,132.65,131.49,130.44,127.26,126.74,126.62,124.40,57.78,54.22,33.41,32.53,32.06,29.55,29.41,28.17,27.65,21.12.
实施例12 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶基-11-烯基)哌啶-1-基))丙基)-3-(三氟甲基)苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-三氟甲基-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例12化合物95mg，白色固体，收率24.9％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.32(dd,J 1＝1.2Hz,J 2＝5.2Hz,1H,ArH),7.67-7.63(m,2H,ArH),7.56-7.54(m,1H,ArH),7.27-7.22(m,3H,ArH),7.18-7.16(m,1H,ArH),7.11(d,J＝4.0Hz,1H,ArH),3.44-3.34(m,2H,ArH-CH 2),3.13-3.05(m,2H,ArH-CH 2),2.91-2.67(m,8H,N(CH 2) 4),2.61-2.55(m,2H,ArH-CH 2),2.49-2.33(m,2H,ArH-CH 2),1.93-1.85(m,2H,ArH-CH 2),1.50(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):182.30,156.42,146.60,145.76,139.91,138.37,(136.83,136.77),134.72,134.51,(134.08,133.05),130.50,130.12,129.82,129.00,127.51,127.22,125.80,123.05,122.93,56.46,52.94,52.92,31.13,30.63,28.97,28.29,28.16,26.55.
实施例13 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶基-11-烯基)哌啶-1-基))丙基)-2-(三氟甲基)苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(2-三氟甲基-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例13化合物72mg，白色固体，收率18.9％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.36(dd,J 1＝1.2Hz,J 2＝4.8Hz,1H,ArH),7.68(dd,J 1＝1.6Hz,J 2＝11.6Hz,1H,ArH),7.61-7.44(m,3H,ArH),7.31-7.27(m,2H,ArH),7.22-7.13(m,2H,ArH),3.45-3.38(m,2H,ArH-CH 2),3.25-3.21(m,2H,ArH-CH 2),2.95-2.83(m,6H,ArH-CH 2,N(CH 2) 3),2.77-2.60(m,4H,ArH-CH 2),2.55-2.41(m,2H,(CH 2)),2.07-1.98(m,2H,(CH 2)),1.61(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):181.33,156.14,145.81,141.94,139.96,139.36,138.47,136.64,134.69,134.52,133.52,133.17,131.48,129.98,129.02,128.18,(128.09,128.04,127.88,127.85),126.64,125.85,123.92,123.01,56.04,52.75,52.72,47.11,31.53,31.06,30.61,27.83,27.67,25.69.
实施例14 2-(3-溴-4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-溴-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例14化合物85mg，淡黄色固体，收率40％。
1H NMR 400MHz(CD 3OD)δ(ppm):8.23(dd,J 1＝1.2Hz,J 2＝4.8Hz,1H,ArH),7.54(dd,J 1＝1.6Hz,J 2＝7.6Hz,1H,ArH),7.47(d,J＝2.0Hz,1H,ArH),7.22-7.14(m,3H,ArH),7.07(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H,ArH),7.03-7.01(m,2H,ArH),3.35-3.24(m,2H,ArH-CH 2),3.13-3.06(m,2H,ArH-CH 2),2.82-2.70(m,6H,ArH-CH 2,N(CH 2) 2),2.60(t,J＝7.6Hz,2H,N(CH 2)),2.55-2.49(m,2H,N(CH 2)),2.43-2.39(m,1H,ArH-CH 2),2.33-2.28(m,1H,ArH-CH 2),1.84-1.77(m,2H,ArH-CH 2),1.38(s,6H,(CH 3) 2).
13C NMR 100MHz(CD 3OD)δ(ppm):181.75,156.19,147.93,145.80,139.96,138.46,137.24,136.66,134.52,133.84,133.09,130.04,129.97,129.67,129.01,125.85,125.40,125.35,123.56,123.00,56.08,52.72,32.33,31.09,30.63,27.89,27.74,26.39,26.37,24.67.
实施例15 2-(3-氯-4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-氯-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例15化合物100mg，淡黄色固体，收率33％。
1H NMR 400MHz(CD 3OD)δ(ppm):8.33(dd,J 1＝1.6Hz,J 2＝4.8Hz,1H,ArH),7.65(dd,J 1＝1.6Hz,J 2＝7.6Hz,1H,ArH),7.40(d,J＝2.0Hz,1H,ArH),7.29-7.24(m,3H,ArH),7.07(dd,J 1＝2.4Hz,J 2＝8.4Hz,1H,ArH),7.12(d,J＝8.0Hz,1H,ArH),3.45-3.35(m,2H,ArH-CH 2),3.20-3.17(m,2H,ArH-CH 2),2.93-2.80(m,6H,ArH-CH 2,N(CH 2) 2),2.70(t,J＝8.0Hz,2H,ArH-CH 2),2.67-2.59(m,2H,N(CH 2)),2.53-2.48(m,1H,ArH-CH 2),2.43-2.37(m,1H,ArH-CH 2),1.96-1.88(m,2H,ArH-CH 2),1.49(s,6H,(CH 3) 2).
13C NMR 100MHz(CD 3OD)δ(ppm):181.75,156.19,147.93,145.80,139.96,138.46,137.24,136.66,134.52,133.84,133.09,130.04,129.97,129.67,129.01,125.85,125.40,125.35,123.56,123.00,56.08,52.72,32.33,31.09,30.63,27.89,27.74,26.39,26.37,24.67；
实施例16 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-2-硝基苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(2-硝基-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例16化合物260mg，白色固体，收率72.0％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.34(d,J＝4.8Hz,1H,ArH),7.75(s,1H,ArH),7.67(d,J＝3.6Hz,1H,ArH),7.62(d,J＝8.0Hz,1H,ArH),7.51(dd,J 1＝1.6Hz,J 2＝8.4Hz,1H,ArH),7.25-7.29(m,2H,ArH),7.20(d,J＝8.4Hz,1H,ArH),7.14(d,J＝8.0Hz,1H,ArH),3.27-3.45(m,4H,ArH-CH 2),2.48-3.01(m,12H,ArH-CH 2,N(CH 2) 4),2.03-2.06(m,2H,ArH-CH 2),1.61(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):179.00,155.05,148.47,144.79,139.23,138.98,137.77,137.48,135.58,133.85,133.53,132.16,132.08,131.54,128.95,128.00,127.36,124.84,123.53,122.01,54.74,51.47,45.75,30.23,30.02,29.59,26.47,26.28,24.23.
实施例17 2-(4-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-硝基苯基)-2-甲基丙酸
参考化合物实施例3的合成方法，以2-(3-硝基-4-碘苯基)-2-甲基丙酸乙酯替换2-(4-碘苯基)-2-甲基丙酸甲酯，制得实施例17化合物115mg，淡黄色固体，收率13％。
1H NMR 400MHz(CD 3OD)δ(ppm):8.33(dd,J 1＝1.6Hz,J 2＝4.8Hz,1H),7.96(d,J＝2.0Hz,1H),7.85(dd,J 1＝1.2Hz,J 2＝7.6Hz,1H),7.60(dd,J 1＝2.0Hz,J 2＝8.4Hz,1H),7.24-7.29(m,3H),7.18(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),3.36-3.45(m,2H),3.23-3.27(m,2H),2.79-2.99(m,8H),2.62-2.69(m,2H),2.49-2.55(m,1H),2.39-2.46(m,1H),1.92-1.98(m,2H),1.52(s,6H)；
13C NMR 100MHz(CD 3OD)δ(ppm):181.31,156.21,148.89,147.91,145.80,139.95,138.43,136.67,134.52,133.84,133.14,132.82,131.20,131.03,130.02,128.99,125.84,122.97,121.82,56.17,52.73,31.08,30.63,29.25,27.87,27.72,26.23,26.21,25.48.
实施例18 2-(4-(3-(4-(8-氯-5-羟基-5,6-二氢-11H--苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-硝基苯基)-2-甲基丙酸
Figure PCTCN2021090073-appb-000031
参考化合物实施例4的合成方法，以5-羟基地氯雷他定替换地氯雷他定，制得实施例18化合物43mg，淡黄色固体，收率10.2％。
ESI-HRMS:m/z calcd for C 32H 34ClN 3O 4[M+H] +531.2414,found 531.2408.
实施例19 2-(4-(3-(4-(8-氯-6-羟基-5,6-二氢-11H--苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-硝基苯基)-2-甲基丙酸
Figure PCTCN2021090073-appb-000032
参考化合物实施例4的合成方法，以5-羟基地氯雷他定替换地氯雷他定，制得实施例19化合物71mg，淡黄色固体，收率26.1％。
ESI-HRMS:m/z calcd for C 32H 34ClN 3O 4[M+H] +531.2414,found 531.2407.
实施例20 2-(4-(3-(4-(8-氯-3-羟基-5,6-二氢-11H--苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)-3-硝基苯基)-2-甲基丙酸
Figure PCTCN2021090073-appb-000033
参考化合物实施例3的合成方法，以5-羟基地氯雷他定替换地氯雷他定，制得实施例20化合物53mg，淡黄色固体，收率14.8％。
ESI-HRMS:m/z calcd for C 32H 34ClN 3O 4[M+H] +531.2414,found 531.2412.
实施例21 2-(4-(3-(4-(2-氯-10,11-二氢-5H-二苯并[a，d][7]环戊烯基-亚萘基)哌啶-1-基)丙基)苯基)-2-甲基丙酸
Figure PCTCN2021090073-appb-000034
参考化合物实施例3的合成方法，以4-(2-氯-10,11-二氢-5H-二苯并[a，d][7]年戊烯基-5-亚烷基)哌啶替换地氯雷他定，制得实施例21化合物36mg，淡黄色固体，收率10.4％。HRMS(ESI):m/z Calcd for C 33H 36ClNO 2[M+H] +513.2435,found 513.2346.
实施例22 2-甲基-2-(4-(3-(4-(10-氧代-9,10-二氢-4H-苯并[4,5]环庚[1,2-b]噻吩-4-亚烷基])哌啶1-基)丙基)苯基)丙酸
Figure PCTCN2021090073-appb-000035
参考化合物实施例3的合成方法，以4-(哌啶-4-亚烷基)-4,9-二氢-10H-苯并[4,5]环庚[1,2-b]噻吩-10-酮替换地氯雷他定，制得实施例22化合物63mg，淡黄色固体，收率43.2％。HRMS(ESI):m/z Calcd for C 31H 33NO 3S[M+H] +499.2181,found 499.2178.
实施例23 2-(4-(3-(4-(10-羟基-9,10-二氢-4H-苯并[4,5]环庚[1,2-b]噻吩-4-亚烷基]哌啶-1-基))丙基)苯基)-2-甲基丙酸
Figure PCTCN2021090073-appb-000036
参考化合物实施例3的合成方法，以4-(哌啶-4-亚烷基)-9,10-二氢-4H-苯并[4,5]环庚[1,2-b]噻吩-10-醇替换地氯雷他定，制得实施例23化合物92mg，淡黄色固体，收率51.6％。HRMS(ESI):m/z Calcd for C 31H 35NO 3S[M+H] +501.2338,found 501.2346.
实施例24
Figure PCTCN2021090073-appb-000037
步骤1 2-(4-碘苯基)乙酸甲酯(2)
Figure PCTCN2021090073-appb-000038
将1(10.0g，38.2mmol)溶于甲醇(100mL)，室温搅拌下，向上述反应液滴加浓硫酸(3.74g，38.2mmol)，氮气保护下，65℃反应3h。TLC(V石油醚：V乙酸乙酯＝4：1)检测反应结束。浓缩，加入冰水(100mL)，乙酸乙酯(50mL×3)萃取，收集有机相，饱和氯化钠溶液(50mL×3)洗涤，合并有机相。无水硫酸钠干燥，抽滤，浓缩并经快速制备色谱纯化(120g，V石油醚：V乙酸乙酯＝98:2-95:5)，得到10.0g无色油状物2，收率95.0％。
步骤2 2-(4-碘苯基)-2-甲基丙酸甲酯(3)
Figure PCTCN2021090073-appb-000039
将中间体2(9.00g，32.6mmol)溶于DMF(150mL)中，氮气保护下，降温至-20℃。向上述反应液缓慢滴加NaHMDS(2M in THF，17.9g，97.8mmol)的四氢呋喃溶液(49mL)，保温反应30min。继续滴加碘甲烷(18.5g，130.4mmol)，加毕，保温15min后转移至室温反应7h。TLC(V石油醚：V乙酸乙酯＝10：1)监测反应结束，反应液倒入快速搅拌的1M柠檬酸(200mL)冰水溶液中。乙酸乙酯(100mL×4)萃取，饱和氯化钠溶液(300mL×3)洗涤，收集有机相。无水硫酸钠干燥，抽滤，减压浓缩并经硅胶柱纯化(V石油醚：V乙酸乙酯＝20：1)，得到9.63g黄色油状物3，收率97.1％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.58-7.55(m,2H,ArH),7.02-6.99(m,2H,ArH),3.57(s,3H,OCH 3),1.47(s,6H,(CH 3) 2).
步骤3 2-(4-(4-羟基-1-炔-1-基)苯基)-2-甲基丙酸甲酯(4)
Figure PCTCN2021090073-appb-000040
将3(5.38g，17.7mmol)溶于乙腈(80mL)，再依次加入碘化亚铜(270mg，1.42mmol)和Pd(PPh 3) 2Cl 2(497mg，0.71mmo)l，氮气保护下，-10℃搅拌20min。依次向上述反应液滴加三乙胺(8.06g，79.7mmol)和炔丁醇(1.49g，21.2mmol)，-10℃搅拌10min，转移至室温反应过夜。TLC(V石油醚：V乙酸乙酯＝10：1)监测反应结束后，浓缩，加入乙酸乙酯(50mL)搅拌0.5h，硅藻土铺垫下抽滤，滤液浓缩，硅胶柱纯化(V二氯甲烷：V甲醇＝100：1)，得到5.12g黄色油状物4，收率98％。
步骤4 2-(4-(4-羟基丁基)苯基)-2-甲基丙酸甲酯(5)
Figure PCTCN2021090073-appb-000041
将4(5.12g，85％purity，17.7mmol)溶于甲醇(150mL)，加入10％Pd/C(1.74g,40％Wt)，氢气置换三次，室温反应过夜(15psi)。TLC(V石油醚：V乙酸乙酯＝4：1)监测反应结束，硅藻土铺垫下抽滤，浓缩，快速制备色谱纯化(80g，V石油醚：V乙酸乙酯＝100：1-78：22)，得到3.00g无色油状物5，收率67.7％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.26-7.22(m,2H,ArH),7.15-7.13(m,2H,ArH),3.67-3.64(m,5H,OCH 3,ArH-CH 2),2.62(t,J＝7.2Hz,2H,CH 2OH),1.61-1.73(m,4H,(CH 2) 2),1.56(s,6H,(CH 3) 2).
步骤5 2-(4-(4-溴丁基)苯基)-2-甲基丙酸甲酯(6)
Figure PCTCN2021090073-appb-000042
将5(1.00g，4.00mmol)溶于二氯甲烷(20mL)，加入四溴化碳(1.99g，6.00mmol)，氮气保护下，缓慢加入三苯基膦(1.63g，6.20mmol)，室温反应过夜。TLC(V石油醚：V乙酸乙酯＝10：1)监测反应结束，减压浓缩并经硅胶柱纯化(V石油醚：V乙酸乙酯＝20：1-10：1)，得到1.15g淡黄色油状物6，收率91.8％。
步骤6 2-(4-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丁基)苯基)-2-甲基丙酸甲酯(7)
Figure PCTCN2021090073-appb-000043
将6(1.15g，3.67mmol)溶于DMF(17mL)，再依次加入28(0.95g，3.06mmol)和二异丙基乙胺(0.79g，6.12mmol)，氮气保护下，68℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完成，反应液冷却至室温，加入水(60mL)，乙酸乙酯(20mL×4)萃取，收集有机相，饱和氯化钠溶液(50mL×3)洗涤，合并有机相。无水硫酸钠干燥，抽滤，减压浓缩并经快速制备色谱纯化(40g，V二氯甲烷：V甲醇＝97.5：2.5)，得到787mg类白色固体7，收率47.4％。
步骤7 2-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丁基)苯基)-2-甲基丙酸(实施例24)
Figure PCTCN2021090073-appb-000044
将7(787mg，1.45mmol)溶于甲醇(16mL)，再加入NaOH(232mg，5.80mmol)的水溶液(4mL)，氮气保护下，60℃反应过夜。TLC(V二氯甲烷：V甲醇＝15：1)检测反应结束，浓缩除去溶剂，加入水(2mL)稀释残留水相，乙酸乙酯(3mL)洗涤，用3N稀盐酸调节水相pH至8，然后改用1N稀盐酸调节pH至5-6，析出大量固体，充分搅拌30min后抽滤，水(5mL×3)洗涤，收集滤饼，滤饼用混合溶剂(V甲醇：V水＝1：2，15mL)打浆，抽滤，滤饼烘干得到实施例24化合物101mg，白色固体，收率13.2％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.23(dd,J 1＝4.9Hz,J 2＝1.6Hz,1H,ArH),7.55(dd,J 1＝7.8,J 2＝1.6Hz,1H,ArH),7.23-7.20(m,2H,ArH),7.18-7.14(m,2H,ArH),7.09-7.07(m,1H,ArH),7.03-6.98(m,3H,ArH),3.34-3.24(m,2H,ArH-CH 2),3.04-2.96(m,2H,ArH-CH 2),2.82-2.61(m,6H,N(CH 2) 3),2.54-2.45(m,4H,N(CH 2),(CH 2) 2),2.39-2.23(m,2H,(CH 2)),1.50-1.48(m,4H ArH-CH 2),1.38(s,6H,(CH 3) 2).
13C NMR(100MHz,CD 3OD)δ(ppm):181.61,155.33,144.77,143.99,138.90,138.13,137.37,135.75,133.46,133.38,133.18,132.06,129.08,127.99,126.69,124.81,124.62,121.93,55.58,51.77,33.47,30.11,29.63,27.40,27.10,26.95,25.62,23.09.
实施例25
Figure PCTCN2021090073-appb-000045
步骤1 2-(3-碘苯基)-2-甲基丙酸甲酯(2)
Figure PCTCN2021090073-appb-000046
将1(6.3g，22.82mmol)溶于DMF(100mL)，N 2置换3次，降温至-20℃下滴加NaHMDS(2mol/L，34mL，68.46mmol)，加完后继续反应40min，再滴加MeI(13.0g，91.28mmol)，加完继续反应4h。TLC(V石油醚：V乙酸乙酯＝5：1)检测原料反应完全。加饱和氯化铵(250mL)淬灭，乙酸乙酯(100mL×3)萃取，合并有机相，饱和氯化钠溶液(100mL×5)洗涤，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝100：1)纯化得到4.2g无色油状物2，收率60.5％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.67-7.66(m,1H,ArH),7.59-7.57(m,1H,ArH),7.30-7.28(m,1H,ArH),7.07-7.03(m,1H,ArH),3.66(s,3H,OCH 3),1.55(s,6H,(CH 3) 2).
步骤2 2-(3-(3-羟丙基-1-炔-1-基)苯基)-2-甲基丙酸甲酯(3)
Figure PCTCN2021090073-appb-000047
将2(4.2g，13.81mmol)溶于乙腈(40mL)，再依次加入CuI(260mg，1.38mmol)和Pd(PPh 3)Cl 2(480mg，0.69mmol)，N 2置换3次，降温至-10℃下加入三乙胺(6.3g，62.14mmol)，加完继续搅拌10min，再加入炔丙醇(1.1g，16.57mmol)，加完搅拌10min后移至室温反应4h。TLC(V石油醚：V乙酸乙酯＝5：1)检测原料反应完全。加水(40mL)淬灭，乙酸乙酯(50mL×3)萃取，合并有机相，饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝100：1)纯化得到3.1g黄色油状物3，收率96.6％。
步骤3 2-(3-(3-羟丙基)苯基)-2-甲基丙酸甲酯(4)
Figure PCTCN2021090073-appb-000048
将3(3.1g，13.35mmol)溶于乙醇(30mL)，加入Pd/C(10％Pd，1.2g,40％wt)，氢气(15psi)氛围下室温反应3h。更换氢气球，然后室温反应过夜。TLC(V石油醚：V乙酸乙酯＝2：1)检测原料反应完全。加硅藻土过滤，滤液浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝10：1)纯化得到1.56g无色油状物4，收率49.5％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.25-7.22(m,1H,ArH),7.17-7.15(m,2H,ArH),7.09-7.07(m,1H,ArH),3.70-3.66(m,2H,ArH-CH 2),3.65(s,3H,OCH 3),2.72-2.68(m,2H,CH 2OH),1.91-1.87(m,2H,CH 2),1.57(s,6H,(CH 3) 2).
步骤4 2-(3-(3-溴丙基)苯基)-2-甲基丙酸甲酯(5)
Figure PCTCN2021090073-appb-000049
将4(1.66g，7.02mmol)溶于二氯甲烷(30mL)，加入CBr 4(3.49g，10.54mmol)，加完N 2置换3次，降温至0℃下滴加PPh 3(2.86g，10.89mmol)的二氯甲烷溶液(5mL)，加完RT反应过夜。TLC(V石油醚：V乙酸乙酯＝2：1)检测原料反应完全。直接浓缩并经柱层析(V石油醚：V乙酸乙酯＝50：1)纯化得到1.68g无色油状物5，收率80.0％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.24-7.21(m,1H,ArH),7.16-7.11(m,2H,ArH),7.04-7.01(m,1H,ArH),3.70-3.66(m,2H,Ph-CH 2),3.65(s,3H,OCH 3),2.71-2.64(m,2H,CH 2Br),1.88-1.84(m,2H,CH 2),1.56(s,6H,(CH 3) 2).
步骤5 2-(3-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸甲酯(6)
Figure PCTCN2021090073-appb-000050
将5(1.8g，6.02mmol)溶于DMF(20mL)，再依次加入28(1.56g，5.01mmol)和二异丙基乙胺(1.30g，10.03mmol)，N 2置换3次，升温至70℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完全。冷却至室温，加入水(20mL)淬灭，乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V二氯甲烷：V甲醇＝100：1-50：1)纯化得到1.35g淡黄色油状物6，收率66.0％.
步骤6 2-(3-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸(实施例25)
Figure PCTCN2021090073-appb-000051
将6(600mg，1.13mmol)溶于甲醇(10mL)，加入水(3mL)和NaOH(227mg，5.67mmol)，加热至60℃反应过夜。TLC(V二氯甲烷：V甲醇＝10：1)检测反应完全。浓缩除去甲醇，加水(10mL)淬灭，乙酸乙酯(10mL×2)洗涤，水相再用2N稀盐酸调节pH至5，水相再用混合溶剂萃取(10mL×3，V二氯甲烷：V甲醇＝20：1)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩并经制备板纯化(V二氯甲烷：V甲醇＝10：1)纯化得实施例25化合物170mg，白色固体，收率29.1％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.33-8.31(m,1H,ArH),7.65-7.63(m,1H,ArH),7.27-7.16(m,6H,ArH),7.11(d,J＝8.4Hz,1H,ArH),7.01-6.99(m,1H,ArH),3.42-3.35(m,2H,ArH-CH 2CH 2),3.15-3.11(m,1H,ArH-CH 2CH 2),2.89-2.53(m,10H,(CH 2) 2N(CH 2) 2,(CH 2) 2),2.49-2.44(m,1H,(CH 2) 2),2.39-2.33(m,1H,(CH 2) 2),1.97-1.89(m,2H),1.49(s,6H,CH 3CCH 3).
13C NMR(100MHz,CD 3OD)δ(ppm):182.36,156.30,147.60,145.79,140.23,139.94,138.41,136.74,134.50,134.28,134.25,133.09,130.09,129.01,127.94,125.89,125.83,125.63,123.46,122.97,56.30,52.87,32.75,31.12,30.65,28.15,28.01,26.68,26.67,26.16.
实施例26 2-(3-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基))丙基)-4-氰基苯基)-2-甲基丙酸
参考实施例25的的制备方法，以2-(4-氰基-3-碘苯基)乙酸甲酯替换2-(3-碘苯基)乙酸甲酯为原料，制得实施例26化合物260mg，白色固体,收率63.2％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.34(dd,J 1＝1.6Hz,J 2＝4.8Hz,1H,ArH),7.67-7.65(m,1H,ArH),7.60(d,J＝8.0Hz,1H,ArH),7.46-7.42(m,2H,ArH),7.29-7.25(m,2H,ArH),7.20-7.18(m,1H,ArH),7.12(d,J＝8.4Hz,1H,ArH),3.45-3.35(m,2H,ArH-CH 2CH 2),3.27-3.23(m,2H,ArH-CH 2CH 2),2.96-2.81(m,8H,(CH 2) 2N(CH 2) 2),2.67-2.57(m,2H,(CH 2) 2),2.54-2.38(m,2H,(CH 2) 2),2.08-2.00(m,2H,(CH 2) 2),1.52(s,6H,CH 3CCH 3).
13C NMR(400MHz,CD 3OD)δ(ppm):181.13,156.23,153.61,145.89,144.07,140.05,138.55,136.73,134.68,134.60,133.76,133.22,132.47,130.10,129.10,127.61,125.93,124.94,123.09,117.82,109.22,55.53,52.91,31.31,31.14,30.70,28.07,27.93,26.31,25.62.
实施例27 2-(3-(3-(4-(10-羟基-9,10-二氢-4H-苯并[4,5]环庚[1,2-b]噻吩-4-亚烷基]哌啶-1-基))丙基)苯基)-2-甲基丙酸
参考实施例25的的制备方法，以4-(哌啶-4-亚烷基)-9,10-二氢-4H-苯并[4,5]环庚[1,2-b]噻吩-10-醇替换地氯雷他定为原料，制得实施例27化合物690mg,黄色固体，收率86％。
1H NMR(400MHz,DMSO-d 6):δppm 7.35-7.38(m,1H),7.30-7.32(m,0.5H),7.19-7.24(m,1.5H),7.13-7.18(m,2H),7.07-7.11(m,3H),6.99-7.04(m,1H),6.76(d,J＝5.2Hz,1H),5.89(d,J＝7.2Hz,0.7H),5.37(d,J＝5.6Hz,0.3H),5.04-5.07(m,0.3H),4.56-4.62(m,0.7H),3.57(s,3H),3.25-3.32(m,1H),2.89-2.95(m,1H),2.67(b,1H),2.56-2.60(m,3H),2.40-2.45(m,1H),2.15-2.33(m,5H),1.98-2.02(m,1H),1.67-1.74(m,2H),1.48(s,6H).
实施例28
Figure PCTCN2021090073-appb-000052
步骤1 2-(2-碘苯基)-2-甲基丙酸甲酯(2)
Figure PCTCN2021090073-appb-000053
将1(4.83g，17.50mmol)溶于DMF(70mL)，N 2置换3次，降温至-20℃下滴加NaHMDS(2mol/L，26.2mL，52.49mmol)溶液，加完后继续反应40min，再滴加MeI(9.93g，69.98mmol)，加完继续反应4h。TLC(V石油醚：V乙酸乙酯＝5：1)检测反应完全。加饱和氯化铵(200mL)淬灭，乙酸乙酯(100mL×3)萃取，合并有机相，饱和氯化钠(100mL×5)洗涤，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝200：1)纯化得到4.05g淡黄色油状物2，收率76.1％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.92-7.90(m,1H,ArH),7.42-7.33(m,2H,ArH),6.94-6.91(m,1H,ArH),3.70(s,3H,OCH 3),1.66(s,6H,(CH 3) 2).
步骤2 2-(2-(3-羟丙基-1-炔-1-基)苯基)-2-甲基丙酸甲酯(3)
Figure PCTCN2021090073-appb-000054
将2(4.05g,13.32mmol)溶于乙腈(40mL)，再依次加入CuI(254mg,1.33mmol)和Pd(PPh 3)Cl 2(467mg,0.67mmol)。N 2置换3次，降温至-10℃下加三乙胺(6.06g,59.93mmol)。加完继续搅拌10min，再加入炔丙醇(1.06g,15.98mmol)，加完搅拌10min后移至室温反应4h，再加热至30℃反应过夜。TLC(V石油醚：V乙酸乙酯＝5:1)检测原料剩余约60％。加水(40mL)淬灭，乙酸乙酯(50mL×3)萃取，合并有机相，饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝100:1)纯化得到600mg褐色油状物3，收率19.4％。
步骤3 2-(2-(3-羟丙基)苯基)-2-甲基丙酸甲酯(4)
Figure PCTCN2021090073-appb-000055
将3(1.25g,5.38mmol)溶于乙醇(30mL)，加入Pd/C(10％Pd,500mg,40％wt)，氢气(15psi)氛围下室温反应3h，更换氢气球，然后室温反应过夜。TLC(V石油醚：V乙酸乙酯＝3:1)检测反应完全。加硅藻土过滤，滤液浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝10:1)纯化得到500mg淡黄色油状物4，收率39.4％。
步骤4 2-(2-(3-溴丙基)苯基)-2-甲基丙酸甲酯(5)
Figure PCTCN2021090073-appb-000056
将化合物4(500mg,2.12mmol)溶于二氯甲烷(12mL)，加入CBr 4(1.05g,3.17mmol)。加完N 2置换3次，降温至0℃，滴加PPh 3(860mg,3.28mmol)的二氯甲烷溶液(3mL)，加完RT反应过夜。TLC(V石油醚：V乙酸乙酯＝2:1)检测原料反应完全。直接浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝100:1)纯化得到450mg无色油状物5，收率71.1％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.38-7.36(m,1H,ArH),7.24-7.18(m,3H,ArH),3.68(s,3H,OCH 3),3.47-3.44(m,2H,ArH-CH 2),2.64-2.60(m,2H,CH 2Br),2.16-2.09(m,2H,CH 2),1.59(s,6H,(CH 3) 2).
步骤5 2-(2-(3-溴丙基)苯基)-2-甲基丙酸甲酯2-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸甲酯(6)
Figure PCTCN2021090073-appb-000057
将5(450mg，1.50mmol)溶于DMF(10mL)，再依次加入28(514mg，1.65mmol)和二异丙基乙胺(389mg，3.01mmol)，N 2置换3次，升温至70℃反应过夜。TLC(V二氯甲烷：V甲醇＝20：1)检测反应完全。冷却至室温，加入水(10mL)淬灭，乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析纯化(V二氯甲烷：V甲醇＝50：1)得到650mg淡黄色油状物6，收率81.7％。
步骤6 2-(2-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丙基)苯基)-2-甲基丙酸(实施例28)
Figure PCTCN2021090073-appb-000058
将6(650mg，1.23mmol)溶于甲醇(10mL)，加入水(3mL)和NaOH(492mg，12.27mmol)，加热至70℃反应四天。TLC(V二氯甲烷：V甲醇＝10：1)检测原料剩余约50％。浓缩除去甲醇，加入水(10mL)，乙酸乙酯(15mL×2)洗涤，再向乙酸乙酯中加入水(10mL)，再用2N稀盐酸(10滴)调节pH至5，乙酸乙酯(15mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩并经快速制备色谱(V二氯甲烷：V甲醇＝16：1)纯化得实施例28化合物150mg，白色固体，收率23.7％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.35-8.33(m,1H,ArH),7.67-7.64(m,1H,ArH),7.41-7.38(m,1H,ArH),7.28-7.18(m,4H,ArH),7.15-7.13(m,3H,ArH),3.45-3.35(m,2H,ArH-CH 2CH 2),3.29-3.25(m,2H,ArH-CH 2CH 2),3.14-3.02(m,4H,N(CH 2) 2),2.91-2.68(m,6H,N(CH 2) 2,(CH 2) 3),2.63-2.45(m,2H,(CH 2) 3),2.14-2.07(m,2H,(CH 2) 3),1.49(s,6H,CH 3CCH 3).
13C NMR(100MHz,CD 3OD)δ(ppm):186.31,156.99,146.94,146.76,140.90,139.35,139.21,137.52,135.83,135.41,134.10,133.99,130.88,130.04,129.92,126.78,126.76,126.69,126.14,123.92,57.17,53.91,48.46,31.95,31.53,29.51,28.47,28.33,28.28,25.76.
实施例29
Figure PCTCN2021090073-appb-000059
步骤1 2-(4-(4-氯丁酰基)苯基)-2-甲基丙酸乙酯(2)
Figure PCTCN2021090073-appb-000060
将AlCl 3(13.80g，104mmol)加入二氯甲烷(100mL)中，氮气保护，降温至-20℃。再依次滴加1(10.0g，52mmol)和4-氯丁酰氯(14.6g，104mmol)，加毕，移至室温反应过夜。TLC(V石油醚：V乙酸乙酯＝10：1)检测反应完全。加入二氯甲烷(100mL)稀释反应液，再加水(100mL)淬灭反应。分液，有机相先用饱和碳酸氢钠溶液洗涤(200mL×3)， 再用饱和食盐水洗涤(50mL×3)，无水硫酸钠干燥，过滤，浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝30：1)得到2.86g黄色油状物2，收率18.5％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.98-7.84(m,2H,ArH),7.57-7.41(m,2H,ArH),4.16-4.10(m,2H,OCH 2CH 3),3.70-3.66(m,2H,COCH 2),3.19-3.14(m,2H,ClCH 2),2.27-2.19(m,2H,CH 2),1.61-1.59(m,6H,(CH 3) 2),1.21-1.16(m,3H,CH 2CH 3).
步骤2 2-(4-(4-氯-1-羟基丁基)苯基)-2-甲基丙酸乙酯(3)
Figure PCTCN2021090073-appb-000061
将2(2.96g，9.64mmol)溶于甲醇(20mL)，冰水浴降温，再分批加入硼氢化钠(0.73g，19.27mmol)，加毕移至室温反应1h。TLC(V石油醚：V乙酸乙酯＝5：1)检测反应完全。减压浓缩，加入乙酸乙酯(60mL)溶解产物，用2N稀盐酸溶液洗涤(20mL)，再用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥，过滤，减压浓缩并经硅胶柱层析(V石油醚：V乙酸乙酯＝10：1)得到2.03g黄色油状物3，收率70.5％。
步骤3乙基2-(4-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)-1-羟基丁基)苯基)-2-甲基丙酸酯(4)
Figure PCTCN2021090073-appb-000062
将3(2.03g，6.78mmol)溶于DMF(20mL)，再依次加入地氯雷他定(1.91g，6.18mmol)和二异丙基乙胺(1.59g，12.3mmol)，氮气保护，70℃反应过夜。TLC(V二氯甲烷：V甲醇＝10：1)检测反应完全。冷却至室温，加水(30mL)淬灭，乙酸乙酯萃取(30mL×2)，合并有机相，饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，过滤，浓缩并经快速制备色谱纯化(40g，V二氯甲烷：V甲醇＝50：1)得1.01g黄色固体4，收率25.0％。
步骤4 2-(4-(4-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)-1-羟丁基)苯基)-2-甲基丙酸(实施例29)
Figure PCTCN2021090073-appb-000063
将4(400mg，0.70mmol)溶于EtOH(6mL)，加入H 2O(3mL)和氢氧化钠(112mg，2.80mmol)，80℃反应过夜。TLC(V二氯甲烷：V甲醇＝10：1)检测反应完全。减压浓缩，加入水(6mL)，乙酸乙酯洗涤(6mL×6)，向水相中缓慢滴加1N HCl溶液，有固体析出，调节pH至5，搅拌20min，过滤，滤饼用水洗涤(5mL×2)，烘干得到实施例29化合物110mg，白色固体，收率28.9％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.23(dd,J 1＝1.6Hz,J 2＝4.8Hz,1H,ArH),7.57-7.54(m,1H,ArH),7.29-7.19(m,2H,ArH),7.18-7.09(m,4H,ArH),7.08-7.01(m,2H,ArH),4.57-4.50(m,1H,(CH 2) 3CH),3.33-3.25(m,2H,ArH-CH 2CH 2),2.98-2.95(m,2H,ArH-CH 2CH 2),2.82-2.70(m,2H,N(CH 2) 2),2.66-2.24(m,8H,N(CH 2) 2,(CH 2) 3CH),1.71-1.51(m,4H,(CH 2) 3CH),1.41-1.39(m,6H,CH 3CCH 3).
13C NMR(100MHz,CD 3OD)δ(ppm):155.41,146.56,145.48,144.76,143.24,141.22,138.90,135.76,133.48,133.06,132.07,129.11,128.00,126.74,124.81,124.33,123.44,122.65,122.09,121.93,72.19,71.84,55.87,51.89,35.17,30.14,29.62,27.14,25.66,20.27,20.12.
实施例30
Figure PCTCN2021090073-appb-000064
步骤1 2-(3-溴苯基)-2-甲基丙酸甲酯(2)
Figure PCTCN2021090073-appb-000065
将1(6.87g，30mmol)溶于THF(100mL)，0℃下氮气氛围下分批加入NaH(60％，3.6g，90mmol)，加毕后保温反应0.5h，再加入碘甲烷(10.65g，75mmol)，然后室温反应3h。TLC(V石油醚：V乙酸乙酯＝10：1)检测反应完全，0℃下加入水(100mL)，升至室温后，乙酸乙酯(100mL×3)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到7.7g淡黄色油状物2，收率99％。
步骤2 2-(3-(4-羟基-1-炔-1-基)苯基)-2-甲基丙酸甲酯(3)
Figure PCTCN2021090073-appb-000066
将2(2.57g，10mmol)溶于三乙胺(35mL)，再依次加入溴化亚铜(171mg，1.2mmol)、Pd(PPh 3) 4(462mg，0.4mmol)和3-丁炔-1-醇(1.4g，20mmol)，加毕后氮气氛围下90℃反应4h。TLC(V石油醚：V乙酸乙酯＝5：1)检测原料反应完全，反应液过滤，浓缩，加入乙酸乙酯(100mL)稀释，然后用饱和氯化钠(100mL×3)洗涤，有机层无水Na 2SO 4干燥，过滤，浓缩并经快速制备色谱(40g，V石油醚：V乙酸乙酯＝4：1)纯化得到2.2g淡黄色油状物3，收率89％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.38-7.37(m,1H,ArH),7.29-7.28(m,1H,ArH),7.26-7.22(m,2H,ArH),3.80(t,J＝4.4Hz,2H,CH 2),3.64(s,3H,OCH 3),2.67(t,J＝4.0Hz,2H,OCH 2),1.55(s,6H,(CH 3) 2).
步骤3 2-(3-(4-羟基丁酰基)苯基)-2-甲基丙酸甲酯(4)
Figure PCTCN2021090073-appb-000067
将3(1.2g，4.88mmol)和对甲苯磺酸一水合物(190mg，1mmol)加入水(20mL)中，加毕后氮气氛围下100℃反应2h，TLC(V石油醚：V乙酸乙酯＝2：1)检测原料反应完全，反应液冷却，乙酸乙酯(40mL×3)萃取，合并有机相，饱和氯化钠(60mL×3)洗涤，有机层无水Na 2SO 4干燥，过滤，浓缩并经快速制备色谱(20g，V石油醚：V乙酸乙酯＝2：1)纯化得到1.18g淡黄色油状物4，收率91％。
1H NMR(400MHz,CDCl 3)δ(ppm):7.94(d,J＝9.6Hz,1H,ArH),7.80(dd,J 1＝5.2Hz,J 2＝11.2Hz,1H,ArH),7.52(d,J＝6.0Hz,1H,ArH),7.44-7.39(m,1H,ArH),3.72(t,J＝4.0Hz,2H,COCH 2),3.65(s,3H,OCH 3),3.10(t,J＝4.8Hz,2H,OCH 2),2.03-1.98(m,2H,CH 2),1.60(s,6H,(CH 3) 2).
步骤4 2-(3-(4-溴丁酰基)苯基)-2-甲基丙酸甲酯(5)
Figure PCTCN2021090073-appb-000068
将165a(600mg，2.27mmol)溶于二氯甲烷(10mL)，加入48％溴化氢水溶液(1.15g，6.81mmol)，加毕后室温反应1h，TLC(V石油醚：V乙酸乙酯＝2：1)检测反应完全，反应液用饱和氯化钠(20mL×3)洗涤，有机层无水Na 2SO 4干燥，过滤，浓缩并经快速制备色谱(10g，V石油醚：V乙酸乙酯＝10:1)纯化得到680mg无色透明油状物166a，收率92％。
步骤5甲基2-(3-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸酯(6)
Figure PCTCN2021090073-appb-000069
将5(680mg，2.08mmol)溶于DMF(10mL)，再依次加入二异丙基乙胺(536mg，4.16mmol)和地氯雷他定(774mg，2.5mmol)，加毕后氮气氛围下60℃反应4h。TLC(V石油醚：V乙酸乙酯＝10：1)检测反应完全，反应液加入乙酸乙酯(40mL)，饱和食盐水洗涤(20mL×3)，无水Na 2SO 4干燥，过滤，浓缩并经快速制备色谱纯化(12g，V二氯甲烷：V甲醇＝30：1)纯化得820mg淡黄色固体6，收率71％。
步骤6 2-(3-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)-1-羟基丁基)苯基)-2-甲基丙酸甲酯(7)
Figure PCTCN2021090073-appb-000070
将6(820mg，1.47mmol)溶于MeOH(10mL)，0℃下分批加入硼氢化钠(112mg，2.94mmol)，加毕后保温反应0.5h。TLC(V二氯甲烷：V甲醇＝10：1)检测反应完全，反应液加入水(40mL)，乙酸乙酯萃取(40mL)，有机相用饱和食盐水(20mL×3)洗涤，无水Na 2SO 4干燥，过滤，浓缩并经硅胶柱层析纯化(V二氯甲烷：V甲醇＝10：1)纯化得802mg棕色固体7，收率97％。
步骤7 2-(3-(4-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)-1-羟基丁基)苯基)-2-甲基丙酸(实施例30)
Figure PCTCN2021090073-appb-000071
将7(400mg，0.72mmol)溶于甲醇(10mL)，再加入水(2mL)和氢氧化钠(72mg，1.79mmol)，加毕后60℃反应过夜。TLC(V二氯甲烷：V甲醇＝10：1)检测反应完全，浓缩除去甲醇，加入水(10mL)，乙酸乙酯(10mL×2)洗涤，水相用2N的盐酸调节pH至7，析出固体，过滤，二氯甲烷(20mL)溶解，无水硫酸钠干燥，过滤，浓缩经制备板纯化(V二氯甲烷：V甲醇＝5：1)得到230mg，然后用10％NaOH水溶液(10mL)溶解，2N盐酸调节pH至7，析出固体，过滤，烘干得到实施例30化合物220mg，白色固体，收率56.0％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.31(d,J＝3.2Hz,1H,ArH),7.63(d,J＝5.2Hz,1H,ArH),7.36(s,1H,ArH),7.28-7.23(m,4H,ArH),7.17-7.15(m,2H,ArH),7.09(d,J＝5.2Hz,1H,ArH),4.66-4.64(m,1H,(CH 2) 3CH),3.41-3.33(m,2H,ArH-CH 2CH 2),3.19-3.15(m,2H,ArH-CH 2CH 2),2.89-2.79(m,6H,N(CH 2) 2),2.62-2.57(m,2H,N(CH 2) 2),2.48-2.46(m,1H, (CH 2) 3CH),2.39-2.37(m,1H,(CH 2) 3CH),1.79-1.70(m,3H,(CH 2) 3CH),1.64-1.59(m,1H,(CH 2) 3CH),1.49(s,6H,CH 3CCH 3).
13C NMR(100MHz,CD 3OD)δ(ppm):182.10,156.24,147.26,145.87,144.27,140.03,138.55,136.71,134.66,133.74,133.24,130.10,129.09,127.90,125.91,124.42,123.75,123.27,123.09,73.14,56.71,52.86,52.84,35.92,31.14,30.69,27.99,27.84,26.62,26.52,20.94.
实施例31 2-(3-(3-(4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚[1,2-b]吡啶-11-烯基)哌啶-1-基)-1-羟丙基)苯基)-2-甲基丙酸
Figure PCTCN2021090073-appb-000072
参考实施例29的合成方法，以炔丙醇替换3-丁炔-1-醇中，制得实施例31化合物380mg，类白色固体，收率44％。
1H NMR(400MHz,CD 3OD)δ(ppm):8.36(dd,J 1＝1.6Hz,J 2＝5.2Hz,1H,ArH),7.67(dd,J 1＝1.2Hz,J 2＝7.6Hz,1H,ArH),7.40(s,1H,ArH),7.32-7.30(m,1H,ArH),7.28-7.23(m,3H,ArH),7.19(dd,J 1＝1.6Hz,J 2＝8.0Hz,2H,ArH),7.12(d,J＝8.4Hz,1H,ArH),4.71-4.74(m,1H,(CH 2) 2CH),3.44-3.36(m,2H,ArH-CH 2CH 2),3.20-3.13(m,2H,ArH-CH 2CH 2),3.00-2.74(m,6H,N(CH 2) 2),2.61-2.53(m,2H,N(CH 2) 2),2.48-2.35(m,2H,(CH 2) 2CH),2.07-1.99(m,2H,(CH 2) 2CH),1.51(s,6H,CH 3CCH 3).
13C NMR(100MHz,CD 3OD)δ(ppm):181.61,156.28,147.10,145.86,143.88,140.04,138.53,136.75,134.62,133.85,133.23,130.12,129.08,127.99,125.90,124.80,123.32,123.07,71.87,54.41,53.09,53.02,33.51,31.16,30.70,28.18,28.04,26.50.
实施例32
Figure PCTCN2021090073-appb-000073
向25mL的单口瓶内加入实施例2化合物(190mg,0.36mmol)和甲醇(2mL)，磁力搅拌，N 2保护。向体系内加入NaOH(15mg,0.37mmol)的水(0.5mL)溶液。加毕，反应在室温下搅拌过夜。TLC(DCM:MeOH＝10:1)监测原料与产物在同一位置。将反应液减压浓缩，得到185mg粗品。将粗品用正庚烷(6mL)打浆1h，抽滤，滤饼用正庚烷(3mL×2)洗涤，烘干(-0.1MPa,45℃,18h)，得到实施例32化合物(173mg,86.6％yield)，类白色固体。HPLC:98.637％。
1H NMR(400MHz,CD 3OD):δppm 8.29(dd,J 1＝4.8Hz,J 2＝1.6Hz,1H),7.63(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.41-7.36(m,1H),7.24-7.19(m,2H),7.16-7.13(m,1H),7.11-7.04(m,4H), 3.43-3.34(m,2H),2.89-2.76(m,4H),2.62-2.58(t,J＝7.5Hz,2H),2.48-2.34(m,3H),2.25-2.15(m,3H),1.83-1.78(m,2H),1.44(s,6H).
实施例33
Figure PCTCN2021090073-appb-000074
参考实施例31的制备方法，将NaOH替换为KOH，制得实施例33化合物(173mg,86.6％yield)，类白色固体。HPLC:98.433％。
1H NMR(400MHz,CD 3OD):δppm 8.29(dd,J 1＝4.8Hz,J 2＝1.6Hz,1H),7.63(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.41-7.36(m,1H),7.24-7.19(m,2H),7.16-7.13(m,1H),7.11-7.04(m,4H),3.43-3.34(m,2H),2.89-2.76(m,4H),2.62-2.58(t,J＝7.5Hz,2H),2.48-2.34(m,3H),2.25-2.15(m,3H),1.83-1.78(m,2H),1.44(s,6H),
实施例34
Figure PCTCN2021090073-appb-000075
参考实施例31的制备方法，将起始原料由实施例2替换为实施例25，制得实施例34化合物(152mg,83.3％yield)，类白色固体。HPLC:98.433％。 1H NMR(400MHz,CD 3OD):δppm 8.28-8.33(m,1H),7.64(d,J＝6.80Hz 1H),7.19-7.26(m,4H),7.08-7.18(m,3H),6.96(d,J＝7.3Hz,1H),3.34-3.36(m,2H),2.78-2.91(m,4H),2.60(t,J＝7.55Hz,2H),2.34-2.52(m,5H),2.17-2.30(m,3H),1.84(t,J＝7.55Hz,2H),1.46(s,6H)
参考实施例31的制备方法，制得下列化合物
Figure PCTCN2021090073-appb-000076
Figure PCTCN2021090073-appb-000077
实施例41
Figure PCTCN2021090073-appb-000078
向25mL单口瓶中加入实施例25化合物(500mg,0.97mmol)和盐酸二氧六环(3mL,2.7M)，室温反应3小时。反应液直接浓缩得到残留物，向其中加入DCM(10mL)，搅拌溶清，浓缩，加入正庚烷(6mL)打浆过夜。过滤，收集固体滤饼并置于-0.1MPa、49℃和8小时条件下干燥，得到实施例41化合物(380mg,66.46％yield)，类白色固体。
1H NMR(400MHz,D 2O)：δppm 8.46(d,J＝5.0Hz,1H),8.28(d,J＝7.9Hz,1H),7.78(dd,J 1＝7.9Hz,J 2＝5.8Hz,1H),7.29-7.39(m,2H),7.19-7.29(m,3H),7.11-7.17(m,2H),3.45-3.66(m,3H),3.17-3.44(m,2H),2.91-3.16(m,3H),2.70-2.89(m,4H),2.53-2.67(m,4H),1.98-2.03(m,2H),1.51(s,1.3H),1.48(s,4.7H)。
实施例42
Figure PCTCN2021090073-appb-000079
向25mL单口瓶中加入实施例25化合物(153mg,0.3mmol)、90％乙醇(3mL)、水(0.5mL)和L-赖氨酸(44mg,0.3mmol)，氮气氛围下60℃反应1.5h。反应液浓缩干，呈粘稠油状，加入乙醚(20mL)打浆1h，过滤，固体室温真空干燥2h得到实施例42(167mg,84％yield)，类白色固体。
1H NMR(400MHz,CD 3OD):δppm 8.20(dd,J 1＝1.6Hz,J 2＝5.2Hz,1H),7.53(dd,J 1＝0.8Hz,J 2＝7.6Hz,1H),7.11-7.16(m,4H),7.00-7.09(m,3H),6.87(d,J＝7.6Hz,1H),3.36-3.39(m,1H),3.24-3.34(m,2H),2.69-2.80(m,6H),2.49(t,J＝7.6Hz,2H),2.33-2.42(m,4H),2.13-2.31(m,4H),1.64-1.79(m,4H),1.51-1.59(m,2H),1.37-1.42(m,2H),1.33(s,6H)。
本发明的组合物实施例，以实施例34化合物为例，包含但不限于下列实施例中使用的辅料及处方配比。
实施例43
实施例34化合物包衣片(1000片)
片芯处方
Figure PCTCN2021090073-appb-000080
包衣液处方
Figure PCTCN2021090073-appb-000081
制备方法：实施例34化合物、硬脂酸镁过120目筛，微晶纤维素、磷酸氢钙、预胶化淀粉过100目筛，备用；称取处方配比量的实施例34化合物、微晶纤维素、磷酸氢钙、预胶化淀粉，按等量递增法过80目筛混匀，用30％的乙醇溶液作为润湿剂制软材，20目筛制粒，50～60℃干燥3～4小时，20目筛整粒，加入处方量的硬脂酸镁，混匀，压片制得。
实施例44
实施例34化合物的普通片(1000片)
Figure PCTCN2021090073-appb-000082
Figure PCTCN2021090073-appb-000083
制备方法：实施例34化合物、硬脂酸镁过120目筛，微晶纤维素、羧甲基淀粉钠、乳糖过80目筛，备用；称取处方配比量的实施例34化合物、微晶纤维素、羧甲基淀粉钠和乳糖，按等量递增法过80目筛混匀，用30％的乙醇溶液作为润湿剂制软材，30目筛制粒，50～60℃干燥3～4小时，30目筛整粒，加入处方量的硬脂酸镁，混匀，压片制得。
实施例45
实施例34化合物的胶囊(1000粒)
Figure PCTCN2021090073-appb-000084
制备方法：实施例34化合物、硬脂酸镁过120目筛，低取代羟丙基纤维素、羧甲基淀粉钠、乳糖过80目筛，备用；称取处方配比量的实施例34化合物、低取代羟丙基纤维素、羧甲基淀粉钠和乳糖，按等量递增法过80目筛混匀，用30％的乙醇溶液作为润湿剂制软材，30目筛制粒，50～60℃干燥3～4小时，30目筛整粒，加入处方量的硬脂酸镁，混匀，灌装胶囊即可。
实施例46
实施例34化合物的颗粒剂(1000包)
Figure PCTCN2021090073-appb-000085
制备方法：实施例34化合物、微晶纤维素、蔗糖粉、羧甲基淀粉钠、乳糖、阿斯巴甜过100目筛，橘子香精、十二烷基硫酸钠过80目筛，备用；称取处方配比量的实施例34化合物、微晶纤维素、蔗糖粉、羧甲基淀粉钠、乳糖、阿斯巴甜按等量递增法混匀，用3％聚维酮的30％乙醇溶液制软材，20目筛制粒，50～60℃干燥3～4小时，18目筛整粒，加入处方量的橘子香精、十二烷基硫酸钠，混匀，装袋封口制得。
实施例47
实施例34化合物口服液(1000瓶)
Figure PCTCN2021090073-appb-000086
制备方法：阿斯巴甜、橘子香精、枸橼酸钠溶于现制注射用水中，过滤，常温下加入处方量的实施例34化合物，溶解，过滤，灌装。
实施例48
实施例34化合物糖浆剂
Figure PCTCN2021090073-appb-000087
制备方法：将蔗糖加入900ml注射用水中，加热煮沸，溶解、趁热过滤，冷却至室温备用；将处方量的实施例34化合物、阿斯巴甜、橘子香精、枸橼酸钠溶于60mL注射用水中，过滤，加入至上述糖浆液中，加注射用水至1000mL，混匀，灌装制得。
实施例49
实施例34化合物的滴眼液
Figure PCTCN2021090073-appb-000088
制备方法：将聚山梨醇酯80、柠檬酸、氯化钠、实施例34化合物和氯化苯甲烃铵完全溶解在无菌注射用水70ml中，并用硼砂调pH至7.8，然后用无菌注射用水加至体积为100mL，过滤，滤液灭菌，并装于适于滴眼液的容器内制得。
实施例50
实施例34化合物的注射液(1000支)
Figure PCTCN2021090073-appb-000089
制备方法：将柠檬酸、磷酸氢二钠、乙二胺四乙酸二钠溶解于1600mL注射用水中，加入处方量的实施例34化合物和氯化钠搅拌至完全溶解，0.1mol/L稀盐酸调pH至7.0-7.8，加入处方量活性炭，搅拌吸附后脱碳过滤，加入注射用水至2000mL，然后用0.22μm滤器过滤，灌装于2mL安剖瓶中。安剖瓶封口并115℃灭菌30分钟后制得。
实施例51
实施例34化合物的鼻喷雾剂
Figure PCTCN2021090073-appb-000090
Figure PCTCN2021090073-appb-000091
制备方法：制备过程如下：取处方量约60％的缓冲液于配制容器中，加入生物黏附剂，使其充分溶胀，直至完全溶解；加入抑菌剂、等渗调节剂、金属离子螯合剂搅拌溶解；分次加入环糊精，搅拌溶解后，再加入实施例34化合物，搅拌1～2h，待完全溶解后添加缓冲液至全量，混合均匀。测定pH和含量合格后，药液于0.45μm微孔滤膜过滤至澄明，再于0.22μm微孔滤膜过滤除菌，分装至已灭菌的鼻喷雾瓶中，加带有定量喷雾泵的瓶盖，密闭低温贮存。
实施例52
实施例34化合物的鼻喷雾剂
Figure PCTCN2021090073-appb-000092
制备方法：甘露醇/聚氧乙烯40氢化蓖麻油、维生素E、实施例34化合物加入至注射用水中至10mL，缓慢60℃加热，加入甘油酸酯后高速剪切分散乳化机分散，柠檬酸调pH至6.0后过滤，高压灭菌后置于容器中制得。

Claims (10)

  1. 一种具有下列式(I)结构的三环化合物，或其药学上可接受的盐、前药、互变异构体、立体异构体或者立体异构体的混合物，
    Figure PCTCN2021090073-appb-100001
    式(I)中：
    X为H、OH；
    n为0-6的整数；
    A环为苯环、吡啶环、噻吩环；
    R 1、R 4为H、卤素；
    R 2、R 3选自H、羟基、＝O；
    R 5为H；
    R 6为H，任意单取代或多取代的C 1～C 6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
  2. 根据权利要求1所述的化合物，其特征在于式(I)中：
    n为0-4的整数；
    R 1为H、Cl；
    R 5为H；
    R 6为H、甲基、F、Cl、Br、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基。
  3. 根据权利要求1所述的化合物，其中所述式(I)结构为：
    Figure PCTCN2021090073-appb-100002
    其中：
    n为0-6的整数；
    X为H、OH；
    R 3为H、羟基、＝O；
    R 5为H；
    R 6为H，任意单取代或多取代的C 1～C 6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
  4. 根据权利要求1所述的化合物，其中所述式(I)结构为：
    Figure PCTCN2021090073-appb-100003
    其中：
    n为0-6的整数
    X为H、OH；
    R 5为H。
  5. 根据权利要求1-4任一项所述的化合物，其中所述药学上可接受的盐为式(I)化合物和碱金属或者碱土金属，氨基酸或者含有氨基的碱性化合物形成的盐，或者为式(I)化合物与无机酸或者有机酸形成的盐，或者为式(I)化合物多元酸碱金属或者碱土金属盐复合盐；优选地，其中所述药学上可接受的盐为式(I)化合物的钾盐、钠盐或铵盐；式(I)化合物与盐酸、硫酸、磷酸、氢溴酸、马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸或醋酸形成的盐；或者所述式(I)化合物多元酸碱金属或者碱土金属盐复合盐，其中所述多元酸选自枸橼酸、丁二酸、酒石酸、琥珀酸、富马酸、马来酸、草酸、硫酸、磷酸、亚硫酸、苹果酸，所述碱金属或碱土金属选自钠、钾、钙、镁、锌。
  6. 根据权利要求1-5任一项所述的化合物，其特征在于，所述化合物为选自以下的化合物1～化合物42：
    Figure PCTCN2021090073-appb-100004
    Figure PCTCN2021090073-appb-100005
    Figure PCTCN2021090073-appb-100006
  7. 制备权利要求1-6任一项所述化合物的方法，包括由如下式(II)化合物反应生成所述式(I)化合物的步骤：
    Figure PCTCN2021090073-appb-100007
    其中，X、n、A、R 1、R 2、R 3、R 4和R 6如权利要求1-6所述定义，R 5为C 1～C 6的烷基。
  8. 下式(II)结构的化合物，
    Figure PCTCN2021090073-appb-100008
    其中，X、n、A、R 1、R 2、R 3、R 4和R 6如权利要求1-6所述定义，R 5为C 1～C 6的烷基；
    优选地，所述的式(II)化合物为如下结构的化合物：
    Figure PCTCN2021090073-appb-100009
    其中，
    n为0-6的整数；
    X为H、OH；
    R 3为H、羟基、＝O；
    R 5为C 1～C 6的烷基；
    R 6为H，任意单取代或多取代的C 1～C 6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
    或，所述的式(II)化合物为如下结构的化合物：
    Figure PCTCN2021090073-appb-100010
    其中，
    n为0-6的整数；
    X为H、OH；
    R 5为C 1～C 6的烷基。
  9. 药物组合物，其含有权利要求1-6所述化合物和药学上可接受的辅料；优选地，所述的药物组合物，其剂型选自片剂、胶囊剂、颗粒剂、口服液、口喷剂、栓剂、透皮制剂、注射剂、滴鼻剂、滴眼液、鼻喷剂。
  10. 权利要求1-6所述化合物在制备抗组胺药物中用途；优选地，所述药物为预防或治疗过敏性疾病的药物；优选地，所述过敏性疾病选自：过敏性鼻炎、荨麻疹、慢性荨麻疹、过敏性紫癜、哮喘、过敏性皮炎、湿疹、过敏性结膜炎、特应性皮炎、鼻窦炎、慢性鼻窦炎。
PCT/CN2021/090073 2020-07-03 2021-04-27 一类三环化合物、制备方法及其医药用途 WO2022001331A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP21833899.4A EP4177248A4 (en) 2020-07-03 2021-04-27 CLASS OF TRICYCLIC COMPOUNDS, MANUFACTURE PROCESSES THEREOF AND MEDICAL USE THEREOF
CN202180028913.2A CN115427405B (zh) 2020-07-03 2021-04-27 一类三环化合物、制备方法及其医药用途
JP2022532071A JP2023531338A (ja) 2020-07-03 2021-04-27 三環式化合物、その調製方法および医学的使用
US17/800,361 US20230140276A1 (en) 2020-07-03 2021-04-27 Tricyclic compounds, preparation method and medical use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010629198.5 2020-07-03
CN202010629198.5A CN113880801A (zh) 2020-07-03 2020-07-03 一类三环化合物、其制备方法及其医药用途

Publications (1)

Publication Number Publication Date
WO2022001331A1 true WO2022001331A1 (zh) 2022-01-06

Family

ID=79012913

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/090073 WO2022001331A1 (zh) 2020-07-03 2021-04-27 一类三环化合物、制备方法及其医药用途

Country Status (5)

Country Link
US (1) US20230140276A1 (zh)
EP (1) EP4177248A4 (zh)
JP (1) JP2023531338A (zh)
CN (2) CN113880801A (zh)
WO (1) WO2022001331A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114773386A (zh) * 2022-05-12 2022-07-22 江苏医药职业学院 一种手性双齿配体及其制备方法和应用以及催化剂和盐酸非索非那定中间体的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115960135A (zh) * 2022-07-21 2023-04-14 华创合成制药股份有限公司 抗组胺类化合物及其制备方法和用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
WO1992000293A1 (en) 1990-06-22 1992-01-09 Schering Corporation Bis-benzo or benzopyrido cyclo hepta piperidene, piperidylidene and piperazine compounds and compositions
US5231101A (en) * 1991-01-18 1993-07-27 Ss Pharmaceutical Co., Ltd. Benzo[5,6]cyclohepta[1,2-B]pyridine derivatives and antiallergic agents comprising same
US20140135361A1 (en) * 2011-06-28 2014-05-15 Tongjun Lin Anti-allergy benzocycloheptathiophene derivatives
CN107602534A (zh) 2017-09-05 2018-01-19 合肥医工医药有限公司 具有抗组胺和抗炎活性的化合物及其制备方法和应用
CN109096251A (zh) 2018-09-26 2018-12-28 合肥医工医药有限公司 具有组胺受体双重拮抗活性的化合物及用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE794377A (fr) * 1972-01-24 1973-07-23 Sandoz Sa Nouveaux derives du benzo-cyclohepta-thiophene
US5665726A (en) * 1986-10-31 1997-09-09 Schering Corporation Benzo[5,6]cycloheptapyridines, compositions and methods of use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
WO1992000293A1 (en) 1990-06-22 1992-01-09 Schering Corporation Bis-benzo or benzopyrido cyclo hepta piperidene, piperidylidene and piperazine compounds and compositions
US5231101A (en) * 1991-01-18 1993-07-27 Ss Pharmaceutical Co., Ltd. Benzo[5,6]cyclohepta[1,2-B]pyridine derivatives and antiallergic agents comprising same
US20140135361A1 (en) * 2011-06-28 2014-05-15 Tongjun Lin Anti-allergy benzocycloheptathiophene derivatives
CN107602534A (zh) 2017-09-05 2018-01-19 合肥医工医药有限公司 具有抗组胺和抗炎活性的化合物及其制备方法和应用
CN109096251A (zh) 2018-09-26 2018-12-28 合肥医工医药有限公司 具有组胺受体双重拮抗活性的化合物及用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP4177248A4
ZOLALY MA: "Histamine H1 antagonists and clinical characteristics of febrile seizures[J", INT J GEN MED., vol. 5, 2012, pages 277 - 281

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114773386A (zh) * 2022-05-12 2022-07-22 江苏医药职业学院 一种手性双齿配体及其制备方法和应用以及催化剂和盐酸非索非那定中间体的制备方法
CN114773386B (zh) * 2022-05-12 2023-06-23 江苏医药职业学院 一种手性双齿配体及其制备方法和应用以及催化剂和盐酸非索非那定中间体的制备方法

Also Published As

Publication number Publication date
EP4177248A1 (en) 2023-05-10
CN115427405B (zh) 2024-09-24
CN113880801A (zh) 2022-01-04
JP2023531338A (ja) 2023-07-24
EP4177248A4 (en) 2024-08-07
CN115427405A (zh) 2022-12-02
US20230140276A1 (en) 2023-05-04

Similar Documents

Publication Publication Date Title
US6897222B2 (en) Pyrido[2,1-a]isoquinoline derivatives
KR100496720B1 (ko) (s)(+)-2-에톡시-4[n-[1-(2-피페리디노페닐)-3-메틸-1-부틸]아미노카보닐메틸]-벤조산을함유하는당뇨병치료제
JP4842963B2 (ja) 糖尿病を処置するｄｐｐ−ｉｖ阻害剤としての置換ベンゾキノリジン
WO2022001331A1 (zh) 一类三环化合物、制备方法及其医药用途
PL210019B1 (pl) Związki pirydynoilopiperydyny, sposób ich wytwarzania i zastosowanie oraz sposób wytwarzania związków pośrednich do ich syntezy
JP2005526034A (ja) 新規ピリジン及びキノリン誘導体
JPH0592973A (ja) インドール誘導体およびこれを有効成分とする抗潰瘍薬
EP0533344B1 (en) Methanoanthracenes as dopamine antagonists
CN1856305B (zh) 用作尾加压素ⅱ拮抗剂的吡啶衍生物
US20030191347A1 (en) Venlafaxine base
WO2020108522A1 (zh) 一种氘代大环化合物的制备方法
CN107108575B (zh) 作为抗组胺剂的新型苯并咪唑衍生物
CN111440161A (zh) 一种具有par4拮抗活性的二环杂芳基类化合物及其应用
CN110461838A (zh) 噁二唑瞬时受体电位通道抑制剂
CS221807B2 (en) Method of making the trans-2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3b/indole
CN102946882A (zh) 苯基丙氨酸衍生物及其作为非肽glp-1受体调节剂的用途
US5681840A (en) Tricyclic antipsychotic compounds
EP0104632A2 (en) 1&#39;-(3-(1,2-Benzisoxazol-3-yl)propyl)spiro-(benzofuran-2-(3H),3&#39; or 4&#39;-piperidine or 3&#39;-pyrrolidines), a process for their preparation and their use as medicaments
EP0415103B1 (en) 2,3-Dihydro-1-(pyridinylamino)-indoles, a process for their preparation and their use as medicaments
JPH06211842A (ja) 化合物
CA2798591A1 (en) Polymorphs of alogliptin benzoate
AU2114600A (en) Tetrahydroindazole derivatives as ligands for gaba-a alpha 5 receptors
CN113880808A (zh) 一类三唑类化合物、制备方法及其医药用途
CA2584918A1 (en) Cyanothiophenes, the production thereof and their use as medicaments
CN101479259A (zh) 哌啶或吡咯烷的脲衍生物，它们的制备和治疗应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21833899

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022532071

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2021833899

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE