WO2017211246A1 - Substituted fused imidazole cyclic compound and pharmaceutical composition thereof - Google Patents

Substituted fused imidazole cyclic compound and pharmaceutical composition thereof Download PDF

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Publication number
WO2017211246A1
WO2017211246A1 PCT/CN2017/087137 CN2017087137W WO2017211246A1 WO 2017211246 A1 WO2017211246 A1 WO 2017211246A1 CN 2017087137 W CN2017087137 W CN 2017087137W WO 2017211246 A1 WO2017211246 A1 WO 2017211246A1
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compound
fused imidazole
imidazole ring
ring compound
hydrogen
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PCT/CN2017/087137
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French (fr)
Chinese (zh)
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王义汉
邢青峰
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深圳市塔吉瑞生物医药有限公司
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Priority to CN201780004832.2A priority Critical patent/CN108368118B/en
Publication of WO2017211246A1 publication Critical patent/WO2017211246A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to a substituted fused imidazole ring compound and use thereof, and more particularly to a fused imidazole ring compound and a pharmaceutical composition thereof for use as a histamine H1-receptor antagonist and a mast cell stabilizer For the treatment and prevention of allergy-related symptoms.
  • Allergic diseases also known as allergic diseases, are caused by excessive sensitivity of the patient, producing a specific immunoglobulin E antibody (IgE) that is allergic to a particular allergen in the blood.
  • IgE immunoglobulin E antibody
  • This patient has a genetic predisposition.
  • IgE sensitivity can lead to several typical allergic diseases: asthma, rhinitis, allergic eczema, conjunctivitis, food allergies, drug allergies, and anaphylactic shock.
  • the most common of these are allergic rhinitis and allergic asthma caused by sensitizing factors such as pollen, dust mites, fungi and pets.
  • An ocular allergy is an IgE-dependent (type I) hypersensitivity inflammatory response that most commonly affects adults between the ages of 20 and 40 years.
  • IgE IgE-dependent hypersensitivity inflammatory response
  • the initial contact of the allergen with the surface of the eye stimulates the production of allergen-specific immune antibodies.
  • IgE then binds to membrane-bound Fc ⁇ R-1 receptor mast cells in the ocular mucosa.
  • Mast cells are a type of granulocyte containing many pre-formed mediators including histamine and proteoglycans. Once the mast cells are activated, a newly formed chemical medium is formed which includes prostaglandin D2, leukotrienes, and platelet aggregation factors. Subsequent contact of the allergen with IgE-covered mast cells results in the release of pre-formed and newly formed media contained within the mast cell microparticles.
  • Clinical signs of allergic conjunctivitis include itching, redness, swelling, conjunctival edema, and tearing of the eyelids.
  • Histamine is the primary mediator in this allergy. After mast cell degranulation, histamine binds to receptors located within the conjunctiva. Histamine binds to the H1 receptor on nerve cells to induce itching. Activation of the H1 and H2 receptors on the vascular endothelium induces vasodilation and increases vascular permeability, promoting the migration of inflammatory mediators such as IL-1 ⁇ and IL-1 ⁇ into the blood vessels and secondary granulocyte recruitment into the conjunctival tissue.
  • Activation of histamine receptors causes eye congestion, conjunctival edema, swelling of the eyelids, and infiltration of body fluids from the surrounding blood vessels, leading to inflammation.
  • the chemotaxis of granulocytes such as eosinophils and neutrophils into the conjunctival tissue leads to further tissue damage.
  • Antihistamines H1 receptor antagonists
  • H1 receptor antagonists are the main drugs for the clinical treatment of allergic diseases, and are classified into four categories according to their structural characteristics.
  • the drugs discovered before the 1980s are called first-generation antihistamines, including diphenhydramine and chlorpheniramine. Because of its poor specificity with receptors, it easily enters the central nervous system through the blood-brain barrier, producing significant sedative and anticholinergic side effects, also known as sedative antihistamines.
  • Tefia Ding and astemizole have been withdrawn from the market due to the serious side effects of arrhythmia, which has prompted people to continue to develop a new generation of antihistamines.
  • antihistamines have been the main support for the treatment of ocular allergic diseases. Such treatments differ in the efficacy, specificity, and duration of action.
  • the first generation of antihistamines such as feniramine and anatazoline are known for their rapid action. Unfortunately, such compounds also cause eye irritation and their effectiveness is only attenuated after a few hours.
  • Second-generation H1 antagonists such as levocabastatin and emadastine have less eye discomfort and have a slightly longer duration of action. However, such compounds have limited anti-inflammatory effects and have little effect on the late components that inhibit the inflammatory response.
  • ocular allergy treatment is such as olopatadine, ketotifen and nitrogen.
  • Sting's drug which combines anti-histamine and stable mast cell properties.
  • Such treatments are generally well tolerated and can last up to 8 to 12 hours.
  • compounds that only affect the single component of allergy such compounds generally do not alleviate more than one symptom of ocular allergy.
  • the present invention discloses a fused imidazole ring compound and a composition comprising the same as an effective histamine H1-receptor antagonist and/or having better pharmacodynamics/pharmacokinetics Kinetic performance.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently selected from the group consisting of "hydrogen (H), hydrazine (D)";
  • the fused imidazole ring compound contains at least one ruthenium atom.
  • the cerium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the strontium isotope content of each of the R 9 , R 16 , R 17 , R 18 , R 19 and R 20 is at least 5%, preferably greater than 10%, more preferably greater than 15%, and even more preferably greater than 20%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 of the compound of formula (I), R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 at least one of R contains ruthenium, more preferably two R contains ruthenium, more preferably three R contains ruthenium, more preferably
  • the four Rs contain yttrium, more preferably five R yttrium, more preferably six R yttrium, more preferably seven R yttrium, more preferably eight R yttrium, more preferably nine R ⁇ , preferably ten R ⁇ , more preferably eleven R ⁇ , more preferably twelve R ⁇ , more preferably thirteen R ⁇ , more preferably fourteen R ⁇ , preferably fifteen R ⁇ , more preferably sixteen R ⁇ , more preferably seventeen R ⁇ , more
  • R 1 , R 2 , R 3 and R 4 are each independently hydrazine or hydrogen.
  • R 5 , R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 9 is deuterium or hydrogen.
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently hydrazine or hydrogen.
  • R 18 , R 19 and R 20 are each independently hydrazine or hydrogen
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof, but is not limited to the following compounds:
  • the compound does not include a non-deuterated compound.
  • a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, pharmaceutically acceptable
  • the accepted salt, hydrate or solvate is mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated Or a solvate.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents A dispersing agent, a disintegrating agent, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, Granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • the compounds of the present invention are useful as histamine H1-receptor antagonists for the preparation of a medicament for the prevention or treatment of anti-allergy.
  • the compound and the pharmaceutical composition thereof according to the present invention can be used for alleviating the symptoms associated with allergic rhinitis and the common cold, such as nasal congestion, nasal congestion, sneezing, runny nose, itchy nose, and itching and burning sensation of the eyes. Also used to relieve allergic conjunctivitis related eye itching, burning sensation, red eyes, swollen eyelids, conjunctival edema, tearing and other symptoms.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • compositions of the present invention comprise a fused imidazole compound of formula I, but may alternatively be present in the form of a salt thereof.
  • the pharmaceutically acceptable salt can be formed from an organic acid and an inorganic acid.
  • Suitable acids include, but are not limited to, acetic acid, 4-acetamidobenzoic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, 2,3:4,6-di-O-isopropylidene-2-one-gulo Sugar acid monohydrate, formic acid, fumaric acid, hydrochloric acid, hydrobromic acid, lactic acid, maleic acid, L-(-) malic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, Nitric acid, oxalic acid, citric acid, phosphoric acid, propionic acid, DL-pyroglutamic acid, saccharin, salicylic acid, succinic
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier.
  • the carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, in a quantity which is not deleterious to the recipient thereof.
  • the beneficial effects of the present invention are that the substituted fused imidazole ring compound disclosed by the present invention and the composition comprising the same can be used as a histamine H1-receptor antagonist, and have better pharmacokinetics.
  • the dosage can be varied and a long acting formulation can be formed to improve suitability.
  • Replacing a hydrogen atom in a compound with hydrazine can increase the drug concentration of the compound in an animal to improve the efficacy of the drug due to its strontium isotope effect.
  • Substitution of a hydrogen atom in a compound with hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • N-Benzyloxycarbonylpiperidine-4-carboxylic acid (2.63 g, 10 mmol) was dissolved in 20 mL of dichloromethane, and 6 mL of oxalyl chloride and 1 drop of DMF were added and reacted at room temperature for 2 hours under nitrogen atmosphere.
  • a solution of 1-phenylethyl-1H-imidazole (2.06 g, 12 mmol) in 5 mL of acetonitrile was slowly added dropwise, and the mixture was allowed to warm to room temperature overnight. After completion of the reaction, the mixture was concentrated to dryness.
  • EtOAc EtOAc EtOAc EtOAc EtOAc was dissolved in 20 mL of dichloromethane, and 6 mL of oxalyl chloride and 1 drop of DMF were added and reacted at room temperature for 2 hours under nitrogen atmosphere.
  • the reaction solution was concentrated to dryness ⁇ RT
  • Benzyl-4-(1-phenethyl-1H-imidazole-2-formyl)piperidine-1-carboxylate (3.34 g, 8 mmol) was dissolved in 30 mL of absolute ethanol and 300 mg of 10% palladium carbon was added. The hydrogen was replaced three times and stirred at room temperature under a hydrogen atmosphere of 1 atm. After completion of the reaction, the palladium carbon was filtered off, and the filtrate was concentrated, and then purified by silica gel column (2-phenylethyl-1H-imidazol-2-yl)(piperidin-4-yl)methanone (Compound 4) 2.04 g, yield 90%.
  • ESI-MS 284 [M + +1].
  • Phenylacetic acid (3.15 g, 23 mmol) was added to 10 mL of a 3.5 M aqueous solution of sodium cerium oxide, and reacted at 100 ° C for 24 hours under nitrogen atmosphere, cooled to room temperature, and the reaction mixture was acidified with 4N hydrochloric acid and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was again subjected to the above-mentioned operation, and finally, a silica gel column was separated to obtain about 10.8 g of compound 10 in a yield of 90%.
  • 1 H NMR 400MHz, DMSO- d 6) ⁇ 12.30 (s, 1H), 7.34-7.21 (m, 5H); ESI-MS: 139 [M + +1].
  • Lithium aluminum hydride (1.2 g, 31 mmol) was added to 30 mL of dry tetrahydrofuran, replaced with nitrogen three times, and a solution of compound 10 (2.88 g, 20.8 mmol) in 20 mL of tetrahydrofuran was slowly added dropwise in an ice bath, and the mixture was allowed to rise to room temperature. The reaction was overnight. The reaction was completely detected by TLC. The reaction was quenched by slowly dropping 1.2 mL of water into the bath. Then, 1.2 mL of 15% sodium hydroxide solution and 4 mL of water were added in sequence, and the mixture was stirred at room temperature. After stirring for 15 minutes, the white precipitate was filtered off.
  • N-Benzyloxycarbonylpiperidine-4-carboxylic acid (2.63 g, 10 mmol) was dissolved in 20 mL of dichloromethane, and 6 mL of oxalyl chloride and 1 drop of DMF were added and allowed to react at room temperature for 2 hours.
  • Control group 6,11-dihydro-11 -(1-methyl-4-piperidin)-5H-imidazo[2,1-b][3]benzazepine -3-formaldehyde
  • Test group Example compounds, comparing their pharmacokinetic differences.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • Preparation of stock solution Weigh a certain amount of compound powder and dissolve it to 5 mM with DMSO.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of liver microsomes in human, rat and mouse was evaluated by comparing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 1.
  • the undeuterated compound Alcaftadine (6,11-dihydro-11-(1-methyl-4-piperidin)-5H-imidazo[2,1-b][3]benzophenone is used in Table 1.
  • Aza -3-formaldehyde was used as a control sample.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Alcaftadine.

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Abstract

The present invention relates to a substituted fused imidazole cyclic compound and a composition containing said compound and application thereof. Specifically disclosed is the fused imidazole cyclic compound represented by formula (I), or a pharmaceutical composition of its crystalline form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate. The compound of the present invention may be used as a histamine H1-receptor antagonist and mast-cell stabilizer, and is capable of inhibiting mast-cell release of histamine and preventing histamine function, thereby reducing allergic reaction.

Description

一种取代的稠合咪唑环化合物及其药物组合物Substituted fused imidazole ring compound and pharmaceutical composition thereof 技术领域Technical field
本发明属于医药领域。具体地，本发明涉及一种取代的稠合咪唑环化合物及其用途，更具体地是，涉及稠合咪唑环化合物及其药物组合物可作为组胺H1-受体拮抗剂和肥大细胞稳定剂，用于治疗和预防与过敏相关的症状。The invention belongs to the field of medicine. In particular, the present invention relates to a substituted fused imidazole ring compound and use thereof, and more particularly to a fused imidazole ring compound and a pharmaceutical composition thereof for use as a histamine H1-receptor antagonist and a mast cell stabilizer For the treatment and prevention of allergy-related symptoms.
背景技术Background technique
过敏性疾病又称***反应性疾病，是因为病人敏感性过高，在血液中产生一种对某种特殊的过敏原过敏的特异性免疫球蛋白E抗体(IgE)，这种病人有遗传倾向。IgE敏感可导致以下几种典型的过敏性疾病：哮喘、鼻炎、过敏性湿疹、结膜炎、食物过敏、药物过敏和过敏性休克等。其中最常见的是由花粉、尘螨、真菌和宠物等致敏因素引起的过敏性鼻炎和过敏性哮喘。Allergic diseases, also known as allergic diseases, are caused by excessive sensitivity of the patient, producing a specific immunoglobulin E antibody (IgE) that is allergic to a particular allergen in the blood. This patient has a genetic predisposition. . IgE sensitivity can lead to several typical allergic diseases: asthma, rhinitis, allergic eczema, conjunctivitis, food allergies, drug allergies, and anaphylactic shock. The most common of these are allergic rhinitis and allergic asthma caused by sensitizing factors such as pollen, dust mites, fungi and pets.
眼***反应是一种IgE依赖性的(I型)超敏性炎性反应，最通常影响20至40岁之间的成人。在易感个体中，过敏原与眼睛表面的最初接触刺激过敏原特异性免疫抗体的产生。然后IgE与眼粘膜中膜结合的FcεR-1受体肥大细胞结合。肥大细胞是一种粒细胞，含许多预先形成的介质，包括组胺和蛋白多糖。一旦肥大细胞被激活，新形成的化学介质就形成，其包括***素D2、白细胞三烯和血小板凝聚因子。随后过敏原与IgE覆盖的肥大细胞接触，导致肥大细胞微粒内所含的预先形成和新形成的介质释放。An ocular allergy is an IgE-dependent (type I) hypersensitivity inflammatory response that most commonly affects adults between the ages of 20 and 40 years. In susceptible individuals, the initial contact of the allergen with the surface of the eye stimulates the production of allergen-specific immune antibodies. IgE then binds to membrane-bound FcεR-1 receptor mast cells in the ocular mucosa. Mast cells are a type of granulocyte containing many pre-formed mediators including histamine and proteoglycans. Once the mast cells are activated, a newly formed chemical medium is formed which includes prostaglandin D2, leukotrienes, and platelet aggregation factors. Subsequent contact of the allergen with IgE-covered mast cells results in the release of pre-formed and newly formed media contained within the mast cell microparticles.
***反应性结膜炎的临床症状包括眼睑的发痒、红肿、肿胀、结膜水肿和流泪。组胺是该***反应中的主要介质。肥大细胞脱粒后，组胺与位于结膜内的受体结合。组胺与神经细胞上的H1受体结合诱发痒感。血管内皮上的H1和H2受体的激活诱发血管舒张并增加血管通透性，促进炎症介质如IL-1α和IL-1β迁移进入血管内且继发粒细胞补充到结膜组织内。组胺受体的激活导致眼睛充血、结膜水肿、眼睑肿胀以及体液由血管渗入周围的组织，从而导致炎症。粒细胞如嗜酸性粒细胞和嗜中性粒细胞进入结膜组织内的趋化性从而导致进一步的组织损伤。Clinical signs of allergic conjunctivitis include itching, redness, swelling, conjunctival edema, and tearing of the eyelids. Histamine is the primary mediator in this allergy. After mast cell degranulation, histamine binds to receptors located within the conjunctiva. Histamine binds to the H1 receptor on nerve cells to induce itching. Activation of the H1 and H2 receptors on the vascular endothelium induces vasodilation and increases vascular permeability, promoting the migration of inflammatory mediators such as IL-1α and IL-1β into the blood vessels and secondary granulocyte recruitment into the conjunctival tissue. Activation of histamine receptors causes eye congestion, conjunctival edema, swelling of the eyelids, and infiltration of body fluids from the surrounding blood vessels, leading to inflammation. The chemotaxis of granulocytes such as eosinophils and neutrophils into the conjunctival tissue leads to further tissue damage.
抗组胺药物即H1受体拮抗剂，是临床治疗过敏性疾病的主要药物，根据结构特点分为四类。20世纪80年代以前发现的药物称为第一代抗组胺药物，包括苯海拉明、氯苯那敏等。由于其与受体作用特异性差，易通过血脑屏障进入中枢，产生明显的镇静和抗胆碱副作用，又被称为镇静性抗组胺药。20世纪80年代后开发的第二代抗组胺药，包括特非那定、氯雷他定等药物对H1受体选择性高，无中枢镇静副作用，但在临床应用过程中，特非那定和阿司咪唑由于诱发心律失常这一严重的副作用，先后撤离了市场，这也促使人们继续研发新一代抗组胺药物。目前在临床使用的左西替立嗪，地氯雷他定以及诺阿司咪唑等大都是第三代抗组胺药物，这类药物不但无中枢镇静作用， 同时也不会造成心律失常，具有很高的安全性。Antihistamines, H1 receptor antagonists, are the main drugs for the clinical treatment of allergic diseases, and are classified into four categories according to their structural characteristics. The drugs discovered before the 1980s are called first-generation antihistamines, including diphenhydramine and chlorpheniramine. Because of its poor specificity with receptors, it easily enters the central nervous system through the blood-brain barrier, producing significant sedative and anticholinergic side effects, also known as sedative antihistamines. The second-generation antihistamines developed after the 1980s, including terfenadine and loratadine, have high selectivity for H1 receptors and no central sedative side effects, but in clinical applications, Tefia Ding and astemizole have been withdrawn from the market due to the serious side effects of arrhythmia, which has prompted people to continue to develop a new generation of antihistamines. Currently used in the clinical use of levocetirizine, desloratadine and noosemide are mostly third-generation antihistamines, and these drugs have no central sedative effect. At the same time, it will not cause arrhythmia and has high safety.
历史上，抗组胺药曾经是治疗眼睛***反应病的主要支持。这类治疗在作用的效力、特异性和持续时间方面不同。第一代抗组胺药如非尼拉敏和安他唑啉因其作用迅速而众所周知。不幸地，这类化合物还引起眼睛不适且其效力只在几小时之后减弱。第二代H1拮抗剂如左卡巴斯汀和emadastine存在较小的眼睛不适和具有稍微较长的作用持续时间。然而，这类化合物具有有限的抗炎作用，且对抑制炎性反应的晚期成分几乎没有作用。Historically, antihistamines have been the main support for the treatment of ocular allergic diseases. Such treatments differ in the efficacy, specificity, and duration of action. The first generation of antihistamines such as feniramine and anatazoline are known for their rapid action. Unfortunately, such compounds also cause eye irritation and their effectiveness is only attenuated after a few hours. Second-generation H1 antagonists such as levocabastatin and emadastine have less eye discomfort and have a slightly longer duration of action. However, such compounds have limited anti-inflammatory effects and have little effect on the late components that inhibit the inflammatory response.
目前，对眼***反应治疗最有效的治疗是诸如奥洛他定、酮替芬和氮
Figure PCTCN2017087137-appb-000001
斯汀的药物，其兼有抗组胺和稳定肥大细胞的性能。这类治疗通常耐受性好且其作用能持续高达8至12小时。尽管有报道优于仅仅影响***反应单一成分的化合物，但这类化合物通常不能减轻一种以上的眼***反应症状。Currently, the most effective treatments for ocular allergy treatment are such as olopatadine, ketotifen and nitrogen.
Figure PCTCN2017087137-appb-000001
Sting's drug, which combines anti-histamine and stable mast cell properties. Such treatments are generally well tolerated and can last up to 8 to 12 hours. Although reported to be superior to compounds that only affect the single component of allergy, such compounds generally do not alleviate more than one symptom of ocular allergy.
由于过敏性疾病的发病率逐年升高，研发新的抗组胺药物步伐始终没有停止，但是过敏的病理过程机制非常复杂，因此作用其发病机制中的多个环节对缓解病症有很好的效果。近年来，研究者在开发高效低毒，结构新颖的H1受体拮抗剂的同时将研究重点转移至发现调控H1受体以及与过敏机制相关的炎症因子或受体的功能从而起到抗过敏作用的化合物。As the incidence of allergic diseases has increased year by year, the pace of research and development of new antihistamines has not stopped, but the pathological process of allergies is very complicated, so the multiple links in its pathogenesis have a good effect on relieving the disease. . In recent years, researchers have focused on the development of highly effective, low-toxic, novel H1 receptor antagonists, while shifting research to the discovery of functions that regulate H1 receptors and inflammatory factors or receptors associated with allergic mechanisms. compound of.
发明内容Summary of the invention
针对以上技术问题，本发明公开了一种稠合咪唑环化合物及包含该化合物的组合物，其作为一种有效的组胺H1-受体拮抗剂和/或具有更好药效学/药代动力学性能。In view of the above technical problems, the present invention discloses a fused imidazole ring compound and a composition comprising the same as an effective histamine H1-receptor antagonist and/or having better pharmacodynamics/pharmacokinetics Kinetic performance.
对此，本发明采用的技术方案为：In this regard, the technical solution adopted by the present invention is:
本发明的目的是提供一类新型有效的组胺H1-受体拮抗剂和/或具有更好药效学/药代动力学性能的化合物。It is an object of the present invention to provide a novel class of potent histamine H1-receptor antagonists and/or compounds having better pharmacodynamic/pharmacokinetic properties.
本发明的第一方面中，提供了一种式(I)所示的稠合咪唑环化合物，或其晶型、药学上可接受的盐、前药、同分异构体、N-氧化物、水合物或溶剂化合物：In a first aspect of the invention, there is provided a fused imidazole ring compound of the formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a prodrug, an isomer, an N-oxide , hydrate or solvent compound:
Figure PCTCN2017087137-appb-000002
Figure PCTCN2017087137-appb-000002
式中：In the formula:
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20相互独立地选自由“氢(H)、氘(D)”组成的组；R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently selected from the group consisting of "hydrogen (H), hydrazine (D)";
及其生理学上可接受的盐、前药、水合物、溶剂化物、互变异构体和立体异构体，包括这些化合物以所有比例形成的混合物；And physiologically acceptable salts, prodrugs, hydrates, solvates, tautomers and stereoisomers thereof, including mixtures of these compounds in all ratios;
附加条件是，所述稠合咪唑环化合物至少含有一个氘原子。Additionally, the fused imidazole ring compound contains at least one ruthenium atom.
在另一优选例中，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。In another preferred embodiment, the cerium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. Preferably, the ground is greater than 95%, more preferably greater than 99%.
具体地说，在本发明中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19和R20各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。Specifically, in the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 , The strontium isotope content of each of the R 9 , R 16 , R 17 , R 18 , R 19 and R 20 is at least 5%, preferably greater than 10%, more preferably greater than 15%, and even more preferably greater than 20%. More preferably greater than 25%, more preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, and even more preferably greater than 55%, More preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more Preferably, the ground is greater than 95%, more preferably greater than 99%.
在另一优选例中，式(I)中化合物的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20，至少其中一个R含氘，更佳地两个R含氘，更佳地三个R含氘，更佳地四个R含氘，更佳地五个R含氘，更佳地六个R含氘，更佳地七个R含氘，更佳地八个R含氘，更佳地九个R含氘，更佳地十个R含氘，更佳地十一个R含氘，更佳地十二个R含氘，更佳地十三个R含氘，更佳地十四个R含氘，更佳地十五个R含氘，更佳地十六个R含氘，更佳地十七个R含氘，更佳地十八个R含氘，更佳地十九个R含氘，更佳地二十个R含氘。In another preferred embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 of the compound of formula (I), R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , at least one of R contains ruthenium, more preferably two R contains ruthenium, more preferably three R contains ruthenium, more preferably Preferably, the four Rs contain yttrium, more preferably five R yttrium, more preferably six R yttrium, more preferably seven R yttrium, more preferably eight R yttrium, more preferably nine R氘, preferably ten R 氘, more preferably eleven R 氘, more preferably twelve R 氘, more preferably thirteen R 氘, more preferably fourteen R氘, preferably fifteen R 氘, more preferably sixteen R 氘, more preferably seventeen R 氘, more preferably eighteen R 氘, more preferably nineteen R Oh, better than twenty R.
作为本发明的进一步改进，R1、R2、R3和R4各自独立地为氘或氢。As a further improvement of the present invention, R 1 , R 2 , R 3 and R 4 are each independently hydrazine or hydrogen.
作为本发明的进一步改进，R5、R6、R7和R8各自独立地为氘或氢。As a further improvement of the present invention, R 5 , R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
作为本发明的进一步改进，R9为氘或氢。As a further improvement of the present invention, R 9 is deuterium or hydrogen.
作为本发明的进一步改进，R10、R11、R12、R13、R14、R15、R16和R17各自独立地为氘或氢。As a further improvement of the present invention, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently hydrazine or hydrogen.
作为本发明的进一步改进，R18、R19和R20各自独立地为氘或氢As a further improvement of the present invention, R 18 , R 19 and R 20 are each independently hydrazine or hydrogen
在另一优选例中，所述化合物选自下组化合物或其药学上可接受的盐，但不局限于下列化合物： In another preferred embodiment, the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof, but is not limited to the following compounds:
Figure PCTCN2017087137-appb-000003
Figure PCTCN2017087137-appb-000003
Figure PCTCN2017087137-appb-000004
Figure PCTCN2017087137-appb-000004
Figure PCTCN2017087137-appb-000005
Figure PCTCN2017087137-appb-000005
在另一优选例中，所述化合物不包括非氘代化合物。In another preferred embodiment, the compound does not include a non-deuterated compound.
在本发明的第二方面中，提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。In a second aspect of the invention, there is provided a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, pharmaceutically acceptable The accepted salt, hydrate or solvate is mixed to form a pharmaceutical composition.
在本发明的第三方面中，提供了一种药物组合物，它含有药学上可接受的载体和本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。In a third aspect of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated Or a solvate.
可用于本发明药物组合物中的药学上可接受的载体包括但不限于任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents A dispersing agent, a disintegrating agent, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
本发明药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、 颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, Granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
给予本发明药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选口服给药或注射给药。Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
本发明的药物组合物可以采用本领域周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
本发明化合物可作为组胺H1-受体拮抗剂，用于制备预防或治疗抗过敏的药物中的用途。The compounds of the present invention are useful as histamine H1-receptor antagonists for the preparation of a medicament for the prevention or treatment of anti-allergy.
本发明所涉及的化合物及其药用组合物，可用于缓解过敏性鼻炎和普通感冒有关的症状，如鼻塞、鼻充血、打喷嚏、流涕、鼻痒以及眼部瘙痒和烧灼感。也用于缓解过敏性结膜炎相关的眼部瘙痒、烧灼感、眼睛发红、眼睑肿胀、结膜水肿、流泪等症状。The compound and the pharmaceutical composition thereof according to the present invention can be used for alleviating the symptoms associated with allergic rhinitis and the common cold, such as nasal congestion, nasal congestion, sneezing, runny nose, itchy nose, and itching and burning sensation of the eyes. Also used to relieve allergic conjunctivitis related eye itching, burning sensation, red eyes, swollen eyelids, conjunctival edema, tearing and other symptoms.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。As used herein, unless otherwise specified, "deuterated" means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted. The terms "one or more deuterated" are used interchangeably with "one or more deuterated".
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。As used herein, unless otherwise specified, "non-deuterated compound" means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H，3H，13C，14C，15N，17O，18O，31P，32P，35S，18F以及36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。The invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. Examples of isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention . Certain isotopically-labeled compounds of the present invention, such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates.氚, ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
本发明所述的组合物含式I所示的稠合咪唑化合物，但作为选择可以以其盐的形式存在。该药用盐可由有机酸和无机酸形成。适宜的酸包括但不限于乙酸，4-乙酰胺基苯甲酸，苯磺酸，樟脑磺酸，柠檬酸，2,3:4,6-二-O-异丙叉-2-酮-古洛糖酸一水合物，甲酸，富马酸，盐酸，氢溴酸，乳酸，马来酸，L-(-)苹果酸，苹果酸，丙二酸，扁桃酸，甲磺酸，萘磺酸，硝酸，草酸，酞酸，磷酸，丙酸，DL-焦谷氨酸，糖精，水杨酸，琥珀酸，硫酸，酒石酸，三氟乙酸，L-(+)酒石酸和甲苯磺酸。 The compositions of the present invention comprise a fused imidazole compound of formula I, but may alternatively be present in the form of a salt thereof. The pharmaceutically acceptable salt can be formed from an organic acid and an inorganic acid. Suitable acids include, but are not limited to, acetic acid, 4-acetamidobenzoic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, 2,3:4,6-di-O-isopropylidene-2-one-gulo Sugar acid monohydrate, formic acid, fumaric acid, hydrochloric acid, hydrobromic acid, lactic acid, maleic acid, L-(-) malic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, Nitric acid, oxalic acid, citric acid, phosphoric acid, propionic acid, DL-pyroglutamic acid, saccharin, salicylic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, L-(+) tartaric acid and toluenesulfonic acid.
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。The term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio. "Hydrate" means a complex formed by the coordination of a compound of the invention with water.
本发明还提供了包含式(I)的化合物或其药学上可接受的盐或所述化合物的药学上可接受的盐以及药学上可接受的载体的药物组合物。所述载体在与制剂的其他成分相容以及，在药学上可接受的载体的情况下，在用于药物中的量下不会对其接受者有害的意义上是“可接受的”。The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier. The carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, in a quantity which is not deleterious to the recipient thereof.
与现有技术相比，本发明的有益效果为：本发明公开的取代的稠合咪唑环化合物及包含该化合物的组合物可作为组胺H1-受体拮抗剂，同时具有更好的药代动力学参数特性。可以改变剂量并形成长效制剂，改善适用性。用氘取代化合物中的氢原子，由于其氘同位素效应，能够提高化合物在动物体内的药物浓度，以提高药物疗效。用氘取代化合物中的氢原子，由于某些代谢产物被抑制，可能提高化合物的安全性。Compared with the prior art, the beneficial effects of the present invention are that the substituted fused imidazole ring compound disclosed by the present invention and the composition comprising the same can be used as a histamine H1-receptor antagonist, and have better pharmacokinetics. Kinetic parameter characteristics. The dosage can be varied and a long acting formulation can be formed to improve suitability. Replacing a hydrogen atom in a compound with hydrazine can increase the drug concentration of the compound in an animal to improve the efficacy of the drug due to its strontium isotope effect. Substitution of a hydrogen atom in a compound with hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
具体实施方式detailed description
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。The preparation of the structural compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-24小时。Usually, in the preparation scheme, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C). The reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
实施例1制备6,11-二氢-11-(1-(d3-甲基)哌啶-4-亚基)-5H-咪唑并[2,1-b][3]苯并氮杂
Figure PCTCN2017087137-appb-000006
-3-甲 醛(化合物8) Example 1 Preparation of 6,11-dihydro-11-(1-(d3-methyl)piperidin-4-ylidene)-5H-imidazo[2,1-b][3]benzazepine
Figure PCTCN2017087137-appb-000006
3-aldehyde (Compound 8)
Figure PCTCN2017087137-appb-000007
Figure PCTCN2017087137-appb-000007
具体合成步骤如下： The specific synthesis steps are as follows:
Figure PCTCN2017087137-appb-000008
Figure PCTCN2017087137-appb-000008
步骤1.化合物3的合成。Step 1. Synthesis of Compound 3.
将N-苄氧羰基哌啶-4-羧酸(2.63g，10mmol)溶于20mL二氯甲烷，加入6mL草酰氯和1滴DMF，氮气保护下于室温反应2小时。将反应液减压浓缩至干，加入20mL乙腈溶解，冰浴下加入三乙胺(4.1mL，30mmol)，搅拌3分钟。缓慢滴加1-苯乙基-1H-咪唑(2.06g，12mmol)的5mL乙腈溶液，滴加完毕自然升至室温反应过夜。反应完毕，浓缩至干，加入30mL乙酸乙酯和20mL水，搅拌5分钟，静置分层，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，浓缩，柱层析得到无色油状物苄基-4-(1-苯乙基-1H-咪唑-2-甲酰基)哌啶-1-羧酸酯(化合物3)3.34g，收率80％。ESI-MS:418[M++1]。N-Benzyloxycarbonylpiperidine-4-carboxylic acid (2.63 g, 10 mmol) was dissolved in 20 mL of dichloromethane, and 6 mL of oxalyl chloride and 1 drop of DMF were added and reacted at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was concentrated to dryness <RTI ID=0.0> A solution of 1-phenylethyl-1H-imidazole (2.06 g, 12 mmol) in 5 mL of acetonitrile was slowly added dropwise, and the mixture was allowed to warm to room temperature overnight. After completion of the reaction, the mixture was concentrated to dryness. EtOAc EtOAc EtOAc EtOAc. Color oil benzyl-4-(1-phenethyl-1H-imidazol-2-formyl)piperidine-1-carboxylate (Compound 3) 3.34 g, yield 80%. ESI-MS: 418 [M + +1].
步骤2.化合物4的合成。Step 2. Synthesis of Compound 4.
将苄基-4-(1-苯乙基-1H-咪唑-2-甲酰基)哌啶-1-羧酸酯(3.34g，8mmol)溶于30mL无水乙醇中，加入300mg10％的钯碳，氢气置换三次，在1个大气压的氢气氛下室温搅拌过夜。反应完全后滤除钯碳，滤液浓缩，经硅胶柱分离得(1-苯乙基-1H-咪唑-2-基)(哌啶-4-基)甲酮(化合物4)2.04g，收率90％。ESI-MS:284[M++1]。Benzyl-4-(1-phenethyl-1H-imidazole-2-formyl)piperidine-1-carboxylate (3.34 g, 8 mmol) was dissolved in 30 mL of absolute ethanol and 300 mg of 10% palladium carbon was added. The hydrogen was replaced three times and stirred at room temperature under a hydrogen atmosphere of 1 atm. After completion of the reaction, the palladium carbon was filtered off, and the filtrate was concentrated, and then purified by silica gel column (2-phenylethyl-1H-imidazol-2-yl)(piperidin-4-yl)methanone (Compound 4) 2.04 g, yield 90%. ESI-MS: 284 [M + +1].
步骤3.化合物5的合成。Step 3. Synthesis of Compound 5.
将(1-苯乙基-1H-咪唑-2-基)(哌啶-4-基)甲酮(2.04g，7.2mmol)溶于10mL DMF中，加入碳酸钾(1.98g，14.4mmol)，降至-15℃，氮气保护下缓慢滴加氘代碘甲烷(1.02g，7.2mmol)，滴加完毕后移至室温反应0.5小时。加入20mL水淬灭，用乙酸乙酯萃取，有机相用20mL水和20mL饱和食盐水各洗涤一次，无水硫酸钠干燥，浓缩，经硅胶柱分离得(1-(甲基-d3)哌啶-4-基)(1-苯乙基-1H-咪唑-2-基)甲酮(化合物5)1.5g，收率70％。1H NMR(300MHz,CDCl3)δ7.23(d,J＝2.0Hz,1H),7.06(td,J＝4.2,3.8,1.7Hz,3H),6.86(d,J＝1.0Hz,1H),5.29(s,2H),4.59(t,J＝7.2Hz,2H),3.77(q,J＝7.1Hz,1H),3.29(dd,J＝10.2,5.8Hz,2H),3.01(t,J＝7.2Hz,2H),2.85–2.65(m,2H),2.15(td,J＝ 7.5,3.9Hz,4H)；ESI-MS:301[M++1]。(1-Phenylethyl-1H-imidazol-2-yl)(piperidin-4-yl)methanone (2.04 g, 7.2 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (1.98 g, 14.4 mmol). The mixture was cooled to -15 ° C, and deuterated iodomethane (1.02 g, 7.2 mmol) was slowly added dropwise under a nitrogen atmosphere. After the addition was completed, the mixture was allowed to react at room temperature for 0.5 hour. After quenching with 20 mL of water, the mixture was extracted with ethyl acetate. The organic phase was washed twice with 20 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate and evaporated. 4-yl)(1-phenethyl-1H-imidazol-2-yl)methanone (Compound 5) 1.5 g, yield 70%. 1 H NMR (300MHz, CDCl 3 ) δ7.23 (d, J = 2.0Hz, 1H), 7.06 (td, J = 4.2,3.8,1.7Hz, 3H), 6.86 (d, J = 1.0Hz, 1H) , 5.29 (s, 2H), 4.59 (t, J = 7.2 Hz, 2H), 3.77 (q, J = 7.1 Hz, 1H), 3.29 (dd, J = 10.2, 5.8 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.85 - 2.65 (m, 2H), 2.15 (td, J = 7.5, 3.9 Hz, 4H); ESI-MS: 301 [M + +1].
步骤4.化合物6的合成。Step 4. Synthesis of Compound 6.
将(1-(甲基-d3)哌啶-4-基)(1-苯乙基-1H-咪唑-2-基)甲酮(1.5g，5.1mmol)置于反应瓶中，氮气置换三次，滴加7mL三氟甲磺酸，升温至110℃反应过夜。冷却至室温，将反应液倒入30mL冰水中，滴加50％的氢氧化钠溶液调节pH＝10-11，用二氯甲烷萃取，有机相用20mL水和20mL饱和食盐水各洗涤一次，无水硫酸钠干燥，浓缩，经硅胶柱分离得化合物6 0.85g，收率60％。1H NMR(300MHz,CDCl3)δ7.28(d,J＝4.4Hz,2H),7.23(d,J＝5.0Hz,1H),7.13(d,J＝7.0Hz,1H),7.02(d,J＝1.2Hz,1H),6.81(d,J＝1.3Hz,1H),4.38(dt,J＝12.7,3.9Hz,1H),4.02(td,J＝13.3,3.1Hz,1H),3.59–3.34(m,3H),3.21(s,2H),3.04–2.87(m,3H),2.78–2.63(m,2H).ESI-MS:283[M++1]。(1-(Methyl-d3)piperidin-4-yl)(1-phenethyl-1H-imidazol-2-yl)methanone (1.5 g, 5.1 mmol) was placed in a reaction flask and replaced with nitrogen three times. 7 mL of trifluoromethanesulfonic acid was added dropwise, and the mixture was heated to 110 ° C to react overnight. After cooling to room temperature, the reaction solution was poured into 30 mL of ice water, 50% sodium hydroxide solution was added dropwise to adjust pH=10-11, extracted with dichloromethane, and the organic phase was washed once with 20 mL of water and 20 mL of saturated brine. The aqueous sodium sulfate was dried, concentrated, and then purified by silica gel column to obtain compound 6 0.85 g, yield 60%. 1 H NMR (300MHz, CDCl 3 ) δ7.28 (d, J = 4.4Hz, 2H), 7.23 (d, J = 5.0Hz, 1H), 7.13 (d, J = 7.0Hz, 1H), 7.02 (d , J = 1.2 Hz, 1H), 6.81 (d, J = 1.3 Hz, 1H), 4.38 (dt, J = 12.7, 3.9 Hz, 1H), 4.02 (td, J = 13.3, 3.1 Hz, 1H), 3.59 -3.34 (m, 3H), 3.21 (s, 2H), 3.04 - 2.87 (m, 3H), 2.78 - 2.63 (m, 2H). ESI-MS: 283 [M + +1].
步骤5.化合物7的合成。Step 5. Synthesis of Compound 7.
将化合物6(850mg，3mmol)置于反应瓶中，依次加入0.5mL乙酸，5mL 37％甲醛和乙酸钠(87mg，1.1mmol)，升温至100℃反应过夜。反应完全后冷至室温，向反应液中加入30mL二氯甲烷，滴加50％的氢氧化钠溶液调节pH＝11-12，搅拌0.5小时，静置分层，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得化合物7 340mg，收率36％。ESI-MS:313[M++1]。Compound 6 (850 mg, 3 mmol) was placed in a reaction flask, and then 0.5 mL of acetic acid, 5 mL of 37% formaldehyde and sodium acetate (87 mg, 1.1 mmol) were added, and the mixture was heated to 100 ° C overnight. After the reaction was completed, it was cooled to room temperature, 30 mL of dichloromethane was added to the reaction solution, 50% sodium hydroxide solution was added dropwise to adjust pH = 11-12, stirred for 0.5 hour, and the mixture was allowed to stand for separation, and the organic phase was washed with 10 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. ESI-MS: 313 [M + +1].
步骤6.化合物8的合成。Step 6. Synthesis of Compound 8.
将化合物7(340mg，1.1mmol)溶于20mL二氯甲烷中，氮气保护下依次加入4-二甲氨基吡啶(DMAP，13mg，0.11mmol)和戴斯-马丁试剂(Dess-Martin Periodinane，550mg，1.3mmol)，室温反应3小时。加入20mL饱和碳酸氢钠溶液和20mL二氯甲烷，搅拌5分钟，过滤，滤液分层。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得化合物8 270mg，收率80％。1H NMR(300MHz,CDCl3)δ9.64(s,1H),7.76(s,1H),7.34–7.26(m,3H),7.16(d,J＝6.7Hz,1H),4.74(dt,J＝14.5,3.9Hz,1H),4.31(td,J＝14.1,3.2Hz,1H),3.53(td,J＝14.1,4.1Hz,1H),3.09(d,J＝9.6Hz,1H),3.03–2.89(m,4H),2.64-2.81(m,4H)；ESI-MS:311[M++1]。Compound 7 (340 mg, 1.1 mmol) was dissolved in 20 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP, 13 mg, 0.11 mmol) and Dess-Martin Periodinane (550 mg, 1.3 mmol), reacted at room temperature for 3 hours. 20 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added, stirred for 5 minutes, filtered, and the filtrate was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate 1 H NMR (300MHz, CDCl 3 ) δ 9.64 (s, 1H), 7.76 (s, 1H), 7.34 - 7.26 (m, 3H), 7.16 (d, J = 6.7 Hz, 1H), 4.74 (dt, J = 14.5, 3.9 Hz, 1H), 4.31 (td, J = 14.1, 3.2 Hz, 1H), 3.53 (td, J = 14.1, 4.1 Hz, 1H), 3.09 (d, J = 9.6 Hz, 1H), 3.03 - 2.89 (m, 4H), 2.64 - 2.81 (m, 4H); ESI-MS: 311 [M + +1].
实施例2制备6,6-d2-6,11-二氢-11-(1-甲基哌啶-4-亚基)-5H-咪唑并[2,1-b][3]苯并氮杂
Figure PCTCN2017087137-appb-000009
-3-甲 醛(化合物19) Example 2 Preparation of 6,6-d2-6,11-dihydro-11-(1-methylpiperidin-4-ylidene)-5H-imidazo[2,1-b][3]benzitriazole miscellaneous
Figure PCTCN2017087137-appb-000009
3-aldehyde (Compound 19)
Figure PCTCN2017087137-appb-000010
Figure PCTCN2017087137-appb-000010
具体合成步骤如下：The specific synthesis steps are as follows:
Figure PCTCN2017087137-appb-000011
Figure PCTCN2017087137-appb-000011
步骤1.化合物10的合成。Step 1. Synthesis of Compound 10.
将苯乙酸(3.15g，23mmol)加入到10mL 3.5M的氘氧化钠重水溶液中，氮气保护下于100℃反应24小时，冷却至室温，反应液用4N盐酸酸化，二氯甲烷萃取，有机相用无水硫酸钠干燥，浓缩，得到的粗品再重复上述操作一次，最后经硅胶柱分离得化合物10约2.88g，收率90％。1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),7.34-7.21(m,5H)；ESI-MS:139[M++1]。Phenylacetic acid (3.15 g, 23 mmol) was added to 10 mL of a 3.5 M aqueous solution of sodium cerium oxide, and reacted at 100 ° C for 24 hours under nitrogen atmosphere, cooled to room temperature, and the reaction mixture was acidified with 4N hydrochloric acid and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was again subjected to the above-mentioned operation, and finally, a silica gel column was separated to obtain about 10.8 g of compound 10 in a yield of 90%. 1 H NMR (400MHz, DMSO- d 6) δ12.30 (s, 1H), 7.34-7.21 (m, 5H); ESI-MS: 139 [M + +1].
步骤2.化合物11的合成。Step 2. Synthesis of Compound 11.
将氢化铝锂(1.2g，31mmol)加入到30mL干燥的四氢呋喃中，氮气置换三次，冰浴下缓慢滴加化合物10(2.88g，20.8mmol)的20mL四氢呋喃溶液，滴加完毕，自然升至室温反应过夜。待TLC检测反应完全，于浴下缓慢滴入1.2mL水淬灭反应，再依次加入1.2mL 15％的氢氧化钠溶液和4mL水，移至室温，搅拌15分钟后滤去白色沉淀，滤液旋干，柱层析得到化合物11 2.2g，收率85％。1H NMR(300MHz,DMSO-d6)δ7.31-7.13(m,5H),4.65(t,J＝5.2Hz,1H),3.58(s,2H)；ESI-MS:125[M++1]。Lithium aluminum hydride (1.2 g, 31 mmol) was added to 30 mL of dry tetrahydrofuran, replaced with nitrogen three times, and a solution of compound 10 (2.88 g, 20.8 mmol) in 20 mL of tetrahydrofuran was slowly added dropwise in an ice bath, and the mixture was allowed to rise to room temperature. The reaction was overnight. The reaction was completely detected by TLC. The reaction was quenched by slowly dropping 1.2 mL of water into the bath. Then, 1.2 mL of 15% sodium hydroxide solution and 4 mL of water were added in sequence, and the mixture was stirred at room temperature. After stirring for 15 minutes, the white precipitate was filtered off. Dry, column chromatography gave compound 11 2.2 g, yield 85%. 1 H NMR (300MHz, DMSO- d 6) δ7.31-7.13 (m, 5H), 4.65 (t, J = 5.2Hz, 1H), 3.58 (s, 2H); ESI-MS: 125 [M + + 1].
步骤3.化合物12的合成。Step 3. Synthesis of Compound 12.
将化合物11(2.2g，17.7mmol)置于反应瓶中，加入10mL三溴化磷，氮气保护下于120℃反应5小时。冷却至室温，倒入20mL冰水中，用乙酸乙酯萃取，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得化合物12 2.6g，收率80％。1H NMR(300MHz,CDCl3)δ7.39-7.19(m,5H),3.57(p,J＝1.1Hz,2H)；ESI-MS:187[M++1]。 Compound 11 (2.2 g, 17.7 mmol) was placed in a reaction flask, and 10 mL of phosphorus tribromide was added thereto, and the mixture was reacted at 120 ° C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, it was poured into 20 mL of ice water, and extracted with ethyl acetate. The organic phase was washed with 10 mL of brine, dried over anhydrous sodium sulfate and evaporated. 1 H NMR (300 MHz, CDCl 3 ) δ 7.39-7.19 (m, 5H), 3.57 (p,J=1.1 Hz, 2H); ESI-MS: 187 [M + +1].
步骤4.化合物13的合成。Step 4. Synthesis of Compound 13.
将1H-咪唑(1.16g，17mmol)和碳酸钾(3.9g，28mmol)加入到30mL干燥的四氢呋喃中，氮气保护下搅拌10分钟。向反应液中缓慢滴加化合物12(2.6g，14mmol)的10mL四氢呋喃溶液，滴加完毕升温至回流，反应过夜。将反应液冷却至室温，过滤，滤液浓缩至干，将残留物中溶于30mL二氯甲烷，水洗两次，1M稀盐酸萃取两次。合并水相，用碳酸氢钠固体调至中性，并用二氯甲烷萃取，有机相用无水硫酸钠干燥，旋干，真空干燥得化合物13 2.06g，收率85％。1H NMR(300MHz,CDCl3)δ7.36-7.19(m,4H),7.11-6.97(m,3H),6.82(t,J＝1.3Hz,1H),4.15(s,2H；ESI-MS:175[M++1]。1H-imidazole (1.16 g, 17 mmol) and potassium carbonate (3.9 g, 28 mmol) were added to 30 mL of dry tetrahydrofuran and stirred under nitrogen for 10 min. A solution of the compound 12 (2.6 g, 14 mmol) in 10 mL of tetrahydrofuran was slowly added dropwise to the reaction mixture, and the mixture was warmed to reflux under reflux overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The combined aqueous phases were neutralized with sodium bicarbonate solid and extracted with dichloromethane. 1 H NMR (300MHz, CDCl 3 ) δ7.36-7.19 (m, 4H), 7.11-6.97 (m, 3H), 6.82 (t, J = 1.3Hz, 1H), 4.15 (s, 2H; ESI-MS :175[M + +1].
步骤5.化合物14的合成。Step 5. Synthesis of Compound 14.
将N-苄氧羰基哌啶-4-羧酸(2.63g，10mmol)溶于20mL二氯甲烷，加入6mL草酰氯和1滴DMF，室温下反应2小时。将反应液减压浓缩至干，加入20mL乙腈溶解，冰浴下加入三乙胺(4.1mL，30mmol)，搅拌3分钟。然后在冰浴下向反应液中缓慢滴加化合物13(2.06g，12mmol)的5mL乙腈溶液，滴加完毕撤去冰浴，室温反应过夜。反应完毕后，旋蒸除去大部分溶剂，加入30mL乙酸乙酯和20mL水，搅拌5分钟，静置分层，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，浓缩，柱层析得到无色油状物化合物14 3.34g，收率80％。1H NMR(300MHz,CDCl3)δ7.38-7.33(m,5H),7.27-7.21(m,3H),7.11-7.03(m,3H),6.85(d,J＝1.0Hz,1H),5.13(d,J＝3.9Hz,2H),4.58(d,2H),4.26(d,2H),3.84(tt,J＝11.7,3.7Hz,1H),2.96(s,2H),1.89(s,4.3Hz,2H),1.65(dd,J＝12.7,4.3Hz,2H)；ESI-MS:420[M++1]。N-Benzyloxycarbonylpiperidine-4-carboxylic acid (2.63 g, 10 mmol) was dissolved in 20 mL of dichloromethane, and 6 mL of oxalyl chloride and 1 drop of DMF were added and allowed to react at room temperature for 2 hours. The reaction solution was concentrated to dryness <RTI ID=0.0> Then, a solution of Compound 13 (2.06 g, 12 mmol) in 5 mL of acetonitrile was slowly added dropwise to the reaction mixture under ice-cooling. After the reaction was completed, most of the solvent was removed by rotary evaporation, 30 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for 5 minutes, and the mixture was allowed to stand for separation. The aqueous phase was extracted with ethyl acetate. Chromatography gave 3.34 g of compound 14 as colorless oil. 1 H NMR (300MHz, CDCl 3 ) δ7.38-7.33 (m, 5H), 7.27-7.21 (m, 3H), 7.11-7.03 (m, 3H), 6.85 (d, J = 1.0Hz, 1H), 5.13 (d, J = 3.9 Hz, 2H), 4.58 (d, 2H), 4.26 (d, 2H), 3.84 (tt, J = 11.7, 3.7 Hz, 1H), 2.96 (s, 2H), 1.89 (s) , 4.6 Hz [M + +1].
步骤6.化合物15的合成。Step 6. Synthesis of Compound 15.
将化合物14(3.34g，8mmol)溶于30mL无水乙醇中，加入300mg10％的钯碳，氢气置换三次，在1个大气压的氢气氛下室温搅拌过夜。反应完全后滤除钯碳，滤液浓缩，经硅胶柱分离得化合物15 2.04g，收率90％。1H NMR(300MHz,DMSO-d6)δ7.42(d,J＝1.0Hz,1H),7.29–7.19(m,3H),7.16–7.09(m,2H),7.07(d,J＝1.0Hz,1H),4.56(s,2H),3.65(tt,J＝11.8,3.6Hz,1H),3.00–2.92(m,2H),2.55(dd,J＝12.3,2.6Hz,2H),1.72–1.59(m,2H),1.41(qd,J＝12.2,4.0Hz,2H)；ESI-MS:286[M++1]。Compound 14 (3.34 g, 8 mmol) was dissolved in 30 mL of absolute ethanol, 300 mg of 10% palladium carbon was added, and the mixture was replaced with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere of 1 atm. After the reaction was completed, palladium carbon was filtered off, and the filtrate was concentrated. 1 H NMR (300MHz, DMSO- d 6) δ7.42 (d, J = 1.0Hz, 1H), 7.29-7.19 (m, 3H), 7.16-7.09 (m, 2H), 7.07 (d, J = 1.0 Hz, 1H), 4.56 (s, 2H), 3.65 (tt, J = 11.8, 3.6 Hz, 1H), 3.00 - 2.92 (m, 2H), 2.55 (dd, J = 12.3, 2.6 Hz, 2H), 1.72 -1.59 (m, 2H), 1.41 (qd, J = 12.2, 4.0 Hz, 2H); ESI-MS: 286 [M + +1].
步骤7.化合物16的合成。Step 7. Synthesis of Compound 16.
将化合物15(2.04g，7.2mmol)溶于10mL DMF中，加入碳酸钾(1.98g，14.4mmol)，降至-15℃，氮气保护下缓慢滴加碘甲烷(1.02g，7.2mmol)，滴加完毕后移至室温反应0.5小时。加入20mL水淬灭，用乙酸乙酯萃取，有机相用20mL水和20mL饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，蒸干，经硅胶柱分离得化合物16 1.5g，收率70％。ESI-MS:300[M++1]。 Compound 15 (2.04 g, 7.2 mmol) was dissolved in 10 mL DMF, potassium carbonate (1.98 g, 14.4 mmol) was added, and the mixture was dropped to -15 ° C, and methyl iodide (1.02 g, 7.2 mmol) was slowly added dropwise under nitrogen. After the addition was completed, the mixture was allowed to react to room temperature for 0.5 hour. After adding 20 mL of water, the mixture was extracted with ethyl acetate. The organic phase was washed twice with 20 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. %. ESI-MS: 300 [M + +1].
步骤8.化合物17的合成。Step 8. Synthesis of Compound 17.
将化合物16(1.5g，5.1mmol)置于反应瓶中，氮气置换三次，滴加7mL三氟甲磺酸，升温至110℃反应过夜。冷却至室温，将反应液倒入30mL冰水中，滴加50％的氢氧化钠溶液调节pH＝10-11，用二氯甲烷萃取，有机相用20mL水和20mL饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，蒸干，经硅胶柱分离得化合物16 0.85g，收率60％。ESI-MS:282[M++1]。Compound 16 (1.5 g, 5.1 mmol) was placed in a reaction flask, replaced with nitrogen three times, 7 mL of trifluoromethanesulfonic acid was added dropwise, and the mixture was warmed to 110 ° C overnight. After cooling to room temperature, the reaction solution was poured into 30 mL of ice water, 50% sodium hydroxide solution was added dropwise to adjust pH=10-11, extracted with dichloromethane, and the organic phase was washed once with 20 mL of water and 20 mL of saturated brine. The mixture was dried over sodium sulfate, filtered and evaporated to dryness. ESI-MS: 282 [M + +1].
步骤9.化合物18的合成。Step 9. Synthesis of Compound 18.
将化合物17(850mg，0.4mmol)置于反应瓶中，依次加入0.5mL乙酸，5mL 37％甲醛和乙酸钠(87mg，1.1mmol)，升温至100℃反应过夜。反应完全后冷却至室温，向反应液中加入30mL二氯甲烷，滴加50％的氢氧化钠溶液调节pH＝11-12，搅拌0.5小时，静置分层，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得化合物18 340mg，收率36％。ESI-MS:312[M++1]。Compound 17 (850 mg, 0.4 mmol) was placed in a reaction flask, and then 0.5 mL of acetic acid, 5 mL of 37% formaldehyde and sodium acetate (87 mg, 1.1 mmol) were added, and the mixture was warmed to 100 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, 30 mL of dichloromethane was added to the reaction mixture, and 50% sodium hydroxide solution was added dropwise to adjust pH = 11-12, stirred for 0.5 hour, allowed to stand for separation, and the organic phase was washed with 10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. ESI-MS: 312 [M + +1].
步骤10.化合物19的合成。Step 10. Synthesis of Compound 19.
将化合物18(340mg，1.1mmol)溶于20mL二氯甲烷中，氮气保护下依次加入DMAP(13mg，0.11mmol)和戴斯-马丁试剂(550mg，1.3mmol)，室温反应3小时。加入20mL饱和碳酸氢钠溶液和20mL二氯甲烷，搅拌5分钟，过滤，滤液分层。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得化合物19 270mg，收率80％。1H NMR(300MHz,CDCl3)δ9.61(q,J＝1.9Hz,1H),7.72(d,J＝1.5Hz,1H),7.27–7.18(m,3H),7.17–7.06(m,1H),4.69(dd,J＝14.5,1.5Hz,1H),4.26(d,J＝14.5Hz,1H),3.44(q,J＝2.7,2.1Hz,1H),3.12(ddd,J＝13.5,7.5,3.0Hz,1H),3.04–2.89(m,2H),2.86–2.70(m,2H),2.69–2.59(m,2H),2.50(s,3H)；ESI-MS:310[M++1]。Compound 18 (340 mg, 1.1 mmol) was dissolved in dichloromethane (20 mL), and then Dallas (13 mg, 0.11 mmol) and Dess-Martin reagent (550 mg, 1.3 mmol) were added under a nitrogen atmosphere and allowed to react at room temperature for 3 hours. 20 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added, stirred for 5 minutes, filtered, and the filtrate was separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate 1 H NMR (300MHz, CDCl 3 ) δ 9.61 (q, J = 1.9 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.27 - 7.18 (m, 3H), 7.17 - 7.06 (m, 1H), 4.69 (dd, J = 14.5, 1.5 Hz, 1H), 4.26 (d, J = 14.5 Hz, 1H), 3.44 (q, J = 2.7, 2.1 Hz, 1H), 3.12 (ddd, J = 13.5) , 7.5, 3.0 Hz, 1H), 3.04 - 2.89 (m, 2H), 2.86 - 2.70 (m, 2H), 2.69 - 2.59 (m, 2H), 2.50 (s, 3H); ESI-MS: 310 [M + +1].
生物活性测试。Biological activity test.
(1)大鼠中的药代动力学评价。(1) Pharmacokinetic evaluation in rats.
8只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组4只，单次口服给予5mg/kg；(a)对照组：6,11-二氢-11-(1-甲基-4-哌啶叉)-5H-咪唑并[2,1-b][3]苯并氮杂
Figure PCTCN2017087137-appb-000012
-3-甲醛；(b)试验组：实施例化合物，比较其药代动力学差异。Eight male Sprague-Dawley rats, 7-8 weeks old, weighing 210 g, were divided into 2 groups, 4 in each group, 5 mg/kg in a single oral dose; (a) Control group: 6,11-dihydro-11 -(1-methyl-4-piperidin)-5H-imidazo[2,1-b][3]benzazepine
Figure PCTCN2017087137-appb-000012
-3-formaldehyde; (b) Test group: Example compounds, comparing their pharmacokinetic differences.
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。Rats were fed a standard diet and given water. Fasting began 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
大鼠吸入***后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL1％肝素盐溶液。使用前，试管于60℃烘干过夜。在随后一个时间点血样采集完成之后，大鼠***麻醉后处死。 Rats were briefly anesthetized after inhalation of ether, and 300 μL of blood samples were collected from the eyelids in test tubes. There was 30 μL of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。Immediately after the blood sample is collected, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 μL of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
实验结果表明，相对于对照化合物，本发明化合物在动物体内具有更好的药物动力学，因而具有更好的药效学和治疗效果。The experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.
(2)代谢稳定性评价。(2) Evaluation of metabolic stability.
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；小鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。Microsomal experiments: human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
储备液的配制：精密称取一定量的化合物粉末，并用DMSO分别溶解至5mM。Preparation of stock solution: Weigh a certain amount of compound powder and dissolve it to 5 mM with DMSO.
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。Preparation of phosphate buffer (100 mM, pH 7.4): Mix 150 mL of pre-formed 0.5 M potassium dihydrogen phosphate and 700 mL of 0.5 M potassium dihydrogen phosphate solution, and adjust the mixture with 0.5 M potassium dihydrogen phosphate solution. The pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
配制NADPH再生***溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。A solution of NADPH regeneration system (containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride) was prepared and placed on wet ice before use.
配制终止液：含有50ng/mL盐酸***和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL小鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。Formulation stop solution: acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 μL of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 μL of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of mouse liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体、大鼠或者小鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。Incubation of the sample: The stock solution of the corresponding compound was diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile as a working solution, and was used. 398 μL of human liver microsomes, rat or mouse liver microsome dilutions were added to 96-well incubation plates (N=2), and 2 μL of 0.25 mM working solution was added and mixed.
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生***置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生***溶液，作为0min样 品。再向孵育板每孔加入80μL的NADPH再生***溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。Determination of metabolic stability: 300 μL of pre-cooled stop solution was added to each well of a 96-well deep well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system were placed in a 37 ° C water bath, shaken at 100 rpm, and pre-incubated for 5 min. Remove 80 μL of incubation solution from each well of the incubation plate, add the stop plate, mix, and add 20 μL of NADPH regeneration system solution as 0min. Product. Then, 80 μL of the NADPH regeneration system solution was added to each well of the incubation plate to start the reaction and start timing. The corresponding compound had a reaction concentration of 1 μM and a protein concentration of 0.5 mg/mL. 100 μL of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min. The plate was centrifuged at 5000 x g for 10 min at 4 °C. 100 μL of the supernatant was taken into a 96-well plate to which 100 μL of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
数据分析：通过LC-MS/MS***检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t1/2和CLint，其中V/M即等于1/蛋白浓度。Data analysis: The peak area of the corresponding compound and the internal standard was detected by LC-MS/MS system, and the ratio of the peak area of the compound to the internal standard was calculated. The slope is measured by the natural logarithm of the percentage of the remaining amount of the compound versus time, and t 1/2 and CL int are calculated according to the following formula, where V/M is equal to 1/protein concentration.
Figure PCTCN2017087137-appb-000013
Figure PCTCN2017087137-appb-000013
对本发明化合物及其没有氘代的化合物同时测验比较，评价其在人、大鼠和小鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表1所示。表1中采用未经氘代的化合物Alcaftadine(6,11-二氢-11-(1-甲基-4-哌啶叉)-5H-咪唑并[2,1-b][3]苯并氮杂
Figure PCTCN2017087137-appb-000014
-3-甲醛)作为对照样品。如表2所示，通过与未经氘代的化合物Alcaftadine对照，本发明化合物可以显著改善代谢稳定性。The metabolic stability of liver microsomes in human, rat and mouse was evaluated by comparing the compounds of the present invention and their compounds without deuteration. The half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 1. The undeuterated compound Alcaftadine (6,11-dihydro-11-(1-methyl-4-piperidin)-5H-imidazo[2,1-b][3]benzophenone is used in Table 1. Aza
Figure PCTCN2017087137-appb-000014
-3-formaldehyde) was used as a control sample. As shown in Table 2, the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Alcaftadine.
表1实施例1～2与Alcaftadinen对照样的代谢稳定性对比表Table 1 Comparison of metabolic stability of Examples 1 and 2 with Alcaftadinen control
Figure PCTCN2017087137-appb-000015
Figure PCTCN2017087137-appb-000015
应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围，实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention, and the experimental methods in which the specific conditions are not indicated in the examples, usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated.
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。 The above is a further detailed description of the present invention in connection with the specific preferred embodiments, and the specific embodiments of the present invention are not limited to the description. It will be apparent to those skilled in the art that the present invention may be made without departing from the spirit and scope of the invention.

Claims (10)

  1. 一种取代的稠合咪唑环化合物，其特征在于：如式(I)所示的稠合咪唑环化合物，或其晶型、药学上可接受的盐、N-氧化物、水合物或溶剂化合物，A substituted fused imidazole ring compound characterized by a fused imidazole ring compound of the formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, an N-oxide, a hydrate or a solvent compound ,
    Figure PCTCN2017087137-appb-100001
    Figure PCTCN2017087137-appb-100001
    式中：In the formula:
    R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20相互独立地选自由“氢(H)、氘(D)”组成的组；R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently selected from the group consisting of "hydrogen (H), hydrazine (D)";
    及其生理学上可接受的盐、前药、水合物、溶剂化物、互变异构体和立体异构体，包括这些化合物以所有比例形成的混合物；And physiologically acceptable salts, prodrugs, hydrates, solvates, tautomers and stereoisomers thereof, including mixtures of these compounds in all ratios;
    附加条件是，所述稠合咪唑环化合物至少含有一个氘原子。Additionally, the fused imidazole ring compound contains at least one ruthenium atom.
  2. 根据权利要求1所述的稠合咪唑环化合物，其特征在于：R1、R2、R3和R4各自独立地为氘或氢。The fused imidazole ring compound according to claim 1, wherein each of R 1 , R 2 , R 3 and R 4 is independently hydrazine or hydrogen.
  3. 根据权利要求1所述的稠合咪唑环化合物，其特征在于：R5、R6、R7和R8各自独立地为氘或氢。The fused imidazole ring compound according to claim 1, wherein each of R 5 , R 6 , R 7 and R 8 is independently hydrazine or hydrogen.
  4. 根据权利要求1所述的稠合咪唑环化合物，其特征在于：R9为氘或氢。The fused imidazole ring compound according to claim 1, wherein R 9 is hydrazine or hydrogen.
  5. 根据权利要求1所述的稠合咪唑环化合物，其特征在于：R10、R11、R12、R13、R14、R15、R16和R17各自独立地为氘或氢。The fused imidazole ring compound according to claim 1, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently hydrazine or hydrogen.
  6. 根据权利要求1所述的化合物，其特征在于：R18、R19和R20各自独立地为氘或氢。The compound according to claim 1, wherein R 18 , R 19 and R 20 are each independently hydrazine or hydrogen.
  7. 根据权利要求1所述的稠合咪唑环化合物，其特征在于：所述化合物选自下组化合物或其药学上可接受的盐，但不局限于下列化合物： The fused imidazole ring compound according to claim 1, wherein the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof, but is not limited to the following compounds:
    Figure PCTCN2017087137-appb-100002
    Figure PCTCN2017087137-appb-100002
    Figure PCTCN2017087137-appb-100003
    Figure PCTCN2017087137-appb-100003
    Figure PCTCN2017087137-appb-100004
    Figure PCTCN2017087137-appb-100004
  8. 一种药物组合物，其特征在于：其含有药学上可接受的载体和如权利要求1～7任意一项所述的取代的稠合咪唑环化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物作为有效成分，并含有常规药用载体。A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted fused imidazole ring compound according to any one of claims 1 to 7, or a crystalline form thereof, a pharmaceutically acceptable salt thereof A pharmaceutical composition of a hydrate or solvate, stereoisomer, prodrug or isotopic variation is used as an active ingredient and contains a conventional pharmaceutical carrier.
  9. 一种如权利要求1～7任意一项所述的稠合咪唑环化合物的用途，其特征在于：用于制备预防或治疗抗过敏的药物中的用途。Use of a fused imidazole ring compound according to any one of claims 1 to 7, for use in the preparation of a medicament for preventing or treating anti-allergy.
  10. 根据权利要求9的用途，其中所述的过敏症状可选自眼睛发痒、眼睛发红、眼睑肿胀、结膜水肿、流泪、鼻充血、流鼻涕或其任何组合。 The use according to claim 9, wherein the allergy symptom is selected from the group consisting of itchy eyes, redness of the eyes, swelling of the eyelids, conjunctival edema, tearing, nasal congestion, runny nose or any combination thereof.
PCT/CN2017/087137 2016-06-07 2017-06-05 Substituted fused imidazole cyclic compound and pharmaceutical composition thereof WO2017211246A1 (en)

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