WO2023184482A1 - 氨基三嗪酮化合物及其制备方法和药物用途 - Google Patents

氨基三嗪酮化合物及其制备方法和药物用途 Download PDF

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WO2023184482A1
WO2023184482A1 PCT/CN2022/084812 CN2022084812W WO2023184482A1 WO 2023184482 A1 WO2023184482 A1 WO 2023184482A1 CN 2022084812 W CN2022084812 W CN 2022084812W WO 2023184482 A1 WO2023184482 A1 WO 2023184482A1
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alkyl
heteroaryl
amino
haloalkoxy
haloalkyl
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PCT/CN2022/084812
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English (en)
French (fr)
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王永钢
廖辉
陈海杰
林寨伟
胡双华
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湖南南新制药股份有限公司
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Priority to PCT/CN2022/084812 priority Critical patent/WO2023184482A1/zh
Publication of WO2023184482A1 publication Critical patent/WO2023184482A1/zh

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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/42—One nitrogen atom
    • C07D251/46—One nitrogen atom with oxygen or sulfur atoms attached to the two other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention provides a heterocyclic compound having an aminotriazinone derivative and having P2X3 receptor antagonist activity, especially having selective and high inhibitory activity against P2X3.
  • the present invention also relates to compositions comprising such compounds, methods for preparing such compounds, and their use as P2X3 receptor antagonists for the treatment and prevention of P2X3-mediated diseases.
  • the P2X family is a purine ligand ATP-gated ion channel composed of homotrimers of P2X subunits P2X1 to P2X7.
  • P2X3 homotrimeric and P2X2/3 heterotrimeric receptors are the best-studied P2X receptors on vagal sensory neurons, which are present at the peripheral terminals of the airways and central terminals of the central nervous system. expression, such as the lower urinary tract and respiratory tract.
  • Chronic cough affects 10% of the global population. While many patients with chronic cough find relief with proper diagnosis and treatment of the associated condition (such as asthma, rhinitis, or reflux disease), many others experience symptoms even if the associated condition is controlled with medication (such as refractory chronic cough (RCC)) or People with undiagnosed (e.g., unexplained chronic cough (UCC)) RCC and UCC often experience physical, social, and psychological stress that may persist for years. Currently, treatment of RCC and UCC represents an important unmet medical need.
  • RCC refractory chronic cough
  • UCC unexplained chronic cough
  • adenosine triphosphate is a key regulatory pathway for injury.
  • the release of ATP from injured tissue or sympathetic nerve efferents has a sensitizing effect on surrounding sensory neurons.
  • the release of ATP from presynaptic vesicles in the central terminal can increase the release of glutamate, thus enhancing the downstream central sensitization mechanism.
  • the purinergic receptors mainly responsible for ATP signal transmission on sensory nerves are P2X3 and P2X2/3. Selective knockout experiments or small molecule inhibition experiments have shown that P2X3-containing receptors are key targets in regulating nociceptive signaling.
  • P2X3 receptors are critical for sensory conduction in bladder function, and clinical studies have shown the promise of P2X3 receptor antagonists in the treatment of bladder pain and osteoarthritis-related pain. Further clinical characterization of P2X3 receptor-containing antagonists may lead to improvements in chronic pain treatment (P2X3receptors contribute to transition from acute to chronic muscle pain, Purinergic Signal. 2020, 16(3):403–414.).
  • Treatment guidelines such as the ACCP Guidelines (American College of Chest Physicians) identify four treatment categories supported by randomized controlled trials: nonpharmacological treatments (e.g., speech-language pathology treatments), off-label use of inhaled corticosteroids, neuromodulation agents and other therapeutic agents (such as proton pump inhibitors in the case of gastroesophageal reflux disease (GERD)).
  • nonpharmacological treatments e.g., speech-language pathology treatments
  • off-label use of inhaled corticosteroids e.g., neuromodulation agents and other therapeutic agents (such as proton pump inhibitors in the case of gastroesophageal reflux disease (GERD)
  • GSD gastroesophageal reflux disease
  • Inhaled corticosteroids are effective in treating eosinophilic airway inflammation.
  • Centrally acting drugs such as neuromodulators (such as gabapentin, pregabalin, amitriptyline and baclofen) and centrally acting drugs such as opioids (such as morphine) are currently used morphine, codeine or pholcodine) to treat RCC and ICC caused by neuronal hypersensitivity.
  • neuromodulators such as gabapentin, pregabalin, amitriptyline and baclofen
  • opioids such as morphine
  • these agents improve patients' cough-specific quality of life, adverse effects can be severe and limit the maximum tolerated dose of these agents (Gibson et al., BMJ 2015, 351:h5590). Serious side effects such as drowsiness, nausea, constipation, sedation, and physical dependence have been reported.
  • the object of the present invention is to provide drugs for long-term oral treatment of diseases related to nerve fiber sensitization, such as chronic cough (CC), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.
  • diseases related to nerve fiber sensitization such as chronic cough (CC), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.
  • the compounds involved in the present invention are used as P2X3 receptor antagonists for the treatment of diseases related to nerve fiber sensitization. Therefore, the present invention provides compounds represented by formula (I), their optical isomers or their mixtures, their pharmaceutically acceptable salts, solvates, their N-oxides or their prodrugs, which have the following structure :
  • R 1 is independently selected from a hydrogen atom, a fluorine atom, a methyl group, and a fluorine-substituted methyl group;
  • R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino or cyano;
  • X is independently selected from 6-membered aryl or heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, halogen or cyano substituted aryl or heteroaryl.
  • R 1 is a hydrogen atom
  • the preferred structure has the following structure as shown in formula (II):
  • R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino or cyano;
  • X is independently selected from 6-membered aryl or heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, halogen or cyano substituted aryl or heteroaryl.
  • R 1 is a fluorine atom
  • the preferred structure has the following structure shown in formula (III):
  • R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino or cyano;
  • X is independently selected from 6-membered aryl or heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, halogen or cyano substituted aryl or heteroaryl.
  • R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino or cyano;
  • X is independently selected from 6-membered aryl or heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, halogen or cyano substituted aryl or heteroaryl.
  • R 1 is a monofluoro-substituted methyl group
  • the preferred structure has the following structure shown in formula (V):
  • R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino or cyano;
  • X is independently selected from 6-membered aryl or heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, halogen or cyano substituted aryl or heteroaryl.
  • R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino or cyano;
  • X is independently selected from 6-membered aryl or heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, halogen or cyano substituted aryl or heteroaryl.
  • the compound that inhibits P2X3 receptors has a wide range of properties as a pharmaceutically acceptable salt, solvates or prodrugs.
  • the invention also provides: a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention
  • the present invention relates to methods of treating symptoms of chronic cough and/or urge cough associated with respiratory diseases or disorders mediated by P2X3 receptor antagonists by administering a compound of formula (I).
  • the invention also relates to compounds of formula (I) for the treatment of symptoms of chronic cough and/or urge cough associated with respiratory diseases or disorders mediated by P2X3 or P2X2/3 receptor antagonists.
  • the present invention also relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of symptoms of chronic cough and/or urge cough associated with respiratory diseases or disorders mediated by P2X3 or P2X2/3 receptor antagonists.
  • the present invention relates to a method of using the compounds of the present invention and compositions thereof to treat pain-related mammalian (including human) conditions and diseases, including but not limited to: pain-related diseases or conditions selected from the following: Hyperalgesia, allodynia, functional bowel disease (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis), burning oral syndrome, burns, hemispheres Headache or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injury (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, Small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgia, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and bone disorders such as joint degeneration.
  • pain-related diseases or conditions selected from the following: Hyperalgesia, allody
  • the present invention relates to a method of using the compounds of the invention and compositions thereof for the treatment of mammalian (including human) conditions and diseases associated with pain or pain syndromes, in particular: pain syndromes (including acute, Chronic, inflammatory and neuropathic pain), preferably inflammatory pain, low back pain, surgical pain, visceral pain, toothache, periodontitis, premenstrual pain, pain associated with endometriosis, pain associated with fibrotic diseases , central pain, pain caused by burning mouth syndrome, pain caused by burns, pain caused by migraine, cluster headache, pain caused by nerve damage, pain caused by neuritis, neuralgia, pain caused by poisoning, ischemia Pain from sexual injury, pain from interstitial cystitis, cancer pain, pain from viruses, parasitic or bacterial infections, pain from traumatic nerve injury, pain from post-traumatic injuries (including fractures and sports injuries) , pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia,
  • the compounds or salts of the invention may be used to treat, for example, pain.
  • pain may be, for example, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, pain caused by rheumatoid arthritis, migraines, and visceral pain.
  • the present invention relates to a method of treating conditions and diseases in mammals, including humans, using compounds of the invention and compositions thereof, including but not limited to: urogenital, gastrointestinal, respiratory or pain-related diseases. , conditions or disorders; gynecological disorders, including dysmenorrhea (primary and secondary dysmenorrhea), dyspareunia, and endometriosis and adenomyosis; endometriosis-related pain; endometriosis-related Symptoms of, inter alia, dysmenorrhea, dyspareunia, difficulty with urination or defecation; endometriosis-related hyperplasia; pelvic allergy; urinary tract disease states related to bladder outlet obstruction; urinary incontinence symptoms such as a reduced bladder Capacity, increased urinary frequency, urge incontinence, stress incontinence, or bladder hypersensitivity; benign prostatic hyperplasia; prostatic hypertrophy; prostatitis; detrusor reflex
  • the present invention also provides a compound that inhibits P2X3 receptors, its optical isomers or their mixtures, including the compound of the present invention, its pharmaceutically acceptable salts, solvates or prodrugs.
  • all isomers are included unless otherwise specified.
  • double bonds, collective isomers in the ring (E type, Z type, cis (cis), trans (trans)), alkyl groups include straight chain alkyl groups and branched chain alkyl groups.
  • Optical isomers R, S type
  • produced by symmetrical carbon atoms, etc. and their mixtures in any proportion, racemic mixtures, and all isomers produced from tautomers are included in the present invention.
  • Salts are preferably water-soluble, pharmaceutically acceptable, non-toxic base addition salts.
  • Examples of salts are carboxylic acids or sulfonic acids and inorganic bases.
  • Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N+ ( C1-4 alkyl) 4 salt.
  • Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like.
  • non-toxic acid addition salts are amino acids with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods known in the art (such as ion exchange methods).
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucoheptonic acid Salt, glycerophosphate, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurate Sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bis Hydroxylate, pectate
  • additional pharmaceutically acceptable salts include nontoxic salts formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate. Ammonium, quaternary ammonium and amine cations.
  • the term "compounds that inhibit P2X3 receptors” provided herein includes compounds having the formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI). Each compound includes different stereoisomers with the same molecular formula.
  • the stereoisomers also include enantiomers and diastereomers. Enantiomers are optical isomers, and diastereomers are Isomers are stereoisomers that do not form chiral enantiomers, and different isomers with the same molecular formula as the compounds of the present invention are also within the protection scope of the present invention.
  • solvate herein may also be referred to as "solvent compound”.
  • solvent refers to a compound containing a solvent, in which the solvent molecules may include coordination bonds, covalent bonds, van der Waals forces, etc. , ionic bonds, hydrogen bonds and other ways to combine with compound molecules.
  • the term “pharmaceutically acceptable salts” as used herein refers to compounds of the present invention and/or salts formed that are chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and are physiologically compatible compatible with the receptor.
  • “Pharmaceutically acceptable salts” may be acidic and/or basic salts with inorganic and/or organic acids and bases, also include zwitterionic salts (internal salts), and also include quaternary ammonium salts, such as alkylammonium salts Salt. These salts can be obtained directly from the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or base. These salts may form a precipitate in the solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by reacting in an aqueous medium and then cooling and drying.
  • alkyl as used herein means having 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Each instance of an alkyl group is independently optionally substituted, ie, unsubstituted (“unsubstituted alkyl”) or substituted with one or two substituents (“substituted alkyl").
  • exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and phenylthio.
  • exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • heterocycloalkyl refers to a non-aromatic ring in which one or more atoms constituting the ring are heteroatoms, and the heteroatoms include but are not limited to nitrogen atoms, oxygen atoms, sulfur atoms, etc. , the rest are groups of stable 3-10 membered saturated heterocyclic systems composed of carbon.
  • a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or higher ring system, which may include and Cyclic (fused), bridged (bridged) or spiro ring systems (e.g., bicyclic ring systems ("bicyclic heterocycloalkyl").
  • Heterocycloalkyl bicyclic ring systems can be in one or include one or more heteroatoms in both rings; and are saturated.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiiranyl , or a stereoisomer thereof;
  • exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietanyl, or isomers thereof and Stereoisomers;
  • exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidine base, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof.
  • Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfonylcyclopentyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinealkyl , or isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxeptanyl, thieptanyl, And diazacycloheptyl, or its isomers and stereoisomers.
  • heterocycloalkyl is a 4-6-membered heterocycloalkyl, in which the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • heteroaryl refers to an aromatic group containing heteroatoms, which can be a single ring or a fused ring, preferably containing 1 to 4 5-12 membered heteroaryl groups independently selected from N, O and S, including but Not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, Triazolyl, tetrahydropyrrolyl.
  • a 5-6 membered monocyclic heteroaryl group typically contains one or more heteroatoms independently selected from N, O, and S.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood as referring to the linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl,” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl group when expressly represented as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halo-C1-C6 alkyl" C1-C6 alkyl in should be understood as C1-C6 alkylene.
  • halo refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • mamal refers to humans, domestic animals, or cats and dogs.
  • the present invention uses traditional methods such as mass spectrometry and nuclear magnetism to identify compounds.
  • Each step and condition can refer to the conventional operating steps and conditions in the art.
  • this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the description method "...independently selected from” used in the present invention should be understood in a broad sense and means that each described individual is selected independently of each other. Accordingly, each substituent may or may not be the same as other substituents.
  • the description "...independently selected from” can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the same symbols The specific options expressed between them do not affect each other.
  • the reagents and raw materials used in the present invention are all commercially available.
  • a compound of the invention, or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a stereoisomer or prodrug of the compound may be in the form of a pharmaceutical composition , which contains a pharmaceutically acceptable carrier, carrier or diluent.
  • the present invention also provides pharmaceutical compositions of the compounds of the present invention and preparation methods thereof.
  • the present invention features P2X3 receptor antagonists for use in methods of treating pain-related mammalian (including human) conditions and diseases, and may also be used to treat or alleviate pain-related conditions and diseases in mammals, including humans. Respiratory disorders and dysfunctions such as chronic cough and desire cough.
  • the present invention has the advantage of addressing the underlying causes driving cough hypersensitivity in these diseases rather than merely inhibiting central regulation of symptom perception.
  • the present invention provides methods to reduce the activity of externally stimulated afferent nerves, overactivation of which triggers persistent and inappropriate urge-inducing coughing in sensitized subjects (eg, humans).
  • the present invention also has the advantage of administering highly selective P2X3 receptor antagonists. Further features and advantages are set forth in the following detailed description, and will be apparent to those skilled in the art.
  • DIAD diisopropyl azodicarboxylate
  • PCC Pyridinium chlorochromate
  • PE petroleum ether
  • Step 1 At 0°C, slowly add 1N borane solution in tetrahydrofuran ((60 mL, 60 mmol)) dropwise to a solution of intermediate (13a) (5.00 g, 29 mmol) in THF (30 mL) protected by nitrogen atmosphere. Add dropwise After the reaction, the reaction system returned to 25°C and reacted at 25°C for 2 hours. After the reaction, MeOH (10 mL) was slowly added dropwise in an ice bath, stirred at 25°C for 2 hours, and concentrated under reduced pressure. The crude product was subjected to column chromatography.
  • Step 5 Add intermediate (13f) (100 mg, 0.36 mmol) and DIEA (95 mg, 0.73 mmol) to the MeCN (5 mL) solution of intermediate (13e) (120 mg, 0.44 mmol) under nitrogen atmosphere protection.
  • the reaction system reacted at 90°C for 6 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined, washed with brine, filtered and concentrated under reduced pressure.
  • LCMS(ESI)calcd for C 17 H 25 N 3 O 4 S[M+H] + ms/z 368, found 368.
  • Step 7 Dissolve intermediate (13i) (80 mg, 0.16 mmol) in THF (3 mL) and MeOH (1 mL), and add 2N aqueous sodium hydroxide solution (1 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was extracted with EtOAc (5 mL), and the organic phase was washed with 2N sodium hydroxide aqueous solution. Combine the aqueous phases and adjust the pH to 3-4 with 2N hydrochloric acid. Extract with DCM (5mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
  • Step 1 Add TBSCl (5.06g, 33.6mmol) and imidazole (3.05g, 44.8mmol) to a solution of intermediate (25a) (3.50g, 22.4mmol) in DMF (40mL) protected by nitrogen atmosphere at 0°C. .
  • the reaction system was returned to 25°C and reacted at 25°C for 2 hours.
  • the reaction was quenched by adding water at 0°C, and extracted with EtOAc (50 mL x 3). The organic phases were combined, washed with brine, filtered and concentrated under reduced pressure.
  • Step 3 Add intermediate (25c) (200 mg, 1.78 mmol), Et 3 N (1.66 g, 16.4 mmol) and 4-DMAP (0.10 g, 0.8 mmol) in DCM (5 mL) under nitrogen atmosphere at 0°C. ) solution was added TsCl (1.88g, 9.8mmol). The reaction system was returned to 25°C and reacted at 25°C for 2 hours. After the reaction was completed, water was added to quench the reaction and extracted with DCM (10 mL x 3). The organic phases were combined, washed with brine, filtered and concentrated under reduced pressure.
  • Step 4 Add intermediate (25e) (365 mg, 1.34 mmol) and DIEA (432 mg, 3.34 mmol) to the MeCN (5 mL) solution of intermediate (25d) (636 mg, 1.60 mmol) under nitrogen atmosphere protection.
  • the reaction system reacted at 90°C for 6 hours.
  • water was added to quench the reaction, and the mixture was extracted with EtOAc (10 mL x 3).
  • the organic phases were combined, washed with brine, filtered and concentrated under reduced pressure.
  • LCMS(ESI)calcd for C 23 H 39 N 3 O 5 SSi[M+H] + ms/z 498, found 498.
  • Step 9 Dissolve intermediate (25k) (30 mg, 0.06 mmol) in THF (1 mL), and add 2N sodium hydroxide aqueous solution (1 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was extracted with EtOAc (5 mL), and the organic phase was washed with 2N sodium hydroxide aqueous solution. Combine the aqueous phases and adjust the pH to 3-4 with 2N hydrochloric acid. Extract with DCM (5mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
  • Step 3 At 0°C, dropwise add DIAD (158mg, 0.78mmol) THF (5mL) solution into PPh 3 (204mg, 0.78mmol) THF (10mL) solution protected by nitrogen atmosphere. After the dropwise addition, stir at 0°C for 5 seconds. minutes, intermediates (19d) (150 mg, 0.52 mmol) and (19e) (93 mg, 0.36 mmol) were dissolved in THF (4 mL) and added to the reaction solution. The reaction system returned to 25°C and reacted at 25°C for 16 hours.
  • Step 5 Dissolve intermediate (19h) (70 mg, 0.13 mmol) in THF (1.2 mL) and MeOH (0.4 mL), and add 2N aqueous sodium hydroxide solution (0.4 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was extracted with EtOAc (5 mL), and the organic phase was washed with 2N sodium hydroxide aqueous solution. Combine the aqueous phases and adjust the pH to 3-4 with 2N hydrochloric acid. Extract with DCM (5mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
  • 2N aqueous sodium hydroxide solution 0.4 mL
  • Step 3 At 0°C, dropwise add DIAD (396mg, 1.95mmol) THF (5mL) solution into PPh 3 (512mg, 1.95mmol) THF (10mL) solution protected by nitrogen atmosphere. After the dropwise addition, stir at 0°C for 5 seconds. Minutes, intermediates (1d) (330 mg, 1.3 mmol) and (1e) (153 mg, 1.3 mmol) were dissolved in THF (8 mL) and added to the reaction solution. The reaction system returned to 25°C and reacted at 25°C for 16 hours.
  • Step 5 Dissolve intermediate (1h) (160 mg, 0.33 mmol) in THF (3.6 mL) and MeOH (1.2 mL), and add 2N aqueous sodium hydroxide solution (1 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was extracted with EtOAc (5 mL), and the organic phase was washed with 2N sodium hydroxide aqueous solution. Combine the aqueous phases and adjust the pH to 3-4 with 2N hydrochloric acid. Extract with DCM (5mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
  • Step 3 Dissolve PPh 3 (406 mg, 1.55 mmol) in THF (5 mL), replace nitrogen, and slowly add DIAD (313 mg, 1.55 mol) at 0°C. The mixture was stirred for 5 minutes, then compound (7d) (280 mg, 1.03 mmol) and compound (7e) (183 mg, 1.55 mmol) were added. The reaction mixture was stirred at 25°C for 6 hours. After the reaction was completed, the mixture was quenched with water and extracted with EtOAc (20 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over Na2SO4 , filtered and concentrated in vacuo .
  • Step 5 Dissolve compound (7h) (284 mg, 0.57 mmol) in THF (3 mL), then add NaOH (1 mL, aq., 2 M) and MeOH (1 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours. Extract with EtOAc (10 mL) and wash with water. The aqueous phases were combined and the pH was adjusted to 5 with 2N HCl (aq., 1M). Extract with EtOAc (20mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over Na2SO4 , filtered and concentrated in vacuo. The product was purified by prep-HPLC to obtain a white solid (Compound 7) (130 mg, 100% purity, 47% yield).
  • Example 6 Determination of antagonistic activity of human P2X3 and P2X2/3 receptors
  • the assay for the human purinergic P2X3 receptor was adapted to an in-house screening instrument using FLEXSTATION as the reader and photoprotein as the luminescence readout. This assay involves recombinant HEK293 cells co-expressing the human P2X3 receptor and Ca2 + -sensitive photoprotein.
  • DMEM F-12 (1:1) mixture (LONZA catalog number BE04-687F/U1) supplemented with 9 mL of 100 mM sodium pyruvate (LONZA catalog number BE13-115E), 29 mL of 7.5% carbonic acid Sodium bihydrogen (LONZA catalog number: BE17-613E), 5.5 mL of 1M Hepes (LONZA catalog number: BE17-737E), 5 mL of 100 ⁇ Penicillin/Streptomycin (LONZA catalog number: DE17-602E), and 50 mL of fetal calf serum (Sigma catalog number F7524), 1 mg/mL G418 (Sigma Cat. No.
  • Standard proliferation conditions include plating twice weekly in P75 flasks, recovering approximately 20x106 cells, equivalent to approximately 80% confluence. Cells were seeded into black-walled clear-bottom 96-well plates at a density of 40,000 cells/well in Tyrode's buffer (standard Tyrode's buffer: internal solution, 130mM NaCl, 5mM KCl, 2mM CaCl2, 5mM NaHCO3, 1mM MgCl2, 20mM HEPES, pH 7.4). After 24 hours, culture medium was treated with 200 ⁇ L/well of coelenterazine in Tyrode's buffer: from BIOSYNTH (Cat.
  • Intracellular calcium test to measure antagonist activity of human P2X2/3 receptors
  • Detect antagonist activity discard the culture medium, add 20uL/well Fluo-8 staining working solution, place it in a 37-degree incubator and incubate in the dark for 1 hour; prepare antagonist working solution (5X); dilute the antagonist with DMSO to the highest concentration ( 200x working solution, antagonist storage solution concentration is 20mM), carry out 3-fold gradient dilution of the antagonist to 12 concentration points, and then dilute all concentration points 40-fold with calcium flow buffer to obtain 5x antagonist working solution: 195uL Buffer + 5uL 200x antagonist working solution.
  • a Selectivity multiple > 500
  • b 100 ⁇ Selectivity multiple ⁇ 500
  • c Selectivity multiple 50 ⁇ Selectivity multiple ⁇ 100
  • d Selectivity multiple 10 ⁇ Selectivity multiple ⁇ 50
  • e Selectivity multiple ⁇ 10.
  • the compound of the present invention has a good antagonistic effect on P2X3 receptors, the compound of the present invention has poor inhibitory activity on P2X2/3 heterodimeric receptors, and has good selectivity among P2X3 and P2X2/3. .

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Abstract

本发明涉及一种具有通式(I)的杂环化合物氨基三嗪酮衍生物，其具有P2X3受体拮抗活性，尤其对P2X3具有选择性的、较高的拮抗活性。本发明还涉及包含这样的化合物其制备的方法、包含其的药物组合物，药学上可接受的盐以及其作为P2X3受体拮抗剂用于治疗和预防P2X3介导的疾病的方法。

Description

氨基三嗪酮化合物及其制备方法和药物用途 技术领域
本发明提供了一种杂环化合物具有氨基三嗪酮基衍生物且具有P2X3受体拮抗活性，尤其对P2X3具有选择性的、较高的抑制活性。本发明还涉及包含这样的化合物的组合物、用于制备这样的化合物的方法，以及其作为P2X3受体拮抗剂用于治疗和预防P2X3介导的疾病的方法。
背景技术
P2X家族是一个嘌呤配体ATP门控离子通道由P2X亚基P2X1到P2X7的同源三聚体组成。P2X3同源三聚体的和P2X2/3异三聚体受体是迷走神经感觉神经元上研究最充分的P2X受体，它们在气道的外周末端和中枢神经系统的中央末端由迷走神经感觉神经元表达，例如下尿路和呼吸道。临床前研究表明，刺激P2X3同源三聚体受体(由颈静脉迷走神经传入神经元表达)会导致一种短暂的、快速失活动电流，而刺激P2X2/3异三聚体受体(由节点型迷走神经传入神经元表达)会导致较长时间的缓慢失活电流，这表明刺激P2X2/3受体可能需要诱发动作电位。用于气道疾病和炎症ATP可通过跨膜蛋白pannexin-1通道从气道上皮细胞释放对多种刺激和机制的反应，包括损伤，炎症和环境刺激(例如，过敏原和污染物)。通过与气道炎症产生的细胞外ATP结合，激活迷走纤维感觉神经元，从而启动咳嗽反射。P2X3拮抗剂在不影响中枢神经系统的情况，通过抑制慢性咳嗽发生的病理达到疗效。
默克的gefapixant(CN105682659)是一种P2X3受体拮抗剂，在一项评估RCC和UCC患者的临床试验中剂量从7.5mg 2次/天到600mg 2次/天的研究中，已证明其在减少客观咳嗽频率和改善患者报告的预后方面的疗效(Smith JA,Kitt MM,Morice AH,et al.Gefapixant,a P2X3 receptor antagonist,for the treatment of refractory or unexplained chronic cough:a randomised,double-blind,controlled,parallel-group,phase 2b trial.Lancet Respir Med 2020；8:775–785.)。虽然未观察到与严重不良事件相关，但是很多患者具有味觉相关的不良事件以剂量依赖的方式发生。
慢性咳嗽影响到全球人口的10％。虽然许多慢性咳嗽患者通过对相关病症的正确诊断和治疗(如哮喘、鼻炎或反流性疾病)得到缓解，但其他许多患者即使在相关病症得到药物控制(如顽固性慢性咳嗽(RCC))或无法确诊(如:不明原因慢性咳嗽(UCC))RCC和UCC患者经常遭受身体、社会和心理压力，可能持续数年。目前，RCC和UCC的治疗是一个尚未满足的重 要医疗需求。
另外，三磷酸腺苷(ATP)是一个关键的调节通路的伤害。从受伤组织或交感神经传出释放ATP对周围的感觉神经元有敏感作用，从中央末端的突触前囊泡释放ATP可以增加谷氨酸的释放，从而增强下游的中枢敏感机制，一种被认为是许多慢性疼痛症状的基础。感觉神经上主要负责ATP信号传递的嘌呤能受体是P2X3和P2X2/3。选择性敲除实验或小分子抑制实验表明，含P2X3受体是调节伤害性感受信号的关键靶点。临床前研究发现，p2x3受体对膀胱功能的感觉传导至关重要，临床研究显示了P2X3受体拮抗剂在治疗膀胱疼痛和骨关节炎相关疼痛的前景。对含P2X3受体拮抗剂的进一步临床表征可能导致慢性疼痛治疗的改进(P2X3receptors contribute to transition from acute to chronic muscle pain，Purinergic Signal.2020，16(3):403–414.)。
目前，尚无批准的治疗慢性咳嗽的方法。治疗指南如ACCP指南(美国胸内科医师学会(American College of Chest Physicians))确定了随机对照试验支持的四个治疗类别：非药物治疗(例如言语病理治疗)、超说明书使用吸入皮质类固醇、神经调节剂及其他治疗剂(例如在胃食管返流疾病(GERD)情况下的质子泵抑制剂)。目前，根据ACCP指南，建议在开始治疗之前先使用言语疗法。吸入皮质类固醇可有效治疗嗜酸细胞性气道炎症。目前使用中枢作用药物如神经调节剂(例如加巴喷丁(gabapentin)、普瑞巴林(pregabalin)、阿米替林(amitriptyline)及巴氯芬(baclofen))以及中枢作用药物如阿片类药物(例如吗啡(morphine)、可待因(codeine)或福尔可定(pholcodine))治疗由神经元过敏性引起的RCC及ICC。尽管这些药剂改善患者的咳嗽特定生活质量，但不良反应可能很严重而限制了这些药剂物的最大耐受剂量(Gibson等人，BMJ2015，351：h5590)。报道了严重副作用，例如嗜睡、恶心、便秘、镇静和生理依赖。
目前，对于具有长效且口服治疗与神经纤维敏感化相关的疾病(如慢性咳嗽(CC)、特发性肺纤维化(IPF)、慢性阻塞性肺病(COPD)和哮喘)并且无如上文所述的现有技术缺点的药物存在持续的需求。本发明的目的在于提供用于长期口服治疗与神经纤维敏感化相关的疾病(如慢性咳嗽(CC)、特发性肺纤维化(IPF)、慢性阻塞性肺病(COPD)和哮喘)的药物。
发明内容
本发明涉及的化合物作为P2X3受体拮抗剂用于治疗与神经纤维敏感化相关的疾病的用途。因此，本发明提供式(I)所示化合物，其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，其具有以下结构：
Figure PCTCN2022084812-appb-000001
R 1独立地选自氢原子，氟原子，甲基，氟取代代甲基；
R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
当R 1为氢原子时，优选结构具有以下如式(II)所示结构：
Figure PCTCN2022084812-appb-000002
其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
当R 1为氟原子时，优选结构具有以下如式(III)所示结构：
Figure PCTCN2022084812-appb-000003
其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
当R 1为甲基时，优选结构具有以下如式(IV)所示结构：
Figure PCTCN2022084812-appb-000004
其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
当R 1为单氟取代甲基时，优选结构具有以下如式(V)所示结构：
Figure PCTCN2022084812-appb-000005
其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
当R 1为二氟取代甲基时，优选结构具有以下如式(VI)所示结构：
Figure PCTCN2022084812-appb-000006
其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
优选地，所述的抑制P2X3受体的化合物,其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物或前药。
在其它方面中，本发明还提供：药物组合物，其包含药学上可接受的载体和本发明的化合物；
本发明涉及通过施用式(I)的化合物治疗与由P2X3受体拮抗剂介导的呼吸疾病或紊乱相关联的慢性咳嗽和/或欲望性咳嗽的症状的方法。
本发明还涉及治疗与由P2X3或P2X2/3受体拮抗剂介导的呼吸疾病或紊乱相关联的慢性咳嗽和/或欲望性咳嗽的症状的式(I)的化合物。本发明还涉及式(I)的化合物在制造治疗与由P2X3或P2X2/3受体拮抗剂介导的呼吸疾病或紊乱相关联的慢性咳嗽和/或欲望性咳嗽的症状的药品中的用途。
本发明涉及一种使用本发明的化合物和其组合物治疗疼痛相关的哺乳动物(包括人类)病症和疾病的方法，所述病症和疾病包括但不限于：选自以下的疼痛相关疾病或病症：痛觉过敏、异常性疼痛、功能性肠病(如肠易激综合征)、痛风、关节炎(如骨关节炎、类风湿性关节炎和强直性脊柱炎)、口腔烧灼综合征、烧伤、偏头痛或丛集性头痛、神经损伤、创伤性神经损伤、创伤后损伤(包括骨折和运动损伤)、神经炎、神经痛、中毒、缺血性损伤、间质性膀胱炎、癌症、三叉神经痛、小纤维神经病变、糖尿病性神经病变、慢性关节炎和相关神经痛、HIV和HIV治疗诱发的神经病变、瘙痒；伤口愈合受损和骨骼疾病如关节退化。
本发明涉及一种使用本发明的化合物和其组合物治疗与疼痛或疼痛综合征相关的哺乳动物(包括人类)病症和疾病的方法，所述病症和疾病特别是：疼痛综合征(包括急性、慢性、炎性和神经性疼痛)，优选炎症性疼痛、下背痛、手术疼痛、内脏痛、牙痛、牙周炎、经前痛、子宫内膜异位相关的疼痛、纤维变性疾病相关的疼痛、中枢性疼痛、口腔烧灼综合征引起的疼痛、烧伤引起的疼痛、偏头痛引起的疼痛、丛集性头痛、神经损伤引起的疼痛、神经炎引起的疼痛、神经痛、中毒引起的疼痛、缺血性损伤引起的疼痛、间质性膀胱炎引起的疼痛、癌症疼痛、病毒引起的疼痛、寄生虫或细菌感染、外伤性神经损伤引起的疼痛、创伤后损伤(包括骨折和运动损伤)引起的疼痛、三叉神经痛引起的疼痛、小纤维神经病变相关的疼痛、糖尿病性神经病变相关的疼痛、带状疱疹后神经痛、慢性下背痛、颈痛、幻肢疼痛、盆腔疼痛综合征、慢性盆腔疼痛、神经性疼痛、复杂的局部疼痛综合征、胃肠道膨胀相关的疼痛、慢性关节炎疼痛及相关神经痛、癌症相关的疼痛、吗啡抗性疼痛、化学疗法相关的疼痛、HIV和HIV治疗诱发的神经病变；与选自以下的疾病或病症相关的疼痛：痛觉过敏、异常性疼痛、功能性肠病(如肠易激综合征)和关节炎(如骨关节炎、类风湿性关节炎和强直性脊柱炎)。本发明的化合物或盐可以用于治疗例如疼痛。这种疼痛可以是例如慢性疼痛、神经性疼痛、急性疼痛、背痛、癌症疼痛、由类风湿性关节炎所引起的疼痛、偏头痛、以及内脏疼痛。
本发明涉及一种使用本发明的化合物和其组合物治疗哺乳动物包括人类病症和疾病的方法，所述病症和疾病包括但不限于：泌尿生殖器的、胃肠的、呼吸的或疼痛相关的疾病、病症或障碍；妇科疾病，包括痛经(原发性和继发性痛经)、性交痛和子宫内膜异位和子宫腺肌症；子宫内膜异位相关的疼痛；子宫内膜异位相关的症状，其中所述症状特别是痛经、性交痛、排尿困难或大便困难；子宫内膜异位相关的增生；盆腔过敏；膀胱出口梗阻相关的尿路疾病状态；尿失禁症状例如减小的膀胱容量、增加的排尿频率、急迫性尿失禁、压力性尿失禁或膀胱高敏性；良性前列腺肥大；前列腺肥大；前列腺炎；逼尿肌反射抗性；膀胱活动过度症以及膀胱活动过度症相关的症状，其中所述症状特别是增加的尿频率、夜尿症、尿急或急迫性尿失禁；盆腔过敏；尿道炎；前列腺炎；前列腺痛；膀胱炎，特别是间质性膀胱炎；原发性膀胱过敏；癌症相关的疼痛；癫痫；局部和全身性癫痫发作；呼吸障碍，包括哮喘、慢性阻塞性肺病、肺纤维化、急性咳嗽、慢性咳嗽包括慢性原发性和慢性难治性咳嗽、支气管痉挛；瘙痒。
本发明还提供了一种抑制P2X3受体的化合物,其光学异构体或它们的混合物、包括本发明化合物、其药学上可接受的盐、溶剂合物或前药。本发明中，如果没有特殊说明，应包括所有异构体。例如，双键，环中的集合异构体(E型，Z型，顺式的(cis)，反式的(trans))，烷基包括直链烷基和支链烷基，由存在不对称碳原子等而产生的光学异构体(R，S型)及它们任意比例的混合物，外消旋混合物，以及所有的由互变异构体产生的异构体均包括在本发明中。
通式I表示的化合物可以通过公知的方法转化为相应的盐。盐优选为水溶性的药学上可接受的无毒的碱加成盐的实例为羧酸或磺酸与无机碱，衍生自适当碱的盐包括碱金属盐、碱土金属盐、铵盐以及N+(C1-4烷基)4盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。无毒酸加成盐的实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸以及高氯酸)或与有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用本领域中已知的其他方法(例如离子交换法)形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、 苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐等。适当时，另外的药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根以及芳基磺酸根等平衡离子形成的无毒铵、季铵以及胺阳离子。
除非另外说明，本文中术语“抑制P2X3受体的化合物”中提供包括具有式(Ⅰ)、式(Ⅱ)、式(Ⅲ)、式(Ⅳ)、式(V)和式(VI)分子式每种化合物均包括具有相同分子式的不同立体异构体，其中的立体异构体还包括对映异构体和非对映异构体，对映异构体即为光学异构体,非对映异构体为不成手性对映的立体异构体，与本发明化合物具有相同分子式的不同异构体也在本发明的保护范围内。
除非另外说明，本文中的术语“溶剂合物”也可以称为“溶剂化合物”、“溶剂化物”指的是含有溶剂的化合物，其中溶剂分子可以以包括配位键、共价键、范德华力、离子键、氢键等其他方式与化合物分子相结合。
除非另外说明，本文中的术语“药学上可接受的盐”是指本发明的化合物和/或所形成的盐，在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。“药学上可接受的盐”可以为与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将本发明的化合物或其立体异构体或溶剂合物，与一定数量的酸或碱适当混合而得到的。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷却干燥制得。
除非另外说明，本文中的术语“烷基”是指具有1至4个碳原子(“C1-4烷基”)。在一些实施例中，烷基基团具有1至3个碳原子(“C1-3烷基”)。在一些实施例中，烷基基团具有1至2个碳原子(“C1-2烷基”)。在一些实施例中，烷基基团具有1个碳原子(“C1烷基”)。烷基基团的每个实例是独立地任选取代地，即未取代的(“未取代的烷基”)或被一个或两个取代基取代的(“取代的烷基”)。
除非另外说明，本文中的术语“5-元杂芳基”除非另外说明，包含一个杂原子的示例性5-元杂芳基基团包括但不限于，吡咯基、呋喃基以及苯硫基。包含两个杂原子的示例性5-元杂芳基基团包括但不限于，咪唑基、吡唑基、噁唑啉基、异噁唑啉基、噻唑基以及异噻唑基。包含三个杂原子的示例性5-元杂芳基基团包括但不限于，噻唑基、噁二唑基以及噻二唑基。包含四个杂原子的示例性5-元杂芳基基团包括但不限于四唑基。
除非另外说明，本文中的术语“杂环烷基”指的是非芳香环的一个或多个构成环的原子是 杂原子，所述的杂原子包括而不限于氮原子、氧原子和硫原子等，其余为碳组成的稳定的3-10元饱和杂环系统的基团。除非本说明书中另外特别指明，否则杂环烷基基团可以是单环的(“单环的杂环烷基”)，或者是双环、三环或更多环的环体系，其可包括并环的(稠合的)、桥联的(桥环的)或螺的环系统(例如二环系统(“二环的杂环烷基”)。杂环烷基二环的环系统可以在一个或两个环中包括一个或多个杂原子；并且是饱和的。示例性3-元杂环基基团包括但不限于，氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于，氮杂环丁烷基，环氧丙烷基，硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于，四氢呋喃基，四氢噻吩基，吡咯烷基，噻唑烷基，异噻唑烷基，噁唑烷基，异噁唑烷基，咪唑烷基，吡唑烷基，二氧戊环基，氧杂硫呋喃基，二硫呋喃基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于，哌啶基，四氢吡喃基，硫化环戊烷基，吗啉基，硫代吗啉基，二噻烷基，二噁烷基，哌嗪基，三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于，氮杂环庚烷基，氧杂环庚烷基，硫杂环庚烷基，以及二氮杂环庚基，或者其同分异构体和立体异构体。在某一方案中，典型的含1个或多个独立选自N、O和S的杂原子的5-6元单环杂环基。方案中，“杂环烷基”为4-6元杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1、2或3个。
术语“杂芳基”是指含有杂原子的芳香基团，可为单环或稠合环，优选含有1-4个独立选自N、O和S的5-12元杂芳基，包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四氢吡咯基。在某一方案中，典型地含1个或多个独立选自N、O和S的杂原子的5-6元单环杂芳基。
当所列举的基团中没有明确指明其具有取代基时，这种基团仅指未被取代。例如当“C1～C4烷基”前没有“取代或未取代的”的限定时，仅指“C1～C4烷基”本身或“未取代的C1～C4烷基”。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“卤代-C1-C6烷基”中的C1-C6烷基应当理解为C1-C6亚烷基。
术语“卤素”(halo和halogen)是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“哺乳动物”是指人、家畜或猫和狗。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。
此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。
除非另有说明，本发明采用质谱、核磁等传统方法鉴定化合物，各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地选自”应做广义理解，是指所描述的各个个体之间彼此独立地被选择。因此，各取代基与其它取代基可以相同或不相同。更详细地，描述方式“…独立地选自”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2022084812-appb-000007
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
在本发明某些实施方式中，本发明的化合物、或其立体异构体或前药，或所述化合物的立体异构体或前药的一种可药用盐可以以药物组合物的形式，其中包含可药用载体、运载剂或稀释剂。
本发明还提供了本发明的化合物的药物组合物和其制备方法。在以下详细描述中说明的，本发明的特征是P2X3受体拮抗剂，这些P2X3受体拮抗剂用于治疗疼痛相关的哺乳动物(包括人类)病症和疾病的方法，也可用于治疗或缓解包括慢性咳嗽的咳嗽和欲望性咳嗽等呼吸系统病症和功能障碍。本发明具有解决驱使这些疾病中的咳嗽高敏感性的根本原因而不是仅仅抑制症状感知的中枢调控的优点。例如，本发明提供方法以降低外部刺激传入神经的活性，神经的过度激活在致敏对象(例如，人)中引发持续的和不适当的欲望性咳嗽。本发明还具有给予高选择性P2X3受体拮抗剂的优点。进一步的特征和优点在以下详细描述中说明，并且 对本领域技术人员将是显而易见的。
具体实施方式
下面通过实施例的方式进一步说明本发明，提供本申请中所述的合成实施例和生物学实施例以说明本文所提供的化合物、药物组合物、以及方法。以下实施例仅用于对本发明进行示例性说明，但不用于限制本发明，在本发明保护范围内所做的修改、改变、变型等都在本发明的保护范围内。
本文所提供的化合物可以使用下文所阐述的特定合成方案的将为本领域技术人员公知的操作方案，由容易获得的起始物质来制备。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，可以由本领域技术人员通过常规的优化程序来确定。
下述实施例中，缩写解释：
Boc 2O：二叔丁基二碳酸酯；
DIEA：N,N-二异丙基乙胺
DBU：1,8-二氮杂二环十一碳-7-烯
DMAP：4-二甲氨基吡啶
DMSO：二甲基亚砜
DAST:二乙胺基三氟化硫
DIAD：偶氮二甲酸二异丙酯
PCC：氯铬酸吡啶
PPh 3：三苯基膦
KOtBu：叔丁醇钾
NaH：氢化钠
NCS：N-氯代琥珀酰胺
NBS：N-溴代琥珀酰胺
TEA：三乙胺
TBSCl：叔丁基二甲基氯硅烷
TFA：三氟乙酸
TsCl：4-甲苯磺酰氯
PE：石油醚；
EA：乙酸乙酯；
DMF：N,N-二甲基甲酰胺；
DCM：二氯甲烷；
THF：四氢呋喃
LCMS：液质
NMR：核磁共振
MeOH：甲醇
Na 2CO 3：碳酸钠
Rf：比移值；
g；克
mg：毫克
h：小时
rt：室温
mol：摩尔
mmol：毫摩尔
mL：毫升
M：摩尔/升
实施例1：(S)-3-(3-((3-甲基双环[1.1.1]戊烷-1-基)甲基)-2,6-二氧基-4-((4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸化合物(13)
参照下面的步骤合成(化合物13):
Figure PCTCN2022084812-appb-000008
步骤1：在0℃下，向氮气氛围保护的中间体(13a)(5.00g,29mmol)的THF(30mL)的溶液中缓慢滴加1N硼烷的四氢呋喃溶液((60mL,60mmol)。滴加结束后，反应体系恢 复至25℃，并在25℃反应2h。反应结束后，在冰浴下，缓慢滴加MeOH(10mL)，在25℃下搅拌2h，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝10:1 to 2:1)，得到无色液体中间体(13b)(3.00g,65％产率)。:LCMS(ESI)calcd for C8H12O3[M+H] +m/z＝157.08,found 157.07；Exact Mass:156.08  1H NMR(400MHz,CDCl 3,ppm)3.68(s,3H),3.61(s,2H),2.40(s,1H),1.99(s,6H)。
步骤2：在0℃下，向氮气氛围保护的中间体(13b)(2.00g,13mmol)，Et 3N(2.59g,26mmol)和DMAP(610mg,5mmol)的DCM(30mL)溶液中加入TsCl(3.00g,16mmol)。反应体系恢复至25℃，并在25℃反应2h。反应结束后，加水淬灭反应，用DCM(30mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到10：1)，得到白色固体中间体(13c)(1.2g,30％产率)。LCMS(ESI)calcd for C15H18O5S
[M+H] +m/z＝311.09,found 311.09； 1H NMR(400MHz,CDCl 3,ppm)7.78(d,J＝8.2Hz,2H),7.35(d,J＝8.1Hz,2H),4.03(s,2H),3.66(s,3H),2.46(s,3H),1.97(s,6H)。
步骤3：在0℃下，向氮气氛围保护的中间体(13c)(1.00g,3mmol)的THF(10mL)溶液中滴加LiAlH 4(12mL,12mmol,1M THF溶液)。滴加完毕反应体系恢复至25℃，并在25℃反应2h。反应结束后，加酒石酸钠钾溶液淬灭反应，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝10:1到2：1)，得到无色液体中间体(13d)(200mg,59％产率)。GCMS(ESI)calcd for C7H12O[M+H] +m/z＝113.09,found 113； 1H NMR(400MHz,CDCl 3,ppm)3.56(s,2H),1.57(s,6H),1.18(s,3H)。
步骤4：在0℃下，向氮气氛围保护的中间体(13d)(200mg,1.78mmol)，Et 3N(360mg,3.56mmol)和DMAP(87mg,0.71mmol)的DCM(5mL)溶液中加入TsCl(406mg,2.14mmol)。反应体系恢复至25℃，并在25℃反应2h。反应结束后，加水淬灭反应，用DCM(10mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到10：1)，得到白色固体中间体(13e)(150mg,32％产率)。LCMS(ESI)calcd for C14H18O3S
[M+H] +m/z＝266,found 267； 1H NMR(400MHz,CDCl 3,ppm)7.77(d,J＝8.2Hz,2H),7.34(d,J＝8.1Hz,2H),3.97(s,2H),2.45(s,3H),1.55(s,6H),1.13(s,3H)。
步骤5：向氮气氛围保护的中间体(13e)(120mg,0.44mmol)MeCN(5mL)溶液中加入中间体(13f)(100mg,0.36mmol)和DIEA(95mg,0.73mmol)。反应体系在90℃反应6h。反应结束后，加水淬灭反应，用EtOAc(10mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝20:1到4：1)，得到黄色液体中间体(13g)(100 mg,75％产率)。LCMS(ESI)calcd for C 17H 25N 3O 4S[M+H] +ms/z＝368,found 368.
步骤6：中间体(13g)(100mg,0.27mmol)，4-(吡啶-2-氧基)苯胺(13h)(61mg,0.33mmol)和乙酸(327mg,5.44mmol)的叔丁醇(3mL)溶液在83℃反应16小时。在反应结束后，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝30:1到2：1)，得到黄色液体中间体(13i)(80mg,60％产率)。LCMS(ESI)calcd for C26H29N5O5[M+H]+ms/z＝492,found 492.
步骤7：将中间体(13i)(80mg,0.16mmol)溶于THF(3mL)和MeOH(1mL)中，在0℃下加入2N氢氧化钠水溶液(1mL)。反应液在25℃搅拌2小时。反应结束后，反应液用EtOAc(5mL)萃取，有机相用2N氢氧化钠水溶液洗涤。合并水相，用2N盐酸调节pH到3-4。用DCM(5mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品使用反相柱层析纯化(H2O(0.05％NH3)/MeCN＝90:10to 15:85)得到中间体(化合物13)(40mg,99％纯的,51％收率)。LCMS(ESI)calcd for C25H27N5O5[M+H]+ms/z＝478,found 478.；1H NMR(400MHz,DMSO,ppm)8.18-8.16(m,1H),7.88-7.83(m,1H),7.33(d,J＝8.8Hz,2H),7.14-7.11(m,3H),7.04(d,J＝8.4Hz,1H),4.17(s,2H),3.90(dd,J＝13.2,6.8Hz,1H),3.81(dd,J＝13.2,8.4Hz,1H),2.78-2.73(m,1H),1.60(s,6H),1.11(s,3H),0.99(d,J＝7.2Hz,3H)。
参考实施例1的合成方法合成了其下列化合物：
Figure PCTCN2022084812-appb-000009
Figure PCTCN2022084812-appb-000010
实施例2：(S)-3-(3-((3-(二氟甲基)双环[1.1.1]戊烷-1-基)甲基)-2,6-二氧基-4-((4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸化合物(化合物25)
参照下面的步骤合成(化合物25):
Figure PCTCN2022084812-appb-000011
步骤1：在0℃下，向氮气氛围保护的中间体(25a)(3.50g,22.4mmol)的DMF(40mL)溶液中加入TBSCl(5.06g,33.6mmol)和咪唑(3.05g,44.8mmol)。反应体系恢复至25℃，并在 25℃反应2h。反应结束后，在0℃下加水淬灭反应，用EtOAc(50mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到20：1)，得到无色液体中间体(25b)(5.92g,97.8％产率)。LCMS(ESI)calcd for C14H26O3Si[M+H]+ms/z＝271,found271.； 1H NMR(400MHz,CDCl 3,ppm)3.67(s,3H),3.60(s,2H),1.95(s,6H),0.88(s,9H),0.03(s,6H)。
步骤2：在0℃下，向氮气氛围保护的中间体(25b)(5.92g,21.9mmol)的THF(70mL)溶液中分批加入LiAlH 4(1.31g,32.9mmol)。反应体系恢复至25℃，并在25℃反应2h。反应结束后，加水淬灭反应，用EtOAc(50mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝20:1到2：1)，得到无色液体中间体(25c)(4.21g,79.1％产率)。LCMS(ESI)calcd for C13H26O2Si[M+H]+ms/z＝243,found243.； 1H NMR(400MHz,CDCl 3,ppm)3.61(s,2H),3.60(s,2H),1.60(s,6H),0.89(s,9H),0.03(s,6H)。
步骤3：在0℃下，向氮气氛围保护的中间体(25c)(200mg,1.78mmol)，Et 3N(1.66g,16.4mmol)和4-DMAP(0.10g,0.8mmol)的DCM(5mL)溶液中加入TsCl(1.88g,9.8mmol)。反应体系恢复至25℃，并在25℃反应2h。反应结束后，加水淬灭反应，用DCM(10mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到10：1)，得到白色固体中间体(25d)(2.1g,64％产率)。LCMS(ESI)calcd for:C20H32O4SSi[M+H] +m/z＝397,found397； 1H NMR(400MHz,CDCl 3,ppm)7.77(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),4.00(s,2H),3.55(s,2H),2.44(s,3H),1.57(s,6H),0.86(s,9H),0.00(s,6H)。
步骤4：向氮气氛围保护的中间体(25d)(636mg,1.60mmol)MeCN(5mL)溶液中加入中间体(25e)(365mg,1.34mmol)和DIEA(432mg,3.34mmol)。反应体系在90℃反应6h。反应结束后，加水淬灭反应，用EtOAc(10mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝20:1到4：1)，得到黄色液体中间体(25f)(240mg,36％产率)。LCMS(ESI)calcd for C 23H 39N 3O 5SSi[M+H] +ms/z＝498,found 498.
步骤5：在0℃下，向氮气氛围保护的中间体(25f)(140mg,0.28mmol)MeOH(3mL)溶液中加入HCl(1mL,6M aq.)。反应体系恢复至25℃，并在25℃反应2h。反应结束后，加水淬灭反应，用DCM(10mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到10：1)，得到无色液体中间体(25g)((85mg,78％产率)。LCMS(ESI)calcd for C 17H 25N 6O 5S[M+H] +ms/z＝384,found 384.
步骤6：在0℃下，向氮气氛围保护的中间体(25g)(85mg,0.22mmol)的DCM(5mL) 溶液中加入PCC(72mg,0.33mmol)。反应体系恢复至25℃反应2h。反应结束后，加水淬灭反应，用EtOAc(50mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到10：1)，得到黄色液体中间体(25h)(56mg,66％产率)。
LCMS(ESI)calcd for C 17H 23N 6O 5S[M+H] +ms/z＝382,found 382。
步骤7：在-78℃下，向氮气氛围保护的中间体(25h)(56mg,0.15mmol)的DCM(1mL)溶液中加入DAST(48mg,0.29mmol)。反应体系恢复至25℃反应2h。反应结束后，加水淬灭反应，用EtOAc(20mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝50:1到10：1)，得到黄色液体中间体(25i)(25mg,42％产率)。
LCMS(ESI)calcd for C 17H 23F 2N 3O 4S[M+H] +ms/z＝404,found 404。
步骤8：中间体(25i)(25mg,0.06mmol)，4-(吡啶-2-氧基)苯胺(25j)(23mg,0.12mmol)和乙酸(75mg,1.2mmol)的叔丁醇(1mL)溶液在83℃反应16小时。在反应结束后，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝30:1到2：1)，得到黄色液体中间体(25k)(30mg,91％产率)。LCMS(ESI)calcd for C 26H 27F 2N 5O 5[M+H] +ms/z＝528,found 528。
步骤9：将中间体(25k)(30mg,0.06mmol)溶于THF(1mL)中，在0℃下加入2N氢氧化钠水溶液(1mL)。反应液在25℃搅拌2小时。反应结束后，反应液用EtOAc(5mL)萃取，有机相用2N氢氧化钠水溶液洗涤。合并水相，用2N盐酸调节pH到3-4。用DCM(5mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品使用反相柱层析纯化(H 2O(0.1％FA)/CH 3CN＝85％to 45％)得到中间体(化合物25)(10mg,97％纯的,34％收率)。LCMS(ESI)calcd for C 25H 25F 2N 5O 5[M+H] +ms/z＝514,found 514.。 1H NMR(400MHz,DMSO,ppm)12.28(s,1H),9.22(s,1H),8.17(dd,J＝4.8,1.2Hz,1H),7.86(t,J＝6.8Hz,1H),7.41(d,J＝7.6Hz,2H),7.18-7.12(m,3H),7.06(d,J＝8.0Hz,1H),6.00(t,J＝56.4Hz,1H),4.25(s,2H),3.93(dd,J＝13.2,7.2Hz,1H),3.80(dd,J＝13.2,8.0Hz,1H),2.77(dd,J＝14.8,7.2Hz,1H),1.83(s,6H),1.02(d,J＝7.2Hz,3H)。
参考实施例2的合成方法合成了其下列化合物：
Figure PCTCN2022084812-appb-000012
Figure PCTCN2022084812-appb-000013
实施例3：(S)-3-(3-((3-(一氟甲基)双环[1.1.1]戊烷-1-基)甲基)-2,6-二氧基-4-((4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸化合物(化合物19)
参照下面的步骤合成(化合物19):
Figure PCTCN2022084812-appb-000014
步骤1：向氮气氛围保护的中间体(19a)(280mg,1.22mmol)MeCN(5mL)溶液中加入中间体(19b)(415mg,1.46mmol)和DIEA(315mg,2.44mmol)。反应体系在90℃反应6h。反应结束后，加水淬灭反应，用EtOAc(10mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝20:1到4：1)，得到黄色液体中间体(19c)(300mg,72％产率)。LCMS(ESI)calcd for C 16H 24FN 3O 2S[M+H]+ms/z＝342,found 342。
步骤2：中间体(19c)(300mg,0.87mmol)溶于TFA(5mL)在25℃下搅拌6小时。反应结束后，加水淬灭，用EtOAc(20mL x 3)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝10:1到1：2)，得到黄色液体中间体(19d)(150mg,60％产率)。LCMS(ESI)calcd for C 12H 16FN 3O 2S[M+H] +ms/z＝286,found 286。
步骤3：在0℃下，向氮气氛围保护的PPh 3(204mg,0.78mmol)THF(10mL)溶液中滴加DIAD(158mg,0.78mmol)THF(5mL)溶液.滴加结束后0℃搅拌5分钟，将中间体(19d)(150mg,0.52mmol)和(19e)(93mg,0.36mmol)溶于THF(4mL)加入反应液中.反应体系恢复至25℃，并在25℃反应16h。反应结束后，加H 2O(50mL)淬灭，用EtOAc(100mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品经过 柱层析纯化(PE/EtOAc＝30:1到2：1)，得到黄色液体中间体(19f)(160mg,53％产率)。LCMS(ESI)calcd for C 17H 24FN 3O 4S[M+H] +ms/z＝386,found 386.。
步骤4：中间体(19f)(160mg,0.41mmol)，4-(吡啶-2-氧基)苯胺(19g)(114mg,0.61mmol)和乙酸(492mg,8.20mmol)的叔丁醇(5mL)溶液在83℃反应12小时。在反应结束后，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝30:1到2：1)，得到黄色液体中间体(19h)(70mg,33％产率)。LCMS(ESI)calcd for C 26H 28FN 5O 5[M+H]+ms/z＝510,found 510。
步骤5：将中间体(19h)(70mg,0.13mmol)溶于THF(1.2mL)和MeOH(0.4mL)中，在0℃下加入2N氢氧化钠水溶液(0.4mL)。反应液在25℃搅拌2小时。反应结束后，反应液用EtOAc(5mL)萃取，有机相用2N氢氧化钠水溶液洗涤。合并水相，用2N盐酸调节pH到3-4。用DCM(5mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品使用反相柱层析纯化(H 2O(0.1％FA)/CH 3CN＝85％to 45％)得到中间体(化合物19)(40mg,98％纯的,62％收率)。LCMS(ESI)calcd for C 25H 26FN 5O 5[M+H] +m/z＝496,found 496；1H NMR(400MHz,DMSO,ppm)12.29(s,1H),9.21(s,1H),8.28-8.08(m,1H),7.99-7.74(m,1H),7.38(s,2H),7.20-6.96(m,4H),4.36(d,J＝48Hz,1H),4.30(s,1H),4.23(s,2H),3.99-3.74(m,2H),2.83-2.70(m,1H),1.73(s,6H),1.01(d,J＝7.1Hz,3H)。
参考实施例3的合成方法合成了其下列化合物：
Figure PCTCN2022084812-appb-000015
Figure PCTCN2022084812-appb-000016
实施例4：(S)-3-(3-((双环[1.1.1]戊烷-1-基)甲基)-2,6-二氧基-4-((4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸化合物(化合物1)
参照下面的步骤合成(化合物1):
Figure PCTCN2022084812-appb-000017
步骤1：向氮气氛围保护的中间体(1a)(600mg,2.62mmol)MeCN(8mL)溶液中加入中间体(1b)(756mg,3.0mmol)和DIEA(676mg,5.24mmol)。反应体系在90℃反应6h。反应结束后，加水淬灭反应，用EtOAc(50mL x 3)萃取。合并有机相，用盐水洗涤，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝20:1到4：1)，得到黄色液体中间体(1c)(680mg,83％产率)。LCMS(ESI)calcd for:C15H23N3O2S[M+H]+ms/z＝310,found 310。
步骤2：中间体(1c)(680mg,2.20mmol)溶于TFA(10mL)在25℃下搅拌6小时。反应结束后，加水淬灭，用EtOAc(50mL x 3)萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝10:1到1：2)，得到黄色液体中间体(1d)(330mg,60％产率)。LCMS(ESI)calcd for C11H15N3O2S[M+H] +ms/z＝254,found 254。
步骤3：在0℃下，向氮气氛围保护的PPh 3(512mg,1.95mmol)THF(10mL)溶液中滴加DIAD(396mg,1.95mmol)THF(5mL)溶液.滴加结束后0℃搅拌5分钟，将中间体(1d)(330mg,1.3mmol)和(1e)(153mg,1.3mmol)溶于THF(8mL)加入反应液中.反应体系恢复至25℃，并在25℃反应16h。反应结束后，加H 2O(20mL)淬灭，用EtOAc(50mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝30:1到2：1)，得到黄色液体中间体(1f)(280mg,61％产率)。LCMS(ESI)calcd fora:C16H23N3O4S[M+H] +ms/z＝354,found 354。
步骤4：中间体(1f)(280mg,0.79mmol)，4-(吡啶-2-氧基)苯胺(1g)(225mg,0.98mmol)和乙酸(974mg,16.2mmol)的叔丁醇(10mL)溶液在83℃反应12小时。在反应结束后，减压浓缩。粗品经过柱层析纯化(PE/EtOAc＝30:1到2：1)，得到黄色液体中间体(1h)(160mg,42％产率)。LCMS(ESI)calcd for C25H27N5O5[M+H]+ms/z＝478,found 478。
步骤5：将中间体(1h)(160mg,0.33mmol)溶于THF(3.6mL)和MeOH(1.2mL)中，在0℃下加入2N氢氧化钠水溶液(1mL)。反应液在25℃搅拌2小时。反应结束后，反应液用EtOAc(5mL)萃取，有机相用2N氢氧化钠水溶液洗涤。合并水相，用2N盐酸调节pH到3-4。用DCM(5mL x 3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品使用反相柱层析纯化(H 2O(0.1％FA)/CH 3CN＝85％to 45％)得到中间体(化合物1)(78mg,99％纯的,51％收率)。LCMS(ESI)calcd for C24H25N5O5[M+H] +m/z＝464.2,found 464.2； 1H NMR(400MHz,DMSO)δ12.26(s,1H),9.24(s,1H),8.28-8.08(m,1H),7.98-7.75(m,1H),7.39(s,2H),7.18-7.00(m,4H),4.40(s,2H),3.96-3.71(m,2H),2.77(d,J＝7.3Hz,1H),2.15-2.10(m,1H),2.05(d,J＝2.3Hz,6H),1.02(d,J＝7.1Hz,3H)。
参考实施例4的合成方法合成了其下列化合物：
Figure PCTCN2022084812-appb-000018
Figure PCTCN2022084812-appb-000019
实施例5：(S)-3-(3-((3-氟-双环[1.1.1]戊烷-1-基)甲基)-2,6-二氧基-4-((4-(吡啶-2-氧基)苯基)氨基)-3,6-二氢-1,3,5-三嗪-1(2H)-基)-2-甲基丙酸化合物(化合物7)
参照下面的步骤合成(化合物7):
Figure PCTCN2022084812-appb-000020
步骤1：将化合物(7b)(390mg,1.70mmol)，化合物(7a)(512mg,1.98mmol)和DIEA(440mg,3.40mmol)溶解到MeCN(10mL)中，在90℃下搅拌16小时。用水淬灭，EtOAc(50mL×3)萃取。合并有机相，用饱和食盐水洗涤，用Na 2SO 4干燥，过滤，真空浓缩。用硅胶色谱法(PE/EtOAc＝50：1到8：1)纯化，得到化合物(7c)(590mg，95％产率)。LCMS(ESI)calcd for:C 15H 22FN 3O 2S[M+H]+ms/z＝328,found 328。
步骤2：化合物(7c)(590mg，1.80mmol)的TFA(5mL)溶液，在25℃下搅拌16小时。用水淬灭并用EtOAc(20mL×3)萃取。将有机相结合并，用饱和食盐水洗涤，用Na 2SO 4干燥，过滤并真空浓缩。将产物用石油醚(10mL)打浆，得到得到白色固体化合物(7d)(470mg，97％产率)。LCMS(ESI)calcd for C 11H 14FN 3O 2S[M+H] +ms/z＝272,found 272。
步骤3：将PPh 3(406mg，1.55mmol)溶解到THF(5mL)中，置换氮气后，在0℃下，缓慢滴加DIAD(313mg，1.55mol)。将混合物搅拌5分钟，然后加入化合物(7d)(280mg，1.03mmol)和化合物(7e)(183mg，1.55mmol)。反应混合物在25℃下搅拌6小时。反应结束后，用水淬灭，用EtOAc(20mL×3)萃取。将有机相合并，用饱和食盐水洗涤，用Na 2SO 4干燥，过滤并真空浓缩。用硅胶色谱法(PE/EtOAc＝50：1到4：1)纯化，得到黄色固体化合物(7f)(310mg，80％产率)。LCMS(ESI)calcd fora:C16H22FN3O4S[M+H] +ms/z＝372,found 372。
步骤4：化合物(7f)(310mg，0.83mmol)、化合物(7g)(186mg，1.00mmol) 和AcOH(1.00g,16.67mmol)加入t-BuOH中的溶液(5mL)，在83℃下搅拌16小时。用水淬灭，用EtOAc(20mL×3)萃取。将有机相合并，用饱和食盐水洗涤，用Na 2SO 4干燥，过滤并真空浓缩。用硅胶色谱法(PE/EtOAc＝50：1到2：1)纯化，得到棕色固体化合物9(400mg，96％产率)。LCMS(ESI)calcd for C25H26FN5O5[M+H]+ms/z＝496,found496。
步骤5：将化合物(7h)(284mg，0.57mmol)溶解到THF(3mL)中，然后在0℃下，加入NaOH(1mL,aq.,2M)和MeOH(1mL)。将反应液在25℃下搅拌2小时。用EtOAc(10mL)萃取，用水洗涤。将水相合并，用2N HCl(aq.,1M)将pH调节至5。用EtOAc(20mL×3)萃取。合并有机相，用饱和食盐水洗涤，用Na 2SO 4干燥，过滤并真空浓缩。将产品用prep-HPLC纯化，得到白色固体(化合物7)(130mg，100％纯度，47％产率)。
LCMS(ESI)calcd for C24H24FN5O5[M+H] +m/z＝482,found 482； 1H NMR(400MHz,DMSO)δ12.22(s,1H),9.22(s,1H),8.30-8.07(m,1H),7.99-7.79(m,1H),7.39(s,2H),7.19-7.01(m,4H),4.41(s,2H),3.97-3.73(m,2H),2.77(d,J＝7.3Hz,1H),2.07(d,J＝2.3Hz,6H),1.01(d,J＝7.1Hz,3H)。
参考实施例5的合成方法合成了其下列化合物：
Figure PCTCN2022084812-appb-000021
Figure PCTCN2022084812-appb-000022
实施例6：对人源的P2X3和P2X2/3受体拮抗活性的测定
生物测定：钙荧光测量
将用于人嘌呤能P2X3受体的测定适配于使用FLEXSTATION作为阅读器和光蛋白作为发光读数的内部筛选仪器。该测定包括重组共表达人P2X3受体的HEK293细胞和Ca 2+敏感性光蛋白。将细胞维持在DMEM F-12(1∶1)混合物(LONZA目录编号BE04-687F/U1)中，该混合物补充有9mL的100mM丙酮酸钠(LONZA目录编号BE13-115E)、29mL的7.5％碳酸氢钠(LONZA目录号：BE17-613E)、5.5mL 1M Hepes(LONZA目录号BE17-737E)、5mL 100×青霉素/链霉素(LONZA目录号DE17-602E)和50mL胎牛血清(Sigma目录号F7524)、1mg/mL G418(Sigma目录号G8168)和5g/ml嘌呤霉素(Sigma目录号P9620)。标准增殖条件包括每周两次在P75烧瓶中接种，回收约20x106个细胞，相当于约80％的汇合。将细胞以40000个细胞/孔的密度接种到黑壁透明底部96孔板中的蒂罗德缓冲液(标准蒂罗德缓冲液：内部溶液，130mM NaCl，5mM KCl，2mM CaCl2、5mM NaHCO3、1mM MgCl2，20mM HEPES，pH 7.4)。24小时后，将培养基用200μL/孔的蒂罗德缓冲液中的腔肠素(腔肠素(Coelenterazine)：来自BIOSYNTH(目录号C-7001)。在DMSO和谷胱甘肽中制备10mM储备液，并在-20℃下储存)替换。将板在37℃下孵育4小时，然后注入10μL/孔的蒂罗德缓冲液中的25×浓度的测试化合物。4分钟后，进行第二次注入50μL/孔的蒂罗德缓冲液中的5×α，β-Met-ATP(α，β-Met-ATP：来自Tocris(目录号3209)，以100mM溶解在水中，并在-20℃下等分储存)，并通过FLEXSTATIONIII(Molecular Devices)记录发射的发光信号。所测试的化合物显示出对人P2X3受体的1nM至10μM的拮抗作用。
细胞内钙测量人P2X2/3受体的拮抗剂活性的测试：
检测板中加入1x Matrigel(5ul/孔)，37度预孵育30分钟；收集HEK293细胞，将细胞浓度调整至7.5*10^6个/mL，检测板中每孔加入20uL；37度培养箱过夜；检测激活剂EC8； 弃去培养基，加入20uL/孔Fluo-8染色工作液，放入37度培养箱避光孵育1小时；用钙流缓冲液稀释α,β-meATP至500uM(5x工作液,α,β-meATP储存液为20mM,终浓度为100uM),然后进行3倍稀释，14个点。将稀释完成的5xα,β-meATP工作液转移至384孔板(Greiner,#781201),30uL/孔；用FLIPR进行检测，用Graphpad prism计算EC80浓度。
检测拮抗剂活性:弃去培养基，加入20uL/孔Fluo-8染色工作液，放入37度培养箱避光孵育1小时；准备拮抗剂工作液(5X)；DMSO稀释拮抗剂至最高浓度(200x工作液，拮抗剂储存液浓度为20mM)，将拮抗剂进行3倍梯度稀释至12个浓度点，再将所有浓度点用钙流缓冲液进行40倍稀释，得到5x拮抗剂工作液：195uL缓冲液+5uL 200x拮抗剂工作液。将稀释好的拮抗剂转移至384孔板(Greiner,#781201),30uL/孔；lipr转移5uL/孔的拮抗剂至检测板，拮抗剂预孵育30分钟；准备6X EC80ofαβ-meATP工作液激活细胞内钙流；利用FLIPR Tetra进行数据的测定和分析，GraphPadPrism四参数方程计算待测化合物对P2X3和P2X2/3受体的半数抑制浓度(IC 50)。
以对根据本发明制备的某些目的化合物的IC 50(nM)表示的人P2X3和P2X2/3受体的选定拮抗剂在下表中示出。
这些数据拟合产生最佳拟合IC 50值，这些测定的结果如下表1所示，其中“A”代表IC 50≤50nM；“B”代表50nM＜IC 50≤100nM；“C”代表100nM＜IC 50≤500nM；“D”代表IC 50为500nM＜IC 50≤1000nM；“E”代表1μM＜IC 50；，“NT”表示未在指定的测定中测试指定的化合物。
选择性倍数＝(对P2X2/3的IC 50)/(对P2X3的IC 50)
a：选择性倍数>500，b：100<选择性倍数≤500，c：选择性倍数50<选择性倍数≤100，d：选择性倍数10<选择性倍数≤50，e：选择性倍数≤10。
表1.本发明选择的化合物对P2X3和P2X2/3受体的拮抗活性。
Figure PCTCN2022084812-appb-000023
Figure PCTCN2022084812-appb-000024
以上的结果表明本发明的化合物对P2X3受体具有良好的拮抗作用，本发明的化合物对P2X2/3异源二聚受体的抑制活性较差，在P2X3和P2X2/3中具有良好的选择性。
对于本领域技术人员，本公开不只局限于前述说明性实施例，在不脱离其必要属性的情况下能以其它特定形式体现。因此期望认为，所有方面均作为说明性而不是限制性、对所附权利要求进行参考的实施例而不是前述实施例，引用文献只是针对附加的权利要求而不是上述的实例，以及落入权利要求等效性的含义和范围之内的所有变化因此预期包含于此。
本说明书中列举的所有专利、专利申请和文献参考均在此以其全部内容引入作为参考。在不一致的情况下，包括定义的本公开将是有说服力的。

Claims (10)

  1. 一种如式I所示化合物、其光学异构体或它们的混合物、及其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药：
    Figure PCTCN2022084812-appb-100001
    其中，R 1独立地选自氢原子，氟原子，甲基，氟取代代甲基；
    R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
    X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
  2. 根据权利要求1所述的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，当R 1为氢原子时，具有以下如式II所示结构：
    Figure PCTCN2022084812-appb-100002
    其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
    X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
  3. 根据权利要求1所述的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，当R 1为氟原子时，具有以下如式III所示结构：
    Figure PCTCN2022084812-appb-100003
    其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
    X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
  4. 根据权利要求1所述的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，当R 1为甲基时，具有以下如式IV所示结构：
    Figure PCTCN2022084812-appb-100004
    其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
    X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
  5. 根据权利要求1所述的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，当R 1为单氟取代甲基时，具有以下如式V所示结构：
    Figure PCTCN2022084812-appb-100005
    其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
    X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤 素或氰基取代的芳基或杂芳基。
  6. 根据权利要求1所述的化合物、其光学异构体或它们的混合物、其药学上可接受的盐、溶剂合物、其N-氧化物或它们的前药，当R 1为二氟取代甲基时，具有以下如式VI所示结构：
    Figure PCTCN2022084812-appb-100006
    其中式中R 2选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基或氰基；
    X独立地选自6元芳基或杂芳基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、卤素或氰基取代的芳基或杂芳基。
  7. 根据权利要求1-6中任意一项所述的化合物,其光学异构体或它们的混合物、同位素标记的衍生物或其药学上可接受的盐、溶剂合物或前药，具有以下结构之一：
    Figure PCTCN2022084812-appb-100007
    Figure PCTCN2022084812-appb-100008
  8. 一种药物组合物，所述药物组合物包含如权利要求1-7中任一项所述的化合物,其光学异构体或它们的混合物、同位素标记的衍生物或其药学上可接受的盐、溶剂合物或前药，以及药学上可接受的辅料。
  9. 权利要求1-7中任意一项所述的化合物,其光学异构体或它们的混合物、同位素标记的衍生物或其药学上可接受的盐、溶剂合物或前药或者权利要求8的药物组合物在制备用于治疗或预防病症或病况的药物中的用途，所述病症或病况为疼痛、慢性疼痛和癌性疼痛，对镇痛剂的成瘾和耐受，以P2X3参与为特征的内脏器官疾病和病症。
  10. 权利要求1-7中任意一项所述的化合物,其光学异构体或它们的混合物、同位素标记的衍生物或其药学上可接受的盐、溶剂合物或前药或者权利要求8的药物组合物在制备用于治疗或预防病症或病况的药物中的用途，所述病症或病况为呼吸障碍，包括哮喘、慢性阻塞性肺病、肺纤维化、急性咳嗽、慢性咳嗽包括慢性原发性和慢性难治性咳嗽、支气管痉挛等呼吸系统病症和功能障碍，以P2X3参与为特征的呼吸道相关疾病。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395571A (zh) * 2009-02-13 2012-03-28 盐野义制药株式会社 新型三嗪衍生物及含有该三嗪衍生物的药物组合物
CN103153968A (zh) * 2010-08-10 2013-06-12 盐野义制药株式会社 三唑衍生物及含有其的具有镇痛作用的药物组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395571A (zh) * 2009-02-13 2012-03-28 盐野义制药株式会社 新型三嗪衍生物及含有该三嗪衍生物的药物组合物
CN103153968A (zh) * 2010-08-10 2013-06-12 盐野义制药株式会社 三唑衍生物及含有其的具有镇痛作用的药物组合物

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