WO2019015640A1 - Sel de dérivé d'amide azacyclique, sa forme cristalline et son procédé de préparation et son utilisation - Google Patents

Sel de dérivé d'amide azacyclique, sa forme cristalline et son procédé de préparation et son utilisation Download PDF

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WO2019015640A1
WO2019015640A1 PCT/CN2018/096250 CN2018096250W WO2019015640A1 WO 2019015640 A1 WO2019015640 A1 WO 2019015640A1 CN 2018096250 W CN2018096250 W CN 2018096250W WO 2019015640 A1 WO2019015640 A1 WO 2019015640A1
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compound
formula
reaction
solvent
dichloromethane
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PCT/CN2018/096250
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Chinese (zh)
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魏用刚
邱关鹏
卢泳华
张晨
严庞科
郑伟
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四川海思科制药有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present invention relates to a salt of a nitrogen heterocyclic amide derivative, a crystal form thereof, a process for the preparation thereof and use thereof in medicine.
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • Bronchodilators in clinical use include widely muscarinic receptor antagonist and ⁇ 2 - adrenergic agonist.
  • a muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle.
  • 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine.
  • drugs with dual effects of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism are currently in clinical trials.
  • This bifunctional drug has the pharmaceutical advantages of a combination of two components, and has a single molecular drug. Generation dynamics. These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action.
  • compounds with muscarinic receptor antagonism and ⁇ 2 -adrenergic agonistic dual action can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple The therapeutic effect of the effect.
  • ICS corticosteroid
  • the present invention provides a salt of a nitrogen heterocyclic amide derivative having a dual action of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism, a crystal form thereof, a preparation method thereof, and use in medicine.
  • the compound represented by the formula (I) of the present invention has the following advantages such as easy processing and crystallization, convenient handling, easy purification, easy industrialization, good stability, good fluidity, easy micronization, etc., which makes them especially Suitable for inhalation preparations.
  • the present invention provides a compound of the formula (I):
  • the compound of formula (I) is in the form of a solid crystalline form.
  • the compound represented by the formula (I) is a crystal form of I, which uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 13.19 ° ⁇ 0.2 °, 16.10° ⁇ 0.2°, 18.23° ⁇ 0.2°, 21.85° ⁇ 0.2°, 24.33° ⁇ 0.2°.
  • the compound represented by the formula (I) is a crystalline form I, and its X-ray powder diffraction pattern is substantially as shown in Fig. 1.
  • the compound of the formula (I) according to the present invention is a crystal form of I, and its differential scanning calorimetry curve (DSC) is shown in Fig. 2.
  • the melting peak height of the DSC curve depends on a number of factors associated with sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the above formula (I), and a pharmaceutically acceptable carrier or excipient, preferably, the compound represented by the formula (I) is a crystal type.
  • the present invention also provides the use of the compound of the above formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for preventing and/or treating an airway obstructive disease, preferably asthma, chronic obstructive pulmonary disease Disease or bronchitis.
  • an airway obstructive disease preferably asthma, chronic obstructive pulmonary disease Disease or bronchitis.
  • the compound represented by the formula (I) is a crystalline form I.
  • the present invention also provides a method for treating an airway obstructive disease, the method comprising administering the compound of any one of the above formula (I) or a pharmaceutical composition thereof, wherein the airway obstructive disease is preferably asthma, chronic obstructive Pulmonary disease or bronchitis, preferably, the compound represented by the formula (I) is a crystalline form I.
  • the airway obstructive disease is preferably asthma, chronic obstructive Pulmonary disease or bronchitis, preferably, the compound represented by the formula (I) is a crystalline form I.
  • the present invention relates to a process for the preparation of a compound of the formula (I), which comprises contacting a compound of the formula (II) with citric acid,
  • the reaction is carried out in a solvent, preferably a C 1-6 alcohol solvent, a C 1-6 halogenated alkane solvent, C 2 - 6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and one or more of water, more preferably methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane Alkane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, 4-methyl-2-pentanone, butanone, acetone, diethyl ether, methyl uncle One or more of butyl ether and water.
  • a solvent preferably a C 1-6 alcohol solvent, a C 1-6 halogenated alkane solvent, C 2 - 6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and one or more of water, more preferably m
  • the reaction temperature is from 0 ° C to reflux, more preferably from 10 to 80 ° C, still more preferably from 10 to 50 ° C.
  • the present invention also includes a process for the preparation of the crystalline form of the compound I represented by the formula (I), which comprises the steps of dissolving the compound of the formula (II) in a first solvent, adding citric acid, and then adding a second The solvent was stirred, crystals were precipitated, and crystals were collected.
  • the present invention relates to an embodiment of the method for preparing the crystalline form of the compound I represented by the formula (I), wherein the first solvent is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 2-6 ester solvent, and a C 2-6 ether.
  • One or more solvents C 1-6 ketone solvents and water, preferably dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane
  • ethyl acetate isopropyl acetate, 4-methyl-2-pentanone, methyl ethyl ketone, acetone, diethyl ether and methyl tert-butyl ether;
  • the second solvent is selected from one or more of a C 1-6 alcohol solvent or a C 1-6 ether solvent, preferably methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl One or more of an ether and water.
  • the present invention relates to an embodiment of the method for producing the crystalline form of the compound I represented by the formula (I), wherein the reaction temperature is from 0 ° C to reflux, more preferably from 10 to 80 ° C, still more preferably from 10 to 50 ° C.
  • the molar ratio of citric acid to the compound of the formula (II) is from 1.5:1 to 0.8:1.
  • a higher purity crystal form of the compound I represented by the formula (I) is obtained, optionally by further recrystallization by a compound represented by the formula (I) or a crystal form thereof (such as a crystal form I). / or be prepared by beating.
  • the temperature for recrystallization and/or beating is from 0 ° C to reflux, preferably from 0 to 80 ° C, more preferably from 10 to 50 ° C.
  • the solvent for recrystallization and/or beating is selected from the group consisting of toluene, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone , one or more of butanone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol and water, more preferably, heavy
  • the solvent for crystallization and/or beating is one or both of dichloromethane and ethanol, and the volume ratio of the two (dichloromethane to ethanol) is preferably from 1:0 to 0:3, more preferably 1:1. .
  • the invention also relates to a process for the preparation of a compound of formula (II), which is obtained using the following reaction:
  • HA is selected from organic or inorganic acids, preferably HF, HBr, HCl, CH3COOH, benzenesulfonic acid or p-toluenesulfonic acid;
  • the reaction is carried out under a reducing agent.
  • the reducing agent is selected from the group consisting of organoboron reducing agents, preferably sodium tris(acetoxy)borohydride, sodium borohydride, sodium cyanoborohydride or hydrazine. Borane.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (II), wherein the solvent for the reaction is selected from the group consisting of a polar solvent, preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide And one or more of dimethyl sulfoxide.
  • a polar solvent preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol
  • the temperature of the reaction is from 0 ° C to reflux, preferably from 0 to 60 ° C.
  • the compound of the formula (III) and the compound of the formula (IV) may be optionally reacted in the presence of a molecular sieve, a dehydrating agent or a water-removing vessel, preferably a molecular sieve, sodium sulfate or magnesium sulfate.
  • the compound of the formula (III) and the compound of the formula (IV) are optionally reacted in the presence of an acidic catalyst, preferably formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, One or more of p-toluenesulfonic acid, zinc chloride, and aluminum chloride.
  • an acidic catalyst preferably formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, One or more of p-toluenesulfonic acid, zinc chloride, and aluminum chloride.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (II), wherein the solvent for the reaction is selected from the group consisting of a polar solvent, preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide And one or more of dimethyl sulfoxide, the temperature of the reaction is preferably 0 to 60 ° C, and optionally, the reaction is carried out in the presence of a molecular sieve, a dehydrating agent or a water separation vessel, and the dehydrating agent is preferably a molecular sieve, Sodium sulphate or magnesium sulphate; alternatively, the reaction is
  • the present invention relates to a process for the preparation of a compound of formula (III), which is obtained using the following reaction:
  • the reaction is carried out under diphenylphosphoryl azide.
  • the solvent of the reaction is selected from the group consisting of an aprotic solvent, preferably a C 6-10 aromatic hydrocarbon solvent, a C 1-6 halogenated alkane or a C 1-8 alkane hydrocarbon.
  • an aprotic solvent preferably a C 6-10 aromatic hydrocarbon solvent, a C 1-6 halogenated alkane or a C 1-8 alkane hydrocarbon.
  • One or more of the solvents more preferably one or more of toluene, benzene, dichloromethane, chloroform and 1,2-dichloroethane;
  • the temperature of the reaction is preferably from 0 ° C to reflux;
  • reaction is optionally carried out further in the presence of an acid-binding agent, preferably an organic amine, more preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methyl One or more of morpholine and morpholine.
  • an acid-binding agent preferably an organic amine, more preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methyl One or more of morpholine and morpholine.
  • the molar ratio of the compound of formula (VI) to diphenyl azide is from 1:1 to 1:5, formula (VI) The molar ratio of the compound shown to the compound of the formula (V) is from 1:0.5 to 1:1.
  • the present invention relates to a process for the preparation of a compound of formula (V) which is obtained using the following reaction:
  • the compound of the formula (VII) is involved in the reaction in the form of an organic amine salt, preferably a triethylamine salt.
  • the reaction is carried out in the presence of a condensing agent and/or a condensing activator, preferably 1,3-(3-dimethylaminopropyl).
  • the solvent to be reacted is selected from one or more of a C 1-6 halogenated alkane solvent, a C 2-6 ester solvent, N,N-dimethylformamide and N,N-dimethylacetamide, preferably One or more of dichloromethane, chloroform, 1,2-dichloromethane, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, and N,N-dimethylacetamide;
  • the reaction temperature is preferably from 0 ° C to reflux, more preferably from 0 ° C to 40 ° C;
  • an organic amine reagent is optionally further added to the reaction, and the organic amine reagent is preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine or morpholine. One or more.
  • the present invention relates to a process for the preparation of a compound of formula (VII), which is obtained using the following reaction:
  • the solvent for the reaction is selected from the group consisting of C 2-6 ether solvents, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1,2-dioxane;
  • the reaction temperature is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux.
  • the present invention relates to an embodiment of a process for the preparation of the compound of the formula (VII), which further comprises the step of purifying the compound of the formula (VII), in the process of purifying the compound of the formula (VII),
  • the organic amine forms a salt therewith to give an organic amine salt of the compound of the formula (VII), which is preferably triethylamine.
  • the invention relates to a method for preparing a compound of the formula (II), which comprises the following steps:
  • a compound of the formula (IX) is reacted with a compound of the formula (X) to give a compound of the formula (VII), and the solvent for the reaction is selected from a C 2-6 ether solvent, preferably tetrahydrofuran or 2-methyltetrahydrofuran. And one or more of 1,2-dioxane; the temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux, during the purification of the compound of formula (VII), preferably organic amine is added. Forming a salt therewith to obtain an organic amine salt of the compound of formula (VII);
  • a compound of the formula (VII) is reacted with a compound of the formula (VIII) to form a compound of the formula (V), and the reaction is carried out under a condensing agent and/or a condensing activator.
  • the formula (VII) The compound is shown to participate in the reaction in the form of a triethylamine salt;
  • HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • a method of preparing a compound of formula (II), the method comprising the steps of:
  • a compound of the formula (IX) is reacted with a compound of the formula (X) to give a compound of the formula (VII), and the solvent of the reaction is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran and 1,2-dioxane.
  • the temperature of the reaction is selected from 0 ° C to reflux, preferably 20 ° C to reflux, and in the process of purifying the compound of the formula (VII), it is preferred to add triethylamine to form a salt thereof, thereby obtaining the formula (VII).
  • a compound of the formula (VII) is reacted with a compound of the formula (VIII) to form a compound of the formula (V), and the reaction is carried out under a condensing agent and/or a condensing activator.
  • the formula (VII) The compound is involved in the reaction in the form of a triethylamine salt selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the condensation activator selected From 1-hydroxybenzotriazole, the solvent of the reaction is selected from one or more of dichloromethane, chloroform and 1,2-dichloromethane, and the temperature of the reaction is selected from 0 ° C to reflux, as an option, in the reaction.
  • Adding triethylamine is reacted with a compound of the formula (VIII) to form a compound of the formula (V), and the reaction is carried out under a condensing agent and/or a condens
  • the compound of the formula (V) and the compound of the formula (VI) are reacted in the presence of diphenyl azide to form a compound of the formula (III),
  • the solvent of the reaction is selected from toluene or benzene, and the temperature of the reaction It is selected from 0 ° C to reflux, and optionally, triethylamine is added to the reaction;
  • a compound of the formula (III) is reacted with a compound of the formula (IV) in the presence of a reducing agent to form a compound of the formula (II), the reducing agent being selected from sodium tris(acetoxy)borohydride.
  • a reducing agent being selected from sodium tris(acetoxy)borohydride.
  • sodium borohydride sodium cyanoborohydride or borane the temperature of the reaction is selected from 0 ° C to 60 ° C
  • the solvent of the reaction is selected from the group consisting of dimethyl sulfoxide, dichloromethane, isopropanol, acetonitrile and acetamide
  • a molecular sieve is added to the reaction, and alternatively, one or both of acetic acid and zinc chloride are added to the reaction.
  • the reaction is carried out in the presence of a reducing agent, preferably a combination of Pd/C and triethylsilane.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (B), wherein the solvent in the reaction is selected from a C 1-6 alcohol solvent, preferably methanol or ethanol;
  • the mass ratio of Pd/C to the compound represented by formula (A) is preferably from 1:1 to 1:100, more preferably from 1:1 to 1:10;
  • the molar ratio of triethylsilane to the compound of formula (A) is preferably from 20:1 to 1:1, more preferably from 10:1 to 1:1;
  • the temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 10 ° C to 40 ° C.
  • the compound of the formula (B) of the present invention is used for the preparation of the compound of the formula (IV), the compound of the formula (B) is prepared in the presence of a desilicon ether reagent to prepare a compound of the formula (IV), the desiliconized ether reagent Preferred is tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridine hydrofluoride, and the solvent for the reaction is preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, dichloromethane, chloroform. One or more of 1,2-dichloromethane and water, the temperature of the reaction is preferably from 0 ° C to reflux.
  • the present invention relates to a process for the preparation of a compound of the formula (IV) which comprises obtaining a compound of the formula (IV) using the following reaction:
  • the reaction is carried out in the presence of a desilicon ether reagent
  • HA is selected from HF, HBr or HCl.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (IV), wherein the desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridinium hydrogen Fluorate
  • the solvent to be reacted is selected from one or more of a C 1-6 halogenated alkane solvent, a C 1-6 alcohol solvent, a C 1-6 ether solvent, acetonitrile and water, preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile. , one or more of methanol, ethanol, dichloromethane, chloroform, 1,2-dichloromethane and water;
  • the reaction temperature is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux.
  • An embodiment of the present invention relates to a process for the preparation of a compound of the formula (IV), which further comprises the preparation of a compound of the formula (B), wherein a reducing agent of the compound of the formula (A) is present to form a compound of the formula (B)
  • the reducing agent is preferably a combination of Pd/C and triethylsilane
  • the solvent in the reaction is selected from a C 1-6 alcohol solvent, preferably methanol or ethanol; Pd/C and the compound represented by formula (A)
  • the mass ratio is preferably from 1:1 to 1:100, more preferably from 1:1 to 1:10;
  • the molar ratio of triethylsilane to the compound of the formula (A) is preferably from 20:1 to 1:1, more preferably 10:1 to 1:1;
  • the temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 10 ° C to 40 ° C.
  • the present invention provides a compound of the formula (V) and (IV):
  • HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • IC50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the crystalline structures of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art including, but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (Thermogravimetric). Analysis, TGA).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • crystal form of the present invention is not limited to the feature maps identical to the feature maps described in the drawings disclosed in the present invention, such as XRD, DSC, TGA, which have substantially the same maps as those depicted in the drawings or Any crystal form of the substantially identical feature map is within the scope of the invention.
  • Figure 1 X-ray powder diffraction pattern of Compound 2I crystalline form.
  • Figure 2 Differential scanning calorimetry curve of Compound 2I crystal form.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the solution means an aqueous solution.
  • the room temperature is 20 ° C to 30 ° C.
  • reaction liquid 10 ml of t-butanol was added, stirred for 30 min, cooled to room temperature, and then 1500 ml of ethyl acetate was added, followed by washing with water, 2 L of sodium carbonate solution and 2 L of saturated sodium chloride.
  • reaction solution was poured into 2.6 L of ice water, filtered through Celite, washed with a mixture of 500 ml of dimethyl sulfoxide / water 1:1 (v / v), and the filtrate was extracted with ethyl acetate (2500 ml ⁇ 3), water
  • the layer was added to a stirred 7 L of saturated sodium bicarbonate solution, a large amount of solid was precipitated, filtered, and the solid was washed with water, then dissolved in 2 L of 30% methanol/dichloromethane, and the organic phase was sequentially treated with 1000 mL of saturated sodium hydrogen carbonate solution.
  • Fig. 1 The X-ray powder diffraction pattern of Compound 2 is shown in Fig. 1, and the peak list is shown in Table 1.
  • Compound 2 was subjected to differential scanning calorimetry analysis as follows:
  • DSC Differential Scanning Calorimetry testing was performed using the NETZSCH DSC 214 Polyma. About 1 mg of the sample was weighed into a pinhole-coated aluminum crucible, and nitrogen gas was used as a purge gas (flow rate: 60 ml/min), and the initial temperature was 35 ° C, and the temperature was raised to 200 ° C at a temperature increase rate of 10 ° C / min.
  • the DSC (differential scanning calorimetry curve) spectrum of Compound 2 is shown in Figure 2.
  • reaction solution was filtered, and the filter cake was beaten with 10% methanol/ethanol (2.5 L) at 60 ° C for 1 hour, filtered, and the filter cake was dried to give 5-(2-amino-1-hydroxy-ethyl)-8-hydroxy-1H- Quinoline-2-one hydrofluoric acid salt (1H), pale yellow solid (454 g, yield: 90.3%).
  • Example 4 Conditional screening for the reaction of compound 1G with compound 1H to form compound 1
  • DMSO dimethyl sulfoxide
  • eq is the molar equivalent ratio
  • phosphate buffer (3.12 g of sodium dihydrogen phosphate dihydrate, dissolved in 1000 ml of water, adjusted to pH 3.0 with phosphoric acid) - acetonitrile (80:20)] dissolved and diluted
  • a solution containing about 0.5 mg of sample per 1 ml was prepared as a test solution.
  • test solution 10 ⁇ l was accurately weighed and injected into a liquid chromatograph to record a chromatogram.
  • the chromatogram of the test solution (excluding the citrate peak and the solvent peak) was calculated by the peak area normalization method, and the results are shown in Table 4.
  • Test Example 1 Methotrexate-induced inhibition of bronchoconstriction in rats
  • rat PenH values were measured using a full volume oximeter. Aerosol was administered at 800 mg/ml Mch (acetylcholine) with an atomization time of 36 seconds and a recording time of 7 minutes. The PenH average was calculated and the results are shown in Table 6.
  • Table 6 shows the inhibitory effect of compound 2 on methacholine-induced rat bronchoconstriction
  • Compound 2 has good inhibitory activity against methacholine-induced bronchoconstriction in rats, which is superior to bafetentorol.

Abstract

La présente invention concerne le sel d'un dérivé d'amide azacyclique, sa forme cristalline et son procédé de préparation et son utilisation. En particulier, le sel du dérivé d'amide azacyclique est le composé tel que présenté dans la formule (I).
PCT/CN2018/096250 2017-07-21 2018-07-19 Sel de dérivé d'amide azacyclique, sa forme cristalline et son procédé de préparation et son utilisation WO2019015640A1 (fr)

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CN1882556A (zh) * 2003-11-21 2006-12-20 施万制药 具有β2肾上腺素能受体激动剂和毒蕈碱性受体拮抗剂活性的化合物
WO2016128456A1 (fr) * 2015-02-12 2016-08-18 Chiesi Farmaceutici S.P.A. Composés présentant une activité d'antagonistes de récepteur muscarinique et d'agonistes de récepteur bêta 2 adrénergique
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CN1759108A (zh) * 2003-02-14 2006-04-12 施万制药 联苯衍生物
CN1882556A (zh) * 2003-11-21 2006-12-20 施万制药 具有β2肾上腺素能受体激动剂和毒蕈碱性受体拮抗剂活性的化合物
WO2016128456A1 (fr) * 2015-02-12 2016-08-18 Chiesi Farmaceutici S.P.A. Composés présentant une activité d'antagonistes de récepteur muscarinique et d'agonistes de récepteur bêta 2 adrénergique
WO2016180349A1 (fr) * 2015-05-14 2016-11-17 四川海思科制药有限公司 Dérivé biphényle présentant des activités d'excitation de récepteur bêta2 et des activités antagonistes au récepteur m et son application dans un médicament
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116655A (zh) * 2019-12-30 2020-05-08 天津天士力圣特制药有限公司 一种高光学纯度替诺福韦苄酯膦酰胺前体药物的制备方法
CN111116655B (zh) * 2019-12-30 2022-10-25 天津天士力圣特制药有限公司 一种高光学纯度替诺福韦苄酯膦酰胺前体药物的制备方法

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