WO2019015639A1 - Azacyclic amide derivative composition and preparation thereof - Google Patents

Azacyclic amide derivative composition and preparation thereof Download PDF

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Publication number
WO2019015639A1
WO2019015639A1 PCT/CN2018/096249 CN2018096249W WO2019015639A1 WO 2019015639 A1 WO2019015639 A1 WO 2019015639A1 CN 2018096249 W CN2018096249 W CN 2018096249W WO 2019015639 A1 WO2019015639 A1 WO 2019015639A1
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group
alkyl
composition according
pharmaceutical composition
compound
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PCT/CN2018/096249
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French (fr)
Chinese (zh)
Inventor
张春雨
王小平
秦践
张轩邈
魏用刚
邱关鹏
雷柏林
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四川海思科制药有限公司
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Publication of WO2019015639A1 publication Critical patent/WO2019015639A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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

Definitions

  • the invention belongs to the field of medicine and relates to a nitrogen heterocyclic amide derivative composition and a preparation method thereof, and the application thereof in airway obstructive diseases, particularly in asthma, chronic obstructive pulmonary disease or bronchitis, It also relates to a method of administering a composition of aziridine amide derivative for asthma, chronic obstructive pulmonary disease or bronchitis.
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • Widely used in clinical bronchodilators include muscarinic receptor antagonist and ⁇ 2 - adrenergic agonist.
  • Muscarinic receptor antagonists exert potency in bronchiectasis by reducing the level of vagal cholinergic energy in airway smooth muscle.
  • Inhaled muscarinic receptor antagonists currently used include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide.
  • 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine.
  • the ⁇ 2 -adrenergic agonists currently used include salbutamol, salmeterol, arformoterol, formoterol, vilantrol and indacaterol. In addition to improving lung function, these drugs can improve the quality of life of patients and reduce the deterioration of their condition.
  • ⁇ 2 -adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD.
  • These compound preparations mainly include Anoro Ellipta (Ambroxol/Vylantro) and Ultibro Breezhaler (Glon Brom). Ammonium / indacaterol) and ipratropium bromide / salbutamol.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof,
  • R 1 is selected from
  • Ring C 3 is selected from a 4 to 7 membered nitrogen-containing heterocyclic ring, and said nitrogen-containing heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, cyano, CF 3 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, and said nitrogen-containing heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
  • R 2 is selected from a bond or a C 1-4 alkylene group, and the alkylene group is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
  • R x is each independently selected from H or C 1-4 alkyl
  • A is selected from a bond, a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R A and the heterocyclic ring contains 1 to 4 a hetero atom from N, O or S;
  • R 3 is selected from C 1-6 alkylene, which is optionally further substituted with 0 to 5 substituents selected from R 3a ;
  • R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
  • R 4 and R 5 are each independently selected from H or C 1-4 alkyl
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 0.3 w/w% to 0.9 w/w% of the active ingredient of the compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable Salt, eutectic or prodrug,
  • R 1 is selected from
  • Ring C 3 is selected from a 4 to 7 membered nitrogen-containing heterocyclic ring, and said nitrogen-containing heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, cyano, CF 3 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, and said nitrogen-containing heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
  • R 2 is selected from a bond or a C 1-4 alkylene group, and the alkylene group is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
  • R x is each independently selected from H or C 1-4 alkyl
  • A is selected from a bond, a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R A and the heterocyclic ring contains 1 to 4 a hetero atom from N, O or S;
  • R 3 is selected from C 1-6 alkylene, which is optionally further substituted with 0 to 5 substituents selected from R 3a ;
  • R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
  • R 4 and R 5 are each independently selected from H or C 1-4 alkyl
  • composition of the present invention in some embodiments, the active ingredient of the compound of formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or former thereof Medicine, of which
  • R1 is selected from
  • R 2 is selected from the group consisting of a bond, a methylene group, an ethylene group or a propylene group;
  • R 3 is selected from the group consisting of methylene, ethylene, propylene, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 -, -C ( CH 3 ) 2 CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -, Or pentylene;
  • A is selected from a bond, a phenylene group or a pyridylene group, and the phenylene or pyridylene group is optionally further selected from 0 to 4, optionally selected from the group consisting of F, Cl, Br, CHF 2 , CF 3 , cyano, and Substituted with a substituent of an ethyl group, an ethyl group, an ethynyl group, a methoxy group, an ethoxy group, an -OCHF 2 , an -OCF 3 , an ethynyl group or a propynyl group;
  • R x is selected from H, methyl, ethyl or propyl;
  • R 4 and R 5 are each independently selected from H, methyl or ethyl
  • composition of the invention in some embodiments, is selected from one of the following compounds:
  • composition of the present invention in some embodiments, the active ingredient is a compound of the formula (I) and a salt thereof (I-1),
  • the pharmaceutical composition of the present invention in some embodiments, comprises at least one pharmaceutically acceptable carrier and excipient selected from the group consisting of lactose, mannitol, dextran, xylitol or amino acids, in some embodiments
  • the medium carrier is selected from the group consisting of lactose, and in some embodiments the carrier is selected from the group consisting of lactose monohydrate.
  • composition of the present invention in some embodiments, the carrier lactose monohydrate particle size distribution is characterized by D 50 ⁇ 145 ⁇ m and D 90 ⁇ 250 ⁇ m.
  • the excipient is selected from one or more of magnesium stearate or colloidal silicon, and in some embodiments, the excipient is selected from magnesium stearate.
  • composition of the present invention in some embodiments, has a magnesium stearate content of from 0.05 w/w% to 1.0% w/w%, and in some embodiments, a content of from 0.05 w/w% to 0.9% w/w.
  • the content is 0.1 w/w% ⁇ 0.9w/w%, 0.1w/w% ⁇ 0.8w/w%, 0.1w/w% ⁇ 0.7w/w% or 0.1w/w% ⁇ 0.6%w/w%, in some In embodiments, the content is from 0.2 w/w% to 0.9% w/w%, from 0.2 w/w% to 0.8% w/w%, from 0.2 w/w% to 0.7% w/w% or from 0.2 w/w%.
  • the content is from 0.3 w/w% to 0.9% w/w%, from 0.3 w/w% to 0.8% w/w%, from 0.3 w/w% to 0.7%. w/w% or 0.3 w/w% to 0.6% w/w%, in some embodiments, the content is from 0.4 w/w% to 0.9% w/w%, from 0.4 w/w% to 0.8% w/w.
  • the content is from 0.5 w/w% to 0.9% w/w%, 0.5 w/w% to 0.8% w/w%, 0.5 w/w% to 0.7% w/w% or 0.5 w/w% to 0.6% w/w%, in some embodiments, the content is 0.6 w /w% to 0.9% w/w%, 0.6 w/w% to 0.8% w/w% or 0.6 w/w% to 0.7% w/w%, in some embodiments, the content is 0.6% w/w %.
  • composition of the present invention in some embodiments, has a particle size distribution characteristic of magnesium stearate of D 50 ⁇ 15 ⁇ m and D90 ⁇ 30 ⁇ m.
  • compositions of the present invention in some embodiments, further comprise finely divided lactose monohydrate.
  • the fine powder lactose monohydrate content is from 1 w/w% to 15 w/w%, from 1 w/w% to 14 w/w%, from 1 w/w% to 13 w/w%, 1w/w% to 12w/w%, 1w/w% to 11w/w%, 1w/w% to 10w/w% or 1w/w% to 9w/w%, in some embodiments, fine powder lactose The hydrate content is 2w/w% to 15w/w%, 2w/w% to 14w/w%, 2w/w% to 13w/w%, 2w/w% to 12w/w%, 2w/w% to 11w /w%, 2w/w% to 10w/w% or 2w/w% to 9w/w%, in some embodiments, the fine powder lactose monohydrate content is from 3w/w% to 15w/w%, 3w/ W% ⁇ 14w/
  • the fine powder lactose monohydrate content is 9w / w% ⁇ 15w / w% 9w/w% to 14w/w%, 9w/w% to 13w/w%, 9w/w% to 12w/w%, 9w/w% to 11w/w% or 9w/w% to 10w/w% In some embodiments, the finely divided lactose monohydrate content is 9 w/w%.
  • composition of the present invention in some embodiments, has a particle size distribution characteristic of fine powder lactose monohydrate of D 50 ⁇ 5 ⁇ m and D 90 ⁇ 10 ⁇ m.
  • composition of the present invention comprises 0.04 w/w% to 1.5 w/w% of the active ingredient of the compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt thereof, or the like.
  • Crystal or prodrug in some embodiments, the active ingredient content is from 0.1 w/w% to 1.5 w/w%, from 0.1 w/w% to 1.4 w/w%, from 0.1 w/w% to 1.3 w/w%.
  • 0.1w/w% to 1.2w/w% 0.1w/w% to 1.0w/w%, 0.1w/w% to 0.9w/w% or 0.1w/w% to 0.8w/w%, in In some embodiments, 0.2 w/w% to 1.5 w/w%, 0.2 w/w% to 1.4 w/w%, 0.2 w/w% to 1.3 w/w%, 0.2 w/w% to 1.2 w are included.
  • composition of the invention in some embodiments, comprises 0.4% of the active ingredient of the compound of formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or anterior thereof
  • the drug is 0.1% to 0.6% magnesium stearate, 3% to 9% fine powder lactose monohydrate and carrier lactose monohydrate.
  • the micronized active ingredient of the compound of formula (II) is produced using known methods, such as milling, direct precipitation, spray drying, freeze drying or supercritical fluids, to produce the desired particle size. Active ingredient.
  • the micronized active ingredient of the compound of the formula (II) has a particle size which satisfies the requirements of the dry powder inhaler.
  • the micronized active ingredient of formula (II) compound D 90 is less than 10um, in some embodiments, the micronized active ingredient of formula (II) compound D 90 is less than 7um, in some embodiments, micronized the active ingredients of formula (II) compound D 90 of less than 5um, in some embodiments, the micronized active ingredient of formula (II) compound D 90 is less than 4um.
  • the pharmaceutical composition of the invention is an inhalable powder.
  • the invention also relates to a method of preparing the pharmaceutical composition, comprising:
  • the carrier and the auxiliary materials are thoroughly mixed, and then thoroughly mixed with the micronized compound of the formula (II) to obtain a dry powder, which is divided into capsules;
  • the carrier and the auxiliary material are thoroughly mixed, and then thoroughly mixed with the fine powdered lactose monohydrate, and then thoroughly mixed with the micronized compound of the formula (II) to obtain a dry powder, which is divided into capsules;
  • compositions of the invention are prepared by mixing in a high shear mixer.
  • the carrier is selected from the group consisting of lactose monohydrate and the adjuvant is selected from magnesium stearate.
  • the invention also relates to the use of a composition thereof for the manufacture of a medicament for the treatment of an airway obstructive disease.
  • composition of the invention in the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
  • the invention in another aspect, relates to a method of treating an airway obstructive disease comprising administering an effective amount of a composition of the invention.
  • the inhalation powder of the present invention is a medicine prepared by filling a substance into a capsule (for example, a gelatin hollow capsule or a hypromellose hollow capsule), a vesicle (for example, an aluminum foam or a plastic foam), or other suitable means.
  • a capsule for example, a gelatin hollow capsule or a hypromellose hollow capsule
  • a vesicle for example, an aluminum foam or a plastic foam
  • a hypromellose hollow capsule is preferred.
  • the carrier amino acid includes alanine, valine, isoleucine, glycine, phenylalanine, valine, tryptophan, serine, tyrosine, cysteine, methionine, glutamic acid, Threonine, aspartic acid, glutamine, lysine, arginine, histidine and asparagine.
  • composition of the present invention may be an inhalation powder formulation, and the inhalation powder mist preparation obtained by the preparation method of the present invention overcomes the technical problem of poor stability of the inhalation powder and low amount of the active ingredient reaching the diseased part.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol Base, n-octyl, n-decyl and n-decyl, etc.; the alkyl group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl,
  • Alkoxy means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy , 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy Wait.
  • alkenyl means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-hep
  • Alkenylene refers to a divalent alkenyl group wherein the alkenyl group is as defined above.
  • Alkynyl means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group
  • Alkynylene refers to a divalent alkynyl group wherein the alkynyl group is as defined above.
  • Cycloalkyl means a monovalent saturated carbocyclic hydrocarbon group, usually having from 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Cycloalkylene refers to a divalent cycloalkyl group wherein cycloalkyl is as defined above.
  • Aryl means a monovalent aromatic hydrocarbon radical having a monocyclic or fused ring, usually having from 6 to 10 carbon atoms, and non-limiting examples include phenyl, naphthalen-1-yl or naphthalen-2-yl.
  • Arylene means a divalent aryl group wherein the aryl group is as defined above.
  • Heteroaryl means a monovalent aryl group having a single ring or two fused rings and containing at least one hetero atom selected from N, O or S in the ring, usually having an atomic composition of 5 to 8 members, Non-limiting examples include pyrrolyl, imidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl or pyrazinyl.
  • Heteroarylene means a divalent heteroaryl group wherein the definition of heteroaryl is as described above.
  • Carbocyclyl or “carbocyclic” means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl -2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, naphthyl,
  • the carbocyclic group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl
  • Heterocyclyl or “heterocyclic” means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system comprising 1 to 4 heteroatoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidations state.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring.
  • ⁇ -adrenergic receptor binding group refers to a group capable of binding to a ⁇ -adrenergic receptor; for example, see review article “ ⁇ -adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ".
  • the above-mentioned groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627.
  • 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.
  • “Pharmaceutically acceptable salt” means safe, non-toxic and neither biologically nor otherwise undesirable, and including its pharmaceutically acceptable use for veterinary use as well as human pharmaceutical use, and having the desired Pharmacologically active salts, such as, but not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and/or phosphoric acid; or with organic acids such as acetic acid, trifluoroacetic acid, Propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4 -hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic
  • 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.
  • Prodrug means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • Effective dose refers to the amount of a compound that causes a physiological or medical response to 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.
  • Solvate means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • PFP refers to the percentage of tiny particles.
  • HPMC refers to hydroxypropyl methylcellulose
  • D50 average particle diameter of a particle group of different particle diameters.
  • the high shear mixer was purchased from Shanghai Dongfulong Technology Co., Ltd.
  • NTI Next Generation Impactor
  • the organic phase was dried over anhydrous sodium sulfate EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the carrier lactose monohydrate, micronized compound (I) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 min to obtain a dry powder 1; the dry powder 1 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule. .
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer and mixed at a speed of 1000 rpm for 10 min, and then mixed with the micronized compound (I) in a high shear mixer at a speed of 1000 rpm. At 20 min, dry powder 2 was obtained; dry powder 2 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer and mixed at a speed of 1000 rpm for 10 min, and then mixed with the micronized compound (I) in a high shear mixer at a speed of 1000 rpm. At 20 min, dry powder 3 was obtained; dry powder 3 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • Carrier lactose monohydrate 241.25g
  • Micronized compound (I) 1g Magnesium stearate 0.25g
  • Fine powder lactose monohydrate 7.5g
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 4; and the dry powder 4 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 5; and the dry powder 5 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • Test subjects Formulation 2, Formulation 4, Formulation 5.
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized baftentetrol was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 min to obtain a baftenterolrol dry powder preparation; the baftenterol dry powder preparation was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • Test substance Formulation 5 (Example 8), a positive compound baftenterol dry powder preparation (Example 11).
  • All male guinea pigs were purchased with Vitallihua (license number: SCXK (Beijing) 2012-0001), weighing 300-400 g, randomly divided into groups of 4 animals, and the experiment was started 1 day later.
  • the guinea pigs were fixed in a small animal single-concentration oral and nasal exposure system (Beijing Huironghe Technology Co., Ltd., HRH-MNE3026), and the guinea pigs were inhaled into a dry powder preparation at a concentration of 2000 mg/m 3 .
  • the dose administered per test article was controlled by adjusting the inhalation time.
  • Guinea pig enhanced respiratory intermittent (PenH) values were measured using a full volume oximeter (BUXCO) at 4 hours and 24 hours after dosing. Atomization was given to 3 mg/mL Mch with an atomization time of 36 seconds and a recording time of 7 minutes. The average PenH (PenH blank ) of the blank group was 1, and the PenH value of the positive and Formulation 5 (PenH sample ) animals was calculated as a fold change with respect to the blank.
  • the test formula for the airway ⁇ inhibition rate of the test substance: inhibition rate (%) (PenH blank -PenH sample ) / PenH blank * 100%. The results are shown in Table 3.
  • Formulation 5 is more potent against airway sputum than the positive compound baftenterol dry powder formulation.
  • the carrier lactose monohydrate, the micronized compound (I-1) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 min to obtain a dry powder 6; the dry powder 6 was filled with an aliquot of 25 mg into the No. 3 HPMC. In the capsule.
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for mixing at 1000 rpm for 10 min, and then the micronized compound (I-1) was added to a high shear mixer at 1000 rpm.
  • the mixture was mixed at a speed of 20 min to obtain a dry powder 7; the dry powder 7 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for mixing at 1000 rpm for 10 min, and then the micronized compound (I-1) was added to a high shear mixer at 1000 rpm.
  • the mixture was mixed at a speed of 20 min to obtain a dry powder 8; the dry powder 8 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • Carrier lactose monohydrate 241.0g Micronized compound (I-1) 1.25g Magnesium stearate 0.25g Fine powder lactose monohydrate 7.5g
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I-1) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 9; and the dry powder 9 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
  • Carrier lactose monohydrate 226.0g Micronized compound (I-1) 1.25g Magnesium stearate 0.25g Fine powder lactose monohydrate 22.5g
  • the carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I-1) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 10; and the dry powder 10 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.

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Abstract

The present invention relates to a pharmaceutical composition comprising a compound of formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, cocrystal, or prodrug thereof and a method for treating an obstructive airway disease. (II)

Description

一种氮杂环酰胺衍生物组合物及其制备Azaheteroamide derivative composition and preparation thereof 技术领域Technical field
本发明属于医药领域，涉及一种氮杂环酰胺衍生物组合物及其制备方法，及其在气道阻塞性疾病的应用，特别是在哮喘、慢性阻塞性肺疾病或支气管炎中的应用，还涉及给予一种氮杂环酰胺衍生物组合物用于哮喘、慢性阻塞性肺疾病或支气管炎的方法。The invention belongs to the field of medicine and relates to a nitrogen heterocyclic amide derivative composition and a preparation method thereof, and the application thereof in airway obstructive diseases, particularly in asthma, chronic obstructive pulmonary disease or bronchitis, It also relates to a method of administering a composition of aziridine amide derivative for asthma, chronic obstructive pulmonary disease or bronchitis.
背景技术Background technique
支气管扩张剂对于呼吸疾病例如慢性阻塞性肺疾病(COPD)及哮喘等的治疗起重要作用。临床中广泛使用的支气管扩张剂包括毒蕈碱受体拮抗剂和β 2-肾上腺素能激动剂。毒蕈碱受体拮抗剂通过降低气道平滑肌的迷走神经胆碱能水平来发挥支气管扩张的效力。目前所使用的吸入毒蕈碱受体拮抗剂包括异丙托溴铵、氧托溴铵、格隆溴铵、噻托溴铵、阿地溴胺和芜地溴胺。β 2-肾上腺素能激动剂通过刺激气道平滑肌的肾上腺素能受体而使支气管扩张，逆转支气管收缩剂对各种介质如乙酰胆碱的反应。目前所使用的β 2-肾上腺素能激动剂包括沙丁胺醇、沙美特罗、阿福特罗、福莫特罗、维兰特罗和茚达特罗。这些药物除了改善肺的功能，也可改善患者生活质量并减少病情恶化。 Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Widely used in clinical bronchodilators include muscarinic receptor antagonist and β 2 - adrenergic agonist. Muscarinic receptor antagonists exert potency in bronchiectasis by reducing the level of vagal cholinergic energy in airway smooth muscle. Inhaled muscarinic receptor antagonists currently used include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide. 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine. The β 2 -adrenergic agonists currently used include salbutamol, salmeterol, arformoterol, formoterol, vilantrol and indacaterol. In addition to improving lung function, these drugs can improve the quality of life of patients and reduce the deterioration of their condition.
随着更多的临床研究发现，证明联合使用毒蕈碱受体拮抗剂和β 2-肾上腺素能激动剂比单独使用其中一种治疗剂更有效，目前临床上将毒蕈碱受体拮抗剂和β 2-肾上腺素能激动剂制备成复方制剂，用于哮喘和中重度COPD的治疗，这类复方制剂主要包括Anoro Ellipta(芜地溴胺/维兰特罗)、Ultibro Breezhaler(格隆溴铵/茚达特罗)和异丙托溴胺/沙丁胺醇等。 As more clinical studies have found that the combination of muscarinic receptor antagonists and β 2 -adrenergic agonists is more effective than the use of one of the therapeutic agents alone, the current muscarinic receptor antagonists are clinically available. And β 2 -adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD. These compound preparations mainly include Anoro Ellipta (Ambroxol/Vylantro) and Ultibro Breezhaler (Glon Brom). Ammonium / indacaterol) and ipratropium bromide / salbutamol.
人们希望开发同时具有蕈毒碱受体拮抗和β 2-肾上腺素能激动双重作用的药物，这种双功能药物具有两种成分组合的药学优点，同时具备单一的分子药代动力学。这些化合物以单一治疗剂的形式给药，可以由两种不同且可能协同起效的作用模式提供支气管扩张作用。 It is desirable to develop while having muscarinic receptor antagonist and β 2 - adrenergic agonists dual-acting drugs, drugs with this dual function the advantages of both pharmaceutical ingredient combination, along with a single molecule pharmacokinetics. These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action.
因此，有必要开发新颖的同时具有蕈毒碱受体拮抗和β 2-肾上腺素能激动的双重活性药物，以提供更有效的单一治疗剂量或者复方制剂，为患者提供更多的临床用药选择。 Therefore, it is necessary to develop novel dual active drugs with both muscarinic receptor antagonism and β 2 -adrenergic agonism to provide more effective single therapeutic doses or combination preparations, providing patients with more clinical drug options.
发明内容Summary of the invention
本发明提供一种药物组合物，其中包含活性成分式(II)化合物或者其立体异构体、 水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，The present invention provides a pharmaceutical composition comprising a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof,
Figure PCTCN2018096249-appb-000001
Figure PCTCN2018096249-appb-000001
其中，among them,
R 1选自
Figure PCTCN2018096249-appb-000002
R 1 is selected from
Figure PCTCN2018096249-appb-000002
环C 1和环C 2各自独立的选自C 6-10碳环或5至10元杂环，所述碳环或杂环任选进一步被0至5个选自F、Cl、Br、I、CF 3、NH 2、OH、羧基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-S(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基或-C(＝O)O-C 1-4烷基的取代基所取代，且所述杂环含有1至3个选自N、O或S的杂原子； Ring C 1 and ring C 2 are each independently selected from a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, which is optionally further further selected from 0 to 5 selected from F, Cl, Br, I. , CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, -NHC 1-4 alkyl, -N (C 1 -4 alkyl) 2 , -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl or -C(=O)OC 1-4 alkyl Substituted, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;
环C 3选自4至7元含氮杂环，且所述的含氮杂环任选进一步被0至4个选自F、Cl、Br、I、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代，且所述含氮杂环含有1至3个选自N、O或S的杂原子； Ring C 3 is selected from a 4 to 7 membered nitrogen-containing heterocyclic ring, and said nitrogen-containing heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, cyano, CF 3 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, and said nitrogen-containing heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
R 2选自键或C 1-4亚烷基，所述亚烷基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 2 is selected from a bond or a C 1-4 alkylene group, and the alkylene group is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
X选自键、-O-、-C(＝O)O-、-OC(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-C(＝O)NR x-、-NR xC(＝O)-、-OC(＝O)NR x-、-NR xC(＝O)O-、-NR xC(＝O)NR x、-NR xS(＝O) 2-、-S(＝O) 2NR x-、-NR xS(＝O) 2NR x或-NR x-； X is selected from the group consisting of a bond, -O-, -C(=O)O-, -OC(=O)-, -S-, -S(=O)-, -S(=O) 2 -, -C( =O)NR x -, -NR x C(=O)-, -OC(=O)NR x -, -NR x C(=O)O-, -NR x C(=O)NR x , - NR x S(=O) 2 -, -S(=O) 2 NR x -, -NR x S(=O) 2 NR x or -NR x -;
R x各自独立选自H或者C 1-4烷基； R x is each independently selected from H or C 1-4 alkyl;
A选自键、C 6-10碳环或5至10元杂环，所述的碳环或杂环任选进一步被0至5个R A取代，且所述杂环含有1至4个选自N、O或S的杂原子； A is selected from a bond, a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R A and the heterocyclic ring contains 1 to 4 a hetero atom from N, O or S;
R A选自F、Cl、Br、I、OH、NH 2、羧基、氰基、硝基、(＝O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-OC 3-6环烷基、C 1-4烷硫基、-S(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-C(＝O)-C 1-4烷基、-C(＝O)O-C 1-4烷基、-OC(＝O)-C 1-4烷基、5至6元杂芳基或-C(＝O)NH 2，所述烷基、烷氧基、环烷基、烯基、炔基、杂芳基、NH 2和-C(＝O)NH 2任选进一步被0至4个选自F、Cl、Br、I、CF 3、C 1-4烷基、C 1-4烷氧基或-C(＝O)-C 1-4烷基的取代基所取代； R A is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, (=O), C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy, -OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1 -4 alkyl, -C(=O)-C 1-4 alkyl, -C(=O)OC 1-4 alkyl, -OC(=O)-C 1-4 alkyl, 5 to 6 Heteroaryl or -C(=O)NH 2 , said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, heteroaryl, NH 2 and -C(=O)NH 2 optionally further From 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O)-C 1-4 alkyl Replace
R 3选自C 1-6亚烷基，所述亚烷基任选进一步被0至5个选自R 3a的取代基所取代； R 3 is selected from C 1-6 alkylene, which is optionally further substituted with 0 to 5 substituents selected from R 3a ;
R 3a选自F、Cl、Br、I、氰基、OH、C 1-4烷基、C 1-4烷氧基、苯基或苯基-C 1-4亚烷 基； R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
作为选择，两个R 3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； Alternatively, two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
R 4、R 5各自独立的选自H或C 1-4烷基； R 4 and R 5 are each independently selected from H or C 1-4 alkyl;
Figure PCTCN2018096249-appb-000003
表示β-肾上腺素受体结合基团。
Figure PCTCN2018096249-appb-000003
Represents a β-adrenergic receptor binding group.
本发明提供一种药物组合物，其中包含0.3w/w％～0.9w/w％活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，The present invention provides a pharmaceutical composition comprising 0.3 w/w% to 0.9 w/w% of the active ingredient of the compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable Salt, eutectic or prodrug,
Figure PCTCN2018096249-appb-000004
Figure PCTCN2018096249-appb-000004
其中，among them,
R 1选自
Figure PCTCN2018096249-appb-000005
R 1 is selected from
Figure PCTCN2018096249-appb-000005
环C 1和环C 2各自独立的选自C 6-10碳环或5至10元杂环，所述碳环或杂环任选进一步被0至5个选自F、Cl、Br、I、CF 3、NH 2、OH、羧基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-S(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基或-C(＝O)O-C 1-4烷基的取代基所取代，且所述杂环含有1至3个选自N、O或S的杂原子； Ring C 1 and ring C 2 are each independently selected from a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, which is optionally further further selected from 0 to 5 selected from F, Cl, Br, I. , CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, -NHC 1-4 alkyl, -N (C 1 -4 alkyl) 2 , -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl or -C(=O)OC 1-4 alkyl Substituted, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;
环C 3选自4至7元含氮杂环，且所述的含氮杂环任选进一步被0至4个选自F、Cl、Br、I、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代，且所述含氮杂环含有1至3个选自N、O或S的杂原子； Ring C 3 is selected from a 4 to 7 membered nitrogen-containing heterocyclic ring, and said nitrogen-containing heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, cyano, CF 3 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, and said nitrogen-containing heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
R 2选自键或C 1-4亚烷基，所述亚烷基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 2 is selected from a bond or a C 1-4 alkylene group, and the alkylene group is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
X选自键、-O-、-C(＝O)O-、-OC(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-C(＝O)NR x-、-NR xC(＝O)-、-OC(＝O)NR x-、-NR xC(＝O)O-、-NR xC(＝O)NR x、-NR xS(＝O) 2-、-S(＝O) 2NR x-、-NR xS(＝O) 2NR x或-NR x-； X is selected from the group consisting of a bond, -O-, -C(=O)O-, -OC(=O)-, -S-, -S(=O)-, -S(=O) 2 -, -C( =O)NR x -, -NR x C(=O)-, -OC(=O)NR x -, -NR x C(=O)O-, -NR x C(=O)NR x , - NR x S(=O) 2 -, -S(=O) 2 NR x -, -NR x S(=O) 2 NR x or -NR x -;
R x各自独立选自H或者C 1-4烷基； R x is each independently selected from H or C 1-4 alkyl;
A选自键、C 6-10碳环或5至10元杂环，所述的碳环或杂环任选进一步被0至5个 R A取代，且所述杂环含有1至4个选自N、O或S的杂原子； A is selected from a bond, a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R A and the heterocyclic ring contains 1 to 4 a hetero atom from N, O or S;
R A选自F、Cl、Br、I、OH、NH 2、羧基、氰基、硝基、(＝O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-OC 3-6环烷基、C 1-4烷硫基、-S(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-C(＝O)-C 1-4烷基、-C(＝O)O-C 1-4烷基、-OC(＝O)-C 1-4烷基、5至6元杂芳基或-C(＝O)NH 2，所述烷基、烷氧基、环烷基、烯基、炔基、杂芳基、NH 2和-C(＝O)NH 2任选进一步被0至4个选自F、Cl、Br、I、CF 3、C 1-4烷基、C 1-4烷氧基或-C(＝O)-C 1-4烷基的取代基所取代； R A is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, (=O), C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy, -OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1 -4 alkyl, -C(=O)-C 1-4 alkyl, -C(=O)OC 1-4 alkyl, -OC(=O)-C 1-4 alkyl, 5 to 6 Heteroaryl or -C(=O)NH 2 , said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, heteroaryl, NH 2 and -C(=O)NH 2 optionally further From 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O)-C 1-4 alkyl Replace
R 3选自C 1-6亚烷基，所述亚烷基任选进一步被0至5个选自R 3a的取代基所取代； R 3 is selected from C 1-6 alkylene, which is optionally further substituted with 0 to 5 substituents selected from R 3a ;
R 3a选自F、Cl、Br、I、氰基、OH、C 1-4烷基、C 1-4烷氧基、苯基或苯基-C 1-4亚烷基； R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
作为选择，两个R 3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； Alternatively, two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
R 4、R 5各自独立的选自H或C 1-4烷基； R 4 and R 5 are each independently selected from H or C 1-4 alkyl;
Figure PCTCN2018096249-appb-000006
表示β-肾上腺素受体结合基团。
Figure PCTCN2018096249-appb-000006
Represents a β-adrenergic receptor binding group.
本发明的药物组合物，在一些实施方案中，所述的活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中The pharmaceutical composition of the present invention, in some embodiments, the active ingredient of the compound of formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or former thereof Medicine, of which
R1选自自
Figure PCTCN2018096249-appb-000007
Figure PCTCN2018096249-appb-000008
R1 is selected from
Figure PCTCN2018096249-appb-000007
Figure PCTCN2018096249-appb-000008
R 2选自键、亚甲基、亚乙基或亚丙基； R 2 is selected from the group consisting of a bond, a methylene group, an ethylene group or a propylene group;
R 3选自亚甲基、亚乙基、亚丙基、-CH 2CH(CH 3)-、-CH(CH 3)CH 2-、-CH 2C(CH 3) 2-、-C(CH 3) 2CH 2-、亚丁基、-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH(CH 3)CH 2-、
Figure PCTCN2018096249-appb-000009
或亚戊基； R 3 is selected from the group consisting of methylene, ethylene, propylene, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 -, -C ( CH 3 ) 2 CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -,
Figure PCTCN2018096249-appb-000009
Or pentylene;
A选自键、亚苯基或亚吡啶基，所述的亚苯基或亚吡啶基任选进一步被0至4个任选自F、Cl、Br、CHF 2、CF 3、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、-OCHF 2、-OCF 3、乙炔基或丙炔基的取代基所取代； A is selected from a bond, a phenylene group or a pyridylene group, and the phenylene or pyridylene group is optionally further selected from 0 to 4, optionally selected from the group consisting of F, Cl, Br, CHF 2 , CF 3 , cyano, and Substituted with a substituent of an ethyl group, an ethyl group, an ethynyl group, a methoxy group, an ethoxy group, an -OCHF 2 , an -OCF 3 , an ethynyl group or a propynyl group;
X选自键、-O-、-C(＝O)NR x-、-NR xC(＝O)-、-OC(＝O)NR x-或-NR xC(＝O)O-；R x选自H、甲基、乙基或者丙基； X is selected from a bond, -O-, -C(=O)NR x -, -NR x C(=O)-, -OC(=O)NR x - or -NR x C(=O)O-; R x is selected from H, methyl, ethyl or propyl;
R 4、R 5各自独立的选自H、甲基或乙基； R 4 and R 5 are each independently selected from H, methyl or ethyl;
B选自
Figure PCTCN2018096249-appb-000010
Figure PCTCN2018096249-appb-000011
B is selected from
Figure PCTCN2018096249-appb-000010
Figure PCTCN2018096249-appb-000011
本发明的组合物，在一些实施方案中，所述式(II)化合物选自一下化合物之一：The composition of the invention, in some embodiments, the compound of formula (II) is selected from one of the following compounds:
Figure PCTCN2018096249-appb-000012
Figure PCTCN2018096249-appb-000013
Figure PCTCN2018096249-appb-000012
Figure PCTCN2018096249-appb-000013
本发明的组合物，在一些实施方案中，所述活性成分为化合物(I)及其盐式(I-1)化合物，The composition of the present invention, in some embodiments, the active ingredient is a compound of the formula (I) and a salt thereof (I-1),
Figure PCTCN2018096249-appb-000014
Figure PCTCN2018096249-appb-000014
本发明的药物组合物，在一些实施方案中，包含至少一种可药用的载体和辅料，所述的载体选自乳糖、甘露醇、葡聚糖、木糖醇或者氨基酸，在一些实施方案中载体选自乳糖，在一些实施方案中载体选自乳糖一水合物。The pharmaceutical composition of the present invention, in some embodiments, comprises at least one pharmaceutically acceptable carrier and excipient selected from the group consisting of lactose, mannitol, dextran, xylitol or amino acids, in some embodiments The medium carrier is selected from the group consisting of lactose, and in some embodiments the carrier is selected from the group consisting of lactose monohydrate.
本发明的组合物，在一些实施方案中，载体乳糖一水合物粒度分布特征为D 50≤145μm且D 90≤250μm。 The composition of the present invention, in some embodiments, the carrier lactose monohydrate particle size distribution is characterized by D 50 ≤ 145 μm and D 90 ≤ 250 μm.
本发明的组合物，在一些实施方案中，辅料选自硬脂酸镁或者胶体硅的一种或几种，在一些实施方案中，辅料选自硬脂酸镁。The composition of the present invention, in some embodiments, the excipient is selected from one or more of magnesium stearate or colloidal silicon, and in some embodiments, the excipient is selected from magnesium stearate.
本发明的组合物，在一些实施方案中，硬脂酸镁含量为0.05w/w％～1.0％w/w％，在一些实施方案中，含量为0.05w/w％～0.9％w/w％、0.05w/w％～0.8％w/w％、0.05w/w％～0.7％w/w％或0.05w/w％～0.6％w/w％，在一些实施方案中，含量为0.1w/w％～0.9w/w％、0.1w/w％～0.8w/w％、0.1w/w％～0.7w/w％或0.1w/w％～0.6％w/w％， 在一些实施方案中，含量为0.2w/w％～0.9％w/w％、0.2w/w％～0.8％w/w％、0.2w/w％～0.7％w/w％或0.2w/w％～0.6％w/w％，在一些实施方案中，含量为0.3w/w％～0.9％w/w％、0.3w/w％～0.8％w/w％、0.3w/w％～0.7％w/w％或0.3w/w％～0.6％w/w％，在一些实施方案中，含量为0.4w/w％～0.9％w/w％、0.4w/w％～0.8％w/w％、0.4w/w％～0.7％w/w％或0.4w/w％～0.6％w/w％，在一些实施方案中，含量为0.5w/w％～0.9％w/w％、0.5w/w％～0.8％w/w％、0.5w/w％～0.7％w/w％或0.5w/w％～0.6％w/w％，在一些实施方案中，含量为0.6w/w％～0.9％w/w％、0.6w/w％～0.8％w/w％或0.6w/w％～0.7％w/w％，在一些实施方案中，含量为0.6％w/w％。The composition of the present invention, in some embodiments, has a magnesium stearate content of from 0.05 w/w% to 1.0% w/w%, and in some embodiments, a content of from 0.05 w/w% to 0.9% w/w. %, 0.05 w/w% to 0.8% w/w%, 0.05 w/w% to 0.7% w/w% or 0.05 w/w% to 0.6% w/w%, in some embodiments, the content is 0.1 w/w%～0.9w/w%, 0.1w/w%～0.8w/w%, 0.1w/w%～0.7w/w% or 0.1w/w%～0.6%w/w%, in some In embodiments, the content is from 0.2 w/w% to 0.9% w/w%, from 0.2 w/w% to 0.8% w/w%, from 0.2 w/w% to 0.7% w/w% or from 0.2 w/w%. ～0.6% w/w%, in some embodiments, the content is from 0.3 w/w% to 0.9% w/w%, from 0.3 w/w% to 0.8% w/w%, from 0.3 w/w% to 0.7%. w/w% or 0.3 w/w% to 0.6% w/w%, in some embodiments, the content is from 0.4 w/w% to 0.9% w/w%, from 0.4 w/w% to 0.8% w/w. %, 0.4 w/w% to 0.7% w/w% or 0.4 w/w% to 0.6% w/w%, in some embodiments, the content is from 0.5 w/w% to 0.9% w/w%, 0.5 w/w% to 0.8% w/w%, 0.5 w/w% to 0.7% w/w% or 0.5 w/w% to 0.6% w/w%, in some embodiments, the content is 0.6 w /w% to 0.9% w/w%, 0.6 w/w% to 0.8% w/w% or 0.6 w/w% to 0.7% w/w%, in some embodiments, the content is 0.6% w/w %.
本发明的组合物，在一些实施方案中，硬脂酸镁粒度分布特征为D 50≤15μm且D90≤30μm。The composition of the present invention, in some embodiments, has a particle size distribution characteristic of magnesium stearate of D 50 ≤ 15 μm and D90 ≤ 30 μm.
本发明的组合物，在一些实施方案中，还包含细粉乳糖一水合物。The compositions of the present invention, in some embodiments, further comprise finely divided lactose monohydrate.
本发明的组合物，在一些实施方案中，细粉乳糖一水合物含量为1w/w％～15w/w％、1w/w％～14w/w％、1w/w％～13w/w％、1w/w％～12w/w％、1w/w％～11w/w％、1w/w％～10w/w％或1w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为2w/w％～15w/w％、2w/w％～14w/w％、2w/w％～13w/w％、2w/w％～12w/w％、2w/w％～11w/w％、2w/w％～10w/w％或2w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为3w/w％～15w/w％、3w/w％～14w/w％、3w/w％～13w/w％、3w/w％～12w/w％、3w/w％～11w/w％、3w/w％～10w/w％或3w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为4w/w％～15w/w％、4w/w％～14w/w％、4w/w％～13w/w％、4w/w％～12w/w％、4w/w％～11w/w％、4w/w％～10w/w％或4w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为5w/w％～15w/w％、5w/w％～14w/w％、5w/w％～13w/w％、5w/w％～12w/w％、5w/w％～11w/w％、5w/w％～10w/w％或5w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为6w/w％～15w/w％、6w/w％～14w/w％、6w/w％～13w/w％、6w/w％～12w/w％、6w/w％～11w/w％、6w/w％～10w/w％或6w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为7w/w％～15w/w％、7w/w％～14w/w％、7w/w％～13w/w％、7w/w％～12w/w％、7w/w％～11w/w％、7w/w％～10w/w％或7w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为8w/w％～15w/w％、8w/w％～14w/w％、8w/w％～13w/w％、8w/w％～12w/w％、8w/w％～11w/w％、8w/w％～10w/w％或8w/w％～9w/w％，在一些实施方案中，细粉乳糖一水合物含量为 9w/w％～15w/w％、9w/w％～14w/w％、9w/w％～13w/w％、9w/w％～12w/w％、9w/w％～11w/w％或9w/w％～10w/w％，在一些实施方案中，细粉乳糖一水合物含量为9w/w％。The composition of the present invention, in some embodiments, the fine powder lactose monohydrate content is from 1 w/w% to 15 w/w%, from 1 w/w% to 14 w/w%, from 1 w/w% to 13 w/w%, 1w/w% to 12w/w%, 1w/w% to 11w/w%, 1w/w% to 10w/w% or 1w/w% to 9w/w%, in some embodiments, fine powder lactose The hydrate content is 2w/w% to 15w/w%, 2w/w% to 14w/w%, 2w/w% to 13w/w%, 2w/w% to 12w/w%, 2w/w% to 11w /w%, 2w/w% to 10w/w% or 2w/w% to 9w/w%, in some embodiments, the fine powder lactose monohydrate content is from 3w/w% to 15w/w%, 3w/ W%～14w/w%, 3w/w%～13w/w%, 3w/w%～12w/w%, 3w/w%～11w/w%, 3w/w%～10w/w% or 3w/ W% ~ 9w / w%, in some embodiments, the fine powder lactose monohydrate content is 4w / w% ~ 15w / w%, 4w / w% ~ 14w / w%, 4w / w% ~ 13w / w %, 4w/w% to 12w/w%, 4w/w% to 11w/w%, 4w/w% to 10w/w% or 4w/w% to 9w/w%, in some embodiments, fine powder The lactose monohydrate content is 5w/w% to 15w/w%, 5w/w% to 14w/w%, 5w/w% to 13w/w%, 5w/w% to 12w/w%, 5w/w% 11w / w%, 5w / w% ~ 10w / w% or 5w / w% ~ 9w / w%, in some embodiments, the fine powder lactose monohydrate content is 6w / w% ~ 15w / w%, 6w /w%～14w/w%, 6w/w%～13w/w%, 6w/w%～12w/w%, 6w/w%～11w/w%, 6w/w%～10w/w% or 6w /w% ~ 9w / w%, in some embodiments, the fine powder lactose monohydrate content is 7w / w% ~ 15w / w%, 7w / w% ~ 14w / w%, 7w / w% ~ 13w / W%, 7w/w% to 12w/w%, 7w/w% to 11w/w%, 7w/w% to 10w/w% or 7w/w% to 9w/w%, in some embodiments, fine The content of the powdered lactose monohydrate is 8w/w% to 15w/w%, 8w/w% to 14w/w%, 8w/w% to 13w/w%, 8w/w% to 12w/w%, 8w/w. % ~ 11w / w%, 8w / w% ~ 10w / w% or 8w / w% ~ 9w / w%, in some embodiments, the fine powder lactose monohydrate content is 9w / w% ~ 15w / w% 9w/w% to 14w/w%, 9w/w% to 13w/w%, 9w/w% to 12w/w%, 9w/w% to 11w/w% or 9w/w% to 10w/w% In some embodiments, the finely divided lactose monohydrate content is 9 w/w%.
本发明的组合物，在一些实施方案中，细粉乳糖一水合物粒度分布特征为D 50≤5μm且D 90≤10μm。The composition of the present invention, in some embodiments, has a particle size distribution characteristic of fine powder lactose monohydrate of D 50 ≤ 5 μm and D 90 ≤ 10 μm.
本发明的组合物，包含0.04w/w％～1.5w/w％的活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，在一些实施方案中，活性成分含量为0.1w/w％～1.5w/w％、0.1w/w％～1.4w/w％、0.1w/w％～1.3w/w％、0.1w/w％～1.2w/w％、0.1w/w％～1.0w/w％、0.1w/w％～0.9w/w％或0.1w/w％～0.8w/w％，在一些实施方案中，包含0.2w/w％～1.5w/w％、0.2w/w％～1.4w/w％、0.2w/w％～1.3w/w％、0.2w/w％～1.2w/w％、0.2w/w％～1.0w/w％、0.2w/w％～0.9w/w％、0.2w/w％～0.8w/w％、0.2w/w％～0.7w/w％、0.2w/w％～0.6w/w％、0.2w/w％～0.5w/w％或0.2w/w％～0.4w/w％，在一些实施方案中，包含0.3w/w％～1.5w/w％、0.3w/w％～1.4w/w％、0.3w/w％～1.3w/w％、0.3w/w％～1.2w/w％、0.3w/w％～1.0w/w％、0.3w/w％～0.9w/w％、0.3w/w％～0.8w/w％、0.3w/w％～0.7w/w％、0.3w/w％～0.6w/w％、0.3w/w％～0.5w/w％或0.3w/w％～0.4w/w％，在一些实施方案中，包含0.4w/w％～1.5w/w％、0.4w/w％～1.4w/w％、0.4w/w％～1.3w/w％、0.4w/w％～1.2w/w％、0.4w/w％～1.0w/w％、0.4w/w％～0.9w/w％、0.4w/w％～0.8w/w％、0.4w/w％～0.7w/w％、0.4w/w％～0.6w/w％或0.4w/w％～0.5w/w％，在一些实施方案中，包含0.4％。The composition of the present invention comprises 0.04 w/w% to 1.5 w/w% of the active ingredient of the compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt thereof, or the like. Crystal or prodrug, in some embodiments, the active ingredient content is from 0.1 w/w% to 1.5 w/w%, from 0.1 w/w% to 1.4 w/w%, from 0.1 w/w% to 1.3 w/w%. 0.1w/w% to 1.2w/w%, 0.1w/w% to 1.0w/w%, 0.1w/w% to 0.9w/w% or 0.1w/w% to 0.8w/w%, in In some embodiments, 0.2 w/w% to 1.5 w/w%, 0.2 w/w% to 1.4 w/w%, 0.2 w/w% to 1.3 w/w%, 0.2 w/w% to 1.2 w are included. /w%, 0.2w/w% to 1.0w/w%, 0.2w/w% to 0.9w/w%, 0.2w/w% to 0.8w/w%, 0.2w/w% to 0.7w/w %, 0.2 w/w% to 0.6 w/w%, 0.2 w/w% to 0.5 w/w% or 0.2 w/w% to 0.4 w/w%, in some embodiments, 0.3 w/w% ~1.5w/w%, 0.3w/w% to 1.4w/w%, 0.3w/w% to 1.3w/w%, 0.3w/w% to 1.2w/w%, 0.3w/w% to 1.0 w/w%, 0.3w/w% to 0.9w/w%, 0.3w/w% to 0.8w/w%, 0.3w/w% to 0.7w/w%, 0.3w/w% to 0.6w/ w%, 0.3w/w% to 0.5w/w% or 0.3w/w% to 0.4w/ W%, in some embodiments, comprises 0.4 w/w% to 1.5 w/w%, 0.4 w/w% to 1.4 w/w%, 0.4 w/w% to 1.3 w/w%, 0.4 w/w %～1.2w/w%, 0.4w/w%～1.0w/w%, 0.4w/w%～0.9w/w%, 0.4w/w%～0.8w/w%, 0.4w/w%～ 0.7 w/w%, 0.4 w/w% to 0.6 w/w% or 0.4 w/w% to 0.5 w/w%, in some embodiments, 0.4%.
本发明的组合物，在一些实施方案中，包含0.4％的活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药、0.1％～0.6％的硬脂酸镁、3％～9％的细粉乳糖一水合物和载体用乳糖一水合物。The composition of the invention, in some embodiments, comprises 0.4% of the active ingredient of the compound of formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or anterior thereof The drug is 0.1% to 0.6% magnesium stearate, 3% to 9% fine powder lactose monohydrate and carrier lactose monohydrate.
本发明的组合物，在一些实施方案中，微粉化的活性成分式(II)化合物是使用已知的方法，例如研磨、直接沉淀、喷雾干燥、冷冻干燥或超临界流体，生产希望的粒度的活性成分。Compositions of the Invention, In some embodiments, the micronized active ingredient of the compound of formula (II) is produced using known methods, such as milling, direct precipitation, spray drying, freeze drying or supercritical fluids, to produce the desired particle size. Active ingredient.
本发明的组合物，微粉化的活性成分式(II)化合物粒径满足干粉吸入剂要求即可。在一些实施方案中，微粉化的活性成分式(II)化合物D 90小于10um，在一些实施方案中，微粉化的活性成分式(II)化合物D 90小于7um，在一些实施方案中，微粉化的活性成分式(II)化合物D 90小于5um，在一些实施方案中，微粉化的活性成分式(II)化合物D 90小于4um。 The composition of the present invention, the micronized active ingredient of the compound of the formula (II) has a particle size which satisfies the requirements of the dry powder inhaler. In some embodiments, the micronized active ingredient of formula (II) compound D 90 is less than 10um, in some embodiments, the micronized active ingredient of formula (II) compound D 90 is less than 7um, in some embodiments, micronized the active ingredients of formula (II) compound D 90 of less than 5um, in some embodiments, the micronized active ingredient of formula (II) compound D 90 is less than 4um.
本发明的药物组合物为可吸入的粉雾剂。The pharmaceutical composition of the invention is an inhalable powder.
本发明还涉及所述的药物组合物的制备方法，其包括：The invention also relates to a method of preparing the pharmaceutical composition, comprising:
(1)、将载体与微粉化的式(II)化合物充分混合，得到干粉，分装入胶囊；(1) fully mixing the carrier with the micronized compound of formula (II) to obtain a dry powder, which is divided into capsules;
或者，(2)、将载体和辅料充分混合，再与微粉化的式(II)化合物充分混合，得到干粉，分装入胶囊；Or, (2), the carrier and the auxiliary materials are thoroughly mixed, and then thoroughly mixed with the micronized compound of the formula (II) to obtain a dry powder, which is divided into capsules;
或者，(3)、将载体和辅料充分混合，接着与细粉乳糖一水合物充分混合，再与微粉化的式(II)化合物充分混合，得到干粉，分装入胶囊；Alternatively, (3), the carrier and the auxiliary material are thoroughly mixed, and then thoroughly mixed with the fine powdered lactose monohydrate, and then thoroughly mixed with the micronized compound of the formula (II) to obtain a dry powder, which is divided into capsules;
本发明组合物的制备是在高剪切混合机中混合的。The compositions of the invention are prepared by mixing in a high shear mixer.
本发明制备方法，在一些实施方案中，载体选自乳糖一水合物，辅料选自硬脂酸镁。The preparation process of the invention, in some embodiments, the carrier is selected from the group consisting of lactose monohydrate and the adjuvant is selected from magnesium stearate.
另一方面，本发明还涉及其组合物在制备用于治疗气道阻塞性疾病药物中的应用。In another aspect, the invention also relates to the use of a composition thereof for the manufacture of a medicament for the treatment of an airway obstructive disease.
本发明的组合物在制备用于治疗哮喘、慢性阻塞性肺疾病或支气管炎的药物中的应用。Use of a composition of the invention in the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
另一方面，本发明还涉及一种治疗气道阻塞性疾病的方法，其包括给予有效剂量的本发明的组合物。In another aspect, the invention relates to a method of treating an airway obstructive disease comprising administering an effective amount of a composition of the invention.
本发明所述的吸入粉雾剂是将物质填充入胶囊(例如明胶空心胶囊或羟丙甲纤维素空心胶囊)、泡囊(例如铝泡或者塑料泡)或其他合适的方式制备而成的药物，优选羟丙甲纤维素空心胶囊。The inhalation powder of the present invention is a medicine prepared by filling a substance into a capsule (for example, a gelatin hollow capsule or a hypromellose hollow capsule), a vesicle (for example, an aluminum foam or a plastic foam), or other suitable means. A hypromellose hollow capsule is preferred.
所述载体氨基酸包括丙氨酸、缬氨酸、异亮氨酸、甘氨酸、苯丙氨酸、脯氨酸、色胺酸、丝氨酸、酪氨酸、半胱氨酸、蛋氨酸、谷氨酸、苏氨酸、天冬氨酸、谷氨酰胺、赖氨酸、精氨酸、组胺酸和天冬酰胺。The carrier amino acid includes alanine, valine, isoleucine, glycine, phenylalanine, valine, tryptophan, serine, tyrosine, cysteine, methionine, glutamic acid, Threonine, aspartic acid, glutamine, lysine, arginine, histidine and asparagine.
本发明的组合物可为吸入粉雾制剂，通过本发明的制备方法获得的吸入粉雾制剂，克服了吸入粉雾剂稳定性差、有效成分到达患病部位量较低等技术难题。The composition of the present invention may be an inhalation powder formulation, and the inhalation powder mist preparation obtained by the preparation method of the present invention overcomes the technical problem of poor stability of the inhalation powder and low amount of the active ingredient reaching the diseased part.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
“烷基”是指直链和支链的一价饱和烃基，主链包括1至10个碳原子，优选为1至8 个碳原子，进一步优选为1至6个碳原子，更优选为1至4个碳原子的直链与支链基团，最优选1至2个碳原子，烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、正己基、正庚基、正辛基、正壬基和正癸基等；所述的烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) kC(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代，其中R 19和R 19a各自独立选自H、羟基、氨基、羧基、C 1-8烷基、C 1-8烷氧基、C 2-8烯基、C 2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环基氧基或者4至10元杂环基氧基，k选自0、1、2、3、4或者5，j选自0、1或者2。本文中出现的烷基、k、j、R 19和R 19a，其定义如上所述。 "Alkyl" means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol Base, n-octyl, n-decyl and n-decyl, etc.; the alkyl group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, - CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy Carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, -(CH 2 ) k C(=O)-R 19 , -(CH 2 ) k -C(=O ) -OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a group substituted with a substituent, wherein R 19 and R 19a are each Li is selected from H, hydroxyl, amino, carboxyl, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-10 yuan carbocyclyl, 4 to a 10-membered heterocyclic group, a 3 to 10 membered carbocyclic oxy group or a 4 to 10 membered heterocyclic oxy group, k is selected from 0, 1, 2, 3, 4 or 5, and j is selected from 0, 1 or 2. The alkyl groups, k, j, R 19 and R 19a appearing herein are as defined above.
“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；所述的亚烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代，当亚烷基中的取代基数量大于等于2个时，取代基可以稠合在一起形成环状结构。本文中出现的亚烷基，其定义如上所述。 "Alkylene" means a straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10), and alkylene examples include, but are not limited to, methylene, sub Ethyl, propylene, butylene, etc.; the alkylene group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, Carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O) -OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or - When the substituent of NR 19 R 19a is substituted, when the number of substituents in the alkylene group is 2 or more, the substituents may be fused together to form a cyclic structure. The alkylene groups appearing herein are as defined above.
“烷氧基”是指O-烷基的一价基团，其中，烷基如本文所定义，烷氧基实施例包括但不限于甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基等。"Alkoxy" means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy , 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy Wait.
“烯基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1- 辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；所述的烯基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的烯基，其定义如上所述。 "Alkenyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octene , 3-octenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2, -CF 3, -OCH 2 F, -OCHF 2, -OCF 3, hydroxyl, -SR 19, a nitro group, a cyano group, Cyano, alkyl, hydroxyalkyl, alkoxy, carbocyclic group, heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl, - (CH 2) a -C (= O) -R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j - Substituents of R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The alkenyl groups appearing herein are as defined above.
“亚烯基”是指二价烯基基团，其中烯基的定义如上所述。"Alkenylene" refers to a divalent alkenyl group wherein the alkenyl group is as defined above.
“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等；所述的炔基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的炔基，其定义如上所述。 "Alkynyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group may be optionally Further, 0, 1 , 2 , 3 , 4 or 5 are selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , - OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkyne Base, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a, - (CH 2) k -S (= O) j -R 19, -OC (= O) -OR 19 or -NR 19 R 19a substituents taken . The alkynyl groups appearing herein are as defined above.
“亚炔基”是指二价炔基基团，其中炔基的定义如上所述。"Alkynylene" refers to a divalent alkynyl group wherein the alkynyl group is as defined above.
“环烷基”是指一价饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的环烷基，其定义如上所述。 "Cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group, usually having from 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The cycloalkyl groups appearing herein are as defined above.
“亚环烷基”是指二价环烷基，其中环烷基的定义如上所述。"Cycloalkylene" refers to a divalent cycloalkyl group wherein cycloalkyl is as defined above.
“芳基”是指具有单环或稠合环的一价芳香族烃基，通常有6至10个碳原子，非限制性实施例包括苯基、萘-1-基或萘-2-基。所述的芳基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、 C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的芳基，其定义如上所述。 "Aryl" means a monovalent aromatic hydrocarbon radical having a monocyclic or fused ring, usually having from 6 to 10 carbon atoms, and non-limiting examples include phenyl, naphthalen-1-yl or naphthalen-2-yl. The aryl group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2-8 Alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k -C (=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or a substituent of -NR 19 R 19a is substituted. The aryl groups appearing herein are defined as described above.
“亚芳基”是指二价芳基，其中芳基的定义如上所述。"Arylene" means a divalent aryl group wherein the aryl group is as defined above.
“杂芳基”是指具有单环或两个稠合环并且在环中包含至少1个选自N、O或S的杂原子的一价芳基，通常有5至8元的原子组成，非限制性实施例包括吡咯基、咪唑基、噻唑基、噻吩基、呋喃基、吡唑基、异恶唑基、恶唑基、吡啶基或吡嗪基。所述的杂芳基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的杂芳基，其定义如上所述。 "Heteroaryl" means a monovalent aryl group having a single ring or two fused rings and containing at least one hetero atom selected from N, O or S in the ring, usually having an atomic composition of 5 to 8 members, Non-limiting examples include pyrrolyl, imidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl or pyrazinyl. The heteroaryl group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The heteroaryl groups appearing herein are as defined above.
“亚杂芳基”是指二价杂芳基，其中杂芳基的定义如上所述。"Heteroarylene" means a divalent heteroaryl group wherein the definition of heteroaryl is as described above.
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、苯基、萘基、
Figure PCTCN2018096249-appb-000015
所述的碳环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的碳环基，其定义如上所述。 "Carbocyclyl" or "carbocyclic" means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member. A tricyclic system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl -2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, naphthyl,
Figure PCTCN2018096249-appb-000015
The carbocyclic group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The carbocyclic group appearing herein is defined as described above.
“杂环基”或“杂环”是指饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系，且包含1至4个选自N、O或S的杂原子，优选3至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、 氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH 2F、-CHF 2、-CF 3、-OCH 2F、-OCHF 2、-OCF 3、羟基、-SR 19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C 2-8烯基、C 2-8炔基、-(CH 2) a-C(＝O)-R 19、-(CH 2) k-C(＝O)-O-R 19、-(CH 2) k-C(＝O)-NR 19R 19a、-(CH 2) k-S(＝O) j-R 19、-O-C(＝O)-O-R 19或者-NR 19R 19a的取代基所取代。本文中出现的杂环基，其定义如上所述。“β-肾上腺素受体结合基团”是指能够与β-肾上腺素能受体结合的基团；诸如参见综述文章“β-adrenergic receptors in Comprehensive Medicinal Chemistry，1990，B.E.Main，p187(Pergamon Press)”。上述基团也参见例如WO/2005092841、US/20050215542、WO/2005070872、WO/2006023460、WO/2006051373、WO/2006087315和WO/2006032627。非限制性实施例包括，R 4、R 5各自独立的选自H或C 1-4烷基，B选自
Figure PCTCN2018096249-appb-000016
Figure PCTCN2018096249-appb-000017
其中Q选自-CH＝CH-、-CH 2CH 2-、-O-、-S-、-CH 2O-、-OCH 2-、-C(CH 3) 2O-或-OC(CH 3) 2-。 "Heterocyclyl" or "heterocyclic" means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member. a tricyclic system comprising 1 to 4 heteroatoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidations state. The heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring. Butyl, azetidinyl, thioheterobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azacycloheptyl , oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyridyl Cyclo, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidine , dihydrofuranyl, dihydropyranyl, dithylpentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetra Hydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrroline, 3-pyrrolyl, indanyl, 2H-pyranyl, 4H-pyranyl, dioxa Cyclohexyl, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithienylalkyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2, 3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indole Quinazine, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]decyl, oxygen Heterotricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The heterocyclic group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The heterocyclic group appearing herein is as defined above. "β-adrenergic receptor binding group" refers to a group capable of binding to a β-adrenergic receptor; for example, see review article "β-adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ". The above-mentioned groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627. Non-limiting examples include that R 4 and R 5 are each independently selected from H or C 1-4 alkyl, and B is selected from
Figure PCTCN2018096249-appb-000016
Figure PCTCN2018096249-appb-000017
Wherein Q is selected from -CH=CH-, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -OCH 2 -, -C(CH 3 ) 2 O- or -OC(CH) 3 ) 2 -.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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.
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物，其中其它组分包含生理学/药学上可接受的载体和赋形剂。"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.
“药学上可接受的盐”是指安全、无毒的并且既不在生物学上也不在其它方面不合乎需要，并且包括其对于兽医使用以及人类药物使用上药学可接受的，并且具有所期望的药理学活性的盐，这样的盐包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸和/或磷酸等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、o-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、三氟甲磺酸、1,2-乙二磺酸、苯磺酸、对氯苯磺酸、2-萘磺酸、对甲苯磺酸、樟脑磺酸、4-甲基二环[2.2.2]辛-2-烯-1-羧酸、葡萄糖醛酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、2-羟基丙酸、草酸和/或黏糠酸等形成的酸加成盐。"Pharmaceutically acceptable salt" means safe, non-toxic and neither biologically nor otherwise undesirable, and including its pharmaceutically acceptable use for veterinary use as well as human pharmaceutical use, and having the desired Pharmacologically active salts, such as, but not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and/or phosphoric acid; or with organic acids such as acetic acid, trifluoroacetic acid, Propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4 -hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2- Naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucuronic acid, glucoheptonic acid, 3-phenylpropionic acid , trimethylacetic acid, t-butyl acetic acid, dodecyl sulfate, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, citric acid, lysine Acid addition salts of arginine, aspartic acid, 2-hydroxypropanoic acid, oxalic acid and / or clay and the like furoate.
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。"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.
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of 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.
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。"Effective dose" refers to the amount of a compound that causes a physiological or medical response to 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.
“溶剂化物”指本发明化合物或其盐，它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时，则为水合物。"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
“PFP”指微小粒子的百分比。"PFP" refers to the percentage of tiny particles.
“DD”：从吸入装置释放量。"DD": The amount released from the inhalation device.
“HPMC”指羟丙基甲基纤维素。"HPMC" refers to hydroxypropyl methylcellulose.
“D50”：不同粒径组成的粒子群的平均粒径。"D50": average particle diameter of a particle group of different particle diameters.
“D 90”90％的粒径范围值。 "D 90 " 90% particle size range value.
具体实施方式Detailed ways
以下结合实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solutions of the present invention are described in detail below with reference to the embodiments, but the scope of protection of the present invention includes but is not limited thereto.
高剪切混合机购自上海东富龙科技股份有限公司。The high shear mixer was purchased from Shanghai Dongfulong Technology Co., Ltd.
新一代撞击器(Next Generation Impactor，NGI)为购自英国COPLEY公司的设备。The Next Generation Impactor (NGI) is a device purchased from COPLEY, UK.
中间体1：[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-(4-甲酰基苯基)氨基甲酸酯(中间体1)Intermediate 1: [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-( 4-formylphenyl)carbamate (intermediate 1)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(4-formylphenyl)carbamate[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(4-formylphenyl)carbamate
Figure PCTCN2018096249-appb-000018
Figure PCTCN2018096249-appb-000018
第一步：4-[[4-(1,3-二氧戊环-2-基)苯基]氨基甲酰氧基甲基]哌啶-1-羧酸叔丁酯(1b)First step: 4-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyloxymethyl]piperidine-1-carboxylic acid tert-butyl ester (1b)
tert-butyl 4-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyloxymethyl]piperidine-1-carboxylateTert-butyl 4-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyloxymethyl]piperidine-1-carboxylate
Figure PCTCN2018096249-appb-000019
Figure PCTCN2018096249-appb-000019
将4-(羟基甲基)哌啶-1-羧酸叔丁酯(1a)(1.0g,4.64mmol)溶于二氯甲烷(20mL)中， 加入N,N-二异丙基乙胺(1.8g,13.9mmol)，0℃滴加三光气(0.689g,2.32mmol)的二氯甲烷(10mL)溶液，逐渐升至室温反应1小时，得反应液1，将4-(1,3-二氧戊环-2-基)苯胺(0.767g,4.64mmol)溶于四氢呋喃(20mL)中，加入N,N-二异丙基乙胺(1.8g,13.9mmol)，0℃滴加反应液1，逐渐升至室温反应1小时。反应液浓缩，加入二氯甲烷(30mL)和水(30mL)，萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:9～3:7)，得到标题化合物4-[[4-(1,3-二氧戊环-2-基)苯基]氨基甲酰氧基甲基]哌啶-1-羧酸叔丁酯(1b)，白色固体(0.850g，产率45％)。4-(Hydroxymethyl)piperidine-l-carboxylic acid tert-butyl ester (1a) (1.0 g, 4.64 mmol) was dissolved in dichloromethane (20 mL) and N,N-diisopropylethylamine ( 1.8 g, 13.9 mmol), a solution of triphosgene (0.689 g, 2.32 mmol) in dichloromethane (10 mL) was added dropwise at 0 ° C, and the mixture was gradually warmed to room temperature for 1 hour to obtain a reaction liquid 1 and 4-(1,3- Dioxol-2-yl)aniline (0.767 g, 4.64 mmol) was dissolved in tetrahydrofuran (20 mL), N,N-diisopropylethylamine (1.8 g, 13.9 mmol) was added, and the reaction mixture was added dropwise at 0 ° C. 1. Gradually raise to room temperature for 1 hour. The reaction mixture was concentrated, and dichloromethane (30 mL) was evaporated. (v/v) = 1:9 to 3:7), the title compound 4-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyloxymethyl]piperidyl tert-Butyl 1-carboxylic acid (1b), white solid (0.850 g, yield 45%).
LCMS m/z＝429.3[M+23]。LCMS m/z = 429.3 [M+23].
第二步：4-哌啶基甲基N-(4-甲酰基苯基)氨基甲酸酯(1c)Second step: 4-piperidinylmethyl N-(4-formylphenyl)carbamate (1c)
4-piperidylmethyl N-(4-formylphenyl)carbamate4-piperidylmethyl N-(4-formylphenyl)carbamate
Figure PCTCN2018096249-appb-000020
Figure PCTCN2018096249-appb-000020
将4-[[4-(1,3-二氧戊环-2-基)苯基]氨基甲酰氧基甲基]哌啶-1-羧酸叔丁酯(1b)(0.850g,2.09mmol)溶于二氯甲烷(15mL)中，加入三氟乙酸(1.19g,10.5mmol)，室温反应2小时。反应液加入氨水调节pH为8～9，加入二氯甲烷(20mL)和水(20mL)，萃取，水相用二氯甲烷(20mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物4-哌啶基甲基N-(4-甲酰基苯基)氨基甲酸酯(1c)，白色固体(0.490g，产率89.3％)。tert-Butyl 4-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyloxymethyl]piperidine-1-carboxylate (1b) (0.850 g, 2.09 Methyl) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (1.19 g, 10.5 mmol). The reaction solution was adjusted to pH 8 to 9 by addition of aqueous ammonia, and dichloromethane (20 mL) and water (20 mL) were added, and the aqueous phase was extracted with dichloromethane (20 mL × 1), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield was 89.3%).
LCMS m/z＝263.1[M+1]。LCMS m/z = 263.1 [M + 1].
第三步：[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-(4-甲酰基苯基)氨基甲酸酯(中间体1)Third step: [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-( 4-formylphenyl)carbamate (intermediate 1)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(4-formylphenyl)carbamate[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(4-formylphenyl)carbamate
Figure PCTCN2018096249-appb-000021
Figure PCTCN2018096249-appb-000021
将4-哌啶基甲基N-(4-甲酰基苯基)氨基甲酸酯(1c)(0.427g,1.63mmol)溶于二氯甲烷(15mL)中，依次加入3-[4-[(2-苯基苯基)氨基甲酰基氧基]-1-哌啶基]丙酸(1d)(0.600g,1.63mmol)，HATU(0.929g,2.44mmol)，2-异丙基乙基胺(1.68g,13.0mmol)，室温反应3 小时。反应液加入二氯甲烷(50mL)和水(50mL)，萃取，水相用二氯甲烷(20mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝3:97～1:19)，得到标题化合物[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-(4-甲酰基苯基)氨基甲酸酯(中间体1)，白色固体(0.740g，产率74.2％)。4-piperidinylmethyl N-(4-formylphenyl)carbamate (1c) (0.427 g, 1.63 mmol) was dissolved in dichloromethane (15 mL). (2-Phenylphenyl)carbamoyloxy]-1-piperidinyl]propionic acid (1d) (0.600 g, 1.63 mmol), HATU (0.929 g, 2.44 mmol), 2-isopropylethyl Amine (1.68 g, 13.0 mmol) was reacted at room temperature for 3 hours. The reaction mixture was poured into dichloromethane (50 mL) and water (50 mL), and evaporated. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 1:1 to 1:0, methanol: methylene chloride (v/v) = 3:97 to 1:19). The title compound [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-(4- Formylphenyl)carbamate (Intermediate 1), white solid (0.740 g, yield 74.2%).
1H NMR(400MHz,CDCl 3)δ9.88(s,1H),7.96(d,1H),7.85–7.76(m,2H),7.68–7.53(m,3H),7.52–7.43(m,2H),7.43–7.31(m,4H),7.23(dd,1H),7.20-7.12(m,1H),6.75(s,1H),4.90(s,1H),4.57(d,1H),4.06(d,2H),3.86(d,1H),3.28–2.82(m,10H),2.82–2.71(m,1H),2.64-2.51(m,1H),2.18-2.06(m,2H),2.00–1.85(m,3H),1.73(t,2H)。 1H NMR (400MHz, CDCl 3 ) δ 9.88 (s, 1H), 7.96 (d, 1H), 7.85 - 7.76 (m, 2H), 7.68 - 7.53 (m, 3H), 7.52 - 7.43 (m, 2H) , 7.43–7.31 (m, 4H), 7.23 (dd, 1H), 7.20-7.12 (m, 1H), 6.75 (s, 1H), 4.90 (s, 1H), 4.57 (d, 1H), 4.06 (d) , 2H), 3.86 (d, 1H), 3.28–2.82 (m, 10H), 2.82–2.71 (m, 1H), 2.64–2.51 (m, 1H), 2.18-2.06 (m, 2H), 2.00–1.85 (m, 3H), 1.73 (t, 2H).
LCMS m/z＝613.2[M+1]。LCMS m/z = 613.2 [M + 1].
实施例1Example 1
[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯二(2,2,2-三氟乙酸)(化合物1)[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate di(2,2 , 2-trifluoroacetic acid) (Compound 1)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate；di(2,2,2-trifluoroacetic acid)[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8 -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate;di(2,2,2-trifluoroacetic acid)
Figure PCTCN2018096249-appb-000022
Figure PCTCN2018096249-appb-000022
第一步：[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基] 苯基]氨基甲酸酯(1B)First step: [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[ 4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]phenyl]carbamate (1B)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]methyl]phenyl]carbamate[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-[tert-butyl(dimethyl) )silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ami no]methyl]phenyl]carbamate
Figure PCTCN2018096249-appb-000023
Figure PCTCN2018096249-appb-000023
将[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-(4-甲酰基苯基)氨基甲酸酯(中间体1)(0.400g,0.653mmol)溶于甲醇(10mL)中，加入(R)-5-(2-氨基-1-((叔丁基二甲基硅基)氧)乙基)-8-羟基喹啉-2(1H)-酮(1A)(0.262g,0.783mmol)，加入无水氯化锌(0.356g,2.61mmol)，55℃反应1小时，加入氰基硼氢化钠(0.123g,1.96mmol)，55℃反应2小时，反应液加入二氯甲烷(50mL)和饱和碳酸氢钠溶液(20mL)，萃取，水相用二氯甲烷(30mL×1)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(1B)，黄色固体(0.40g，产率65.8％)。[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-(4-A Acylphenyl)carbamate (Intermediate 1) (0.400 g, 0.653 mmol) was dissolved in methanol (10 mL) and (R)-5-(2-amino-1-((tert-butyldimethyl) Silyl)oxy)ethyl)-8-hydroxyquinolin-2(1H)-one (1A) (0.262 g, 0.783 mmol), added anhydrous zinc chloride (0.356 g, 2.61 mmol), reaction at 55 ° C After the addition of sodium cyanoborohydride (0.123 g, 1.96 mmol), and the mixture was reacted at 55 ° C for 2 hours. The reaction mixture was added dichloromethane (50 mL) and saturated sodium hydrogen carbonate (20 mL) The mixture was extracted with EtOAc (3 mL). Oxy]-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate (1B), yellow solid (0.40 g, yield 65.8 %).
LCMS m/z＝466.4[(M+2)/2]。LCMS m/z = 466.4 [(M+2)/2].
第二步：[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯二(2,2,2-三氟乙酸)(化合物1)Second step: [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[ 4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate II (2,2,2-trifluoroacetic acid) (Compound 1)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate；di(2,2,2-trifluoroacetic acid)[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8 -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate;di(2,2,2-trifluoroacetic acid)
Figure PCTCN2018096249-appb-000024
Figure PCTCN2018096249-appb-000024
将[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(1B)(0.400g,0.430mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟 酸盐(0.692g,4.30mmol)，室温反应24小时，反应液加入10％甲醇/二氯甲烷(v/v)溶液(50mL)，加入饱和碳酸氢钠溶液调节pH至8左右，萃取，水相用10％甲醇/二氯甲烷(v/v)溶液(20mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，乙腈(B)，等度洗脱B:A＝25％，洗脱时间20分钟)，得到标题化合物[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯；二(2,2,2-三氟乙酸)(化合物1)，白色固体(0.050g，产率11％)。[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[ [[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]- The phenyl]carbamate (1B) (0.400 g, 0.430 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (0.692 g, 4.30 mmol) was added and reacted at room temperature for 24 hours. Add 10% methanol / dichloromethane (v / v) solution (50mL), add saturated sodium bicarbonate solution to adjust the pH to about 8, extract, the aqueous phase with 10% methanol / dichloromethane (v / v) solution ( 20 mL x 2) extraction, combining the organic phases. The organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing Deionized water (A) of 0.05% TFA, acetonitrile (B), isocratic elution B: A = 25%, elution time 20 min), the title compound [1-[3-[4-[(2-) Phenylphenyl)carbamoyloxy]-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate; bis(2,2,2-trifluoroacetic acid) (Compound 1), White solid (0.050 g, yield 11%).
1H NMR(400MHz,CD 3OD)δ8.20(d,1H),7.54(d,3H),7.47–7.22(m,11H),7.02(d,1H),6.63(d,1H),5.37(t,1H),4.90(s,1H),4.56(d,1H),4.24(s,2H),4.05(d,2H),3.94(d,1H),3.59(s,1H),3.48(d,1H),3.39(s,2H),3.22–3.03(m,5H),2.92(s,2H),2.70(t,1H),2.22-1.95(m,4H),1.93-1.70(m,3H),1.40–1.10(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ8.20 (d, 1H), 7.54 (d, 3H), 7.47-7.22 (m, 11H), 7.02 (d, 1H), 6.63 (d, 1H), 5.37 (t, 1H), 4.90 (s, 1H), 4.56 (d, 1H), 4.24 (s, 2H), 4.05 (d, 2H), 3.94 (d, 1H), 3.59 (s, 1H), 3.48 ( d,1H), 3.39 (s, 2H), 3.22–3.03 (m, 5H), 2.92 (s, 2H), 2.70 (t, 1H), 2.22-1.95 (m, 4H), 1.93-1.70 (m, 3H), 1.40–1.10 (m, 2H).
19F NMR(376MHz,CD 3OD)δ-75.49。 19 F NMR (376 MHz, CD 3 OD) δ - 75.49.
LCMS m/z＝817.4[M+1]。LCMS m/z = 817.4 [M + 1].
实施例2Example 2
[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(化合物2)[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate (Compound 2)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8 -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate
Figure PCTCN2018096249-appb-000025
Figure PCTCN2018096249-appb-000025
将化合物1(0.040g,0.038mmol)溶于二氯甲烷(10mL)，加入饱和碳酸氢钠溶液，搅拌15分钟左右，检测反应液pH为8～9，分液，水层用二氯甲烷萃取，合并有机层，用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物2，淡黄色固体(0.025g，产率80.6％)。Compound 1 (0.040 g, 0.038 mmol) was dissolved in dichloromethane (10 mL), saturated sodium bicarbonate solution was added, stirred for about 15 minutes, the pH of the reaction mixture was 8-9, and the aqueous layer was extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate
1H NMR(400MHz,CD 3OD)δ8.27(d,1H),7.59(d,1H),7.48–7.36(m,8H),7.34-7.21(m,4H),7.22(d,1H),7.00(d,1H),6.63(d,1H),5.24(m,1H),4.65(m,1H),4.58(d,1H),4.07(m,3H),3.84(m,2H),3.17(m,1H),2.95-2.83(m,2H),2.72-2.61(m,7H),2.38(t,2H),2.02(m,1H),1.88(m,4H),1.66(m,2H),1.40-1.21(m,2H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.27 (d, 1H), 7.59 (d, 1H), 7.48 - 7.36 (m, 8H), 7.34-7.21 (m, 4H), 7.22 (d, 1H) , 7.00 (d, 1H), 6.63 (d, 1H), 5.24 (m, 1H), 4.65 (m, 1H), 4.58 (d, 1H), 4.07 (m, 3H), 3.84 (m, 2H), 3.17 (m, 1H), 2.95-2.83 (m, 2H), 2.72-2.61 (m, 7H), 2.38 (t, 2H), 2.02 (m, 1H), 1.88 (m, 4H), 1.66 (m, 2H), 1.40-1.21 (m, 2H).
LCMS m/z＝817.4[M+1]。LCMS m/z = 817.4 [M + 1].
实施例3Example 3
[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯柠檬酸盐(化合物3)[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate citrate (compound 3)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate；citric acid[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8 -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]car bamate;citric acid
Figure PCTCN2018096249-appb-000026
Figure PCTCN2018096249-appb-000026
将[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(化合物2)(60g,73mmol)溶于二氯甲烷(300mL)中，加入柠檬酸(14g,73mmol)，慢慢加入乙醇0.7L，常温搅拌20小时，将反应液过滤。用二氯甲烷/乙醇(0.5L,v/v＝9:1)打浆，过滤，重复打浆一次。真空干燥，得到化合物3，浅黄色固体(55g，HPLC:98.40％，产率74％)。[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[ [[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate (Compound 2) (60 g, 73 mmol) was dissolved in dichloromethane (300 mL), citric acid (14 g, 73 mmol) was added, and 0.7 L of ethanol was slowly added thereto, and the mixture was stirred at room temperature for 20 hours, and the reaction mixture was filtered. Beat with methylene chloride/ethanol (0.5 L, v/v = 9:1), filter, and repeat the beating once. Drying in vacuo gave compound 3 as a pale yellow solid (5 g, HPLC: 98.40%, yield 74%).
LCMS m/z＝409.4[(M+2)/2]。LCMS m/z = 409.4 [(M+2)/2].
1H NMR(400MHz,DMSO-d 6)δ9.72(s,1H),8.63(s,1H),8.07(d,1H),7.35(m,12H),7.10(d,1H),6.96(d,1H),6.54(d,1H),5.26(s,1H),4.49(s,1H),4.40(d,1H),3.96(m,5H),2.97(m,3H),2.66(m,4H),2.56(s,2H),2.53(s,2H),2.34(s,2H),1.91(s,1H),1.72(m,4H),1.48(s,2H),1.11(m,2H)。 1 H NMR (400MHz, DMSO- d 6) δ9.72 (s, 1H), 8.63 (s, 1H), 8.07 (d, 1H), 7.35 (m, 12H), 7.10 (d, 1H), 6.96 ( d, 1H), 6.54 (d, 1H), 5.26 (s, 1H), 4.49 (s, 1H), 4.40 (d, 1H), 3.96 (m, 5H), 2.97 (m, 3H), 2.66 (m) , 4H), 2.56 (s, 2H), 2.53 (s, 2H), 2.34 (s, 2H), 1.91 (s, 1H), 1.72 (m, 4H), 1.48 (s, 2H), 1.11 (m, 2H).
实施例4 制剂1的制备Example 4 Preparation of Formulation 1
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 249g249g
微粉化的化合物(I)Micronized compound (I) 1g1g
制备方法：Preparation:
将载体乳糖一水合物、微粉化的化合物(I)加入高剪切混合机中以1000转/min速度混合20min，得到干粉1；将干粉1以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate, micronized compound (I) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 min to obtain a dry powder 1; the dry powder 1 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule. .
实施例5 制剂2的制备Example 5 Preparation of Formulation 2
处方：prescription:
载体用乳糖一水合物Lactose monohydrate 248.75g248.75g
微粉化的化合物(I)Micronized compound (I) 1g1g
硬脂酸镁Magnesium stearate 0.25g0.25g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I)加入高剪切混合机中以1000转/min速度混合20min，得到干粉2；将干粉2以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer and mixed at a speed of 1000 rpm for 10 min, and then mixed with the micronized compound (I) in a high shear mixer at a speed of 1000 rpm. At 20 min, dry powder 2 was obtained; dry powder 2 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例6 制剂3的制备Example 6 Preparation of Formulation 3
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 247.5g247.5g
微粉化的化合物(I)Micronized compound (I) 1g1g
硬脂酸镁Magnesium stearate 1.5g1.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I)加入高剪切混合机中以1000转/min速度混合20min，得到干粉3；将干粉3以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer and mixed at a speed of 1000 rpm for 10 min, and then mixed with the micronized compound (I) in a high shear mixer at a speed of 1000 rpm. At 20 min, dry powder 3 was obtained; dry powder 3 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例7 制剂4的制备Example 7 Preparation of Formulation 4
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 241.25g241.25g
微粉化的化合物(I)Micronized compound (I) 1g1g
硬脂酸镁Magnesium stearate 0.25g0.25g
细粉乳糖一水合物Fine powder lactose monohydrate 7.5g7.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与细粉乳糖一水合物加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I)加入高剪切混合机中以1000转/min速度混合20min，得到干粉4；将干粉4以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 4; and the dry powder 4 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例8 制剂5的制备Example 8 Preparation of Formulation 5
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 226.25g226.25g
微粉化的化合物(I)Micronized compound (I) 1g1g
硬脂酸镁Magnesium stearate 0.25g0.25g
细粉乳糖一水合物Fine powder lactose monohydrate 22.5g22.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与细粉乳糖一水合物加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I)加入高剪切混合机中以1000转/min速度混合20min，得到干粉5；将干粉5以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 5; and the dry powder 5 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例9 制剂稳定性测试Example 9 Formulation Stability Test
测试对象：制剂1、制剂2、制剂3。Test subjects: Formulation 1, Formulation 2, Formulation 3.
方法：使用新一代撞击器(NGI)，以60L/min的流速测定各胶囊样品的DD值、FPF值，具体结果见表1。Methods: The DD value and FPF value of each capsule sample were measured by a new generation impactor (NGI) at a flow rate of 60 L/min. The specific results are shown in Table 1.
表1 各制剂样品的DD值和FPF值Table 1 DD value and FPF value of each preparation sample
Figure PCTCN2018096249-appb-000027
Figure PCTCN2018096249-appb-000027
结论：表明本发明处方粉雾剂有良好的物理稳定性。Conclusion: It shows that the prescription powder of the invention has good physical stability.
实施例10 制剂性能测试Example 10 Formulation Performance Test
测试对象：制剂2、制剂4、制剂5。Test subjects: Formulation 2, Formulation 4, Formulation 5.
方法：使用新一代撞击器(NGI)，以60L/min的流速测定各胶囊样品的FPF值，具体结果见表2。Method: The FPF value of each capsule sample was measured using a new generation impactor (NGI) at a flow rate of 60 L/min. The specific results are shown in Table 2.
表2 各制剂样品的FPF值Table 2 FPF values of each preparation sample
测定参数Measuring parameter 制剂2Formulation 2 制剂4Formulation 4 制剂5Formulation 5
FPF(％)FPF (%) 19.219.2 28.528.5 32.132.1
结论：表明本发明处方粉雾剂有良好的FPF值。Conclusion: It is shown that the prescription powder of the present invention has a good FPF value.
实施例11 Batefenterol干粉制剂的制备Example 11 Preparation of Batefenterol Dry Powder Formulation
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 226.52g226.52g
BatefenterolBatefenterol 0.73g0.73g
硬脂酸镁Magnesium stearate 0.25g0.25g
细粉乳糖一水合物Fine powder lactose monohydrate 22.5g22.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与细粉乳糖一水合物加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的batefenterol加入高剪切混合机中以1000转/min速度混合20min，得到batefenterol干粉制剂；将batefenterol干粉制剂以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized baftentetrol was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 min to obtain a baftenterolrol dry powder preparation; the baftenterolrol dry powder preparation was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例12 生物测试实验Example 12 Biological Test Experiment
1、测试物：制剂5(实施例8)、阳性化合物batefenterol干粉制剂(实施例11)。1. Test substance: Formulation 5 (Example 8), a positive compound baftenterol dry powder preparation (Example 11).
2、实验步骤：2. Experimental steps:
全雄豚鼠购置维通利华(许可证号：SCXK(京)2012-0001)，体重300-400g，随机分组，每组4只动物，适应1天后开始实验。将豚鼠固定于小动物单浓度口鼻暴露系统中(北京慧荣和科技有限公司，HRH-MNE3026)，使豚鼠吸入干粉制剂，给药浓度2000mg/m 3。通过调整吸入时间，控制每个测试物给药剂量。于给药后4小时和24小时，使用全体积描计仪(BUXCO)测量豚鼠增强呼吸间歇(PenH)值。雾化给予3mg/mL Mch，雾化时间36秒，记录时间7分钟。以blank组平均PenH(PenH blank)为1，计算阳性和制剂5(PenH 样品)动物PenH值相对于blank改变倍数。测试物气道痉挛抑制率计算公式：抑制率(％)＝(PenH blank-PenH 样品)/PenH blank*100％。结果见表3。 All male guinea pigs were purchased with Vitallihua (license number: SCXK (Beijing) 2012-0001), weighing 300-400 g, randomly divided into groups of 4 animals, and the experiment was started 1 day later. The guinea pigs were fixed in a small animal single-concentration oral and nasal exposure system (Beijing Huironghe Technology Co., Ltd., HRH-MNE3026), and the guinea pigs were inhaled into a dry powder preparation at a concentration of 2000 mg/m 3 . The dose administered per test article was controlled by adjusting the inhalation time. Guinea pig enhanced respiratory intermittent (PenH) values were measured using a full volume oximeter (BUXCO) at 4 hours and 24 hours after dosing. Atomization was given to 3 mg/mL Mch with an atomization time of 36 seconds and a recording time of 7 minutes. The average PenH (PenH blank ) of the blank group was 1, and the PenH value of the positive and Formulation 5 (PenH sample ) animals was calculated as a fold change with respect to the blank. The test formula for the airway 痉挛 inhibition rate of the test substance: inhibition rate (%) = (PenH blank -PenH sample ) / PenH blank * 100%. The results are shown in Table 3.
表3 气道痉挛抑制率Table 3 Airway enthalpy inhibition rate
Figure PCTCN2018096249-appb-000028
Figure PCTCN2018096249-appb-000028
结论：制剂5相比阳性化合物batefenterol干粉制剂对气道痉挛抑制更强。Conclusion: Formulation 5 is more potent against airway sputum than the positive compound baftenterol dry powder formulation.
实施例13 制剂6的制备Example 13 Preparation of Formulation 6
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 248.75g248.75g
微粉化的化合物(I-1)Micronized compound (I-1) 1.25g1.25g
制备方法：Preparation:
将载体乳糖一水合物、微粉化的化合物(I-1)加入高剪切混合机中以1000转/min速度混合20min，得到干粉6；将干粉6以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate, the micronized compound (I-1) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 min to obtain a dry powder 6; the dry powder 6 was filled with an aliquot of 25 mg into the No. 3 HPMC. In the capsule.
实施例14 制剂7的制备Example 14 Preparation of Formulation 7
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 248.5g248.5g
微粉化的化合物(I-1)Micronized compound (I-1) 1.25g1.25g
硬脂酸镁Magnesium stearate 0.25g0.25g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I-1)加入高剪切混合机中以1000转/min速度混合20min，得到干粉7；将干粉7以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for mixing at 1000 rpm for 10 min, and then the micronized compound (I-1) was added to a high shear mixer at 1000 rpm. The mixture was mixed at a speed of 20 min to obtain a dry powder 7; the dry powder 7 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例15 制剂8的制备Example 15 Preparation of Formulation 8
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 247.25g247.25g
微粉化的化合物(I-1)Micronized compound (I-1) 1.25g1.25g
硬脂酸镁Magnesium stearate 1.5g1.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I-1)加入高剪切混合机中以1000转/min速度混合20min，得到干粉8；将干粉8以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for mixing at 1000 rpm for 10 min, and then the micronized compound (I-1) was added to a high shear mixer at 1000 rpm. The mixture was mixed at a speed of 20 min to obtain a dry powder 8; the dry powder 8 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例16 制剂9的制备Example 16 Preparation of Formulation 9
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 241.0g241.0g
微粉化的化合物(I-1)Micronized compound (I-1) 1.25g1.25g
硬脂酸镁Magnesium stearate 0.25g0.25g
细粉乳糖一水合物Fine powder lactose monohydrate 7.5g7.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与细粉乳糖一水合物加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I-1)加入高剪切混合机中以1000转/min速度混合20min，得到干粉9；将干粉9以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I-1) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 9; and the dry powder 9 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例17 制剂10的制备Example 17 Preparation of Formulation 10
处方：prescription:
载体乳糖一水合物Carrier lactose monohydrate 226.0g226.0g
微粉化的化合物(I-1)Micronized compound (I-1) 1.25g1.25g
硬脂酸镁Magnesium stearate 0.25g0.25g
细粉乳糖一水合物Fine powder lactose monohydrate 22.5g22.5g
制备方法：Preparation:
将载体乳糖一水合物、硬脂酸镁加入高剪切混合机中以1000转/min速度混合10min，再与细粉乳糖一水合物加入高剪切混合机中以1000转/min速度混合10min，再与微粉化的化合物(I-1)加入高剪切混合机中以1000转/min速度混合20min，得到干粉 10；将干粉10以等分试样25mg装入3号HPMC胶囊中。The carrier lactose monohydrate and magnesium stearate were added to a high shear mixer for 10 min at 1000 rpm, and then mixed with fine powder lactose monohydrate in a high shear mixer at a speed of 1000 rpm for 10 min. Then, the micronized compound (I-1) was added to a high shear mixer and mixed at a speed of 1000 rpm for 20 minutes to obtain a dry powder 10; and the dry powder 10 was placed in an aliquot of 25 mg in a No. 3 HPMC capsule.
实施例18 制剂稳定性测试Example 18 Formulation Stability Test
测试对象：制剂6、制剂7、制剂8、制剂9、制剂10。Test subjects: Formulation 6, Formulation 7, Formulation 8, Formulation 9, Formulation 10.
方法：使用新一代撞击器(NGI)，以60L/min的流速测定各胶囊样品的FPF值，具体结果见表4。Method: The FPF value of each capsule sample was measured using a new generation impactor (NGI) at a flow rate of 60 L/min. The specific results are shown in Table 4.
表4 各制剂样品的FPF值Table 4 FPF values of each preparation sample
Figure PCTCN2018096249-appb-000029
Figure PCTCN2018096249-appb-000029
结论：表明本发明处方粉雾剂有良好FPF值。Conclusion: It is shown that the prescription powder of the present invention has a good FPF value.
虽然已经对本发明的具体实施方案进行了描述，但是本领域技术人员应认识到，在不偏离本发明的范围或精神的前提下可以对本发明进行多种改变与修饰。因而，本发明意欲涵盖落在附属权利要求书及其同等物范围内的所有这些改变与修饰。While the invention has been described with respect to the specific embodiments of the present invention, it will be understood that Accordingly, the invention is intended to embrace all such modifications and alternatives

Claims (22)

  1. 一种药物组合物，其特征在于包含0.3w/w％～0.9w/w％活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，A pharmaceutical composition comprising 0.3 w/w% to 0.9 w/w% of an active ingredient of a compound of formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt thereof , eutectic or prodrug,
    Figure PCTCN2018096249-appb-100001
    Figure PCTCN2018096249-appb-100001
    其中，among them,
    R 1选自
    Figure PCTCN2018096249-appb-100002
    R 1 is selected from
    Figure PCTCN2018096249-appb-100002
    环C 1和环C 2各自独立的选自C 6-10碳环或5至10元杂环，所述碳环或杂环任选进一步被0至5个选自F、Cl、Br、I、CF 3、NH 2、OH、羧基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-S(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基或-C(＝O)O-C 1-4烷基的取代基所取代，且所述杂环含有1至3个选自N、O或S的杂原子； Ring C 1 and ring C 2 are each independently selected from a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, which is optionally further further selected from 0 to 5 selected from F, Cl, Br, I. , CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, -NHC 1-4 alkyl, -N (C 1 -4 alkyl) 2 , -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl or -C(=O)OC 1-4 alkyl Substituted, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;
    环C 3选自4至7元含氮杂环，且所述的含氮杂环任选进一步被0至4个选自F、Cl、Br、I、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代，且所述含氮杂环含有1至3个选自N、O或S的杂原子； Ring C 3 is selected from a 4 to 7 membered nitrogen-containing heterocyclic ring, and said nitrogen-containing heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, cyano, CF 3 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, and said nitrogen-containing heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
    R 2选自键或C 1-4亚烷基，所述亚烷基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 2 is selected from a bond or a C 1-4 alkylene group, and the alkylene group is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
    X选自键、-O-、-C(＝O)O-、-OC(＝O)-、-S-、-S(＝O)-、-S(＝O) 2-、-C(＝O)NR x-、-NR xC(＝O)-、-OC(＝O)NR x-、-NR xC(＝O)O-、-NR xC(＝O)NR x、-NR xS(＝O) 2-、-S(＝O) 2NR x-、-NR xS(＝O) 2NR x或-NR x-； X is selected from the group consisting of a bond, -O-, -C(=O)O-, -OC(=O)-, -S-, -S(=O)-, -S(=O) 2 -, -C( =O)NR x -, -NR x C(=O)-, -OC(=O)NR x -, -NR x C(=O)O-, -NR x C(=O)NR x , - NR x S(=O) 2 -, -S(=O) 2 NR x -, -NR x S(=O) 2 NR x or -NR x -;
    R x各自独立选自H或者C 1-4烷基； R x is each independently selected from H or C 1-4 alkyl;
    A选自键、C 6-10碳环或5至10元杂环，所述的碳环或杂环任选进一步被0至5个R A取代，且所述杂环含有1至4个选自N、O或S的杂原子； A is selected from a bond, a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R A and the heterocyclic ring contains 1 to 4 a hetero atom from N, O or S;
    R A选自F、Cl、Br、I、OH、NH 2、羧基、氰基、硝基、(＝O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-OC 3-6环烷基、C 1-4烷硫基、-S(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-C(＝O)-C 1-4烷基、-C(＝O)O-C 1-4烷基、-OC(＝O)-C 1-4烷基、5至6元杂芳基或-C(＝O)NH 2，所述烷基、烷氧基、环烷基、烯基、炔基、杂芳基、NH 2和-C(＝O)NH 2任选进一步被0至4个选自F、Cl、Br、I、CF 3、C 1-4烷基、C 1-4烷氧基或-C(＝O)-C 1-4烷基的取代基所取代； R A is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, (=O), C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy, -OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1 -4 alkyl, -C(=O)-C 1-4 alkyl, -C(=O)OC 1-4 alkyl, -OC(=O)-C 1-4 alkyl, 5 to 6 Heteroaryl or -C(=O)NH 2 , said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, heteroaryl, NH 2 and -C(=O)NH 2 optionally further From 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O)-C 1-4 alkyl Replace
    R 3选自C 1-6亚烷基，所述亚烷基任选进一步被0至5个选自R 3a的取代基所取代； R 3 is selected from C 1-6 alkylene, which is optionally further substituted with 0 to 5 substituents selected from R 3a ;
    R 3a选自F、Cl、Br、I、氰基、OH、C 1-4烷基、C 1-4烷氧基、苯基或苯基-C 1-4亚烷基； R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
    作为选择，两个R 3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； Alternatively, two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
    R 4、R 5各自独立的选自H或C 1-4烷基； R 4 and R 5 are each independently selected from H or C 1-4 alkyl;
    Figure PCTCN2018096249-appb-100003
    表示β-肾上腺素受体结合基团。
    Figure PCTCN2018096249-appb-100003
    Represents a β-adrenergic receptor binding group.
  2. 根据权利要求1所述的组合物，其特征在于包含0.3w/w％～0.9w/w％活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的The composition according to claim 1, characterized in that it comprises 0.3 w/w% to 0.9 w/w% of the active ingredient of the compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically Acceptable
    盐、共晶或前药，其中Salt, eutectic or prodrug, of which
    R 1选自
    Figure PCTCN2018096249-appb-100004
    Figure PCTCN2018096249-appb-100005
    R 1 is selected from
    Figure PCTCN2018096249-appb-100004
    Figure PCTCN2018096249-appb-100005
    R 2选自键、亚甲基、亚乙基或亚丙基； R 2 is selected from the group consisting of a bond, a methylene group, an ethylene group or a propylene group;
    R 3选自亚甲基、亚乙基、亚丙基、-CH 2CH(CH 3)-、-CH(CH 3)CH 2-、-CH 2C(CH 3) 2-、-C(CH 3) 2CH 2-、亚丁基、-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH(CH 3)CH 2-、
    Figure PCTCN2018096249-appb-100006
    或亚戊基；     R 3 is selected from the group consisting of methylene, ethylene, propylene, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 -, -C ( CH 3 ) 2 CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -,
    Figure PCTCN2018096249-appb-100006
    Or pentylene;
    A选自键、亚苯基或亚吡啶基，所述的亚苯基或亚吡啶基任选进一步被0至4个任选自F、Cl、Br、CHF 2、CF 3、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、-OCHF 2、-OCF 3、乙炔基或丙炔基的取代基所取代； A is selected from a bond, a phenylene group or a pyridylene group, and the phenylene or pyridylene group is optionally further selected from 0 to 4, optionally selected from the group consisting of F, Cl, Br, CHF 2 , CF 3 , cyano, and Substituted with a substituent of an ethyl group, an ethyl group, an ethynyl group, a methoxy group, an ethoxy group, an -OCHF 2 , an -OCF 3 , an ethynyl group or a propynyl group;
    X选自键、-O-、-C(＝O)NR x-、-NR xC(＝O)-、-OC(＝O)NR x-或-NR xC(＝O)O-；R x选 自H、甲基、乙基或者丙基； X is selected from a bond, -O-, -C(=O)NR x -, -NR x C(=O)-, -OC(=O)NR x - or -NR x C(=O)O-; R x is selected from H, methyl, ethyl or propyl;
    R 4、R 5各自独立的选自H、甲基或乙基； R 4 and R 5 are each independently selected from H, methyl or ethyl;
    B选自
    Figure PCTCN2018096249-appb-100007
    Figure PCTCN2018096249-appb-100008
    B is selected from
    Figure PCTCN2018096249-appb-100007
    Figure PCTCN2018096249-appb-100008
  3. 根据权利要求2所述的组合物，其特征在于活性成分式(II)化合物选自一下化合物之一：The composition according to claim 2, wherein the active ingredient compound of formula (II) is selected from one of the following compounds:
    Figure PCTCN2018096249-appb-100009
    Figure PCTCN2018096249-appb-100009
    Figure PCTCN2018096249-appb-100010
    Figure PCTCN2018096249-appb-100010
  4. 根据权利要求3所述的组合物，其特征在于活性成分式(II)化合物选自化合物(I)及其盐式(I-1)，The composition according to claim 3, wherein the active ingredient compound of the formula (II) is selected from the group consisting of the compound (I) and a salt thereof (I-1).
    Figure PCTCN2018096249-appb-100011
    Figure PCTCN2018096249-appb-100011
  5. 根据权利要求1所述的药物组合物，其特征在于包含至少一种可药用的载体和辅料。A pharmaceutical composition according to claim 1 comprising at least one pharmaceutically acceptable carrier and adjuvant.
  6. 根据权利要求5所述的药物组合物，其特征在于所述的载体选自乳糖、甘露醇、葡聚糖、木糖醇或者氨基酸，优选乳糖，再优选乳糖一水合物。The pharmaceutical composition according to claim 5, characterized in that the carrier is selected from the group consisting of lactose, mannitol, dextran, xylitol or an amino acid, preferably lactose, and more preferably lactose monohydrate.
  7. 根据权利要求6所述的药物组合物，其特征在于所述的乳糖一水合物粒度分布特征为D 50≤145μm且D 90≤250μm。 The pharmaceutical composition according to claim 6, wherein said lactose monohydrate has a particle size distribution characteristic of D 50 ≤ 145 μm and D 90 ≤ 250 μm.
  8. 根据权利要求5所述的药物组合物，其特征在于所述的辅料选自硬脂酸镁或者胶体硅的一种或几种，优选硬脂酸镁。The pharmaceutical composition according to claim 5, characterized in that the adjuvant is selected from one or more of magnesium stearate or colloidal silicon, preferably magnesium stearate.
  9. 根据权利要求8所述的药物组合物，其特征在于所述的硬脂酸镁含量为0.05w/w％～1.0％w/w％，优选0.1w/w％～0.6％w/w％，再优选0.6％w/w％。The pharmaceutical composition according to claim 8, wherein the magnesium stearate content is from 0.05 w/w% to 1.0% w/w%, preferably from 0.1 w/w% to 0.6% w/w%, More preferably, it is 0.6% w/w%.
  10. 根据权利要求9所述的药物组合物，其特征在于所述的硬脂酸镁粒度分布特征为D50≤15μm且D90≤30μm。The pharmaceutical composition according to claim 9, wherein said magnesium stearate has a particle size distribution characteristic of D50 ≤ 15 μm and D90 ≤ 30 μm.
  11. 根据权利要求5所述的药物组合物，其特征在于还包含细粉乳糖一水合物。The pharmaceutical composition according to claim 5, which further comprises finely divided lactose monohydrate.
  12. 根据权利要求11所述的药物组合物，其特征在于所述的细粉乳糖一水合物含量为1w/w％～15w/w％，优选3w/w％～9w/w％，再优选9w/w％。The pharmaceutical composition according to claim 11, wherein the fine powdered lactose monohydrate has a content of from 1 w/w% to 15 w/w%, preferably from 3 w/w% to 9 w/w%, more preferably 9 w/ w%.
  13. 根据权利要求12所述的药物组合物，其特征在于所述的细粉乳糖一水合物粒度分布特征为D50≤5μm且D90≤10μm。The pharmaceutical composition according to claim 12, wherein said fine powder lactose monohydrate has a particle size distribution characteristic of D50 ≤ 5 μm and D90 ≤ 10 μm.
  14. 根据权利要求1所述的药物组合物，其特征在于包含：0.4w/w％的活性成分式(II)化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药。The pharmaceutical composition according to Claim 1, which comprises: 0.4 w/w% of the active ingredient of the compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable Salt, eutectic or prodrug.
  15. 根据权利要求14所述的药物组合物，其特征在于还包含0.1％～0.6％的硬脂酸镁，3％～9％的细粉乳糖一水合物和余量的载体乳糖一水合物。The pharmaceutical composition according to claim 14, further comprising 0.1% to 0.6% of magnesium stearate, 3% to 9% of finely divided lactose monohydrate and the balance of carrier lactose monohydrate.
  16. 根据权利要求1-15任一项所述的药物组合物，其特征在于所述组合物为可吸入的粉雾剂。The pharmaceutical composition according to any one of claims 1 to 15, characterized in that the composition is an inhalable powder.
  17. 一种权利要求1所述的药物组合物的制备方法，其包括：A method of preparing a pharmaceutical composition according to claim 1, comprising:
    (1)、将载体与微粉化的式(II)化合物充分混合，得到干粉，分装入胶囊；(1) fully mixing the carrier with the micronized compound of formula (II) to obtain a dry powder, which is divided into capsules;
    或者，(2)、将载体和辅料充分混合，再与微粉化的式(II)化合物充分混合，得到干粉，分装入胶囊；Or, (2), the carrier and the auxiliary materials are thoroughly mixed, and then thoroughly mixed with the micronized compound of the formula (II) to obtain a dry powder, which is divided into capsules;
    或者，(3)、将载体和辅料充分混合，接着与细粉乳糖充分混合，再与微粉化的式(II)化合物充分混合，得到干粉，分装入胶囊。Alternatively, (3), the carrier and the auxiliary material are thoroughly mixed, and then thoroughly mixed with the fine powdered lactose, and then thoroughly mixed with the micronized compound of the formula (II) to obtain a dry powder, which is then filled into capsules.
  18. 根据权利要求17所述的制备方法，其特征在于在高剪切混合机中混合。The preparation method according to claim 17, wherein the mixing is carried out in a high shear mixer.
  19. 根据权利要求18所述的制备方法，其特征在于所述的载体选自乳糖一水合物，辅料选自硬脂酸镁。The method according to claim 18, wherein the carrier is selected from the group consisting of lactose monohydrate and the adjuvant is selected from magnesium stearate.
  20. 权利要求1-15任一项所述的药物组合物，在制备用于治疗气道阻塞性疾病药物中的应用。Use of the pharmaceutical composition according to any one of claims 1 to 15 for the preparation of a medicament for the treatment of an airway obstructive disease.
  21. 权利要求1-15任一项所述的药物组合物，在制备用于治疗哮喘、慢性阻塞性肺疾病或支气管炎的药物中的应用。Use of the pharmaceutical composition according to any one of claims 1 to 15 for the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
  22. 一种治疗气道阻塞性疾病的方法，其包括给予有效剂量的权利要求1至15中任一项定义的组合物。A method of treating an airway obstructive disease, comprising administering an effective amount of the composition as defined in any one of claims 1 to 15.
PCT/CN2018/096249 2017-07-21 2018-07-19 Azacyclic amide derivative composition and preparation thereof WO2019015639A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1759108A (en) * 2003-02-14 2006-04-12 施万制药 Biphenyl derivatives
CN1882556A (en) * 2003-11-21 2006-12-20 施万制药 Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity
WO2017125060A1 (en) * 2016-01-22 2017-07-27 四川海思科制药有限公司 Nitrogenous heterocyclic amide derivative, preparation method thereof, and pharmaceutical application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1759108A (en) * 2003-02-14 2006-04-12 施万制药 Biphenyl derivatives
CN1882556A (en) * 2003-11-21 2006-12-20 施万制药 Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity
WO2017125060A1 (en) * 2016-01-22 2017-07-27 四川海思科制药有限公司 Nitrogenous heterocyclic amide derivative, preparation method thereof, and pharmaceutical application

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