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WO2018108089A1 - 一类具有季铵盐结构的双功能化合物 - Google Patents

一类具有季铵盐结构的双功能化合物 Download PDF

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Publication number
WO2018108089A1
WO2018108089A1 PCT/CN2017/115807 CN2017115807W WO2018108089A1 WO 2018108089 A1 WO2018108089 A1 WO 2018108089A1 CN 2017115807 W CN2017115807 W CN 2017115807W WO 2018108089 A1 WO2018108089 A1 WO 2018108089A1
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Prior art keywords
hydroxy
phenyl
ethoxy
cyclopentyl
ethylamino
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PCT/CN2017/115807
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English (en)
French (fr)
Inventor
温守明
高泽军
王君逸
陈小平
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Beijing Showby Pharmaceutical Co Ltd
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Beijing Showby Pharmaceutical Co Ltd
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Priority to AU2017376363A priority Critical patent/AU2017376363B2/en
Priority to US16/469,457 priority patent/US11447485B2/en
Priority to JP2019533093A priority patent/JP6963616B2/ja
Priority to ES17880998T priority patent/ES2836113T3/es
Priority to RU2019121119A priority patent/RU2722720C1/ru
Priority to EP17880998.4A priority patent/EP3556435B1/en
Priority to CN201780076957.6A priority patent/CN110087729B/zh
Priority to MYPI2019003398A priority patent/MY196804A/en
Priority to CA3047023A priority patent/CA3047023C/en
Priority to KR1020197017003A priority patent/KR102278197B1/ko
Publication of WO2018108089A1 publication Critical patent/WO2018108089A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a class of compounds having a beta 2 adrenergic receptor agonist and a muscarinic receptor (M receptor) antagonist bifunctional active quaternary ammonium salt structure.
  • the invention also relates to pharmaceutical compositions comprising such quaternary ammonium salts, to methods of preparing such quaternary ammonium salts and intermediates thereof, and to the use in the treatment of pulmonary diseases.
  • COPD chronic obstructive pulmonary disease
  • Bronchodilators are the drug of choice for asthma and COPD treatment.
  • Commonly used bronchodilators include ⁇ 2 adrenergic receptor agonists (such as salbutamol, formoterol, salmeterol, indacaterol, etc.) and M receptor antagonists (eg, glycopyrrolate, ipratropium bromide) Ammonium, tiotropium bromide, etc.).
  • M receptor antagonists eg, glycopyrrolate, ipratropium bromide
  • Ammonium tiotropium bromide, etc.
  • a combination preparation consisting of a ⁇ 2 adrenergic receptor agonist and an M receptor antagonist is also used for the treatment of pulmonary diseases such as asthma and COPD, and is more effective.
  • the treatment group of the M receptor antagonist tiotropium bromide and the ⁇ 2 adrenergic receptor agonist formoterol fumarate is disclosed in U.S. Patent No. 6,433,0
  • MABA M receptor antagonistic activity
  • MABA M receptor antagonistic activity
  • bifunctional compounds are capable of producing bronchodilation through two separate modes of action and have a single molecular pharmacokinetics.
  • a phase II clinical study of representative compound TD5959 has shown that this compound has a good effect on moderate and severe COPD.
  • bifunctional compounds reported in the literature are currently less selective for the M receptor subtype.
  • the shortcoming of the prior art is that the vast majority of such bifunctional compounds in the literature are tertiary amine structural compounds, which may pass through the blood-brain barrier, produce other central side effects, and have no obvious selectivity for the M 3 receptor subtype. Blocking the M 2 receptor produces many adverse reactions such as increased heart rate, elevated blood pressure, and aggravation of asthma.
  • Quaternary ammonium salts are not easily passed through the blood-brain barrier, and the bioavailability of the inhaled preparation is low. Therefore, it is an ideal choice to design and synthesize a MABA compound having a quaternary ammonium salt structure, but the literatures WO2004074246 and WO2008017827 report the use of a known active M.
  • the receptor antagonist and the ⁇ 2 adrenergic receptor agonist active unit are linked to each other to form a plurality of compounds by linking the N atoms of the two active units, and the biological activity screening results are not ideal.
  • WO2004074246 shows M The partial activity of the body antagonist was significantly reduced by a factor of 100; WO2008017827 significantly reduced the activity of the ⁇ 2 adrenergic receptor agonistic activity by more than 100 times.
  • This type of MABA did not achieve the desired result, which led to the abandonment of a similar method to find the ideal MABA quaternary ammonium. Salt, a similar study has not been reported since.
  • the present invention has been shocked to discover a class.
  • the compound of the invention has high selectivity to the M receptor subtype, has the characteristics of fast action, long action time, lower toxic and side effects, and is difficult to pass the blood brain due to the quaternary ammonium salt structure. Barriers are easily metabolized and are less prone to cardiovascular-related side effects.
  • the structure of this class of compounds is shown in formula I.
  • L is (4-10C) aryl or heteroaryl, wherein the hetero atom of the heteroaryl is selected from N, O, S, and the above group may be unsubstituted or optionally selected by one or more Linear chain from halogen, -OR 1 , -SR 1 , -NR 1 R 2 , -NHCOR 1 , -CONR 1 R 2 , -CN, -NO 2 , -COOR 1 , -CF 3 or C 1 -C 4 Or a substituent of a branched hydrocarbon group;
  • R 1 and R 2 may be a hydrogen atom or a C 1 -C 4 linear or branched hydrocarbon group
  • L is preferably an unsubstituted phenyl group, pyridyl group, furyl group or thienyl group.
  • W independently selected from substituted or unsubstituted (3-7C)cycloalkyl, the substituent is selected from halogen, (1-4C)alkyl, (1-4C) alkoxy, alkoxyalkyl, heterocycle; Preference is given to unsubstituted (3-7C)cycloalkyl, most preferably cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 is a divalent group -(R 1a ) d -(A 1 ) e -(R 1b ) f -, wherein d, e, and f are independently selected from 0, 1 , 2 or 3, and R 1 is attached
  • the number of contiguous atoms of the shortest chain between the two nitrogen atoms is in the range of 3-14.
  • R 1a and R 1b are each independently selected from (1-10C)alkylene, (2-10C)alkenylene, (1-4C)alkyleneoxy, alkyleneoxyalkyl, alkyleneamide, An alkylacyloxy group, an alkyleneamine group or the like, wherein each alkylene group, alkenylene group, alkyleneoxy group, alkyleneoxyalkyl group, alkyleneamino group, alkyleneoxy group, and alkylene amide group All are unsubstituted or substituted by (1-4C)alkyl, chloro, fluoro, hydroxy, phenyl and substituted phenyl, and R 1a and R 1b may be the same or different;
  • R 1a and R 1b in the divalent group R 1 are each independently selected from the group consisting of (1-10C)alkylene, -(1-4C)alkyleneoxy, alkyleneamide, etc.;
  • a 1 independent It is selected from (6-10C) arylene and the like, wherein the arylene group may be unsubstituted or independently selected from halogen, (1-6C) alkyl, (1-6C) alkoxy, carboxyl, nitro Substituted with 1-2 substituents of a nitrile group, an amide group or an ester group;
  • R 1 is further selected from the group consisting of: -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 10 -, -(CH 2 2 O(CH 2 ) 2 -, -(CH 2 ) 2 O(CH 2 ) 4 -, -(CH 2 ) 3 O(CH 2 ) 4 -, -(CH 2 ) 4 O(CH 2 ) 4 -, -(CH 2 ) 5 O(CH 2 ) 4 -, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 -, -(CH 2 ) 2 O(CH 2 ) 3 O ( CH 2 ) 2 -, -CH 2 O(CH 2 ) 5 OCH 2 -, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 -,
  • R 2 is selected from -N(R 2a )C(R 2b )(O), -C(R 2c )(R 2d )OR 2e , -N(R 2f )- or -O-, etc.
  • R 2a-2f and R 3a-2h are each independently selected from hydrogen or (1-4C)alkyl
  • R 2 is preferably -NHCHO, -CH 2 OH, -NH-, -O-;
  • T represents the position of the hydroxyl group on the benzene ring and is selected from the ortho or meta position of the benzene ring R 2 .
  • Y - is selected from pharmaceutically acceptable acid radicals including, for example, inorganic acid radicals such as Br - , Cl - , I - , hydrogencarbonate, carbonate, hydrogen sulfate, sulfate, nitrate, phosphate, hydrogen phosphate, Dihydrogen phosphate, phosphite; organic acid radicals such as formate, acetate, propionate, isobutyrate, mesylate, p-toluenesulfonate, benzoate, oxalate, tartrate, fumarate, C two phosphonate, succinate, suberate, mandeloate, phthalate, benzenesulfonate, citrate, glucuronate, galactose amino acid radical or roots, preferably Br - or Cl -.
  • inorganic acid radicals such as Br - , Cl - , I -
  • organic acid radicals such as formate, acetate, propionate, is
  • the invention also includes the compounds of formula Ia-Id as follows:
  • the quaternary ammonium salt compound of the present invention has M receptor antagonism and ⁇ 2 adrenergic receptor agonism. They are readily available from the market, prepared by the general methods described below, and may also be prepared by the application of other information readily available to those skilled in the art. Specific embodiments and related methods are described herein, and those skilled in the art can prepare the corresponding compounds by using the methods of the present invention, and can also be prepared by using other reagents, methods, and starting materials. Unless otherwise stated, in addition to the conditions of the general or preferred methods (i.e., reaction temperature, pressure, time, solvent used, molar ratio of reactants, etc.) given in the present invention, other methods and conditions may be employed. While the optimum reaction conditions vary with the particular reactants or solvents, those skilled in the art can readily determine these reaction conditions by conventional optimization procedures.
  • the present invention relates to a process for the preparation of a compound of formula I, and pharmaceutically acceptable salts, solvates thereof, or mixtures thereof, and to the use of novel intermediates in the preparation of these compounds.
  • the preparation of a compound of formula I, a pharmaceutically acceptable salt, solvate thereof, optical isomer thereof comprises:
  • intermediate 2 is reacted with intermediate 3 to form intermediate 4 with a protecting group
  • T represents the position of the group on the phenyl ring and is selected from the ortho and meta positions of the benzene ring R 2 .
  • Q 1 is a hydrogen or a hydroxy protecting group
  • the hydroxy protecting group is selected from a silicone ether such as a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or the like, and an ester (acyl group) such as a formyl group.
  • arylmethyl group such as benzyl, p-methoxybenzyl, 9-fluorenylmethyl, diphenylmethyl, etc.
  • Q 2 is hydrogen or an amino protecting group, and the amino protecting group is selected from benzyl group (Bn), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9- fluorenyl-methoxycarbonyl (Fmoc), formyl, acetyl and the like
  • compound X 1 -R 1 -X 2 of X 1 X 2 is independently selected from -NHQ 2 , halogen such as chlorine, bromine, iodine, sulfonate such as mesylate, p-toluenesulfonate and carbonyl
  • Z is selected from -NHQ 2 , halogen such as chlorine, bromine, iodine , sulfonates such as methane
  • the salt when one of the raw materials is a salt, the salt is usually neutralized before or during the reaction, and the neutralization is usually carried out with a molar equivalent of a base with the salt.
  • Q 1 and Q 2 are protecting groups, they can be removed by methods well known to those skilled in the art.
  • step (a) with a compound of the reaction between X 2 1 -R 1 -X is a substitution reaction, i.e. the compound nucleophilic nitrogen atom substituted with X 1 -R 1 -X 2 is X 1, is formed Quaternary ammonium salt.
  • Step (a) is usually carried out in a protic solvent, a dipolar solvent or an inert solvent such as methanol, ethanol, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylene Sulfone or the like; the reaction is usually carried out in the range of 10 to 100 ° C until the reaction is substantially completed; the separation of the product is carried out by a usual purification method, that is, extraction, recrystallization, column chromatography and the like.
  • the molar ratio of the body 6 is 1-2:1, preferably 1.2:1; and the reaction time is 2-10 hours, preferably 5-8 hours.
  • Q 3 is selected from a methyl group, a phenyl group, a p-tolyl group and the like.
  • Intermediate 7 removes one molecule of sulfonic acid in the molecule under basic conditions to form epoxy compound intermediate 5, and the reaction solvent is selected from the group consisting of methanol, ethanol, acetone, N,N-dimethylformamide, N,N-dimethyl Base acetamide, dimethyl sulfoxide, etc.; base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.; reaction time 2-10 hours, preferably 3-6 hours; reaction temperature 10-100 ° C, preferably 20 -50 ° C.
  • Intermediate 8 is reacted with a sulfonyl chloride under basic conditions to form Intermediate 7, which is an inert solvent such as dichloromethane, chloroform, acetonitrile, acetone, N,N-dimethylformamide, N,N. - dimethylacetamide, dimethyl sulfoxide, etc.;
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine, N-methylmorpholine, etc.; reaction time 2-10 hours Preferably, it is 3-6 hours; the reaction temperature is 10-100 ° C, preferably 20-50 ° C.
  • reaction solvent is an inert solvent such as dichloromethane, trichloromethane, acetonitrile, acetone, N, N-dimethyl Formamide, N,N-dimethylacetamide or a mixture thereof;
  • Lewis acid is aluminum trichloride, tin tetrachloride or titanium tetrachloride; the reaction time is 2-10 hours, preferably 3-6 hours; reaction temperature 10-100 ° C, preferably 20-50 ° C.
  • step (b) intermediate 2 and intermediate 3 are subjected to nucleophilic substitution to form intermediate 4, i.e., an amino nitrogen atom is substituted for the leaving group.
  • the reaction is usually carried out in a protic solvent, a dipolar solvent or an inert solvent such as methanol, ethanol, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.
  • the reaction is usually carried out at a temperature of from 10 to 100 ° C, preferably from 60 to 100 ° C, until the reaction is substantially completed.
  • the preparation of Formula 10 is prepared by reacting Formula 11 with a sulfonyl chloride under basic conditions.
  • the reaction solvent is dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, acetonitrile, acetone or a mixture thereof;
  • the reaction temperature is a greenhouse;
  • the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, and triethyl ethane.
  • the sulfonyl chloride is selected from the group consisting of methanesulfonyl chloride and p-toluenesulfonyl chloride.
  • the molar ratio of the formula 11 to the sulfonyl chloride is 1:1 to 2, preferably 1:1.05; the molar ratio of 2 to the base is 1:1 to 2, preferably 1:1.2.
  • Z is a leaving group such as Br, and when Q 1 is as defined above, the structural formula of the intermediate 3 is Formula 13:
  • R 3 is hydrogen
  • R 2 is -CH 2 OQ 4
  • Q 1 and Q 2 are respectively as described above
  • Q 4 is hydrogen or a hydroxy protecting group
  • the hydroxy protecting group is selected from a silyl ether.
  • a silyl ether for example, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc., esters (acyl groups) such as formyl, acetyl, etc., arylmethyl groups such as benzyl, Methoxybenzyl, 9-fluorenylmethyl, diphenylmethyl, etc.;
  • the structural formula of the compound of formula 12 is formula 14:
  • the preparation of Formula 14 is carried out by reacting Formula 15 with Q 2 NH 2 under basic conditions under pressure or heating.
  • the reaction solvent is an alcohol, water or Q 2 NH 2 ; the reaction temperature is 50-120 ° C, preferably 80-110 ° C; and the reaction time is 1-10 hours, preferably 4-6 hours.
  • R configuration product is obtained by the chiral reduction of pentane dimethyl sulfide or tetrahydrofuran solution of formula 15 in the presence of a chiral catalyst to give the R configuration product.
  • the reaction solvent is selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, dichloromethane, and the like; the reaction time is 1-6 hours; the reaction temperature is -5 to 50 ° C, preferably 0 to 40 ° C.
  • Q 1 and Q 4 are the same as defined above, and a preparation method thereof is prepared by reacting bromine in a solution of the formula 17.
  • the reaction solvent is selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dichloromethane, chloroform or a mixture thereof; the reaction time is 1-6 hours; the reaction temperature is -5 to 50 ° C, preferably -5 to 30 ° C.
  • Q 1 and Q 4 are the same as defined above, and a preparation method thereof is prepared by reacting 4-hydroxy-3-hydroxymethylacetophenone with a hydroxyl group-containing protecting group under basic conditions, for example, with benzyl bromide.
  • Formula 18 is prepared by reacting Formula 19 with Q 2 NH 2 under pressure or heating.
  • the reaction solvent is selected from the group consisting of alcohols, water, tetrahydrofuran, dioxane or Q 2 NH 2 ; the reaction temperature is 50-120 ° C, preferably 80-110 ° C; and the reaction time is 1-10 hours.
  • Q 1 is the same as above, and its preparation is carried out by chiral reduction from a borane dimethyl sulfide or tetrahydrofuran solution in the presence of a chiral catalyst of the formula 20 to give an R configuration.
  • the reaction conditions were the same as those for the preparation of Compound 15.
  • Q 1 is the same as defined above, and is prepared from a compound of the formula 21 and anhydrous formic acid, and the reaction condensing agent is selected from the group consisting of 1,3-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide. (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), etc.; can also be prepared by reacting acetic anhydride with formic acid to prepare a mixed acid anhydride and reacting with Formula 21.
  • DCC 1,3-dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • the reaction solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, anhydrous formic acid or a mixture thereof; the reaction time is 2-8 hours; the reaction temperature is 5-50 ° C, preferably the temperature is 5-30 ° C.
  • the definition of Q 1 in the compound of formula 21 is the same as above, and the compound of formula 22 is prepared by reduction of a metal with ammonium chloride.
  • the reaction solvent is selected from the group consisting of water, alcohols such as methanol, ethanol and the like.
  • the metal is selected from the group consisting of reduced iron powder, zinc powder, and the like.
  • Q 1 is the same as defined above, and is prepared by reacting bromine in a solution of Formula 23 in a solution.
  • the reaction solvent is tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dichloromethane, chloroform or the like; the reaction time is 1-6 hours; the reaction temperature is -5 to 50 ° C, preferably the temperature is 5 to 30 ° C.
  • Q 1 in the formula 23 is the same as defined above, and is prepared by reacting 4-hydroxy-3-nitroacetophenone with a hydroxyl group-containing protecting group under basic conditions, for example, by reacting with benzyl bromide.
  • the preparation method is prepared by a nucleophilic addition reaction of the formula 25 and Q 2 NH 2 , and the reaction solvent is selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether or a mixture thereof, preferably methanol.
  • the reaction solvent is selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether or a mixture thereof, preferably methanol.
  • Ethanol, acetonitrile, tetrahydrofuran, dioxane reaction temperature 10-100 ° C; reaction time 2-8 hours.
  • Q 1 and Q 2 are as described above.
  • Q 1 is the same as defined above, and is cyclized by the formula 26 under basic conditions.
  • the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like;
  • the reaction solvent is water, methanol, ethanol, acetonitrile, acetone, methyl ethyl ketone or the like, preferably methanol, ethanol, acetone and water;
  • the reaction temperature is 10-100 ° C.
  • the temperature is 10-30 ° C
  • the reaction time is 1-5 hours.
  • Q 1 is the same as defined above.
  • the preparation thereof is carried out by selective reduction with borane in the presence of a chiral catalyst of the formula 27 to form an alcohol of the R configuration.
  • the catalyst used in the reaction is (1R, 2S)-(+)-nonanol, and the reaction solvent is selected from the group consisting of N,N-dimethylformamide, N,N-diethylacetamide, dimethyl sulfoxide, dichloromethane.
  • the preparation method is prepared by reacting the bromine in a solution of the formula 28 with a bromine according to the above method.
  • the reaction solvent is selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dichloromethane, chloroform and the like; the reaction time is 1-6 hours; the reaction temperature is -5 to 50 ° C, preferably 0 to 30 ° C.
  • the preparation of formula 28 is carried out by reacting with Q 1 X under basic conditions using 5-acetyl-8-hydroxyquinoline as a starting material to give the formula 28.
  • X is a leaving group selected from halogen such as chlorine, bromine, iodine, sulfonate such as mesylate, p-toluenesulfonate; base is selected from potassium carbonate or sodium carbonate; the reaction solvent is selected from the group consisting of methanol and ethanol.
  • the preparation method is prepared by a nucleophilic addition reaction of the formula 30 and Q 2 NH 2 , and the reaction conditions are similar to those of the formula 24; Q 1 and Q 2 are respectively as described above.
  • Formula 30 is prepared in Formula 31 and is prepared in a similar manner to Formula 25. Wherein Q 1 is the same as defined above.
  • Formula 31 is prepared in Formula 32 and is prepared in a similar manner to Formulation 26. Wherein Q 1 is the same as defined above.
  • Formula 32 is prepared in Formula 33, and its preparation method is referred to the 27 preparation method. Wherein Q 1 is the same as defined above.
  • Formula 33 is prepared by reacting Formula 34 with chloroacetyl chloride under basic conditions.
  • the preparation condition is that the molar ratio of the formula 34 to the chloroacetyl chloride is 1:1-2, preferably 1:1.05; the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate or a low-concentration sodium hydroxide solution, etc.
  • the molar ratio of 34 to base is 1:1 to 3, preferably 1:1.5; and the reaction temperature is 10 to 100 ° C, preferably 20 to 60 ° C.
  • Formula 34 is obtained by reducing the nitro group to an amino group of Formula 35.
  • the preparation method can adopt a hydrogenation method, using a platinum oxide as a catalyst for selective hydrogenation, the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran or a mixture thereof; the temperature is 10-50 ° C, preferably 20-30 ° C; the pressure is 0.5-4 MPa; Or selective reduction with a reducing iron powder in an aqueous solution of ammonium chloride to reduce the nitro group to an amino group, the solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran or a mixture thereof, and the molar ratio of the formula 34 to ammonium chloride is 1:1- 4. Preferably, it is 1:2; the molar ratio of the formula 35 to the reducing iron powder is from 1:1 to 5, preferably 1:2.
  • Formula 35 is prepared by the nitration reaction of Formula 36.
  • the reaction solvent is glacial acetic acid, and the reaction temperature is -5 to 50 ° C, preferably 0 to 30 ° C.
  • Formula 36 was prepared by the reaction of 2,4-dihydroxyacetophenone in alkaline conditions Q 1 X, Q 1 X same as defined above.
  • the base is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof; the molar ratio of 2,4-dihydroxyacetophenone to base is 1:1; the molar ratio of 2,4-dihydroxyacetophenone to Q 1 X It is 1:1; the reaction temperature is 10-50 ° C, and the reaction time is 2-5 hours.
  • the intermediate 4 or other target compound having a protecting group in the step (c) is reduced to form the target compound, and any suitable reducing agent such as catalytic hydrogenation may be used in the reaction, and the catalyst is selected from the group consisting of Pd/C, Raney nickel, and platinum oxide. Or a mixture thereof, a metal hydride reagent such as sodium triacetylborohydride or the like may be used; the reaction solvent is methanol, ethanol or a mixture thereof.
  • Step (d) The compound of the formula I is formed by a basic anion exchange resin to form a hydroxide of the formula I, such as an OH - resin or the like, and then reacted with various acids to prepare various quaternary ammonium salts of different acid groups, including the above.
  • a basic anion exchange resin to form a hydroxide of the formula I, such as an OH - resin or the like, and then reacted with various acids to prepare various quaternary ammonium salts of different acid groups, including the above.
  • the various acid salt salts obtained; or the compound of formula I is exchanged with a specific anion exchange resin to prepare a quaternary ammonium salt of a specific acid group; or the halide of formula I is reacted with silver oxide to form a hydroxide of formula I and reacted with other acids to form each a quaternary ammonium salt of the acid group; or a quaternary ammonium salt of the formula I halide and the silver salt to form the corresponding acid group, such as silver sulfate, silver nitrate, and the like.
  • certain specific compounds of Formula I are prepared by the methods (a1)-(d1).
  • the method comprises a compound of the formula: or a pharmaceutically acceptable optional salt or solvate thereof, or an optical isomer thereof, and mixtures thereof.
  • the invention relates to a pharmaceutical composition of a compound of formula I, comprising an acceptable pharmaceutical carrier, which may optionally contain other therapeutic ingredients, such as steroidal anti-inflammatory drugs, phosphodiesterase inhibitors. (PDE-4) and the like and their pharmacologically acceptable salts, solvates, effective therapeutic doses of optical isomers.
  • an acceptable pharmaceutical carrier which may optionally contain other therapeutic ingredients, such as steroidal anti-inflammatory drugs, phosphodiesterase inhibitors. (PDE-4) and the like and their pharmacologically acceptable salts, solvates, effective therapeutic doses of optical isomers.
  • compositions of formula I of the invention are typically administered to a patient in the form of a composition or formulation.
  • These compositions can be administered to a patient by any acceptable route of administration including, but not limited to, inhalation, oral, nasal, topical (including transdermal) and parenteral administration. That is, any form of the compound of the present invention (including a free base, a pharmaceutically acceptable salt or a solvate thereof, etc.) suitable for any particular mode of administration can be used in the pharmaceutical composition of the present invention.
  • the pharmaceutical composition of the present invention usually comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a pharmaceutical composition of the present invention will comprise from about 0.001 to about 100% by weight of active ingredient.
  • any conventional carrier or excipient can be used in the present invention, and the particular carrier or excipient, or the combination of carrier and excipient, will be selected depending on the mode of administration or medical condition or type of disease being treated for a particular patient.
  • the preparation techniques for pharmaceutical compositions for a particular mode are well within the knowledge of those skilled in the art. Further carriers or excipients or combinations of carriers and excipients are commercially available.
  • pharmaceutically acceptable carriers include, but are not limited to, the following: (1) saccharides such as glucose, lactose, sucrose, etc.; (2) starches such as corn starch; (3) cellulose and Derivatives such as sodium carboxymethylcellulose, cellulose acetate, etc.; (4) talc; (5) excipients such as cocoa butter, waxes; (6) oils such as olive oil, large Soybean oil, etc.; (7) alcohols, such as ethanol, propylene glycol, Glycerin, sorbitol, polyethylene glycol, mannitol, etc.; (8) esters such as ethyl oleate, ethyl laurate; (9) non-pyrogenic water; (10) isotonic saline; (11) phosphate Buffer; (12) compressed propellant gas, such as chlorofluorocarbon, hydrofluorocarbon, etc.; (12) other non-toxic, compatible substances used in pharmaceutical compositions.
  • saccharides such as glucose, lactose
  • compositions of the present invention are typically prepared by thoroughly mixing the compound of the invention with an optional carrier or carriers. If necessary, the homogeneous mixture obtained in the present invention can be plasticized or loaded into a tablet, capsule, pill, can or cartridge using conventional equipment and methods.
  • compositions for administration by inhalation are usually in the form of an aerosol or a powder.
  • Such compositions are typically administered by known delivery devices such as nebulizer inhalers, metered dose inhalers (MDI) or dry powder inhalers (DPI) or other similar devices.
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • compositions of the present invention comprising the active ingredient are administered nebulized by a nebulizer.
  • An atomizing device typically produces a high velocity gas stream that atomizes the pharmaceutical composition containing the active ingredient into the respiratory tract by the patient.
  • the active ingredient is usually dissolved in a suitable solvent to form a solution which is placed in a nebulizer.
  • the active ingredient is micronized and combined with a suitable carrier to form a suspension of micronized particles suitable for inhalation.
  • Micronization is generally defined as having a particle diameter of greater than or equal to 90% of less than 10 [mu]m. Suitable atomizing devices are commercially available.
  • a representative pharmaceutical composition using a nebulizer inhaler comprises an isotonic aqueous solution containing 0.05 ⁇ g/ml to 10 mg/ml of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an optical isomer thereof, or weak.
  • the invention encompasses administration of a pharmaceutical composition by inhalation using a dry powder inhaler.
  • Dry powder inhaler administration typically results in the active ingredient forming a free flowing powder in the patient's gas stream during inhalation.
  • the active ingredient is therefore usually formulated with suitable excipients to obtain a free-flowing powder, such as lactose.
  • a representative pharmaceutical composition for use in a dry powder inhaler comprises a powder of dry lactose having a particle size of between about 1 ⁇ m and about 100 ⁇ m and a powder of the formula I or a pharmaceutically acceptable salt thereof or a solvate thereof or an optical isomer thereof Granules.
  • the dry powder preparation may be prepared by dry mixing of the active ingredient with excipients, or without excipients, and then the pharmaceutical composition may be incorporated into a dry powder dispenser or into an inhalation cartridge or capsule for use with a dry powder delivery device.
  • Dry powder delivery devices are commercially available.
  • the pharmaceutical composition of the present invention comprising the active ingredient is administered by inhalation using a metered dose inhaler.
  • the metered dose inhalation device utilizes a compressed propellant gas to release a measured amount of the active ingredient or a pharmaceutically acceptable salt.
  • a pharmaceutical composition for administration by means of a metered dose inhaler is contained in a liquefied propellant solution or suspension.
  • a representative pharmaceutical composition for a metered dose inhaler comprises from 0.001% to about 3% by weight of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof or an optical isomer thereof; from about 0% to about 40% % of the latent solvent ethanol or glycol, preferably from 5% to about 30%; from about 0% to 3% by weight of surfactant; the balance being a hydrofluoroalkane (HFA) propellant.
  • HFA hydrofluoroalkane
  • compositions are typically prepared by the addition of ice-cold or pressurized hydrofluorocarbons to a suitable container containing the active ingredient, ethanol (if present), and a surfactant (if present).
  • the active ingredient is micronized and then mixed with a propellant.
  • the formulation is then placed into an aerosol canister to form a portion of the metered dose inhalation device.
  • Such suspension formulations can also be prepared by spray drying on the surface of the active ingredient microparticles to form a surfactant.
  • compositions of the invention are suitable for oral administration.
  • the pharmaceutical composition for oral administration may be a capsule, a tablet, a pill, a powder, a granule, a flat capsule, and a dragee. Or as an aqueous or non-aqueous solution or suspension; or as a water-in-oil or oil-in-water emulsion; or as a syrup. They all comprise a predetermined amount of the active ingredient of the compound of the invention.
  • compositions of the present invention comprise, as an active ingredient, a compound of the invention together with one or more pharmaceutically acceptable pharmaceutical carriers.
  • a pharmaceutically acceptable pharmaceutical carriers For example, (1) fillers or extenders such as starch, sucrose, silicic acid, etc.; (2) binders such as carboxymethylcellulose, polyvinylpyrrolidone, etc.; (3) wetting agents such as glycerin; a disintegrating agent such as calcium carbonate, starch or the like; (5) a lubricant such as magnesium stearate, talc, solid polyethylene glycol or a mixture thereof; (6) an absorbent such as kaolin or the like.
  • fillers or extenders such as starch, sucrose, silicic acid, etc.
  • binders such as carboxymethylcellulose, polyvinylpyrrolidone, etc.
  • wetting agents such as glycerin
  • a disintegrating agent such as calcium carbonate, starch or the like
  • a lubricant such as magnesium stearate,
  • antioxidants include, but are not limited to, water-soluble antioxidants such as sodium sulfite, ascorbic acid, cysteine hydrochloride, etc.; fat-soluble antioxidants such as propyl gallate, alpha-tocopherol Etc.; metal chelating agents such as citric acid, sorbitol, and ethylenediaminotetraacetic acid (EDTA).
  • water-soluble antioxidants such as sodium sulfite, ascorbic acid, cysteine hydrochloride, etc.
  • fat-soluble antioxidants such as propyl gallate, alpha-tocopherol Etc.
  • metal chelating agents such as citric acid, sorbitol, and ethylenediaminotetraacetic acid (EDTA).
  • Coating agents for tablets, capsules, pills, and the like include, but are not limited to, cellulose acetate (CAP), carboxymethylethyl cellulose (CMEC), and the like.
  • CAP cellulose acetate
  • CMEC carboxymethylethyl cellulose
  • compositions of the present invention may also be formulated as sustained release agents to control the slow release of the active ingredient, such as by utilizing different ratios
  • sustained release agents such as by utilizing different ratios
  • Examples of carboxymethylcellulose or other polymeric matrices, liposomes or microspheres are used as retarders.
  • Suitable liquid dosage forms for oral administration include suspensions, syrups, emulsions, microemulsions, solutions, and the like.
  • Liquid dosage forms comprise the active ingredient and inert diluents such as water and other solvents, solubilizers and emulsifiers. Typical representatives are as follows: oils (olive oil, etc.), glycerin, polyethylene glycol, fatty acid esters of sorbitan or mixtures thereof.
  • the pharmaceutical compositions of the present invention may also comprise a mixture of a compound of formula I, or a pharmaceutically acceptable salt, solvate thereof, or optical isomer thereof, and mixtures thereof, with other drugs for co-administration.
  • the pharmaceutical composition according to the invention comprises one or more other bronchodilators, such as PDE 3 inhibitors, ⁇ 2 adrenergic receptor agonists, etc.; anti-inflammatory agents, such as steroidal anti-inflammatory agents, non-steroidal Anti-inflammatory agents, PDE 4 inhibitors, etc.; M receptor antagonists; anti-infective agents, such as Gram-negative and Gram-positive antibiotics, antiviral drugs, etc.; antihistamines; protease inhibitors; Agents such as D 2 agonists and the like.
  • Other therapeutic agents can be used in the form of a pharmaceutically acceptable salt or solvate.
  • other therapeutic agents can also be used in the form of optical isomers.
  • Representative ⁇ 2 adrenergic receptor agonists that can be used in combination with the compounds of the invention include, but are not limited to, salmeterol, albuterol, levocetamine, formoterol, indacaterol, Verantrol, arformoterol, salbutamol, felototerol, iso-allin, oxulinaline, bitoterol, pyrbuterol, and the like, or a pharmaceutically acceptable salt thereof.
  • steroidal anti-inflammatory agents other than the compounds of the invention
  • Representative steroidal anti-inflammatory agents which can be used in combination with the compounds of the invention include, but are not limited to, methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, chlorinated Misonone, budesonide, flunisolide, mometasone, triamcinolone, roflunolide, ciclesonide, etc., or their pharmaceutically acceptable salts.
  • the steroidal anti-inflammatory agent will be present in the composition in a therapeutically effective amount, typically between 0.05 [mu]g and 500 [mu]g of steroid.
  • compositions of the compounds represented by Formula I of the present invention with other classes of anti-inflammatory agents.
  • typical representative drugs are as follows: NSAIDs, such as nedocromil sodium, sodium cromoglycate, etc.; phosphodiesterase (PDE) inhibitors, such as theophylline, PDE 4 inhibitors Or a mixture of PDE 3 /PDE 4 inhibitors; leukotriene antagonists, such as montelukast; protease inhibitors; cytokine antagonists; or cytokine synthesis inhibitors.
  • PDE phosphodiesterase
  • M receptor antagonists other than the compounds of the invention which may be used in combination with the compounds of the invention include, but are not limited to, glycopyrrolate, ipratropium bromide, tiotropium bromide, atropine, atropine sulfate, Oxytropine, methyl atropine nitrate, horse hydrotropone after hydrobromic acid, guanidine hydrobromide, oxitropium bromide, bromomethylamine, propylamine bromide, bromomethyl tropine, clear ammonium bromide, iso Propiodamine, bromopyran, pirenzepine, cilenzepine, mesoxozide, etc., or a pharmaceutically acceptable salt thereof.
  • Antihistamines which can be used in combination with the compounds of the present invention include, but are not limited to, the following classes: ethanolamines, clemastine fumarate, carbamide maleate, diphenhydramine hydrochloride, dimenhydrinate, etc.; ethylenediamine Such as, for example, mepyramine maleate, benzpiride hydrochloride and benzalidium citrate; alkylamines such as chlorpheniramine, avastin, etc.; piperazines such as hydroxyzine hydrochloride , acid-resistant hydroxyzine, benzomethazine hydrochloride, lactic acid celecazine, meclizine hydrochloride, cetirizine hydrochloride, etc.; piperidines, such as astemizole, levocabastine hydrochloride, loratadine And analogs thereof, terfenadine, fesofidine hydrochloride, azozolast hydrochloride, and the like, or a pharmaceutically acceptable salt
  • Effective therapeutic doses of other drugs administered in combination with the compounds of the invention range from about 0.005 mg to about 10 mg per dose.
  • the invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, optical isomer thereof, or mixture thereof, for the manufacture of a medicament for the treatment of a respiratory disorder, including COPD, asthma, rhinitis Wait.
  • a respiratory disorder including COPD, asthma, rhinitis Wait.
  • the compounds of the present invention have both ⁇ 2 adrenergic receptor agonism and M receptor antagonistic activity, and thus they are suitable for the treatment of ⁇ 2 adrenergic receptors and M receptor mediated diseases. That is, a disease that can be alleviated by using a ⁇ 2 adrenergic receptor agonist and an M receptor antagonist.
  • diseases include pulmonary disorders or diseases associated with reversible airway obstruction, such as COPD, asthma, pulmonary fibrosis, and the like.
  • the present invention relates to a method of treating a pulmonary disease comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an optical isomer thereof.
  • the compounds of the invention are usually administered by inhalation in a multi-dose daily, single daily dose or weekly single dose.
  • the dose is about 1.0 ⁇ g to about 200 ⁇ g each time.
  • the compound of the invention has a bronchodilating effect upon administration by inhalation, and thus the present invention relates to a method of providing bronchodilation to a patient comprising administering to a patient in need of treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof or Its optical isomers.
  • the dose is about 1.0 ⁇ g to about 200 ⁇ g each time.
  • the invention relates to a method of treating chronic obstructive pulmonary or asthma comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an optical isomer thereof.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an optical isomer thereof.
  • When treating COPD or asthma it is administered in a daily multi-dose, daily single-dose regimen at a dose of about 1.0 ⁇ g to about 200 each time. Gg.
  • the compounds of the invention may optionally be administered in combination with other therapeutic agents.
  • the two active ingredient compositions of the present invention provide triple therapy, i.e., ⁇ 2 adrenergic receptor agonism, M receptor antagonism, and anti-inflammatory action.
  • the compositions containing the two active ingredients of the present invention are generally easier to prepare than compositions comprising the three active ingredients.
  • the two-component composition is therefore superior to the three-component composition.
  • the pharmaceutical compositions of the invention may comprise a therapeutically effective amount of a steroidal anti-inflammatory agent.
  • the compounds of the present invention exhibit both ⁇ 2 adrenergic receptor agonism and M receptor antagonistic activity.
  • compounds of particular attention is the M 3 receptor subtype binding inhibition constant Ki values and ⁇ 2 adrenergic receptor agonistic activity of the compound EC 50 less than 100nm, especially the value of both compounds is less than 10nm.
  • those compounds in which the M 3 receptor subtype binds to an inhibition constant Ki value and the ⁇ 2 adrenergic receptor agonistic activity have similar EC 50 values are also of concern.
  • a compound having a ratio of the M 3 receptor subtype binding inhibition constant Ki value to the EC 50 value of the ⁇ 2 adrenergic receptor agonistic activity of from about 1:30 to about 30:1, including 1:20 to 20:1, Those compounds are included in the range of from about 1:10 to about 10:1, and also include from about 1:5 to about 5:1.
  • the present invention also provides a method of treating COPD, and ⁇ 2 adrenergic receptor agonistic activity of the compounds comprising administering to a patient in need of treatment with an effective dose of a M 3 receptor antagonist.
  • the compounds of the invention may have weak M receptor antagonist activity or beta 2 adrenergic receptor agonist receptor binding activity, but they may still act as M receptor antagonists or beta 2 The adrenergic receptor agonist receptor is used alone.
  • alkyl refers to a straight or branched unsubstituted saturated hydrocarbon. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.
  • alkoxy refers to a monovalent group of formula (alkyl)-O- wherein alkyl is as defined herein.
  • Representative alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • arylene refers to a divalent group of an aromatic ring, including substituted and unsubstituted aromatic rings.
  • Representative The arylene group includes a 1,4-phenylenediylene group, a 2-methoxy-1,4-phenylenediylene group, a 2,5-furanylene group, and the like.
  • heterocyclylene refers to a divalent group of a heteroatom cyclic hydrocarbon, including substituted and unsubstituted heterocycloalkanes. Representative examples include 2,3-tetrahydrofuranylene, 2,4-tetrahydropyrroleylene and the like.
  • alkylenediamide refers to a divalent group containing both an alkyl group and an amide group, including substituted and unsubstituted alkylene amide groups.
  • Representative alkylene amide groups include 2-oxopropylamine-1,4-diaryylene, 2-oxoethylamine-1,3-diylene, and the like.
  • halogen refers to fluoro, chloro, bromo and iodo.
  • salts refers to a salt that can be used to administer to a patient.
  • Such salts can be derived from pharmaceutically acceptable inorganic and organic bases, as well as from pharmaceutically acceptable inorganic and organic acids. Salts of the active compounds prepared using relatively non-toxic acids or bases according to the particular substituents present on the compounds described herein are included. Examples of salts derived from pharmaceutically acceptable inorganic bases include, but are not limited to, ammonium, calcium, potassium, sodium, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines including substituted amines, cyclic amines, natural amines and the like such as, but not limited to, betaines, caffeine, choline and the like.
  • the salt can be obtained by contacting the compound in its free form with a sufficient amount of the desired acid, either alone or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as, but not limited to, nitrates, carbonates, bicarbonates, phosphates, sulfates, hydrogen sulfates, hydrochloric acids.
  • a salt, a hydrobromide salt or the like a salt derived from a relatively non-toxic organic acid, such as, but not limited to, acetic acid, succinic acid, fumaric acid, mandelic acid, benzenesulfonic acid, p-toluenesulfonic acid, lemon Acid, tartaric acid, methanesulfonic acid, etc.
  • the form of the compound and its salt involved in the present invention can be converted into each other by a conventional method in the art.
  • an ammonium salt can be isolated in a conventional form by contacting the salt with a base or an acid to obtain a compound in a free form. Further forms of the salt are obtained by adding the free form compound to the acid or base.
  • the invention provides a compound in the form of a prodrug ester.
  • Prodrugs of the compounds described herein are those compounds which readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • Precursor group refers to a class of protecting groups that are capable of converting a drug into a prodrug when used to mask a functional group in the active drug to form a "precursor moiety.”
  • the precursor group is usually linked to the functional group of the drug by a bond. The bond is cleavable under specific conditions of use. Thus, the precursor group is part of a precursor moiety that cleaves under specific conditions of use, releasing functional groups.
  • Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; racemic, diastereomeric, geometric isomers, optical isomers thereof are included within the scope of the invention.
  • These isomers can be resolved or asymmetrically synthesized by conventional methods to render the isomer "optically pure", i.e., substantially free of other isomers thereof.
  • a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved. The pure desired enantiomer is obtained.
  • the separation of different diastereomers formed according to their multiple chiral centers is carried out by using a preparative column.
  • some compounds such as compounds 61, 70, 82, 98 contain a chiral carbon in the structure of R 1 , that is, separation by this method.
  • a salt of an asymmetric isomer is formed with a suitable optically active acid or base, and then formed by fractional crystallization or chromatographic methods well known in the art. The diastereomers are resolved and the pure enantiomers are recovered.
  • solvate refers to a complex or polymer of one or more molecules of a compound of Formula I or a pharmaceutically acceptable salt thereof, with one or more molecules of a solvent. Such solvates are typically crystalline with a fixed molar ratio of solute and solvent.
  • Representative solvents include, for example, ethanol, acetic acid, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, water, and the like.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • terapéuticaally effective dose refers to an amount sufficient to effect treatment in a patient in need of treatment.
  • leaving group refers to a functional group or atom that is substituted by another group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • Representative leaving groups include, for example, chlorine, bromine, iodine, etc.; sulfonate groups such as mesylate, p-toluenesulfonate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, etc.
  • An acyloxy group such as an acetoxy group, a trifluoroacetoxy group or the like.
  • amino protecting group refers to a suitable amino group to prevent an unnecessarily irreversible reaction of the amino group during the reaction, after which the protecting group can be removed without affecting other moieties in the molecular structure.
  • Representative amino protecting groups include, but are not limited to, the following groups benzyl (Bn), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, Acetyl and the like.
  • hydroxy protecting group refers to a protecting group suitable for the prevention of unwanted reactions by the hydroxyl group.
  • Representative Hydroxy protecting groups include, but are not limited to, silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc., esters (acyl groups) such as formyl, acetyl Etyl, an arylmethyl group such as benzyl, p-methoxybenzyl, 9-fluorenylmethyl, benzhydryl or the like.
  • the two hydroxyl groups may be protected by a protecting group such as a propylene diylene ether formed by reacting acetone with a diol.
  • the potassium carbonate was removed by filtration, the N,N-dimethylformamide in the solution was removed under reduced pressure, and the residue was added with 1500 mL of water, and the mixture was extracted three times with diethyl ether, 1000 mL each time, and the ether extracts were combined, and the ether layer was washed three times, each time 1000 mL, diethyl ether The layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, diethyl ether was removed, and the residue was dissolved with 150 mL of ethanol, and then allowed to cool. The solid was collected by filtration to give 4-benzyloxy-3-acetoxymethylacetophenone as a white solid.
  • the desiccant was filtered off, and the solvent was distilled off under reduced pressure at 40 ° C to obtain a crude product.
  • the crude column was chromatographed to give 113.1 g of oily viscous material.
  • the aqueous layer is extracted with ethyl acetate (300 ml ⁇ 3 times), and the organic layer is combined. Dry over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was removed under reduced pressure at 45 ° C to give an oil.
  • the above oil was added to ethyl acetate (160 ml) and stirred to dissolve.
  • the crystals were crystallised on ice-cooled, and the white solid was filtered and washed with a small amount of ethyl acetate.
  • the product was air-dried at 60 ° C for 2 hours to obtain 64.8 g of a crystalline product.
  • the reaction yield was 75.5%.
  • reaction mixture was then poured into 1 liter of hot water at 80 ° C, maintained at this temperature for 30 minutes, then filtered as hot, and the solid was washed with water and dried under vacuum at 80 ° C to give pale yellow 5-acetyl-8-hydroxy-(1H)- Quinolin-2-one 50.3 g, yield 82.6%.
  • reaction mixture was washed with brine (3 ⁇ 100 mL) Magnesium sulfate was filtered off, and the solvent was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the oil was added to 260 ml of ethyl acetate and stirred to dissolve.
  • the crystals were crystallised on ice-cooled, and the white solid was filtered and washed with a small amount of ethyl acetate.
  • the product was dried at 60 ° C for 2 hours to obtain a crystalline product of 19.65 g.
  • the reaction yield was 80.1%.
  • the reaction mixture was evaporated under reduced pressure. EtOAc m.
  • the magnesium sulfate was filtered off, and the solvent was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the mixture was stirred at room temperature, and the mixture was stirred at room temperature.
  • the mixture was stirred at room temperature for 5 min, then transferred to a separating funnel, and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 ml ⁇ 3 times).
  • the magnesium sulfate is dried.
  • the desiccant was filtered off, and the pump was depressurized at 45 ° C or lower to remove the solvent to obtain an oil.
  • the solid was filtered off, and the solution was evaporated to dryness to drynessjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the ethyl ester was washed three times, and the ethyl acetate solution was combined and washed with a saturated sodium hydrogen carbonate solution (3 mL) (150 mL ⁇ 3), washed three times (150 mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. , yield 82.8%, m/z 348.97, 350.97.
  • the target compound solid was 1.48 g, and the yield was 70.7%.
  • Guinea pig isolated tracheal smooth muscle specimen preparation guinea pigs were anesthetized with urethane and quickly removed the trachea between the larynx and the carina, placed in Krebs-Henseleit (KH) solution with 5% CO 2 and 95% O 2 mixture (composition ( g/L): NaCl 6.92, KCl 0.35, CaCl 2 0.28, KH 2 PO 4 0.16, MgSO 4 ⁇ 7H 2 O 0.4568, NaHCO 3 2.1, Glucose 2.0).
  • KH Krebs-Henseleit
  • Method of administration After the tracheal sheet is stabilized, add 3 ⁇ 10 -6 mol/LCCh to the bath, and after the peak tension of the trachea is reached, the cumulative dose of 10 -9 ⁇ 10 -5 mol is added to the medicinal method.
  • the example compound, ipratropium bromide and tiotropium bromide were added to the bath to observe the relaxation of the tracheal strip. If the reaction did not occur (under-threshold concentration), continue to add the next dose in sequence, if the reaction occurs, wait for the diastolic After the platform, add the next dose. Repeat the above operation until the shrinkage curve reaches a minimum. Finally, 10 -6 mol/L isoproterenol was added to maximize relaxation and record the curve.
  • 3 ⁇ 10 -6 mol/LCCh can produce a long-lasting stable contractile response in guinea pig tracheal smooth muscle.
  • Cumulative dose dosing method adding the test compound and the control drugs ipratropium bromide and tiotropium bromide in the wheat bath, each of the compound of the example and the control drug can relax the contraction of the tracheal smooth muscle caused by CCh. Table 1.
  • Table 1 show that the compounds designed by the present invention all block the inhibition of carbachol-induced contraction of guinea pig tracheal smooth muscle. A considerable number of compounds are more potent than the positive control agent ipratropium bromide, and some compounds have strong effect and positive effects.
  • the contrast agent tiotropium bromide was comparable. Both the compound of the present invention and ipratropium bromide have a shorter onset time than tiotropium bromide, whereas tiotropium bromide has a slower onset of action.
  • the compound of the present invention has a long duration of action with tiotropium bromide and a short duration of action of ipratropium bromide.
  • urethane 1.5 g/kg was intraperitoneally injected into anesthetized guinea pigs.
  • the guinea pig was fixed on the back, the tracheal intubation was performed, and the external jugular vein was inserted into the indwelling needle; the guinea pig was placed in the body plethysmograph box, and the blunt needle of the thoracic cannula was inserted into the 4th to 5th intercostal space of the guinea pig front chest, and the chest was measured.
  • Internal pressure the sign is that the water gauge is negative for the water column and fluctuates with the guinea pig's breathing).
  • the MedLab biosignal acquisition and treatment system was used to record the tidal volume, airway velocity and transpulmonary pressure value of Mch pre-guinea pigs as the base value. 10 ⁇ g/kg body weight of Mch was injected intravenously. The changes in airway velocity, tidal volume and transpulmonary pressure in guinea pigs were observed within 5 minutes. Calculation of R aw and C dyn : The change in the percentage of increase in R aw value and the decrease in the percentage of C dyn after inhalation of Mch by aerosol was calculated.
  • Dose-effect relationship 27 guinea pigs of each example compound were randomly divided into 3 groups, vehicle control group 15 guinea pigs, the compound of the present invention [48, 70, 99, 138] 0.1 ⁇ g / kg group, the compound of the present invention [48, 70, 99, 138] 0.3 ⁇ g / kg and the compound of the invention [48, 70, 99, 138] 1 ⁇ g / kg group; airway drip into the above concentration of drugs for 30min, intravenous injection of 10 ⁇ g / kg body weight Mch excitation, determination of gas within 5min airway resistance (R aw) and dynamic lung compliance (C dyn).
  • Dose-effect relationship the compound of the present invention [48, 70, 99, 138] was administered at a dose of 0.1 ⁇ g/kg, 0.3 ⁇ g/kg, and 1 ⁇ g/kg, respectively, and after instillation of airway for 30 minutes, an intravenous injection of 10 ⁇ g/kg of body weight Mch was used. Airway resistance (R aw ) and lung dynamic compliance (C dyn ) within 5 min were measured. The results are shown in the table below:
  • the guinea pig airway instilled compounds [48, 70, 99, 138] 0.1, 0.3, 1 ⁇ g / kg, dose-dependent inhibition of airway resistance and decreased lung dynamic compliance.
  • the inhibition rates of airway resistance increase in the three dose groups of compound 48 were 66.2% (p ⁇ 0.01), 88.3% (p ⁇ 0.001), and 91.6% (p ⁇ 0.001), respectively.
  • the inhibition rates of airway resistance increase in the three dose groups of compound 70 were 69.6% (p ⁇ 0.01), 86.5% (p ⁇ 0.001), and 92.1% (p ⁇ 0.001), respectively.
  • the inhibition rates of lung dynamic compliance decreased. They were 34.2% (p>0.05), 47.8% (p ⁇ 0.001), and 49.3% (p ⁇ 0.001).
  • the inhibition rates of airway resistance increase in the three dose groups of Compound 99 were 73.5% (p ⁇ 0.01), 86.8% (p ⁇ 0.001), and 91.9% (p ⁇ 0.001), respectively.
  • the inhibition rates of lung dynamic compliance decreased. It was 35.0% (p>0.05), 48.8% (p ⁇ 0.001), and 49.7% (p ⁇ 0.001).
  • the inhibition rates of airway resistance increased in the three dose groups of Compound 138 were 74.8% (p ⁇ 0.01), 88.9% (p ⁇ 0.001), and 92.6% (p ⁇ 0.001), respectively.
  • Time-effect relationship intravenous injection of Mch 10 ⁇ g/kg, guinea pig airway resistance increased by 328%.
  • the guinea pig airway drops into the compound [48, 70, 99, 138] 1 ⁇ g / kg 0.25h, the inhibition rate of airway resistance increase is 80% or more; after 1h, the maximum inhibition rate can reach more than 90%.
  • the inhibition rate of airway resistance increased after 24h was still more than 85%, and there were statistical differences compared with the vehicle control group. (p ⁇ 0.01 to 0.001).
  • the dose of the compound [48, 70, 99, 138] was reduced to 0.5 ⁇ g / kg, and the results showed that the guinea pig airway instilled the compound [48, 70, 99, 138] 0.5 ⁇ g / After kg, the airway resistance inhibition rate was more than 85% (p ⁇ 0.001) after 12h, and the airway resistance inhibition rate was more than 75% after 24h (p ⁇ 0.01). Airway instillation of compounds [48, 70, 99, 138] 1 ⁇ g / kg and 0.5 ⁇ g / kg 12h after comparison, airway resistance inhibition rate was not significantly different.
  • the amount of cAMP accumulation in each recombinant cell line expressing receptor was measured.
  • the cAMP was determined by homologous radioimmunoassay, that is, the cells were washed with PBS buffer, and suspended in a buffer at room temperature to grow to 30,000-40,000 cells per well. Test compounds were diluted in PBS buffer containing 0.1% BSA and tested at 11 step concentrations ranging from 100 uM to 0.1 pM.
  • 10 nM of ICI 118551 was added to block the expression of the ⁇ 2 adrenergic receptor in HEK293 cells. After the compound was added to the suspended cells, the scintillation plate was incubated at 37 ° C for 10 minutes, and the reaction was terminated with ice-cold detection buffer, and the radioactivity was measured after storage at 4 ° C overnight.
  • Example compound EC 50 ( ⁇ 1 )nM EC 50 ( ⁇ 2 )nM Sel( ⁇ 1 / ⁇ 2 ) Compound 1 197 ⁇ 87 12.8 ⁇ 4.2 15.4 Compound 2 210 ⁇ 89 32 ⁇ 15 7.8 Compound 3 160 ⁇ 72 10.3 ⁇ 2.4 15.6 Compound 4 43 ⁇ 16 1.2 ⁇ 0.38 36.8 Compound 25 33 ⁇ 15 1.1 ⁇ 0.35 30.8 Compound 26 8.6 ⁇ 2.1 0.46 ⁇ 0.23 18.8 Compound 27 252 ⁇ 112 3.2 ⁇ 1.4 78.9 Compound 45 216 ⁇ 87 8.2 ⁇ 78 120.3 Compound 46 52 ⁇ 21 0.75 ⁇ 0.21 68.9
  • the compounds of the present invention have good agonistic activity and functional selectivity for ⁇ 2 adrenergic receptors.
  • the transfected CHOm 1 , CHOm 2 and CHOm 3 cells were respectively placed in DMEM medium (containing 15% fetal bovine serum, 4mML-glutamine, 1% non-essential amino acid, 1% antibiotic/anti-fungal). Culture in °C, 5% CO 2 incubator.
  • the collected cells were homogenized with a Teflon glass homogenizer, and the homogenate was centrifuged at 20000 r ⁇ 20 min, and the reaction buffer was homogenized to form a membrane protein suspension.
  • the amount of protein added to each reaction tube was: m1 (about 0.05 mg), m2 (0.05 mg), m3 (0.1 mg); the concentration of [ 3 H]-QNB was 0.1-2.16 nmol/L; non-specific binding tube Add 1 ⁇ mol/L of atropine; the total volume of the reaction was 300 ⁇ L.
  • the reaction was then carried out at 25 ° C for 5 h, quenched with ice-cold reaction buffer, and collected on a glass fiber filter using a multi-head cell harvester.
  • the filter was placed in a liquid flash bottle, 5 ml of liquid scintillator was added, and the light was measured overnight, and the cpm was measured with a liquid scintillation meter. Bmax and Kd values were calculated using Graphpad prism software.
  • Each experimental tube was added with 3 H-QNB which is not selective for M receptor as a labeling ligand, and the final concentration of each tube was: m1, m3 (1.042 nmol/L), m2 (1.81 nmol/L); Tiotropium bromide, ipratropium bromide and each test compound, the final concentration is 10 -10 ⁇ 10 -4 mol / L, a total of 11 doses; then add the same amount of membrane protein specimens (same as the aforementioned saturation test); The total reaction volume was 300 ⁇ L, and a competitive binding reaction was carried out. A non-specific binding tube was also provided, and non-specific binding was measured with a large amount of atropine (final concentration of 1 ⁇ mol/L).
  • the reaction was allowed to stand at 25 ° C for 5 h, and the reaction was stopped with ice-cold reaction buffer, and then collected on a glass fiber filter using a multi-head cell harvester. After drying at 80 ° C, the filter was placed in a liquid flash bottle, 5 ml of liquid scintillator was added, and the light was measured overnight, and the cpm was measured with a liquid scintillation meter.
  • Ki values of the respective compounds for each of the three M receptor subtypes were calculated by Graphpad prism software. The tiotropium bromide, ipratropium bromide and each test compound were selected for selectivity to the M receptor subtype.
  • the experimental results show that the compound of the present invention has the highest selectivity to the M 3 receptor, the M 1 receptor is the second, and the M 2 receptor has the lowest selectivity; among them, the M 3 and M 1 receptors have strong effects. It has obvious advantages compared with the prior art in the treatment of diseases such as rhinitis, airway hyperresponsiveness, old chronic bronchitis, COPD and the like.
  • Example compounds antagonize carbachol (CCh)-induced contraction of guinea pig tracheal smooth muscle
  • Method of administration After the tracheal tablet is stabilized, add carbachol at a final concentration of 3 ⁇ 10 -6 mol/L, and start dosing when the pressure value of the tracheal piece rises to a stable platform.
  • the experiment was divided into a blank group and each test drug administration group. Each group was separately added with DMSO solution prepared from KH solution and 50 ⁇ l of each test solution, and the test drug administration group was added to the final concentration at a final concentration of 10 -9 , 0.3 ⁇ 10 -8 , 10 -8 , and 0.3 ⁇ 10 -7 .
  • Method of administration After the trachea slice is stabilized, a propranolol hydrochloride solution with a final concentration of 10 -5 mol/L is added for 10 min to block the ⁇ receptor, and a final concentration of 3 ⁇ 10 -6 mol/L of carbachol is added. Alkali (after propranolol blocks the ⁇ receptor, observe the M receptor antagonism of the compound), and start adding the drug when the pressure value of the tracheal piece rises to a stable platform. The experiment was divided into blank group, propranolol + blank group, each test drug administration group and propranolol + each test drug administration group.
  • Each group of the blank group and each test group was added with DMSO solution prepared by KH solution and 50 ⁇ l of the test solution; 50 ⁇ l of propranolol + blank group and propranolol + each test group were added respectively. After 10 minutes of propranolol solution, the DMSO solution prepared by KH solution and 50 ⁇ l of the test solution were added. The test drug-administered group was added to the final concentrations of 10 -9 , 0.3 ⁇ 10 -8 , 10 -8 , 0.3 ⁇ 10 -7 , 10 -7 , 0.3 ⁇ 10 -6 and 10 -6 mol/L at cumulative concentrations.
  • the blank group was added with the corresponding diluted DMSO solution; propranolol + each test group was added with propranolol for 10 min, and the final concentration was 10 -9 and 0.3 ⁇ 10 -8 at the cumulative concentration.
  • the degree of relaxation of the smooth muscle of the tracheal piece was recorded by Medlab, and finally sodium nitroprusside at a final concentration of 2 ⁇ 10 -4 mol/L was added as 100% relaxation.
  • Table 5 The results are shown in Table 5.
  • Method of administration After the trachea sheet is stabilized, a histamine solution with a final concentration of 3 ⁇ 10 -5 mol/L is added for 10 min, and a final concentration of 3 ⁇ 10 -6 mol/L of carbachol is added (observation of ⁇ receptor) Excitatory action), when the pressure value of the tracheal piece rises to the stable platform, the dosing begins.
  • the experiment was divided into blank group, histamine + blank group, each test drug administration group and histamine + each test drug administration group. Each group of the blank group and each test group was added with DMSO solution prepared by KH solution and 50 ⁇ l of the test solution; histamine + blank group and histamine + each test group were added with 50 ⁇ l of histamine solution.
  • a DMSO solution prepared from KH solution and 50 ⁇ l of the test solution were added.
  • the test drug-administered group was added to the final concentrations of 10 -9 , 0.3 ⁇ 10 -8 , 10 -8 , 0.3 ⁇ 10 -7 , 10 -7 , 0.3 ⁇ 10 -6 and 10 -6 mol/L at cumulative concentrations.
  • the blank group was added with the corresponding diluted DMSO solution; the histamine + each test group was added with histamine for 10 min, and the final concentration was 10 -9 , 0.3 ⁇ 10 -8 , 10 -8 at the cumulative concentration.
  • Beagle dogs were randomly divided into groups of 2, half male and half female, respectively.
  • (iv) intravenously iv) a compound of the present invention and a 7.5% ethanol solution of a comparative compound, each of which was administered at a dose of 0.01 mg/kg and 0.10 mg/kg. group.
  • Heart rate changes were observed after administration (30 min - 4 h after drug administration), and the results are shown in Table 6.
  • the heart rate of the Beagle dogs did not change significantly after the iv administration of the compound of the present invention at the dose of 0.1 mg/kg, while the control compound significantly increased the heart rate of the Beagle dogs at the dose of 0.01 mg/kg. Raise.
  • the compounds of the invention have lower toxic side effects.
  • the compound of the present invention and the comparative compound were respectively incubated with the liver microsomes of SD rats and Beagle dogs at 37 ° C for 0, 2, 5, 10, 15, 20, 30 min, and the reaction was terminated by LC-MS/MS. analysis. Take the area ratio of the 0min sample as 100%, and compare the percentage of the compound after each time point to the remaining percentage after the incubation of the compound at different time points. The natural logarithm of the percentage is plotted on the ordinate and the time is plotted on the abscissa. Combine a straight line with a negative slope of k. Calculate each parameter according to the formula.
  • Liver weight indicates the liver weight g per kilogram of body weight
  • P450 indicates the amount of mg of P450 enzyme per gram of liver.
  • ERh ⁇ 0.3 is a compound with good hepatic metabolic stability
  • 0.3 ⁇ ERh ⁇ 0.7 is a compound with moderate hepatic metabolic stability
  • ERh > 0.7 is a compound with poor liver metabolism stability.
  • the compounds of the present invention have poor metabolic stability in SD rat and Beagle dog liver microsomes, and metabolism is faster, and it is not easy to accumulate in the body, while the comparative compound has better metabolic stability and is more likely to accumulate.
  • the compound of the present invention and the comparative compound were respectively incubated with the lung homogenate of Beagle dogs for 8 hours in a water bath at 37 ° C, and the reaction was terminated by LC-MS/MS.
  • the area ratio of the sample at 0 min was taken as 100%, and after 8 hours, the remaining percentage of the compound after incubation for 8 hours was obtained. The results are shown in Table 8.
  • the compound of the present invention is micronized, thoroughly mixed with micronized lactose, and the mixture is placed in a gelatin inhalation cartridge and administered by a powder inhaler.
  • a dry powder formulation for use in a dry powder inhalation device was prepared as follows:
  • the compound 70 of the present invention is micronized and thoroughly mixed with micronized lactose to form a preparation having a combination ratio of 1:200, and the preparation composition is charged into a dry powder inhalation device capable of transferring 10 ⁇ g to 100 ⁇ g of the compound of the present invention per dose. .
  • a dry powder formulation for inhalation administration in a metered dose inhaler was prepared as follows:
  • 10 g of the micronized compound 99 of the present invention having an average particle diameter of less than 10 ⁇ m was dispersed in a softening aqueous solution containing 0.2 g of lecithin in 200 mL to prepare a suspension containing 5 wt% of the compound of the present invention and 0.1 wt% of lecithin, and the suspension was suspended.
  • the liquid was spray dried to form particles having an average particle diameter of less than 1.5 ⁇ .
  • the granules were loaded into a pressurized 1,1,1,2-tetrafluoroethane cartridge.
  • a pharmaceutical composition for use in a metered dose inhaler is prepared as follows:
  • 5 g of the micronized compound 138 of the invention having an average particle diameter of less than 10 ⁇ m was dispersed in a 100 mL demineralized water colloidal solution containing 0.5 g of trehalose and 0.5 g of lecithin to prepare a compound containing 5 wt% of the present invention, 0.5% of trehalose and 0.5 wt%.

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Abstract

本发明提供一类式I所示的具有β2肾上腺受体激动剂和M受体拮抗剂双功能活性季铵盐类结构的化合物、其药学上可接受的盐、溶剂化物、光学异构体，以及包含这类季铵盐结构化合物的药物组合物，制备这类季铵盐结构化合物和中其间体的方法，及其在治疗肺部疾病方面的应用。本发明的化合物对M受体亚型选择性高，在治疗COPD和哮喘等肺部疾病中具有不良反应少、毒副作用低的特点。

Description

一类具有季铵盐结构的双功能化合物 技术领域
本发明涉及一类具有β2肾上腺素受体激动剂和毒蕈碱受体(M受体)拮抗剂双功能活性季铵盐类结构的化合物。本发明也涉及包含这类季铵盐类化合物的药物组合物，制备这类季铵盐类化合物及其中间体的方法，以及在治疗肺部疾病方面的应用。
背景技术
哮喘和慢性阻塞性肺病(COPD，简称：慢阻肺)是肺部疾病中最常见的疾病种类，其中COPD为世界第四大致死性疾病，预计到2020年上升为第三位。COPD的产生多数与吸烟有关，但职业性有害灰尘、气体、烟尘、烟雾等环境污染也容易使人患上COPD。
支气管扩张剂是哮喘和COPD治疗的首选药物。常用的支气管扩张剂包括β2肾上腺素受体激动剂(如沙丁胺醇、福莫特罗、沙美特罗和茚达特罗等)和M受体拮抗剂(如格隆溴铵、异丙托溴铵、噻托溴铵等)。除单方制剂外，由β2肾上腺素受体激动剂和M受体拮抗剂组成的复方制剂也用于肺部疾病如哮喘和COPD的治疗，且疗效更强。如美国专利US6433027中公开用M受体拮抗剂噻托溴铵和β2肾上腺素受体激动剂福莫特罗富马酸盐的治疗组方。
此外，同时具有β2肾上腺素受体激动剂活性和M受体拮抗剂活性的化合物在治疗哮喘和COPD方面已在诸多文献中报道，如WO2004074246、WO2009098448、WO2010004517、WO2008096127、WO2008149110、WO2008017827、WO2010126025、WO2010015792、WO2005111004、WO2010015792、WO2008041095、WO2005051946、WO2011012896、WO2010123766等。这类具有β2肾上腺素受体激动活性和M受体拮抗活性的化合物(简称MABA)其化学结构由三部分构成，即M受体拮抗活性部分，β2肾上腺素受体激动活性部分和连接部分。MABA典型化合物的结构式如下：
Figure PCTCN2017115807-appb-000001
这类双功能化合物能够通过两种独立的作用模式产生支气管扩张作用，而且具有单一的分子药物动力学。其中代表性化合物TD5959已进行的Ⅱ期临床研究表明，该化合物对中度及重度的COPD有良好疗效。但目前文献中报道的这类具有双功能的化合物对M受体亚型的选择性均较低。现有技术的不足是文献中有关此类双功能化合物绝大数均为叔胺型结构化合物，有可能通过血脑屏障，产生其它中枢副作用，且对M3受体亚型的选择性不明显，对M2受体阻断而产生心率增 加、血压升高和加重哮喘病情等诸多不良反应。季铵盐不易通过血脑屏障，吸入制剂被吞咽部分生物利用度低，因此设计合成具有但季铵盐类结构的MABA化合物是一种理想选择，但文献WO2004074246和WO2008017827报道采用已知活性的M受体拮抗剂和β2肾上腺素受体激动剂活性单元通过连接基团将两个活性单元的N原子连接起来制备多个化合物较少，且但生物活性筛选结果不理想显示，WO2004074246显示M受体拮抗剂部分活性显著降低100倍；WO2008017827使β2肾上腺素受体激动活性部分活性显著降低大于100倍，这类MABA没有获得理想结果，导致了人们放弃了采用类似方法寻找理想的MABA季铵盐，类似的研究此后未见报道。有鉴于此我们通过不断地改变M受体拮抗剂和β2肾上腺素受体激动剂活性单元以及连接基团，通过大量的研究和筛选，经过不懈努力，本发明令人震惊地发现了一类新的理想的MABA季铵盐结构化合物，初步动物实验证明该类化合物活性达到设计比现有技术的MABA具有更突出的优点的要求：(1)与现有技术相比，本发明化合物静脉注射引起心率增加的剂量大于现有技术化合物的十倍以上；(2)本发明化合物肝脏首过作用强烈，但在肺中稳定，即使进入循环系统，也不能积累足够的毒性剂量；(3)本发明化合物M受体阻断作用和β2受体激动作用的匹配度十分理想。
发明内容
本发明的目的在于提供一种具有β2肾上腺素受体激动和M受体拮抗活性的季铵盐类化合物，以及其药学上可接受的盐、溶剂化物、光学异构体和前体。与现有技术相比，本发明的化合物对M受体亚型有高度选择性，具有起效快、作用时间长、毒副作用更低的特点，且由于具有季铵盐结构，不易通过血脑屏障，容易被代谢，不易产生心血管有关的副作用。该类化合物的结构如式I所示
Figure PCTCN2017115807-appb-000002
式Ⅰ结构式中*标记的碳均为(R)构型。
其中：
L为(4-10C)的芳基或杂芳基，其中杂芳基的杂原子选自N、O、S，以上基团可以是未取代的，也可以任选地被一个或多个选自卤素、-OR1，-SR1、-NR1R2、-NHCOR1、-CONR1R2、-CN、-NO2、-COOR1、-CF3或C1-C4的直链或支链烃基的取代基取代；
R1、R2可以是氢原子、C1-C4的直链或支链烃基；
L优选未取代的苯基、吡啶基、呋喃基或噻吩基。
W独立的选自取代或未取代的(3-7C)环烷基，取代基选自卤素、(1-4C)烷基，(1-4C)烷氧基、烷氧基烃基、杂环；优选未取代的(3-7C)环烷基，最优选环丁基、环戊基、环己基。
R1为二价基团-(R1a)d-(A1)e-(R1b)f-，其中d、e、f分别独立的选自0、1、2或3，且R1连接的两个氮原子之间的最短链的邻接原子数目在3-14范围内。
R1a、R1b各自独立的选自(1-10C)亚烷基、(2-10C)亚烯基、(1-4C)亚烷氧基、亚烷氧基烷基、亚烷酰胺基、亚烷酰氧基、亚烷胺基等，其中每个亚烷基、亚烯基、亚烷氧基、亚烷氧基烷基、亚烷胺基、亚烷酰氧基和亚烷酰胺基都是未取代的或被独立的选自(1-4C)烷基、氯、氟、羟基、苯基及取代苯基所取代，R1a、R1b可以相同或不同；
A1独立的选自(3-7C)亚环烷基、(2-7C)亚烷基、(6-10C)亚芳基、(4-9C)亚杂芳基、和(3-8C)亚杂环烷基等，其中亚环烷基可以是未取代的，或被独立选自(1-6C)烷基的1-4个取代基取代；每个亚芳基、亚杂芳基和亚杂环烷基可以是未取代的，或被独立选自卤素、(1-6C)烷基、(1-6C)烷氧基、-S-(1-4C)烷基、-S(O)-(1-4C)烷基、-S(O)2-(1-4C)烷基、-C(O)-O-(1-4C)烷基、-NH-(1-4C)烷基、-N＝【(1-4C)烷基】2、羧基、硝基、腈基、酰胺基、酯基、三氟甲基、三氟甲氧基的1-3个取代基取代；
特别地，二价基团R1中R1a、R1b各自独立的选自(1-10C)亚烷基、-(1-4C)亚烷氧基、亚烷酰胺基等；A1独立的选自(6-10C)亚芳基等，其中亚芳基可以是未取代的，或被独立选自卤素、(1-6C)烷基、(1-6C)烷氧基、羧基、硝基、腈基、酰胺基、酯基的1-2个取代基取代；
R1进一步选自：-(CH2)3-、-(CH2)4-、-(CH2)8-、-(CH2)9-、-(CH2)10-、-(CH2)2O(CH2)2-、-(CH2)2O(CH2)4-、-(CH2)3O(CH2)4-、-(CH2)4O(CH2)4-、-(CH2)5O(CH2)4-、-(CH2)2O(CH2)2O(CH2)2-、-(CH2)2O(CH2)3O(CH2)2-、-CH2O(CH2)5OCH2-、-(CH2)2O(CH2)2O(CH2)2O(CH2)2-、-(CH2)2O(苯-1,4-亚基)(CH2)2-、-(CH2)3O(苯-1,4-亚基)CH2-、-(CH2)3O(3，5-二氯-苯-1,4-亚基)CH2-、-(CH2)2CONH(2-甲氧基-5-氯-苯-1,4-亚基)CH2-、-(CH2)2CONH(3-甲基-苯-1,4-亚基)CH2-、-(CH2)2CONH(2-甲氧基-苯-1,4-亚基)CH2-、-(CH2)2CONH(苯-1,4-亚基)CH2-、-(CH2)3CONH(苯-1,4-亚基)CH(CH3)-、-(CH2)3O CH2(3-甲氧基-苯-1,4-亚基)CH(CH3)-、-(CH2)3O(苯-1,4-亚基)C(CH3)2-、-(CH2)3O(苯-1,4-亚基)CH(CH2CH3)-、-(CH2)3O(苯-1,4-亚基)(CH2)2-、-(CH2)3O(苯-1,4-亚基)(CH2)3-、-(CH2)3O(苯-1,4-亚基)CH2CH(CH3)-、-(CH2)2OCH2(苯-1,4-亚基)CH2O(CH2)2–、-(CH2)2O CH2(苯-1,4-亚基)CH(CH3)–、-(CH2)2O(苯-1,4-亚基)O(CH2)2-、-(CH2)3O(2-甲氧基-苯-1,4-亚基)O(CH2)3-、-(CH2)3O(苯-1,4-亚基)O(CH2)3-、-(CH2)3O(苯-1,4-亚基)CH2C(CH3)2-、-(CH2)2O(苯-1,4-亚基)CH2C(CH3)2-、-(CH2)2O(苯-1,4-亚基)CH2CH(CH3)-、-(CH2)2O(苯-1,4-亚基)(CH2)2-、-(CH2)2O(CH2)3O(CH2)2-；
R2选自-N(R2a)C(R2b)(O)、-C(R2c)(R2d)OR2e、-N(R2f)-或-O-等，R3选自氢、-C(R3a)＝C(R3b)-C(O)-、-OC(R3C)(R3d)C(O)-、-N(R3e)CH(R3f)C(O)-、-C(R3g)(R3h)S(O)2-、-SCO-等，条件是当R3为氢时，R2选自-N(R2a)C(R2b)(O)或-C(R2c)(R2d)OR2e，当R3选自-C(R3a)＝C(R3b)-C(O)-、-OC(R3C)(R3d)C(O)-、-N(R3e)CH(R3f)C(O)-、-C(R3g)(R3h)S(O)2-或-SCO-时，R2选自-N(R2f)-或-O-；
其中R2a-2f和R3a-2h分别独立选自氢或(1-4C)烷基；
R2优选-NHCHO、-CH2OH、-NH-、-O-；
R3优选氢、-CH＝CH-C(O)-、-OCH2C(O)-、-NHCH2C(O)-、-CH2S(O)2-、-SCO-；
T代表羟基在该苯环上的位置，选自该苯环R2的邻位或间位。
Y-选自药学上可接受的酸根，其中包括，无机酸根例如Br-、Cl-、I-、碳酸氢根、碳酸根、硫酸氢根、硫酸根、硝酸根、磷酸根、磷酸氢根、磷酸二氢根、亚磷酸根；有机酸根例如甲酸根、乙酸根、丙酸根、异丁酸根、甲磺酸根、对甲 苯磺酸根、苯甲酸根、草酸根、酒石酸根、富马酸根、丙二酸根、琥珀酸根、辛二酸根、扁桃酸根、苯二甲酸根、苯磺酸根、柠檬酸、葡糖醛酸根、半乳糖酸根或氨基酸根，优选Br-或Cl-。
本发明也包括如下结构式Ia-Id所示的化合物：
Figure PCTCN2017115807-appb-000003
Figure PCTCN2017115807-appb-000004
式Ia-Id中：*标记的碳均为(R)构型碳，L、W、R1、Y与前文定义的基团一致。
本发明所述的季铵盐类化合物具有M受体拮抗和β2肾上腺素受体激动作用。它们很容易从市场中获得原料，利用下述的通用方法进行制备，也可以通过应用本领域熟练技术人员容易获得的其他信息进行制备。本文中对特定实施方案及相关方法进行了描述，本领域熟练技术人员除可利用本发明中的方法制备相应的化合物，也可利用其它试剂、方法、原料进行制备。除非特别注明，除了本发明中给出的一般或优选方法的条件(即反应温度、压力、时间、所用溶剂、反应物的摩尔比等)外，也可用其它的方法和条件进行制备。虽然最佳的反应条件随特定的反应物或溶剂发生变化，但本领域熟练的技术人员可以通过常规的优化程序很容易地决定这些反应条件。
此外，对本领域熟练技术人员显而易见的是，常规的保护基是必要的，以阻止特定的官能团发生不必要的化学反应而干扰目标反应的实现。对于特定官能团的适宜的保护基以及这种官能团的保护和脱保护的适宜条件，在本领域内是熟知的。如有必要，也可采用本文之外的保护基。各种官能团的保护基的保护和脱保护的条件在各种文献中均有详细的描述。
本发明涉及式I化合物、及其药学上可接受的盐、溶剂化物、或其混合物的制备方法，以及新的中间体在这些化合物制备中的应用。式I化合物、其药学上可接受的盐、溶剂化物、光学异构体的制备方法包括：
(a)使中间体1或其盐与X1-R1-X2反应生成中间体2；
(b)中间体2与中间体3反应生成带有保护基的中间体4；
(c)中间体4或其它带有保护基的式I化合物脱去保护基得到式I化合物。
(d)式I化合物通过碱性阴离子交换树脂生成式I的氢氧化物，然后与各种不同的酸反应而制备各种不同酸根的季铵盐；或者式I化合物与特定的阴离子交换树脂交换而制备特定酸根的季铵盐；或者式I卤化物与氧化银反应生成式I的氢氧化物再与其它酸反应生成各种酸根的季铵盐；或式I卤化物与银盐反应生成相应酸根的季铵盐。
Figure PCTCN2017115807-appb-000005
中间体1，2，3，4中带*号碳原子指定为R构型，下文亦同；
T代表该基团在该苯环上的位置，选自该苯环R2的邻位和间位。
Q1为氢或羟基保护基，羟基保护基选自硅醚类例如三甲硅基、叔丁基二甲硅基、叔丁基二苯基硅基等，酯类(酰基基团)如甲酰基、乙酰基等，芳基甲基基团如苄基、对甲氧基苄基、9-芴基甲基、二苯甲基等；Q2为氢或氨基保护基，氨 基保护基选自苄基(Bn)、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、9-芴基甲氧羰基(Fmoc)、甲酰基、乙酰基等；化合物X1-R1-X2中X1、X2独立地选自-NHQ2，卤素如氯、溴、碘，磺酸酯如甲磺酸酯、对甲苯磺酸酯和羰基；Z选自-NHQ2，卤素如氯、溴、碘，磺酸酯如甲磺酸酯、对甲苯磺酸酯，条件是当X2为卤素或磺酸酯时Z为-NHQ2，当X2为-NHQ2时Z为卤素或磺酸酯，X2为羰基时Z为-NQ2且Q2为氢；R为(1-6C)烷基、苯基或取代苯基，优选甲基、乙基、对甲苯基或苯基，R1、R2、R3、Y与上文定义相同。
在上述方法中，原料之一为盐时，通常该盐在反应前或在反应过程中被中和，这种中和通常用与该盐等摩尔当量的碱进行。
当Q1、Q2为保护基时，用本领域人员熟知的方法即可除去。
在步骤(a)中化合物1与X1-R1-X2之间的反应为取代反应，即化合物1中的亲核性氮原子取代X1-R1-X2中的X1，形成季铵盐。
步骤(a)通常在质子溶剂、偶极溶剂或惰性溶剂中进行，例如甲醇、乙醇、乙腈、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜等；该反应通常在10-100℃范围内进行直到反应实质性完成；产物的的分离采用通常的纯化方法，即萃取、重结晶、柱层析等。
中间体1的制备采用文献报道的方法(WO2015007073A1)，即(中间体5和中间体6在强碱存在条件下制备。
Figure PCTCN2017115807-appb-000006
二者的摩尔比为中间体5：中间体6＝1：1-2，优选为1:1.2；反应在偶极溶剂、非质子性溶剂、或惰性溶剂中进行，常用溶剂通常为乙腈、丙酮、N,N-二甲 基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜等；反应温度范围为10-100℃，优选70-100℃；强碱选自氢化钠、氨基钠等；强碱与中间体6的摩尔比为1-2:1，优选1.2:1；反应时间为2-10小时，优选为5-8小时。
中间体6可商业购买。
中间体5通过中间体7制备：
Figure PCTCN2017115807-appb-000007
中间体7中Q3选自甲基、苯基、对甲苯基等。中间体7在碱性条件下分子中脱去一分子磺酸生成环氧化合物中间体5，反应溶剂选自甲醇、乙醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜等；碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等；反应时间2-10小时，优选3-6小时；反应温度10-100℃，优选20-50℃。
中间体7的制备源于中间体8：
Figure PCTCN2017115807-appb-000008
中间体8与磺酰氯在碱性条件下反应生成中间体7，反应所用溶剂为惰性溶剂，如二氯甲烷、三氯甲烷、乙腈、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜等；碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、吡啶、三乙胺、N-甲基吗啡啉等；反应时间2-10小时，优选3-6小时；反应温度10-100℃，优选20-50℃。
中间体8用R构型的中间体9制备：
Figure PCTCN2017115807-appb-000009
Figure PCTCN2017115807-appb-000010
中间体9在路易斯酸存在下，用还原剂如硼氢化钠还原，直接得到中间体8，反应溶剂为惰性溶剂，如二氯甲烷、三氯甲烷、乙腈、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或其混合物；路易斯酸为三氯化铝、四氯化锡或四氯化钛等；反应时间2-10小时，优选3-6小时；反应温度10-100℃，优选20-50℃。
中间体9是以其消旋体经手性拆分而得，拆分方法参见专利WO9942460，CN100408549C。
式X1-R1-X2所代表的各类化合物的制备方法在制备与实施例中均有详细描述。
在步骤(b)中中间体2与中间体3经亲核取代反应生成中间体4，即氨基氮原子取代离去基团。该反应通常在质子溶剂、偶极溶剂或惰性溶剂中进行，例如甲醇、乙醇、乙腈、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜等；该反应通常在10-100℃，优选60-100℃，范围内进行，直到反应实质性完成。
中间体2中X2为-OSO2R时，R如前所述，中间体2结构式为式10：
Figure PCTCN2017115807-appb-000011
式10的制备由式11与磺酰氯在碱性条件下反应制备。反应溶剂为二氯甲烷、四氢呋喃、乙醚、异丙醚、乙腈、丙酮或其混合物；反应温度为温室；碱选自碳酸钾、碳酸钠、氢氧化钠、碳酸氢钠、碳酸氢钾、三乙胺、N-甲基吗啡啉或二异丙基胺等；磺酰氯选自甲磺酰氯、对甲苯磺酰氯。式11与磺酰氯摩尔比为1:1-2，优选为1:1.05；2与碱摩尔比为1:1-2，优选为1:1.2。
Figure PCTCN2017115807-appb-000012
中间体3中Z为-NHQ2，Q1、Q2分别如前所述时，中间体3结构式为式12：
Figure PCTCN2017115807-appb-000013
中间体3中Z为离去基团如Br，Q1如前所述时，中间体3结构式为式13：
Figure PCTCN2017115807-appb-000014
式12中R3为氢，R2为-CH2OQ4，T在邻位时，Q1、Q2分别如前所述，Q4为氢或羟基保护基，羟基保护基选自硅醚类例如三甲硅基、叔丁基二甲硅基、叔丁基二苯基硅基等，酯类(酰基基团)如甲酰基、乙酰基等，芳基甲基基团如苄基、对甲氧基苄基、9-芴基甲基、二苯甲基等；式12化合物结构式为式14：
Figure PCTCN2017115807-appb-000015
式14的制备由式15与Q2NH2在碱性条件下加压或加热进行反应制备。反应溶剂为醇类、水或Q2NH2；反应温度为50-120℃，优选80-110℃；反应时间1-10小时，优选4-6小时。
Figure PCTCN2017115807-appb-000016
式15中，Q4如前所述。式15由式16在手性催化剂存在时，用硼烷二甲硫醚或四氢呋喃溶液经手性还原得到R构型产物。反应溶剂选自四氢呋喃、二氧六环、乙醚、二氯甲烷等；反应时间1-6小时；反应温度-5-50℃，优选0-40℃。
Figure PCTCN2017115807-appb-000017
式16中，Q1、Q4定义与上文相同，其制备方法由式17在溶液中与溴反应制备。反应溶剂选自四氢呋喃、二氧六环、乙醚、异丙醚、二氯甲烷、三氯甲烷或其混合物；反应时间1-6小时；反应温度-5-50℃，优选-5-30℃。
Figure PCTCN2017115807-appb-000018
式17中Q1、Q4与上文定义相同，其制备方法由4-羟基-3-羟甲基苯乙酮在碱性条件下与含羟基保护基化合物反应制备，例如与溴苄反应。
式12中，当R3为氢，R2为-NHCHO，T为邻位时，Q1、Q2分别如前所述，其结构式为18：
Figure PCTCN2017115807-appb-000019
式18由式19与Q2NH2在加压或加热条件下进行反应制备。反应溶剂选自醇类、水、四氢呋喃、二氧六环或Q2NH2；反应温度为50-120℃，优选80-110℃；反应时间1-10小时。
Figure PCTCN2017115807-appb-000020
式19中Q1与上文相同，其制备由式20在手性催化剂存在时，用硼烷二甲硫醚或四氢呋喃溶液经手性还原得到R构型。反应条件与制备化合物15相同。
Figure PCTCN2017115807-appb-000021
式20中，Q1与上文定义相同，由式21化合物与无水甲酸制备，反应缩合剂选自1,3-二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)等；也可用乙酸酐与甲酸制备混合酸酐与式21反应制备。反应溶剂选自二氯甲烷、四氢呋喃、无水甲酸或其混合物；反应时间时间2-8小时；反应温度5-50℃，优选温度5-30℃。
Figure PCTCN2017115807-appb-000022
Figure PCTCN2017115807-appb-000023
式21化合物中Q1定义与上文相同，由式22化合物经金属与氯化铵还原制备。反应溶剂选自水、醇例如甲醇、乙醇等。金属选自还原性铁粉、锌粉等。
Figure PCTCN2017115807-appb-000024
式22中，Q1与上文定义相同，由式23在溶液中与溴反应制备。反应溶剂为四氢呋喃、二氧六环、乙醚、异丙醚、二氯甲烷、三氯甲烷等；反应时间1-6小时；反应温度-5-50℃，优选温度5-30℃。
Figure PCTCN2017115807-appb-000025
式23中Q1与上文定义相同，由4-羟基-3-硝基苯乙酮在碱性条件下与含羟基保护基化合物反应制备，例如与溴苄反应制备。
式12中，Q1、Q2与上文定义相同；当R2为-NH-，R3为-CH＝CH-CO-，T为邻位时，其代表的化合物为式24：
Figure PCTCN2017115807-appb-000026
其制备方法是以式25与Q2NH2经亲核加成反应制备，反应溶剂选自甲醇、乙醇、乙腈、四氢呋喃、二氧六环、乙醚、异丙基醚或其混合物，优选甲醇、乙醇、乙腈、四氢呋喃、二氧六环；反应温度10-100℃；反应时间2-8小时。Q1、Q2 分别如前所述。
Figure PCTCN2017115807-appb-000027
式25中Q1与上文定义相同，由式26在碱性条件下环合而成。碱选自碳酸钾、碳酸钠、氢氧化钠、氢氧化钾等；反应溶剂为水、甲醇、乙醇、乙腈、丙酮、丁酮等，优选甲醇、乙醇、丙酮和水；反应温度10-100℃，优选温度10-30℃，反应时间1-5小时。
Figure PCTCN2017115807-appb-000028
式26结构式中Q1与上文定义相同。其制备方法以式27在手性催化剂存在时，用硼烷进行选择性还原生成R构型的醇。反应中所用催化剂为(1R,2S)-(+)-茚醇，反应溶剂选自N,N-二甲基甲酰胺、N,N-二乙基乙酰胺、二甲亚砜、二氯甲烷、三氯甲烷、四氢呋喃、乙醚或异丙醚等，优选四氢呋喃或乙醚；式27与(1R,2S)-(+)-茚醇的摩尔比为1：0.01-0.2，式27与硼烷摩尔比为1:1.1-2.5；反应温度为0-50℃，优选温度0-30℃；反应时间4-10小时。
Figure PCTCN2017115807-appb-000029
式27中Q1与上文定义相同。其制备方法参考上文方法由式28在溶液中与溴反应制备。反应溶剂选自四氢呋喃、二氧六环、乙醚、异丙醚、二氯甲烷、三氯甲烷等；反应时间1-6小时；反应温度-5-50℃，优选0-30℃。
Figure PCTCN2017115807-appb-000030
式28的制备以5-乙酰基-8-羟基喹啉为起始原料，在碱性条件下与Q1X反应生成式28。X为离去基团，选自卤素如氯、溴、碘，磺酸酯如甲磺酸酯、对甲苯磺酸酯；碱选自碳酸钾或碳酸钠等；反应溶剂选自甲醇、乙醇、丙酮、丁酮、四氢呋喃、二氧六环、二氯甲烷、三氯甲烷、乙醚、异丙醚、乙腈等，优选丙酮、四氢呋喃或乙腈。
式12中，Q1，Q2与上文定义相同；当R2为-NH-，R3为-O-CH2-CO-，T为间位时，其代表的化合物为式29：
Figure PCTCN2017115807-appb-000031
其制备方法是以式30与Q2NH2经亲核加成反应制备，反应条件与式24类似；Q1、Q2分别如前所述。
Figure PCTCN2017115807-appb-000032
式30以式31制备，其制备方法与制备式25相似。其中Q1与上文定义相同。
Figure PCTCN2017115807-appb-000033
式31以式32制备，其制备方法与制备式26相似。其中Q1与上文定义相同。
Figure PCTCN2017115807-appb-000034
式32以式33制备，其制备方法参考27制备方法。其中Q1与上文定义相同。
Figure PCTCN2017115807-appb-000035
式33由式34与氯乙酰氯在碱性条件下反应制备。制备条件为式34与氯乙酰氯的摩尔比为1:1-2，优选1:1.05；碱选自碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠或低浓度氢氧化钠溶液等，式34与碱的摩尔比为1:1-3，优选为1:1.5；反应温度为10-100℃，优选20-60℃。
Figure PCTCN2017115807-appb-000036
Figure PCTCN2017115807-appb-000037
式34由式35将硝基还原为氨基而得。其制备方法可采用氢化法，用氧化铂为催化剂进行选择性氢化，反应溶剂选自甲醇、乙醇、四氢呋喃或其混合物；温度为10-50℃，优选20-30℃；压力为0.5-4MPa；或用还原性铁粉在氯化铵水溶液中进行选择性还原，将硝基还原为氨基，溶剂选自甲醇、乙醇、四氢呋喃或其混合物，式34与氯化铵的摩尔比为1:1-4，优选1：2；式35与还原性铁粉的摩尔比为1:1-5，优选为1:2。
Figure PCTCN2017115807-appb-000038
式35由式36经硝化反应制备。反应溶剂为冰乙酸，反应温度为-5-50℃，优选0-30℃。
Figure PCTCN2017115807-appb-000039
式36由2,4-二羟基苯乙酮在弱碱性条件下与Q1X反应制备，Q1X与上文定义相同。碱选自碳酸氢钠、碳酸氢钾或其混合物等；2,4-二羟基苯乙酮与碱的摩尔比为1:1；2,4-二羟基苯乙酮与Q1X的摩尔比为1：1；反应温度为10-50℃，反应时间为2-5小时。
步骤(c)中中间体4或其它带保护基的目标化合物经还原生成目标化合物，该反应中可以使用任何合适的还原剂，如催化氢化，催化剂选自Pd/C、雷尼镍、氧化铂或其混合物，也可用金属氢化物试剂，如三乙酰基硼氢化钠等；反应溶剂为甲醇、乙醇或其混合物。
步骤(d)式I化合物通过碱性阴离子交换树脂生成式I的氢氧化物，如OH-树脂等，然后与各种不同的酸反应而制备各种不同酸根的季铵盐，包括上文提到 的各种酸根盐；或者式I化合物与特定的阴离子交换树脂交换而制备特定酸根的季铵盐；或者式I卤化物与氧化银反应生成式I的氢氧化物再与其它酸反应生成各种酸根的季铵盐；或式I卤化物与银盐反应生成相应酸根的季铵盐，如与硫酸银，硝酸银等。
在特定的实施方案中，式I的某些特定化合物通过(a1)-(d1)方法制备。该方法包括如下结构式化合物或其药学上可接受的任选盐或溶剂化物或其光学异构体及其混合物。
Figure PCTCN2017115807-appb-000040
Figure PCTCN2017115807-appb-000041
另一方面，本发明涉及式I化合物的药物组合物，包括可接受的药学载体,上述的药物组合物可以选择性地含有其他治疗成分，诸如甾体类抗炎药、磷酸二酯酶抑制剂(PDE-4)等以及它们药效学上可接受的盐、溶剂化物、有效治疗剂量的光学异构体。
本发明的式I化合物通常是以组合物或制剂的形式用于患者。这些组合物可以通过任何可接受的给药途径用于患者，包括但不限于吸入、口服、鼻用、局部(包括透皮)和肠胃外给药方式。即适于任何特定给药模式的本发明化合物的任何形式(包括游离碱，药学上可接受的盐或其溶剂化物等)可被用在本发明的药物组合物中。
本发明的药物组合物通常包含治疗有效剂量的本发明的化合物或其药学上可接受的盐或其溶剂化物。通常这种药物组合物包含约0.001至约100％重量的活性成分。
任何常规载体或赋形剂都可用于本发明中，特定的载体或赋形剂，或载体与赋形剂的组合物的选择取决于治疗特定患者的给药模式或医学状况或疾病类型。用于特定模式的药物组合物的制备技术都在本领域技术人员的知识范围内。此外载体或赋形剂或载体与赋形剂的组合物都可从商业购买。
作为药学上可接受的载体的代表性例子包括但不限于如下所述：(1)糖类，如葡萄糖、乳糖、蔗糖等；(2)淀粉类，如玉米淀粉；(3)纤维素及其衍生物类，如羧甲基纤维素钠、醋酸纤维素等；(4)滑石粉；(5)赋形剂类，如可可豆脂、蜡类；(6)油类，如橄榄油、大豆油等；(7)醇类，如乙醇、丙二醇、 甘油、山梨醇、聚乙二醇、甘露醇等；(8)酯类，如油酸乙酯、月桂酸乙酯；(9)无热源水；(10)等渗盐水；(11)磷酸盐缓冲液；(12)压缩推进气体，如氯氟碳，氢氟碳等；(12)其它用于药物组合物中的无毒相溶性物质。
本发明的组合物通常是彻底混合本发明化合物与任选的一种或多种载体进行制备。如有必要，本发明中得到的均匀混合物可以利用常规设备和方法进行塑性或加载到片剂、胶囊、丸剂、罐或药筒中。
本发明的药物组合物适于吸入给药。用于吸入给药的组合物通常是气雾剂或粉雾剂形式。这种组合物通常用公知的给药装置给药，如雾化吸入器，定量吸入器(MDI)或干粉吸入器(DPI)或其他类似的给药装置。
本发明包含活性成分的组合物通过雾化吸入器雾化给药。雾化装置通常能产生高速气流，使含有活性成分的药物组合物雾化而被患者吸入呼吸道。因此活性成分通常被溶解于合适的溶剂中制成溶液而置于雾化吸入器中。或者活性成分微粉化与适宜的载体组合形成适于吸入的微粉化颗粒混悬液。微粉化通常定义为大于或等于90％的颗粒直径小于10μm。适宜的雾化装置商业上可以提供。
使用雾化吸入器的代表性药物组合物包括含有0.05μg/ml至10mg/ml式I化合物或其药学上可接受的盐，或其溶剂化物，或其光学异构体的等渗水溶液，或乙醇溶液。
本发明包含药物组合物利用干粉吸入器吸入给药。干粉吸入器给药方式通常在吸入期间使活性成分在患者气流中形成自由流动的粉末。因此活性成分通常与适宜的赋形剂一起配制以获得自由流动的粉末，如以乳糖为赋形剂。
用于干粉吸入器有代表性的药物组合物包括颗粒大小约1μm至约100μm之间的干乳糖与式I化合物或其药学上可接受的盐或其溶剂化物或其光学异构体形成的微粉化颗粒。
干粉制剂可以通过干混合活性成分与赋形剂制备，也可不加赋形剂，然后将药物组合物装入干粉分配器中，或装入与干粉给药装置一起使用的吸入药筒或胶囊。
干粉给药装置商业上可获得。
本发明包含活性成分的药物组合物是利用定量吸入器通过吸入方式给药。这种定量吸入装置利用压缩推进气体放出测定量的活性成分或其药学上可接受的 盐。因此利用定量吸入器给药的药物组合物包含在液化推进的溶液或混悬液中。
用于定量吸入器的有代表性的药物组合物包含0.001％至约3％重量的式I化合物或其药学上可接受的盐或其溶剂化物或其光学异构体；约0％至约40％的潜溶剂乙醇或二醇类，优选5％至约30％；约0％至3％重量的表面活性剂；其余为氢氟烷类(HFA)推进剂。
这种组合物通常用含活性成分、乙醇(如存在)和表面活性剂(如存在)的适宜容器中加入冰冷的或加压的氢氟烷类制备。为制备混悬液，将活性成分微粉化然后与推进剂混合。然后将该制剂置入气雾剂罐，形成定量吸入装置的一部分。这种混悬制剂也可利用喷雾干燥法在活性成分微粒表面形成表面活性剂的包衣制备。
制备可吸入颗粒的方法和制剂以及适宜于吸入给药的其它实例在文献中都有论述。
本发明的组合物适于口服给药。用于口服给药的药物组合物可以是胶囊、片剂、丸剂、粉剂、颗粒剂、扁胶囊和糖衣丸。或制成含水或无水溶液或混悬液；或制成油包水或水包油乳剂；或制成糖浆。它们都包含本发明化合物预定量的活性成分。
固体剂型给药时，本发明的组合物包含作为活性成分的本发明化合物与适宜的一种或多种药物学上可接受药物载体。例如(1)填充剂或增充剂，如淀粉、蔗糖、硅酸等；(2)粘合剂，如羧甲基纤维素、聚乙烯吡咯烷酮等；(3)湿润剂，如甘油；(4)崩解剂，如碳酸钙、淀粉等；(5)润滑剂，如硬脂酸镁、滑石粉、固体聚乙二醇或它们的混合物；(6)吸收剂，如高岭土等。
释放剂、湿润剂、包衣剂、甜味剂、抗氧剂、香味剂、调味剂和防腐剂也可存在于本发明的组合物中。药学上可接受的抗氧剂包括但不限于以下物质：水溶性抗氧剂，如亚硫酸钠、抗坏血酸、盐酸半胱氨酸等；脂溶性抗氧剂，如丙基没食子酸酯、α-生育酚等；金属螯合剂，如柠檬酸、山梨醇、和乙二氨基四乙酸(EDTA)等。
用于片剂、胶囊、丸剂的包衣剂包括但不限于醋酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)等。
本发明组合物也可制成缓释剂，以控制活性成分的缓慢释放，如利用不同比 例的羧甲基纤维素或其它聚合物基质、脂质体或微球制成缓控制剂。
用于口服给药的合适的液体剂型包括混悬液、糖浆、乳剂、微乳和溶液等。液体剂型包含活性成分和惰性稀释剂，如水和其它溶剂，增溶剂和乳化剂等。典型代表如下：油类(橄榄油等)、甘油、聚乙二醇、脱水山梨糖醇的脂肪酸酯或它们的混合物。
本发明的药物组合物也可以包含式I化合物或其药学上可接受的盐、溶剂化物或其光学异构体及其混合物与其它药物形成的混合物，用于共同给药治疗。如本发明的药物组合物包含一种或多种其它支气管扩张剂，如PDE3抑制剂、β2肾上腺素受体激动剂等；抗炎剂，如甾体类抗炎剂、非甾体类抗炎剂、PDE4抑制剂等；M受体拮抗剂；抗感染剂，如革兰氏阴性和革兰氏阳性抗生素、抗病毒药物等；抗组胺药物；蛋白酶抑制剂；传入阻滞剂，如D2激动剂等。其他治疗剂可以以药学上可接受的盐或溶剂化物形式应用。此外，其它治疗剂也可以光学异构体形式应用。
能够与本发明化合物组合使用的(除本发明化合物以外)有代表性的β2肾上腺素受体激动剂包括但不限于沙美特罗、沙丁胺醇、左旋沙丁胺醇、福莫特罗、茚达特罗、维兰特罗、阿福特罗、沙甲胺醇、非洛特罗、异他林、奥西那林、比托特罗、吡布特罗等，或其药学上可接受的盐。
能够与本发明化合物组合使用的(除本发明化合物以外)有代表性的甾体抗炎剂包括但不限于甲基泼尼松龙、泼尼松龙、地塞米松、丙酸氟替卡松、倍氯米松酯、布地奈德、氟尼缩松、莫米松酯、曲安西龙、罗氟奈德、环索奈德等，或它们在药学上可接受的盐。在使用时，甾体抗炎剂将以有效治疗剂量存在于组合物中，通常甾体的量为0.05μg至500μg之间。
其它适宜的组合物包括本发明式I所代表的化合物与其他类的抗炎药形成的组合物。如与非甾体类抗炎药，其典型代表性药物如下：NSAIDs类，如奈多罗米钠、色甘酸钠等；磷酸二酯酶(PDE)抑制剂类，如茶碱、PDE4抑制剂或混合PDE3/PDE4抑制剂等；白三烯拮抗剂，如孟鲁司特；蛋白酶抑制剂；细胞因子拮抗剂；或细胞因子合成抑制剂等。
可以与本发明化合物组合使用的(除了本发明化合物之外)有代表性的M受体拮抗剂包括但不限于格隆溴铵、异丙托溴铵、噻托溴铵、阿托品、硫酸阿托品、 氧阿托品、硝酸甲基阿托品、氢溴酸后马托品、氢溴酸莨菪碱、氧托溴铵、溴甲胺太林、丙胺太林溴化物、溴甲辛托品、克利溴铵、异丙碘胺、溴美喷酯、哌仑西平、替仑西平、美索曲明等，或它们药学上可接受的盐。
可以与本发明化合物组合使用的抗组胺药物包括但不限于如下种类：乙醇胺类，富马酸氯马斯汀、马来酸卡比沙明、盐酸苯海拉明、茶苯海明等；乙二胺类，如马来酸美吡拉敏、盐酸苄吡二胺和柠檬酸苄吡二胺等；烷基胺类，如氯苯那敏、阿伐斯汀等；哌嗪类，如盐酸羟嗪、耐酸羟嗪、盐酸苯甲嗪、乳酸赛克力嗪、盐酸美克洛嗪、盐酸西替利嗪等；哌啶类，如阿司咪唑、左卡巴斯汀盐酸盐、氯雷他定及其类似物、特非那定、盐酸非索那定、盐酸氮唑斯汀等，或他们药学上可接受的盐。
与本发明化合物组合给药的其它药物的有效治疗剂量大约每次0.005mg至约10mg范围内。
本发明也涉及式I化合物，或其药学上可接受的盐、溶剂化物、光学异构体或其混合物用于制备治疗呼吸系统疾病的药物的用途，所述呼吸系统疾病包括COPD、哮喘、鼻炎等。
本发明的化合物同时具有β2肾上腺素受体激动和M受体拮抗活性，因此它们适宜于治疗β2肾上腺素受体和M受体介导的疾病。即通过使用β2肾上腺素受体激动剂和M受体拮抗剂能缓解的疾病。这种疾病包括与可逆的气道阻塞有关的肺部紊乱或疾病，如COPD、哮喘、肺纤维化等。
本发明涉及治疗肺部疾病的方法，包括给予需要治疗的患者有效剂量的式I化合物或其药学上可接受的盐或其溶剂化物或其光学异构体。进行疾病治疗时，本发明的化合物通常以每日多剂量、每日单剂量或每周单剂量形式吸入给药。剂量约为每次1.0μg至约200μg。
吸入给药时，本发明化合物具有支气管扩张作用，因此本发明涉及为患者提供支气管扩张的方法，包括给予需要治疗的患者有效剂量的式I化合物或其药学上可接受的盐或其溶剂化物或其光学异构体。剂量约为每次1.0μg至约200μg。
本发明涉及治疗慢阻肺或哮喘的方法，包括给予需要治疗的患者有效剂量的式I化合物或其药学上可接受的盐或其溶剂化物或其光学异构体。治疗COPD或哮喘时，以每日多剂量、每日单剂量方式给药，剂量约为每次1.0μg至约200 μg。
当本发明的化合物用于肺病治疗时，本发明化合物可任选地与其他治疗剂组合给药。尤其是本发明化合物与甾体抗炎药组合时，本发明的两种活性成分组合物能提供三重治疗，即β2肾上腺素受体激动、M受体拮抗和抗炎作用。与包含三种活性成分的组合物相比，本发明的含两种活性成分的组合物通常更易制备。因此双组分组合物优于三组分组合物。本发明的药物组合物可以包含有效治疗剂量的甾体抗炎剂。
本发明的化合物显示β2肾上腺素受体激动和M受体拮抗两种活性。除其它性质外，特别引起注意的化合物是M3受体亚型结合抑制常数Ki值和β2肾上腺素受体激动活性的EC50小于100nm的化合物，尤其是二者数值小于10nm的化合物。此外，在体外实验或相似的实验中，M3受体亚型结合抑制常数Ki值和β2肾上腺素受体激动活性的EC50值相近的那些化合物也是必须关注的。例如M3受体亚型结合抑制常数Ki值与β2肾上腺素受体激动活性的EC50值的比值约为1:30至约30:1的化合物，包括1:20至20:1,也包括约1:10至约10:1那些化合物，也包括约1:5至约5:1那些化合物。
本发明也提供治疗COPD的方法，包括给予需要治疗的患者有效剂量的具有M3受体拮抗和β2肾上腺素受体激动活性的化合物。
在某些特定的实施例中，本发明的化合物可能有弱的M受体拮抗剂活性或β2肾上腺素受体激动剂受体结合活性，但它们仍可作为M受体拮抗剂或β2肾上腺素受体激动剂受体单独使用。
当描述本发明的化合物、组合物、方法和过程时，除非另外指出，下述术语具有下述含义。
术语“烷基”指直链或支链未取代饱和烃。除非另外定义，这种烷基基团通常包含1-10个碳原子。代表性的烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。
术语“烷氧基”指式(烷基)-O-的一价基团，其中烷基如本文所定义。有代表性的烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
术语“亚芳基”指芳香环的二价基团，包括取代和非取代的芳香环。代表性 亚芳基包括1，4-苯二亚基、2-甲氧基-1，4-苯二亚基、2，5-呋喃亚基等。
术语“亚杂环基”指杂原子环烃的二价基团，包括取代和非取代的杂环烷烃。代表性包括2，3-四氢呋喃亚基、2，4-四氢吡咯亚基等。
术语“亚烷酰胺基”指既含有烷基又含有酰胺基的二价基团，包括取代和非取代的亚烷酰胺基。代表性的亚烷酰胺基包括2-氧代丙胺-1，4-二亚基、2-氧代乙胺-1，3-二亚基等。
术语“卤素”指氟、氯、溴和碘。
术语“药学上可接受的盐”指可以用来给予患者使用的盐。这种盐可以衍生于药学上可接受的无机和有机碱，也可衍生于药学上可接受的无机酸和有机酸。包括根据本文中所述化合物上存在的特定取代基采用相对无毒的酸或碱制备的活性化合物的盐。由药学上可接受的无机碱衍生的盐的实例包括但不限于铵、钙、钾、钠等。由药学上可接受的有机碱衍生的盐包括伯、仲和叔胺的盐，它们包括取代的胺、环胺、天然胺等，例如但不限于甜菜碱、咖啡因、胆碱等。当本发明化合物含相对碱性的官能团时，可通过使游离形式的这种化合物与足量的需要的酸单独或在合适的惰性溶剂中接触得到盐。药学上可接受的酸加成盐的实例包括由无机酸衍生的那些盐，无机酸盐例如但不限于硝酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、硫酸氢盐、盐酸盐、氢溴酸盐等；由相对无毒的有机酸衍生的盐，所述有机酸为但不限于例如乙酸、琥珀酸、富马酸、扁桃酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。
本发明中涉及的化合物与其盐的形式可以通过本领域常规的方法相互转换，例如铵盐可通过使盐与碱或酸接触再按常规方式分离得到游离形式的化合物。再通过将游离形式化合物加入酸或碱得到其它盐的形式。化合物游离形式的某些物理性质例如在极性溶剂中的溶解度与各种盐形式的不同，但对于本发明目的，盐与母体形式的化合物具有同样的治疗效果。
除盐形式外，本发明提供前药酯形式的化合物。本文中所述化合物的“前药”是在生理环境下容易发生化学变化得到本发明化合物的那些化合物。
“前体基团”是指当用于掩盖活性药物中的官能团形成“前体部分”时能够将药物转化为前药的一类保护基团。前体基团通常通过键与药物的官能团连接， 所述键在特定使用条件下可裂解。因此，前体基团为前体部分的一部分，该前体部分在特定使用条件下裂解，释放官能团。
合适的前体基团和它们的相应前体部分的特定实例对本领域技术人员而言是显而易见的。
本发明某些化合物具有不对称碳原子(旋光中心)或双键；其外消旋体、非对映体、几何异构体、旋光异构体均包括在本发明范围内。可用常规方法将这些异构体拆分或不对称合成，以使异构体“旋光纯”，即基本上不含它的其它异构体。例如，如果需要本发明化合物的特定对映体，可通过不对称合成制备，或通过用手性助剂衍生化，其中将得到的非对映异构的混合物分离，再将助剂基团裂解得到纯的需要的对映体。或者依据其多个手性中心形成的不同非对映异构体用制备柱进行分离，例如化合物61,70,82,98等一些化合物R1结构中含有手性碳，即用此方法进行分离；或者，当分子含碱性官能团例如氨基或酸性官能团例如羧基时，用适当的旋光活性酸或碱形成不对称异构体的盐，然后通过本领域中熟知的分级结晶或色谱方法将由此形成的非对映体拆分，然后回收纯对映体。
术语“溶剂化物”指式I中的化合物或其药学上可接受的盐的一个或多个分子与一种溶剂的一个或多个分子形成的复合物或聚合体。这种溶剂化物通常是具有固定摩尔比的溶质和溶剂的结晶体。有代表性的溶剂包括，如乙醇、乙酸、异丙醇、N，N-二甲基甲酰胺、四氢呋喃、二甲亚砜和水等。一般而言，溶剂化形式等同于非溶剂化形式，并包括在本发明范围内。
术语“治疗有效剂量”指给予需要治疗的患者足以实现治疗的量。
术语“离去基团”指在取代反应中，例如亲核取代反应，被另一个基团或原子取代的一个官能团或原子。代表性的离去基团包括，例如氯、溴、碘等；磺酸酯基团如，甲磺酸酯、对甲苯磺酸酯、对溴苯磺酸酯、对硝基苯磺酸酯等；酰氧基基团如，乙酰氧基、三氟乙酰氧基等。
术语“氨基保护基”指适宜的氨基基团以阻止氨基在反应过程中发生不必要的不可逆反应，事后可将保护基除去，而不影响到分子结构中的其它部分。有代表性的氨基保护基包括，但不限于如下基团苄基(Bn)、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、9-芴基甲氧羰基(Fmoc)、甲酰基、乙酰基等。
术语“羟基保护基”指适于羟基基团防止不必要反应发生的保护基团。代表 性的羟基保护基团包括但不限于：硅醚类例如三甲硅基、叔丁基二甲硅基、叔丁基二苯基硅基等，酯类(酰基基团)如甲酰基、乙酰基等，芳基甲基基团如苄基、对甲氧基苄基、9-芴基甲基、二苯甲基等。此外，两个羟基基团可以被一个保护基保护，如用丙酮与二醇反应形成的丙二亚基醚等。
具体实施方式
用下述的制备和实施例举例说明本发明的特定实施方案，除非特别指明，这些特定实施方案不以任何形式限制本发明的范围。
制备1：
(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇
(a)4-羟基-3-氯甲基苯乙酮
将360克(2.637mol)4-羟基苯乙酮置于5000mL三口瓶中，加入775.5克(10.34mol)甲醛水溶液，搅拌下加入浓盐酸3216克，固体完全溶解，冷水浴使反应混合物温度为20℃，通入HCl，继续搅拌，反应溶液变成红色，有固体析出。继续搅拌5小时，将反应混合物倒入冰水中，搅拌30分钟，滤集固体，用水洗涤固体5次，每次1000mL，然后用石油醚洗涤2次。固体在50℃下烘箱中干燥，得400克4-羟基-3-氯甲基苯乙酮红色固体，收率82.1％。
(b)4-羟基-3-乙酰氧甲基苯乙酮
将397.5克(2.153mol)4-羟基-3-氯甲基苯乙酮置于2000mL三口瓶中，加入1000mL冰乙酸，搅拌下加入乙酸钠215克(2.62mol)，将反应混合物加热至100℃，反应溶液呈棕色，在此温度下继续搅拌反应3小时，反应终止。冷却至室温，将反应混合物倒入冰水中，用二氯甲烷萃取3次，每次600mL，合并有机相，水洗3次，有机相用无水硫酸镁干燥。过滤，滤除干燥剂，减压除去二氯甲烷，残留固体用200mL乙酸乙酯加热溶解，冷却结晶。滤集固体，得4-羟基-3-乙酰氧甲基苯乙酮白色固体211克，收率47％。
(c)4-苄氧基-3-乙酰氧甲基苯乙酮
将4-羟基-3-乙酰氧甲基苯乙酮315克(1.51mol)置于3000mL三口瓶中，加入1800DMF(N,N-二甲基甲酰胺)溶解。冷却至内温10℃，加入无水碳酸钾215克，在此温度下，滴加溴苄291克(1.65mol)，2小时滴加完毕。将反应混合 物温度升至30℃，继续反应10小时。过滤除去碳酸钾，减压除去溶液中的N,N-二甲基甲酰胺，残留物加水1500mL，用乙醚萃取三次，每次1000mL，合并乙醚提取液，水洗乙醚层三次，每次1000mL，乙醚层用无水硫酸镁干燥。滤除干燥剂，除去乙醚，残留物用150mL乙醇加热溶解，放置冷却结晶。滤集固体，得4-苄氧基-3-乙酰氧甲基苯乙酮白色固体334克，收率74％。
(d)4-苄氧基-3-羟甲基苯乙酮
将4-苄氧基-3-乙酰氧甲基苯乙酮238克(0.798mol)置于3000mL三口瓶中，加入甲醇1900mL，加热搅拌使原料溶解。然后加入氢氧化钠83.11克(1.995mol)，加热回流反应1小时，停止反应，减压除去溶剂，加水1000mL，用二氯甲烷萃取三次。每次800mL，合并二氯甲烷层，用无水硫酸镁干燥。滤除硫酸镁，溶液减压浓缩，除去部分二氯甲烷后，加入等体积的乙酸乙酯，置于冰箱中结晶。滤集固体，得4-苄氧基-3-羟甲基苯乙酮白色固体172.56克，收率84.4％。
(e)4-苄氧基-3-苄氧甲基苯乙酮
将4-苄氧基-3-羟甲基苯乙酮172.56克(0.673mol)溶解于1000mL四氢呋喃置于2L三口瓶中，加热至内温为30℃，分批加入氢化钠，共34.65克(1.0mol),加毕，继续搅拌20分钟，在此温度下滴加溴苄(176.28克(1.0mol),滴加时间约为1小时。加毕，继续搅拌反应10小时。减压除去溶剂，残留物加水800mL，用乙酸乙酯萃取三次，每次600Ml，合并萃取液，用无水硫酸镁干燥。滤除干燥剂，减压浓缩至干，残留物用乙醇溶解结晶，滤集固体，得白色4-苄氧基-3-苄氧甲基苯乙酮164.15克，收率70.4％。
(f)4-苄氧基-3-苄氧甲基苯溴代乙酮
取4-苄氧基-3-苄氧甲基苯乙酮178.5g(500.1mmol)置于3L三口瓶中，加入2200ml二氯甲烷,搅拌30min，内温20-25℃滴加溴88克(510mmol)，2小时滴毕，再反应30min，有大量固体产物，TLC分析，原料少许未反应完全。滤除固体，，固体用混合溶剂2000ml二氯甲烷溶解，用饱和碳酸氢钠水溶液洗(1000mL×3次)，有机层用无水硫酸镁干燥,滤除干燥剂，水泵减压(20℃)抽尽溶剂，得固体。用无水乙醇重结晶，凉干得产物180.5克，收率83.1％。
(g)(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-溴乙醇
取(1R,2S)-(+)-1-氨基-2-茚醇0.360g(2.37mmol)置于2L三口烧瓶中加入THF145ml，20-25℃搅拌。加入硼烷二甲硫醚3.3ml(34.8mmol)搅拌20min，20-25℃同时滴加4-苄氧基-3-苄氧甲基溴代苯乙酮130.72g(300.0mmol)与THF1396ml溶液和硼烷二甲硫醚24.54ml(258.8mmol)与THF364ml溶液，3小时滴毕。保持20-25℃氮气保护下反应30min。TLC分析，反应完全。外用冰浴冷却(＜10℃)滴加甲醇145.4ml，滴毕后保持冰浴(＜10℃)搅拌10分钟。40℃水泵减压抽尽溶剂。加入水和乙酸乙酯各500ml室温搅拌，有气泡产生，室温搅拌5min，移入分液漏斗中，分出有机层，水层再用乙酸乙酯(150ml×3次)提取，合并有机层，用无水硫酸镁干燥。
滤除干燥剂，40℃水泵减压抽尽溶剂，得粗品。粗品柱层析得油状粘稠物113.1g，收率86.0％。
1HNMR(ppm):(CD3Cl)，7.52-7.38(5H),7.36-7.29(5H)，7.27-7.19(2H),6.88(d,1H),5.19(s,2H),5.10(s,2H),4.92(t,1H),3.86-3.79(m,1H),3.66-3.52(m,1H),2.18(Br,1H)
HPLC分析(手型柱，大赛璐AD-H柱，4.6mm*250mm)，96.831％(R-构型)，2.54％(S-构型)
(h)(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇
取中间体(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-溴乙醇87.4g(200.0mmol)置于500ml三口瓶中，加入苄胺162.3克(1.517mol)，二氧六环100mL，油浴100-110℃反应3h，TLC分析，中间体反应完全。45℃水泵减压，除去溶剂。加入乙酸乙酯500ml和水500ml搅拌，加入碳酸氢钠调节水层PH8-9，移入分液漏斗中分出有机层，水层再用乙酸乙酯(300ml×3次)提取，合并有机层，无水硫酸镁干燥。滤除干燥剂，45℃水泵减压除去溶剂，得油状物。
取上述油状物加入乙酸乙酯160ml搅拌溶解，冰浴冷却结晶，滤集白色固体并用少量乙酸乙酯洗涤，产物60℃鼓风干燥2小时，得结晶产物64.8g，反应收率为75.5％。
1HNMR(ppm，DMSO(d6)):7.52-7.38(5H),7.36-7.09(10H)，7.27-7.19(2H),6.88(d,1H),5.19(s,2H),5.10(s,2H),4.92(t,1H),3.86-3.79(m,1H),3.66-3.52(m,1H),2.18(Br,1H)
制备2
(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷
(a)R-环戊基扁桃酸
在5L三口瓶中，加入环戊基扁桃酸消旋体320克(1.453mol),乙腈2670mL，水211mL，搅拌并加热溶解，反应混合物温度为40-45℃，此时固体完全溶解。在此温度下加入D-酪氨酸甲酯141.53克(0.725mol)，析出固体，加热至反应混合物回流，固体完全溶解，溶液澄清透明。停止加热，将反应混合物冰浴冷却至0℃，继续搅拌4小时，析出大量结晶。滤集固体，固体用乙腈洗三次(3X150mL)，晾干得R-环戊基扁桃酸D-酪氨酸甲酯盐230.69克，收率76.6％。
将上述R-环戊基扁桃酸D-酪氨酸甲酯盐230.69克加至5L三口瓶中，加入甲苯2000mL，水1000mL，搅拌下加入浓盐酸66mL，水浴加热至40℃，固体完全溶解。冷却，用分液漏斗分离水相和有机相。水相中加入浓盐酸20mL，并用甲苯萃取2次(2X250mL)。合并有机相，用无水硫酸镁干燥。滤除干燥剂，减压除去溶剂，残留物加入正己烷500mL，搅拌，出现大量固体。滤集固体，45℃干燥3小时，得R-环戊基扁桃酸白色固体134.4克，收率83.4％。
(b)(R)-2-羟基-2-苯基-2-环戊基乙醇
在10L反应釜中，加入R-环戊基扁桃酸134克(0.608mol)，乙二醇二甲醚2L，搅拌溶解。将反应混合物冷却至-5℃，缓慢加入三氯化铝243.21克(1.824mol)，保持此温度，分批加入硼氢化钠92克(2.43mol)，半小时内加毕。将反应混合物温度升至50℃，继续搅拌反应4小时，反应完毕，冷却至10℃左右，滴加2mol/L的盐酸1.1L，控制反应混合物的温度不变。滴加完毕，用异丙醚萃取3次(3X500mL)，合并有机相，有机相用饱和碳酸氢钠溶液洗涤3次(3X200mL)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂，残留物加入石油醚研磨，滤集固体得(R)-2-羟基-2-苯基-2-环戊基乙醇99.88克，收率79.6％。
(c)(R)-2-羟基-2-苯基-2-环戊基乙醇对甲苯磺酸酯
350mL二氯甲烷置于2L三口瓶中，加入(R)-2-羟基-2-苯基-2-环戊基乙醇98.88克(0.479mol)，搅拌溶解。将反应混合物冷却至-5℃，加入N-甲基吗 啡啉121.17克(1.198mol)，滴加含对甲苯磺酰氯91.32克(0.479mol)二氯甲烷溶液400mL，1小时滴加完毕，继续在此温度下反应4小时。反应混合物用水洗涤3次(3X500mL)，分出有机相，有机相用无水硫酸镁干燥。滤出干燥剂，溶液减压除去溶剂，残留物中加入异丙醚研磨，滤集固体，得(R)-2-羟基-2-苯基-2-环戊基乙醇对甲苯磺酸酯140克，收率81.1％。
(d)(R)-1-苯基-1-环戊基-环氧乙烷
700mmL二甲亚砜置于2L三口瓶中，加入(R)-2-羟基-2-苯基-2-环戊基乙醇对甲苯磺酸酯139克(0.386mol)，将反应混合物温度升至30℃，搅拌使固体完全溶解。加入固体氢化钠(60％)20.07克(0.502mol)，加毕，将反应混合物温度提升至50℃，继续反应3小时，原料完全消失。冷却反应液至10℃，滴加300mL水，加异丙醚萃取三次(3X500mL)，合并有机相，用无水硫酸镁干燥。滤除干燥剂，减压除去溶剂，得(R)-1-苯基-1-环戊基-环氧乙烷固体70克，收率96.3％。
(e)(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷
500mL二甲亚砜置于2L反应釜中，加入R-(-)-3-奎宁醇47.5克(0.373mol)，搅拌，但固体不溶。加入氢化钠(60％)7.5克(0.313mol)，有气泡产生，加热反应混合物至80℃，并在此温度下搅拌反应1小时。滴加含(R)-1-苯基-1-环戊基-环氧乙烷70克(0.372mol)的二甲亚砜溶液100mL，滴加时间约1小时。滴加完毕，继续在此温度下反应2小时，冷却反应混合物至20℃，滴加水785mL，加毕，再用乙酸乙酯萃取3次(3X500mL)，合并有机相，水洗有机相3次(3X200mL)，分出有机相，用无水硫酸镁干燥。滤除干燥剂，减压除去溶剂，得固体(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷88.5克，收率75.2％。
制备3
8-苄氧基-5-[(R)-2-苄胺基-1-羟基乙基]-(1H)-喹啉-2-酮
(a)8-乙酰氧基-(1H)-喹啉-2-酮
将8-羟基喹啉氮氧化物80克(0.5mol)加至500mL三口瓶中，加入乙酸酐 300mL(3.15mol)，搅拌加热至90-100℃，保持此温度继续搅拌反应4小时，将反应混合物冰浴冷却，析出固体。滤集固体，固体用冰冷的乙酸酐洗涤2次(2X50ml),真空干燥得8-乙酰氧基-(1H)-喹啉-2-酮固体82.2克，收率81.0％。
(b)5-乙酰基-8-羟基-(1H)-喹啉-2-酮
在500mL三口瓶中，加入1,2-二氯乙烷200mL，然后加入8-乙酰氧基-(1H)-喹啉-2-酮61克(0.30mol)悬浮于溶剂中，将反应混合物加热至80℃，分批加入三氯化铝120克(0.90mol)，继续在此温度下反应1.5小时，使其完全转化为5-乙酰基-8-羟基-(1H)-喹啉-2-酮。然后将反应混合物倒入1升80℃热水中，保持此温度30分钟，然后呈热过滤，用水研磨洗涤固体，80℃真空干燥得淡黄色5-乙酰基-8-羟基-(1H)-喹啉-2-酮50.3克，收率82.6％。
(c)5-乙酰基-8-苄氧基-(1H)-喹啉-2-酮
将5-乙酰基-8-羟基-(1H)-喹啉-2-酮32.52克(0.16mol)加至500mL反应瓶中，加入N，N-二甲基甲酰胺200mL溶解，加入无水碳酸钾27.2克(0.20mol)，搅拌下滴加溴苄27.4克(0.16mol)，室温搅拌反应4小时。过滤除去碳酸钾，残留物用1500mL二氯甲烷溶解。用水洗3次(3X300mL)，无水硫酸镁干燥。过滤，浓缩除去二氯甲烷，残留物用丙酮研磨，滤集固体并用丙酮/水(1/1，2X35mL)洗涤，得5-乙酰基-8-苄氧基-(1H)-喹啉-2-酮42.8克，收率91.5％。
(d)8-苄氧基-5-溴乙酰基-(1H)-喹啉-2-酮
将5-乙酰基-8-苄氧基-(1H)-喹啉-2-酮40.0克(0.137mol)加至1升三口瓶中，加入二氯甲烷500mL搅拌溶解。冰浴冷却反应液至0℃左右，加入无水三氯化铝0.267克(0.002mol)。然后滴加溴20克(0.15mol)，约30分钟滴加完毕，使反应混合物升至室温。在此温度下，继续搅拌反应4小时，薄层色谱检测反应完全。将反应混合物用饱和碳酸氢钠溶液洗涤三次(3X100mL),有机相用无水硫酸镁干燥3小时。滤除硫酸镁，减压浓缩除去溶剂，得8-苄氧基-5-(2-溴乙酰基)-(1H)-喹啉-2-酮固体42.2克，收率82.9％。
(e)8-苄氧基-5-[(R)-2-溴-1-羟基乙基]-(1H)-喹啉-2-酮
取(1R,2S)-(+)-1-氨基-2-茚醇0.12g(0.79mmol)置于500mL三口烧瓶中加入THF50ml，20-25℃搅拌。加入硼烷二甲硫醚1.1ml(11.6mmol)搅拌20min，20-25℃同时滴加8-苄氧基-5-(2-溴乙酰基)-(1H)-喹啉-2-酮37.2g(100.0mmol) 与THF500ml溶液和硼烷二甲硫醚8.1ml(86.3mmol)与THF120ml溶液，3小时滴毕。保持20-25℃氮气保护下反应30min。TLC分析，反应完全。外用冰浴冷却(＜10℃)滴加甲醇50ml，滴毕后保持冰浴(＜10℃)搅拌10分钟。45℃以下水泵减压，除去溶剂。加入水和乙酸乙酯各200ml室温搅拌，有气泡产生，室温搅拌5min，移入分液漏斗中，分出有机层，水层再用乙酸乙酯(50ml×3次)提取，合并有机层，用无水硫酸镁干燥。滤除干燥剂，45℃以下水泵减压，除去溶剂，得粗品。粗品用400mL乙腈热溶解，加入活性炭3克，回流5分钟，呈热过滤，冷却析出结晶，滤集固体得8-苄氧基-5-[(R)-2-溴-1-羟基乙基]-(1H)-喹啉-2-酮31.8克，收率85.5％。
(f)8-苄氧基-5-[(R)-2-苄胺基-1-羟基乙基]-(1H)-喹啉-2-酮
取中间体8-苄氧基-5-[(R)-2-溴-1-羟基乙基]-(1H)-喹啉-2-酮29.9g(80.0mmol)置于500ml三口瓶中，加入苄胺40.3克(0.51mol)，二氧六环30mL，油浴100-110℃反应3h，TLC分析，中间体反应完全。45℃以下水泵减压，除去溶剂。加入乙酸乙酯150ml和水200ml搅拌，加入碳酸氢钠调节水层PH8-9，移入分液漏斗中分出有机层，水层再用乙酸乙酯(100ml×3次)提取，合并有机层，无水硫酸镁干燥。滤除干燥剂，45℃以下水泵减压，除去溶剂，得油状物。
取上述油状物加入乙酸乙酯160ml搅拌溶解，冰浴冷却结晶，滤集白色固体并用少量乙酸乙酯洗涤，产物60℃鼓风干燥2小时，得结晶产物25g，反应收率为81.2％。
制备4
(R)-2-苄氨基-1-【(4-苄氧基-3-甲酰胺基)苯基】乙醇
(a)(R)-2-溴-1-【(4-苄氧基-3-硝基)苯基】乙醇
取(1R,2S)-(+)-1-氨基-2-茚醇0.132g(0.87mmol)置于2L三口烧瓶中加入THF180ml，10℃左右搅拌。加入硼烷二甲硫醚9.2ml(97.0mmol)搅拌25min，保持反应混合物温度5-10℃，同时滴加4-苄氧基-3-硝基-溴代苯乙酮63.6g(180.16mmol)与THF600ml溶液和硼烷二甲硫醚8.1ml(86.3mmol)与THF120ml溶液，3小时滴毕。保持5-10℃氮气保护下反应30min。TLC分析，反应完全。外用冰浴冷却(＜10℃)滴加甲醇50ml，滴毕后保持冰浴(＜10℃) 搅拌10分钟。45℃以下水泵减压，除去溶剂剂。残留物加入水和乙酸乙酯各200ml，室温搅拌，有气泡产生，室温搅拌5min，移入分液漏斗中，分出有机层，水层再用乙酸乙酯(100ml×3次)提取，合并有机层，用无水硫酸镁干燥。滤除干燥剂，45℃以下水泵减压，除去溶剂，得油状物。油状物用正己烷研磨冷却析出固体，滤集固体得(R)-2-溴-1-【(4-苄氧基-3-硝基)苯基】乙醇57.9克，收率90.5％。
(b)(R)-2-溴-1-【(4-苄氧基-3-氨基)苯基】乙醇
取(R)-2-溴-1-【(4-苄氧基-3-硝基)苯基】乙醇55克(156.15mmol)置于1L氢化反应釜中，加甲醇600mL搅拌溶解，完毕，加入10％钯碳5克，通入氢气，保持压力在0.4MPa，维持反应温度不超过5℃。在此条件下反应12小时，过滤。钯碳用甲醇洗涤3次(3X100mL)，减压除去溶剂。残留物用乙酸乙酯/石油醚(1/1)溶解，在0℃冷却结晶，滤集固体，干燥得(R)-2-溴-1-【(4-苄氧基-3-氨基)苯基】乙醇41.9克，收率83.3％。
(c)(R)-2-溴-1-【(4-苄氧基-3-甲酰氨基)苯基】乙醇
在500mL三口瓶中，加入无水甲酸88克，冷却至0-5℃，在搅拌下滴加乙酸酐19.6克(18.7mmol)，保持反应温度为0-5℃，搅拌15分钟，将(R)-2-溴-1-【(4-苄氧基-3-氨基)苯基】乙醇40.0克(12.4mmol)加至反应液中，继续在此温度下反应10小时，原料(R)-2-溴-1-【(4-苄氧基-3-氨基)苯基】乙醇反应完全。减压除去多余甲酸，残留物加二氯甲烷400mL溶解，水洗二氯甲烷层三次(3X100mL)，有机相用无水硫酸镁干燥，滤除干燥剂，溶液减压除去溶剂，残留物加甲醇300mL加热溶解，冷却结晶，滤集固体得(R)-2-溴-1-【(4-苄氧基-3-甲酰氨基)苯基】乙醇30.2克，收率72.8％。
(d)(R)-2-苄胺基-1-【(4-苄氧基-3-甲酰氨基)苯基】乙醇
取中间体(R)-2-溴-1-【(4-苄氧基-3-甲酰氨基)苯基】乙醇30.0g(85.7mmol)置于500ml三口瓶中，加入苄胺40.3克(0.51mol)，二氧六环30mL，油浴100-110℃反应3h，TLC分析，中间体反应完全。水泵减压(45℃，-0.095MPa)抽尽溶剂。加入乙酸乙酯250ml和水200ml搅拌，加入碳酸氢钠调节水层PH8-9，移入分液漏斗中分出有机层，水层再用乙酸乙酯(100ml×3次)提取，合并有机层，无水硫酸镁干燥。滤除干燥剂，45℃以下水泵减压，除去溶剂，得油状物。
取上述油状物加入乙酸乙酯260ml搅拌溶解，冰浴冷却结晶，滤集白色固体并用少量乙酸乙酯洗涤，产物60℃鼓风干燥2小时，得结晶产物19.65g，反应收率为80.1％。
制备5
8-【(1R)-1-羟基-2-苄胺】乙基-5-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮(式28)
(a)2-羟基-5-苄氧基苯乙酮
将2,5-二羟基苯乙酮152克(1.0mol)加至1L三口瓶中，加入无水乙醇400mL，搅拌溶解。在室温下加入碳酸氢钠92.4克(1.1mol)搅拌5分钟，保持反应混合物温度为0-10℃，滴加溴苄180克(1.05mol)，20分钟滴加完毕。并在此温度下继续搅拌反应3小时，薄层检测，原料2,5-二羟基苯乙酮反应完全，减压除去溶剂，残留物用二氯甲烷400mL溶解，用饱和柠檬酸水溶液洗涤3次(3X150mL)，无水硫酸镁干燥二氯甲烷溶液。滤除无水硫酸镁，溶液减压除去二氯甲烷，残留物用无水乙醇300mL溶解，冷却结晶，得2-羟基-5-苄氧基苯乙酮白色固体213.7克，收率88.3％。化学纯度为99.0％(HPLC)。
(b)2-羟基-3-硝基-5-苄氧基苯乙酮
在2L三口瓶中，加入2-羟基-5-苄氧基苯乙酮210克(0.868mol)，加入冰乙酸900mL溶解，将反应混合物冷却至10-20℃，滴加63％的浓硝酸64.3mL(0.90mol)，20分钟滴加完毕。继续在此温度下搅拌1小时，反应完毕。将反应混合物倒入900mL冰水中，继续搅拌1小时，析出结晶，滤集固体，固体用冰水洗涤三次，50℃真空干燥，得2-羟基-3-硝基-5-苄氧基苯乙酮固体224克，收率89.9％。化学纯度为99.2％(HPLC)。
(c)2-羟基-3-氨基-5-苄氧基苯乙酮
将2-羟基-3-硝基-5-苄氧基苯乙酮固体220克(0.767mol)置于2L氢化反应釜中，加入二氧六环800mL，再加入氧化铂11克，在室温下，通入氢气，保持压力3MPa，直到吸氢停止，滤除催化剂，不经处理直接用于下步反应。
(d)8-乙酰基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮
在3L三口瓶中加入无水碳酸钾272克(2.0mol)，加入上述步骤(c)滤液， 搅拌。在室温下滴加800mL二氧六环溶解的氯乙酰氯112.5克(0.90mol),30分钟滴加完毕。将反应混合物升温至70℃，继续搅拌反应2小时。减压除去溶剂，残留物加入1L水，用1L二氯甲烷溶解并萃取水相，分出有机相。水相另用二氯甲烷萃取2次(2X500mL)，合并有机相，并用水洗涤三次(3X500mL)，有机相用无水硫酸镁干燥，滤除干燥剂，减压除去部分二氯甲烷至体积500mL左右，加入石油醚1500mL，搅拌结晶。滤集晶体，在50℃干燥，得8-乙酰基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮固体156.7克，两步总收率68.8％。化学纯度99.1％(HPLC)。
(e)8-(溴乙酰基)-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮
将8-乙酰基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮固体148.5克0.50mol)加至2升三口瓶中，加入二氧六环1000mL搅拌溶解。冰浴冷却反应液至0℃左右，加入无水三氯化铝1.0克(0.01mol)。然后滴加溴176克(0.55mol)，约30分钟滴加完毕，使反应混合物升至室温。在此温度下，继续搅拌反应4小时，薄层色谱检测反应完全。将反应混合物减压除去溶剂，残留物用二氯甲烷1000mL溶解，用饱和碳酸氢钠溶液洗涤三次(3X100mL),有机相用无水硫酸镁干燥3小时。滤除硫酸镁，减压浓缩除去溶剂，所得油状物用石油醚研磨，得8-(溴乙酰基)-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮固体161.2克，收率85.7％。化学纯度98.3％(HPLC)。
(f)8-【(1R)-1-羟基-2-溴】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮
取(1R,2S)-(+)-1-氨基-2-茚醇0.308g(2.61mmol)置于3L三口烧瓶中加入THF380ml，10℃左右搅拌。加入硼烷二甲硫醚21.4ml(0.226mol)搅拌25min，保持反应混合物温度5-10℃，同时滴加8-(溴乙酰基)-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮固体158.2克(0.42mol)与THF1200ml溶液和硼烷二甲硫醚18.9ml(0.20mol)与THF120ml溶液，3小时滴毕。保持5-10℃氮气保护下反应30min。TLC分析，反应完全。外用冰浴冷却(＜10℃)滴加甲醇120ml，滴毕后保持冰浴(＜10℃)搅拌10分钟。45℃以下水泵减压，除去溶剂。残留物加入水和乙酸乙酯室温搅拌各500ml，有气泡产生，室温搅拌5min，移入分液漏斗中，分出有机层，水层再用乙酸乙酯(100ml×3次)提取，合并有机层，用无水硫 酸镁干燥。滤除干燥剂，45℃以下水泵减压，除去溶剂，得油状物。油状物用正己烷研磨冷却析出固体，滤集固体得8-【(1R)-1-羟基-2-溴】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮144.5克，收率91.0％。化学纯度98.5％(HPLC)，ee值95％。
(g)8-【(1R)-1-羟基-2-苄胺】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮
取中间体(8-【(1R)-1-羟基-2-溴】乙基-5-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮143.6克(0.38mol)置于1000ml三口瓶中，加入苄胺321.0克(3.0mol)，二氧六环120mL，油浴100-110℃反应3.5小时，TLC分析，中间体反应完全。水泵减压(45℃，-0.095MPa)抽尽溶剂。加入二氯甲烷1050ml和水400ml搅拌，加入碳酸氢钠调节水层PH8-9，移入分液漏斗中分出有机层，水层再用二氯甲烷(200ml×3次)提取，合并有机层，无水硫酸镁干燥。滤除干燥剂，45℃以下水泵减压，除去溶剂，得油状物。
取上述油状物加入乙酸乙酯460ml搅拌溶解，冰浴冷却结晶，滤集白色固体并用少量乙酸乙酯洗涤，产物60℃鼓风干燥2小时，得8-【(1R)-1-羟基-2-苄胺】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮结晶产物123.6g，反应收率为83.6％。异构体纯度98.5％。
实施例1
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000042
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(3-
溴丙基)-1-氮杂双环【2,2,2】辛鎓盐
在250mL三口瓶中，加入无水乙醇30mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷6.0克(19.02mmol)(制备2)，搅拌溶解后，再加入1,3-二溴丙烷153.6克(760.8mmol)，室温下搅拌反 应12小时。减压除去乙醇和多余的1,3-二溴丙烷，残留物用二氯甲烷和正己烷(1/2)结晶，得溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(3-溴丙基)-1-氮杂双环【2,2,2】辛鎓盐固体9.5克，收率96.1％。MS(m/z)436.3，438.3。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-(3-苄氧甲基-4-苄氧基)苯基-2-羟基乙基苄氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇2.396克(5.283mmol)(制备1)和(a)2.733克(5.283mmol)加至50mL反应瓶中，加入20mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.566mmol)，将反应混合物温度升至80℃，并在此温度下反应5小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物3.0克。收率63.8％。MS(m/z)809.9。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物2.5克(4.83mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.5克，通入氢气，保持压力为0.43MPa，温度为室温。反应10小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用乙醇结晶。得目标化合物固体1.6克，收率53.5％。1HNMR(δppm)(DMSO-d6)7.19-7.24(m,5H),6.95-7.01(m,3H),5.0(s,1H),4.80(s,2H),4.74(m,1H),3.93(s,2H),3.68(d,2H),3.15(m,1H),2.90(m,1H),2.84(m,1H),2.55(m,2H),2.43(S,1H),2.36(m,2H),2.21(S,1H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,6H)；C32H47BrN2O5的MS(m/z)：计算值619.63，实测值539.27(M-Br)。
实施例2
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)乙氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000043
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(3-溴丙基)-1-氮杂双环【2,2,2】辛鎓盐
按实施例1(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-羟基-2-(8-苄氧基-2-氧-1,2-二氢喹啉-5-基)乙基苄氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例1(b)方法制备。
将8-苄氧基-5-[(R)-2-苄胺基-1-羟基乙基]-(1H)-喹啉-2-酮2.0克(5.0mmol)(制备2)和(a)2.587克(5.0mmol)加至50mL反应瓶中，加入20mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.566mmol)，将反应混合物温度升至80℃，并在此温度下反应5小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物2.3克。收率54.9％。MS(m/z)758.65。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)乙氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例1(c)方法制备。
取(b)产物2.2克(2.62mmol)置于氢化反应釜中，加入20mL甲醇溶解，加入10％Pd-C 0.4克，通入氢气，保持压力为0.43MPa，温度为室温。反应10小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.3克，收率90.0％。
1HNMR(δppm)(DMSO-d6)8.0(s,1H),7.36(d,1H),7.19-7.24(m,5H),6.71(d,1H)6.57(d,1H),6.52(d,1H),5.01(s,1H),4.79(s,2H),4.73(m,1H),3.93(s,2H),3.68(d,2H),3.15(m,1H),2.90(m,1H),2.84(m,1H),2.54(m,2H),2.43(S,1H),2.36(m,2H),2.10(s,1H),2.0(m,3H),1.79-1.82(m,3H),1.75(m,1H),1.68(m,2H),1.55-1.61(m,6H),1.35-1.46(m,6H)。
C34H46BrN3O5的MS(m/z)：计算值656.65，实测值576.26(M-Br)。
实施例3
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{4-[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]丁基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000044
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-溴丁基)-1-氮杂双环【2,2,2】辛鎓盐
参照实施例1(a)方法制备。
在250mL三口瓶中，加入无水乙醇25mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷5.0克(15.85mmol)(制备2)，搅拌溶解后，再加入1,4-二溴丁烷78.4mL(634.0mmol)，室温下搅拌反应18小时。减压除去乙醇和多余的1,4-二溴丁烷，残留物用二氯甲烷和正己烷(1/2)结晶，得溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-溴丁基)-1-氮杂双环【2,2,2】辛鎓盐固体8.1克，收率96.1％。MS(m/z)450.3，452.3。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{4-[(R)-2-(3-苄氧甲基-4-苄氧基)苯基-2-羟基乙基苄氨基]丁基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇4.096克(7.253mmol)(制备1)和(a)3.854克(7.253mmol)加至50mL反应瓶中，加入30mLN,N-二甲基甲酰胺搅拌10分钟后，再加入无 水碳酸钾3.038克(21.759mmol)，将反应混合物温度升至55-60℃，并在此温度下反应12小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物3.24克。收率48.0％。MS(m/z)823.811。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{4-[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]丁基}-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物2.8克(3.11mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.7克，通入氢气，保持压力为0.43MPa，温度为室温。反应12小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用乙醇结晶。得目标化合物固体1.5克，收率76.5％。1HNMR(δppm)(DMSO-d6)7.18-7.23(m,5H),6.96-7.01(m,3H),5.0(s,1H),4.80(s,2H),4.74(m,1H),3.93(s,2H),3.68(d,2H),3.15(m,1H),2.90(m,1H),2.83(m,1H),2.55(m,2H),2.43(S,1H),2.35(m,2H),2.21(S,1H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,8H),1.34-1.46(m,6H)；C33H49BrN2O5的MS(m/z)：计算值633.66，实测值553.38(M-Br)。
实施例4
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁基-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000045
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-溴丁基)-1-氮杂双环【2,2,2】辛鎓盐
按实施例3(a)制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-{(R)- [2-羟基-2-(3-甲酰胺基-4-苄氧基)苯基]乙基苄氨基}丁基)-1-氮杂双环【2,2,2】辛鎓盐
参考实施例3(b)方法。
将(R)-2-苄氨基-1-【(4-苄氧基-3-甲酰胺基)苯基】乙醇1.882克(5.0mmol)(制备4)和(a)2.66克(5.0mmol)加至50mL反应瓶中，加入30mL乙腈搅拌10分钟后，再加入无水碳酸钾1.5克(11.0mmol)，将反应混合物温度升至55-60℃，并在此温度下反应12小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL乙醇冷冻结晶，滤集固体得目标产物3.04克。收率73.6％。MS(m/z)746.911。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{4-[(R)-2-羟基-2-(3-甲酰胺基-4-羟基)苯基乙氨基]丁基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例3(c)方法制备。
取(b)产物2.9克(3.42mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.6克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应15小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用乙醇结晶。得目标化合物固体1.5克，收率67.8％。1HNMR(δppm)(DMSO-d6)8.21(s,1H),7.40(m,1H),7.18-7.23(m,5H),6.66-6.71(m,2H),5.0(s,1H),4.74(m,1H),4.0(s,1H),3.92(s,2H),3.68(d,2H),3.15(m,1H),2.91(m,1H),2.83(m,1H),2.54(m,2H),2.42(S,1H),2.35(m,2H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,8H),1.34-1.46(m,6H)；C33H48BrN3O5的MS(m/z)：计算值646.65，实测值566.28。
实施例5
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9{-(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐
甲磺酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}壬基)-1- 氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000046
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-溴壬基)-1-氮杂双环【2,2,2】辛鎓盐
参考实施例1(a)方法制备。
在250mL三口瓶中，加入无水乙醇35mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷5.0克(15.85mmol)(制备2)，搅拌溶解后，再加入1,9-二溴壬烷60.69克(212.2mmol)，室温下搅拌反应18小时。减压除去乙醇和多余的1,9-二溴壬烷，残留物用二氯甲烷和石油醚(1/3)结晶，得目标产物9.1克，收率95.4％。MS(m/z)520.18，522.18。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-9-{(R)-[2-羟基-2-(5-苄氧基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙基苄氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐
将8-【(1R)-1-羟基-2-苄胺】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮2.02克(5.0mmol)(制备5)和(a)3.0克(5.0mmol)加至50mL反应瓶中，加入30mL二氧六环搅拌10分钟后，再加入无水碳酸钾1.0克(7.35mmol)，将反应混合物温度升至65-70℃，并在此温度下反应12小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物3.56克。收率77.0％。MS(m/z)844.35(M-Br)。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物3.4克(3.67mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.6克，通入氢气，保持压力为0.43MPa，温度为室温。反应15小时后，吸氢停止，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.5克，收率54.8％。1HNMR(δppm)(DMSO-d6)8.0(s,1H)，7.15-7.20(m,5H),6.60(d,1H),6.20(d,1H),5.0(s,1H),4.88(s,2H),4.73(m,1H),3.93(s,1H),3.68(d,1H),3.14(m,1H),2.91(m,1H),2.84(m,1H),2.55(m,2H),2.36(m,2H),2.21(S,1H),2.10(s,1H),2.0(m,2H),1.96(m,1H),1.79-1.80(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,6H),1.34-1.46(m,10H),1.27-1.29(m,10H)；C39H58BrN3O6的MS(m/z)：计算值744.80，实测值664.35(M-Br)。
(d)甲磺酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐
将(c)产物0.56克(0.75mmol)溶于10mL甲醇水(v/v 1:1)中,加入氧化银0.10克，室温搅拌30分钟，滤除固体，固体用水5mL洗涤，合并滤液，减压浓缩除去部分溶剂，加甲磺酸82毫克，搅拌10分钟，溶液加0.2克活性炭，继续搅拌5分钟，过滤，滤液浓缩至干，残留物用异丙醇3mL结晶，得目标产物0.45克，收率59.2％。C40H61N3O9S元素分析(％)(计算值)C 63.10(63.21),H 7.97(8.09),N 5.36(5.53)
利用上述类似方法和原料可以合成以下化合物。
Figure PCTCN2017115807-appb-000047
Figure PCTCN2017115807-appb-000048
Figure PCTCN2017115807-appb-000049
Figure PCTCN2017115807-appb-000050
制备6
4-叔丁氧甲酰氨基-1-丁醇
将碳酸钠318克(3.0mol)置于3L三口瓶中，加入二氧六环500mL，水500mL溶解，4-氨基-1-丁醇178克(2.0mol)一次性加至反应瓶中，搅拌均匀。维持反应混合物温度为10℃左右，滴加含二碳酸二叔丁酯545克(2.50mol)的二氧六环溶液500mL，维持此反应温度继续搅拌反应4小时。减压除去二氧六环，水相用二氯甲烷萃取3次(3X1000mL)，无水硫酸镁干燥，减压除去溶剂得目标产物343克，收率90.7％。
制备7
4-叔丁氧甲酰氨基丁基-2-溴乙基醚
在500mL三口瓶中，加入4-叔丁氧甲酰氨基-1-丁醇37.8克(0.20mol)，用200mL四氢呋喃溶解。加入氢化钠(60％)8.0克(0.20mol)，搅拌15分钟，滴加1，2-二溴乙烷75.2克(0.40mol)，加毕，将反应混合物温度升至50℃，继续反应4小时。减压除去溶剂和多余的1,2-二溴乙烷，残留物用乙酸乙酯300mL溶解，水洗3次(3X100mL)。无水硫酸镁干燥，滤除干燥剂，减压出去溶剂得目标产物48.5克，收率77.2％。
实施例25
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000051
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-叔丁氧甲酰氨基丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
在250mL三口瓶中，加入无水乙醇25mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷5.0克(15.85mmol)(制备2)，搅拌溶解后，再加入4-叔丁氧甲酰氨基丁基-2-溴乙基醚(制备7)16.2克(50.0mmol)，室温下搅拌反应24小时。减压除去乙醇，残留物用二氯甲烷和正己烷(2/1)结晶，得目标产物固体6.1克，收率63.1％。MS(m/z)531.3(M-Br)。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-氨基丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
将(a)产物5.9克(8.92mmol)置于50mL单口瓶中，加入2摩尔HBr二氧六环溶液30mL，室温搅拌2小时。减压除去溶剂，剩余固体用N-甲基吗啡啉中和后经柱层析，得目标产物3.3克，收率72.3％。MS(m/z)431.3(M-Br)。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-苄氧基)苯基]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
取中间体(R)-2-溴-1-【(4-苄氧基-3-甲酰氨基)苯基】乙醇(制备4)3.20g(9.39mmol)置于50ml三口瓶中，加入(b)3.20克(6.26mmol)，无水碳酸钾2.76克(20mmol)，二氧六环5mL，油浴100-110℃反应3h，TLC分析，中间体反应完全。水泵减压(45℃，-0.095MPa)抽尽溶剂。残留物石油醚和二氯甲烷混合溶剂(3/1)研磨，得固体。固体用异丙醇结晶得目标产物3.8克， 收率77.7％。MS(m/z)700.3(M-Br)
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物3.50克(4.48mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.5克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应10小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用乙醇结晶。得目标化合物固体1.8克，收率58.2％。1HNMR(δppm)(DMSO-d6)8.20(s,1H),7.40(m,1H),7.18-7.23(m,5H),6.64-6.71(m,2H),5.0(s,1H)，4.74(m,1H),4.0(s,1H),3.93(s,1H),3.67(d,1H),3.37-3.47(m,4H),3.15(m,1H),2.91(m,1H),2.83(m,1H),2.53-2.55(m,4H),2.25(m,2H),2.10(s,1H),1.96-2.0(m,3H),1.75-1.81(m,3H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,6H)；C35H52BrN3O6的MS(m/z)：计算值690.71，实测值MS(m/z)610.30(M-Br)。
制备8
4-叔丁氧甲酰胺丁基-5-溴戊基醚
参照制备7方法制备。
制备9
4-叔丁氧甲酰胺丁基-4-溴丁基醚
参照制备7方法制备。
制备10
4-叔丁氧甲酰胺丁基-3-溴丙基醚
参照制备7方法制备。
制备11
2-叔丁氧甲酰胺乙基-2-溴乙基醚
参照制备7方法制备。
实施例26
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000052
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-叔丁氧甲酰氨基丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐
在250mL三口瓶中，加入无水乙醇25mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷5.0克(15.85mmol)(制备2)，搅拌溶解后，再加入4-叔丁氧甲酰氨基丁基-5-溴戊基醚(制备8)17.58克(52.0mmol)，40℃下搅拌反应4小时。减压除去乙醇，残留物用二氯甲烷和正己烷(2/1)结晶，得目标产物固体6.0克，收率60.1％。MS(m/z)573.3(M-Br)。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-氨基丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐
将(a)产物5.9克(9.02mmol)置于50mL单口瓶中，加入2摩尔HBr二氧六环溶液30mL，室温搅拌2小时。减压除去溶剂，剩余固体用N-甲基吗啡啉中和后经柱层析，得目标产物3.2克，收率64.2％。MS(m/z)473.3(M-Br)。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-羟基-2-(6-苄氧基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐
取中间体8-【(1R)-1-羟基-2-溴】乙基-5-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮(制备5(f))4.20g(11.2mmol)置于50ml三口瓶中，加入(b)3.10克(5.60mmol)，碳酸钾2.76克(20mmol)，二氧六环5mL，油浴100-110℃反应3h，TLC分析，中间体反应完全。45℃以下水泵减压，抽尽溶剂。残留物石油 醚和二氯甲烷混合溶剂(3/1)研磨，得固体。固体用异丙醇结晶得目标产物3.9克，收率81.8％。MS(m/z)770.4(M-Br)
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物3.80克(4.47mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.5克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应10小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.9克，收率55.8％。1HNMR(δppm)(DMSO-d6)8.0(s,1H),7.18-7.20(m,5H),6.65(d,1H),6.20(d,1H),5.0(s,1H)，4.88(s,2H),4.74(m,1H),3.93(d,1H),3.68(d,1H),3.37-3.40(m,4H),3.15(m,1H),2.91(m,1H),2.84(m,1H),2.55(m,2H),2.36(t,2H),2.10(s,1H),1.98-2.0(m,3H),1.75-1.81(m,4H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,12H)，1.29(m,2H)；C39H58BrN3O7的MS(m/z)：计算值760.80，实测值MS(m/z)680.35(M-Br)。
实施例27
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000053
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-叔丁氧甲酰氨基丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐
参照实施例25(a)制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4- 氨基丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐
参照实施例25(b)方法制备。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-(3-苄氧羟甲基-4-苄氧基)苯基-2-羟基]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐
取中间体(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-溴乙醇(制备1(g))3.50g(8.19mmol)置于50ml三口瓶中，加入(b)3.20克(5.09mmol)，碳酸钾2.76克(20mmol)，二氧六环5mL，油浴100-110℃反应3h，TLC分析，中间体反应完全。45℃以下水泵减压，抽尽溶剂。残留物石油醚和二氯甲烷混合溶剂(3/1)研磨，得固体。固体用异丙醇结晶得目标产物4.1克，收率93.8％。MS(m/z)777.4(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物4.0克(4.10mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.8克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应20小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用乙醇结晶。得目标化合物固体1.6克，收率55.4％。1HNMR(δppm)(DMSO-d6)7.17-7.20(m,5H),6.95(m,2H),6.64(d,1H),5.0(s,1H)，4.79(s,2H),4.74(m,1H),3.93(d,1H),3.67(d,1H),3.37-3.47(t,4H),3.14(m,1H),2.90(m,1H),2.84(m,1H),2.53-2.55(m,2H),2.36(m,2H),1.96-2.0(m,5H),1.74-1.81(m,4H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,14H)；C37H57BrN2O6的MS(m/z)：计算值705.76，实测值625.34(M-Br)。
以下化合物可用上述原料按上述方法制备。
Figure PCTCN2017115807-appb-000054
Figure PCTCN2017115807-appb-000055
Figure PCTCN2017115807-appb-000056
Figure PCTCN2017115807-appb-000057
制备12
1,3-二(2-溴乙氧基)丙烷
将1,3-丙二醇38克(0.50mol)溶于500mL四氢呋喃中，加入氢化钠(60％)40克(1.0mol)，室温搅拌15分钟，滴加1,2-二溴乙烷752克(4.0mol)，加毕，回流反应3小时，减压除去溶剂和多余的1,2-二溴乙烷。残留物加二氯甲烷500mL溶解，水洗三次(3X200mL)，无水硫酸镁干燥，滤除干燥剂，减压除去溶剂，得目标产物80克，收率61％。
制备13
二(2-溴乙氧基乙基)醚
将二(2-羟基乙基)醚42.4克(0.40mol)溶于400mL四氢呋喃中，加入氢化钠(60％)33.6克(1.05mol)，室温搅拌25分钟，滴加1,2-二溴乙烷752克(4.0mol)，加毕，回流反应5小时，减压除去溶剂和多余的1,2-二溴乙烷。残留物加二氯甲烷400mL溶解，水洗三次(3X200mL)，无水硫酸镁干燥，滤除干燥剂，减压除去溶剂，得目标产物70克，收率54.7％。
实施例45
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)乙氧基】乙氧基}乙基)-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000058
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-乙氧基)乙氧基】乙氧基}溴乙基)-1-氮杂双环【2,2,2】辛鎓盐
在250mL三口瓶中，加入无水乙醇30mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷6.0克(19.02mmol)(制备2)，搅拌溶解后，再加入二(2-溴乙氧基乙基)醚(制备13)243.6克(760.8mmol)，室温下搅拌反应10小时。减压除去乙醇，用柱层析除去残留物中多余的二(2-溴乙氧基乙基)醚，粗品用二氯甲烷和正己烷(1/1)结晶，得目标产物9.3克，收率76.9％。MS(m/z)654.2，656.2。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-(3-苄氧甲基-4-苄氧基)苯基-2-羟基]乙氨基}乙氧基)乙氧基】乙氧基}乙基)-1-氮杂双环【2,2,2】辛鎓盐
将(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇2.396克(5.283mmol)(制备1)和(a)3.46克(5.283mmol)加至50mL反应瓶中，加入20mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.566mmol)，将反应混合物温度升至80℃，并在此温度下反应3小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物2.8克。收率57.7％。C51H69BrN2O8的MS(m/z)：计算值918.0，实测值838.4(M-Br)。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)乙氧基】乙氧基}乙基)-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物2.4克(2.61mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.5克，通入氢气，保持压力为0.43MPa，温度为室温。反应20小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.3克，收率67.5％。1HNMR(δppm)(DMSO-d6) 7.18-7.21(m,5H),6.59-6.95(m,3H),5.0(s,1H),4.79(s,2H),4.74(m,1H),3.93(d,1H),3.68(d,1H),3.47-3.54(m,12H),3.15(m,1H),2.90(m,1H),2.83(m,1H),2.72(t,2H),2.53(m,2H),2.36(m,1H),2.21(S,1H),2.10(s,1H),1.96-2.0(m,3H),1.79-1.81(m,3H),1.74(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.33-1.45(m,6H)；
C37H57BrN2O8的MS(m/z)：计算值737.76，实测值657.3(M-Br)。
实施例46
氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000059
(a)氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-氯乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
在250mL三口瓶中，加入无水乙醇30mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷6.0克(19.02mmol)(制备2)，搅拌溶解后，再加入1,2-二(2-氯乙氧基)乙烷(上海瀚鸿化工)142.3克(760.8mmol)，升温至45℃，搅拌反应6小时。减压除去乙醇，用柱层析除去残留物中多余的1,2-二(2-氯乙氧基)乙烷，粗品用二氯甲烷和正己烷(3/1)结晶，得目标产物8.3克，收率86.8％。C26H41ClNO4的MS(m/z)：计算值502.51，实测值466.24(M-Cl),468.23(M-Cl)。
(b)氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-苄氧基)苯基]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-2-苄氨基-1-【(4-苄氧基-3-甲酰胺基)苯基】乙醇1.882克(5.0mmol)(制备4)和(a)2.568克(5.0mmol)加至50mL反 应瓶中，加入30mL乙腈搅拌10分钟后，再加入无水碳酸钾1.5克(11.0mmol)，将反应混合物温度升至75-80℃，并在此温度下反应8小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物2.4克。收率63.8％。C42H58ClN3O7的MS(m/z)：计算值752.38，实测值716.84(M-Cl)。
(c)氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物2.1克(2.79mmol)置于氢化反应釜中，加入25mL甲醇溶解，加入10％Pd-C 0.4克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应10小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.1克，收率59.5％。1HNMR(δppm)(DMSO-d6)8.20(s,1H),7.40(dd,1H),7.19-7.21(m,5H),6.64-6.76(m,2H),5.01(s,1H),4.73(m,1H),4.0(s,1H),3.93(d,2H),3.68(d,2H),3.47-3.54(m,8H),3.15(m,1H),2.90(m,1H),2.84(m,1H),2.72(t,2H),2.53(d,2H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.68(m,2H),1.55-1.61(m,6H),1.34-1.46(m,6H)；C35H52ClN3O7的MS(m/z)：计算值662.26，实测值626.74(M-Cl)。
依据以上原料和实施例45和46方法可制备以下化合物：
Figure PCTCN2017115807-appb-000060
Figure PCTCN2017115807-appb-000061
制备14
2-[(4-溴乙氧基)苯基]乙基醇
(a)4-【2-羟乙基】苯酚
将对羟基苯乙酸甲酯166克(1.0mol)溶于500mL甲醇中，冰浴冷却，分批加入硼氢化钠56.75克(1.50mol)，约2小时加毕。继续搅拌反应2小时，薄层检测，原料反应完全。减压除去溶剂，残留物加水溶解，并用2M的盐酸调节pH至2，用二氯甲烷萃取三次(300Mlx3)，合并萃取液，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂，剩余物用乙酸乙酯和石油醚(1/5)结晶。得目标化合物120.0克，收率86.9％。
(b)2-[(4-溴乙氧基)苯基]乙基醇
将(a)产物30克(0.217mol)溶于300mL乙醇中，加入碳酸氢钠22.4(0.26mol)，同时加入1,2-二溴乙烷188克(1.0mol)，加热搅拌，在50℃下反应5小时，减压除去溶剂和多余的1,2-二溴乙烷。剩余物用二氯甲烷300mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物35.0克，收率65.8％。m/z 245.01，247.05(M+H).
制备15
2-[(4-溴丙氧基)苯基]乙基醇
将制备14(a)产物30克(0.217mol)溶于300mL乙醇中，加入碳酸氢钠22.4克(0.26mol)，同时加入1,3-二溴丙烷202克(1.0mol)，加热搅拌，在50℃下反应6小时，减压除去溶剂和多余的1,2-二溴丙烷。剩余物用二氯甲烷300mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物40克，收率71.1％。m/z 259.03，261.04(M+H)。
制备16
3-(4-溴丙氧基苯基)丙醇
(a)4-(3-羟丙基)苯酚
将对羟基苯丙酸甲酯45.0克(0.25mol)溶于200mL甲醇中，冰浴冷却，分批加入硼氢化钠14.2克(0.375mol)，约1小时加毕。继续室温搅拌反应2小时，薄层检测，原料反应完全。减压除去溶剂，残留物加水溶解，并用2M的盐酸调节pH至2，用二氯甲烷萃取三次(200Mlx3)，合并萃取液，无水硫酸镁干 燥。滤除干燥剂，减压除去溶剂，剩余物用二氯甲烷和石油醚(1/5)结晶。得目标化合物32.0克，收率84.2％。
(b)3-(4-溴丙氧基苯基)丙醇
将(a)产物30克(0.197mol)溶于300mL乙醇中，加入碳酸氢钠22.4(0.26mol)，同时加入1,3-二溴丙烷161.6克(0.80mol)，加热搅拌，在50℃下反应5小时，减压除去溶剂和多余的1,3-二溴丙烷。剩余物用二氯甲烷250mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物25克，收率46.5％。m/z 273.03，275.04(M+H).
制备17
4-溴丙氧基苯甲醇
参照制备16(b)方法制备，收率75.1％，m/z 245.01，247.0(M+H).
制备18
1-(4-溴丙氧基苯基)丙酮
将1-(4-羟基苯基)丙酮45克(0.30mol)溶于300mL乙醇中，加入碳酸钾62.1(0.45mol)，同时加入1,3-二溴丙烷161.6克(0.80mol)，搅拌，在室温下反应5小时，减压除去溶剂和多余的1,3-二溴丙烷。剩余物用二氯甲烷250mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物44.8克，收率52.5％。m/z 285.01，287.02(M+H).
制备19
1-(4-溴乙氧基苯基)丙酮
参照制备18方法制备。收率62.3％，m/z 271.03，273.02(M+H).
制备20
4-溴丙氧基-3，5-二氯苯甲醇
(a)4-羟基-3，5-二氯苯甲酸甲酯
将4-羟基-3，5-二氯苯甲酸62.1克(0.30mol)溶于300mL甲醇中，加入 对甲苯磺酸3克，反应混合物加热回流6小时，减压除去溶剂，残留物用500mL二氯甲烷溶解，水洗3次(200mLX3)，无水硫酸镁干燥。滤除干燥剂，除去溶剂得目标产物56.3克,收率84.9％。m/z219.01(M-H)。
(b)4-羟基-3，5-二氯苯甲醇
将(a)56克(0.253mol)溶于300mL甲醇中，冰浴冷却，分批加入硼氢化钠15.13克(0.40mol)，约1.5小时加毕。继续搅拌反应2小时，薄层检测，原料反应完全。减压除去溶剂，残留物加水溶解，并用2M的盐酸调节pH至2，用二氯甲烷萃取三次(200Mlx3)，合并萃取液，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂，剩余物用二氯甲烷和石油醚(1/5)结晶。得目标化合物30.3克，收率62.0％。m/z192.02(M-H)。
(c)4-溴丙氧基-3，5-二氯苯甲醇
参照制备16(b)方法制备，收率68,5％，m/z311.03(M-H)。
制备21
4-(3-溴丙氧基)苯乙酮
将4-羟基苯乙酮40.8克(0.30mol)溶于400mL甲醇中，加入碳酸钾62.1(0.45mol)，同时加入1,3-二溴丙烷161.6克(0.80mol)，搅拌，在室温下反应10小时，减压除去溶剂和多余的1,3-二溴丙烷。剩余物用二氯甲烷250mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物44.8克，收率58.1％。m/z 257.01，259.01(M+H)。
制备22
2-(4-溴丙氧基苯基)-2-丙醇
(a)2-(4-苄氧基苯基)-2-丙醇
4-苄氧基溴苯62.3克(0.25mol)溶于300mL四氢呋喃中，在氩气保护下加入金属镁6.3克(0.263mol)，加入催化量的碘，加热回流30分钟。滴加丙酮58克(1mol)，加毕，继续回流反应3小时，反应混合物冷却至室温，冰浴冷却下滴加2M的盐酸132mL，减压除去四氢呋喃和多余的丙酮。剩余水相用乙醚萃取3次(200mLx3)，用无水硫酸镁干燥过夜。滤除干燥剂，浓缩至干得目标 产物38.8克，收率68.0％。m/z 228.11。
(b)2-(4-羟基苯基)-2-丙醇
(a)产物35克(0.153mol)溶于150mL甲醇中，加入10％Pd-C 2.4克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应4小时后，停止反应，滤除催化剂，减压浓缩至干，，得目标产物18.8克，收率80.7％。m/z152.08。
(c)2-(4-溴丙氧基苯基)-2-丙醇
(b)产物15.8克(0.104mol)溶于200mL甲醇中，加入碳酸钾31.1(0.225mol)，同时加入1,3-二溴丙烷80.8克(0.40mol)，搅拌，在室温下反应20小时，减压除去溶剂和多余的1,3-二溴丙烷。剩余物用二氯甲烷250mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物24.8克，收率87.3％。m/z 272.04，274.0。
制备23
4-(3-溴丙氧基)丙酰基苯
参照制备22(c)方法制备，收率65.8％，m/z270.02，272.02.
制备24
1-【4-(2-溴乙氧基)苯基】-2-甲基-2-丙醇
(a)1-[(4-苄氧基)苯基]-2-甲基-2-丙醇
4-苄氧基溴苄131.50克(0.50mol)溶于600mL四氢呋喃中，在氩气保护下加入金属镁12.6克(0.526mol)，加入催化量的碘，室温搅拌30分钟。滴加丙酮116克(2.0mol)，加毕，继续室温搅拌反应4小时，反应混合物用冰浴冷却，滴加2M的盐酸266mL，减压除去四氢呋喃和多余的丙酮。剩余水相用二氯甲烷萃取3次(400mLx3)，用无水硫酸镁干燥过夜。滤除干燥剂，浓缩至干得目标产物91.2克，收率75.28％。m/z 242.31。
(b)1-[(4-羟基)苯基]-2-甲基-2-丙醇
(a)产物88.0克(0.363mol)溶于400mL甲醇中，加入10％Pd-C4.4克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应5小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用二氯甲烷/石油醚(1：1)结晶,得目标产物53.4 克，收率88.6％。m/z166.1.
(c)1-【4-(2-溴乙氧基)苯基】-2-甲基-2-丙醇
(b)产物20.8克(0.125mol)溶于200mL甲醇中，加入碳酸钾31.1(0.225mol)，同时加入1,2-二溴乙烷75.2克(0.40mol)，搅拌，加热至50℃反应20小时，过滤，减压除去溶剂和多余的1,2-二溴乙烷。剩余物用二氯甲烷250mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物21.9克，收率80.3％。m/z 272.04，274.0。
制备25
1-【4-(2-溴丙氧基)苯基】-2-甲基-2-丙醇
参照制备24(b)方法制备，收率78.9％，m/z 286.05，288.0。
制备26
3-甲基-4-(3-溴丙氧基)苯乙酮
4-羟基-3-甲基苯乙酮30.38克(0.20mol)溶于300mL甲醇中，加入碳酸钾31.1(0.225mol)，同时加入1,3-二溴丙烷121.2克(0.60mol)，搅拌，在室温下反应20小时，减压除去溶剂和多余的1,3-二溴丙烷。剩余物用二氯甲烷250mL溶解，水洗3次(100mLX3)，无水硫酸镁干燥。滤除干燥剂，减压除去溶剂的目标化合物28.3克，收率52.2％。m/z 270.02，272.0。
制备27
3-甲氧基-4-(3-溴丙氧基)苯乙酮
参照制备26方法制备，收率65.8％，m/z 286.02，288.0。
制备28
(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷
制备2(e)产物31.45克(0.10mol)溶于300mL二氯甲烷中，冰浴冷却，加入三乙胺20.0克，搅拌5分钟，控制反应温度为10℃以下，滴加苄氧基甲酰 氯20.40克(0.12mol)，在此温度反应4小时，过滤，滤液加入200mL二氯甲烷稀释，用碳酸氢钠饱和溶液洗涤三次(200mLX3)，无水硫酸镁干燥，减压除去部分溶剂约350mL，加入石油醚200mL冷却结晶，得目标化合物40.50克，收率90.1％。MS 449.26.
实施例57
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
苯甲酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000062
(a)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-【2-(4-羟乙基苯氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
在250mL三口瓶中，加入无水乙醇30mL，(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷20.0克(44.50mmol)(制备28)，搅拌溶解后，再加入(4-溴乙氧基)苯乙基醇(制备14)69.9克(285.3mmol)，室温下搅拌反应12小时。减压除去乙醇，用柱层析除去残留物中多余的(4-溴乙氧基)苯乙基醇，粗品用二氯甲烷和正己烷(2/1)结晶，得 目标产物20.61克，收率75.4％。MS(m/z)614.23。
(b)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-【2-(4-甲磺酰氧乙基苯氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
将(a)产物19.3克(31.4mmol)溶于150mL二氯甲烷中，加入N-甲基吗啡啉5.0克(50.0(mmol)，冰浴冷却，滴加甲磺酰氯5.50克(48.0mmol)，在此温度下继续搅拌反应4小时，减压除去溶剂,柱层析得目标产物18.8克，收率87.8％，MS(m/z)682.21。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-苄氧甲基-4-苄氧基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇2.396克(5.283mmol)(制备1)和(b)3.57克(5.283mmol)加至50mL反应瓶中，加入20mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.566mmol)，将反应混合物温度升至80℃，并在此温度下反应5小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物2.85克。收率51.87％。C61H61BrN2O8的MS(m/z)：计算值1040.0，实测值959.4(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物2.60克(2.50mmol)置于氢化反应釜中，加入18mL甲醇溶解，加入10％Pd-C 0.5克，通入氢气，保持压力为0.43MPa，温度为室温。反应24小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.2克，收率66.0％。1HNMR(δppm)(DMSO-d6)7.19-7.21(m,5H),7.01(d,2H),6.59-6.95(m,5H),5.0(s,1H),4.79(s,2H),4.74(m,1H),4.04(t,2H),3.93(d,1H),3.68(d,1H),3.15(m,1H),2.67-2.90(m,8H),1.96-2.0(m,5H),1.79-1.81(m,3H),1.74(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.45(m,6H)；
C39H53BrN2O6的MS(m/z)：计算值725.75，实测值645.32(M-Br)。
(e)苯甲酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
取(d)产物0.545克(0.75mmol)溶于50mL水中，用强碱性阴离子交换柱吸附洗脱，洗脱液减压浓缩至50mL，加入含苯甲酸100毫克2mL乙醇溶液，搅拌5分钟，减压浓缩至干，残留物用异丙醇结晶，得目标产物0.42克，收率72.9％。元素分析(％)(计算值)C 71.98(72.04),H 7.52(7.62),N3.61(3.65).
实施例58
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000063
(a)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-【3-(4-羟甲基苯氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-【3-(4-甲磺酰氧甲基苯氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(b)方法制备。
(c)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-苄氧基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
将8-苄氧基-5-[(R)-2-苄胺基-1-羟基乙基]-(1H)-喹啉-2-酮2.0克(5.0mmol)(制备2)和(b)3.20克(5.0mmol)加至50mL反应瓶中， 加入20mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.566mmol)，将反应混合物温度升至80℃，并在此温度下反应5小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物2.6克。收率52.6％。C56H64BrN3O8的MS(m/z)：计算值986.89，实测值906.35(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物2.40克(2.43mmol)置于氢化反应釜中，加入20mL甲醇溶解，加入10％Pd-C 0.5克，通入氢气，保持压力为0.43MPa，温度为室温。反应15小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.08克，收率58.2％。
1HNMR(δppm)(DMSO-d6)8.01(s,1H),7.35(d,1H),7.19-7.21(m,5H),6.95(d,2H),6.71(d,1H)6.57-6.65(m,3H),6.52(d,1H),5.01(s,1H),4.74(m,1H),3.94(m,3H),3.81(t,2H),3.68(d,1H),3.15(m,1H),2.90(m,1H),2.84(m,1H),2.36(m,2H),2.10(s,1H),2.0(m,4H),1.79-1.82(m,5H),1.75(m,1H),1.68(m,2H),1.56-1.60(m,6H),1.35-1.46(m,6H)。
C41H52BrN3O6的MS(m/z)：计算值762.772.，实测值682.30(M-Br)。
实施例59
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【(3，5-二氯-4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000064
(a)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{3-[3，5-二氯-4-(羟甲基)苯氧基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{3-[3，5-二氯-4-(甲磺酰氧甲基)苯氧基]丙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例57(b)方法制备。
(c)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{3-【(3，5-二氯-4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-苄氧基)苯基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-2-苄氨基-1-【(4-苄氧基-3-甲酰胺基)苯基】乙醇1.882克(5.0mmol)(制备4)和(b)3.69克(5.0mmol)加至50mL反应瓶中，加入30mL乙腈搅拌10分钟后，再加入无水碳酸钾1.5克(11.0mmol)，将反应混合物温度升至65-70℃，并在此温度下反应10小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL异丙醇冷冻结晶，滤集固体得目标产物2.92克。收率56.6％。C54H62BrCl2N3O8的MS(m/z)：计算值1031.76，实测值950.27(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【(3，5-二氯-4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物2.80克(2.71mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C 0.8克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应15小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.38克，收率63.1％。1HNMR(δppm)(DMSO-d6)8.20(s,1H),7.40(m,1H),7.18-7.21(m,5H),6.84(d,2H)6.64-6.76(m,2H),5.01(s,1H),4.73(m,1H),4.01(s,1H),3.93(m,3H),3.81(d,2H),3.68(d,1H),3.15(m,1H),2.90(m,1H),2.83(m,1H),2.36(m,2H),2.10(s,2H),1.98-2.0(m,3H),1.79-1.81(m,5H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,6H),1.34-1.46(m,6H)；C39H50BrCl2N3O6的MS(m/z)：计算值807.64，实测值726.22(M-Br)。
实施例60
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)[-2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000065
(a)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{2-[4-(2-羟基-2-甲基)丙基苯氧基]乙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{2-[4-(2-甲磺酰氧基-2-甲基)丙基苯氧基]乙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例57(b)方法制备。
(c)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(6-苄氧基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将8-【(1R)-1-羟基-2-苄胺】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮2.02克(5.0mmol)(制备5)和(b)3.57克(5.0mmol)加至50mL反应瓶中，加入30mL二氧六环搅拌10分钟后，再加入无水碳酸钾1.0克(7.35mmol)，将反应混合物温度升至55-60℃，并在此温度下反应10小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入10mL异丙醇冷冻结晶，滤集固体得目标产物2.98克。收率58.5％。
C57H68BrN3O9的MS(m/z)：计算值1018.93，实测值938.38(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯乙氧基】-1-{2-【4-(2-{(R)[-2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物2.80克(2.75mmol)置于氢化反应釜中，加入20mL甲醇溶解，加入10％Pd-C 0.8克，通入氢气，保持压力为0.43MPa，温度为室温。反应12小时后，吸氢停止，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.46克，收率66.8％。1HNMR(δppm)(DMSO-d6)8.01(s,1H)，7.18-7.20(m,5H),7.01(d,2H),6.72(d,2H),6.65(d,1H),6.20(d,1H),5.01(s,1H),4.87(s,2H),4.74(m,1H),4.04(t,2H),3.93(s,1H),3.68(d,1H),3.14(m,1H),2.91(m,1H),2.84(m,1H),2.78(t,2H),2.59(s,2H),2.10(m,2H),2.0(m,2H),1.96(m,1H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,6H),1.15(s,6H)。
C42H56BrN3O7的MS(m/z)：计算值794.93，实测值714.33(M-Br)。
制备29
(R)-1-【(4-羟基-3-羟甲基)苯基】-2-氨基乙醇
取制备1(g)产物44克(0.10mol)溶于300mL甲醇，置于氢化反应釜中，，加入10％Pd-C 6.6克，通入氢气，保持压力为0.43MPa，室温氢化反应20小时后，吸氢停止，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体15.6克，收率85.1％。MS(m/z)182.09(M-H)。
制备30
8-羟基-5-[(R)-2-氨基-1-羟基乙基]-(1H)-喹啉-2-酮
取制备3(f)产物，按制备29方法制备。
制备31
(R)-2-氨基-1-【(4-羟基-3-甲酰胺基)苯基】乙醇
取制备4(d)产物，按制备29方法制备。
制备32
8-【(1R)-1-羟基-2-氨基】乙基-6-羟基-2H-1,4-苯并噁嗪-3(4H)-酮
取制备5(g)产物，按制备29方法制备。
实施例61
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000066
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-丙酮基苯氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例3(b)方法。
将(R)-2-氨基-1-【(4-羟基-3-甲酰胺基)苯基】乙醇0.981克(5.0mmol)(制备31)和(a)2.86克(5.0mmol)加至50mL反应瓶中，加入50mL二氯甲烷搅拌10分钟后，再加入三乙酰基硼氢化钠1.27克(6.0mmol)，并加入1一滴乙酸催化。反应混合物室温下反应24小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入5mL乙醇冷冻结晶，滤集固体得目标产物1.56克。收率73.6％。1HNMR(δppm)(DMSO-d6)8.20(s,1H),7.40(m,1H),7.18-7.20(m,5H),7.01(d,2H),6.72(d,2H),6.66-6.71(m,2H),5.0(s,1H),4.74(m,1H),4.04(t,2H),4.0(s,1H),3.92(d,1H),3.67(d,1H),3.15-3 .18(m,2H),2.91(m,1H),2.78(t,2H),2.54(m,2H),2.76-2.51(dd,2H),2.10(s,1H),1.96-2.0(m,4H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,6H),1.34-1.46(m,6H)，1.10(d,3H)；C40H54BrN3O6的MS(m/z)：计算值752.78，实测值671.32(M-Br)。
(C)化合物61-S和化合物61-R的制备
将(b)产物0.80克溶于5mL甲醇中，采用制备柱进行分离纯化，用乙腈和水混合进行梯度洗脱，分别收集61-S和61-R组分,减压除去溶剂，残留物，分别用乙醇结晶得化合物(61-S)0.28克，化合物(63-R)0.31克。
实施例62
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000067
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(4-丙酰基苯氧基)丙基)-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
将三乙酰基硼氢化钠1.27克(6.0mmol)，悬浮于50mL二氯甲烷中，加入8-羟基-5-[(R)-2-氨基-1-羟基乙基]-(1H)-喹啉-2-酮(制备30)1.10克(5.0mmol)和(a)3.0克(5.0mmol)，并加入1一滴乙酸催化。在室温下继续搅拌反应20小时，薄层检测，反应完全。停止反应，冷却至 室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入8mL异丙醇冷冻结晶，滤集固体得目标产物2.3克。收率58.2％。
1HNMR(δppm)(DMSO-d6)8.01(s,1H),7.36(d,1H),7.19-7.21(m,5H),7.02(d,2H),6.71(m,3H)6.56(d,1H),6.52(d,1H),5.01(s,1H),4.74(m,1H),3.94-3.90(m,4H),3.67(d,1H),3.16(m,1H),2.91(m,1H),2.84(m,1H),2.36(m,2H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,5H),1.75-1.74(m,3H),1.69(m,2H),1.55-1.61(m,6H),1.35-1.46(m,6H)，0.96(t,3H)。
C43H56BrN3O6的MS(m/z)：计算值790.82，实测值719.32(M-Br)。
(C)化合物62-S和化合物62-R的制备
将(b)产物1.10克溶于10mL甲醇中，采用制备柱进行分离纯化，用甲醇和水混合进行梯度洗脱，收集62-S和62-R组分洗脱液,减压除去溶剂，残留物，分别用异丙醇结晶得化合物62-S 0.35克，化合物62-R 0.30克。
实施例63
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【(4-(3-甲基-1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000068
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【(4-乙酰基-3-甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-甲基-1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
将三乙酰基硼氢化钠1.27克(6.0mmol)，悬浮于50mL二氯甲 烷中，加入8-羟基-5-[(R)-2-氨基-1-羟基乙基]-(1H)-喹啉-2-酮(制备32)1.12克(5.0mmol)和(a)2.93克(5.0mmol)，并加入1滴乙酸催化。在室温下继续搅拌反应18小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入6mL乙醇冷冻结晶，滤集固体得目标产物1.86克。收率46.8％。1HNMR(δppm)(DMSO-d6)8.02(s,1H)，7.19-7.21(m,5H),6.82(m,2H),6.65-6.60(m,2H),6.20(d,1H),5.0(s,1H),4.88s,2H),4.74(m,1H),4.08(q,1H),3.94(m,3H),3.68(d,1H),3.15(m,1H),2.91(m,1H),2.84(m,1H),2.35(m,4H),2.09(m,1H),2.0(m,2H),1.96(m,1H),1.79-1.81(m,5H),1.75(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,9H)。
C42H56BrN3O7的MS(m/z)：计算值794.81，实测值714.30(M-Br)。
(C)化合物63-S和化合物63-R的制备
将(b)产物0.60克溶于3mL甲醇中，采用制备柱进行分离纯化，用乙腈和水混合进行梯度洗脱，收集63-S和63-R组分,减压除去溶剂，残留物，分别用乙醇结晶得化合物63-S 0.146克，化合物63-R 0.187克。
以下化合物可按照上述原料和类似方法制备。
Figure PCTCN2017115807-appb-000069
Figure PCTCN2017115807-appb-000070
Figure PCTCN2017115807-appb-000071
Figure PCTCN2017115807-appb-000072
Figure PCTCN2017115807-appb-000073
Figure PCTCN2017115807-appb-000074
Figure PCTCN2017115807-appb-000075
Figure PCTCN2017115807-appb-000076
Figure PCTCN2017115807-appb-000077
Figure PCTCN2017115807-appb-000078
Figure PCTCN2017115807-appb-000079
Figure PCTCN2017115807-appb-000080
制备33
1,4-二(3-溴丙氧基)苯
1,4-对苯二酚110.1克(1.0mol)溶于800mL甲醇中，加入1,3-二溴丙烷606克(3.0mol)，无水碳酸钾276克(2.0mol)，回流反应6小时，停止反应。滤除固体，溶液减压除去溶剂至干，加入乙酸乙酯500mL溶解，水洗三次(200mLX3)，有机相用无水硫酸镁干燥过夜。滤除干燥剂，浓缩至干，得目标产物209克，收率59.4％，m/z351.95。
制备34
2-甲氧基-1,4-二(3-溴丙氧基)苯
2-甲氧基-1,4-对苯二酚98.1克(0.70mol)溶于600mL甲醇中，加入1,3-二溴丙烷404克(2.0mol)，无水碳酸钾207克(1.50mol)，回流反应8小时，停止反应。滤除固体，溶液减压除去甲醇和多余1,3-二溴丙烷至干，加入乙酸乙酯400mL溶解，水洗三次(200mLX3)，有机相用无水硫酸镁干燥过夜。滤除干燥剂，浓缩至干，得目标产物189克，收率49.5％，m/z381.96。
制备35
1,4-二(2-溴乙氧基)苯
参考制备32方法制备。
制备36
2-甲氧基-5-氯-4-(3-溴丙酰胺基)苯甲醇
(a)2-甲氧基-5-氯-4-氨基苯甲酸甲酯盐酸盐
将无水甲醇500mL置于1000mL三口瓶中，冰盐浴冷却至-5℃左右，滴加氯化亚砜130mL，滴加完毕，搅拌下加入2-甲氧基-5-氯-4-氨基苯甲酸100.5克(0.50mol)，固体未完全溶解，反应混合物自然升温至室温，继续搅拌反应24小时，滤集固体。固体用250mL甲醇加热溶解，冷冻结晶，滤集固体，晾干，得目标产物94.9克，收率75.7％。
(b)2-甲氧基-5-氯-4-(3-溴丙酰氨基)苯甲酸甲酯
(a)产物94.0克(0.373mol)溶于300mLDMF中，加入N-甲基吗啡啉37.4克(0.373mol)，冰浴冷却搅拌10分钟，再加入3-溴丙酸57.1克(0.373mol)和二环己基碳二亚胺103克(0.50mol)，加毕反应混合物升至室温，继续搅拌反应24小时，减压除去溶剂，残留物用300mL乙酸乙酯溶解，滤除固体，固体用200mL乙酸乙酯洗涤三次，合并乙酸乙酯溶液，用饱和碳酸氢钠溶液洗涤3次(150mLX3)，水洗3次(150mLX3)，无水硫酸镁干燥，滤除干燥剂，浓缩至干得目标产物108.3克，收率82.8％，m/z348.97，350.97。
(c)2-甲氧基-5-氯-4-(3-溴丙酰胺基)苯甲醇
(b)产物107克(0.306mol)溶于400mL甲醇中，冰浴冷却，分批加入硼氢化钠18.9克(0.50mol)，约1小时加完，加毕，继续在此温度下搅拌反应2小时，逐渐升至室温，继续反应4小时。减压除去溶剂，残留物用500mL二氯甲烷溶解，水洗3次(150mLX3)，无水硫酸镁干燥，滤除干燥剂，浓缩至干得目标产物77.9克，收率78.9％。m/z320.98，322.97。
制备37
2-甲氧基-4-(3-溴丙酰胺基)苯甲醇
按制备36制备方法制备。
制备38
3-甲基-4-(3-溴丙酰胺基)苯甲醇
按制备36制备方法制备。
制备39
4-(3-溴丙酰胺基)苯甲醇
按制备36制备方法制备。
制备40
1,1-二甲氧基-1-【4-(2-溴乙氧基甲基)苯基】乙烷
(a)1,1-二甲氧基-1-(4-甲氧甲酰基)苯基乙烷
将4-乙酰基苯甲酸甲酯89克(0.50mol)溶于400mL甲醇中，通入氯化氢20克，加热至50℃反应4小时，反应终止。减压除去多余甲醇和盐酸气，残留物用400mL二氯甲烷溶解，用饱和碳酸氢钠溶液洗涤3次(150mLX3)，水洗3次(150mLX3)，无水硫酸镁干燥，滤除干燥剂，减压除去溶剂得目标产物100.80克，收率90.0％，m/z224.1。
(b)1,1-二甲氧基-1-(4-羟甲基)苯基乙烷
将(a)产物98.0克(0.437mol)溶于300mL甲醇中，冰浴冷却，分次加入硼氢化钠37.6克(1.0mol)，2小时内加完。加毕，反应混合物升至室温，继续搅拌反应2小时。减压除去甲醇，残留物用400mL二氯甲烷溶解，二氯甲烷层水洗3次(150mLX3)，无水硫酸镁干燥有机相，滤除干燥剂，减压除去溶剂得目标产物68.80克，收率80.2％，m/z196.1。
(C)1，1-二甲氧基-1-【4-(2-溴乙氧基甲基)苯基】乙烷
将(b)产物67.0克(0.341mol)溶于300mL四氢呋喃中，加入氢化钠(60％)15.0克(0.375mol)，室温搅拌15分钟，滴加1,2-二溴乙烷263.2克(1.40mol)，加毕，回流反应4小时，减压除去溶剂，残留物用400mL二氯甲烷溶解，二氯甲烷层水洗3次(150mLX3)，无水硫酸镁干燥有机相，滤除干燥剂，减压除去溶剂得目标产物88.90克，收率86.0％，m/z302.0(M-H)。
制备41
1,4-二(2-溴乙氧基甲基)苯
(a)1，4-二(羟甲基)苯
对苯二甲酸二甲酯138.0克(0.75mol)溶于400mL甲醇中，冰浴冷却，分次加入硼氢化钠75.20克(2.0mol)，2小时内加完。加毕，反应混合物加热回流反应4小时。减压除去甲醇，残留物用500mL二氯甲烷溶解，二氯甲烷层水洗3次(150mLX3)，无水硫酸镁干燥有机相，滤除干燥剂，减压除去溶剂得目标产物80.80克，收率77.9％，m/z138.07。
(b)1,4-二(2-溴乙氧基甲基)苯
将(a)产物78.0克(0.565mol)溶于500mL四氢呋喃中，加入氢化钠24.86克(0.622mol)，室温搅拌15分钟，滴加1,2-二溴乙烷526.4克(2.80mol)， 加毕，回流反应8小时，减压除去溶剂和多余的1,2-二溴乙烷，残留物用800mL二氯甲烷溶解，二氯甲烷层水洗3次(250mLX3)，无水硫酸镁干燥有机相，滤除干燥剂，减压除去溶剂得目标产物138.80克，收率69.8％，m/z352.0。
实施例113
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000081
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-溴丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
按实施例3(a)制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-苄氧基)苯基]乙基苄氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-2-苄氨基-1-【(4-苄氧基-3-甲酰胺基)苯基】乙醇1.882克(5.0mmol)(制备4)和(a)3.38克(5.0mmol)加至50mL反应瓶中，加入30mL二氧六环搅拌10分钟后，再加入无水碳酸钾1.5克(11.0mmol)，将反应混合物温度升至55-60℃，并在此温度下反应12小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入10mL异丙醇冷冻结晶，滤集固体得目标产物3.26克。收率67.7％。C55H68BrN3O7的MS(m/z)：计算值963.0，实测值883.4(M-Br)。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物3.10克(3.22mmol)置于氢化反应釜中，加入30mL甲醇溶解， 加入10％Pd-C 0.6克，通入氢气，保持压力为0.4-0.43MPa，温度为室温。反应20小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.38克，收率54.7％。1HNMR(δppm)(DMSO-d6)8.21(s,1H),7.40(m,1H),7.18-7.23(m,5H),6.66-6.71(m,2H),5.0(s,1H),4.74(m,1H),4.0(s,1H),3.92(s,2H),3.68(d,2H),3.15(m,1H),2.91(m,1H),2.83(m,1H),2.54(m,2H),2.42(S,1H),2.35(m,2H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,8H),1.34-1.46(m,6H)；C41H56BrN3O7的MS(m/z)：计算值782.8，实测值702.3(M-Br)。
实施例114
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000082
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-溴乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例1(a)方法制备
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-苄氧甲基-4-苄氧基)苯基-2-羟基]乙基苄氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-1-【(4-苄氧基-3-苄氧甲基)苯基】-2-苄胺基乙醇2.40克(5.28mmol)(制备1)和(a)3.38克(5.28mmol)加至50mL反应瓶中，加入20mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.60mmol)，将反应混合物温度升至65-70℃，并在此温度下反应8小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出 去不溶物。滤液减压除去溶剂，残留物加入异丙醇溶解并冷冻结晶，滤集固体得目标产物3.42克。收率64.0％。C60H71BrN2O7的MS(m/z)：计算值1012.1，实测值932.4(M-Br)。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
取(b)产物3.30克(3.26mmol)置于氢化反应釜中，加入20mL甲醇溶解，加入10％Pd-C 0.8克，通入氢气，保持压力为0.43MPa，温度为室温。反应10小时后，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇溶解，冷冻结晶。得目标化合物固体1.38克，收率57.1％。1HNMR(δppm)(DMSO-d6)7.19-7.22(m,5H),6.95-7.01(m,2H),6.66(d,2H),6.63-6.59(m,3H),5.0(s,1H),4.79(s,2H),4.74(m,1H),4.04(t,2H),4.06(t,2H),3.93(d,1H),3.68(d,1H),3.15(m,1H),2.97(t,2H),2.90(m,1H),2.74(m,1H),2.78(t,2H),2.21(S,1H),2.10(s,1H),2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,6H)；C39H53BrN2O7的MS(m/z)：计算值741.8，实测值661.3(M-Br)。
实施例115
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【5-氯-2-甲氧基-4-({(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000083
(a)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{3-【(5-氯-2-甲氧基-4-羟甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{2-【(5-氯-2-甲氧基-4-甲磺酰氧甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐
按实施例57(b)方法制备。
(c)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{2-【5-氯-2-甲氧基-4-({(R)-[(2-羟基-2-(8-苄氧基-2-氧-1,2-二氢喹啉-5-基)]乙基苄氨基}甲基)苯胺基】氧代丙基)-1-氮杂双环【2,2,2】辛鎓盐
将8-苄氧基-5-[(R)-2-苄胺基-1-羟基乙基]-(1H)-喹啉-2-酮2.0克(5.0mmol)(制备2)和(b)4.28克(5.0mmol)加至50mL反应瓶中，加入30mL二氧六环，搅拌10分钟后，再加入无水碳酸钾1.475克(10.57mmol)，将反应混合物温度升至65-70℃，并在此温度下反应5小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，出去不溶物。滤液减压除去溶剂，残留物加入10mL乙醇溶解，冷冻结晶，滤集固体，晾干得目标产物2.96克。收率51.2％。C64H70BrClN4O9的MS(m/z)：计算值1154.49，实测值1073.86(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【5-氯-2-甲氧基-4-({(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物2.88克(2.49mmol)置于氢化反应釜中，加入20mL甲醇溶解，加入10％Pd-C 0.7克，通入氢气，保持压力为0.43MPa，温度为室温。反应18小时后，停止吸氢，滤除催化剂，减压浓缩至干，残留物用乙醇溶解结晶。得目标化合物固体1.48克，收率70.7％。
1HNMR(δppm)(DMSO-d6)8.10(s,1H),8.01(s,1H),7.36(d,1H),7.18-7.21(m,5H),6.97(d,1H),6.94(d,1H),6.71(d,1H),6.52(d,1H),5.0(s,1H),4.74(m,1H),3.93(m,1H),3.81(d,2H),3.73(s,3H),3.68(d,1H),3.15(m,1H),2.90(m,1H),2.84(m,1H),2.74(t,2H),2.33(t,2H),2.05(s,1H),2.0(m,4H),1.79-1.81(m,3H),1.75(m,1H),1.68(m,2H),1.56-1.60(m,6H),1.35-1.46(m,6H)。
C42H52BrClN4O7的MS(m/z)：计算值840.24，实测值759.77(M-Br)。
实施例116
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-({(R)-2[-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000084
(a)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-【3-(4-羟甲基苯胺基)氧代丙基】-1-氮杂双环【2,2,2】辛鎓盐
参考实施例57(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-【3-(4-甲磺酰氧甲基苯胺基)氧代丙基】-1-氮杂双环【2,2,2】辛鎓盐
参考实施例57(b)方法制备。
(c)溴化(R)-(-)-3-【(R)-2-苄氧甲酰氧基-2-环戊基-2-苯基】乙氧基-1-{2-【4-({(R)-[2-羟基-2-(6-苄氧基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙基苄氨基}甲基)苯胺甲酰基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将8-【(R)-1-羟基-2-苄胺】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮2.02克(5.0mmol)(制备5)和(b)3.96克(5.0mmol)加至50mL反应瓶中，加入30mL二氧六环搅拌10分钟后，再加入无水碳酸钾1.0克(7.35mmol)，将反应混合物温度升至65-70℃，并在此温度下反应10小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，除去不溶物。滤液减压除去溶剂，残留物加入10mL异丙醇冷冻结晶，滤集固体得目标产物2.88克。收率60.0％。
C62H69BrN4O9的MS(m/z)：计算值1094.0，实测值1014.38(M-Br)。
(d)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3- 【4-({(R)-2[-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐
取(c)产物2.70克(2.47mmol)置于氢化反应釜中，加入20mL甲醇溶解，加入10％Pd-C 0.6克，通入氢气，保持压力为0.43MPa，室温反应16小时后，吸氢停止，停止反应，滤除催化剂，减压浓缩至干，残留物用异丙醇结晶。得目标化合物固体1.26克，收率65.4％。1HNMR(δppm)(DMSO-d6)8.05(s,1H)，8.0(s,1H)，7.52(d,2H),7.19-7.21(m,5H),7.04(d,2H),6.65(d,1H),6.20(d,1H),5.0(s,1H),4.88(s,2H),4.74(m,1H),3.93(d,1H),3.81(d,2H),3.68(d,1H),3.15(m,1H),2.91(m,1H),2.84(m,1H),2.74(t,2H),2.33(t,2H),2.10(m,2H),2.0(m,2H),1.96(m,1H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.56-1.60(m,6H),1.34-1.46(m,6H)。
C40H51BrN4O7的MS(m/z)：计算值779.76，实测值700.33(M-Br)。
实施例117
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚乙基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000085
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(1,1-二甲氧基乙基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
按实施例1(a)方法制备。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚乙基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将(R)-2-氨基-1-【(4-羟基-3-甲酰胺基)苯基】乙醇0.981克(5.0mmol)(制备30)和(a)3.09克(5.0mmol)加至250mL反应瓶中，加入50mL二氯甲烷搅拌10分钟后，再加入三乙酰基硼氢化钠2.54 克(12.0mmol)，并加入1一滴乙酸催化。反应混合物室温下反应24小时，薄层检测，反应完全。停止反应，，过滤，除去不溶物。滤液减压除去溶剂，残留物加入5mL乙醇冷冻结晶，滤集固体得目标产物1.62克。收率43.0％。1HNMR(δppm)(DMSO-d6)8.21(s,1H),7.40(m,1H),7.18-7.20(m,5H),7.14(d,2H)7.05(d,2H),6.76(dd,1H),6.64(dd,1H),5.0(s,1H),4.74(m,1H),4.63(s,2H),4.08(m,1H),4.0(s,1H),3.93(d,1H),3.68(d,1H),3.47(t,2H),3.15(m,1H),2.91(m,1H),2.84(m,1H),2.53(t,2H),2.10(s,1H),1.96-2.0(m,3H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,6H),1.34-1.46(m,6H)，1.38(d,3H)；C40H54BrN3O6的MS(m/z)：计算值752.78，实测值672.32(M-Br)。
(C)117-S异构体和117-R异构体拆分
Figure PCTCN2017115807-appb-000086
将(b)产物0.80克溶于甲醇，用制备柱进行分离，用甲醇和水进行梯度洗脱，分别收取S-异构体和R-异构体组分峰，减压抽干，残留物用乙醇重结晶，得S-异构体0.24克和R异构体0.28克。
实施例118
溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
Figure PCTCN2017115807-appb-000087
(a)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-溴乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
参考实施例1(a)方法制备。
在250mL三口瓶中，加入无水乙醇35mL，(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-氮杂双环【2,2,2】辛烷5.0克(15.85mmol)(制备2)，搅拌溶解后，再加入1,4-二(2-溴乙氧甲基)苯(制备40)44.66克(126.3mmol)，室温下搅拌反应18小时。减压除去乙醇，残留物用柱层析目标产物8.50克，收率80.4％。MS(m/z)686.18，688.17。
(b)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(5-苄氧基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙基苄氨基}乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐
将8-【(1R)-1-羟基-2-苄胺】乙基-6-苄氧基-2H-1,4-苯并噁嗪-3(4H)-酮2.02克(5.0mmol)(制备5)和(a)3.38克(5.0mmol)加至50mL反应瓶中，加入30mL二氧六环搅拌10分钟后，再加入无水碳酸钾1.0克(7.35mmol)，将反应混合物温度升至75-80℃，并在此温度下反应12小时，薄层检测，反应完全。停止反应，冷却至室温，过滤，除去不溶物。滤液减压除去溶剂，残留物加入15mL乙醇冷冻结晶，滤集固体得目标产物3.36克。收率67.8％。MS(m/z)901.45。
(c)溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐、取(b)产物3.20克(3.23mmol)置于氢化反应釜中，加入30mL甲醇溶解，加入10％Pd-C0.6克，通入氢气，保持压力为0.43MPa，温度为室温。反应18小时后，吸氢停止，停止反应，滤除催化剂，减压浓缩至干，残留物用乙醇结晶。得目标化合物 固体1.48克，收率56.5％。1HNMR(δppm)(DMSO-d6)8.0(s,1H)，7.15-7.20(m,5H),7.12(d,4H),6.65(d,1H),6.20(d,1H),5.0(s,1H),4.88(s,2H),4.73(m,1H),4.63(s,4H),3.93(d,1H),3.68(d,1H),3.49(t,2H0,3.47(t,2H),3.15(m,1H),2.91(m,1H),2.84(m,1H),2.72(t,2H),2.53(t,2H),2.10(s,1H),2.0(m,2H),1.96(m,1H),1.79-1.81(m,3H),1.75(m,1H),1.69(m,2H),1.55-1.61(m,6H),1.34-1.46(m,6H)。C42H56BrN3O8的MS(m/z)：计算值810.8，实测值730.3(M-Br)。
利用以上合成的原料及合成方法可制备以下化合物：
Figure PCTCN2017115807-appb-000088
Figure PCTCN2017115807-appb-000089
Figure PCTCN2017115807-appb-000090
Figure PCTCN2017115807-appb-000091
Figure PCTCN2017115807-appb-000092
实验例1：本发明化合物拮抗卡巴胆碱(CCh)诱导豚鼠气管平滑肌收缩反应强度
豚鼠离体气管平滑肌标本制备：豚鼠用乌拉坦麻醉后迅速取出喉与隆突之间气管，置于通5％CO2和95％O2混合气的Krebs-Henseleit(K-H)液中(组成(g/L)： NaCl 6.92、KCl 0.35、CaCl2 0.28、KH2PO4 0.16、MgSO4·7H2O 0.4568、NaHCO3 2.1、Glucose 2.0)。分离气管周围疏松结缔组织和脂肪后，分离成宽约3mm、长20mm的气管片，结扎两端，放入含5ml K-H液的37℃恒温浴槽中(pH 7.4)，持续通含5％CO2和95％O2的混合气。上端接肌张力换能器，给予标本静息张力1.0g，记录肌张力变化，每20min换1次营养液，平衡60min后开始实验。
给药方法：待气管片稳定后，向浴槽中加入3×10-6mol/LCCh，待气管片收缩张力达高峰后，分别以10-9～10-5mol累积剂量加药法在麦式浴槽中加入实施例化合物、异丙托溴铵和噻托溴铵，观察气管条舒张情况，如果不出现反应(阈下浓度)，继续按顺序加入下一剂量，如出现反应，待其达舒张平台后，再加入下一剂量。重复上述操作直至收缩曲线达最小值。最后加入10-6mol/L异丙肾上腺素，使其达最大松弛并记录曲线。
统计方法：用Sigma Stat统计软件包统计,数据采用方差分析，多个样本均数间比较采用Student-Newman-Keuls(SNK)检验；统计学检验水准α＝0.05(双侧)。EC50(95％可信限)用上海科学技术出版社POMS 2.0版软件计算。
3×10-6mol/LCCh可使豚鼠气管平滑肌产生一个持久稳定的收缩反应。累积剂量加药法在麦式浴槽中加入待测化合物以及对照药异丙托溴铵和噻托溴铵，各个实施例化合物和对照药均能使由CCh引起的气管平滑肌收缩产生松弛，结果见表1。
表1：本发明部分化合物体外对抗浓度为3×10-6mol/L的CCh引起的豚鼠气管平滑肌收缩EC50(μM)
Figure PCTCN2017115807-appb-000093
Figure PCTCN2017115807-appb-000094
表1结果显示，本发明设计的化合物均有阻断卡巴胆碱诱导豚鼠气管平滑肌收缩作用，相当多的化合物阻断作用强于阳性对照剂异丙托溴铵，有部分化合物的作用强度与阳性对照剂噻托溴铵相当。本发明化合物和异丙托溴铵起效时间都比噻托溴铵短，相反，噻托溴铵起效慢。本发明化合物与噻托溴铵作用持续时间长，而异丙托溴铵作用时间短。
实验例2：本发明化合物对乙酰甲胆碱(Mch)诱导的豚鼠支气管收缩反应的拮抗强度和作用持续时间的测定
潮气量、气道流速、跨肺压测定：乌拉坦1.5g/kg腹腔注射麻醉豚鼠。将豚鼠仰卧固定，行气管插管，分离颈外静脉插入留置针；将豚鼠装入身体容积描记 箱内，用胸腔插管的钝针头插入豚鼠前胸第4～5肋间，可测得胸内压(其标志为水检压计水柱为负值，且随豚鼠呼吸上下波动)。待稳定后，利用MedLab生物信号采集处理系统记录给予Mch前豚鼠潮气量、气道流速和跨肺压值，作为基础值。静脉注射10μg/kg体重Mch。观察5分钟内豚鼠气道流速、潮气量和跨肺压的变化。Raw和Cdyn的计算：计算出气雾吸入Mch后Raw值增加百分率和Cdyn下降百分率的变化。
Raw和Cdyn计算公式分别为：
Figure PCTCN2017115807-appb-000095
Figure PCTCN2017115807-appb-000096
量效关系：各实施例化合物27只豚鼠均随机分3组,溶媒对照组15只豚鼠，本发明化合物【48、70、99、138】0.1μg/kg组、本发明化合物【48、70、99、138】0.3μg/kg和本发明化合物【48、70、99、138】1μg/kg组；气道滴入上述浓度药物30min后，静脉注射10μg/kg体重Mch激发，测定5min内的气道阻力(Raw)和肺动态顺应性(Cdyn)。
时效关系：豚鼠麻醉后，气道滴入本发明化合物【48、70、99、138】0.5μg/kg和1μg/kg。分别于给药后0.25h、0.5h、1h、1.5h、2h、4h、6h、12h和24h静脉注射10μg/kg体重Mch激发，测定5min内的气道阻力(Raw)和肺动态顺应性(Cdyn)。
量效关系：本发明化合物【48、70、99、138】给药剂量分别为0.1μg/kg、0.3μg/kg、1μg/kg，气道滴入30min后，静脉注射10μg/kg体重Mch激发，测定5min内的气道阻力(Raw)和肺动态顺应性(Cdyn)，结果见下表：
表2.本发明化合物实施例48、70、99、138拮抗Mch诱导的豚鼠支气管收缩反应作用—量效(Mean±S.E.M)关系
Figure PCTCN2017115807-appb-000097
Figure PCTCN2017115807-appb-000098
统计方法：one-way ANOVA，各组间比较Bonferroni法检验；与溶媒对照组比较*P＜0.05，**P＜0.01，***P<0.001.
静脉注射Mch 10μg/kg，豚鼠气道阻力上升320％，肺动态顺应性下降71％。豚鼠气道滴入化合物【48、70、99、138】化合物0.1、0.3、1μg/kg，呈剂量依赖性抑制气道阻力的上升以及肺动态顺应性的下降。化合物48三个剂量组对气道阻力上升的抑制率分别为66.2％(p<0.01)、88.3％(p<0.001)和91.6％(p<0.001)；对肺动态顺应性下降的抑制率分别为32.2％(p>0.05)、48.9％(p<0.001)和50.1％(p<0.001)。化合物70三个剂量组对气道阻力上升的抑制率分别为69.6％(p<0.01)、86.5％(p<0.001)和92.1％(p<0.001)；对肺动态顺应性下降的抑制率分别为34.2％(p>0.05)、47.8％(p<0.001)和49.3％(p<0.001)。化合物99三个剂量组对气道阻力上升的抑制率分别为73.5％(p<0.01)、86.8％(p<0.001)和91.9％(p<0.001)；对肺动态顺应性下降的抑制率分别为35.0％(p>0.05)、48.8％(p<0.001)和49.7％(p<0.001)。化合物138三个剂量组对气道阻力上升的抑制率分别为74.8％(p<0.01)、88.9％(p<0.001)和92.6％(p<0.001)；对肺动态顺应性下降的抑制率分别为31.0％(p>0.05)、48.2％(p<0.001)和49.9％(p<0.001)。
时效关系：静脉注射Mch 10μg/kg，豚鼠气道阻力上升328％。豚鼠气道滴入化合物【48、70、99、138】1μg/kg 0.25h后，对气道阻力上升的抑制率为80％以上；1h后即可达到最大抑制率90％以上。随着时间的延长，24h后对气道阻力上升的抑制率仍有85％以上，且与溶媒对照组比较均有统计学差异 (p<0.01～0.001)。为确证结果的正确性，将化合物【48、70、99、138】的给药剂量降低为0.5μg/kg，结果显示，豚鼠气道滴入化合物【48、70、99、138】0.5μg/kg，12h后气道阻力抑制率为85％以上(p<0.001)，24h后气道阻力抑制率为75％以上(p<0.01)。气道滴入化合物【48、70、99、138】1μg/kg与0.5μg/kg 12h后比较，气道阻力抑制率无显著性差异。而24h后，化合物【48、70、99、138】1μg/kg与0.5μg/kg比较，气道阻力抑制率无显著性差异(p<0.05)。以上结果提示：化合物【48、70、99、138】1μg/kg和0.5μg/kg气道滴入给药作用时间均超过了24h，是长效的气管扩张剂。
实验例3.本发明化合物对HEK和CHO细胞表达的人重组β1和β2肾上腺素受体活性和选择性研究
为测定激动剂对人β1和β2肾上腺素受体的活性和选择性，测量各重组细胞系表达受体的cAMP累积量。用同源性放射免疫分析法测定cAMP，即将细胞用PBS缓冲液洗涤，在室温下悬浮在缓冲液中生长至每孔30000-40000细胞。试验化合物用含0.1％BSA的PBS缓冲液稀释，对11个梯次浓度进行试验，浓度范围为100uM至0.1pM。对β1肾上腺素受体的分析，加入10nM的ICI118551以阻断β2肾上腺素受体在HEK293细胞内的表达。化合物加至悬浮的细胞后，闪烁板在37℃孵化10分钟，反应用冰冷的检测缓冲液终止，在4℃储存过夜后，测定其放射活性。
激动活性(pEC50值)采用软件包(GraphPad Software,San Diego,CA)的S型剂量响应模型进行回归分析。选择性由测定的β1和β2肾上腺素受体cAMP分析所得的比值计算得到，其表述为sel.β1/β2＝(EC50(β1)/EC50(β2))。
表3.本发明部分化合物β1和β2肾上腺素受体活性和选择性研究结果
实施例化合物 EC50(β1)nM EC50(β2)nM Sel(β1/β2)
化合物1 197±87 12.8±4.2 15.4
化合物2 210±89 32±15 7.8
化合物3 160±72 10.3±2.4 15.6
化合物4 43±16 1.2±0.38 36.8
化合物25 33±15 1.1±0.35 30.8
化合物26 8.6±2.1 0.46±0.23 18.8
化合物27 252±112 3.2±1.4 78.9
化合物45 216±87 8.2±78 120.3
化合物46 52±21 0.75±0.21 68.9
化合物48 284±105 0.67±0.12 423.8
化合物50 256±101 4.5±1.3 56.9
化合物57 172±64 2.5±0.9 68.8
化合物58 246±81 2.7±1.2 89.8
化合物59 83±31 0.32±0.12 213.4
化合物60 9.7±2.3 0.79±0.32 12.3
化合物62 251±87 1.98±0.31 126.7
化合物63 17±5.8 0.41±0.18 80.8
化合物70 156±78 0.41±0.11 379.8
化合物71 150±64 0.32±0.09 468.2
化合物75 238±73 4.1±1.4 56.8
化合物78 201±79 1.9±0.6 108.6
化合物84 196±81 0.82±0.31 238.8
化合物97 678±201 12.0±3.1 56.7
化合物99 117±45 0.30±0.13 389
化合物102 224±103 2.2±1.2 102.6
化合物104 39±18 1.32±0.56 29.6
化合物106 63±28 0.22±0.08 288.9
化合物114 227±104 2.3±1.5 98.9
化合物115 201±78 2.36±0.87 85.5
化合物116 56±24 0.82±0.31 68.8
化合物117 70±33 1.75±0.64 39.8
化合物118 23±9 0.98±0.33 23.8
化合物128 108±51 0.42±0.11 258.8
化合物138 94±32 0.41±0.10 228.3
化合物140 76±26 0.88±0.23 86.9
化合物141 91±33 0.67±0.22 135.9
化合物143 12±3 1.2±0.56 9.8
福莫特罗 46±3.6 0.22±0.10 209
结果分析:本发明化合物对β2肾上腺素受体具有良好的激动活性和功能选择性。
实验例4.本发明化合物CHO细胞表达的人重组M1、M2、M3受体亚型体外活性测定和选择性的研究
将已转染的CHOm1、CHOm2、CHOm3细胞分别在DMEM培养基(含15％胎牛血清，4mML-谷氨酰胺，1％非必需氨基酸，1％抗生素/抗真菌)内，置37℃、5％的CO2培养箱培养。
参照文献[胡雅儿,施菊,夏宗勤.M2受体cDNA转染CHOm2细胞的某些药理 学和生物学特性[J].核技术,1999,11(22):642-646]，待培养瓶内细胞生长增殖形成单层细胞，至铺满瓶底约90％时(约为接种后48小时)，弃培养基，用PBS(PH7.4)缓冲液洗两次，然后用冰冷的磷酸盐缓冲液(PH7.7，含5mmol/LMgCl2)刮下细胞。收集到的细胞用Teflon玻璃匀浆器匀浆，匀浆液低温离心20000r×20min，沉淀加反应缓冲液匀浆成膜蛋白悬液。加入每一反应管的蛋白量分别为：m1(约0.05mg)、m2(0.05mg)、m3(0.1mg)；[3H]-QNB的浓度为0.1-2.16nmol/L；非特异结合管加1μmol/L的阿托品；反应总体积为300μL。然后于25℃反应5h，用冰冷的反应缓冲液终止反应，再用多头细胞收集器收集于玻璃纤维滤膜。80℃烘干后，将滤膜片置于液闪瓶中，加入5ml液闪剂，避光过夜，用液体闪烁仪测量cpm。以Graphpad prism软件算出Bmax和Kd值。
各实验管加入以对M受体无选择性的3H-QNB为标记配基，各管终浓度为：m1、m3(1.042nmol/L)，m2(1.81nmol/L)；同时加入不同浓度的噻托溴铵、异丙托溴铵和各受试化合物，终浓度为10-10～10-4mol/L，共11个剂量；再加入相同量膜蛋白标本(同前述饱和实验)；反应总体积为300μL，进行竞争结合反应。另设非特异结合管，以大量阿托品(终浓度为1μmol/L)测量非特异结合。25℃反应5h，用冰冷的反应缓冲液终止反应，然后用多头细胞收集器收集于玻璃纤维滤膜。80℃烘干后，将滤膜片置于液闪瓶中，加入5ml液闪剂，避光过夜，用液体闪烁仪测量cpm。以Graphpad prism软件算出各化合物对3种M受体亚型各自的Ki值。比较噻托溴铵、异丙托溴铵和各受试化合物对M受体亚型选择性。
表4.本发明中部分化合物M受体拮抗剂活性测定和选择性实验结果
Figure PCTCN2017115807-appb-000099
Figure PCTCN2017115807-appb-000100
Figure PCTCN2017115807-appb-000101
*：Mx/My＝Ki(y)/Ki(x)
实验结果显示，本发明化合物对M3受体的选择性最高、M1受体次之、M2受体的选择性最低；其中对M3和M1受体均有较强的作用。在治疗鼻炎、气道高反应、老慢支、COPD等疾病时与现有技术相比具有明显优势。
实验例5.在豚鼠离体气管测定化合物MABA,M受体和β2肾上腺素受体活性
(1)实施例化合物拮抗卡巴胆碱(CCh)诱导豚鼠气管平滑肌收缩作用
豚鼠离体气管平滑肌标本制备：同实验例1。
给药方法：待气管片稳定后，加入终浓度为3×10-6mol/L的卡巴胆碱，待气管片压力值上升到稳定平台时开始加药。实验分为空白组和各供试品给药组。每组分别加入K-H液配制的DMSO溶液和各供试品溶液50μl，供试品给药组以累积浓 度加入终浓度为10-9、0.3×10-8、10-8、0.3×10-7、10-7、0.3×10-6和10-6mol/L的待测化合物和对照品，空白组加入相应稀释的DMSO溶液，用Medlab记录气管片平滑肌的舒张程度，最后加入终浓度为10-5mol/L的异丙肾上腺素作为100％舒张。结果见表5。
(2)实施例化合物对豚鼠气管平滑肌M受体的阻断作用
豚鼠离体气管平滑肌标本制备：同实验例1。
给药方法：待气管片稳定后，加入终浓度为10-5mol/L的盐酸普萘洛尔溶液作用10min阻断β受体，加入终浓度为3×10-6mol/L的卡巴胆碱(普萘洛尔阻断β受体后，观察化合物的M受体拮抗作用)，待气管片压力值上升到稳定平台时开始加药。实验分为空白组、普萘洛尔+空白组、各供试品给药组和普萘洛尔+各供试品给药组。空白组和各供试品给药组每组分别加入K-H液配制的DMSO溶液和供试品溶液50μl；普萘洛尔+空白组和普萘洛尔+各供试品给药组分别加入50μl普萘洛尔溶液作用10min后，再加入K-H液配制的DMSO溶液和供试品溶液50μl。供试品给药组以累积浓度加入终浓度为10-9、0.3×10-8、10-8、0.3×10-7、10-7、0.3×10-6和10-6mol/L的待测化合物，空白组加入相应稀释的DMSO溶液；普萘洛尔+各供试品给药组加入普萘洛尔作用10min后，以累积浓度加入终浓度为10-9、0.3×10-8、10-8、0.3×10-7、10-7、0.3×10-6和10-6mol/L的待测化合物，普萘洛尔+空白组加入普萘洛尔作用10min后，加入相应稀释的DMSO溶液。用Medlab记录气管片平滑肌的舒张程度，最后加入终浓度为2×10-4mol/L的硝普钠作为100％舒张。结果见表5.
(3)实施例化合物对豚鼠气管平滑肌β2受体的激动作用
豚鼠离体气管平滑肌标本制备：同实验例1。
给药方法：待气管片稳定后，加入终浓度为3×10-5mol/L的组胺溶液作用10min，加入终浓度为3×10-6mol/L的卡巴胆碱(观察β受体激动作用)，待气管片压力值上升到稳定平台时开始加药。实验分为空白组、组胺+空白组、各供试品给药组和组胺+各供试品给药组。空白组和各供试品给药组每组分别加入K-H液配制的DMSO溶液和供试品溶液50μl；组胺+空白组和组胺+各供试品给药组分别加 入50μl组胺溶液作用10min后，再加入K-H液配制的DMSO溶液和供试品溶液50μl。供试品给药组以累积浓度加入终浓度为10-9、0.3×10-8、10-8、0.3×10-7、10-7、0.3×10-6和10-6mol/L的待测化合物，空白组加入相应稀释的DMSO溶液；组胺+各供试品给药组加入组胺作用10min后，以累积浓度加入终浓度为10-9、0.3×10-8、10-8、0.3×10-7、10-7、0.3×10-6和10-6mol/L的待测化合物，组胺+空白组加入组胺作用10min后，加入相应稀释的DMSO溶液。用Medlab记录气管片平滑肌的舒张程度，最后加入终浓度为2×10-4mol/L的茶碱作为100％舒张。结果见表5。
表5.本发明部分化合物在预收缩离体气管M受体拮抗剂(MA)，β2受体激动剂(BA)和双功能(MABA)药效学活性实验结果
化合物 MA(EC50，nM) BA(EC50，nM) MABA(EC50，nM)
化合物7 289.7±12.3 162.5±9.8 72.3±14.6
化合物12 20.1±2.8 13.8±2.3 5.8±1.4
化合物61 20.6±1.8 12.9±1.8 5.0±1.1
化合物69 27.7±3.4 18.7±2.8 7.6±1.8
化合物94 43.5±4.2 33.5±5.7 19.8±5.4
化合物113 15.6±2.6 17.6±1.9 7.2±1.4
化合物122 56.7±6.6 36.8±4.1 15.6±3.6
化合物131 30.2±8.1 9.2±1.6 4.0±1.0
化合物80 13.3±1.2 9.9±1.7 3.3±0.9
化合物82 24.3±2.5 7.9±1.3 2.8±1.1
噻托溴铵 12.2±0.8 *NA *NA
沙美特罗 *NA 93.8±6.8 *NA
*NA表示不适用。
结果显示：本发明化合物同时具有很强的M受体阻断和β受体激动功能，大量化合物的该两种功能的匹配度MA:BA基本达到1-1.5：1，其中实施例化合物113几乎达到了1:1。
实验例6本发明化合物单次灌胃给予Beagle犬的急性毒性试验
试验化合物：
本发明实施例化合物7、12、61、69、80、82、94、113、122、131
对比化合物：
(1)WO2010126025实施例1化合物：4-({[5-(2-{[4-({[(2R)-2-羟基-2-(8-羟基-2-氧代-1,2-二氢喹啉-5-基)乙基]氨基}甲基)苯基]氨基甲酰基}乙基)-2-苯基苯基]氨基甲酰基}氧基)-1,1-二甲基哌啶-1-鎓三氟乙酸盐(按文献方法制备)
(2)WO2010004517实施例1化合物：5-[(1R)-2-({9-[4-({3-[(R)-环己基(羟基)苯甲基]-1H-1,2,4-三唑-1-基}甲基)哌啶-1-基]壬基}氨基)-1-羟乙基]-8-羟基喹啉-2(1H)-酮(按文献方法制备)
试验方法：
将Beagle犬随机分组，每组2只，雌雄各半，分别静脉注射(iv)给予本发明化合物和对比化合物7.5％的乙醇溶液，每种化合物设0.01mg/kg和0.10mg/kg两个剂量组。给药后(药后30min-4h)观察心率变化，结果见表6。
表6 本发明化合物Beagle犬iv给药后心率变化情况
Figure PCTCN2017115807-appb-000102
从表6中可看出，本发明化合物在0.1mg/kg剂量下iv给药后Beagle犬的心率均无明显变化，而对照化合物在0.01mg/kg剂量下即可使Beagle犬心率发生明显的升高。由此可见，本发明的化合物具有更低的毒副作用。
实验例7本发明化合物体外肝微粒体和肺匀浆中稳定性试验
1、肝微粒体试验化合物：
本发明实施例化合物7、12、61、69、80、82、94、113、122、131
对比化合物：
(1)WO2010126025实施例1化合物、(2)WO2010004517实施例1化合物。
试验方法：
本发明实施例化合物和对比化合物分别与SD大鼠、Beagle犬的肝微粒体在37℃水浴孵育0、2、5、10、15、20、30min后终止反应，LC-MS/MS分别进样分析。以0min样品的面积比作为100％，每个时间点与其比较后得到化合物经过不同时间孵育后的剩余的百分比，以此百分比的自然对数为纵坐标，时间为横坐标绘制散点图，拟合成一条直线，直线的斜率负数为k。根据公式计算各参数。
t1/2(min)＝0.693/k
Figure PCTCN2017115807-appb-000103
Liver weight表示每千克体重含有的肝重g，P450表示每克肝含有P450酶的量mg。
各个不同种属的值见下表：
种属 Liver weight(g/kg) P450protein/liver(mg/g) Qh(mL/min/kg)
犬 32 45 30
大鼠 40 45 55
Figure PCTCN2017115807-appb-000104
Qh表示肝血流量，不同种属的数值见上表。
按ERh＝Clhep/Qh，计算肝提取率(ERh)，结果见表7。
表7 本发明化合物体外肝微粒体代谢稳定性情况
Figure PCTCN2017115807-appb-000105
Figure PCTCN2017115807-appb-000106
*微粒体稳定性判定标准为：ERh<0.3属于肝代谢稳定性较好的化合物，0.3<ERh<0.7属于肝代谢稳定性中等的化合物，ERh>0.7属于肝代谢稳定性较差的化合物。
从表7中可看出，本发明化合物在SD大鼠和Beagle犬肝微粒体中代谢稳定性均较差，代谢较快，不易在体内蓄积，而对比化合物代谢稳定性较好，更易蓄积。
2、肺匀浆试验化合物：
本发明实施例化合物7、12、61、69、80、82、94、113、122、131
本发明实施例化合物和对比化合物分别与Beagle犬的肺匀浆在37℃水浴孵育8小时后终止反应，LC-MS/MS分别进样分析。以0min样品的面积比作为100％，8小时后与其比较后得到化合物经过8小时孵育后的剩余的百分比。结果见表8
表8 本发明化合物体外肺匀浆中代谢稳定性情况(8h)
试验化合物 人肺匀浆孵化后剩余率(％) 狗肺匀浆孵化后剩余率(％)
化合物7 93 95
化合物12 98 91
化合物61 92 89
化合物69 94 90
化合物80 92 92
化合物82 98 97
化合物94 91 96
化合物113 93 93
化合物122 95 92
化合物131 90 94
结论：以上试验说明，本发明化合物在肺部稳定，所以产生了长效作用；从表7中可看出，本发明化合物在SD大鼠和Beagle犬肝微粒体中代谢稳定性均较差，代谢较快，不易在体内蓄积，而对比化合物代谢稳定性较好，更易蓄积。说 明本发明化合物即使也不能积累有效的毒性剂量。
制剂例1
通过如下方法制备吸入给药干粉制剂
组合物中各组分及其用量
本发明化合物59 0.20mg
乳糖           30mg
将本发明化合物微粉化，与微粉化乳糖充分混合，将该混合物装入明胶吸入药筒，利用粉末吸入器给药。
制剂例2
用如下方法制备用于干粉吸入装置中的干粉制剂：
将本发明化合物70微粉化，与微粉化乳糖充分混合均匀制成制剂，该制剂的组合比为1:200，将该制剂组合物装入每剂量能转移10μg至100μg本发明化合物的干粉吸入装置。
制剂例3
用如下方法制备用于定量吸入器中吸入给药的干粉制剂：
将10g平均粒径小于10μm的微粉化的本发明化合物99分散于含0.2g卵磷脂200mL软化水溶液中，制成包含5wt％本发明化合物和0.1wt％卵磷脂的混悬液，将该混悬液喷雾干燥制成平均粒径小于1.5μ的颗粒。将颗粒装入有加压的1，1,1,2-四氟乙烷药筒中。
制剂例4
用如下方法制备用于用于定量吸入器的药物组合物：
将5g平均粒径小于10μm的微粉化的本发明化合物138分散于含0.5g海藻糖和0.5g卵磷脂100mL软化水胶体溶液中，制成包含5wt％本发明化合物、0.5％海藻糖和0.5wt％卵磷脂的混悬液，将该混悬液喷雾干燥制成平均粒径小于1.5μ的颗粒。将颗粒装入有加压的1，1,1,2-四氟乙烷药筒中。

Claims (18)

  1. 式I所示化合物、其药学上可接受的盐、溶剂化物、光学异构体：
    Figure PCTCN2017115807-appb-100001
    式Ⅰ结构式中*标记的碳均为(R)构型，其中：
    L为(4-10C)的芳基或杂芳基，其中杂芳基的杂原子选自N、O、S，以上基团可以是未取代的，也可以任选地被一个或多个选自卤素、-OR1，-SR1、-NR1R2、-NHCOR1、-CONR1R2、-CN、-NO2、-COOR1、-CF3或C1-C4的直链或支链烃基的取代基取代；
    W独立的选自取代或未取代的(3-7C)环烷基，取代基选自卤素、(1-4C)烷基，(1-4C)烷氧基、烷氧基烃基、杂环；
    R1为二价基团-(R1a)d-(A1)e-(R1b)f-，其中d、e、f分别独立的选自0、1、2或3，且R1连接的两个氮原子之间的最短链的邻接原子数目在3-14范围内。
    R1a、R1b各自独立的选自(1-10C)亚烷基、(2-10C)亚烯基、(1-4C)亚烷氧基、亚烷氧基烷基、亚烷酰胺基、亚烷酰氧基、亚烷胺基等，其中每个亚烷基、亚烯基、亚烷氧基、亚烷氧基烷基、亚烷胺基、亚烷酰氧基和亚烷酰胺基都是未取代的或被独立的选自(1-4C)烷基、氯、氟、羟基、苯基及取代苯基所取代，R1a、R1b可以相同或不同；
    A1独立的选自(3-7C)亚环烷基、(2-7C)亚烷基、(6-10C)亚芳基、(4-9C)亚杂芳基、和(3-8C)亚杂环烷基等，其中亚环烷基可以是未取代的，或被独立选自(1-6C)烷基的1-4个取代基取代；每个亚芳基、亚杂芳基和亚杂环烷基可以是未取代的，或被独立选自卤素、(1-6C)烷基、(1-6C)烷氧基、-S-(1-4C)烷基、-S(O)-(1-4C)烷基、-S(O)2-(1-4C)烷基、-C(O)-O-(1-4C)烷基、-NH-(1-4C)烷基、-N＝[(1-4C)烷基]2、羧基、硝基、腈基、酰胺基、酯基、三氟甲基、三氟甲氧基的1-3个取代基取代；
    R2选自-N(R2a)C(R2b)(O)、-C(R2c)(R2d)OR2e、-N(R2f)-或-O-等，R3选自氢、-C(R3a)＝C(R3b)-C(O)-、-OC(R3C)(R3d)C(O)-、-N(R3e)CH(R3f)C(O)-、-C(R3g)(R3h)S(O)2-、-SCO-等，条件是当R3为氢时，R2选自-N(R2a)C(R2b)(O)或-C(R2c)(R2d)OR2e，当R3选自-C(R3a)＝C(R3b)-C(O)-、-OC(R3C)(R3d)C(O)-、-N(R3e)CH(R3f)C(O)-、-C(R3g)(R3h)S(O)2-或-SCO-时，R2选自-N(R2f)-或-O-；
    其中R2a-2f和R3a-2h分别独立选自氢或(1-4C)烷基；
    Y-选自药学上可接受的酸根，包括无机酸根和有机酸根；
    T代表羟基在该苯环上的位置，选自该苯环R2的邻位或间位。
  2. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中L为未取代的苯基、吡啶基、呋喃基或噻吩基。
  3. 根据权利要求1或2的任一化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中W为未取代的(3-7C)环烷基。
  4. 根据权利要求3的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中W为环丁基、环戊基或环己基。
  5. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中R1a、R1b各自独立的选自(1-10C)亚烷基、-(1-4C)亚烷氧基、亚烷酰胺基；A1独立的选自(6-10C)亚芳基，其中亚芳基可以是未取代的，或被独立选自卤素、(1-6C)烷基、(1-6C)烷氧基、羧基、硝基、腈基、酰胺基、酯基的1-2个取代基取代。
  6. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中R1选自-(-(CH2)3-、-(CH2)4-、-(CH2)8-、-(CH2)9-、-(CH2)10-、-(CH2)2O(CH2)2-、-(CH2)2O(CH2)4-、-(CH2)3O(CH2)4-、-(CH2)4O(CH2)4-、-(CH2)5O(CH2)4-、-(CH2)2O(CH2)2O(CH2)2-、-(CH2)2O(CH2)3O(CH2)2-、-CH2O(CH2)5OCH2-、-(CH2)2O(CH2)2O(CH2)2O(CH2)2-、-(CH2)2O(苯-1,4-亚基)(CH2)2-、-(CH2)3O(苯-1,4-亚基)CH2-、-(CH2)3O(3，5-二氯-苯-1,4-亚基)CH2-、-(CH2)2CONH(2-甲氧基-5-氯-苯-1,4-亚基)CH2-、-(CH2)2CONH(3-甲基-苯-1,4-亚基)CH2-、-(CH2)2CONH(2-甲氧基-苯-1,4-亚基)CH2-、-(CH2)2CONH(苯-1,4-亚基)CH2-、-(CH2)3CONH(苯-1,4-亚基)CH(CH3)-、-(CH2)3OCH2(3-甲氧基-苯-1,4-亚基)CH(CH3)-、-(CH2)3O(苯-1,4-亚基)C(CH3)2-、-(CH2)3O(苯-1,4-亚基)CH(CH2CH3)-、-(CH2)3O(苯-1,4-亚基)(CH2)2-、-(CH2)3O(苯-1,4-亚基)(CH2)3-、-(CH2)3O(苯-1,4-亚基)CH2CH(CH3)-、-(CH2)2OCH2(苯-1,4-亚基)CH2O(CH2)2–、-(CH2)2OCH2(苯-1,4-亚基)CH(CH3)–、-(CH2)2O(苯-1,4-亚基)O(CH2)2-、-(CH2)3O(2-甲氧基-苯-1,4-亚基)O(CH2)3-、-(CH2)3O(苯-1,4-亚基)O(CH2)3-、-(CH2)3O(苯-1,4-亚基)CH2C(CH3)2-、-(CH2)2O(苯-1,4-亚基)CH2C(CH3)2-、-(CH2)2O(苯-1,4-亚基)CH2CH(CH3)-、-(CH2)2O(苯-1,4-亚基)(CH2)2-、-(CH2)2O(CH2)3O(CH2)2-。
  7. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，R2a-2f分别为氢。
  8. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，R3a-3f分别为氢。
  9. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中Y-选自Br-、Cl-、I-、碳酸氢根、碳酸根、硫酸氢根、硫酸根、硝酸根、磷酸根、磷酸氢根、磷酸二 氢根、亚磷酸根、甲酸根、乙酸根、丙酸根、异丁酸根、甲磺酸根、对甲苯磺酸根、苯甲酸根、草酸根、酒石酸根、富马酸根、丙二酸根、琥珀酸根、辛二酸根、富马酸根、扁桃酸根、苯二甲酸根、苯磺酸根、柠檬酸、葡糖醛酸根、半乳糖酸根或氨基酸根。
  10. 根据权利要求9的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其中Y-选自Br-或Cl-。
  11. 根据权利要求1所述化合物、其药学上可接受的盐、溶剂化物、光学异构体，其具有如下式Ia、Ib、Ic或Id结构：
    Figure PCTCN2017115807-appb-100002
    其中：*标记的碳均为(R)构型碳，L、W、R1、Y与权利要求1一致。
  12. 根据权利要求1或11的任一化合物、其药学上可接受的盐、溶剂化物、光学异构体，其具有如下式Ia1、Ib1、Ic1或Id1结构：
    Figure PCTCN2017115807-appb-100003
    其中：*标记的碳均为(R)构型碳，R1、Y与权利要求1一致。
  13. 根据权利要求1的化合物、其药学上可接受的盐、溶剂化物、光学异构体，其为：
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[(R)-2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)乙氨基]丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{4-[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]丁基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁基-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9{-(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环丙基-2-苯基】乙氧基-1-(8-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}辛基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐；
    对甲苯磺酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(10-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}癸基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(11-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}十四烷基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丁基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环丁基-2-苯基】乙氧基-1-(8-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}辛基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(10-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}癸基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(11-{((R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}十一烷基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-(3-甲基)苯基】乙氧基-1-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(8-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}辛基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(9-{(R)-[2-羟基-2-(3- 甲酰胺基-4-羟基)苯基]乙氨基}壬基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(10-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}癸基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(11-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}十一烷基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(3-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丙基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-(4-异丁基)苯基】乙氧基-1-(8-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}辛基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(10-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}癸基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(11-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}十一烷基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(4-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丁氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-(4-甲氧基)苯基】乙氧基-1-【2-(2-{(R)-[2-(3- 羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}庚氧基)己基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(4-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丁氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【5-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁氧基)戊基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-(3-甲基-4-甲氧基)苯基】乙氧基-1-【3-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)乙氨基]丁氧基}丙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【4-(4-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丁氧基)丁基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【2-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧基)乙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)乙氧基】乙氧基}乙基)-1-氮杂双环【2,2,2】辛鎓盐；
    氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【3-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)丙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙氧基)丙氧基】丙氧基}丙基)-1-氮杂双环【2,2,2】辛鎓盐；
    氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【3-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙氧基)丙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧基)乙氧基】乙氧基}乙基)-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【3-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙氧基)戊氧基】丁基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-(2-{2-【2-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧基)乙氧基】乙氧基}乙基)-1-氮杂双环【2,2,2】辛鎓盐；
    氯化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【2-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧基)乙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【3-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧基)丙氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    苯甲酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【(3，5-二氯-4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)[-2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【(4-(3-甲基-1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-噻吩基】乙氧基-1-{3-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-2[-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-(3- 羟甲基-4-羟基)苯基-2-羟基]乙氨基}丙基)苯氧基】庚烷基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3，5-二氯-1-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(4-{[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]亚乙基}苯氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(3-甲氧基-4-{[(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基乙氨基]亚乙基}苯氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}亚异丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[4-(1-{(R)-2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}亚丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}异丁基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓)盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-(1-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}亚乙基)苯氧基】丙基-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    乙酸(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-(4-氯)苯基】乙氧基-1-{3-【4-(2-{(R)-[2- 羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙基苯)氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-呋喃基】乙氧基-1-{3-【3，5-二氯-(4-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(3-甲氧基-4-{[((R)-2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)乙氨基]亚乙基}苯氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-2[-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚异丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-【3-(4-{2-[(R)-2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)乙氨基]异丁基}苯氧基)丙基】-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4(-2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双 环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲氧基-4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙(氨基}亚异丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}异丁基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环己基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}异丁基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-(1-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】 辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(5-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-吡啶基】乙氧基-1-{3-【3，5-二氯-4-(1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}亚乙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲氧基-4-(1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}亚乙基)苯氧基】丙基-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)乙氨基}亚异丙基)苯氧基】丙基}-1-氮杂]双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(1-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}亚丙基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环庚基-2-苯基】乙氧基-1-{3-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}异丁基)苯氧基】丙基-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-【2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8[-基)]乙氨基}丙基)苯氧基】乙基-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【5-氯-2-甲氧基-4-({(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-({(R)-2[-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}亚乙基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-萘基】乙氧基-1-{2-【4-(2-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}乙氧基甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(1-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}亚乙基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-[2-甲氧基-4-(3-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【5-氯-2-甲氧基-4-({(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-(4-羟基)苯基】乙氧基-1-{3-【2-甲氧基-4-({(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-({(R)-[2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-({(R)[-2-(3-羟甲基-4-羟基)苯基-2-羟基]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(1-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}亚乙基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)基]乙氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【2-甲氧基-4-(3-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【2-甲氧基-4-({(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基-)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-({(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基-)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-({(R)-[2-羟基-2-(8-羟基-2-氧-1,2-二氢喹啉-5-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-(3-乙基)环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧甲基)苯甲氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【2-甲氧基-4-(3-{(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【5-氯-2-甲氧基-4-({(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【2-甲氧基-4-({(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯胺基】氧代丙基-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-({((R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-(3-甲氧基)环戊基-2-苯基】乙氧基-1-{3-【4-({(R)-[2-羟基-2-(3-甲酰胺基-4-羟基)苯基]乙氨基}甲基)苯胺基】氧代丙基-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)基]乙氨基}亚乙基)苯甲氧基乙基}-1-氮杂双环【2,2,2】辛鎓盐(外消旋体、S异构体、R异构体)；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{2-【4-(2-{(R)-[2-羟 基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}乙氧基)苯氧基】乙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【2-甲氧基-4-(3-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【4-(3-{(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}丙氧基)苯氧基】丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【5-氯-2-甲氧基-4-({(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)乙]氨基}甲基)苯胺基】氧代丙基-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【2-甲氧基-4-({(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐；
    溴化(R)-(-)-3-【(R)-2-羟基-2-环戊基-2-苯基】乙氧基-1-{3-【3-甲基-4-({(R)-[2-羟基-2-(6-羟基-2H-1，4-苯并噁嗪-3(4H)-酮-8-基)]乙氨基}甲基)苯胺基】氧代丙基}-1-氮杂双环【2,2,2】辛鎓盐。
  14. 一种药物组合物，含有权利要求1-13中任一项的化合物、其药学上可接受的盐、溶剂化物、光学异构体和药学可接受载体，组合物可以是任何合适的剂型，优选是吸入给药、鼻腔给药的剂型；并且组合物中还可以含有或不含有一种或多种其他的可用于联合给药的药物。
  15. 根据权利要求14的药物组合物，其中包含治疗有效剂量的甾体抗炎药。
  16. 根据权利要求14的药物组合物，其中包含治疗有效剂量的PDE4抑制剂。
  17. 式I化合物、其药学上可接受的盐、溶剂化物、光学异构体的制备方法，包括以下步骤：
    (a)使中间体1或其盐与X1-R1-X2反应生成中间体2；
    (b)中间体2与中间体3反应生成带有保护基的中间体4；
    (c)中间体4或其它带有保护基的式I化合物脱去保护基得到式I化合物；
    (d)式I化合物通过碱性阴离子交换树脂生成式I的氢氧化物，然后与各种不同的酸反应而制备各种不同算根的季铵盐；或者式I化合物与特定的阴离子交换树脂交换而制备特定酸根的季铵盐；或者式I卤化物与氧化银反应生成式I的氢氧化物再与其它酸反应生成各种酸根的季铵盐；或式I卤化物与银盐反应生成相应酸根的季铵盐；
    Figure PCTCN2017115807-appb-100004
    中间体1，2，3，4中带*号碳原子指定为R构型；
    化合物X1-R1-X2中X1、X2为离去基团或氨基，离去基团选自卤素如氯、溴、碘，磺酸酯如甲磺酸酯、对甲苯磺酸酯和羰基；Z为离去基团或-NHQ2，离去基团选自卤素如氯、溴、碘，磺酸酯如甲磺酸酯、对甲苯磺酸酯和羰基，条件是当X2为离去基团时，Z为-NHQ2，当X2选自氨基时Z为离去基团；Q1为氢或羟基保护基，羟基保护基选自硅醚类例如三甲硅基、叔丁基二甲硅基、叔丁基二苯基硅基，酯类(酰基基团)如甲酰基、乙酰基，芳基甲基基团如苄基、对甲氧基苄基、9-芴基甲基、二苯甲基；Q2为氢或氨基保护基，氨基保护基选自苄基(Bn)、 叔丁氧羰基(Boc)、苄氧羰基(Cbz)、9-芴基甲氧羰基(Fmoc)、甲酰基、乙酰基，R为(1-6C)烷基、苯基或取代苯基，优选甲基、乙基、对甲苯基或苯基，R1、R2、R3、Y与权利要求1定义相同；
    在上述方法中，原料之一为盐时，通常该盐在反应前或在反应过程中被中和，这种中和通常用与该盐等摩尔当量的碱进行。
  18. 权利要求1-13所述任一项化合物、其药学上可接受的盐、溶剂化物、光学异构体或权利要求14-16所述的任一组合物在制备作为支气管扩张剂的药物中的用途。
PCT/CN2017/115807 2016-12-14 2017-12-13 一类具有季铵盐结构的双功能化合物 Ceased WO2018108089A1 (zh)

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CN111704912A (zh) * 2020-06-29 2020-09-25 烟台丰蓬液晶材料有限公司 一种3-烯基苯炔液晶化合物的制备新方法
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