CN107304208A - Crystal formation II of compound and its production and use - Google Patents
Crystal formation II of compound and its production and use Download PDFInfo
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- CN107304208A CN107304208A CN201610239248.2A CN201610239248A CN107304208A CN 107304208 A CN107304208 A CN 107304208A CN 201610239248 A CN201610239248 A CN 201610239248A CN 107304208 A CN107304208 A CN 107304208A
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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
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention relates to crystal formation II of 3 [(phenyl of 2 cyclopenta, 2 hydroxyl 2) ethyoxyl] 1 methyl bromide 1 azabicyclo [2,2,2] octanes and its production and use.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically it is to provide selective anticholinergic drug --- 3- [(2- rings penta
Base -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II and its preparation side
Method and purposes.
Background technology
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
For selective anticholinergic drug, there is obvious selectivity to m receptor (to M2 acceptors without obvious effect).It is absent-minded by antagonism fan
Suppress vagal reflection through the transmitter acetylcholine of release.Pharmacodynamics test shows：3- [(2- cyclopenta -2- hydroxyls -
2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane has obvious antiallergy, anti-inflammatory, antipruritic work
With, moreover it is possible to reduce capillary permeability.3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- nitrogen
Miscellaneous bicyclic [2,2,2] octane can suppress airway inflammation, Airway Remodeling and airway hyper-reaction caused by the attack of sensitized mice antigen, its
Mechanism of action is relevant with the balance, reduction cell factor and ECF expression that adjust Th1/Th2 cells.
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
It is a kind of quaternary ammonium salt, it is minimum through the ability of schneiderian membrane, intestines and stomach and blood-brain barrier, causes systemic anticholinergic effect very
Low (including spirit, eyes, angiocarpy and intestines and stomach effect).Pharmacological toxicology result of study shows：3- [(2- cyclopenta -2- hydroxyls
Base -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane toxicity is very low, and clinic recommends dosage
In the range of safety coefficient it is larger.
I, II and III clinical trial phase result show：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- first
Base-bromination -1- azabicyclos [2,2,2] octane sprays in 90 μ g/, 4 times a day, every time can be with the dosage of each 1 spray per side nostril
Runny nose, rhiocnesmus, sneeze and nasal obstruction symptom caused by rhinitis effectively after prevention and treatment continuation allergic rhinitis and flu.Respectively
Item research shows subject for 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
Preferably, adverse reaction rate is low, mild degree for the tolerance of [2,2,2] octane.
The studies above result shows：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- nitrogen
Runny nose, rhiocnesmus, spray caused by rhinitis after miscellaneous bicyclic [2,2,2] octane is used to prevent and treats continuation allergic rhinitis and catch a cold
Sneeze and have a stuffy nose symptom, it is safely and effectively, quality controllable.
Up to the present, both at home and abroad still without disclosed document report 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethoxies
Base] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II and its preparation and use.
Summary of the invention
The present invention relates to the 3- shown in Fig. 1 [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1-
Novel crystal forms II of azabicyclo [2,2,2] octane and its production and use.
The XRPD characteristic peaks of compound crystal form II shown in Fig. 1 with 2 θ (± 0.2 ° of 2 θ) represent be located at 4.9 °, 6.9 °, 9.7 °,
10.9°、13.8°、14.6°、15.1°、17.4°、17.6°、19.5°、20.1°、20.5°、21.8°、22.2°、23.8°、
24.5°、24.9°、25.8°、26.3°、28.0°、28.6°、29.8°、31.0°、31.5°、32.5°、33.0°、34.1°、
At 34.4 °, 34.8 °, 35.6 °, 38.2 °, 38.6 °.Characteristic feature peak be located at 15.1 ° (10), 17.4 ° (25), 20.5 ° (10),
22.2°(16)、23.8°(8)、25.8°(9)、26.3°(7)、28.0°(10)、32.5°(6)、34.1°(6)、34.4°(6)、
35.6 ° (5), 38.2 ° (5) and 38.6 ° (5)；Relative line intensity for more than 30 X-ray diffraction spectral line be located at 4.9 ° (32),
9.7 ° (31), 10.9 ° (46) and 24.5 ° (100).
Its preparation method is：
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] is pungent
Alkane bulk drug is positioned in round-bottomed flask, adds acetone, and stirring makes solid fully dissolve in 50-80 DEG C of oil bath, Ran Hou
Continue to filter while hot after stirring 5-60 minutes under the conditions of 50-80 DEG C, collect filtrate, to filtrate evaporation solvent, treat that solvent is remaining big
Stop revolving when about 1/3, add ether, stirring mixes solution, there is solid precipitation, mistake after suspension is stood into 10-20 hours
Filter, solid is dried in vacuo 6-10 hours at 50-100 DEG C.Obtained white solid be suspended in 2- butanone stirring 0.5-24 it is small
When after filter, collect solid.
The invention further relates to 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azepines
Purposes of the crystal formation II of bicyclic [2,2,2] octane in terms of selective anticholinergic agents is prepared.
Brief description of the drawings
Fig. 1 is 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
The structural formula of octane.
Fig. 2 is 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
The XRPD diagrams of the crystal formation II of octane.
Fig. 3 is 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
The powder diffraction data of crystal formation II of octane.
Fig. 4 is 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
TGA and the DSC figure of the crystal formation II of octane；The fusing point of compound crystal form II is 176.34 DEG C, and decomposition temperature is 296.28 DEG C.
Fig. 5 is 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
The microscope figure of the crystal formation II of octane；Image of the crystal formation II under 200 power microscopes shows that the crystal formation solid is bar-shaped crystallization.
Embodiment
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos that the present invention is obtained
The crystal formation II of [2,2,2] octane is higher in solid-state and solution state stability inferior.So that 3- [(2- cyclopenta -2- hydroxyls -
2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane can stablize presence, be easy to store and transport,
It can be easily made preparation.
Characteristic, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- nitrogen of the invention
Have under the weightless platform of heat analysis (TG-DSC or TG-DTA) collection of illustrative plates of the crystal formation II of miscellaneous bicyclic [2,2,2] octane corresponding
Endothermic peak.
The present invention 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] crystal formation II of octane can stable storage.
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] is pungent
The solid of alkane crystal formation II be respectively placed in 25 DEG C/90%RH, 40 DEG C/75%RH, under 60 DEG C/air humidity conditions, in the 0th, 5 and 10
It when sample, HPLC analysis with determine laboratory sample purity change, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -
The stability result of 1- methyl-bromination -1- azabicyclos [2,2,2] octane solid is listed in Table 1 below, and shows the 3- [(2- of the present invention
Cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II it is good
Solid-state stability.
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] is pungent
The solid of crystal formation II of alkane is soluble in water, is sampled when experiment the 0th, 1,3 and 7 days, HPLC analyses are carried out after dilution to determine solid
Purity change in test solvent, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azepines
The results are shown in Table 2 for the stability of solution of bicyclic [2,2,2] octane solid.Purity of the solid of the crystal formation II of the present invention in water
There is no significant change.Show 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- nitrogen of the present invention
The good stability of solution of miscellaneous bicyclic [2,2,2] octane crystal formation II.
Above result of the test illustrates 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromine of the present invention
Change -1- azabicyclos [2,2,2] octane crystal formation II has good storage stability.
The present invention 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] preparation method of octane crystal formation II is as follows：
A) to 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
Octane raw material adds acetone；
B) heating stirring makes solid fully dissolve；
C) continue to filter while hot after stirring under heating, filtrate is collected, to filtrate evaporation solvent；
D) ether is added, stirring mixes solution, there is solid precipitation, is filtered after suspension is stood；
E) solid is dried in vacuo under heating；
F) obtained white solid is suspended in 2- butanone after stirring and filtered；
G) solid is collected.
It is highly preferred that 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- nitrogen of the present invention
The preparation method of miscellaneous bicyclic [2,2,2] octane crystal formation II is as follows：
A) by 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
Octane bulk drug is positioned in round-bottomed flask, adds acetone；
B) stirring makes solid fully dissolve in 60-70 DEG C of oil bath；
C) filtered while hot after continuing to stir 10-50 minutes under the conditions of 60-70 DEG C, collect filtrate, to filtrate evaporation solvent,
Stop revolving when solvent residue about 1/3；
D) ether is added, stirring mixes solution, there is solid precipitation, is filtered after suspension is stood into 10-20 hours；
E) solid is dried in vacuo 6-10 hours at 70-90 DEG C；
F) obtained white solid is suspended in 2- butanone after stirring 1-23 hours and filtered；
G) solid is collected.
The present invention a kind of pharmaceutical preparation is provided on the other hand, including the present invention 3- [(2- cyclopenta -2- hydroxyls -
2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II, and one or more pharmacy can connect
The excipient received.
The present invention further provides the method for preparing pharmaceutical preparation, including by the 3- [(2- cyclopenta -2- of the present invention
Hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II and at least one or pharmacy
Acceptable excipient merges.
The present invention further provides 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azepines
The crystal formation II of bicyclic [2,2,2] octane has obvious selectivity in preparation for treating m receptor (to M2 acceptors without obvious effect)
Purposes in selective anticholinergic agents preparation.
Pharmaceutical preparation
" pharmaceutical preparation " used herein refers to the composition of medicine, and described pharmaceutical preparation can contain at least one pharmacy
Upper acceptable carrier.
" pharmaceutically acceptable excipient " used herein refers to be applied to the medicinal of compound provided in this article administration
Carrier or solvent, it is included well known to a person skilled in the art any examples of such carriers suitable for specific administration mode, for example, with
It can include sterile diluent (for example, injection in the solution or suspending agent of parenteral, intradermal, subcutaneous or topical application
Water, salting liquid, expressed oi etc.)；The fatty solvent (for example, polyethylene glycol, glycerine, propane diols etc.) of synthesis；Antiseptic (example
Such as, benzylalcohol, to the methyl formate of hydroxyl third, to Ethyl formate of hydroxyl third etc.)；Antioxidant is (for example, ascorbic acid, bisulfite
Sodium etc.)；Chelating agent (for example, EDTA etc.)；Buffer (phosphate, citrate etc.)；And/or for tonicity-adjusting substances
(e.g., sodium chloride, glucose etc.), or their mixture.Other example includes, when intravenous administration, appropriate carrier
Solution including physiological saline, phosphate buffer and containing thickener, such as glucose, polyethylene glycol and they mixed
Compound.
It is used as non-limiting example, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromine of the invention
The crystal formation II of change -1- azabicyclos [2,2,2] octane can be mixed optionally with one or more pharmaceutically acceptable excipient,
These pharmaceutical preparations can contain e.g., from about 25% to about 90% active component and carrier, more generally containing 0.1% to
The active ingredient of 99.9% (weight).
The present invention 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] crystal formation II of octane can be used for preparing the pharmaceutical preparation containing the crystal formation II, and the pharmaceutical preparation includes 3- [(2- rings penta
Base -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II liquid dosage form
(such as solution, injection), solid dosage forms (such as tablet, capsule), semisolid dosage form (such as ointment, gel),
Gas formulation (such as aerosol, spray).
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
The liquid dosage form (such as solution, injection) of crystal formation II, solid dosage forms (such as tablet, capsule), semisolid dosage form (such as
Ointment, gel etc.), gas formulation (such as aerosol, spray), specific formulation its preparation method is respectively：
Solution：By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] crystal formation II of octane, which is added in purified water, is dissolved, and is produced.
Injection：By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] crystal formation II of octane, which is added in water for injection, is dissolved, and adds osmotic pressure regulator, after membrane filtration, point
Dress, is produced.
Tablet：By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,
2] crystal formation II of octane, which is added in auxiliary material, is fully mixed, and is added adhesive and is pelletized, and after drying, carries out tabletting, i.e.,
.
Capsule：By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,
2] crystal formation II of octane, which is added in auxiliary material, is fully mixed, and is added adhesive and is pelletized, after drying, and is carried out capsule and is filled out
Fill, produce.
Ointment：By oily matter (such as vaseline, lanolin, stearic acid, higher aliphatic, glycerin monostearate)
Being heated to 80 DEG C or so makes fusing, is filtered with fine cloth；Separately by water soluble ingredient (such as borax, sodium hydroxide, triethanolamine, bay
Alcohol sodium sulphate and NMF, preservative etc.) water is dissolved in, when being heated to slightly higher compared with oil phase temperature (when preventing two-phase mixtures in oil phase
Component too early separate out or condense), the aqueous solution is slowly added into oil phase, side edged is stirred, and emulsion bases is made.Add 3- [(2-
Cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II and stir
To condensation.
Aerosol：By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] crystal formation II of octane, which is added in ethanol, is dissolved, and decoction is cooled to -20 DEG C or so by cooling device, and propellant is cold
But at least 5 DEG C below boiling point.First the decoction of cooling is poured into container, the propellant cooled down is subsequently added.Immediately by valve
Door is loaded onto and tightened, and operation must be quickly completed.
Spray：Sodium chloride is dissolved with water for injection, plus 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1-
The crystal formation II of methyl-bromination -1- azabicyclos [2,2,2] octane makes dissolving, adjusts pH with HCl, adds water to scale.It will be made up a prescription
Liquid is filtered with 0.22 μm of sterilizing filter, is then distributed into nose sprayer bottle, capping.
Powder spray：By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- nitrogen of micronizing
The crystal formation II of miscellaneous bicyclic [2,2,2] octane is well mixed with auxiliary material, is fitted into special powder inhaler, you can.
Pharmaceutically acceptable cosolvent can be glycerine, propane diols, polyethylene glycol, ethanol ethyl acetate, acetone etc..Medicine
Acceptable propellant nitrogen, carbon dioxide or nitrous oxide, F-11, difluoromethane, trichloroethanes, tetrafluoro second on
Alkane etc..
Pharmaceutically acceptable excipient can be glucose, lactose, xylitol, sorbierite, mannitol, dextran etc.
In one or more, the above include anhydrous, aqueous or solvation carbohydrate, such as lactose include Lactis Anhydrous, a water
Lactose etc..
Pharmaceutically acceptable cosolvent can be pharmaceutically acceptable inorganic acid or organic acid, inorganic base or organic
The lewis acid or alkali of alkali or broad sense, can containing one or several kinds, can be hydrochloric acid, phosphoric acid, propionic acid, acetic acid,
Lactic acid, citric acid, tartaric acid, boric acid, multi-hydroxy carboxy acid for example glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid,
One or several kinds in glucoheptonic acid, DHB, Acidic amino acids, such as L-aminobutanedioic acid, glutamic acid.
Pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable inorganic acid or organic acid, inorganic base or organic
The lewis acid or alkali of alkali or broad sense, can be able to be hydrochloric acid, phosphoric acid, propionic acid, acetic acid containing one or several kinds
And acetate, such as sodium acetate, lactic acid and lactic acid pharmaceutical salts, citric acid pharmaceutical salts, sodium carbonate, sodium acid carbonate, saleratus,
Sodium hydroxide, potassium hydroxide, phosphate, tartaric acid and its pharmaceutical salts, borax, boric acid, succinic acid, caproic acid, adipic acid, anti-butylene
Diacid, maleic acid, multi-hydroxy carboxy acid and pharmaceutical salts, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threose
One or several kinds in acid, glucoheptonic acid etc..
Pharmaceutically acceptable antioxidant and stabilizer can be sulfurous acid, sulphite, bisulfites, pyrosulfurous acid
Salt, dithionite, thiosulfate, organosulfur compound thiocarbamide, glutathione, dimercaprol dimercaptopropanol, TGA and salt,
Thiolactic acid and salt, thio-2 acid and salt, phenol compound, such as gallic acid and salt, caffeic acid or its pharmaceutical salts, asafoetide
Acid or its pharmaceutical salts, di-t-butyl Pyrogentisinic Acid, DHB or its salt, salicylic acid or its salt；Ascorbic acid and anti-
Bad hematic acid salt, arabo-ascorbic acid and erythorbate, niacinamide, tartaric acid, nitrate, phosphate, acetic acid pharmaceutical salts, lemon
One or several kinds in hydrochlorate, EDTA and edta salt, such as EDETATE SODIUM, the sodium of EDTA tetra-.
It can add the activated carbon with liquid measure 0.005~3% to remove thermal source to go thermal source and degerming mode, and miillpore filter is degerming
And pressure sterilizing, it would however also be possible to employ heat sterilization, remove thermal source.In hyperfiltration process, ultrafilter can select flat, rolling, tubular type,
Hollow fiber form or circle boxlike etc., preferably rolling and hollow fiber form ultrafilter, use retention relative molecular mass for 5 ten thousand to 30
Ten thousand filter membrane is removed after most of heat generation material and bacterium, then using the ultrafiltration of retention relative molecular mass 4000~30000
Film removes the milipore filter of remaining thermal source, preferably relative molecular mass 6000~30000.
The present invention 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] the crystal formation I of octane, it is adaptable to：There is obvious selectivity (to M2 acceptors without obvious effect) selection to m receptor for preparing
Application in the medicine of the anticholinergic treatment or prevention of property.
Consumption usage：Generally, for 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- of the present invention
The consumption of crystal formation II of methyl-bromination -1- azabicyclos [2,2,2] octane is 1mg-1g.
Except in embodiment and when indicated otherwise, all numerical value used should be by specification and claims
It is interpreted as in all examples being modified with term " about " or " about ", therefore, unless the contrary indication, this explanation
The numerical parameter gone out given in book and appended claims is approximation, and it can be according to sought by by present disclosure
Required property and change, at least, and not be intended to limit the application of doctrine of equivalents right, per number
The number and routine that value parameter is considered as effective digital round up method to explain.
Although the number range and parameter that set the wide scope of disclosure are approximations.But institute in a particular embodiment
The numerical value provided is reported as precisely as possible, and any number is substantially comprising some by finding in their own test
The error that standard deviation is necessarily led to.
It is pointed out that unless in text clearly in addition explanation, used in this specification and the appended claims
Singulative " one ", " one kind " and "the" include the plural form of referring to thing, so, if for example, referred to containing " one
During the composition of kind compound ", include the mixture of two or more compounds.It is further noted that unless this civilization
Really illustrate in addition, term "or" generally includes "and/or".
In order to further appreciate that the present invention, the preferred embodiment of the invention is described with reference to embodiment, still
It should be appreciated that these descriptions are simply to further illustrate the features and advantages of the present invention, rather than to the claims in the present invention
Limitation.
Illustrate the effect of the present invention with specific embodiment below, but protection scope of the present invention is not limited by following examples
System.
Embodiment 1：The preparation example 1 of the crystal formation II of the present invention
Weigh about 5g 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
[2,2,2] octane bulk drug is positioned in round-bottomed flask, adds 2000ml acetone, and stirring makes solid abundant in 65 DEG C of oil bath
Dissolving, filters, collects filtrate, to filtrate evaporation solvent, treat solvent while hot after then continuing to stir 10 minutes under the conditions of 65 DEG C
Stop revolving during residue about 1/3, add 100mL ether, stirring mixes solution, there is solid precipitation, and suspension is stood into 16
Filtered after hour, solid is dried in vacuo 8 hours at 80 DEG C.Obtained white solid be suspended in 2- butanone stirring 1 hour after
Filtering, collects solid.
Embodiment 2：The preparation example 2 of the crystal formation II of the present invention
Weigh about 10g 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
[2,2,2] octane bulk drug is positioned in round-bottomed flask, adds 5000ml acetone, and stirring fills solid in 65 DEG C of oil bath
Divide dissolving, filtered while hot after then continuing to stir 10 minutes under the conditions of 65 DEG C, collect filtrate, to filtrate evaporation solvent, treat molten
Stop revolving during agent residue about 1/3, add 300mL ether, stirring mixes solution, has solid precipitation, suspension is stood
Filtered after 18 hours, solid is dried in vacuo 9 hours at 80 DEG C.Obtained white solid is suspended in 2- butanone to be stirred 2 hours
After filter, collect solid.
Embodiment 3：Test
Powder X-ray diffraction approach
Test condition：
By using the powder x-ray diffraction (Bruker D8Advance) equipped with Lynxeye detectors to solid
Sample is detected.Take sample 120mg to be laid in the middle part of zero Background Samples disk, sample is carried out with 0.1sec/step speed
Scanning, instrument is scanned to 40o (2 θ) since 3o (2 θ), and X-ray light pipe voltage and current is respectively 40KV and 40mA during scanning
Determine 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
The x-ray diffractogram of powder of crystal formation II, whole peak positions are in ± 0.2 ° of 2 θ.
Gravitational thermal analysis method
Thermogravimetric analysis test condition：Solid sample carries out thermogravimetric analysis using TA Instrument TGA Q500.About
3.0mg solid sample is placed in Balanced platinum sample disc, sample quality automatic weighing in TGA heating furnaces.Sample
300 DEG C are heated to 10 DEG C/min speed.In test process, the nitrogen flow in balance room and sample room is 40mL/ respectively
Min and 60mL/min.
Micro- sem observation
Test condition：Take a small amount of sample to be laid on slide, slide is placed on Nikon Instruments
On the microscopical objective table of Eclipse 80i types, polarized light microscopy analyzer is used as in this experiment, passes through DS camera shooting images
It is sent in computer, and picture is handled with NIS-Elements D3.0 softwares.
Stability
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] is pungent
The solid of alkane crystal formation II be respectively placed in 25 DEG C/90%RH, 40 DEG C/75%RH, under 60 DEG C/air humidity conditions, in the 0th, 5 and 10
It when sample, HPLC analysis with determine laboratory sample purity change, refer to table 1,3- [(2- cyclopenta -2- hydroxyl -2- phenyl)
Ethyoxyl] -1- methyl-solid-state stability the result of bromination -1- azabicyclos [2,2,2] octane crystal formation II.
Table 1：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
The solid-state stability result of the crystal formation II of octane
Stability of solution
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] is pungent
The solid of crystal formation II of alkane is soluble in water, is sampled when experiment the 0th, 1,3 and 7 days, HPLC analyses are carried out after dilution to determine solid
Purity change in test solvent, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azepines
The results are shown in Table 2 for the stability of solution of the solid of crystal formation II of bicyclic [2,2,2] octane.The solid of the crystal formation II of the present invention is in water
In purity there is no significant change.Refer to the 3- of table 2 [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-brominations -
The stability of solution test result of 1- azabicyclos [2,2,2] octane bulk drug crystal formation II
Table 2：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2]
The stability of solution test result of the crystal formation II of octane bulk drug
Embodiment 4：Include 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- of the present invention
Liquid dosage form (such as solution, injection), solid dosage forms (such as tablet, capsule of the crystal formation II of azabicyclo [2,2,2] octane
Agent etc.), semisolid dosage form (such as ointment, gel), gas formulation (such as aerosol, spray).
Solution：10 grams of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azepines is double
The crystal formation II of ring [2,2,2] octane, which is added in 800ml purified waters, fully to be dissolved, and adds 0.5 gram of aspartoyl phenylalanine first
Ester is dissolved, plus purified water, to 1000ml, packing is produced.
Injection：0.5 gram of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azepines is double
The crystal formation II of ring [2,2,2] octane, which is added in 800ml waters for injection, to be dissolved, and adds 9 grams of sodium chloride osmotic pressure regulators,
4M hydrochloric acid adjusts pH value to 7-8, passes through, after 0.22 μm of membrane filtration, and packing is produced.
Tablet：By 10 grams of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
The crystal formation II of [2,2,2] octane is added in 400 grams of lactose and fully mixed, and adds 30%pvp adhesives and is pelletized, is done
After dry, tabletting is carried out, is produced.
Capsule：By 10 grams of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
The crystal formation II of [2,2,2] octane is added in 100 grams of microcrystalline celluloses and 300 grams of starch and fully mixed, and adds 30%pvp
Adhesive is pelletized, after drying, and is carried out capsule filling, is produced.
Ointment：By 300 grams of vaseline, 100 grams of higher aliphatics, 50 grams of glycerin monostearates are heated to 80 DEG C makes to melt
Change, filtered with fine cloth；5 grams of sldium lauryl sulfates are separately dissolved in water, 95 DEG C is heated to, the aqueous solution is slowly added into oil phase, side
Edged is stirred, and emulsion bases is made.Add 0.5 gram of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -
The crystal formation II of 1- azabicyclos [2,2,2] octane is simultaneously stirred to condensing, and packing is produced.
Spray：9g sodium chloride is dissolved with 800ml waters for injection, plus 1g 3- [(2- cyclopenta -2- hydroxyl -2- phenyl)
Ethyoxyl] crystal formation II of -1- methyl-bromination -1- azabicyclos [2,2,2] octane makes dissolving, and pH is adjusted to 7-8 with 2%HCl,
Inject water to 1000ml.Institute's vehicle is filtered with 0.22 μm of sterilizing filter, is then distributed into nose sprayer bottle, plus
Lid.
Aerosol：By 2g 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
The crystal formation II of [2,2,2] octane, which is added in 50mL ethanol, to be dissolved, and decoction carries out being cooled to -20 DEG C of left sides by polyethylene glycol
It is right.First the decoction of cooling is poured into container, the HFC-134a that 950g has been cooled down is subsequently added.Valve is loaded onto and pricked immediately
Tightly, operation must be quickly completed.
Inhalation powder spray：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromine that 5g is micronized
The crystal formation II of change -1- azabicyclos [2,2,2] octane is well mixed with the mannitol 300g of gentle breeze, is loaded special dry powder and is inhaled
Enter in device, you can.
It is appreciated that from this professional angle, the change of many details is possible, and this is simultaneously not so limited the scope of the invention
And spirit, the present invention is not limited to above-described embodiment.
Claims (7)
1.3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
Crystal formation II, it is characterised in that with the diffracted signal in following location determined as follows in powder x-ray diffraction method：(2θ
± 0.2 degree)：
。
2. claim 1 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,
2,2] crystal formation II of octane, it is characterized in that, when carrying out heat analysis using DSC, there is endothermic peak at 176 ± 2 DEG C.
3. such as 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-brominations-of any one of claim 1 or 2
The preparation method of the crystal formation II of 1- azabicyclos [2,2,2] octane, it is characterised in that
A) to 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
Raw material adds acetone；
B) heating stirring makes solid fully dissolve；
C) continue to filter while hot after stirring under heating, filtrate is collected, to filtrate evaporation solvent；
D) ether is added, stirring mixes solution, there is solid precipitation, is filtered after suspension is stood；
E) solid is dried in vacuo under heating；
F) obtained white solid is suspended in 2- butanone after stirring and filtered；
G) solid is collected.
4. method as claimed in claim 3, it is characterised in that
A) by 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane
Bulk drug is positioned in round-bottomed flask, adds acetone；
B) stirring makes solid fully dissolve in 60-70 DEG C of oil bath；
C) filtered while hot after continuing to stir 10-50 minutes under the conditions of 60-70 DEG C, collect filtrate, to filtrate evaporation solvent, treat molten
Stop revolving during agent residue about 1/3；
D) ether is added, stirring mixes solution, there is solid precipitation, is filtered after suspension is stood into 10-20 hours；
E) solid is dried in vacuo 6-10 hours at 70-90 DEG C；
F) obtained white solid is suspended in 2- butanone after stirring 1-23 hours and filtered；
G) solid is collected.
5. a kind of be used for having obvious selectively and to the anticholinergic medicine of selectivity of the M2 acceptors without obvious effect to m receptor
Preparation, it is characterised in that it contains 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethoxies such as any one of claim 1 to 2
Base] -1- methyl-bromination -1- azabicyclos [2,2,2] octane crystal formation II and at least one or pharmaceutically acceptable excipient.
6. pharmaceutical preparation as claimed in claim 5, it is characterised in that it is liquid dosage form (such as solution, injection), solid formulation
Type (such as tablet, capsule), semisolid dosage form (such as ointment, gel), gas formulation (such as aerosol, spray
Deng).
7. such as 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-brominations-of any one of claim 1 to 2
The crystal formation II of 1- azabicyclos [2,2,2] octane has obvious selectively and to M2 acceptors without bright in preparation for treating m receptor
Purposes in the selective anticholinergic agents preparation of aobvious effect.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1532196A (en) * | 2003-03-21 | 2004-09-29 | 北京小伙伴医药生物技术有限公司 | Quinic compound containing quaternary ammonium group and its preparation and medicina use |
| CN101585835A (en) * | 2008-05-22 | 2009-11-25 | 北京嘉事联博医药科技有限公司 | Preparation method and application of bencycloquidium bromide optical isomer and composition of bencycloquidium bromide optical isomer |
| CN101856327A (en) * | 2009-04-08 | 2010-10-13 | 北京嘉事堂生物医药有限公司 | A kind of phencycloquinium bromide quantitative inhalation aerosol and preparation method thereof |
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2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1532196A (en) * | 2003-03-21 | 2004-09-29 | 北京小伙伴医药生物技术有限公司 | Quinic compound containing quaternary ammonium group and its preparation and medicina use |
| CN101585835A (en) * | 2008-05-22 | 2009-11-25 | 北京嘉事联博医药科技有限公司 | Preparation method and application of bencycloquidium bromide optical isomer and composition of bencycloquidium bromide optical isomer |
| CN101856327A (en) * | 2009-04-08 | 2010-10-13 | 北京嘉事堂生物医药有限公司 | A kind of phencycloquinium bromide quantitative inhalation aerosol and preparation method thereof |
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Application publication date: 20171031 |