CN105732538B - Than Si Tapamo hydrochlorates and preparation method thereof, pharmaceutical composition and purposes - Google Patents
Than Si Tapamo hydrochlorates and preparation method thereof, pharmaceutical composition and purposes Download PDFInfo
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- CN105732538B CN105732538B CN201410747242.7A CN201410747242A CN105732538B CN 105732538 B CN105732538 B CN 105732538B CN 201410747242 A CN201410747242 A CN 201410747242A CN 105732538 B CN105732538 B CN 105732538B
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Abstract
The present invention relates to a kind of Anti-HIV agents synergist than Si Tapamo hydrochlorates and its amorphous article.The invention further relates to the preparation method of the comparable Si Tapamo hydrochlorates and its amorphous article, its pharmaceutical composition and its preparing the purposes in being used to treat the medicine of HIV infection.
Description
Technical field
The present invention relates to pharmaceutical chemistry crystallization technique field.In particular to Anti-HIV agents synergist than his pa of department
Not hydrochlorate, further relates to its preparation method, pharmaceutical composition and purposes.
Background technology
It is a kind of pharmacodynamics reinforcing agent that Gilid Science Co. develops than his (English name Cobicista) is taken charge of,
Improve the blood concentration of specific HIV medicines.Trade name Tybost, in September 25 in 2013 obtain European Union approval, for once a day,
Dosage be 150mg tablet, suitable for hiv protease inhibitor atazanavir (atazanavir, 300mg, once a day) or
Darunavir (darunavir, 800mg, once a day) drug combination, for treating HIV-1 infection.Cobicistat is also
One of component of HIV compound medicines Stribild, Stribild obtain FDA approvals in August, 2012.
Than take charge of his chemical name for (3R, 6R, 9S) -12- methyl isophthalic acids 3- [2- (1- Methylethyls) -4- thiazolyls] -
Four azepine tridecanoic acid 5- of double (the phenyl methyl) -2,7,10,12- of 9- [2- (4- morpholinyls) ethyl] -8,11- dioxos -3,6-
Thiazole methanol ester, molecular formula C40H53N7O5S2, molecular weight 776, chemical structural formula is as follows：
Patent document WO2013/116715A1, WO2008/103949A1, WO2010/115000A2 and WO2008/
010921A2 disclose than take charge of he and preparation method thereof.
Patent document WO2012/151165A1 is disclosed than his amorphous article and preparation method thereof is taken charge of, and also disclosing can
Than his citrate of department, tartrate, oxalates, fumarate, hydrochloride, lactate, phosphate, sulfate, malic acid
Salt and they XRPD figure,1H-NMR, Tg data, hygroscopicity data and preparation method thereof, also disclose than his 1- hydroxyls of department
Base -2- naphthoates, toluene fulfonate, bromate, dichloroacetate, naphthalene sulfonate, camsilate, nicotinate, hippuric acid
Salt, esilate, malonate, succinate, ketoglutarate, benzoate, benzene sulfonate, ethanedisulphonate, adjacent benzene first
Acyl sulfimide salt, ascorbate, maleate, gentisate and their Tg and hygroscopicity data.The present inventor according to
The description of the patent document has carried out repeating to test, and finds：As described in the patent document, than his citrate, wine of department
Stone hydrochlorate, oxalates, fumarate, hydrochloride, lactate, phosphate, sulfate, malate, toluene fulfonate, bromic acid
Salt, dichloroacetate, naphthalene sulfonate, camsilate, nicotinate, hippurate, esilate, malonate, succinate,
Ketoglutarate, benzoate, benzene sulfonate, ethanedisulphonate, o-benzoic sulfimide salt, ascorbate, maleic acid
Salt is easy to moisture absorption into grease, it is difficult to applied to preparation；The present inventor also found under study for action than take charge of his amorphous article, than department
His 1- hydroxy-2-naphthoic acids salt and than take charge of his gentisate it is long-term place in experiment can moisture absorption into grease, it is unstable,
It is dfficult to apply to preparation.
It is the comparable characteristic for being difficult to large-scale operation and processing for taking charge of him of improvement, for example, its lower glass transition temperatures, suction
It is moist and lack crystallinity and its characteristic that cannot flow freely causes it is particularly difficult to process and prepares (such as to prepare in flakes
Agent), patent document WO2009/135179A2 discloses that (such as silica derives than Si Ta and some solid carrier particles
Thing) merge using to improve its physical characteristic.The present inventor has found that support control is tighter in this improvement project under study for action
It is severe, such as granular size, there is certain difficulty to production industrialization.
Therefore, this area stills need his salt of new comparable department of the exploitation with more advantage performances or its crystal form, is particularly
In hygroscopicity, stability, machinability etc., to overcome solid pharmaceutical preparation to the granular size of active constituents of medicine, carrier-mediated
Strict demand in terms of matter.
The content of the invention
Purpose according to the present invention, the present invention provide shown than Si Tapamo hydrochlorates, its structural formula such as formula (I)：
Nuclear magnetic resonance spectroscopy (1HNMR) shown with high-efficient liquid phase analysis (HPLC) characterization, the comparable Si Tapamo hydrochlorates
It than Si Ta and Pa Mo acid with molar ratio is about 1 to be:1 compound formed.
Purpose according to the present invention, the present invention provide the preparation method of the comparable Si Tapamo hydrochlorates, it includes following step
Suddenly：Formed respectively than solution system of the Si Ta and Pa Mo acid in soluble solvent, the molar ratio than Si Ta and Pa Mo acid is
1:1~1:2, two solution systems of mixing are stirred, and when holding 1~8 is small under 10~60 DEG C of operation temperature, and then are removed
Solvent, obtains the comparable Si Tapamo hydrochlorates.
Preferably, the soluble solvent is selected from tetrahydrofuran, dimethyl sulfoxide or its mixture.
Preferably, the concentration of the comparable Si Ta and Pa Mo acid in soluble solvent be operation temperature under its described solvable
0.5~1 times of solubility in solvent.
Preferably, solvent is removed using the method that is spin-dried for；It is highly preferred that the temperature for being spin-dried for method is 10 DEG C~60 DEG C.
" stirring ", using the conventional method of this area, agitating mode includes magnetic agitation, mechanical agitation etc., stirring
Speed is 50~1800 revs/min, is preferably 300~900 revs/min.
In the preparation method of above-mentioned comparable Si Tapamo hydrochlorates, starting material can be according to patent document than Si Ta
The method that WO2010/115000A2 embodiments 14 describe is prepared.
Purpose according to the present invention, the present invention provide a kind of amorphous article of above-mentioned comparable Si Tapamo hydrochlorates.
One representative instance of the amorphous article of the comparable Si Tapamo hydrochlorates has X-ray powder as shown in Figure 2
Diffraction pattern.
Detected by differential thermal analysis (DSC), the amorphous article of the comparable Si Tapamo hydrochlorates has glass transition temperature
Spend for 68 DEG C, it is known that his free state of comparable department glass transition temperature less than room temperature, than taking charge of his 1- hydroxy-2-naphthoic acids
The glass transition temperature of salt is 42 DEG C and is 61 DEG C than the glass transition temperature of his gentisate of department.Therefore, it is of the invention
Comparable Si Tapamo hydrochlorates amorphous article there is more preferable heat endurance, its bin stability and processing stability are also more preferable.
The FTIR spectrum of the amorphous article of the comparable Si Tapamo hydrochlorates wave number for 1711,1635,1566,
1510th, 1446,1392,1337,1259,1230,1049,909,809,751 and 700cm-1Place has characteristic peak.
In the present invention, " amorphous article " refers to what is confirmed by shown X-ray powder diffraction figure characterization, wherein
Without can be by the amorphous material of X-ray powder diffraction analysis and characterization.It will be appreciated by those skilled in the art that experimental error therein
The preparation of condition, sample and the purity of sample depending on instrument.Well known to those skilled in the art, X-ray powder diffraction figure is led to
It can often be changed with the condition of instrument, the relative intensity at peak may also change with the change of experiment condition, peak angle
The experimental error of degree should also be considered into, allow generally for ± 0.2 error.Further, since height of specimen etc. experiment because
The influence of element, can cause the overall offset of peak angle degree, allow generally for certain offset.Thus, those skilled in the art can manage
Solution, any solid-state form consistent with X-ray powder diffraction figure of the present invention is within the scope of the present invention.
In specific embodiments of the present invention, " amorphous article " is that one kind can flow freely, is easy to process and match somebody with somebody
The powder of system, eliminates the material of glassy state, rubbery state and colloidal state in " amorphous article ".
Comparable the Si Tapamo hydrochlorates and its amorphous article of the present invention has following beneficial property：
1. with it is known than take charge of his amorphous article, than taking charge of his 1- hydroxy-2-naphthoic acids salt and than taking charge of his gentianic acid
Salt is compared, and comparable Si Tapamo hydrochlorates and its amorphous article of the invention have the hygroscopicity of smaller.
2. placed 6 months in 25 DEG C, 60%RH environment, it is known that his amorphous article of comparable department, than take charge of his 1- hydroxyls-
2- naphthoates and it is transformed into grease by original solid than his gentisate is taken charge of, and under the same terms, it is of the invention
Original powder type is still kept than Si Tapamo hydrochlorates and its amorphous article, phase in version does not occur, is had preferably long-term
Stability.
3. comparable the Si Tapamo hydrochlorates and its amorphous article of the present invention place 4 in the drier of 10%~90%RH
Month, the property such as its appearance, XRPD collection of illustrative plates, hygroscopicity is all constant, illustrates the comparable Si Tapamo hydrochlorates of the present invention and its unformed
The excellent storage stability of thing.
Above-mentioned beneficial property shows：Compared with known comparable Si Ta and its salt, its amorphous article, comparable department of the invention
Ta Pamo hydrochlorates and its amorphous article have more excellent physical and chemical performance, especially excellent in terms of hygroscopicity, stability, machinability
Gesture is notable, is more suitable for the active ingredient of solid pharmaceutical preparation, can preferably resist the processes such as medicine manufacture and/or storage
In the problems such as active component content as caused by the factors such as environment temperature, humidity is uneven, purity reduces, impurity increase, reduce
Thus the effect of bringing downside risk and security risk, and be conducive to the accurate quantitative analysis in medicine manufacture, improve preparation homogeneity,
And facilitate the storage and transport in later stage.
Purpose according to the present invention, the present invention provide the preparation method of the amorphous article of the comparable Si Tapamo hydrochlorates, its
Comprise the following steps：By the comparable Si Tapamo hydrochlorates of the present invention in C6~C7Suspension is formed in alkane and is stirred, by precipitation
Solid separation, drying, obtain the amorphous article of the comparable Si Tapamo hydrochlorates.
The C6~C7Alkane includes n-hexane, hexamethylene, normal heptane, hexahydrotoluene or its mixture；Preferably, institute
State C6~C7Alkane is selected from n-hexane, normal heptane or its mixture.
Preferably, than Si Tapamo hydrochlorates and C in the suspension6~C7The mass volume ratio of alkane is 10~50mg:
1mL。
Preferably, the temperature of the stirring is 10 DEG C~60 DEG C；More preferably room temperature.
Preferably, the time of the stirring is 1~5 day；More preferably 1~3 day.
" room temperature " refers to 10~30 DEG C.
" stirring ", can use the conventional method of this area, and agitating mode includes magnetic agitation, mechanical agitation etc.,
Mixing speed is 50~1800 revs/min, is preferably 300~900 revs/min.
" separation " and " drying ", can use the conventional method of this area.Separation method can be filtering or centrifugation.
" filtering " is usually to be filtered at ambient temperature with the pressure less than atmospheric pressure, and preferably pressure is less than 0.09MPa.Institute
The concrete operations for stating " centrifugation " are：It is intended to separated sample to be placed in centrifuge tube, high speed centrifugation, until solid is all sink to centrifugation
Bottom of the tube.Drying means can be air drying, be dried under reduced pressure or forced air drying, drying equipment is fume hood, vacuum drying oven or
Convection oven.Drying temperature is 10~60 DEG C, is preferably 10~40 DEG C；It is preferably 10~48 when drying time is 10~72 small
Hour, more preferably 10~24 it is small when.It is preferred that being dried under reduced pressure, pressure is preferably smaller than 0.09MPa.
The methods of comparable Si Tapamo hydrochlorates amorphous article of the present invention can also be by being spray-dried, being freeze-dried
To be prepared.
Purpose according to the present invention, the present invention provide a kind of pharmaceutical composition, and it includes treatment and/or the sheet of prevention effective dose
Comparable the Si Tapamo hydrochlorates or its amorphous article of invention or the comparable Si Tapamo hydrochlorates obtained by preparation method of the present invention
Or its amorphous article, and at least one pharmaceutically acceptable carrier.Optionally, described pharmaceutical composition can include other
Pharmaceutically useful comparable Si Ta or its salt or amorphous article, for example, it is including but not limited to known than department he, comparable his lemon of department
Lemon hydrochlorate, tartrate, oxalates, fumarate, hydrochloride, lactate, phosphate, sulfate, malate, 1- hydroxyls-
2- naphthoates, toluene fulfonate, bromate, dichloroacetate, naphthalene sulfonate, camsilate, nicotinate, hippurate,
Esilate, malonate, succinate, ketoglutarate, benzoate, benzene sulfonate, ethanedisulphonate, o-benzoyl sulphur
Imide salts, ascorbate, maleate, gentisate or its amorphous article.Optionally, described pharmaceutical composition can wrap
Containing one or more other pharmaceutically useful therapeutic agents, such as including but not limited to hiv protease inhibitor, hiv reverse transcriptase are non-
Nucleosidic inhibitors, hiv reverse transcriptase nucleosidic inhibitors, the class of hiv reverse transcriptase nucleotide inhibitor and hiv integrase inhibitor
Type, the instantiation of these other therapeutic agents are such as referred to patent document WO2013106732A1, CN101679325A and disclose
Content.
It, can be administered mammalian hosts such as human patient, be suitable for using a variety of by described pharmaceutical composition
The method of administration of selection.Suitable method of administration includes oral, rectum, nose, local (including mouth containing and sublingual), vagina and non-
Enteron aisle (including it is subcutaneous, in machine, intravenously, and intradermal, intrathecal and Epidural cavity) etc..It is appreciated that preferable approach can be according to example
Change as received the difference of illness.The advantages of the compounds of this invention, is them to be orally bioavailable and can be with
It is administered orally.
Therefore, can be by the composition of the present invention and one or more pharmaceutically acceptable components, such as inert diluent
Or assimilable usable carrier combination medicine-feeding.They can be encapsulated in hard or soft shell gelatin capsules, they can be pressed
Tablet is made or they can be directly incorporated into the food of patient's meals., can be by active ingredient for oral therapeutic administration
Thing merges and can take in tablet, buccal tablet, ingot with one or more carriers, optional one or more other therapeutic agents
The forms such as agent, capsule, elixir, supensoid agent, syrup, wafer, pill use.This composition and preparation are typically
Include at least 0.1% reactive compound.Certainly, the percentage of composition and preparation can change, and can advantageously specify single
About the 2%~6% of position formulation weight.The amount of reactive compound makes it possible to obtain effective agent in the useful composition of this treatment
Amount is horizontal.
Acceptable carrier includes but not limited in described pharmaceutical composition Chinese pharmacology：Adhesive, such as hydroxy propyl cellulose
Element, povidone or hydroxypropyl methyl cellulose；Filler, for example, microcrystalline cellulose, pregelatinized starch, starch, mannitol or
Lactose monohydrate；Disintegrant, such as cross-linked carboxymethyl cellulose sodium, crospovidone or primojel；Lubricant, such as
Magnesium stearate, stearic acid or other metallic stearates；Glidant, such as cataloid etc.；And sweetener, such as sugarcane
Sugar, fructose, lactose or aspartame or flavouring, such as peppermint, wintergreen or Cherry flavor can be added.Work as unit dosage forms
When being capsule, it can also include liquid-carrier, such as vegetable oil or polyethylene glycol in addition to materials of the above type.It is various other
Material can be used as coating to exist, or change solid unit preparation with other physical forms.For example, can use gelatin, polymer,
Wax, shellac or sugar etc. are to tablet, pill or capsule coating.Certainly, it is used to prepare the arbitrary substance of arbitrary unit preparation typically
It is pharmaceutically acceptable and substantially non-toxic under usage amount.Furthermore, it is possible to composition incorporation preparation and dress by the present invention
Put.
Described pharmaceutical composition can use that well known to a person skilled in the art method to prepare.Preparing pharmaceutical composition
When, comparable Si Tapamo hydrochlorates or its amorphous article of the invention and one or more pharmaceutically acceptable carriers, optional
One or more other therapeutic agents mix.Solid pharmaceutical preparation can be prepared by the technique such as directly mixing, pelletizing.
Purpose according to the present invention, the present invention provides comparable Si Tapamo hydrochlorates of the present invention or its amorphous article or
Comparable the Si Tapamo hydrochlorates or its amorphous article that are obtained by preparation method of the present invention or the comparable Si Tapa containing the present invention
The foregoing pharmaceutical composition of hydrochlorate or its amorphous article is not being prepared for treatment and/or pre- preventing virus infection, such as HIV infection
Medicine in purposes.Comparable the Si Tapamo hydrochlorates or its amorphous article of the present invention can be used for improving the AntiHIV1 RT activity being co-administered
The pharmacokinetics of medicine, such as by suppressing cytochrome P 450 monooxygenases.
Purpose according to the present invention, the present invention provide a kind for the treatment of and/or pre- preventing virus infection, the method for such as HIV infection,
Including patient in need is given effective dose selected from the present invention comparable Si Tapamo hydrochlorates or its amorphous article, by
Comparable Si Tapamo hydrochlorates or its amorphous article that preparation method of the present invention obtains or the comparable Si Tapamo acid containing the present invention
The combination of the foregoing pharmaceutical composition of salt or its amorphous article and one or more other therapeutic agents, other treatments
Agent refers to be metabolized by cytochrome P 450 monooxygenases and is suitable for treating virus infection, the therapeutic agent of such as HIV infection, example
Such as include but not limited to hiv protease inhibitor, hiv reverse transcriptase non-nucleosidic inhibitors, hiv reverse transcriptase nucleosidic inhibitors,
The type of hiv reverse transcriptase nucleotide inhibitor and hiv integrase inhibitor, the instantiation of these other therapeutic agents for example may be used
With with reference to patent document WO2013106732A1, CN101679325A disclosure.Under any circumstance, this hair given
The effective dose of bright active component depends on treating property, the toxicity of illness, either with precautionary approach use compound (compared with
Low dosage) or for active type disease or illness, delivering method and pharmaceutical preparation, and pressed by clinician using convention amount
Ratio, which rises, to be determined.It is anticipated that effective dose is about 0.0001~about 100mg/kg body weight/days.In general, about
0.01~about 10mg/kg body weight/days.More generally, about 0.01~about 5mg/kg body weight/days.More generally, about 0.05~about
0.5mg/kg body weight/days.For example, the daily candidate dosage of the adult of about 70kg weight 1mg~1000mg or 5mg~
500mg and single dose or multiple dose administration can be used.
Brief description of the drawings
Fig. 1 is known than the XRPD collection of illustrative plates for taking charge of his amorphous article.
Fig. 2 is XRPD collection of illustrative plates of the present invention than the amorphous article of Si Tapamo hydrochlorates.
Fig. 3 is IR collection of illustrative plates of the present invention than the amorphous article of Si Tapamo hydrochlorates.
Embodiment
It will be helpful to further understand the present invention by following embodiments, but be not used in the limitation present invention.The implementation
Preparation method and application of the present invention than Si Tapamo hydrochlorates salt and its amorphous article are described in detail in example.To people in the art
Member is it is readily apparent that many changes for both material and method can be implemented without departing from the present invention.
Instrument and method used in gathered data：
Instrument used in X-ray powder diffraction (XRPD) is Bruker D8Advance Diffractometer, configuration
There are θ -2 θ angular instruments, Mo monochromators, Lynxeye detectors.Acquisition software is Diffrac Plus XRPD Commander.Instrument
Standard items (generally corundum) calibration that device is carried with instrument before use.Testing conditions are：2 3~40 ° of θ scanning angles scopes,
0.02 ° of step-length, 0.2 second/step of speed.Detection process：Ka X-ray of the copper target wavelength for 1.54nm is used, in 40kV and 40mA
Operating condition under, sample is tested at ambient temperature, and the sample that needs are detected is placed on areflexia plate.Except non-specifically saying
Bright, sample is not ground before detection.
It is Thermal that differential thermal analysis (DSC) data, which are picked up from TA Instruments Q200MDSC, instrument control software,
Advantage, analysis software are Universal Analysis.Usually take 1~10mg sample be positioned over it is uncapped (unless special
Do not mentionlet alone bright) aluminium crucible in, with the programming rate of 10 DEG C/min under the protection of 40mL/min drying nitrogens by sample from room temperature
Rise to 150 DEG C, while thermal change of the TA software records samples in temperature-rise period.
The adsorption analysis of dynamic moisture content (DVS) data are picked up from
Thermal Advantage, analysis software are Universal Analysis.The sample of 1~10mg is usually taken to be positioned over platinum
In crucible, TA software records sample relative humidity from 20% to 80% to the weight change in 20% change procedure, draw etc.
Warm adsorption curve.According to the concrete condition of sample, can also different absorption and De contamination step be used to sample.
Infrared spectrum analysis (IR) data are picked up from BrukerTensor 27, instrument control software and Data Analysis Software
All it is OPUS, generally use ATR equipment, in 600-4000cm-1In the range of gather infrared absorption spectroscopy, sample and blank background
Sweep time is 16 seconds, instrumental resolution 4cm-1。
Nuclear magnetic resonance spectroscopy (1HNMR) data are picked up from BrukerAvance II DMX 500M HZ NMR spectrums
Instrument.1-5mg samples are weighed, are dissolved with 0.5mL deuterated dimethyl sulfoxides, are made into the solution of 2mg/mL-10mg/mL.
High-efficient liquid phase analysis (HPLC) data are picked up from Agilent 1260.Using C18 chromatographic columns, 50mm × 4.6mm, column
30 DEG C, wavelength 220nm, flow velocity 1.0mL/min of temperature, sample size 3 μ L, run time 5min.Mobile phase A is 0.05% trifluoro second
Aqueous acid, Mobile phase B be 0.05% trifluoroacetic acid acetonitrile solution, gradient such as following table：
| Time (min) | A (%) | B (%) |
| 0 | 70 | 30 |
| 2 | 10 | 90 |
| 4.5 | 10 | 90 |
| 4.51 | 70 | 30 |
| 5 | 70 | 30 |
Indicated except no special, embodiment operates at room temperature.
Various reagents used are commercially available purchase unless otherwise instructed in embodiment.
Ultrasound procedure in embodiment is conducive to the dissolving of sample, and equipment is ultrasonic cleaner, generally uses 40Khz work(
Rate ultrasound 5min.
Preparation example 1Known comparable his preparation of department
It is prepared by the method that known comparable Si Ta can be described according to patent document WO2010/115000A2 embodiments 14.Tool
Body is：
Into solution of the L- thiazole morpholine ethyl ester oxalates (36.5kg) in water (66.0kg), dichloromethane is added
(264kg), is then slowly added into 15wt%KHCO3Solution (184.8kg).By obtained mixture stir about 1 it is small when.Separation
Each layer, and wash organic layer with water (132kg).Organic layer is concentrated under vacuum to drying.Water (26.5kg) is added by content
Temperature adjustment is then slowly added into 45%KOH solution (9.8kg), while maintain contents temperature to be less than or wait to about 10 DEG C
In 20 DEG C.Less than or equal to 20 DEG C, mixture is stirred, until judging that reaction terminates by HPLC.Reaction is concentrated under vacuum
Mixture co-evaporates 5 times to drying with dichloromethane (each 132kg) under reduced pressure to drying.Continuation and dichloromethane
(132kg) is co-evaporated, until measuring water content by Karl Fischer titration<4%.Add other dichloromethane
(264kg), contents temperature is adjusted to -18 DEG C to -20 DEG C, then adds single-amido acid ester HCl salt (26.4kg).Will
Obtained mixture is when -18 DEG C to -20 DEG C stir abouts 1 are small.HOBt (11.4kg) is added, and by reaction mixture again -18
DEG C to -20 DEG C of stir abouts 1 it is small when.By the solution (- 20 of precoolings of the EDCHCl (21.4kg) in dichloromethane (396kg)
DEG C) add in reaction mixture, while maintain contents temperature to be less than or equal to -20 DEG C.In -18 DEG C to -20 DEG C stirring reactions
Mixture, until judging that reaction terminates.Contents temperature is adjusted to about 3 DEG C, and with 10wt% aqueous citric acid solutions (290kg)
Reaction mixture is quenched.Each layer is separated, organic layer is washed 1 time with 15wt% potassium bicarbonate solutions (467kg) and water (132kg).
Organic layer is concentrated under reduced pressure, is then co-evaporated with absolute ethyl alcohol, that is, is obtained than taking charge of him.
1H-NMR(500MHz,d6-DMSO):1.31(d,6H),1.40-1.55(m,4H),1.62(m,1H),1.75(m,
1H),2.10-2.35(m,6H),2.55-2.70(m,4H),2.88(s,3H),3.22(m,1H),3.45-3.57(m,4H),
3.59-3.68(m,1H),3.85-3.97(m,1H),4.08-4.10(m,1H),4.46(s,2H),5.16(s,2H),6.60(d,
1H),7.06-7.22(m,12H),7.51(d,1H),7.86(s,1H),9.07(s,1H).It is shown as comparable and takes charge of him.
Preparation example 2The known preparation than his amorphous article of department
The known method that can be described than his amorphous article of department according to patent document WO2012/151165A1 embodiments 1
Prepare.Specially：
Taking 3.4g, he is dissolved in 12.2g toluene than department, under stirring condition, adds 122g toluene, when 5 DEG C of stirrings 1 are small,
It is filtered under diminished pressure, when room temperature in vacuo drying 24 is small, that is, obtains than taking charge of his amorphous article.
XRPD collection of illustrative plates is as shown in Figure 1.
Preparation example 3The known preparation than his 1- hydroxy-2-naphthoic acid salt of department
7mL dichloromethane is added after 2.0g is mixed than Si Ta and 485mg1- hydroxy-2-naphthoic acids, ultrasonic dissolution, is stirred
Under the conditions of mixing, add 50mL methyl tertiary butyl ether(MTBE)s, be stirred at room temperature 2 it is small when, be filtered under diminished pressure, that is, obtain than taking charge of his 1- hydroxyls -2-
Naphthoate.
1H-NMR(500MHz,d6-DMSO):1.31(d,6H),1.40-1.55(m,4H),1.62(m,1H),1.75(m,
1H),2.10-2.35(m,6H),2.55-2.70(m,4H),2.88(s,3H),3.22(m,1H),3.45-3.57(m,4H),
3.59-3.68(m,1H),3.85-3.97(m,1H),4.08-4.10(m,1H),4.46(s,2H),5.26(s,2H),6.60(d,
1H),7.06-7.22(m,12H),7.25-7.40(m,2H),7.56(t,1H),7.58(d,1H),7.70(d,1H),7.96(s,
1H),8.00-8.14(m,2H),9.07(s,1H)。
Preparation example 4The known preparation than his gentisate of department
Add 10mL isopropanols after 1.5g is mixed than Si Ta and 298mg gentianic acids, ultrasonic dissolution, under stirring condition,
Add 20mL normal heptanes, be stirred at room temperature 3 it is small when, be filtered under diminished pressure, that is, obtain than taking charge of his gentisate.
1H-NMR(500MHz,d6-DMSO):1.31(d,6H),1.40-1.55(m,4H),1.62(m,1H),1.75(m,
1H),2.10-2.35(m,6H),2.55-2.70(m,4H),2.88(s,3H),3.22(m,1H),3.45-3.57(m,4H),
3.59-3.68(m,1H),3.85-3.97(m,1H),4.08-4.10(m,1H),4.46(s,2H),5.20(s,2H),6.60-
6.65(m,2H),6.85(d,1H),7.06-7.22(m,12H),7.48(d,1H),7.55(d,1H),7.90(s,1H),9.07
(s,1H).
Embodiment 1
Take 100mg preparation examples 1 prepare comparable department he, addition 1mL tetrahydrofuran ultrasonic dissolutions；Pa not acid 50mg is taken, is added
Enter 3.8mL tetrahydrofuran ultrasonic dissolutions；Under stirring condition, by pa, sour tetrahydrofuran solution is not added dropwise to than his tetrahydrochysene of department
In tetrahydrofuran solution, when 60 DEG C of stirrings 1 are small, 10 DEG C are spin-dried for removing solvent, when 40 DEG C of vacuum drying 10 are small, obtain the present invention than department
Ta Pamo hydrochlorates.Yield is 144mg, yield 96.0%.
HPLC characterization displays, comparable Si Ta and Pa Mo acid are about 1 with molar ratio:1 into than Si Tapamo hydrochlorates.
1H-NMR characterization displays, comparable Si Ta and Pa Mo acid are about 1 with molar ratio:1 into than Si Tapamo hydrochlorates.1H-
NMR(500MHz,d6-DMSO):1.31(d,6H),1.40-1.55(m,4H),1.62(m,1H),1.75(m,1H),2.10-
2.35(m,6H),2.55-2.70(m,4H),2.88(s,3H),3.22(m,1H),3.45-3.57(m,4H),3.59-3.68(m,
1H),3.85-3.97(m,1H),4.08-4.10(m,1H),4.46(s,2H),4.74(s,2H),5.18(s,2H),6.60(d,
1H),7.06-7.22(m,12H),7.26(d,2H),7.53(d,1H),7.63(d,2H),7.75(d,2H),7.88(s,1H),
8.16(d,2H),8.33(s,2H),9.07(s,1H).
Embodiment 2
His amorphous article of comparable department for taking 150mg preparation examples 2 to prepare, adds 3.0mL tetrahydrofuran ultrasonic dissolutions；Take pa
Not acid 113mg, adds 3.8mL dimethyl sulfoxide ultrasonic dissolutions；Under stirring condition, the not sour dimethyl sulfoxide solution of pa is added dropwise to can
Than in his tetrahydrofuran solution of department, when 30 DEG C of stirrings 5 are small, 40 DEG C are spin-dried for removing solvent, when 30 DEG C of vacuum drying 24 are small, obtain
The present invention is than Si Tapamo hydrochlorates.Yield is 212mg, yield 94.2%.
Embodiment 3
Take 450mg preparation examples 1 prepare comparable department he, addition 15.0mL dimethyl sulfoxide ultrasonic dissolutions；Take pa not sour
450mg, adds 9.0mL dimethyl sulfoxide ultrasonic dissolutions；Under stirring condition, by pa, sour dimethyl sulfoxide solution is not added dropwise to than department
In his dimethyl sulfoxide solution, when 10 DEG C of stirrings 8 are small, 60 DEG C are spin-dried for removing solvent, when 10 DEG C of vacuum drying 48 are small, obtain this hair
Bright comparable Si Tapamo hydrochlorates.Yield is 614mg, yield 90.9%.
Embodiment 2,3 samples and 1 sample of embodiment have the same or similar HPLC and1HNMR testing results, illustrate real
It is identical material to apply example 2,3 samples and 1 sample of embodiment.
Embodiment 4
Comparable Si Tapamo hydrochlorates prepared by the 100mg present invention are taken, 10mL normal heptanes is added and forms suspension, 10 DEG C of stirrings
3 days, it is filtered under diminished pressure, when 40 DEG C of vacuum drying 10 are small, obtains amorphous article powder of the present invention than Si Tapamo hydrochlorates.Yield
For 96mg, yield 96.0%.
XRPD collection of illustrative plates is as shown in Figure 2.
IR collection of illustrative plates is as shown in Figure 3.
HPLC characterization displays, comparable Si Ta and Pa Mo acid are about 1 with molar ratio:1 into than Si Tapamo hydrochlorates.
1H-NMR characterization displays, comparable Si Ta and Pa Mo acid are about 1 with molar ratio:1 into than Si Tapamo hydrochlorates.
Embodiment 5
Comparable Si Tapamo hydrochlorates prepared by the 150mg present invention are taken, 10mL n-hexanes is added and forms suspension, 25 DEG C of stirrings
3 days, it is filtered under diminished pressure, when 30 DEG C of vacuum drying 16 are small, obtains amorphous article powder of the present invention than Si Tapamo hydrochlorates.Yield
For 142mg, yield 94.7%.
Embodiment 6
Comparable Si Tapamo hydrochlorates prepared by the 300mg present invention are taken, 10mL normal heptanes is added and forms suspension, 30 DEG C of stirrings
1 day, it is filtered under diminished pressure, when 10 DEG C of vacuum drying 24 are small, obtains amorphous article powder of the present invention than Si Tapamo hydrochlorates.Yield
For 279mg, yield 93.0%.
Embodiment 7
Take comparable Si Tapamo hydrochlorates prepared by the 450mg present invention, add 10mL hexahydrotoluenes and form suspension, 50 DEG C
Stirring 4 days, is filtered under diminished pressure, and when 50 DEG C of vacuum drying 48 are small, obtains amorphous article powder of the present invention than Si Tapamo hydrochlorates.
Yield is 379mg, yield 84.2%.
Embodiment 8
Comparable Si Tapamo hydrochlorates prepared by the 500mg present invention are taken, 10mL hexamethylenes is added and forms suspension, 60 DEG C of stirrings
5 days, it is filtered under diminished pressure, when 60 DEG C of vacuum drying 72 are small, obtains amorphous article powder of the present invention than Si Tapamo hydrochlorates.Yield
For 394mg, yield 78.8%.
5~8 sample of embodiment and 4 sample of embodiment have the same or similar XRPD collection of illustrative plates, IR collection of illustrative plates, HPLC and1HNMR testing results, illustrate that 5~8 sample of embodiment and 4 sample of embodiment are identical materials.
Embodiment 9
Tablet (every the comparable department containing 150mg he) formula is as follows：
The amorphous article of the comparable Si Tapamo hydrochlorates of the present invention：225.0mg
Cataloid：1.0mg
Microcrystalline cellulose：188.0mg
Hydroxypropyl cellulose：9.0mg
Ac-Di-Sol：22.5mg
Magnesium stearate:4.5mg
Amount to：450.0mg
The preparation process of tablet is as follows：
By the amorphous article of the comparable Si Tapamo hydrochlorates of the present invention and cataloid, microcrystalline cellulose, hydroxypropyl
Cellulose, Ac-Di-Sol, magnesium stearate, which are uniformly mixed, is placed on tabletting in tablet press machine, adjustment sheet weight, up to phase
Tablet is answered, prepares 1000 altogether.
Embodiment 10
Tablet (every the comparable department containing 100mg he) formula is as follows：
The amorphous article of the comparable Si Tapamo hydrochlorates of the present invention：150.0mg
Lactose：52.5mg
Povidone：15.0mg
Ac-Di-Sol：12.0mg
Microcrystalline cellulose：67.5mg
Magnesium stearate:3.0mg
Amount to：300.0mg
The preparation process of tablet is as follows：
The amorphous article of the comparable Si Tapamo hydrochlorates of the present invention is uniformly mixed with lactose using equal increments method, then
With microcrystalline cellulose, Ac-Di-Sol, povidone, magnesium stearate after mixing, tabletting in tablet press machine is placed in, is adjusted
Nodal plate weight, up to respective tablets, prepares 1000 altogether.
Embodiment 11
Tablet (every the comparable department containing 20.0mg he) formula is as follows：
The amorphous article of the comparable Si Tapamo hydrochlorates of the present invention：30.0mg
Microcrystalline cellulose：400.0mg
Starch：50.0mg
Primojel：15.0mg
Magnesium stearate:5.0mg
Amount to：500.0mg
The preparation process of tablet is as follows：
The amorphous article of the comparable Si Tapamo hydrochlorates of the present invention is mixed with microcrystalline cellulose using equal increments method
Uniformly, then with starch, primojel, magnesium stearate after mixing, it is placed in tabletting in tablet press machine, adjustment sheet weight, to obtain the final product
Respective tablets, prepare 1000 altogether.
Embodiment 12
Capsule (every comparable department containing 10.0mg he) formula is as follows：
The amorphous article of the comparable Si Tapamo hydrochlorates of the present invention：15.0mg
Cataloid：1.5mg
Lactose：460.5mg
Pregelatinized starch：120.0mg
Magnesium stearate:3.0mg
Amount to：600.0mg
The preparation process of capsule is as follows：
By amorphous article and the pregelatinized starch of comparable the Si Tapamo hydrochlorates of the present invention, lactose, cataloid, firmly
Fatty acid magnesium is uniformly mixed to be placed in dry granulating machine and pelletizes, and obtained dry particl is inputted in capsule filling machine and pours into capsule,
Up to corresponding capsule, 1000 are prepared altogether.
Comparative example 1
The amorphous article of the comparable Si Tapamo hydrochlorates of the invention prepared and comparable Si Tapamo hydrochlorates, preparation example 2 is taken to make
His 1- hydroxy-2-naphthoic acids salt of comparable department prepared by his amorphous article of standby comparable department, preparation example 3 and the preparation of preparation example 4 can
Than his gentisate of department, hygroscopicity and long-term stable experiment are carried out.
The wettability test：Detected and obtained by DVS adsorption isothermal curves, taken in 20%~80% RH range
Weight change value.
The long-term stable experiment：By the way that sample is positioned over 25 DEG C, in the environment of 60%RH, observation sample is long-term
Cosmetic variation under experiment condition, and detect the XRPD collection of illustrative plates of sample.
It the results are shown in Table 1.
1 hygroscopicity of table and long-time stability contrast
As seen from the results in Table 1：Compared by the hygroscopicity in 20%~80% RH range, it can be seen that the present invention
Comparable Si Tapamo hydrochlorates and its amorphous article hygroscopicity it is more known than take charge of his amorphous article, than taking charge of his 1- hydroxyls
Base -2- naphthoates and than taking charge of his gentisate hygroscopicity smaller.Pass through the long-time stability ratio under the conditions of 25 DEG C, 60%RH
It is more known compared with the long-time stability of, it can be seen that comparable Si Tapamo hydrochlorates and its amorphous article of the invention than taking charge of his nothing
Shape thing, than taking charge of his 1- hydroxy-2-naphthoic acids salt and more preferable than his gentisate is taken charge of.
All patent documents that this specification is quoted, quoting in being incorporated herein in a manner of its full text.
The above, is only the specific embodiment of the invention, but the scope of the present invention is not limited thereto, any to be familiar with
Those skilled in the art disclosed herein technical scope in, without the change that creative work is expected or can replace
Change, should all cover within the scope of the present invention.
Claims (10)
1. comparable Si Tapamo hydrochlorate of the structural formula as shown in formula (I)
2. than the preparation method of Si Tapamo hydrochlorates described in a kind of claim 1, it comprises the following steps：Formed respectively comparable
He and solution system of the Pa Mo acid in soluble solvent are taken charge of, is 1 than the molar ratio of Si Ta and Pa Mo acid:1~1:2, mixing two
A solution system is stirred, kept under 10~60 DEG C of operation temperature 1~8 it is small when, and then remove solvent, obtain it is described can
Than Si Tapamo hydrochlorate.
3. according to claim 2 than the preparation method of Si Tapamo hydrochlorates, it is characterised in that the soluble solvent is selected from
Tetrahydrofuran, dimethyl sulfoxide or its mixture, the concentration of the comparable Si Ta and Pa Mo acid in soluble solvent is operation temperature
It is lower its 0.5~1 times of solubility in the soluble solvent, solvent is removed using the method that is spin-dried for.
4. than the amorphous article of Si Tapamo hydrochlorates described in a kind of claim 1, it is characterised in that the comparable Si Tapamo
The amorphous article of hydrochlorate has X-ray powder diffraction figure substantially as shown in Figure 2.
5. according to claim 4 than the amorphous article of Si Tapamo hydrochlorates, it is characterised in that the comparable Si Tapamo
The FTIR spectrum of the amorphous article of hydrochlorate wave number for 1711,1635,1566,1510,1446,1392,1337,
1259th, 1230,1049,909,809,751 and 700cm-1Place has characteristic peak.
6. a kind of preparation method of the amorphous article of claim 4 or 5 comparable Si Tapamo hydrochlorates, it includes following step
Suddenly：The comparable Si Tapamo hydrochlorates that the preparation method according to Claims 2 or 3 is obtained are in C6~C7Formed and suspended in alkane
Liquid simultaneously stirs, and by solid separation, the drying of precipitation, obtains the amorphous article than Si Tapamo hydrochlorates.
7. according to claim 6 than Si Tapamo hydrochlorates amorphous article preparation method, it is characterised in that the C6
~C7Alkane is selected from n-hexane, normal heptane or its mixture, than Si Tapamo hydrochlorates and C in the suspension6~C7Alkane
Mass volume ratio is 10~50mg:1mL, the temperature of the stirring is 10 DEG C~60 DEG C, and the time of the stirring is 1~5 day.
8. a kind of pharmaceutical composition, it includes treatment and/or prevention effective dose selected from described in claim 1 than Si Tapamo
Comparable Si Tapamo hydrochlorates that hydrochlorate, the preparation method according to any one of claim 2~3 obtain, claim 4~5
Any one of the amorphous article than Si Tapamo hydrochlorates or the preparation method according to any one of claim 6~7
The amorphous article of obtained comparable Si Tapamo hydrochlorates, and at least one pharmaceutically acceptable carrier.
9. pharmaceutical composition according to claim 8, it is characterised in that described pharmaceutical composition is selected from Orally-administrable
Tablet, lozenge, capsule, elixir, supensoid agent, syrup, wafer or pill.
10. than Si Tapamo hydrochlorates, preparation method obtains according to any one of claim 2~3 described in claim 1
Comparable Si Tapamo hydrochlorates, any one of claim 4~5 than the amorphous article of Si Tapamo hydrochlorates, according to power
Profit requires the amorphous article or claim 8~9 for the comparable Si Tapamo hydrochlorates that preparation method any one of 6~7 obtains
Any one of pharmaceutical composition prepare be used for treat the medicine of HIV infection in purposes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410747242.7A CN105732538B (en) | 2014-12-09 | 2014-12-09 | Than Si Tapamo hydrochlorates and preparation method thereof, pharmaceutical composition and purposes |
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| CA2865491A1 (en) * | 2012-03-01 | 2013-09-06 | Gilead Sciences, Inc. | Spray dried formulations |
| WO2014057498A2 (en) * | 2012-10-08 | 2014-04-17 | Mylan Laboratories Ltd. | Process for the preparation of cobicistat intermediates |
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Effective date of registration: 20190821 Address after: 310018 Room 2B05, Building 452, No. 6 Street, Hangzhou Economic and Technological Development Zone, Zhejiang Province Patentee after: Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd Address before: 310018 room 2B12, building 452, No. 6, Hangzhou Economic & Technological Development Zone, Hangzhou, Zhejiang, China Patentee before: HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY CO., LTD. |