CN106279122A - The salt of a kind of compound and crystal formation or amorphous article, its preparation method, containing their pharmaceutical composition and purposes - Google Patents
The salt of a kind of compound and crystal formation or amorphous article, its preparation method, containing their pharmaceutical composition and purposes Download PDFInfo
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- CN106279122A CN106279122A CN201610664633.1A CN201610664633A CN106279122A CN 106279122 A CN106279122 A CN 106279122A CN 201610664633 A CN201610664633 A CN 201610664633A CN 106279122 A CN106279122 A CN 106279122A
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- 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
- C07D403/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to the salt of solid-state pharmaceutically useful ((1S) 1 (((2S) 2 (5 (4 ' (2 ((2S) 1 ((2S) 2 ((methoxycarbonyl group) amino) 3 methylbutyryl bases) 2 pyrrolidinyls) 1H imidazoles 5 base) 4 xenyls) 1H imidazoles 2 base) 1 pyrrolidinyl) carbonyl) 2 methyl-propyls) methyl carbamate and crystal formation thereof and amorphous article, compared with prior art, the described specific salts of this compound and crystal formation and amorphous article thereof have slow release effect and the aqueous stability being substantially better than prior art, it is suitable for slow releasing preparation application, its preparation method simple process, carry out routine operation at ambient temperature, be conducive to the industrialization of product.The invention still further relates to described compound salt and crystal formation thereof and the preparation method of amorphous article, its pharmaceutical composition and for preparing the purposes in the medicine that treatment hepatitis C virus (HCV) is infected.
Description
The application is the Application No. 201480009595.5 (PCT/CN2014/ entering China on February 11st, 2015
071020, international filing date on January 21st, 2014) patent application " salt of a kind of compound and crystal formation or amorphous article, its system
Preparation Method, containing its drug regimen and purposes " divisional application.
Technical field
The invention belongs to field of pharmaceutical chemistry technology, in particular to hepatitis C medicine ((1S)-1-(((2S)-2-
(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl group) amino)-3-methylbutyryl base)-2-pyrrolidinyl)-1H-imidazoles-
5-yl)-4-xenyl)-1H-imidazoles-2-base)-1-pyrrolidinyl) carbonyl)-2-methyl-propyl) methyl carbamate salt and
Its crystal formation or amorphous article, the invention still further relates to described compound salt and the preparation method of crystal formation, its pharmaceutical composition and use
On the way.
Background technology
Daclatasvir, also known as BMS-790052, is by Bristol-Myers Squibb Co. (Bristol-Myers Squibb)
The one of exploitation treats the replication inhibitors that hepatitis C virus (HCV) infects.The chemical name of this compound is ((1S)-1-
(((2S)-2-(5-(4 '-(2-((2S)-1-((2S)-2-((methoxycarbonyl group) amino)-3-methylbutyryl base)-2-pyrrolidine
Base)-1H-imidazoles-5-base)-4-xenyl)-1H-imidazoles-2-base)-1-pyrrolidinyl) carbonyl)-2-methyl-propyl) amino first
Acid methyl ester, its chemical structural formula is as follows:
BMS-790052 chemical genetics method is defined as a kind of potent specificity HCV inhibitive factor, is the most known
One little molecules in inhibiting factor of the third viruses molecule (i.e. non-structural protein 5A, referred to as " NS5A ") of enzymatic activity.Hundred
The research worker of Shi Mei Shi Guibao company reports discovery and the virus characteristic thereof of this medicine, and discloses with this compound just
Clinical observation result conducted in normal healthy volunteer and HCV infection person.In vitro tests data show this medicine with
Synergistic action effect is had between the HCV suppression medicine known.In I clinical trial phase, HCV infection person takes single dose 100 milli
After gram this compound, 24 hourly average virus loads decline 3.3log10, in 2 example HCV genotype 1 b the infecteds, this effect
Maintain 120 hours.So this medicine is expected to become the new drug combination that potent suppression HCV replicates.
Patent documentation WO2009020828A1 discloses BMS-790052 compound and its dihydrochloride and their conjunction
One-tenth method, and disclose the crystal formation data of BMS-790052 dihydrochloride, DSC figure, solid state nmr light collection of illustrative plates and its medicine
The relevant information of compositions.
The present inventor repeats the method that the document provides, and has prepared the BMS-790052 dihydrochloride of the document.Should
In the water of salt, dissolubility is more than 200 mg/ml, but its aqueous solution is at room temperature placed 24 hours, occurs that solid separates out, solution
The phenomenon become cloudy, through HPLC content detection, separating out solid is BMS-790052 free alkali, in view of this phenomenon, BMS-790052
Dihydrochloride is not suitable for preparing slow releasing preparation.
Therefore, this area remain a need for exploitation can extend drug effect and be suitable to slow releasing preparation application new BMS-790052 salt and
Its form, such as crystal formation or amorphous article, to ensure that this medicine can play inhibitory action to virus in the patient for a long time, subtract
Few times for spraying and the clinical efficacy of raising patient.
Summary of the invention
For the deficiencies in the prior art, it is an object of the invention to provide and there is favourable slow release effect and more preferable aqueous solution
Stability, the solid-state BMS-790052 salt being suitable for slow releasing preparation application and crystal formation thereof or amorphous article, including BMS-
Two tosilate of 790052, diphenyl sulfonate, a citrate, a glycollate, two mandelates, two pairs of chlorobenzene sulphurs
Hydrochlorate, two ethanedisulphonates, two α-one-glutarate, two 1,5-napadisilates and two 2-naphthalene sulfonates.
One of present disclosure is to provide BMS-790052 bis-tosilate and the crystal formation thereof of solid-state, and they
Preparation method.
Described BMS-790052 bis-tosilate, is BMS-790052 and p-methyl benzenesulfonic acid is about 1:2 with mol ratio
The compound formed, its structural formula is as follows:
The preparation method of described BMS-790052 bis-tosilate, comprises the following steps: forms BMS-790052 and exists
Solution in soluble solvent, adds p-methyl benzenesulfonic acid solid, the mole dosage of BMS-790052 and p-methyl benzenesulfonic acid than for 1:2～
1:3, is mixed to form serosity and stirs, and then separates solid, obtains described BMS-790052 bis-tosilate.
Preferably, described soluble solvent is selected from ketone, alcohol or its mixture, preferably C3～C4Ketone, C1～C4Alcohol or its mixing
Thing, more preferably acetone, isopropanol or its mixture.
Preferably, described preparation method is at room temperature carried out.
Preferably, the time of described stirring is 8～16 hours.
Preferably, described BMS-790052 concentration in soluble solvent is 25～50 mg/ml.
Preferably, the mole dosage of described BMS-790052 and p-methyl benzenesulfonic acid is than for 1:2～1:2.2.
Measuring through HPLC, in described BMS-790052 bis-tosilate, the actual content of BMS-790052 free alkali is
67.6%, theoretical content is 68.3%.Show in described BMS-790052 bis-tosilate BMS-790052 free alkali with
P-methyl benzenesulfonic acid is about 1:2 with mol ratio and becomes salt.
Preferably, described BMS-790052 bis-tosilate is BMS-790052 bis-tosilate monohydrate
Crystal formation, its X-ray powder diffraction spectrum the angle of diffraction 2 θ be 5.1 ± 0.2 °, 6.3 ± 0.2 °, 13.4 ± 0.2 °, 14.6 ±
At 0.2 °, 15.4 ± 0.2 ° and 21.1 ± 0.2 °, there is characteristic peak.
Further, described BMS-790052 bis-tosilate monohydrate crystal form, its X-ray powder diffraction pattern
The angle of diffraction 2 θ be 5.1 ± 0.2 °, 6.3 ± 0.2 °, 10.2 ± 0.2 °, 10.7 ± 0.2 °, 13.4 ± 0.2 °, 13.7 ± 0.2 °,
At 14.6 ± 0.2 °, 15.4 ± 0.2 °, 18.3 ± 0.2 °, 19.2 ± 0.2 °, 19.9 ± 0.2 ° and 21.1 ± 0.2 °, there is feature
Peak.
Further, described BMS-790052 bis-tosilate monohydrate crystal form, its X-ray powder diffraction figure
Compose and there is at the following angle of diffraction 2 θ characteristic peak and relative intensity thereof:
Without limitation, a representative instance of described BMS-790052 bis-tosilate monohydrate crystal form has
X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 5.
The TGA collection of illustrative plates of described BMS-790052 bis-tosilate monohydrate crystal form shows: had about before 120 DEG C
2.0% step is weightless, suitable with containing hydrone weightlessness ratio (1.6%), and decomposition temperature is about 236 DEG C.
Described BMS-790052 bis-tosilate monohydrate crystal form DSC collection of illustrative plates shows: had a wide suction before 80 DEG C
Thermal spike, the endothermic peak between 80～150 DEG C is to slough the hydrone of combination.
The preparation method of described BMS-790052 bis-tosilate monohydrate crystal form, comprises the following steps: by root
BMS-790052 bis-tosilate obtained according to aforementioned preparation process forms suspension in a solvent, stirring and crystallizing, and then
Separating crystal, room temperature to 40 DEG C is vacuum dried, and obtains described BMS-790052 bis-tosilate monohydrate crystal form, wherein
Described solvent is selected from water, the ketone (V/V) containing 1% water, water saturated ester, water saturated ether or its mixture.
Preferably, described ketone is C3～C4Ketone, preferably acetone；Described ester is C3～C5Ester, preferably ethyl acetate；Institute
Stating ether is C4～C6Ether, preferably methyl tertiary butyl ether(MTBE).
Preferably, the preparation method of described BMS-790052 bis-tosilate monohydrate crystal form is at room temperature entered
OK.
Preferably, the time of described crystallize is 24～72 hours, preferably 24～48 hours.
Preferably, described drying time is 8～24 hours, preferably 8～16 hours.
Preferably, described BMS-790052 bis-tosilate is 10～16mg:1mL with the mass volume ratio of solvent.
Described water saturated ester (or ether) solvent preparation is: after taking isopyknic water and the mixing of ester (or ether) solvent,
It is stirred vigorously 10 minutes, stratification, takes organic layer and be water saturated ester (or ether) solvent.
Compare with known BMS-790052 dihydrochloride and crystal formation thereof, BMS-790052 bis-p-methyl benzenesulfonic acid of the present invention
The aqueous stability that the slow release effect that salt and monohydrate crystal form thereof have had is become reconciled, applicable slow releasing preparation application, it is prepared
Method simple process, carries out the industrialization of routine operation, beneficially product at ambient temperature.Particularly slow release effect and water-soluble
Liquid stability, can avoid active substance to exist in solid form and cause and absorb unstable and that bioavailability is low wind
Danger.
The two of present disclosure are to provide BMS-790052 diphenyl sulfonate and the crystal formation thereof of solid-state, and their system
Preparation Method.
Described BMS-790052 diphenyl sulfonate, is that BMS-790052 and benzenesulfonic acid are about, with mol ratio, the change that 1:2 is formed
Compound, its structural formula is as follows:
The preparation method of described BMS-790052 diphenyl sulfonate, comprises the following steps: form BMS-790052 solvable
Solution in solvent, adds benzenesulfonic acid solid, and the mole dosage of BMS-790052 and benzenesulfonic acid ratio for 1:2～1:3, is mixed to form
Serosity also stirs, and then separates solid, obtains described BMS-790052 diphenyl sulfonate.
Preferably, described soluble solvent is selected from ketone, alcohol or its mixture, preferably C3～C4Ketone, C1～C4Alcohol or its mixing
Thing, more preferably acetone, isopropanol or its mixture.
Preferably, described preparation method is at room temperature carried out.
Preferably, the time of described stirring is 8～16 hours.
Preferably, described BMS-790052 concentration in soluble solvent is 25～50 mg/ml.
Preferably, the mole dosage of described BMS-790052 and benzenesulfonic acid is than for 1:2～1:2.2.
Measuring through HPLC, in BMS-790052 diphenyl sulfonate, the actual content of BMS-790052 free alkali is 70.3%,
Theoretical content is 70.1%.Show in described BMS-790052 diphenyl sulfonate BMS-790052 free alkali and benzenesulfonic acid with mole
Salt is become than about 1:2.
Preferably, described BMS-790052 diphenyl sulfonate is BMS-790052 diphenyl sulfonate B crystal form, its X-ray powder
End diffracting spectrum the angle of diffraction 2 θ be 6.7 ± 0.2 °, 9.7 ± 0.2 °, 15.0 ± 0.2 °, 17.8 ± 0.2 °, 18.3 ± 0.2 ° and
At 22.1 ± 0.2 °, there is characteristic peak.
Further, described BMS-790052 diphenyl sulfonate B crystal form, its X-ray powder diffraction pattern is at the angle of diffraction 2 θ
Be 6.7 ± 0.2 °, 7.2 ± 0.2 °, 9.0 ± 0.2 °, 9.7 ± 0.2 °, 10.0 ± 0.2 °, 13.7 ± 0.2 °, 15.0 ± 0.2 °,
At 16.6 ± 0.2 °, 17.8 ± 0.2 °, 18.3 ± 0.2 °, 21.3 ± 0.2 ° and 22.1 ± 0.2 °, there is characteristic peak.
Further, described BMS-790052 diphenyl sulfonate B crystal form, its X-ray powder diffraction pattern is spread out following
There is at firing angle 2 θ characteristic peak and relative intensity thereof:
Without limitation, a representative instance of described BMS-790052 diphenyl sulfonate B crystal form has as shown in Figure 9
X-ray powder diffraction (XRPD) collection of illustrative plates.
The preparation method of described BMS-790052 diphenyl sulfonate B crystal form, comprises the following steps: will be according to aforementioned preparation side
The BMS-790052 diphenyl sulfonate that method obtains forms suspension, stirring and crystallizing in water, obtains described BMS-790052 hexichol
Sulfonate B crystal form.
Preferably, the preparation method of described BMS-790052 diphenyl sulfonate B crystal form is at room temperature carried out.
Preferably, the time of described crystallize is 10～24 hours.
Preferably, described BMS-790052 diphenyl sulfonate is 15～30mg:1mL with the mass volume ratio of water.
Compare with known BMS-790052 dihydrochloride and crystal formation thereof, the BMS-790052 diphenyl sulfonate of the present invention and
The aqueous stability that the slow release effect that its B crystal form has had is become reconciled, applicable slow releasing preparation application, the letter of its preparation method technique
Just, the industrialization of routine operation, beneficially product is carried out at ambient temperature.Particularly slow release effect and aqueous stability,
Active substance can be avoided to exist in solid form and cause and absorb unstable and that bioavailability is low risk.
The three of present disclosure are to provide BMS-790052 tri hydrochloride and the amorphous article thereof of solid-state, and they
Preparation method.
Described BMS-790052 tri hydrochloride, is that BMS-790052 and hydrochloric acid are about, with mol ratio, the compound that 1:3 is formed,
Its structure is as follows:
The preparation method of described BMS-790052 tri hydrochloride, comprises the following steps: form BMS-790052 solvable molten
Solution system in agent, adds hydrochloric acid, and the mole dosage of BMS-790052 and hydrochloric acid ratio for 1:3～1:10, is mixed to form serosity
And stir, and then separate solid, obtain described BMS-790052 tri hydrochloride.
Preferably, described soluble solvent is ester, more preferably C3～C5Ester.
Preferably, described preparation method is at room temperature carried out.
Preferably, the time of described stirring is 3～10 hours, more preferably 3～5 hours.
Preferably, described BMS-790052 concentration in soluble solvent is 10～50mg/mL.
Preferably, the mole dosage of described BMS-790052 and hydrochloric acid is than for 1:6～1:10.
Preferably, the concentration range of hydrochloric acid used is 0.1～12mol/L, more preferably 6～12mol/L.
Measuring through HPLC, in described BMS-790052 tri hydrochloride, the actual content of BMS-790052 free alkali is
87.6%, theoretical content is 87.1%.Show in described BMS-790052 tri hydrochloride BMS-790052 free alkali and hydrochloric acid with
Mol ratio is about 1:3 and becomes salt.
Preferably, described BMS-790052 tri hydrochloride is BMS-790052 hydrochlorate amorphous article.
Further, described BMS-790052 tri hydrochloride amorphous article, it is characterised in that its X-ray powder diffraction figure
Spectrum is substantially as shown in Figure shown in 13.
Described BMS-790052 tri hydrochloride amorphous article, its preparation method comprises the following steps: according to aforementioned preparation side
The BMS-790052 tri hydrochloride that method obtains forms suspension in a solvent, stirring, separates out solid, obtains described BMS-790052
Tri hydrochloride amorphous article, wherein said solvent is selected from alcohol, ester or ether.
Preferably, described alcohol is C2～C3Alcohol, more preferably isopropanol；
Preferably, described ester is C3～C5Ester, more preferably ethyl acetate；
Preferably, described ether is C4～C6Ether, more preferably methyl tertiary butyl ether(MTBE).
Preferably, the preparation method of described BMS-790052 tri hydrochloride amorphous article is at room temperature carried out.
Preferably, the time of described stirring is 8～48 hours, more preferably 8～16 hours.
Preferably, described BMS-790052 tri hydrochloride is 10～50mg:1mL with the mass volume ratio of solvent.
The BMS-790052 tri hydrochloride of the present invention and amorphous article thereof have dissolubility and stability in preferable water, suitable
Close wet granulation and make oral suspension, its preparation method simple process, carry out routine operation at ambient temperature, be conducive to
The industrialization of product.
In the process of the present invention, it was found that following BMS-790052 salt and crystal formation thereof, including a pair of BMS-790052
Toluene fulfonate, a benzene sulfonate, two citrates, diethanol hydrochlorate, malate, malonate, a mandelate, phosphoric acid
Salt, sulfate, tartrate, a closilate, an ethanedisulphonate, a α-one-glutarate, a 1,5-naphthalenedisulfonic acid
Salt and a 2-naphthalene sulfonate.
Described BMS-790052 malate, is BMS-790052 and the compound of malic acid formation.
The preparation method of described BMS-790052 malate, comprises the following steps: form BMS-790052 in acetone
Solution, add malic acid solid, be mixed to form serosity and stir, so separate solid, obtain described BMS-790052 Fructus Mali pumilae
Hydrochlorate.
Described BMS-790052 malonate, is BMS-790052 and the compound of malonic acid formation.
The preparation method of described BMS-790052 malonate, comprises the following steps: form BMS-790052 solvable molten
Solution in agent, adds malonic acid, is mixed to form serosity and stirs, and then separates solid, obtains described BMS-790052 the third two
Hydrochlorate.
Described BMS-790052 phosphate, is BMS-790052 and the compound of phosphoric acid formation.
Described BMS-790052 method for production of phosphate salt, comprises the following steps: form BMS-790052 in ethyl acetate
In solution, add phosphoric acid, be mixed to form serosity and stir, so separate solid, obtain described BMS-790052 phosphate.
Described BMS-790052 sulfate, is BMS-790052 and the compound of sulphuric acid formation.
The preparation method of described BMS-790052 sulfate, comprises the following steps: form BMS-790052 in ethyl acetate
In solution, add sulphuric acid, be mixed to form serosity and stir, so separate solid, obtain described BMS-790052 sulfate.
Described BMS-790052 tartrate, is BMS-790052 and the compound of tartaric acid formation.
The preparation method of described BMS-790052 tartrate, comprises the following steps: form BMS-790052 at isopropanol
In solution, add tartaric acid, be mixed to form serosity and stir, so separate solid, obtain described BMS-790052 tartaric acid
Salt.
In the preparation method of above-mentioned various BMS-790052 salt and crystal formation thereof, consolidating of gained BMS-790052 salt or its crystal formation
Body, uses the conventional method of this area to carry out separating and being dried.Described " separation ", uses the conventional method such as mistake of this area
Filter, be centrifuged.The concrete operations filtered are: the sample being intended to separate is placed on filter paper, and reduce pressure sucking filtration.Centrifugal concrete operations
For: the sample being intended to separate is placed in centrifuge tube, and high speed rotating is until solid is all sink to bottom centrifuge tube afterwards, centrifugation rate
For example, 6000 revs/min.The conventional method of described " being dried " employing this area, such as forced air drying, drying under reduced pressure etc., preferably
Pressure is less than the drying under reduced pressure under 0.09MPa.Baking temperature is room temperature～50 DEG C, about 10～72 hours drying times, preferably from about
10～24 hours.
The term used in the present invention is explained as follows:
The present invention uses " magma " crystallization mode, is by the supersaturated solution (with the presence of the suspension of insoluble solids) of sample
Dicyandiamide solution stirs with crystallize.
Described " room temperature " refers to 10-30 DEG C.
Described " stirring ", the conventional method of this area, such as alr mode can be used to include, and magnetic agitation, machinery stir
Mixing, mixing speed is 50～1800 revs/min, preferably 300～900 revs/min.
Described " ultrasonic " operates, and the beneficially dissolving of sample, concrete operations are: the container that will be equipped with solution or suspension is put
In ultrasonic cleaner, process with the power of 20～40Khz.General employing 40Khz power ultrasonic processes 5 minutes.
In the preparation method of BMS-790052 salt of the present invention or its crystal formation, initiation material BMS-790052 can be purchased and obtain
, it is also possible to obtaining with reference to preparation method disclosed in patent documentation WO2009020828A1, the document is the most also
Enter in the application.
Further, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises treatment and/or prevention is effective
The active constituents of medicine of amount is selected from the BMS-790052 salt of the present invention or its crystal formation or amorphous article or by the inventive method system
The standby BMS-790052 salt obtained or its crystal formation or amorphous article, and at least one pharmaceutically acceptable carrier；Wherein institute
State the BMS-790052 salt of the present invention or its crystal formation or amorphous article selected from BMS-790052 bis-tosilate, BMS-
790052 2 tosilate monohydrate crystal forms, BMS-790052 diphenyl sulfonate, BMS-790052 diphenyl sulfonate B are brilliant
Type, BMS-790052 mono-citrate, BMS-790052 mono-citrate amorphous article, BMS-790052 mono-glycollate,
BMS-790052 mono-glycollate amorphous article, BMS-790052 bis-mandelate, BMS-790052 bis-mandelate are unformed
Thing, BMS-790052 bis-closilate, BMS-790052 bis-closilate C crystal form, BMS-790052 diethyl two sulphur
Hydrochlorate, BMS-790052 bis-ethanedisulphonate crystal form E, BMS-790052 bis-α-one-glutarate, BMS-790052 bis-α-one-
Glutarate G crystal formation, BMS-790052 bis-1,5-napadisilate, BMS-790052 bis-1,5-napadisilate Nd crystal formation,
BMS-790052 bis-2-naphthalene sulfonate, BMS-790052 bis-2-naphthalene sulfonate Ns crystal formation, BMS-790052 tri hydrochloride, BMS-
790052 tri hydrochloride amorphous articles, BMS-790052 malate, BMS-790052 malonate, BMS-790052 phosphoric acid
Salt, BMS-790052 sulfate or BMS-790052 tartrate.Additionally, described pharmaceutical composition can also comprise BMS-
Other pharmaceutically useful salt, crystal formation or the amorphous article of 790052, such as known BMS-790052 dihydrochloride and crystal formation thereof.Appoint
Selection of land, described pharmaceutical composition can also comprise other active constituents of medicine, includes but not limited to other anti-HCV activity
Compound；Immunomodulator, such as interferons；Other antiviral agents such as ribavirin, amantadine；Other of NS5A press down
Preparation；The inhibitor of other targets in HCV life cycle.
Pharmaceutical composition of the present invention can be solid-state or liquid；Dosage form such as solid oral dosage form, including tablet,
Granule, powder, pill and capsule；Liquid oral dosage form, including solution, syrup, suspensoid, dispersant and Emulsion；Nothing
Bacterium injectable formulation, including solution, dispersant and lyophilized preparation；Formula may be adapted to the quickly release of active component, postpones release
Or regulation release.It can be conventional, dispersible, masticable, Orally dissolving or the preparation of rapid melting.Route of administration
Can be administered by oral, parenteral or by implanting reservoir, described parenteral include subcutaneous, Intradermal, intravenous,
In intramuscular, intraarticular, intrasynovial, breastbone, in sheath and intralesional injection or infusion techn.If this pharmaceutical composition is liquid, then
The BMS-790052 salt of the present invention or its crystal formation or amorphous article remain solid in this fluid composition, such as suspending
Liquid.
On described pharmaceutical composition Chinese materia medica, acceptable carrier includes but not limited to: diluent, such as starch, modified shallow lake
Powder, lactose, Powderd cellulose, microcrystalline Cellulose, calcium phosphate dibasic anhydrous, tricalcium phosphate, mannitol, sorbitol, sugar etc.；Bonding
Agent, such as arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, poly-second
Glycol, copolyvidone etc.；Disintegrating agent, such as starch, carboxymethyl starch sodium, sodium starch glycollate, pregelatinized Starch, crosslinking gather
Dimension ketone, cross-linking sodium carboxymethyl cellulose, silica sol etc.；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, benzene
Sodium formate, sodium acetate etc.；Fluidizer, such as silica sol etc.；Complex forming agents, the cyclodextrin of the most various ranks and
Resin；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose
Element, methylcellulose, methyl methacrylate, wax etc..Other available pharmaceutically acceptable carriers include but not limited to into
Membrane, plasticizer, coloring agent, flavoring agent, viscosity modifier, preservative, antioxidant etc..In the case of oral tablet, logical
The carrier often used includes lactose and corn starch, it is also possible to add lubricant such as magnesium stearate；Situation at oral capsule
In, useful carriers/diluents includes lactose, height and low molecular poly and dried corn starch；When being administered orally with suspension
During administration, described active component mixes with emulsifying agent and suspending agent；It is possible if desired to add some sweeting agent and/or seasoning
Agent and/or coloring agent.
Described pharmaceutical composition can use the method for well known to a person skilled in the art to prepare.Preparing pharmaceutical composition
Time, the BMS-790052 salt of the present invention or its crystal formation or amorphous article mix mutually with one or more pharmaceutically acceptable carriers
Close, optionally, mix mutually with the other drug active component of one or more.Solid preparation can be by directly mixing, granulation
Prepare etc. technique.
Further, the present invention provides BMS-790052 bis-tosilate of the present invention, BMS-790052 bis-
Tosilate monohydrate crystal form, BMS-790052 diphenyl sulfonate, BMS-790052 diphenyl sulfonate B crystal form, BMS-
790052 1 citrates, BMS-790052 mono-citrate amorphous article, BMS-790052 mono-glycollate, BMS-790052
One glycollate amorphous article, BMS-790052 bis-mandelate, BMS-790052 bis-mandelate amorphous article, BMS-
790052 2 closilate, BMS-790052 bis-closilate C crystal form, BMS-790052 bis-ethanedisulphonate,
BMS-790052 bis-ethanedisulphonate crystal form E, BMS-790052 bis-α-one-glutarate, BMS-790052 bis-α-one-1,3-propanedicarboxylic acid
Salt G crystal formation, BMS-790052 bis-1,5-napadisilate, BMS-790052 bis-1,5-napadisilate Nd crystal formation, BMS-
790052 2 2-naphthalene sulfonates, BMS-790052 bis-2-naphthalene sulfonate Ns crystal formation, BMS-790052 tri hydrochloride, BMS-790052
Tri hydrochloride amorphous article, BMS-790052 malate, BMS-790052 malonate, BMS-790052 phosphate, BMS-
790052 sulfate or BMS-790052 tartrate infect for treatment and/or prevention of hepatitis C (HCV) in preparation
Medicine in purposes.
Further, the present invention provides one to treat the method that hepatitis C virus (HCV) infects, described method include to
Give the patient treatment of needs and/or prevention effective dose selected from selected from the BMS-790052 salt of the present invention or its crystal formation or unformed
Thing or the present invention containing BMS-790052 salt or its crystal formation or the pharmaceutical composition of amorphous article；Wherein, the described present invention
BMS-790052 salt or its crystal formation or amorphous article are selected from BMS-790052 bis-tosilate, BMS-790052 bis-to toluene
Sulfonate monohydrate crystal form, BMS-790052 diphenyl sulfonate, BMS-790052 diphenyl sulfonate B crystal form, BMS-790052
One citrate, BMS-790052 mono-citrate amorphous article, BMS-790052 mono-glycollate, BMS-790052 mono-ethanol
Hydrochlorate amorphous article, BMS-790052 bis-mandelate, BMS-790052 bis-mandelate amorphous article, BMS-790052 bis-are right
Closilate, BMS-790052 bis-closilate C crystal form, BMS-790052 bis-ethanedisulphonate, BMS-790052 bis-
Ethanedisulphonate crystal form E, BMS-790052 bis-α-one-glutarate, BMS-790052 bis-α-one-glutarate G crystal formation, BMS-
790052 2 1,5-napadisilates, BMS-790052 bis-1,5-napadisilate Nd crystal formation, BMS-790052 bis-2-LOMAR PWA EINECS 246-676-2
Salt, BMS-790052 bis-2-naphthalene sulfonate Ns crystal formation, BMS-790052 tri hydrochloride, BMS-790052 tri hydrochloride are unformed
Thing, BMS-790052 malate, BMS-790052 malonate, BMS-790052 phosphate, BMS-790052 sulfate or
BMS-790052 tartrate.
Accompanying drawing explanation
The XRPD figure of the BMS-790052 dihydrochloride crystal formation that Fig. 1 is prepared according to WO2009020828A1
The PLM figure of the BMS-790052 dihydrochloride crystal formation that Fig. 2 is prepared according to WO2009020828A1
The TGA figure of the BMS-790052 dihydrochloride crystal formation that Fig. 3 is prepared according to WO2009020828A1
The DSC figure of the BMS-790052 dihydrochloride crystal formation that Fig. 4 is prepared according to WO2009020828A1
The XRPD figure of Fig. 5 BMS-790052 bis-tosilate monohydrate crystal form
The PLM figure of Fig. 6 BMS-790052 bis-tosilate monohydrate crystal form
The TGA figure of Fig. 7 BMS-790052 bis-tosilate monohydrate crystal form
The DSC figure of Fig. 8 BMS-790052 bis-tosilate monohydrate crystal form
The XRPD figure of Fig. 9 BMS-790052 diphenyl sulfonate B crystal form
The PLM figure of Figure 10 BMS-790052 diphenyl sulfonate B crystal form
The TGA figure of Figure 11 BMS-790052 diphenyl sulfonate B crystal form
The DSC figure of Figure 12 BMS-790052 diphenyl sulfonate B crystal form
The XRPD figure of Figure 13 BMS-790052 tri hydrochloride amorphous article
The PLM figure of Figure 14 BMS-790052 tri hydrochloride amorphous article
The TGA figure of Figure 15 BMS-790052 tri hydrochloride amorphous article
The DSC figure of Figure 16 BMS-790052 tri hydrochloride amorphous article
The Accumulation dissolution curve chart of Figure 17 embodiment 21 tablet 1～3
Detailed description of the invention
The present invention is with further reference to following example, and described embodiment describes the salt of the present invention, crystal formation and unformed in detail
Thing, its preparation method and application.It will be apparent for a person skilled in the art that the many changes for material and method
Can implement without departing from the present invention.
Gather instrument used by data and method:
The instrument that X-ray powder diffraction (XPRD) is used is Bruker D8Advance diffractometer, adopts
By the Ka X-ray that copper target wavelength is 1.54nm, under the operating condition of 40kV and 40mA, θ-2 θ clinometer, Mo monochromator,
Lynxeye detector.Instrument is calibrated with corundum before use.Acquisition software is Diffrac Plus XRD Commander.
Sample is tested at ambient temperature, and the sample needing detection is placed on areflexia plate.Testing conditions in detail is as follows, angle model
Enclose: 3 40 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.2 second/step.
Polarization light microscope (PLM) collection of illustrative plates picks up from XP-500E micropolariscope (the Shanghai limited public affairs of rectangular optical instrument
Department).Take a small amount of powder sample to be placed on microscope slide, drip a small amount of mineral oil with preferably dispersed powders sample, covered,
Then sample is placed on the object stage of XP-500E micropolariscope (Shanghai rectangular optical instrument company limited), selects
The suitably pattern of amplification observing samples taking pictures.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200MDSC, and instrument control software is Thermal
Advantage, analyzing software is Universal Analysis.The sample generally taking 1～10 milligram is positioned in aluminum dish, with 10
DEG C/programming rate of min is dried N at 40mL/min2Protection under sample is risen to 200 DEG C or 300 DEG C from room temperature.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500TGA, and instrument control software is Thermal
Advantage, analyzing software is Universal Analysis.Take 5～15mg samples to be positioned in platinum crucible, use segmentation
High resolution detection mode, is dried N with 10 DEG C/min programming rate at 40mL/min2Under protection, sample is risen to 400 DEG C from room temperature.
Nmr analysis (NMR) data are picked up from Bruker Ascend Tm 500.Full range is generally used to excite, spectrum width
30ppm, pulse, 30 ° of angles excite, and scan 16 times, and digitized quadrature detects, temperature control 298K.
Release data are picked up from RC806 dissolving-out tester, and dissolving-out method is attached with reference to " Chinese Pharmacopoeia 2010 editions " second
Record X, dissolution algoscopy the first method.Parameter is set to: rotating speed 100 revs/min, experimental temperature 37.0 DEG C, the consumption of dissolution medium
500mL, is respectively 1 hour, 6 hours and 12 hours sample time.The detection of data and collection are high-efficient liquid phase analysis instrument
(HPLC).Release screening index is shown in Table 1.
Table 1 release screening index
High-efficient liquid phase analysis (HPLC) data are picked up from and in Waters 2695/2487, instrument control software and analysis software are
Empower.Use C18 chromatographic column, 150mm × 4.6mm, column temperature 25 DEG C, wavelength 210nm, flow velocity 1.0ml/min, sample size
5ul, runs time 15min.Mobile phase A is the water containing 0.05% trifluoroacetic acid, and Mobile phase B is acetonitrile, gradient such as table 2.
Table 2HPLC gradient condition
Single punch tablet machine, tableting pressure is 5MPa, and tablet diameters is 10mm.
Various reagent used in embodiment are commercially available purchase if no special instructions.
Indicate, in the examples below unless special: ultrasound procedure uses 40Khz power ultrasonic 5 minutes；Stirring operation with
300～900 revs/min carry out magnetic agitation；The speed of centrifugally operated is 6000 revs/min.
Preparation example 1
BMS-790052 trip is prepared according to compound (I) crystal seed preparation method disclosed in patent documentation WO2009020828A1
From alkali, as initiation material, concrete operations are as follows:
60.0g (105mmol, 1 equivalent) 4,4 '-two (2-((S)-pyrrolidinyl-2-base)-1H-imidazoles-5-base) is joined
Benzene, 38.7g (221mmol, 1 equivalent) N-(methoxycarbonyl group)-Valine, 44.5g (232mmol, 2.2 equivalents) 1-(3-diformazan
Aminopropyl)-3-ethyl-carbodiimide hydrochloride, 2.89g (21.4mmol, 0.2 equivalent) I-hydroxybenzotriazole join
In 300mL acetonitrile, add 73.3mL (420.3mmol, 4 equivalents) diisopropylethylamine after dispersed with stirring, stir at 24～30 DEG C
Mix about 18 hours.Add 60mL water, be heated to 50 DEG C and reach about 5 hours.After being cooled to room temperature, add 320mL ethyl acetate and
300mL water, isolated organic layer 300mL10wt% sodium bicarbonate aqueous solution, 300mL water and 200mL10wt% sodium chloride
Solution washing.Organic layer anhydrous magnesium sulfate is dried, and filters, and concentrates, obtains thick product.Flash chromatography post method is utilized to carry
Pure (silica gel, 0～10% methanol in dichloromethane), obtain BMS-790052 free alkali.
Nucleus magnetic hydrogen spectrum data:1H NMR (d6-DMSO, 500MHz): 0.86 (d, 6H, J=6.5Hz), 0.92 (d, 6H, J=
6.5Hz), 1.80-2.08 (m, 6H), 2.08-2.22 (s, 4H), 3.55 (s, 6H), 3.81 (m, 4H), 4.08 (t, 2H, J=
8.5Hz), 5.10 (t, 2H), 7.30 (d, 2H, J=8.5Hz), 7.52 (m, 2H), 7.66 (d, 4H, J=8.0Hz), 7.79 (d,
4H, J=8.0Hz), 11.78 (s, 2H).
Comparative example 1
BMS-790052 bis-is prepared according to compound (I) crystal seed preparation method disclosed in patent documentation WO2009020828A1
Hydrochlorate, concrete operations are as follows:
At 20 DEG C, BMS-790052 free alkali (3.0g) is dissolved in 100.0mL isopropanol.Add anhydrous hydrochloric acid ethanol molten
Liquid (7.0mL, 1.25M concentration), stirs reactant mixture.Methyl tertiary butyl ether(MTBE) (100.0mL), gained is added in described solution
Serosity is stirred vigorously 12 hours at 40 DEG C～50 DEG C.The serosity having crystallization being cooled to 20 DEG C, filters, solid is at 20 DEG C of wind
Dry, obtain 2.77g BMS-790052 dihydrochloride white crystalline solid, productivity 84.0%.
XRPD collection of illustrative plates is as it is shown in figure 1, show: this salt is crystalline solid.
PLM collection of illustrative plates is as in figure 2 it is shown, show: this salt is smaller piece shape granule, random.
TGA collection of illustrative plates is as it is shown on figure 3, show: decomposition temperature is about 236 DEG C.
DSC collection of illustrative plates as shown in Figure 4, shows: fusing point is 251 DEG C.
Under room temperature, this salt dissolubility in water is more than 200 mg/ml, and powder dissolution in 5 minutes is more than 95%.
With WO2009020828A1 disclosed in compared with BMS-790052 dihydrochloride crystal formation, the BMS-of comparative example 1 preparation
790052 dihydrochloride samples have 2 θ characteristic peaks, XRPD collection of illustrative plates and the DSC collection of illustrative plates of same or analogous XRPD.Comparative example is described
1 sample has identical crystal formation with the BMS-790052 dihydrochloride of WO2009020828A1.
Embodiment 1The preparation of BMS-790052 bis-tosilate
Under room temperature, take the BMS-790052 free alkali of 500mg preparation example 1 preparation, add ultrasonic dissolution after 10mL acetone, add
Enter 256mg anhydrous p-methyl benzenesulfonic acid solid in the acetone soln of BMS-790052 free alkali, form serosity and also stir, stir 16
After hour, filtering, filter cake 40 DEG C is vacuum dried 16 hours, obtains 521mg BMS-790052 bis-tosilate, productivity
71.1%.
Measuring through HPLC, in BMS-790052 bis-tosilate, the actual content of BMS-790052 free alkali is
67.6%, theoretical content is 68.3%.Testing result shows: in BMS-790052 bis-tosilate, BMS-790052 dissociates
Alkali is about 1:2 with p-methyl benzenesulfonic acid with mol ratio and becomes salt.
Embodiment 2The preparation of BMS-790052 bis-tosilate
Under room temperature, take the BMS-790052 free alkali of 50.0mg preparation example 1 preparation, ultrasonic molten after adding 2.0mL isopropanol
Solve, in addition 23.2mg anhydrous p-methyl benzenesulfonic acid solid to the aqueous isopropanol of BMS-790052 free alkali, form serosity and also stir
Mixing, after stirring 8 hours, filter, filter cake 40 DEG C is vacuum dried 16 hours, obtains 51.5mg BMS-790052 bis-tosilate,
Productivity 70.3%.
The sample of embodiment 2 preparation has and embodiment 1 sample same or analogous HPLC testing result (not shown), says
Bright embodiment 2 sample and embodiment 1 sample are identical materials.
Embodiment 3The preparation of BMS-790052 mono-tosilate
Under room temperature, take the BMS-790052 free alkali of 200mg preparation example 1 preparation, add ultrasonic dissolution after 4mL acetone, take
The anhydrous p-methyl benzenesulfonic acid of 51.2mg, adds ultrasonic dissolution after 0.8mL acetone, the acetone soln of p-methyl benzenesulfonic acid is slowly added dropwise to
In the acetone soln of BMS-790052 free alkali, and stir, after reacting 16 hours, have solid to separate out, filter, 40 DEG C of vacuum drying
16 hours, obtain 160mg BMS-790052 mono-tosilate, productivity 65.1%.
Embodiment 4The preparation of BMS-790052 bis-tosilate monohydrate crystal form
Under room temperature, take BMS-790052 bis-tosilate prepared by the 320mg present invention, add 20ml water, formed outstanding
Supernatant liquid.Stirring 24 hours, filter, filter cake is vacuum dried 16 hours at 40 DEG C, obtains 285mgBMS-790052 bis-tosilate
Monohydrate crystal form, productivity 87.6%.
XRPD collection of illustrative plates is as shown in Figure 5: this salt is crystalline solid.
PLM collection of illustrative plates is as shown in Figure 6: this salt is smaller particle, random.
TGA collection of illustrative plates is as shown in Figure 7: had about 2.0% step weightless before 120 DEG C, and containing a hydrone weightlessness ratio phase
When, decomposition temperature is about 236 DEG C.
DSC collection of illustrative plates is as shown in Figure 8: having a wide endothermic peak before 80 DEG C, the endothermic peak between 80～150 DEG C is for sloughing combination
Hydrone.
Embodiment 5The preparation of BMS-790052 bis-tosilate monohydrate crystal form
Under room temperature, take BMS-790052 bis-tosilate prepared by the 80mg present invention, add the third of 8ml aqueous 1%
Ketone (V/V), forms suspension.Stirring 24 hours, filter, filter cake is vacuum dried 8 hours at 40 DEG C, obtains 65.6mgBMS-790052
Two tosilate monohydrate crystal forms, productivity 80.7%.
Embodiment 6The preparation of BMS-790052 bis-tosilate monohydrate crystal form
Under room temperature, take BMS-790052 bis-tosilate prepared by the 50mg present invention, add the water saturated acetic acid of 5ml
Ethyl ester, forms suspension.Stirring 48 hours, filter, filter cake is dried 16 hours at room temperature in vacuo, obtains 42.3mgBMS-790052 bis-
Tosilate monohydrate crystal form, productivity 83.2%.
Embodiment 7The preparation of BMS-790052 bis-tosilate monohydrate crystal form
Under room temperature, take BMS-790052 bis-tosilate prepared by the 250mg present invention, add the water saturated first of 25ml
Base tertbutyl ether, forms suspension.Stirring 72 hours, filter, filter cake is dried 24 hours at room temperature in vacuo, obtains 195mgBMS-
790052 2 tosilate monohydrate crystal forms, productivity 76.7%.
The sample of embodiment 5～7 preparation has and embodiment 4 sample same or analogous XRPD collection of illustrative plates, PLM collection of illustrative plates, DSC
Collection of illustrative plates and TGA collection of illustrative plates (not shown).Illustrate that embodiment 5～7 sample and embodiment 4 sample are identical materials.
Embodiment 8The preparation of BMS-790052 diphenyl sulfonate
Under room temperature, take the BMS-790052 free alkali of 250.0mg preparation example 1 preparation, add 5mL acetone solution, add
117.5mg benzenesulfonic acid, in the acetone soln of BMS-790052 free alkali, forms serosity and also stirs, after stir 16 hours, and filtration,
Filter cake 40 DEG C is vacuum dried 16 hours, obtains 275mg BMS-790052 diphenyl sulfonate, productivity 77.0%.
Measuring through HPLC, in BMS-790052 diphenyl sulfonate, the actual content of BMS-790052 free alkali is 70.3%,
Theoretical content is 70.1%.Testing result shows: BMS-790052 free alkali and benzenesulfonic acid in BMS-790052 diphenyl sulfonate
It is about 1:2 with mol ratio and becomes salt.
Embodiment 9The preparation of BMS-790052 diphenyl sulfonate
Under room temperature, take the BMS-790052 free alkali of 50.0mg preparation example 1 preparation, add 2mL isopropanol and dissolve, take
21.4mg benzenesulfonic acid, adds ultrasonic dissolution after 0.2mL isopropanol, is slowly added dropwise the aqueous isopropanol of benzenesulfonic acid to BMS-
In the aqueous isopropanol of 790052 free alkalis, forming serosity and stir, stirring 8 hours, filtering, filter cake 40 DEG C vacuum drying 16 is little
Time, obtain 52.3mg BMS-790052 diphenyl sulfonate, productivity 73.3%.
The sample of embodiment 9 preparation has and embodiment 8 sample same or analogous HPLC testing result (not shown).Say
Bright embodiment 9 sample and embodiment 8 sample are identical materials.
Embodiment 10The preparation of BMS-790052 mono-benzene sulfonate
Under room temperature, take the BMS-790052 free alkali of 50.0mg preparation example 1 preparation, add 2mL isopropanol and dissolve, take
12.7mg benzenesulfonic acid, adds ultrasonic dissolution after 0.2mL isopropanol, is slowly added dropwise the aqueous isopropanol of benzenesulfonic acid to BMS-
In the aqueous isopropanol of 790052 free alkalis, separating out solid, filter after stirring 8 hours, filter cake 40 DEG C is vacuum dried 16 hours,
45.1mg BMS-790052 mono-benzene sulfonate, productivity 74.3%.
Embodiment 11The preparation of BMS-790052 diphenyl sulfonate B crystal form
Under room temperature, take BMS-790052 diphenyl sulfonate prepared by the 180mg present invention, add 12ml water, form suspension.
Stirring 10 hours, filter, filter cake is vacuum dried 16 hours at 40 DEG C, obtains 153mg BMS-790052 diphenyl sulfonate B crystal form, produces
Rate 85.0%.
XRPD collection of illustrative plates is as shown in Figure 9: this salt is crystalline solid.
PLM collection of illustrative plates is as shown in Figure 10: this salt is relatively large shape granule, irregularly.
TGA collection of illustrative plates is as shown in figure 11: having about 8.0% step weightless before 200 DEG C, decomposition temperature is about 251 DEG C.
DSC collection of illustrative plates is as shown in figure 12: had a wide endothermic peak before 120 DEG C, has an endothermic peak between 120～180 DEG C.
Embodiment 12The preparation of BMS-790052 diphenyl sulfonate B crystal form
Under room temperature, take BMS-790052 diphenyl sulfonate prepared by the 300mg present invention, add 1ml water, form suspension.
Stirring 24 hours, filter, filter cake is vacuum dried 16 hours at 40 DEG C, obtains 272mg BMS-790052 diphenyl sulfonate B crystal form, produces
Rate 90.7%.
The sample of embodiment 12 preparation has and embodiment 11 sample same or analogous XRPD collection of illustrative plates, PLM collection of illustrative plates, DSC
Collection of illustrative plates and TGA collection of illustrative plates (not shown).Illustrate that embodiment 12 sample and embodiment 11 sample are identical materials.
Embodiment 13The preparation of BMS-790052 tri hydrochloride
Under room temperature, take the BMS-790052 free alkali of 500.0mg preparation example 1 preparation, add 10mL acetic acid ethyl dissolution, add
Enter the concentrated hydrochloric acid of 0.56mL 12mol/L in the ethyl acetate solution of BMS-790052 free alkali, form serosity and also stir, stir
After mixing 3 hours, filtering, 40 DEG C are vacuum dried 16 hours, obtain 485.8mg BMS-790052 tri hydrochloride, productivity 84.6%.
Measuring through HPLC, in BMS-790052 tri hydrochloride, the actual content of BMS-790052 free alkali is 87.6%, reason
Opinion content is 87.1%.Testing result shows: in BMS-790052 tri hydrochloride BMS-790052 free alkali and hydrochloric acid with mole
Salt is become than about 1:3.
Embodiment 14The preparation of BMS-790052 tri hydrochloride
Under room temperature, take the BMS-790052 free alkali of 250.0mg preparation example 1 preparation, add 25mL isopropyl acetate and dissolve,
Add the hydrochloric acid of 10mL0.1mol/L in the isopropyl acetate solution of BMS-790052 free alkali, form serosity and also stir, stir
After mixing 10 hours, filtering, 40 DEG C are vacuum dried 16 hours, obtain 233.5mg BMS-790052 tri hydrochloride, productivity 81.4%.
Embodiment 15The preparation of BMS-790052 tri hydrochloride
Under room temperature, take the BMS-790052 free alkali of 450.0mg preparation example 1 preparation, add 9mL acetic acid ethyl dissolution, add
Enter 0.61mL6mol/L hydrochloric acid in the ethyl acetate solution of BMS-790052 free alkali, form serosity and also stir, stir 5 hours
After, filter, 40 DEG C are vacuum dried 16 hours, obtain 427.6mg BMS-790052 tri hydrochloride, productivity 82.8%.
The sample of embodiment 14,15 preparation has and (does not shows with embodiment 13 sample same or analogous HPLC testing result
Go out).Illustrate that embodiment 14,15 sample and embodiment 13 sample are identical materials.
Embodiment 16The preparation of BMS-790052 tri hydrochloride amorphous article
Under room temperature, take BMS-790052 tri hydrochloride prepared by the 400mg present invention, add 8ml isopropanol, formed and suspend
Liquid.Stirring 8 hours, filter, filter cake is vacuum dried 16 hours at 40 DEG C, obtains 379.3mg BMS-790052 tri hydrochloride unformed
Thing, productivity 94.8%.
As shown in figure 13, this salt is amorphous article to XRPD collection of illustrative plates.
PLM collection of illustrative plates as shown in figure 14, shows: this salt fine particle, random.
TGA collection of illustrative plates as shown in figure 15, shows: having about 5.1% slow weightlessness before 100 DEG C, decomposition temperature is about 171 DEG C.
DSC collection of illustrative plates as shown in figure 16, shows: had a wide endothermic peak before 140 DEG C.
Embodiment 17The preparation of BMS-790052 tri hydrochloride amorphous article
Under room temperature, take BMS-790052 tri hydrochloride prepared by the 200mg present invention, add 5ml ethyl acetate, formed and suspend
Liquid.Stirring 16 hours, filter, filter cake is vacuum dried 16 hours at 40 DEG C, obtains 185.4mg BMS-790052 tri hydrochloride without fixed
Type thing, productivity 92.7%.
Embodiment 18The preparation of BMS-790052 tri hydrochloride amorphous article
Under room temperature, take BMS-790052 tri hydrochloride prepared by the 300mg present invention, add 30ml methyl tertiary butyl ether(MTBE), shape
Become suspension.Stirring 48 hours, filter, filter cake is vacuum dried 16 hours at 40 DEG C, obtains 256.4mg BMS-790052 tri-hydrochloric acid
Salt amorphous article, productivity 85.5%.
Embodiment 17,18 preparation sample have with embodiment 16 sample same or analogous XRPD collection of illustrative plates, PLM collection of illustrative plates,
DSC collection of illustrative plates and TGA collection of illustrative plates (not shown).Illustrate that embodiment 17,18 sample and embodiment 16 sample are identical materials.
Embodiment 19Tablet formulation and preparation thereof
The tablet formulation of the present invention is shown in Table 3 and table 4.
Table 3 tablet formulation one
The preparation method of tablet formulation one: take the API of recipe quantity, hypromellose (K4M), pregelatinized Starch, a water
Lactose, microcrystalline Cellulose and magnesium stearate mix homogeneously are placed on tabletting in tablet machine.
Table 4 tablet formulation two
The preparation method of tablet formulation two: take the API of recipe quantity, hypromellose (E5), lactose monohydrate, microcrystalline cellulose
Element and magnesium stearate mix homogeneously are placed on tabletting in tablet machine.
Embodiment 20The stability test of dissolution fluid
With water as dissolution medium, the parameter of dissolving-out tester is set to temperature 37.0 DEG C, rotating speed 100 revs/min, will implement
The tablet of example 19 preparation was respectively placed in 500mL water, in 1 hour, 6 hours and within 12 hours, carry out the sampling of dissolution fluid.Dissolution fluid
Sample, after 0.45 μm membrane filtration, is at room temperature placed 24 hours, and the tablet of every group of formula is parallel does 3, observes dissolution fluid
Steadiness.
Result of the test is: tablet 3 (containing known BMS-790052 dihydrochloride crystal formation) and tablet 2 are (containing BMS-790052
Sulfate) dissolution fluid sample solution all become cloudy, after turbid solution is centrifugal, solid HPLC assay confirms as BMS-790052
Free alkali；And tablet 1 and 4 is (respectively containing the BMS-790052 bis-tosilate monohydrate crystal form of the present invention, BMS-
790052 diphenyl sulfonate B crystal form) dissolution fluid clarification, do not observe turbid phenomenon.
Result of the test shows: compared with tablet prepared by known BMS-790052 dihydrochloride crystal formation, by BMS-of the present invention
Tablet prepared by 790052 2 tosilate monohydrate crystal forms, BMS-790052 diphenyl sulfonate B crystal form, its aqueous solution
Stability high, be suitable for pharmaceutical preparation application.
Embodiment 21The Accumulation dissolution test of tablet
With simulated gastric fluid as dissolution medium, the parameter of dissolving-out tester is set to temperature 37.0 DEG C, rotating speed 100 revs/min,
The tablet 1～4 embodiment 19 prepared is respectively placed in 500mL simulated gastric fluid, carries out dissolution in 1 hour, 6 hours and 12 hours
The sampling of liquid.The dissolution drug level (μ g/ml) of HPLC detection dissolution fluid sample, then with BMS-790052 free alkali in this tablet
Theoretical 100% release concentration 30 μ g/ml is standard, calculates this tablet Accumulation dissolution (%) at sample point, every group of formula
Tablet does 6 Duplicate Samples.
The cumulative release degrees of data of tablet 1～3 is shown in Table 5.
The Accumulation dissolution curve of tablet 1～3 is shown in Figure 17.Discharged with table 1 by the Accumulation dissolution result of table 5 and Figure 17
Degree screening index comparison, it can be seen that in simulated gastric fluid, tablet 3 (containing known BMS-790052 dihydrochloride crystal formation) with
Tablet 2 (containing BMS-790052 sulfate) dissolution is too fast, has reached more than 85% at the Accumulation dissolution of 6 hours, fails to reach slow
Releasing effect, tablet 1 (the BMS-790052 bis-tosilate monohydrate crystal form containing the present invention) then can reach slow release effect
Really, slow releasing preparation application it is suitable for.
Similarly, being tested by the Accumulation dissolution of tablet 4, the cumulative release degrees of data of tablet 4 is shown in Table 5.Show, tablet
4 (the BMS-790052 diphenyl sulfonate B crystal form containing the present invention) can reach slow release effect, is suitable for slow releasing preparation application.
The Accumulation dissolution of table 5 tablet 1～4
The above, the only detailed description of the invention of the present invention, but protection scope of the present invention is not limited thereto, and any
Those of ordinary skill in the art in the technical scope that disclosed herein, the change that can expect without creative work or
Replace, all should contain within protection scope of the present invention.
Claims (8)
1.BMS-790052 tri hydrochloride, its structural formula is as follows:
2. the preparation method of BMS-790052 tri hydrochloride described in claim 1, comprises the following steps: forms BMS-790052 and exists
Solution system in soluble solvent, adds hydrochloric acid, and the mole dosage of BMS-790052 and hydrochloric acid ratio for 1:3～1:10, mixes shape
Become serosity and stir, and then separating solid, obtaining described BMS-790052 tri hydrochloride；
Preferably, described soluble solvent is ester, more preferably C3～C5Ester；
Preferably, described preparation method is at room temperature carried out；
Preferably, the time of described stirring is 3～10 hours, more preferably 3～5 hours；
Preferably, described BMS-790052 concentration in soluble solvent is 10～50mg/mL；
Preferably, the mole dosage of described BMS-790052 and hydrochloric acid is than for 1:6～1:10；
Preferably, the concentration range of hydrochloric acid used is 0.1～12mol/L, more preferably 6～12mol/L.
3. the amorphous article of the BMS-790052 tri hydrochloride described in a claim 1.
BMS-790052 tri hydrochloride amorphous article the most according to claim 3, it is characterised in that it has such as Figure 13 institute
The X-ray powder diagram shown.
5. the preparation method of the BMS-790052 tri hydrochloride amorphous article described in claim 3 or 4, comprises the following steps: will
The BMS-790052 tri hydrochloride that according to claim 2, preparation method obtains forms suspension in a solvent, stirring, separates out
Solid, obtains described BMS-790052 tri hydrochloride amorphous article, and wherein said solvent is selected from alcohol, ester or ether；
Preferably, described alcohol is C2～C3Alcohol, more preferably isopropanol；
Preferably, described ester is C3～C5Ester, more preferably ethyl acetate；
Preferably, described ether is C4～C6Ether, more preferably methyl tertiary butyl ether(MTBE)；
Preferably, the preparation method of described BMS-790052 tri hydrochloride amorphous article is at room temperature carried out；
Preferably, the time of described stirring is 8～48 hours, preferably 8～16 hours；
Preferably, described BMS-790052 tri hydrochloride is 10～50mg:1mL with the mass volume ratio of solvent.
6. a pharmaceutical composition, comprises the medicine activity component for the treatment of and/or prevention effective dose selected from described in claim 1
BMS-790052 tri hydrochloride amorphous article, Yi Jizhi according to any one of BMS-790052 tri hydrochloride or claim 3-4
Few a kind of pharmaceutically acceptable carrier.
Pharmaceutical composition the most according to claim 6, it is characterised in that described pharmaceutical composition is selected from having slow releasing function
Tablet, granule, powder, pill, capsule, solution, syrup, suspensoid, dispersant or Emulsion.
8. BMS-790052 tri-salt according to any one of BMS-790052 tri hydrochloride described in claim 1 or claim 3-4
Hydrochlorate amorphous article, in preparation purposes in the medicine for the treatment of and/or prevention of hepatitis C infection.
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| CN201610664633.1A CN106279122A (en) | 2014-01-21 | 2014-01-21 | The salt of a kind of compound and crystal formation or amorphous article, its preparation method, containing their pharmaceutical composition and purposes |
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| CN201610664633.1A CN106279122A (en) | 2014-01-21 | 2014-01-21 | The salt of a kind of compound and crystal formation or amorphous article, its preparation method, containing their pharmaceutical composition and purposes |
| PCT/CN2014/071020 WO2015109445A1 (en) | 2014-01-21 | 2014-01-21 | Salt of compound and crystalline or amorphous substance thereof, preparation method therefor, pharmaceutical composition containing same and use thereof |
| CN201480009595.5A CN105073740B (en) | 2014-01-21 | 2014-01-21 | The salt and crystal formation or amorphous article of a kind of compound, its preparation method, the pharmaceutical composition containing them and purposes |
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| CN201480009595.5A Division CN105073740B (en) | 2014-01-21 | 2014-01-21 | The salt and crystal formation or amorphous article of a kind of compound, its preparation method, the pharmaceutical composition containing them and purposes |
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| CN201610661880.6A Active CN106279121B (en) | 2014-01-21 | 2014-01-21 | The salt and crystal form or amorphous article, preparation method, pharmaceutical composition and purposes containing them of a kind of compound |
| CN201480009595.5A Active CN105073740B (en) | 2014-01-21 | 2014-01-21 | The salt and crystal formation or amorphous article of a kind of compound, its preparation method, the pharmaceutical composition containing them and purposes |
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| CN201480009595.5A Active CN105073740B (en) | 2014-01-21 | 2014-01-21 | The salt and crystal formation or amorphous article of a kind of compound, its preparation method, the pharmaceutical composition containing them and purposes |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675998A (en) * | 2018-06-28 | 2018-10-19 | 北京凯因科技股份有限公司 | A kind of crystallinity methyl carbamate class compound |
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| EP3237405A1 (en) * | 2014-12-26 | 2017-11-01 | Cipla Limited | Polymorphic forms of methyl((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2-methylpropyl)carbamate and salts thereof |
| CZ2015366A3 (en) * | 2015-05-29 | 2016-12-07 | Zentiva, K.S. | Daclatasvir solid forms |
| WO2017021904A1 (en) * | 2015-08-03 | 2017-02-09 | Laurus Labs Private Limited | Daclatasvir free base and process for the preparation thereof |
| CN105153128A (en) * | 2015-10-15 | 2015-12-16 | 上海众强药业有限公司 | Novel method for synthesizing daclatasvir intermediate |
| CN105566303A (en) * | 2016-01-25 | 2016-05-11 | 上海众强药业有限公司 | Novel daclatasvir crystal form and preparing method thereof |
| CN106188016A (en) * | 2016-07-04 | 2016-12-07 | 福建广生堂药业股份有限公司 | Dihydrate of his Wei of hydrochloric acid Dacca and preparation method thereof |
| BR112019001163A2 (en) * | 2016-07-22 | 2019-04-30 | Medshine Discovery Inc. | nitroimidazole crystal and salt and method of manufacture thereof |
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| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
| CN101778840A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101558059B (en) * | 2006-08-11 | 2014-12-03 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| EA201490254A1 (en) * | 2011-08-24 | 2014-07-30 | ГЛАКСОСМИТКЛАЙН ЭлЭлСи | COMBINED TREATMENT OF HEPATITIS C |
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2014
- 2014-01-21 CN CN201610664633.1A patent/CN106279122A/en active Pending
- 2014-01-21 CN CN201610661880.6A patent/CN106279121B/en active Active
- 2014-01-21 CN CN201480009595.5A patent/CN105073740B/en active Active
- 2014-01-21 WO PCT/CN2014/071020 patent/WO2015109445A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
| CN101778840A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108675998A (en) * | 2018-06-28 | 2018-10-19 | 北京凯因科技股份有限公司 | A kind of crystallinity methyl carbamate class compound |
Also Published As
| Publication number | Publication date |
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| CN106279121A (en) | 2017-01-04 |
| CN106279121B (en) | 2019-05-24 |
| CN105073740A (en) | 2015-11-18 |
| CN105073740B (en) | 2017-06-27 |
| WO2015109445A1 (en) | 2015-07-30 |
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