[go: up one dir, main page]

WO2017076358A1 - 咪唑基联苯基化合物盐的新晶型及其制备方法 - Google Patents

咪唑基联苯基化合物盐的新晶型及其制备方法 Download PDF

Info

Publication number
WO2017076358A1
WO2017076358A1 PCT/CN2016/104741 CN2016104741W WO2017076358A1 WO 2017076358 A1 WO2017076358 A1 WO 2017076358A1 CN 2016104741 W CN2016104741 W CN 2016104741W WO 2017076358 A1 WO2017076358 A1 WO 2017076358A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
preparation
formula
ray powder
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/104741
Other languages
English (en)
French (fr)
Inventor
陈敏华
张炎锋
刁小娟
张晓宇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Crystal Pharmatech Co Ltd
Original Assignee
Crystal Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Crystal Pharmatech Co Ltd filed Critical Crystal Pharmatech Co Ltd
Publication of WO2017076358A1 publication Critical patent/WO2017076358A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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

Definitions

  • the invention relates to the field of chemical medicine, in particular to a novel crystal form of an imidazolyl biphenyl compound dihydrochloride and a preparation method thereof.
  • BMS Bristol-Myers Squibb
  • Daklinza hepatitis D drug Daklinza
  • HCV hepatitis C
  • dacavitavir is ((1S)-1-((2S)-2-(5-(4'-(2-((2S)-1-((2S)-2-) Oxycarbonyl)amino)-3-methylbutyryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenyl)-1H-imidazol-2-yl)-1-pyrrolidine Methyl)carbonyl)-2-methylpropyl)carbamate having a structure as shown in the formula (I) and having a market form of a dihydrochloride salt as shown in the formula (II).
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, in the development of drugs, the issue of drug polymorphism should be fully considered.
  • the patent CN101778840A discloses the N-2 crystal form of dacarevir dihydrochloride having 10.3 ⁇ 0.1, 12.4 ⁇ 0.1, 12.8 ⁇ 0.1, 13.3 ⁇ 0.1, 13.6 ⁇ 0.1 in the powder X-ray diffraction pattern. Characteristic peaks at 2 ⁇ values of 15.5 ⁇ 0.1, 20.3 ⁇ 0.1, 21.2 ⁇ 0.1, 22.4 ⁇ 0.1, 22.7 ⁇ 0.1, and 23.7 ⁇ 0.1.
  • the patent CN 101778840A discloses the N-2 crystal form, but does not study and explain its properties such as stability and fluidity, and the inventors of the present application found that the present property is superior to the N-2 crystal form during the research.
  • the crystal form has good stability and fluidity better than the existing crystal form. Therefore, in view of the unpredictability of the development of dominant crystal forms, it is necessary to develop other crystal forms of daclitaxel dihydrochloride to stabilize the drug during preparation, storage and formulation development, and to provide drug development. More and better choices.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and to provide a novel crystal form of the compound dihydrochloride of the formula (I) which has better stability and solubility in accordance with pharmaceutical requirements.
  • the present invention adopts the following technical solutions:
  • the crystal form A provided by the present invention is characterized in that the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has characteristics at 2 ⁇ values of 8.7 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °. peak.
  • the X-ray powder diffraction pattern of Form A has a diffraction peak at one or more of 2 ⁇ values of 12.9 ⁇ 0.2°, 20.8° ⁇ 0.2°, 11.6° ⁇ 0.2°; preferably, the crystal form A of the present invention
  • the X-ray powder diffraction pattern also has diffraction peaks at 2 ⁇ values of 12.9 ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 11.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A has a diffraction peak at one or more of 2 ⁇ values of 26.2° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 16.3° ⁇ 0.2°; preferably, the crystal form of the present invention
  • the X-ray powder diffraction pattern of A also has diffraction peaks at 2 ⁇ values of 10.6 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, and 26.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a diffraction peak at a value of 8.7 ° ⁇ 0.1 °, 9.4 ° ⁇ 0.1 °, 10.6 ° ⁇ 0.1 °, at 12.9 ⁇ 0.1 °,
  • One or more of 20.8° ⁇ 0.1°, 11.6° ⁇ 0.1°, 26.2° ⁇ 0.1°, 18.7° ⁇ 0.1°, and 16.3° ⁇ 0.1° have diffraction peaks.
  • the X-ray powder diffraction pattern of Form A is shown in Figure 1. Further, a total of 30 diffraction peaks are shown in the X-ray diffraction pattern, and the positions and peak intensities of these diffraction peaks are shown in Table 1.
  • a total of 28 diffraction peaks are shown in the X-ray diffraction pattern of Form A, and the positions and peak intensities of these diffraction peaks are shown in Table 3.
  • the crystal form A provided by the present invention is further characterized in that an endothermic peak appears near the peak temperature of 92 ° C, and another endothermic peak appears near the initial temperature of 206 ° C.
  • the DSC chart is substantially as shown in the drawing. 2 is shown.
  • the crystalline form A provided by the present invention is further characterized by having a weight loss gradient of about 5.2% when heated to 150 ° C, the TGA of which is substantially as shown in FIG.
  • the crystal form A provided by the present invention is further characterized in that it is placed under 80% relative humidity, and the weight gain after equilibrium is 2.21%, and the DVS pattern is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of Form A, which can be obtained by any of the following two methods:
  • the alcohols include, but are not limited to, lower alkyl alcohols, preferably methanol;
  • the halogenated hydrocarbons include, but are not limited to, dichloromethane, chloroform, preferably dichloromethane;
  • the temperature condition is 0 to 25 ° C, preferably 0 to 10 ° C, more preferably 5 ° C.
  • the temperature condition is 0 to 25 ° C, preferably 0 to 10 ° C, more preferably 5 ° C.
  • halogenated hydrocarbons include, but are not limited to, dichloromethane, chloroform, preferably dichloromethane.
  • the alkanes include, but are not limited to, heptane, hexane, cyclohexane, preferably n-heptane.
  • the ketones include, but are not limited to, acetone, methyl ethyl ketone, methyl t-butyl ketone, preferably acetone.
  • the separation method may be volatilization, filtration, centrifugation, preferably centrifugation.
  • Another object of the present invention is to provide a novel crystalline form of the compound dihydrochloride salt of formula (I), designated as Form B.
  • the crystal form B provided by the present invention has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C having a characteristic peak at 2 ⁇ values of 8.9 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, and 13.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form B has a diffraction peak at one or more of 2 ⁇ values of 17.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, and 11.8° ⁇ 0.2°; preferably, the crystal form of the present invention
  • the X-ray powder diffraction pattern of B also has a diffraction peak at 2 ⁇ values of 17.9 ° ⁇ 0.2 °, 9.6 ° ⁇ 0.2 °, and 11.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form B has a diffraction peak at one or more of 2 ⁇ values of 22.4° ⁇ 0.2°, 18.8° ⁇ 0.2°, 16.2° ⁇ 0.2°; preferably, the crystal form of the present invention
  • the X-ray powder diffraction pattern of B also has a diffraction peak at 2 ⁇ values of 22.4 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 °, and 16.2 ° ⁇ 0.2 °.
  • Form B the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a diffraction peak at 2 ⁇ values of 8.9 ° ⁇ 0.1 °, 11.1 ° ⁇ 0.1 °, 13.0 ° ⁇ 0.1 °, at 22.4 ° ⁇ 0.1 °
  • a diffraction peak at 2 ⁇ values of 8.9 ° ⁇ 0.1 °, 11.1 ° ⁇ 0.1 °, 13.0 ° ⁇ 0.1 °, at 22.4 ° ⁇ 0.1 °
  • 9.6° ⁇ 0.1°, 11.8° ⁇ 0.1°, 17.9° ⁇ 0.1°, 18.8° ⁇ 0.1°, and 16.2 ⁇ 0.1° have diffraction peaks.
  • the X-ray powder diffraction pattern of Form B is as shown in FIG. Further, a total of 26 diffraction peaks are shown in the X-ray diffraction pattern, and the positions and peak intensities of these diffraction peaks are shown in Table 4.
  • a total of 28 diffraction peaks are shown in the X-ray diffraction pattern of Form B, and the positions and peak intensities of these diffraction peaks are shown in Table 5.
  • the crystal form B is heated to a peak temperature of about 97 ° C to have an endothermic peak, and another endothermic peak appears near the initial temperature of 206 ° C.
  • the DSC chart is substantially as shown in FIG. 7 .
  • Form B has a weight loss gradient of about 5.4% when heated to 150 ° C, the TGA of which is substantially as shown in FIG.
  • the crystalline form B provided by the present invention is further characterized in that it is placed under 80% relative humidity, and the weight gain after reaching equilibrium is 2.14%, and the DVS pattern is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of Form B, which can be obtained by heating Form A solid and cooling to room temperature to obtain Form B.
  • the heating temperature is heated to 90 to 200 ° C, preferably 110 to 160 ° C.
  • Another object of the present invention is to provide a pharmaceutical combination comprising a therapeutically effective amount of a crystalline form A or a crystalline form B of a compound of the formula (I), or a mixture of both, and a pharmaceutically acceptable pharmaceutical excipient. Things. Typically, a therapeutically effective amount of Form A or Form B of a compound of the formula (I) dihydrate or a mixture of both is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, The pharmaceutical compositions or formulations are prepared in a manner well known in the pharmaceutical art.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms such as: solid oral preparations, including but not limited to such as powders, granules, pellets, tablets and capsules; liquid oral preparations including, but not limited to, syrups, suspensions, dispersions and emulsions And injections including, but not limited to, solutions, dispersing agents, and lyophilized formulations.
  • the dosage form may be immediate release, delayed release or sustained release, and the immediate release preparation may be ordinary, dispersed, chewed, orally disintegrated or rapidly dissolved; the sustained release preparation may be hydrophilic or hydrophobic, or controlled release rate by hydrophilic and hydrophobic combination.
  • the substance forms a skeleton or reservoir system, or both forms a skeleton and a reservoir system.
  • the formulation process may use, for example, direct pressure, dry granulation, wet granulation, and extrusion spheronization.
  • the formulations may be presented in a non-coating, film coating, sugar coating, powder coating, enteric or sustained release coating, and the like.
  • the route of administration is oral, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, vaginal and the like.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release; dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agent, patch; dosage form suitable for nasal administration Including aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • the above formulations can be prepared by any method known in the art of pharmacy.
  • the crystalline form A or the crystalline form B of the compound dihydrochloride salt of the formula (I) or a mixture of the two can be used for the preparation of a pharmaceutical preparation for treating liver diseases such as hepatitis, particularly hepatitis C.
  • the crystalline form A or the crystalline form B of the compound dihydrochloride salt of the formula (I) of the present invention or a mixture of the two and a pharmaceutically acceptable pharmaceutical excipient can be used for the preparation of a liver disease such as hepatitis. It is a use in a hepatitis C pharmaceutical preparation.
  • the crystalline form A or the crystalline form B of the compound dihydrochloride salt of the formula (I) or a mixture of the two may be used in combination with one or more drugs for the preparation of a pharmaceutical preparation for the treatment of liver diseases such as hepatitis, particularly hepatitis C.
  • a pharmaceutical composition of the crystalline form A or the crystalline form B of the compound dihydrochloride of the formula (I) or a mixture of the two and a pharmaceutically acceptable pharmaceutical excipient may be used in combination with one or more drugs.
  • the present invention may be administered together with or separately from other anti-HCV active compounds, including the combination drug disclosed in CN101778840A, and sofosbuvir and the like.
  • the invention provides a method of treating an HCV infection in a patient, the method comprising administering to the patient a therapeutically effective amount of Form A or Form B of a compound dihydrochloride salt of Formula (I) or a mixture of the two.
  • the invention provides a method of treating an HCV infection in a patient, the method comprising administering to the patient a therapeutically effective amount of Form A or Form B of a compound dihydrochloride salt of Formula (I), or a mixture of the two, and Sophi Buwe.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or showing a disease or condition of the disease, condition or disorder; and (3) improving the disease A disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a disease or condition of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease.
  • Preventing the disease, condition or disorder in the individual (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • polymorph refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound.
  • the phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs. It is known that a pharmaceutical compound having such a polymorph has an influence on pharmacological activity, solubility, bioavailability, stability, and the like due to its physicochemical properties. Therefore, in the case where a compound which is useful as a drug has a polymorph, it is desirable to produce a crystal compound having high usefulness from these polymorphs.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • the X-ray powder diffraction pattern was characterized by peak position and peak intensity.
  • the present invention has the following advantages compared with the prior art:
  • the crystal form A and the crystal form B of the invention have good stability.
  • the stability of the crystal form A at a specific water activity is superior to the existing N-2 crystal form; the preparation process of the crystal form A and B is convenient. , solvent is easy to obtain; Forms A and B can be used in the future drug development of Dac.
  • Figure 1 is an XRPD pattern of the crystal form A of dacarevir Dihydrochloride
  • FIG. 2 is a DSC diagram of the crystal form A of dacarevir Dihydrochloride
  • FIG. 3 is a TGA diagram of the crystal form A of dacarevir Dihydrochloride
  • FIG. 4 is a DVS diagram of the crystal form A of dacarevir Dihydrochloride
  • Figure 5 is a 1 H-NMR chart of the crystal form A of Dakatavir dihydrochloride
  • Figure 6 is an XRPD pattern of the crystal form B of dacarevir Dihydrochloride
  • FIG. 7 is a DSC diagram of the crystal form B of dacarevir Dihydrochloride
  • FIG. 8 is a TGA diagram of the crystal form B of dacarevir Dihydrochloride
  • Figure 9 is a DVS diagram of the crystal form B of dacarevir Dihydrochloride
  • Figure 10 is a 1 H-NMR chart of the crystal form B of Dakatavir dihydrochloride
  • Figure 11 is an XRPD overlay of Form A placed at 25 ° C / 60% RH for 90 days (from top to bottom, XRPD pattern for 90 days under starting Form A and 25 ° C / 60% RH)
  • Figure 12 is an XRPD overlay of Form A placed at 40 °C / 75% RH for 90 days (from top to bottom, XRPD pattern for 90 days under starting Form A and 40 °C / 75% RH)
  • Figure 13 is an XRPD overlay of Form B placed at 25 ° C / 60% RH for 90 days (from top to bottom, XRPD pattern for 90 days under starting Form B and 25 ° C / 60% RH)
  • Figure 14 is an XRPD overlay of Form B placed at 40 °C / 75% RH for 90 days (from top to bottom, XRPD pattern for 90 days under starting Form B and 40 °C / 75% RH)
  • Figure 15 is a PLM diagram of the N-2 crystal form of dacabavir dihydrochloride of CN101778840A
  • Figure 16 is a PLM diagram of Form A
  • Figure 17 is a PLM diagram of Form B
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the dakotavir free base, dihydrochloride starting material is prepared by a known method.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the polarizing microscope (PLM) pattern of the present invention was collected on an Axio Lab. A1 upright microscope manufactured by ZEISS.
  • the XRPD pattern of the compound dihydrochloride salt form A of the formula (I) obtained in this example is shown in Fig. 1.
  • the DSC chart is shown in Fig. 2.
  • the endothermic peak appears near heating to 92 ° C, and the other is heated to 206 ° C. Endothermic peak.
  • Its TGA pattern is shown in Figure 3.
  • the DVS diagram is shown in Fig. 4.
  • the 1 H-NMR chart is shown in Fig. 5.
  • the 1 H-NMR data is as follows:
  • Form A is a hydrate.
  • the obtained Form A was determined by ion chromatography and high performance liquid chromatography for the compound of the formula (I) (dacavir).
  • the XRPD pattern of the compound dihydrochloride salt form B of the formula (I) obtained in this example is shown in Fig. 6, and the DSC chart thereof is shown in Fig. 7. Its TGA pattern is shown in Figure 8. When Form B is heated to 150 ° C, it has a weight loss gradient of about 5.4%.
  • the DVS pattern is shown in Fig. 9.
  • the 1 H-NMR chart is shown in Fig. 10.
  • the 1 H-NMR data is as follows:
  • the new Form A and Form B prepared by the present invention were placed under conditions of 25 ° C / 60% RH and 40 ° C / 75% RH for 90 days, respectively, and the crystal form XRPD change of the sample was examined.
  • the test results show that both Form A and Form B have good physical stability, and Figures 11 and 12 show XRPD of Form A placed at 25 ° C / 60% RH and 40 ° C / 75% RH for 90 days, respectively.
  • Results (Fig. 11: XRPD pattern of starting crystal form A, 90°C/60% RH for 90 days from top to bottom; Figure 12: starting crystal form A from top to bottom, 40 °C/ A 90-day XRPD pattern was placed under 75% RH conditions).
  • Figure 13 and Figure 14 show XRPD results for 90 days of Form B placed at 25 ° C / 60% RH and 40 ° C / 75% RH, respectively (Figure 13: starting from top to bottom, starting form B, 25 Placed under °C/60%RH The XRPD pattern was set for 90 days; Figure 14: XRPD pattern of starting Form B from top to bottom and 90 days at 40 °C/75% RH).
  • the polarized microscope sample test method is as follows: place about 0.5 mg of the sample onto the glass slide, add a small amount of mineral oil to disperse the sample, cover the cover slip and gently press with the fingertip to ensure that the slide and the cover slip are There are no bubbles at the tip. Adjust the eyepiece and objective of the microscope and fine tune the moving sample stage to focus on the sample.
  • the results of polarized light microscopy (PLM) of Form N-2 and Form A and Form B of dacarevir Dihydrochloride of Patent CN101778840A are shown in Figures 15, 16 and 17.
  • the patent CN101778840A crystal form hydrochloride form N-2 particles are small and agglomerated, while the hydrochloride salt forms A and B of the present invention are larger flakes and blocks, have better fluidity and are easy to be industrially produced.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供式（I）化合物二盐酸盐的新晶型及其制备方法。本发明提供的新晶型命名为晶型A、晶型B，与现有技术相比，稳定性更好、流动性更好，溶解度符合药用要求。特别地，晶型A在特定条件下的稳定性优于现有N-2晶型；晶型A、B制备工艺操作便利，溶剂易得，对未来该药物的优化和开发具有重要价值。本发明提供的式（I）化合物二盐酸盐的晶型A、晶型B或其混合可用于制备治疗肝脏疾病例如肝炎特别是丙型肝炎的药物制剂。

Description

咪唑基联苯基化合物盐的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及咪唑基联苯基化合物二盐酸盐的新晶型及其制备方法。
背景技术
达卡他韦(daclatasvir)原研厂家是百时美施贵宝(BMS)公司，2014年底时BMS丙肝新药Daklinza(daclatasvir)获欧盟批准，联合其他药物，用于所有1、2、3、4基因型慢性丙型肝炎(HCV)成人感染者的治疗。美国FDA 2015年批准“索非布韦+达卡他韦”用于基因型3的治疗，并授予“索非布韦+达卡他韦”突破性药物资格，用于治疗伴有晚期肝硬化的基因型1患者和肝移植后复发的基因型1患者。达卡他韦的化学名称为((1S)-1-(((2S)-2-(5-(4’-(2-((2S)-1-((2S)-2-((甲氧羰基)氨基)-3-甲基丁酰基)-2-吡咯烷基)-1H-咪唑-5-基)-4-联苯基)-1H-咪唑-2-基)-1-吡咯烷基)羰基)-2-甲基丙基)氨基甲酸甲酯，其结构如式(I)所示，其上市形态为二盐酸盐，如式(II)所示。
Figure PCTCN2016104741-appb-000001
Figure PCTCN2016104741-appb-000002
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效产生不同的影响。因此，在药品研发中，应全面考虑药物多晶型问题。
目前，专利CN101778840A公开了达卡他韦二盐酸盐的N-2晶型，在粉末X射线衍射图案中具有位于10.3±0.1，12.4±0.1，12.8±0.1，13.3±0.1，13.6±0.1，15.5±0.1，20.3±0.1，21.2±0.1，22.4±0.1，22.7±0.1和23.7±0.1的2θ值处的特征峰。
目前专利CN 101778840A公开了N-2晶型，但是并未对其稳定性及流动性等性质进行研究和说明，而本申请发明人在研究过程中发现，存在性质比N-2晶型更优的其它晶型，该晶型稳定性好、流动性比现有晶型好。因此，鉴于优势晶型开发的不可预见性，有必要开发出达卡他韦二盐酸盐的其他晶型，以使药物在制备、储存以及制剂开发过程中都能够保持稳定，为药物开发提供更多更好的选择。
发明内容
本发明所要解决的技术问题是克服现有技术的不足提供一种稳定性更好、溶解度符合药用要求的式(Ⅰ)化合物二盐酸盐新晶型。
为解决以上技术问题，本发明采取如下技术方案：
本发明的一个目的是提供一种式(Ⅰ)化合物二盐酸盐的新晶型，命名为晶型A。
本发明提供的晶型A，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为8.7°±0.2°、9.4°±0.2°、18.7°±0.2°处具有特征峰。
进一步的，晶型A的X射线粉末衍射图在2θ值为12.9±0.2°、20.8°±0.2°、11.6°±0.2°的一处或多处具有衍射峰；优选的，本发明晶型A的X射线粉末衍射图还在2θ值为12.9±0.2°、20.8°±0.2°、11.6°±0.2°处具有衍射峰。
进一步的，晶型A的X射线粉末衍射图在2θ值为26.2°±0.2°、10.6°±0.2°、16.3°±0.2°的一处或多处具有衍射峰；优选的，本发明晶型A的X射线粉末衍射图还在2θ值为10.6°±0.2°、16.3°±0.2°、26.2°±0.2°处具有衍射峰。
晶型A，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为8.7°±0.1°、9.4°±0.1°、10.6°±0.1°处具有衍射峰，在12.9±0.1°、20.8°±0.1°、11.6°±0.1°、26.2°±0.1°、18.7°±0.1°、16.3°±0.1°中的一处或多处具有衍射峰。
根据本发明的一个具体且优选方面，晶型A的X射线粉末衍射图如图1所示。进一步地，该X射线衍射图中显示了共30个衍射峰，这些衍射峰的位置以及峰强度如表1所示。
根据本发明的又一具体且优选方面，晶型A的X射线衍射图中显示了共28个衍射峰，这些衍射峰的位置以及峰强度如表3所示。
优选地，本发明提供的晶型A，其特征还在于，加热至峰值温度92℃附近出现吸热峰，加热至起始温度206℃附近出现另一吸热峰，其DSC图基本如附图2所示。
优选地，本发明提供的晶型A，其特征还在于，加热至150℃时，具有约5.2％的重量损失梯度，其TGA图基本如附图3所示。
优选地，本发明提供的晶型A，其特征还在于，80％相对湿度条件下放置,达到平衡后的增重为2.21％，其DVS图基本如附图4所示。
本发明的另一个目的是提供晶型A的制备方法，晶型A可以通过以下两种方法的任一种得到：
1)将式(Ⅰ)化合物(达卡他韦)二盐酸盐溶解于醇类溶剂中，室温下挥发所得固体置于卤代烃溶剂中，在一定温度条件下搅拌，分离得到固体；
所述醇类包括但不限于低级烷基醇，优选甲醇；所述卤代烃类包括但不限于二氯甲烷、三氯甲烷，优选二氯甲烷；
所述温度条件为0～25℃，优选0～10℃，更优选5℃。
2)将式(Ⅰ)化合物(达卡他韦)游离碱在卤代烃类、烷烃类、酮类的一种或多种混合体系内与盐酸反应，在一定温度条件下搅拌得到，分离得到固体。
所述温度条件为0～25℃，优选0～10℃，更优选5℃。
所述卤代烃类包括但不限于二氯甲烷、三氯甲烷，优选二氯甲烷。
所述烷烃类包括但不限于庚烷、己烷、环己烷，优选正庚烷。
所述酮类包括但不限于丙酮、甲基乙基酮、甲基叔丁基酮，优选丙酮。
所述分离方法可以是挥发、过滤、离心，优选离心。
本发明的另一个目的是提供一种式(Ⅰ)化合物二盐酸盐的新晶型，命名为晶型B。
本发明提供的晶型B，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为8.9°±0.2°、11.1°±0.2°、13.0°±0.2°处具有特征峰。
进一步的，晶型B的X射线粉末衍射图在2θ值为17.9°±0.2°、9.6°±0.2°、11.8°±0.2°的一处或多处具有衍射峰；优选的，本发明晶型B的X射线粉末衍射图还在2θ值为17.9°±0.2°、9.6°±0.2°、11.8°±0.2°处具有衍射峰。
进一步的，晶型B的X射线粉末衍射图在2θ值为22.4°±0.2°、18.8°±0.2°、16.2°±0.2°的一处或多处具有衍射峰；优选的，本发明晶型B的X射线粉末衍射图还在2θ值为22.4°±0.2°、18.8°±0.2°、16.2°±0.2°处具有衍射峰。
晶型B，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为8.9°±0.1°、11.1°±0.1°、13.0°±0.1°处具有衍射峰，在22.4°±0.1°、9.6°±0.1°、11.8°±0.1°、17.9°±0.1°、18.8°±0.1°、16.2±0.1°中的一处或多处具有衍射峰。
根据本发明的一个具体且优选方面，晶型B的X射线粉末衍射图如图6所示。进一步地，该X射线衍射图中显示了共26个衍射峰，这些衍射峰的位置以及峰强度如表4所示。
根据本发明的又一具体且优选方面，晶型B的X射线衍射图中显示了共28个衍射峰，这些衍射峰的位置以及峰强度如表5所示。
优选地，晶型B加热至峰值温度97℃附近出现吸热峰，加热至起始温度206℃附近出现另一吸热峰，其DSC图基本如附图7所示。
优选地，晶型B加热至150℃时，具有约5.4％的重量损失梯度，其TGA图基本如附图8所示。
优选地，本发明提供的晶型B，其特征还在于，80％相对湿度条件下放置,达到平衡后的增重为2.14％，其DVS图基本如附图9所示。
本发明的另一个目的是提供晶型B的制备方法，晶型B可以通过以下方法得到：将晶型A固体加热，冷却至室温得到晶型B。
更进一步的，所述加热温度为加热到90～200℃，优选110～160℃。
本发明的另一个目的是提供一种包含有效治疗量的式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物和药学上可接受的药用辅料的药用组合物。一般是将治疗有效量的式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
上述药物组合物可制成一定的剂型，通过适合的途径给药。剂型如：固体口服制剂，其包括但不局限于如散剂、颗粒剂、微丸、片剂和胶囊剂；液体口服制剂，其包括但不局限于如糖浆剂、混悬剂、分散剂和乳剂；以及注射剂，其包括但不局限于如溶液剂、分散剂和冻干制剂。剂型可能是速释、迟释或缓释，且速释制剂可能是普通、分散、咀嚼、口崩或速溶；缓释制剂可能由亲水或疏水，或由亲水和疏水结合的控制释放速率的物质来形成骨架或储库系统，或同时形成骨架和储库系统。处方工艺可能使用如直压、干法制粒、湿法制粒和挤出滚圆。制剂可能的呈现方式有不包衣、薄膜包衣、糖衣、粉末包衣、肠溶或缓释包衣等。给药途径如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型 包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。上述制剂可通过药学领域已知的任何方法来制备。
更进一步的，式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物可用于制备治疗肝脏疾病例如肝炎特别是丙型肝炎药物制剂中的用途。
本发明所述的式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物和药学上可接受的药用辅料的药用组合物可用于制备治疗肝脏疾病例如肝炎特别是丙型肝炎药物制剂中的用途。
式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物可以和一种或多种药物联合应用于制备治疗肝脏疾病例如肝炎特别是丙型肝炎药物制剂中的用途。
式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物和药学上可接受的药用辅料的组成的药用组合物可以和一种或多种药物联合应用于制备治疗肝脏疾病例如肝炎特别是丙型肝炎药物制剂中的用途。
在联合用药的疗法中，本发明可以与其它的抗-HCV活性化合物共同或单独给药，所述其它化合物包括CN101778840A公开的联合用药药物，以及索非布韦等。
本发明提供在患者中治疗HCV感染的方法，该方法包括向所述患者给予治疗有效量的式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物。
本发明提供在患者中治疗HCV感染的方法，该方法包括向所述患者给予治疗有效量的式(Ⅰ)化合物二盐酸盐的晶型A或晶型B或二者的混合物，以及索非布韦。
本发明中的术语，如没有明确定义，按照本领域技术人员的理解取其通常 的意思。
本文所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本文所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
本文所使用的术语“多晶型”是指相同化合物的不同晶型且包括但不限于包含相同化合物的水合物及溶剂合物的其它固态分子形式。同一种药物分子形成多种晶型的现象称为药物多晶型，药物多晶型是固体药物中普遍存在的现象。已知具有这样的多晶型的药物化合物由于其物理化学性质不同而对药理活性、溶解性、生物利用度及稳定性等带来影响。因此，在作为药品有用的化合物存在多晶型的情况下，希望从这些多晶型中制造有用性高的晶型化合物。
本文所使用的术语“X射线粉末衍射图”是指实验观测到的衍射图或源自其的参数。通过峰位置及峰强度表征X射线粉末衍射图。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明的晶型A、晶型B具有良好的稳定性，特别地，晶型A在特定水活度下的稳定性优于现有N-2晶型；晶型A、B制备工艺操作便利，溶剂易得； 晶型A、B可用于未来达卡他韦的药物开发中。
附图说明
图1为达卡他韦二盐酸盐晶型A的XRPD图
图2为达卡他韦二盐酸盐晶型A的DSC图
图3为达卡他韦二盐酸盐晶型A的TGA图
图4为达卡他韦二盐酸盐晶型A的DVS图
图5为达卡他韦二盐酸盐晶型A的1H-NMR图
图6为达卡他韦二盐酸盐晶型B的XRPD图
图7为达卡他韦二盐酸盐晶型B的DSC图
图8为达卡他韦二盐酸盐晶型B的TGA图
图9为达卡他韦二盐酸盐晶型B的DVS图
图10为达卡他韦二盐酸盐晶型B的1H-NMR图
图11为晶型A放置在25℃/60％RH条件下90天的XRPD叠图(从上到下依次为起始晶型A和25℃/60％RH条件下放置90天的XRPD图)
图12为晶型A放置在40℃/75％RH条件下90天的XRPD叠图(从上到下依次为起始晶型A和40℃/75％RH条件下放置90天的XRPD图)
图13为晶型B放置在25℃/60％RH条件下90天的XRPD叠图(从上到下依次为起始晶型B和25℃/60％RH条件下放置90天的XRPD图)
图14为晶型B放置在40℃/75％RH条件下90天的XRPD叠图(从上到下依次为起始晶型B和40℃/75％RH条件下放置90天的XRPD图)
图15为CN101778840A的达卡他韦二盐酸盐的N-2晶型的PLM图
图16为晶型A的PLM图
图17为晶型B的PLM图
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
下述实施例中，所述达卡他韦游离碱、二盐酸盐起始物通过已知方法制备得到。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
PLM：偏光显微镜
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Figure PCTCN2016104741-appb-000003
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明所述的偏光显微镜(PLM)图在ZEISS公司生产的Axio Lab.A1正置式显微镜上采集。
实施例1
晶型A的制备：
将101.5mg式(Ⅰ)化合物(达卡他韦)二盐酸盐溶解于0.5mL甲醇中，置于室温下快速挥发，所得固体悬浮于3.0mL二氯甲烷中，5℃下搅拌48小时，离心取下层固体，置于室温干燥过夜，所得固体为晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表1所示。
表1
2θ d间隔 强度％
6.00 14.73 13.84
6.66 13.27 8.36
8.72 10.14 100.00
9.38 9.43 44.64
10.60 8.35 43.24
10.93 8.10 41.53
11.62 7.62 33.32
12.20 7.26 6.85
12.86 6.89 28.99
13.46 6.58 17.14
13.97 6.34 15.73
14.51 6.11 6.58
14.99 5.91 4.43
15.97 5.55 15.91
16.29 5.44 23.77
17.40 5.10 3.93
18.81 4.72 27.02
20.09 4.42 18.66
20.83 4.26 35.49
21.49 4.14 15.79
22.07 4.03 8.51
22.87 3.89 18.77
23.37 3.81 32.78
23.94 3.72 10.82
24.79 3.59 13.83
26.19 3.40 26.73
26.95 3.31 5.96
27.58 3.23 19.82
28.62 3.12 5.52
29.82 3.00 6.04
本实施例得到的式(Ⅰ)化合物二盐酸盐晶型A的XRPD图如图1，其DSC图如图2，在加热至92℃附近出现吸热峰，加热至206℃附近出现另一吸热峰。其TGA图如图3，加热至150℃时，具有约5.2％的重量损失梯度。其DVS图如图4，其1H-NMR图如图5，其1H-NMR数据如下：
1H-NMR(400MHz,DMSO-d6)δ14.85(br.s,2H),8.15(s,1H),8.02-7.91(m,4H),7.31(d,J＝8.5Hz,1H),5.17(t,J＝7.0Hz,1H),4.13(t,J＝7.8Hz,1H),3.98-3.81(m,2H),3.55(s,3H),2.44-2.32(m,1H),2.24-2.12(m,2H),2.10-1.97(m,2H),0.81(dd,J1＝24.0Hz,J2＝6.7Hz,6H)
根据TGA失重及1H-NMR结果，晶型A为水合物。
得到的晶型A经离子色谱和高效液相色谱测定式(Ⅰ)化合物(达卡他韦) 与盐酸的摩尔比如表2所示，表明其为式(Ⅰ)化合物(达卡他韦)二盐酸盐。
表2
Figure PCTCN2016104741-appb-000004
实施例2
晶型A的制备：
将99.8mg式(Ⅰ)化合物(达卡他韦)游离碱溶解于5mL二氯甲烷、1mL正庚烷和4mL丙酮的混合溶剂中，加入0.14mL的2mol/L盐酸乙醇溶液，5℃下搅拌48小时，离心取下层固体，置于室温干燥过夜，所得固体为晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表3所示。
表3
2θ d间隔 强度％
5.38 16.43 8.77
6.03 14.66 14.34
6.66 13.26 14.76
8.72 10.14 100.00
9.36 9.45 47.56
10.59 8.36 59.02
10.86 8.15 51.73
11.13 7.95 28.59
11.66 7.59 43.56
12.15 7.29 21.01
12.86 6.89 37.59
13.47 6.57 40.26
13.92 6.36 37.08
14.96 5.92 18.98
15.97 5.55 25.73
16.25 5.46 38.28
18.65 4.76 36.69
20.04 4.43 20.30
20.75 4.28 54.19
21.35 4.16 19.67
22.06 4.03 12.91
22.41 3.97 22.22
23.52 3.78 28.97
25.01 3.56 13.64
26.21 3.40 27.39
27.55 3.24 22.35
29.61 3.02 5.67
31.69 2.82 4.06
实施例3
晶型B的制备：
将2.5mg式(Ⅰ)化合物(达卡他韦)二盐酸盐晶型A以10℃/分钟的速度升温到160℃后，快速冷却到室温，所得固体为晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表4所示。
表4
2θ d间隔 强度％
4.59 19.25 3.70
6.02 14.69 16.36
6.74 13.12 12.97
8.92 9.91 100.00
9.71 9.11 36.86
10.60 8.35 16.58
11.19 7.91 72.60
11.84 7.47 43.12
12.93 6.85 37.74
13.47 6.57 18.31
14.54 6.09 18.29
15.14 5.85 14.90
16.22 5.46 22.75
17.80 4.98 25.44
18.69 4.75 17.64
20.21 4.39 32.70
22.48 3.96 43.15
23.95 3.71 30.72
24.96 3.57 19.75
25.32 3.52 16.32
26.58 3.35 19.06
27.10 3.29 10.72
27.73 3.22 9.65
30.91 2.89 10.53
31.50 2.84 2.29
34.10 2.63 6.23
本实施例得到的式(Ⅰ)化合物二盐酸盐晶型B的XRPD图如图6，其DSC图如图7。其TGA图如图8，晶型B加热至150℃时，具有约5.4％的重量损失梯度。其DVS图如图9，其1H-NMR图如图10，其1H-NMR数据如下：
1H-NMR(400MHz,DMSO-d6)δ14.72(br.s,2H),8.12(s,1H),8.01-7.89(m,4H),7.32(d,J＝8.5Hz,1H),5.15(t,J＝7.0Hz,1H),4.12(t,J＝7.7Hz,1H),3.93-3.82(m,2H),3.55(s,3H),2.42-2.31(m,1H),2.23-2.09(m,2H),2.07-1.96(m,2H),0.82(dd,J1＝21.5Hz,J2＝6.7Hz,6H)
实施例4
晶型B的制备：
将10.2mg式(Ⅰ)化合物(达卡他韦)二盐酸盐晶型A置于110℃烘箱中加热4小时，缓慢冷却到室温，所得固体为晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表5所示。
表5
2θ d间隔 强度％
4.52 19.55 5.66
5.88 15.03 16.77
6.75 13.09 20.63
8.92 9.91 100.00
9.70 9.12 60.90
10.56 8.38 35.78
11.13 7.95 86.91
11.22 7.89 93.39
11.74 7.54 70.27
11.86 7.46 72.27
12.99 6.81 69.21
13.51 6.55 36.78
14.44 6.13 45.07
14.97 5.92 46.14
16.14 5.49 61.34
16.25 5.46 63.05
18.07 4.91 90.20
18.71 4.74 55.54
19.11 4.65 53.97
20.07 4.42 65.39
20.21 4.39 68.29
20.70 4.29 66.55
21.82 4.07 68.23
22.38 3.97 92.87
23.80 3.74 66.55
25.07 3.55 49.50
25.74 3.46 39.46
26.50 3.36 38.84
27.77 3.21 34.20
29.05 3.07 23.44
31.26 2.86 12.45
31.43 2.85 9.53
34.71 2.58 2.02
实施例5
晶型A与专利CN101778840A中的N-2晶型稳定性对比：
取10.0mg N-2晶型加入1.0mL溶剂中搅拌，制成悬浊液，置于5℃以500转每分钟的速率磁力搅拌，离心，取固体测试XRPD，结果如表6。
表6
Figure PCTCN2016104741-appb-000005
结果表明，专利CN101778840A中的N-2晶型转为本发明的晶型A。本发明的晶型A在本实验条件下比现有N-2晶型更稳定。
实施例6
晶型A和晶型B的稳定性研究：
将本发明制得的新的晶型A和晶型B分别放置于25℃/60％RH和40℃/75％RH的条件下90天，分别检测样品的晶型XRPD变化。试验结果显示晶型A和晶型B都具有良好的物理稳定性，图11和图12分别表示晶型A放置于25℃/60％RH和40℃/75％RH的条件下90天的XRPD结果(图11：从上到下依次为起始晶型A，25℃/60％RH条件下放置90天的XRPD图；图12：从上到下依次为起始晶型A，40℃/75％RH条件下放置90天的XRPD图)。图13和图14分别表示晶型B放置于25℃/60％RH和40℃/75％RH的条件下90天的XRPD结果(图13：从上到下依次为起始晶型B，25℃/60％RH条件下放 置90天的XRPD图；图14：从上到下依次为起始晶型B，40℃/75％RH条件下放置90天的XRPD图)。
表7
Figure PCTCN2016104741-appb-000006
结果表明，晶型A和晶型B在长期稳定(25℃/60％RH)及加速稳定(40℃/75％RH)条件下，放置过程中晶型保持不变，样品稳定。可见，本专利所述晶型A和晶型B稳定性能优越，方便后期开发。
实施例7
偏光显微镜样品测试方法为：放置约0.5mg的样品至载玻片上，滴加少量的矿物油使样品分散，覆盖上盖玻片后轻轻用指尖按压，确保载玻片与盖玻片指尖没有气泡。调整显微镜的目镜和物镜，并微调移动样品台，聚焦至样品清晰。专利CN101778840A的达卡他韦二盐酸盐的N-2晶型与晶型A和晶型B的偏光显微镜(PLM)结果如图15、16和17所示。专利CN101778840A晶型盐酸盐晶型N-2颗粒较小，有团聚，而本发明的盐酸盐晶型A和B为较大的片状和块状，流动性较好，易于工业化生产。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范 围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (16)

  1. 一种式(Ⅰ)化合物二盐酸盐的晶型A，其特征在于，其X射线粉末衍射图在2θ值为8.7°±0.2°、9.4°±0.2°、18.7°±0.2°处具有特征峰。
    Figure PCTCN2016104741-appb-100001
  2. 根据权利要求1所述的晶型A，其特征还在于，其X射线粉末衍射图在2θ值为12.9±0.2°、20.8°±0.2°、11.6°±0.2°的一处或多处具有衍射峰。
  3. 根据权利要求1或2所述的晶型A，其特征还在于，其X射线粉末衍射图在2θ值为26.2°±0.2°、10.6°±0.2°、16.3°±0.2°的一处或多处具有衍射峰。
  4. 权利要求1-3任一项所述式(Ⅰ)化合物二盐酸盐晶型A的制备方法，其特征在于，晶型A可以通过以下两种方法的任一种得到：
    1)将式(Ⅰ)化合物二盐酸盐溶解于醇类溶剂中，室温下挥发所得固体置于卤代烃溶剂中，在0℃～25℃温度条件下搅拌，分离得到固体；
    2)将式(Ⅰ)化合物游离碱在卤代烃类、烷烃类、酮类的一种或多种混合体系内与盐酸反应，在0℃～25℃温度条件下搅拌得到，分离得到固体。
  5. 根据权利要求4所述的制备方法，其特征在于，所述温度条件为5℃。
  6. 根据权利要求4或5所述的制备方法，其特征在于，所述醇类为甲醇，卤代烃类溶剂为二氯甲烷。
  7. 根据权利要求4或5所述的制备方法，其特征在于，所述卤代烃类溶剂为二氯甲烷，烷烃类为正庚烷，酮类溶剂为丙酮。
  8. 一种式(Ⅰ)化合物二盐酸盐的晶型B，其特征在于，其X射线粉末衍射图在2θ值为8.9°±0.2°、11.1°±0.2°、13.0°±0.2°处具有特征峰。
  9. 根据权利要求8所述的晶型B，其特征还在于，其X射线粉末衍射图在2θ值为17.9°±0.2°、9.6°±0.2°、11.8°±0.2°的一处或多处具有衍射峰。
  10. 根据权利要求8或9所述的晶型B，其特征还在于，其X射线粉末衍射图在2θ值为22.4°±0.2°、18.8°±0.2°、16.2°±0.2°的一处或多处具有衍射峰。
  11. 权利要求8-10任一项所述式(Ⅰ)化合物二盐酸盐晶型B的制备方法，其特征在于，将晶型A固体加热，冷却至室温得到晶型B。
  12. 根据权利要求11所述的制备方法，其特征在于，所述加热温度为90℃～200℃。
  13. 根据权利要求11所述的制备方法，其特征在于，所述加热温度为110℃～160℃。
  14. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1-3中的任一条的晶型A或权利要求8-10中的任一条的晶型B或二者的混合物及药学上可接受的辅料。
  15. 根据权利要求1-3中任一项所述的晶型A或权利要求8-10中任一项所述的晶型B或二者的混合物或根据权利要求14所述的药用组合物可用于制备治疗丙型肝炎药物制剂中的用途。
  16. 根据权利要求1-3中任一项所述的晶型A或权利要求8-10中任一项所述的晶型B或二者的混合物或根据权利要求14所述的药用组合物，与索非布韦联合使用在制备治疗丙型肝炎药物制剂中的用途。
PCT/CN2016/104741 2015-11-06 2016-11-04 咪唑基联苯基化合物盐的新晶型及其制备方法 Ceased WO2017076358A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510752103 2015-11-06
CN201510752103.8 2015-11-06

Publications (1)

Publication Number Publication Date
WO2017076358A1 true WO2017076358A1 (zh) 2017-05-11

Family

ID=58661903

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/104741 Ceased WO2017076358A1 (zh) 2015-11-06 2016-11-04 咪唑基联苯基化合物盐的新晶型及其制备方法

Country Status (1)

Country Link
WO (1) WO2017076358A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018007984A1 (en) * 2016-07-08 2018-01-11 Lupin Limited Crystalline forms of daclatasvir dihydrochloride

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021927A2 (en) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
CN101558059A (zh) * 2006-08-11 2009-10-14 百时美施贵宝公司 丙型肝炎病毒抑制剂
CN101778840A (zh) * 2007-08-08 2010-07-14 百时美施贵宝公司 ((1s)-1-(((2s)-2-(5-(4’-(2-((2s)-1-((2s)-2-((甲氧羰基)氨基)-3-甲基丁酰基)-2-吡咯烷基)-1h-咪唑-5-基)-4-联苯基)-1h-咪唑-2-基)-1-吡咯烷基)羰基)-2-甲基丙基)氨基甲酸甲酯二盐酸盐的晶型
CN105153128A (zh) * 2015-10-15 2015-12-16 上海众强药业有限公司 一种合成达卡他韦中间体的新方法
CN105753844A (zh) * 2016-02-16 2016-07-13 江苏苏利精细化工股份有限公司 一种合成二氨基甲酸二甲酯二盐酸盐类化合物的新方法
CN105777719A (zh) * 2016-03-29 2016-07-20 安徽联创生物医药股份有限公司 一种达卡他韦的合成方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021927A2 (en) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
CN101558059A (zh) * 2006-08-11 2009-10-14 百时美施贵宝公司 丙型肝炎病毒抑制剂
CN101778840A (zh) * 2007-08-08 2010-07-14 百时美施贵宝公司 ((1s)-1-(((2s)-2-(5-(4’-(2-((2s)-1-((2s)-2-((甲氧羰基)氨基)-3-甲基丁酰基)-2-吡咯烷基)-1h-咪唑-5-基)-4-联苯基)-1h-咪唑-2-基)-1-吡咯烷基)羰基)-2-甲基丙基)氨基甲酸甲酯二盐酸盐的晶型
CN105153128A (zh) * 2015-10-15 2015-12-16 上海众强药业有限公司 一种合成达卡他韦中间体的新方法
CN105753844A (zh) * 2016-02-16 2016-07-13 江苏苏利精细化工股份有限公司 一种合成二氨基甲酸二甲酯二盐酸盐类化合物的新方法
CN105777719A (zh) * 2016-03-29 2016-07-20 安徽联创生物医药股份有限公司 一种达卡他韦的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SONG, BAOHUI ET AL.: "Synthesis of Anti Hepatitis C Drug Daclatasvir Dihydrochloride", CHINESE JOURNAL OF NEW DRUGS, vol. 22, no. 22, 31 December 2013 (2013-12-31), pages 2679 - 2682 *
SULKOWSKI, M.S. ET AL.: "Daclatasvir Plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 370, no. 3., 16 January 2014 (2014-01-16), pages 211 - 221, XP055380856 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018007984A1 (en) * 2016-07-08 2018-01-11 Lupin Limited Crystalline forms of daclatasvir dihydrochloride

Similar Documents

Publication Publication Date Title
WO2018196805A1 (zh) 化合物的多晶型、其制备方法和用途
BR112019021447A2 (pt) sal fumarato, forma cristalina i do referido sal, métodos para preparação dos mesmos, composição farmacêutica compreendendo o sal e a forma cristalina i e uso do sal fumarato, da forma cristalina i e da composição farmacêutica
WO2017107972A1 (zh) 一种选择性s1p1受体激动剂的新晶型及其制备方法
WO2018050091A1 (zh) 奥扎莫德盐酸盐的晶型及其制备方法
WO2018103726A1 (zh) 一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途
JP2022068350A (ja) Ｎ－（４－（（３－（２－アミノ－４－ピリミジニル）－２－ピリジニル）オキシ）フェニル）－４－（４－メチル－２－チエニル）－１－フタラジンアミンの薬学的に許容される塩の結晶形態及びその使用
WO2017152707A1 (zh) 吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用
WO2016155670A1 (zh) 一种cdk抑制剂和mek抑制剂的共晶及其制备方法
WO2025167362A1 (zh) 6-((5,6-二苯基-1,2,4-三嗪-3-基)(异丙基)氨基)-n-(甲基磺酰基)己酰胺晶型b及其用途和制备方法
WO2016090257A1 (en) Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib)
CN104540822B (zh) 达拉菲尼甲磺酸盐的晶型及其制备方法
WO2018157803A1 (zh) 维奈妥拉的晶型及其制备方法
JP2018516946A (ja) ヒストン脱アセチル化阻害剤の結晶形態
WO2016155578A1 (zh) 达格列净的新晶型及其制备方法
WO2017063572A1 (zh) 细胞凋亡诱导剂的新晶型及其制备方法
WO2017025045A1 (zh) 3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法
WO2022194252A1 (zh) 一种化合物的多晶型及其制备方法和应用
WO2018133705A1 (zh) Gft-505的晶型及其制备方法和用途
WO2017162139A1 (zh) 用于治疗或预防jak相关疾病药物的盐酸盐晶型及其制备方法
WO2017076358A1 (zh) 咪唑基联苯基化合物盐的新晶型及其制备方法
WO2018072742A1 (zh) 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2018103027A1 (zh) 替吡法尼的晶型及其制备方法及药物组合物
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
WO2016131406A1 (zh) 一种口服丝裂原活化蛋白激酶抑制剂的晶型及其制备方法
WO2016155631A1 (zh) 托吡司他的新晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16861626

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16861626

Country of ref document: EP

Kind code of ref document: A1