WO2015109925A1 - Forme cristalline de médicament contre l'hépatite c et son procédé de préparation, sa composition pharmaceutique et son utilisation - Google Patents

Forme cristalline de médicament contre l'hépatite c et son procédé de préparation, sa composition pharmaceutique et son utilisation Download PDF

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WO2015109925A1
WO2015109925A1 PCT/CN2014/095517 CN2014095517W WO2015109925A1 WO 2015109925 A1 WO2015109925 A1 WO 2015109925A1 CN 2014095517 W CN2014095517 W CN 2014095517W WO 2015109925 A1 WO2015109925 A1 WO 2015109925A1
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Prior art keywords
sodium salt
tmc435
crystal form
tmc435 sodium
preparation
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PCT/CN2014/095517
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English (en)
Chinese (zh)
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劳海萍
盛晓霞
盛晓红
贾强
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杭州普晒医药科技有限公司
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Priority to CN201480007231.3A priority Critical patent/CN104995189B/zh
Publication of WO2015109925A1 publication Critical patent/WO2015109925A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • This application belongs to the technical field of medicinal chemical crystallization. Specifically, it relates to hepatitis C drugs (2R, 3aR, 10Z, 11aS, 12aR, 14aR)-N-(cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9 ,11a,12,13,14,14a-tetradehydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]- 4-quinolinyl]oxy]-5-methyl-4,14-dioxocyclopenta[c]cyclopropyl[g][1,6]diazepinetetradecene-12a (1H
  • TMC435 The crystalline form of the sodium salt of formamide (TMC435), also relates to a process for the preparation of the crystalline form, to pharmaceutical compositions thereof and to uses thereof.
  • TMC435 is a new generation of hepatitis C virus (HCV) NS3/4A protease inhibitor developed by Medivir and Janssen. TMC435 is used in combination with pegylated interferon and ribavirin for the treatment of adult patients with chronic hepatitis C and may be accompanied by compensatory liver disease (including liver fibrosis at various stages). Its principle of action is to inhibit the replication of HCV in liver cells by inhibiting the NS3/4A protease of HCV.
  • HCV hepatitis C virus
  • OLYSIO is a once daily oral capsule (containing 150 mg of active ingredient) administered by OLYSIO in combination with pegylated interferon and ribavirin for 12 weeks followed by peginterferon and ribavi Lin's combination therapy for 12 weeks or 36 weeks.
  • TMC435 The chemical name of TMC435 is: (2R, 3aR, 10Z, 11aS, 12aR, 14aR)-N-(cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a, 12,13,14,14a-tetradehydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinoline Polinyl]oxy]-5-methyl-4,14-dioxocyclopenta[c]cyclopropyl[g][1,6]diazepinetetradecene-12a(1H)-A Amide, English name is Simeprevir, the molecular formula is C 38 H 47 N 5 O 7 S 2 , the molecular weight is 749.94, and the chemical structural formula is as follows:
  • the patent document WO2007014926A1 discloses a TMC435 compound and a process for its preparation.
  • Patent document WO2008092954A2 discloses six crystal forms of TMC435 (Form I, Form II, Form III, Form IV, Form V and Form VI) and a preparation method thereof, and discloses solubility, XRPD, FT- IR and DSC data, and stated that Form I is an anhydrate and the most stable crystalline form.
  • Patent document WO2010097229A2 discloses TMC435 sodium salt amorphous form and its preparation method, and provides XRPD, FTIR, TGA, DSC, MDSC, DVS and stability data. In addition, this patent document also discloses a formulation scheme for the amorphous form of TMC435 sodium salt.
  • TMC435 and its six crystal forms have the following drawbacks: poor solubility, and solubility in water at room temperature is less than 1 ⁇ g/mL.
  • the present inventors have found that the known TMC435 sodium salt amorphous form has the following drawbacks: The amorphous substance is left at 40 ° C / 75% RH for 10 days and cannot maintain its original form.
  • the present invention provides Form A of the sodium salt of TMC435 (hereinafter referred to as "Form A”) and a process for the preparation thereof.
  • the X-ray powder diffraction pattern of the crystal form A expressed in terms of 2 ⁇ angle has the following characteristic peaks: 4.3 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.6 ⁇ 0.2°, 11.0 ⁇ 0.2°, 12.3 ⁇ 0.2 ° and 18.1 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form A represented by the 2 ⁇ angle has the following characteristic peaks: 4.3 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.6 ⁇ 0.2°, 11.0 ⁇ 0.2°, 12.3 ⁇ 0.2°, 15.1. ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 22.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A represented by the 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • a typical example of the crystal form A has an X-ray powder diffraction pattern as shown in FIG.
  • the FT-IR pattern of the crystal form A has characteristic peaks at wave numbers of 3423, 3331, 2961, 2932, 2866, 1633, 1611, 1451, 1232, 1187, 1119, 870, and 780 cm -1 ;
  • the differential scanning calorimetry (DSC) of the crystal form A is shown in FIG. 2;
  • thermogravimetric analysis (TGA) pattern of Form A is shown in Figure 3.
  • the crystalline form A has the following beneficial effects:
  • Form A is crystalline and has good crystallinity
  • Form A has better crystal form stability and chemical stability.
  • TMC435 sodium salt form A of the present invention has a higher melting point, better crystal form stability and chemical stability than the known TMC435 sodium salt amorphous form, and is better able to counteract Problems such as uneven content and reduced purity caused by factors such as time, temperature and humidity during the manufacture and/or storage of drugs are more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and lower activity
  • Problems such as uneven content and reduced purity caused by factors such as time, temperature and humidity during the manufacture and/or storage of drugs are more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and lower activity
  • the risk of decreased efficacy due to unstable material content and increased levels of impurities is more suitable for solid formulation applications.
  • the preparation method of TMC435 sodium salt crystal form A comprises the following steps: forming a suspension of TMC435 crystal form I in alcohol, adding sodium hydroxide and stirring, maintaining 2-5 at a crystallization temperature of -10 ° C - 50 ° C Days, the TMC435 sodium salt crystal form A was obtained.
  • the alcohol is a C 2 -C 4 alcohols
  • the C 2 -C 4 alcohol may be ethanol, propanol, isopropanol, butanol, sec-butanol or a mixture thereof; and more preferably ethanol.
  • the molar ratio of the TMC 435 Form I to sodium hydroxide is from 1:1 to 1:2, more preferably from 1:1 to 1:1.2.
  • the amount of Form I of TMC 435 in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the alcohol at the crystallization temperature.
  • the sodium hydroxide may be added as a solid or a suspension formed in the alcohol; when it forms a suspension, the amount of sodium hydroxide is its solubility in the alcohol at the crystallization temperature. 2-10 times, preferably 2-5 times.
  • the crystallization temperature is from 10 ° C to 40 ° C, more preferably room temperature.
  • the present invention also provides Form B of the sodium salt of TMC435 (hereinafter referred to as "Form B”) and a process for the preparation thereof.
  • the X-ray powder diffraction pattern of the crystal form B expressed in terms of 2 ⁇ angle has the following characteristic peaks: 5.0 ⁇ 0.2°, 6.0 ⁇ 0.2°, 6.5 ⁇ 0.2°, 13.0 ⁇ 0.2°, 18.5 ⁇ 0.2 ° and 23.2 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form B represented by the 2 ⁇ angle has the following characteristic peaks: 3.6 ⁇ 0.2°, 4.2 ⁇ 0.2°, 5.0 ⁇ 0.2°, 6.0 ⁇ 0.2°, 6.5 ⁇ 0.2°, 10.6. ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.6 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.5 ⁇ 0.2°, 22.6 ⁇ 0.2°, and 23.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B represented by the 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • a typical example of the crystal form B has an X-ray powder diffraction pattern as shown in FIG.
  • the FT-IR pattern of the Form B has characteristic peaks at wave numbers of 3453, 3327, 2960, 2931, 2863, 1635, 1611, 1548, 1408, 1352, 1235, 1118, 1022, 869, and 780 cm -1 ;
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) pattern of Form B is shown in Figure 7.
  • the crystalline form B has the following beneficial effects:
  • Form B is crystalline and has good crystallinity
  • Form B has better crystal form stability and chemical stability.
  • Form B indicates that the TMC435 sodium salt form B of the present invention has a higher melting point, better crystal form stability and chemical stability than the known TMC435 sodium salt amorphous form, and is capable of better resisting the drug. Problems such as uneven content and reduced purity caused by factors such as time, temperature and humidity during manufacturing and/or storage are more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and reduction of active substances. The risk of decreased efficacy due to unstable content and increased levels of impurities is more suitable for solid formulation applications.
  • the preparation method of TMC435 sodium salt crystal form B comprises the steps of: forming a suspension of TMC435 sodium salt amorphous form in a solvent selected from the group consisting of acetonitrile, acetone, methyl ethyl ketone water saturated solution or a mixture thereof, stirring Crystallization gave the TMC435 sodium salt crystal form B.
  • the temperature of the crystallization is 10-40 ° C, more preferably room temperature.
  • the crystallization time is 1-2 weeks, more preferably 7-9 days.
  • the amount of the TMC435 sodium salt amorphous form in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the solvent at the crystallization temperature.
  • the water-saturated solution of the butanone is prepared by mixing an equal volume of methyl ethyl ketone and water, stirring vigorously for 10 minutes, and standing still, and taking the organic layer as a water-saturated solution of methyl ethyl ketone.
  • the present invention also provides a crystal form C of a sodium salt of TMC435 (hereinafter referred to as "crystal form C”) and a process for producing the same.
  • the X-ray powder diffraction pattern of the crystal form C expressed in 2 ⁇ angle has the following characteristic peaks: 3.4 ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.6 ⁇ 0.2°, 12.4 ⁇ 0.2 ° and 18.4 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form C expressed by 2 ⁇ angle has the following characteristic peaks: 3.4 ⁇ 0.2°, 4.2 ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.6 ⁇ 0.2°, 9.1 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 22.4 ⁇ 0.2°, 22.7 ⁇ 0.2°, and 23.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C represented by the 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • crystalline form C has an X-ray powder diffraction pattern as shown in FIG.
  • the FT-IR pattern of the Form C has characteristic peaks at wave numbers of 3500, 3323, 2957, 2932, 2865, 1632, 1610, 1552, 1350, 1234, 1186, 1119, 1017, 870, and 780 cm -1 ;
  • the differential scanning calorimetry (DSC) of the crystal form C is shown in FIG. 10;
  • thermogravimetric analysis (TGA) pattern of Form C is shown in FIG.
  • the crystalline form C has the following beneficial effects:
  • Form C is crystalline and has good crystallinity
  • Form C has better crystal form stability and chemical stability.
  • Form C indicates that the TMC435 sodium salt form C of the present invention has a higher melting point, better crystal form stability and chemical stability than the known TMC435 sodium salt amorphous form, and is better able to counteract Problems such as uneven content and reduced purity caused by factors such as time, temperature and humidity during the manufacture and/or storage of drugs are more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and lower activity
  • Problems such as uneven content and reduced purity caused by factors such as time, temperature and humidity during the manufacture and/or storage of drugs are more conducive to accurate quantification and later transportation and storage in the preparation of unit preparations, and lower activity
  • the risk of decreased efficacy due to unstable material content and increased levels of impurities is more suitable for solid formulation applications.
  • the preparation method of TMC435 sodium salt crystal form C comprises the steps of: forming a suspension of TMC435 sodium salt amorphous form in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, chloroform or a mixture thereof, and stirring Crystallization, the TMC435 sodium salt crystal form C is obtained.
  • the temperature of the crystallization is 10-40 ° C, more preferably room temperature.
  • the crystallization time is 1-2 weeks, more preferably 7-9 days.
  • the amount of the TMC435 sodium salt amorphous form in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the solvent at the crystallization temperature.
  • the present invention also provides Form D of the sodium salt of TMC435 (hereinafter referred to as "Form D”) and a process for the preparation thereof.
  • the X-ray powder diffraction pattern of the crystal form D expressed in 2 ⁇ angle has the following characteristic peaks: 5.4 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.5 ⁇ 0.2°, 8.8 ⁇ 0.2°, 12.8 ⁇ 0.2 ° and 20.0 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form D represented by the 2 ⁇ angle has the following characteristic peaks: 5.4 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.5 ⁇ 0.2°, 8.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.5. ⁇ 0.2°, 12.8 ⁇ 0.2°, 15.3 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.4 ⁇ 0.2°, and 22.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form D represented by the 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • a typical example of the crystal form D has an X-ray powder diffraction pattern as shown in FIG.
  • the FT-IR pattern of the crystal form D has characteristic peaks at wave numbers of 3474, 2955, 2930, 2868, 1658, 1609, 1510, 1452, 1351, 1232, 1186, 1120, 1105, and 844 cm -1 ;
  • Form D is crystalline and has better crystallinity than the known TMC435 sodium salt amorphous.
  • the preparation method of the TMC435 sodium salt crystal form D comprises the steps of: forming a suspension of the TMC435 sodium salt amorphous substance in methyl ethyl ketone, and stirring and crystallization to obtain the TMC435 sodium salt crystal form D.
  • the temperature of the crystallization is 10-40 ° C, more preferably room temperature.
  • the crystallization time is 1-2 weeks, more preferably 7-9 days.
  • the amount of TMC435 sodium salt amorphous in the suspension is from 2 to 10 times, preferably from 2 to 5 times, the solubility in methyl ethyl ketone at the crystallization temperature.
  • the stirring may be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring or the like.
  • the stirring rate is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the precipitated crystals are separated, washed and dried by a conventional method in the art.
  • the separation using conventional methods in the art For example, filtration, centrifugation, etc.; the specific operation of the filtration is: placing the sample to be separated on the filter paper and vacuum filtration; the specific operation of the centrifugation is: placing the sample to be separated in a centrifuge tube, and then rotating at high speed until the solid is completely Sink to the bottom of the centrifuge tube at a rate of, for example, 6000 rpm.
  • the solvent to be washed is preferably the same as the solvent used in the method for preparing the crystal form, and the amount of the washing solvent is 2 to 10 times that of the crystallization solvent.
  • the drying is carried out by a conventional method in the art such as natural drying, blast drying or reduced pressure drying; the drying device is a fume hood, a blast oven or a vacuum oven; the drying is carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09. Mpa; drying temperature is about room temperature to 60 ° C; drying time is 1 to 48 hours, preferably 1 to 16 hours.
  • the "room temperature” means about 10 to 30 °C.
  • crystal in the present invention, “crystal”, “crystal form” or “amorphous” means that it is confirmed by the X-ray diffraction pattern characterization shown.
  • the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Form A, Form B, Form C and Form D of the sodium salt of TMC435 of the present invention are pure, unitary, and are substantially free of any other crystal form or amorphous form.
  • substantially free when used to refer to a new crystalline form means that the other crystalline form or amorphous substance contained in the new crystalline form is less than 20% by weight, more preferably less than 10% by weight. In particular, it means less than 5% by weight, especially less than 1% by weight.
  • the starting material TMC435 of the present invention can be obtained by the preparation method of the patent document WO2007014926A1 or can be obtained commercially.
  • the TMC435 crystal form I can be obtained by the preparation method of the patent document WO2008092954A2, and the TMC435 sodium salt amorphous substance can be prepared by referring to the preparation of the patent document WO2010097229A2. Method made.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more novel crystalline forms of the sodium salt of TMC435 of the present invention or sodium TMC435 prepared by the method of the present invention.
  • the new crystalline form of the sodium salt of TMC435 comprises Form A, Form B, Form C or Form D of the sodium salt of TMC435.
  • the pharmaceutical compositions may also comprise other pharmaceutically acceptable crystalline forms or amorphous forms of the sodium salt of TMC435, or pharmaceutically acceptable crystalline forms or amorphous forms of other salts of TMC435 and TMC435.
  • the pharmaceutical composition may also comprise one or more other pharmaceutically active ingredients, such as other antiviral compounds, especially anti-HCV compounds.
  • the above pharmaceutical composition may be formulated into a certain dosage form, preferably by oral administration, parenteral administration (including subcutaneous, intramuscular and intravenous), rectal administration, transdermal administration, buccal administration, nasal administration.
  • Dosage forms include, but are not limited to, solid dosage forms, liquid dosage forms, semi-liquid dosage forms, aerosols or suppositories.
  • dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions;
  • suitable forms for parenteral administration include aqueous or nonaqueous solutions or Emulsions;
  • dosage forms suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers;
  • dosage forms suitable for transdermal administration include ointments, creams;
  • formulations suitable for nasal administration include aerosols, sprays.
  • the above dosage forms may be adapted to the rapid release, delayed release or modified release of the active ingredient, as desired.
  • the pharmaceutically acceptable carrier of the present invention includes a solid carrier, and specifically includes, but not limited to, a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate.
  • a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate.
  • binders such as acacia, guar, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, etc.
  • disintegration Agents such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.
  • lubricants such as stearic acid, magnesium stearate, hard Zinc citrate, sodium benzoate, sodium acetate, etc.
  • glidants such as colloidal silica
  • complex forming agents such as various grades of cyclodextrins and resins
  • release rate controlling agents such as hydroxypropylcellulose, Hydroxymethyl cellulose, hydroxypropyl methyl fiber Vitamins, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, and the like.
  • the pharmaceutically acceptable carrier of the present invention further comprises a liquid carrier, and specifically includes, but not limited to, a solvent of an aqueous, oily or alcoholic solution such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil. , ethanol, propanol, glycerin, etc. Further, a carrier such as polyethylene glycol or polypropylene glycol can also be used. Other pharmaceutically acceptable carriers may also be selected depending on the dosage form, including, but not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, penetrants, buffers. Wait. Each carrier must be acceptable, compatible with the other ingredients in the formulation and not deleterious to the patient.
  • a solvent of an aqueous, oily or alcoholic solution such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • Form A, Form B, Form C, Form D, or a combination thereof, of the sodium salt of TMC435 of the present invention is admixed with one or more pharmaceutically acceptable carriers, optionally, with One or more other pharmaceutically active ingredients are mixed.
  • the solid preparation can be prepared by a process such as mixing, granulation, or the like, and the liquid or semi-liquid dosage form can be prepared by a process of mixing, dissolving, dispersing, emulsifying, or the like.
  • the present invention provides a novel crystalline form of the sodium salt of TMC435 of the present invention or a novel crystalline form of the sodium salt of TMC435 obtained by the preparation method of the present invention, which is prepared for the treatment and/or prevention of hepatitis C virus (HCV) infection or with type C
  • HCV hepatitis C virus
  • the new crystalline form of the sodium salt of TMC435 comprises Form A, Form B, Form C, Form D or a combination thereof of the sodium salt of TMC435
  • the liver diseases associated with HCV infection include conditions caused by HCV, including progressive liver fibrosis, inflammation or necrosis that causes cirrhosis, terminal liver disease, and hepatocellular carcinoma (HCC).
  • the present invention provides a method of treating and/or preventing hepatitis C virus (HCV) infection or liver disease associated with hepatitis C virus (HCV) infection, the method comprising administering to a patient in need thereof for treatment and/or A prophylactically effective amount of a novel crystalline form of the sodium salt of TMC435 of the present invention, or a combination thereof, or a pharmaceutical composition thereof, wherein the novel crystalline form of the sodium salt of TMC435 comprises Form A, Form B, Form C of the sodium salt of TMC435, Form D or a combination thereof.
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • the liver diseases associated with HCV infection include conditions caused by HCV, including progressive liver fibrosis, inflammation or necrosis that causes cirrhosis, terminal liver disease, and hepatocellular carcinoma (HCC). Such patients include, but are not limited to, mammals.
  • the amount administered refers to an amount effective to inhibit or reduce HCV infection or to effectively inhibit or reduce the disease associated with HCV infection.
  • a typical effective daily dose is from 0.01 to 500 mg/kg body weight, preferably from 0.1 to 50 mg/kg body weight.
  • the daily dose required may be administered in a single dose in unit dosage form or multiple times at suitable intervals, containing from 1 to 1000 mg, especially from 5 to 200 mg, for example about 25 mg, or about 50 mg, per unit dosage form, or About 75 mg, or about 100 mg, or about 150 mg, or about 200 mg of the TMC435 active ingredient.
  • anti-HCV compounds such as interferon-[alpha] (IFN-[alpha]), pegylated interferon-[alpha] and/or triazole nucleosides, and optionally other anti-HCV compounds
  • TMC435 Form A of the sodium salt, Form B, Form C, Form D or a combination thereof for use as a drug in combination therapy
  • said other anti-HCV compound is selected from the group consisting of HCV polymer inhibitors, HCV protease inhibitors, Inhibitors, immunomodulatory drugs, other antiviral drugs or combinations thereof for other targets in the HCV life cycle.
  • the combination therapy comprises pegylated interferon-[alpha], ribavirin, and Form A of the sodium salt of TMC435 of the invention, Form B, Form C, Form D, or a combination thereof.
  • Figure 1 is an XRPD pattern of the crystalline form A of the sodium salt of TMC435 of the present invention.
  • FIG. 2 is a DSC pattern of the TMC435 sodium salt form A of the present invention.
  • Figure 3 is a TGA pattern of the crystalline form A of the sodium salt of TMC435 of the present invention.
  • FIG. 4 is an FT-IR spectrum of the TMC435 sodium salt form A of the present invention.
  • Figure 5 is an XRPD pattern of the TMC435 sodium salt form B of the present invention.
  • FIG. 6 is a DSC chart of the TMC435 sodium salt form B of the present invention.
  • FIG. 7 is a TGA map of the TMC435 sodium salt form B of the present invention.
  • Figure 8 is an FT-IR spectrum of the TMC435 sodium salt Form B of the present invention.
  • Figure 9 is an XRPD pattern of the crystalline form C of the sodium salt of TMC435 of the present invention.
  • Figure 10 is a DSC chart of the TMC435 sodium salt form C of the present invention.
  • Figure 11 is a TGA map of the crystalline form C of the sodium salt of TMC435 of the present invention.
  • Figure 12 is an FT-IR spectrum of the crystalline form C of the sodium salt of TMC435 of the present invention.
  • Figure 13 is an XRPD pattern of the crystalline form D of the sodium salt of TMC435 of the present invention.
  • Figure 14 is an FT-IR spectrum of the crystalline form D of the sodium salt of TMC435 of the present invention.
  • Figure 15 is an XRPD pattern of TMC435 Form I prepared in accordance with WO2008092954A2.
  • Figure 16 is an XRPD pattern of the TMC435 sodium salt amorphous form prepared in accordance with WO2010097229A2.
  • Figure 17 is a FT-IR spectrum of the TMC435 sodium salt amorphous form prepared in accordance with WO2010097229A2.
  • Fig. 18 shows the results of the stability test of the TMC435 sodium salt crystal form A in Comparative Example 1 (from the bottom to the top, the samples before and after the placement).
  • Fig. 19 shows the results of the stability test of the TMC435 sodium salt crystal form B in Comparative Example 1 (from the bottom to the top, the samples before and after the placement).
  • Fig. 20 shows the results of the stability test of the TMC435 sodium salt crystal form C in Comparative Example 1 (from the bottom to the top, the samples before and after the placement).
  • Fig. 21 shows the results of the stability test of the TMC435 sodium salt amorphous substance in Comparative Example 1 (from the bottom to the top, the samples before and after the placement).
  • the instrument used for X-ray powder diffraction was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a ⁇ -2 ⁇ goniometer at 40 kV and 40 mA, and a Mo color.
  • Instrument, Lynxeye detector The instrument is calibrated with silicon carbide before use.
  • the acquisition software is Diffrac Plus XRD Commander.
  • the sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate.
  • the detailed detection conditions are as follows, the angle range is 3 - 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • the differential thermal analysis data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of 1-10 mg was usually placed in an aluminum pan, and the sample was raised from 0 ° C to 300 ° C under the protection of 40 mL/min dry N 2 at a temperature increase rate of 10 ° C/min.
  • thermogravimetric analysis data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 1-15 mg of the sample was placed in a platinum crucible, and the sample was raised from room temperature to 350 ° C under the protection of 40 mL/min dry N 2 at a heating rate of 10 ° C/min.
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400 MHZ NMR spectrometer. A 1-5 mg sample was weighed and dissolved in 0.5 mL of deuterated chloroform (CDCl 3 ) to prepare a solution of 2 mg/mL - 10 mg/mL.
  • FT-IR Fourier infrared spectroscopy
  • Raman spectroscopy (Raman) data was taken from the Nikola DXR 780, and the instrument control software and data analysis software were onmic 8.2. The sample was subjected to Raman spectroscopy usually under a 10x mirror, in the range of wave number 50-3400 cm -1 , 8 times of exposure, and 1 second of exposure time.
  • the ultrasonic operation in the examples facilitated dissolution of the sample and the apparatus was an ultrasonic cleaner operated at 40 kHz for 15 minutes.
  • TMC435 can be obtained by referring to the preparation method of Example 5 of the patent document WO2007014926A1. Specifically: 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14 -dioxo-3,13-diazatricyclo[13.3.0.04,6]octadecyl-7-ene-4-carboxylic acid (2.80 g, 4.335 mmol) and carbonylbiimidazole (1.54 g, 9.5 mmol) The solution in anhydrous tetrahydrofuran (50 mL) was stirred under nitrogen for 2 hr.
  • TMC435 The crystal form I of TMC435 can be obtained by referring to the preparation method of Example 3 of the patent document WO2008092954A2. Specifically, TMC 4352.1 g was refluxed in 5 mL of n-butanol, and 45 mL of n-butanol was added to the boiled suspension to obtain a clear solution. The solution was stirred under reflux for 48 hours and allowed to cool to room temperature. Filtration, filter cake washed with n-butanol, dried under vacuum at 40 ° C overnight to give TMC 435.
  • the TMC435 sodium salt amorphous form can be obtained by referring to the preparation method of Example 1 of the patent document WO2010097229A2. Specifically, sodium hydroxide solution (dissolved 24.10 g of sodium hydroxide in 60.03 g of purified water) was added to 5,905.30 g of vigorously stirred dichloromethane. Under stirring, TMC 435 (450.09 g) was added and the gradual evolution was continued with stirring until a clear solution was obtained. The resulting clear solution was spray dried under nitrogen, and the spray dried product was collected and dried under vacuum at 50 ° C to give a sodium salt of TMC435.
  • the FT-IR spectrum is shown in Figure 17, and the FT-IR analysis is the TMC435 sodium salt amorphous.
  • TMC435 Form I (173.01 mg, 0.231 mmol) and 2.0 mL of ethanol were added to a 5 mL glass vial and sonicated for 15 minutes to obtain a white suspension (the amount of TMC435 Form I in the suspension was at this temperature).
  • the TGA map is shown in Figure 3.
  • the FT-IR spectrum is shown in Fig. 4.
  • the crystal form A has characteristic peaks at wave numbers of 3423, 3331, 2961, 2932, 2866, 1633, 1611, 1451, 1232, 1187, 1119, 870, and 780 cm -1 .
  • TMC435 Form I (69.12 mg, 0.092 mmol) and 6.2 mL of n-propanol were added to a 20 mL glass vial at -10 ° C. Ultrasonic for 15 minutes gave a white suspension (the amount of TMC435 Form I in the suspension was It is twice the solubility in n-propanol at this temperature), sodium hydroxide (4.42 mg, 0.1105 mmol) is added, and the mixture is stirred and whitened. The color suspension was stirred at -10 ° C for 4 hours to obtain a clear solution.
  • TMC435 Form I 120.01 mg, 0.160 mmol
  • 3.0 mL of sec-butanol were added in a 5 mL glass vial and sonicated for 15 minutes to obtain a white suspension
  • the amount of TMC435 Form I in the suspension was At this temperature, 5 times the solubility in sec-butanol
  • a suspension prepared by adding sodium hydroxide (6.40 mg, 0.160 mmol) and 0.2 mL of sec-butanol, mixed and stirred to obtain a white suspension (the suspension)
  • the amount of sodium hydroxide in the liquid is 5 times the solubility in the sec-butanol at this temperature; stirring at 50 ° C for 1 hour to obtain a clear solution, stirring is continued for 3 days to precipitate a white solid; filtered and washed 3 times with sec-butanol It was dried under vacuum at 60 ° C for 48 hours to obtain a crystal form A of TMC435 sodium salt.
  • the yield was 100.17 mg and the
  • TMC435 Form I 46.08 mg, 0.061 mmol
  • propanol 3.8 mL of propanol
  • the amount of TMC435 Form I in the suspension was At this temperature, twice the solubility in n-propanol), sodium hydroxide (2.44 mg, 0.061 mmol) was added, and the mixture was stirred and stirred to obtain a white suspension; the mixture was stirred at 10 ° C for 1 hour to obtain a clear solution, and stirring was continued for 5 days.
  • White solid filtered and washed 3 times with propanol, dried under vacuum at 60 ° C for 1 hour to give TMC435 sodium salt crystal form A.
  • the yield was 21.85 mg and the yield was 46.0%.
  • TMC435 Form I (60.00 mg, 0.080 mmol) and 1.5 mL of butanol were added to a 5 mL glass vial at 40 ° C. Ultrasonic for 15 minutes gave a white suspension (the amount of TMC435 Form I in the suspension was At this temperature, 5 times the solubility in butanol), a suspension prepared by adding sodium hydroxide (3.84 mg, 0.096 mmol) and 0.12 mL of butanol, and mixing and stirring to obtain a white suspension (hydrogen in the suspension) The amount of sodium oxide is 5 times the solubility in butanol at this temperature; stirring at 40 ° C for 5 hours to obtain a clear solution, stirring is continued for 2 days to precipitate a white solid; filtered and washed 3 times with butanol, vacuum dried at 60 ° C After 16 hours, TMC435 sodium salt crystal form A was obtained. The yield was 50.27 mg and the yield was 82.1%.
  • the samples prepared in Examples 2 to 5 had the same or similar XRPD patterns, DSC patterns, TGA patterns, FT-IR patterns, and Raman patterns (not shown) as the samples of Example 1.
  • the samples of Examples 2 to 5 were identical to the samples of Example 1.
  • TMC435 sodium salt amorphous form 50.47 mg
  • 2.0 mL acetonitrile in a 5 mL glass vial at room temperature and obtain a white suspension by sonication for 15 minutes
  • the amount of TMC435 sodium salt amorphous in the suspension is At a temperature of 10 times the solubility in acetonitrile, stirring at room temperature for one week, filtering and washing twice with acetonitrile, and drying under vacuum at 40 ° C for 16 hours to obtain TMC435 sodium salt form B.
  • the yield was 45.75 mg; the yield was 90.6%.
  • the TGA map is shown in Figure 7.
  • the FT-IR spectrum is shown in Fig. 8.
  • the crystal form B has characteristics at wave numbers of 3453, 3327, 2960, 2931, 2863, 1635, 1611, 1548, 1408, 1352, 1235, 1118, 1022, 869 and 780 cm -1 . peak.
  • TMC435 sodium salt amorphous 11.15 mg
  • 2.0 mL of acetone were added to a 5 mL glass vial and sonicated for 15 minutes to obtain a white suspension (the amount of TMC435 sodium salt amorphous in the suspension was At this temperature, the solubility in acetone was twice (2 times), stirred at 40 ° C for 9 days, filtered and washed twice with acetone, and vacuum dried at room temperature for 48 hours to obtain TMC435 sodium salt form B.
  • the yield was 4.73 mg; the yield was 42.4%.
  • TMC435 sodium salt amorphous (30.47 mg) and 3.0 mL of methyl ethyl ketone in a 5 mL glass vial at 10 ° C.
  • Ultrasonic for 15 minutes to obtain a white suspension (TMC435 sodium salt amorphous in the suspension)
  • the amount is 5 times of the solubility in the water-saturated solution of methyl ethyl ketone at this temperature, stirred at 10 ° C for 2 weeks, filtered, washed 3 times with a water-saturated solution of methyl ethyl ketone, and dried under vacuum at 60 ° C for 1 hour.
  • TMC435 sodium salt Form B The yield was 27.89 mg; the yield was 91.5%.
  • the samples prepared in Examples 7 and 8 had the same or similar XRPD patterns, DSC patterns, TGA patterns, FT-IR patterns, and Raman patterns (not shown) as the samples of Example 6.
  • the samples of Examples 7 and 8 were identical to the samples of Example 6.
  • TMC435 sodium salt amorphous 71.85 mg
  • 1.5 mL of ethyl acetate were added to a 5 mL glass vial and sonicated for 15 minutes to obtain a white suspension (the amount of TMC435 sodium salt amorphous in the suspension was The solution was stirred at room temperature for 10 times at room temperature, stirred at room temperature for one week, filtered and washed three times with ethyl acetate, and dried under vacuum at 40 ° C for 16 hours to obtain TMC435 sodium salt crystal form C.
  • the yield was 62.57 mg; the yield was 87.1%.
  • the XRPD pattern is shown in Figure 9, which is the TMC435 sodium salt crystal form C.
  • the DSC spectrum is shown in Figure 10.
  • the TGA map is shown in Figure 11.
  • the FT-IR spectrum is shown in Fig. 12, and the crystal form C has characteristics at wave numbers of 3500, 3323, 2957, 2932, 2865, 1632, 1610, 1552, 1350, 1234, 1186, 1119, 1017, 870, and 780 cm -1 . peak;
  • TMC435 sodium salt amorphous substance 11.93 mg
  • 1.0 mL of isopropyl acetate in a 5 mL glass vial at 40 ° C.
  • Ultrasonic for 15 minutes to obtain a white suspension (the amount of TMC435 sodium salt amorphous in the suspension) It was stirred at 40 ° C for 9 days at this temperature, stirred at 40 ° C for 9 days, filtered and washed 3 times with isopropyl acetate, and vacuum dried at room temperature for 48 hours to obtain TMC435 sodium salt crystal form C.
  • the yield was 5.47 mg and the yield was 45.9%.
  • TMC435 sodium salt amorphous (10.55 mg) and 1.0 mL of chloroform were added to a 5 mL glass vial and sonicated for 15 minutes to obtain a white suspension (the amount of TMC435 sodium salt amorphous in the suspension was At this temperature, the solubility in chloroform was 5 times), the mixture was stirred at 10 ° C for 2 weeks, filtered and washed three times with chloroform, and vacuum dried at 60 ° C for 1 hour to obtain TMC435 sodium salt crystal form C. The yield was 7.20 mg and the yield was 68.2%.
  • the samples prepared in Examples 10 and 11 had the same or similar XRPD patterns, DSC patterns, TGA patterns, FT-IR patterns, and Raman patterns (not shown) as the samples of Example 9.
  • the samples of Examples 10 and 11 were identical to the samples of Example 9.
  • the FT-IR spectrum is as shown in FIG. 14 , and the crystal form D has characteristic peaks at wave numbers of 3474, 2955, 2930, 2868, 1658, 1609, 1510, 1452, 1351, 1232, 1186, 1120, 1105, and 844 cm -1 ;
  • TMC435 sodium salt amorphous 50.93 mg
  • 0.4 mL of methyl ethyl ketone were added in a 5 mL glass vial and sonicated for 15 minutes to obtain a white suspension (the amount of TMC435 sodium salt amorphous in the suspension was At this temperature, 10 times the solubility in methyl ethyl ketone), stirred at 40 ° C for 9 days, filtered and washed three times with methyl ethyl ketone, and vacuum dried at room temperature for 48 hours to obtain TMC 435 sodium salt form D. The yield was 10.11 mg and the yield was 19.8%.
  • TMC435 sodium salt amorphous (18.17 mg) and 10 mL of methyl ethyl ketone were added in a 20 mL glass vial and sonicated for 15 minutes to obtain a white suspension (the amount of TMC435 sodium salt amorphous in the suspension was At this temperature, the solubility in methyl ethyl ketone was twice (2 times), the mixture was stirred at 10 ° C for 2 weeks, filtered and washed three times with methyl ethyl ketone, and vacuum dried at 60 ° C for 1 hour to obtain TMC435 sodium salt crystal form D. The yield was 5.45 mg and the yield was 30.0%.
  • the samples prepared in Examples 13 and 14 had the same or similar XRPD patterns, FT-IR patterns, and Raman patterns (not shown) as the samples of Example 12.
  • the samples of Examples 13 and 14 were identical to the samples of Example 12.
  • a capsule containing the crystalline form A of the sodium salt of TMC435 of the present invention is prepared.
  • the unit dose formulation is as follows.
  • Preparation Method 72.0 g of the TMC435 sodium salt form A of the present invention, 1.2 g of sodium lauryl sulfate, 1.2 g of anhydrous colloidal silica, and 159.0 g of lactose monohydrate were sieved and mixed by a three-dimensional mixer for 10 minutes. 1.2 g of sieved magnesium stearate was added to the mixture and mixed for 5 minutes. The resulting mixture was filled into a hard gelatin capsule to prepare 700 capsules containing the crystal form A of the sodium salt of TMC435 of the present invention.
  • a capsule containing the crystalline form A of the sodium salt of TMC435 of the present invention is prepared.
  • the unit dose formulation is as follows.
  • Preparation method 108.0 g of the TMC435 sodium salt form A of the present invention, 1.8 g of sodium lauryl sulfate, 1.8 g of anhydrous colloidal silica, and 238.5 g of lactose monohydrate were sieved and mixed by a three-dimensional mixer for 10 minutes. 1.8 g of sieved magnesium stearate was added to the mixture and mixed for 5 minutes. The resulting mixture was filled into a hard gelatin capsule to prepare 700 capsules containing the crystal form A of the sodium salt of TMC435 of the present invention.
  • a capsule containing the crystalline form B of the sodium salt of TMC435 of the present invention is prepared.
  • Example 15 and Example 16 The "TMC435 sodium salt crystal form A" in Example 15 and Example 16 was replaced with "TMC435 sodium salt form B", and the other operations were the same as those in Example 15 and Example 16, to obtain the crystal form B containing the sodium salt of the present invention. Capsules.
  • a capsule containing the crystalline form C of the sodium salt of TMC435 of the present invention is prepared.
  • Example 15 and Example 16 The "TMC435 sodium salt crystal form A" in Example 15 and Example 16 was replaced with "TMC435 sodium salt crystal form C", and the other operations were the same as those in Example 15 and Example 16, to obtain the crystal form C containing the sodium salt of the present invention. Capsules.
  • a capsule containing the crystalline form D of the sodium salt of TMC435 of the present invention is prepared.
  • Example 15 and Example 16 The "TMC435 sodium salt crystal form A" in Example 15 and Example 16 was replaced with "TMC435 sodium salt crystal form D", and the other operations were the same as those in Example 15 and Example 16, to obtain the crystal form D containing the sodium salt of the present invention. Capsules.
  • Crystalline type A, Form B and Form C of the sodium salt of TMC435 of the present invention, and the known TMC435 sodium salt amorphous form prepared in Preparation Example 3 were subjected to a crystal form stability comparison test.
  • each 20 mg sample is placed in a 20 ml glass bottle, and placed in an open environment at 40 ° C, 75% RH for 10 days, and characterized by XRPD before and after standing.
  • Correlation maps for Form A, Form B and Form C of the sodium salt of TMC435 of the present invention, and the known amorphous form of TMC435 sodium salt are shown in Figures 18-21, respectively.
  • the crystal form A, the crystal form B and the crystal form C of the sodium salt of TMC435 of the present invention, and the known TMC435 sodium salt amorphous form prepared in Preparation Example 3 were subjected to a chemical stability comparison test.
  • each 20mg sample is placed in a 20ml glass bottle, respectively placed in a 25 ° C dryer, or 60 ° C blast oven, or 40 ° C / 75% RH environment, or 40 ° C / hydrogen peroxide urea environment Or, at 25 ° C / light (4500 ⁇ 500 Lux) for 10 days, HPLC purity characterization before and after placement.

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Abstract

La présente invention concerne une forme cristalline d'un médicament contre l'hépatite C constitué de sel sodique de (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropyl sulphonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tétradécahydro-2-[[7-méthoxyl-8-méthyl-2-[4-(1-méthyléthyl)-2-thiazolyl]-4-quinolinyl] oxyl]-5-méthyl-4,14-dioxocyclopentano[c]cyclopropo[g][1,6] diazacyclotétradécène-12a(1H)-méthanamine(TMC435), la forme cristalline ayant une bonne cristallinité et stabilité comparées aux formes cristallines connues. La présente invention concerne en outre un procédé de préparation, une composition pharmaceutique et l'utilisation de la forme cristalline, l'utilisation dans la préparation de médicaments permettant le traitement et/ou la prévention de l'infection hépatique virale C ou de l'insuffisance hépatique liée à l'infection hépatique virale C.
PCT/CN2014/095517 2014-01-21 2014-12-30 Forme cristalline de médicament contre l'hépatite c et son procédé de préparation, sa composition pharmaceutique et son utilisation WO2015109925A1 (fr)

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WO2007014926A1 (fr) * 2005-07-29 2007-02-08 Tibotec Pharmaceuticals Ltd. Inhibiteurs macrocycliques du virus de l'hépatite c
WO2010097229A2 (fr) * 2009-02-27 2010-09-02 Ortho-Mcneil-Janssen Pharmaceuticals Inc Sel amorphe d'un inhibiteur macrocyclique du vhc
CN101921269A (zh) * 2009-06-12 2010-12-22 中国中化股份有限公司 一种制备hcv抑制剂的方法

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RU2533830C2 (ru) * 2007-02-01 2014-11-20 Тиботек Фармасьютикалз Лтд. Полиморфные формы макроциклического ингибитора hcv
JP5872539B2 (ja) * 2010-03-31 2016-03-01 ギリアド ファーマセット エルエルシー プリンヌクレオシドホスホルアミダート

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Publication number Priority date Publication date Assignee Title
WO2007014926A1 (fr) * 2005-07-29 2007-02-08 Tibotec Pharmaceuticals Ltd. Inhibiteurs macrocycliques du virus de l'hépatite c
WO2010097229A2 (fr) * 2009-02-27 2010-09-02 Ortho-Mcneil-Janssen Pharmaceuticals Inc Sel amorphe d'un inhibiteur macrocyclique du vhc
CN101921269A (zh) * 2009-06-12 2010-12-22 中国中化股份有限公司 一种制备hcv抑制剂的方法

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