WO2015149270A1 - Crystal of trelagliptin semi-succinate and preparation method and pharmaceutical composition thereof - Google Patents

Crystal of trelagliptin semi-succinate and preparation method and pharmaceutical composition thereof Download PDF

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Publication number
WO2015149270A1
WO2015149270A1 PCT/CN2014/074518 CN2014074518W WO2015149270A1 WO 2015149270 A1 WO2015149270 A1 WO 2015149270A1 CN 2014074518 W CN2014074518 W CN 2014074518W WO 2015149270 A1 WO2015149270 A1 WO 2015149270A1
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WIPO (PCT)
Prior art keywords
troglitazone
hemisuccinate
crystal
trozastatin
crystals
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PCT/CN2014/074518
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French (fr)
Chinese (zh)
Inventor
宋小叶
盛晓霞
盛晓红
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杭州普晒医药科技有限公司
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Priority to PCT/CN2014/074518 priority Critical patent/WO2015149270A1/en
Priority to CN201480022426.5A priority patent/CN105228988B/en
Publication of WO2015149270A1 publication Critical patent/WO2015149270A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of medicinal chemical crystallization technology.
  • it relates to a crystal of an antidepressant troglitazone hemisuccinate, to a method for preparing the crystal, a pharmaceutical composition thereof, and use thereof.
  • Background technique
  • Triglitastat succinate is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor developed by Takeda and Furiex Pharmaceuticals for the treatment of type 2 diabetes.
  • the drug is in clinical phase III.
  • the oral solid preparation is troglitazone succinate as a pharmaceutically active ingredient, and the dosage form is a tablet and a capsule, and the specification is 1-20 mg, once a week orally.
  • troglitazone succinate 2-[6-[(3R)-3-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4- Dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate, English name: Trelagliptin succinate or SYR-472 succinate, molecular formula C 22 H 26 FN 5 0 6 , molecular weight 475.47, chemistry The structure ⁇ is shown below:
  • Patent document WO2007/035629A2 discloses treglistatin succinate and a process for the preparation thereof, and also discloses triflurane salt, hydrochloride, benzoate, tosylate, methanesulfonic acid of troglitazone. Salt, besylate, (R; -; >-mandelic acid salt and methods for their preparation).
  • Patent documents WO2007/033350A1 and WO2008/033851A2 disclose pharmaceutical compositions of troglitazone succinate, their use for the treatment of diabetes, cancer, autoimmune disorders, HIV infection, and methods of administration.
  • the above document also discloses statastatin hemisuccinate, but does not disclose any characterization data of the compound or its crystalline form and a process for its preparation.
  • the patent document WO 2008/067465 A1 discloses a polymorphic form of troglitazone succinate and a preparation method thereof, wherein the polymorphic type includes A type, B type, C type, D type, E type, F type, G type and Its amorphous form.
  • Type A is anhydrous and stable under ambient conditions
  • Type A is needle crystal or needle crystal/spherical crystal
  • Type B is a hydrated solid form, which is obtained by Form B and A.
  • Type mixture A+B type
  • type B will be converted to type A under dehydration conditions, and type A+B will be stressed by relative humidity.
  • the test will also be converted to Form A; Form C is needle crystal and preparation takes about 8 days; Type D is a hydrated solid form with >20% weight loss from 25 ° C to 85 ° C; It is a hydrated solid form which is converted to Form A under dehydration conditions; A+F type mixture is obtained when Form F is prepared; A+E+G type mixture is obtained when Form G; Amorphous form is at 58% Stress produces a type A at 88% relative humidity and stress in water vapor produces a mixture of type A and type D. It is known from the patent literature that there are seven crystal forms of troglitazone succinate, which makes the crystallization process difficult to obtain a single crystal form, affects process repeatability and product quality, and also contains more Impurities.
  • the present inventors have found that a variety of solvents which should be restricted, such as acetonitrile, dichloromethane, methanol, toluene, hexane, tetrahydrofuran, are used in the preparation method of Form A.
  • solvents such as acetonitrile, dichloromethane, methanol, toluene, hexane, tetrahydrofuran.
  • the patent document WO 2009/147125 A1 discloses a novel use of troglitazone or a pharmaceutically acceptable salt thereof for the treatment and/or prevention of nonalcoholic fatty liver disease (NAFLD).
  • NAFLD nonalcoholic fatty liver disease
  • the main object of the present invention is to solve the problems of the presence of known salts and their crystals by providing new troglitin salts and their crystals.
  • the present invention also relates to the novel method for preparing troglitazone salt and crystals thereof, a pharmaceutical composition thereof and use thereof.
  • novel troglitazone salt and its crystals have at least one of the following advantageous properties compared to known salts and crystals thereof: good stability, such as crystal form stability, thermal stability, chemical stability, Mechanical stability, storage stability, etc.; Good solubility; Fast dissolution rate; High crystallinity; Not easy to absorb moisture; Easy to purify and handle; High chemical purity; Low residual solvent; Low toxicity; Good particle morphology; Such as good fluidity, favorable powder viscosity, tightness and compactability; improved formulation appearance; high drug loading; improved bioavailability, efficacy; extended formulation shelf life; suitable for new dosage form applications.
  • statastatin hemisuccinate was a compound formed from trozastatin and succinic acid in a molar ratio of about 2:1.
  • the present invention provides a process for preparing treglistatin hemisuccinate, which comprises the steps of: respectively forming a solution system of troglitazone hydrochloride and disodium succinate in a soluble solvent; ,
  • the molar ratio of troglitazone hydrochloride to disodium succinate in the two solution systems is 10:1 ⁇ 2:1, and the two solution systems are mixed to carry out the reaction. After the reaction is completed, the solvent is removed to obtain the troglitazone.
  • the soluble solvent is selected from the group consisting of water, alcohol or a mixture thereof.
  • the preparation method has an operating temperature of 20 to 40 ° C and a reaction time of 1 to 8 hours.
  • the "removal of the solvent” can be accomplished by conventional techniques in the art, such as filtration, centrifugation or spin drying.
  • the "filtration” is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the specific operation of the "centrifugation” is to place the sample to be separated in a 2 mL centrifuge tube and centrifuge at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • the “spinning” is generally carried out by steaming at a pressure less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa.
  • the solvent is removed by spin-drying; more preferably, the spin-drying method has a temperature of from 10 ° C to 60 ° C.
  • the spin-drying method has a temperature of from 10 ° C to 60 ° C.
  • a crystal of troglitazone hemisuccinate (hereinafter referred to as "crystal") using Cu- ⁇ radiation, the crystal having an X-ray powder diffraction pattern expressed at an angle of 2 ⁇
  • crystal having an X-ray powder diffraction pattern expressed at an angle of 2 ⁇
  • the following locations have characteristic peaks: 12.3 ⁇ 0.2. 17.0 ⁇ 0.2. 18.4 ⁇ 0.2. , 19.0 ⁇ 0.2 °, 20.1 ⁇ 0.2 ° and 21.6 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal at a 2 ⁇ angle has a characteristic peak at 4.8 ⁇ 0.2. 12.3 ⁇ 0.2. 14.9 ⁇ 0.2. 15.2 ⁇ 0.2. , 17.0 ⁇ 0.2. , 18.4 ⁇ 0.2 ⁇ , 19.0 ⁇ 0.2 ⁇ , 20.1 ⁇ 0.2 ⁇ , 21.6 ⁇ 0.2 ⁇ , 22.5 ⁇ 0.2 ⁇ , 23.1 ⁇ 0.2 ⁇ and 26.7 ⁇ 0.2 ⁇ .
  • the X-ray powder diffraction pattern of the crystal at a 2 ⁇ angle has characteristic peaks and relative intensities at:
  • a typical example of the crystal has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of the crystal has characteristic peaks at wavenumbers of 3374, 2925, 1701, 1658, 1611, 1559, 1438, 1364, 1273, 1213, 958, 882, 820, 758, and 662 cm.
  • HPLC characterization revealed that the crystals were treglistatin hemisuccinate formed from trozastatin and succinic acid at a molar ratio of about 2:1.
  • the polarized light microscopy (PLM) pattern of the crystal showed a good particle morphology and a large particle size.
  • the crystal size analyzer (PSD) pattern of the crystal shows that the average diameter D 1Q of the crystal particles accounting for 10% of the total particle volume is at least about ⁇ , for example, about 10 to 80 ⁇ , about 20 to 70 ⁇ or about 40 to 60 ⁇ ;
  • the median volume diameter D 5 Q of the particles is at least about 60 ⁇ m, such as about 60 to: 150 ⁇ m, about 80 to 130 ⁇ m, or about 90 to 120 ⁇ m; and/or the average diameter D 9Q of the crystal particles, which is 90% of the total particle volume, is at least about It is 140 ⁇ m, for example, about 140 to 220 ⁇ m, about 160 to 210 ⁇ m, or about 180 to 200 ⁇ m.
  • the differential thermal analysis (DSC) pattern of the crystal showed a broad endothermic peak at 40 to 148 °C.
  • Thermogravimetric analysis (TGA) of the crystals showed a weight loss of 4.1% before 150 ° C, indicating that the crystals were hydrates and contained about 2 moles of water per mole of crystals.
  • the present invention provides a method for preparing crystals of statastine hemisuccinate, comprising the steps of: respectively forming a solution system of troglitazone hydrochloride and disodium succinate in a solvent, wherein The solvent is selected from the group consisting of water, d-C 4 alcohol or a mixture thereof, and the molar ratio of troglitazone hydrochloride to disodium succinate in the two solution systems is 10:1 to 2:1, and the two solution systems are mixed.
  • crystals of trozastatin hemisuccinate as a seed crystal are added, and the crystals are stirred and stirred to obtain crystals of the troglitazone hemisuccinate.
  • the C-C 4 alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol.
  • the solvent is selected from the group consisting of water, ethanol or isopropanol.
  • the molar ratio of statastine hydrochloride to disodium succinate is from 4:1 to 2:1.
  • the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
  • the crystallization time is from 1 to 48 hours, more preferably from 2 to 4 hours.
  • the concentration of the troglitin hydrochloride solution system is 0.1 to 1 times, more preferably 0.5 to 1 times, the solubility in the solvent at the operating temperature.
  • the concentration of the disodium succinate solution system is 0.1 to 1 times, more preferably 0.5 to 1 times, the solubility in the solvent at the operating temperature.
  • the two solution systems are mixed by adding a solution system of troglitazone hydrochloride to a solution system of disodium succinate or adding a solution system of disodium succinate to trozastatin hydrochloride.
  • Salt solution In the system, the two solution systems may be simultaneously added dropwise; preferably, the solution system of troglitazone hydrochloride is added dropwise to the solution system of disodium succinate; more preferably, the solution system of troglitazone hydrochloride is The solution was added dropwise to a solution of disodium succinate at a rate of 10 to 20 mL/min.
  • the seed crystal is used in an amount of from 1% to 5% by weight based on the weight of troglitazone hydrochloride.
  • the "room temperature” means 10 ⁇ 30 °C o
  • the “stirring” can be carried out by a conventional method in the art, and the stirring method includes magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to: 1800 rpm, preferably 300 to 900 rpm.
  • the crystal of the above trestratatide hemisuccinate obtained by the present invention can be isolated and dried by a conventional method in the art.
  • the separation method can be filtration or centrifugation.
  • the "filtration” is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the specific operation of the "centrifugation” is as follows: The sample to be separated is placed in a 2 mL centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • the drying method may be drying at room temperature, drying under reduced pressure or blast drying, and the drying device is a fume hood, a vacuum oven or a blast oven.
  • the drying temperature is 10 to 60 ° C, preferably 10 to 40 ° C; and the drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours. It is preferred to dry under reduced pressure, and the pressure is preferably less than 0.09 MPa.
  • trozastatin hemisuccinate crystals can be obtained in the present invention by the following procedure: Addition sequence (e.g., a solution system of troglitazone hydrochloride is added dropwise to a solution system of disodium succinate).
  • Addition sequence e.g., a solution system of troglitazone hydrochloride is added dropwise to a solution system of disodium succinate.
  • Feed rate for example, adding a solution system of troglitazone hydrochloride to a solution system of disodium succinate at a rate of 10-20 mL/min.
  • adding seed crystals for example, adding the equivalent of Qugrid column
  • Between 1% and 5% of statin hydrochloride weight of trozastatin hemisuccinate crystals for example, after adding a solution system of troglitazone hydrochloride to a solution system of disodium succinate Add the above seed crystals.
  • the starting material troglitazone hydrochloride can be prepared according to the method described in the synthesis scheme 3 of WO2007/033350A1 or the synthesis scheme 3 of WO2007/035629A2. It can also be prepared by a conventional method for forming an acid addition salt, for example, by reacting known troglitazone succinate with hydrochloric acid, optionally, stirring, filtering, washing and drying the reaction mixture to obtain a grid.
  • the statin hydrochloride, wherein the known trozastatin succinate can be prepared according to the method described in the embodiment 1A 1E of the patent document WO2008/067465A1.
  • trozastatin succinate type A particles are fine, and 0 1 () , 0 5 () , 0 9 () are, for example, 8 ⁇ , 22 ⁇ , 66 ⁇ , respectively; the trozastatin hemisuccinate of the present invention
  • the particles of the crystal increase significantly overall, with D 10 , D 50 , D 9 . They are at least 10 ⁇ m, 60 ⁇ m, 140 ⁇ m, respectively, for example, 55 ⁇ m, 114 ⁇ m, and 192 ⁇ m, respectively.
  • large particles have better fluidity, can reduce the filtration time of the drug substance, and the screening time of the preparation, which is beneficial to the accurate measurement and improvement of efficiency in the preparation of the preparation; the large particles with better morphology have better
  • the processability of the preparation can be used for direct compression of the powder, which avoids the influence of the wet granulation solvent on the raw material medicine, is beneficial to the control of the preparation quality, and improves the stability of the batch;
  • the quetiastatine hemi-succinate crystal of the present invention contains 0.5 succinic acid molecules in a molecule, which is higher than the known medicinal active ingredient of trozastatin succinate type A, so that the preparation application has a higher drug loading. the amount.
  • a plurality of solvents which should be restricted such as acetonitrile, dichloromethane, methanol, toluene, hexane, tetrahydrofuran;
  • the solvent used in the preparation method of the semi-succinate crystal can be only water or C-C 4 alcohol, and the residual solvent is non-toxic or less toxic, making the formulation safer.
  • the known trozastatin succinate has a polymorphic phenomenon, and the crystal form of the treglistatin hemisuccinate crystal of the invention has a single crystal form, and the crystallization process has good reproducibility, which is favorable for improving product quality and reducing impurities. .
  • the known trozastatin succinate contains an impurity N of the following structural formula, and its HPLC content is 0.2%;
  • the present inventors have surprisingly found that in the crystal of trexagliptin hemisuccinate obtained by increasing the particle size, the content of the impurity N is lowered, and the HPLC content is ⁇ 0.1%, so that the quality of the product of the present invention is higher. It is more suitable for formulation application, which reduces the stability of the preparation, the risk of decreased efficacy and the safety risk caused by the increase of the impurity content.
  • the crystal of the present invention is pure, single, and substantially free of any other crystals, such as known crystals without the addition of troglitazone succinate, including its type A, type B, type C, type D, type E, Type F, Type G and its amorphous form.
  • substantially free when used to refer to a new crystal means that the new crystal contains less than 20% by weight of other crystals, especially less than 10% by weight of other crystals, more preferably less than 5 % (by weight) of other crystals, more preferably less than 1% by weight of other crystals.
  • crystal refers to the characterization of the X-ray diffraction pattern shown.
  • the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. It is well known to those skilled in the art that X-ray diffraction patterns typically vary with instrumental conditions. In particular, the relative intensity of the X-ray diffraction pattern 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 an error of ⁇ 0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • single crystal means a single crystal by X-ray powder diffraction.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of troxliptin hemisuccinate of the present invention or a crystal thereof or troglitazone half obtained by the preparation method of the present invention Succinate or crystals thereof, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may comprise crystals or amorphous forms of other pharmaceutically acceptable troglitazone or a salt thereof, for example, including but not limited to the known type A, B of troglitazone succinate. Type, C type, D type, E type, F type, G type or its amorphous substance.
  • the pharmaceutical composition may comprise one or more other pharmaceutically acceptable pharmaceutically active ingredients such as, but not limited to, other DPP-IV inhibitors such as sitagliptin, vildagliptin, Shag Lenin, hypoglycemic agents such as metformin, acarbose, sputum glucosamine, pioglitazone, rosiglitazone, immunosuppressive agents, therapeutic cell proliferation drugs, etc.
  • other pharmaceutically acceptable pharmaceutically active ingredients such as, but not limited to, other DPP-IV inhibitors such as sitagliptin, vildagliptin, Shag Lenin, hypoglycemic agents such as metformin, acarbose, sputum glucosamine, pioglitazone, rosiglitazone, immunosuppressive agents, therapeutic cell proliferation drugs, etc.
  • the pharmaceutical composition may be in the form of a suitable pharmaceutical preparation, for example, a tablet, capsule, pill, powder, granule, sterile parenteral containing an appropriate amount of troglitin trisuccinate or a crystal thereof of the present invention. Solutions or suspensions, oral solutions or suspensions, oil-water emulsions, sustained release formulations, and the like.
  • the pharmaceutically acceptable carrier in the pharmaceutical composition includes, but is not limited to: a diluent; a lubricant; a binder; a wetting agent; a disintegrant; a glidant; a sweetener; a flavoring agent; an emulsifier; ; pH buffer; flavoring agent; surface stabilizer; suspending agent; and other conventional, pharmaceutically inactive substances.
  • the pharmaceutical compositions may include lactose, sucrose, sodium hydrogen phosphate, carboxymethylcellulose, magnesium stearate, calcium stearate, talc, starch, natural gums such as acacia, gelatin, glucose, molasses, Polyvinylpyrrolidine, cellulose and its derivatives), povidone, crospovidone, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate , and other such substances.
  • the pharmaceutical composition can be administered in a variety of ways.
  • the pharmaceutical composition according to the invention may be orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transpulmonarily, transmucosally, intranasally, liposomes, Inhalation, vaginal, intraocular, topical delivery (eg, via a catheter or stent), subcutaneous, intra-, intra-articular, or intrathecal administration, optionally in a slow release dosage form.
  • the pharmaceutical composition is administered by oral, inhalation or subcutaneous injection, intramuscularly, intravenously or directly into the cerebrospinal fluid.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the troglitazone hemi-succinate of the present invention or a crystal thereof is mixed with one or more pharmaceutically acceptable carriers, optionally one or more other active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • tablets or capsules which can be prepared by mixing the active component with one or more of the aforementioned pharmaceutically acceptable carriers, and subsequently compressing the resulting mixture in a conventional tablet machine
  • Capsules are prepared by tableting or filling into a capsule shell, examples of which include: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, corn starch, mannitol, potato starch, talc, magnesium stearate, gelatin, lactose, gum, etc., can also be used frequently for the above purposes.
  • Carriers such as coloring agents, flavoring agents, preservatives, and the like.
  • the present invention provides the treglistatin hemisuccinate of the present invention or a crystal thereof or the treglistatin hemisuccinate obtained by the preparation method of the present invention or a crystal thereof for the preparation of a treatment and/or prevention I Type 2 diabetes, type 2 diabetes, diabetic lipemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolic acidosis, ketosis, appetite regulation and obesity, autoimmune disorders Uses in medicines such as inflammatory bowel disease, multiple sclerosis, psoriasis and rheumatoid arthritis, AIDS or cancer.
  • the present invention provides a condition for treating and/or preventing type I diabetes, type II diabetes, diabetic lipemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolism Acidosis, ketosis, appetite regulation and obesity, autoimmune disorders such as inflammatory bowel disease, multiple sclerosis, psoriasis and rheumatoid arthritis, AIDS or cancer, the method comprising administering to a patient in need thereof And/or a prophylactically effective amount of trozastatin hemi-succinate or a crystal thereof selected from the present invention, troglitazone hemi-succinate obtained by the preparation method of the present invention or a crystal thereof or containing the trozastatin of the present invention
  • the pharmaceutical composition administered should contain a sufficient amount of troglitazone to substantially reduce dipeptidyl peptidase activity in the body to provide the desired therapeutic effect.
  • the patient is a mammal including a human.
  • the treglistatin hemi-succinate of the present invention or a crystal thereof is administered in a single dose comprising troglitazone hemi-succinate or a crystal thereof (calculated as trozastatin free base) Amounts of from about 1 to 250 mg, optionally from 2.5 mg to 200 mg, optionally from 2.5 mg to 150 mg, optionally from 5 mg to 100 mg; wherein administration is administered once a week, optionally for at least 30 days The time period, optionally for a period of at least 60 days.
  • Figure 1 is a XRPD pattern of the known trozastatin succinate Form A.
  • Figure 2 is a PLM map of the known trozastatin succinate Form A.
  • Figure 3 is a PSD map of the known trozastatin succinate Form A.
  • Figure 4 is an XRPD pattern of the crystal of troxliptin hemisuccinate of the present invention.
  • Figure 5 is a PLM map of crystals of troxliptin hemisuccinate of the present invention.
  • Figure 6 is a DSC spectrum of the crystal of troxliptin hemisuccinate of the present invention.
  • Figure 7 is a TGA spectrum of crystals of troglitinine hemisuccinate of the present invention.
  • Figure 8 is an IR spectrum of the crystal of trozastatin hemisuccinate of the present invention.
  • Figure 9 is a PSD spectrum of the crystal of troxliptin hemisuccinate of the present invention. detailed description
  • the XRD powder diffraction (XRPD) instrument used was a Bruker D8 Advance Diffractometer equipped with a ⁇ -2 ⁇ goniometer, a Mo monochromator, and a Lynxeye detector.
  • the acquisition software is a Diffiac Plus XRPD Commanded instrument that is calibrated with the standard (usually corundum) supplied with the instrument before use.
  • the detection conditions are: 2 ⁇ scanning angle range 3 ⁇ 40°, step size 0.02°, speed 0.2 sec/step.
  • Detection process Ka X-ray with a copper target wavelength of 1.54 nm was used. Under the operating conditions of 40 kV and 40 mA, the sample was tested at room temperature, and the sample to be tested was placed on a non-reflecting plate.
  • the polarized light microscope (PLM) pattern was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on a glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, then place the sample on the stage, select the appropriate magnification to observe the shape of the sample and Take a photo.
  • PLM polarized light microscope
  • the differential thermal analysis (DSC) data is taken from the TA Instruments Q200 MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually, a sample of 1 ⁇ 10mg is placed in the aluminum crucible at a heating rate of 10 °C/min. The sample was raised from 0 ° C to 250 ° C under the protection of 40 mL / min dry N 2 o
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis o. Usually 5 to 15 mg of the sample was placed in a platinum crucible, using a segmented high-resolution detection method to 10 The temperature rise rate of ° C/min was raised from room temperature to 300 ° C under a dry N 2 protection of 40 mL/min.
  • Infrared spectroscopy (IR) data is taken from BmkerTensor 27, instrument control software and data analysis software are OPUS, usually using ATR equipment, infrared absorption spectrum is collected in the range of ⁇ - 1 , scanning of samples and blank background The time is 16 seconds, the resolution of the instrument is ⁇
  • the laser particle size analyzer (PSD) data was taken from the Microtrac FLEX S3500 to measure the standard particle size distribution.
  • D 10 represents the average diameter of the particles below the diameter of 10% of the total particle volume
  • D 50 is the median volume diameter, that is, the average diameter of the particles of 50% of the total particle volume
  • D 9 () is The average diameter of the particles below the diameter of 90% of the total particle volume.
  • the nuclear magnetic resonance spectrum ( ⁇ HNMR) data was obtained from a Bmker Avance II DMX 400 MHz magnetic resonance spectrometer. A sample of l-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • High performance liquid phase analysis (HPLC) data was taken from Agilent 1260. Using C18 column, 150mmx4.6mm, column temperature 30°C, wavelength 220nm, flow rate 1.0mL/min, injection volume 5 L, operation Time 15min.
  • the solvent is 50% acetonitrile and 50% water
  • the mobile phase A is 0.05% trifluoroacetic acid
  • the mobile phase B is acetonitrile.
  • the gradient is as follows:
  • the ultrasonic operation in the embodiment is beneficial to the dissolution of the sample, and the device is an ultrasonic cleaner, generally adopted
  • trozastatin succinate Form A can be prepared according to the method described in Examples 1A to 1E of the patent document WO2008/067465A1. Specifically:
  • troglitazone trifluoroacetate was suspended in 50 mL of dichloromethane, then adjusted to pH 9 with saturated sodium carbonate, and the organic layer was washed three times with water, the organic layer was dried and solvent was evaporated in vacuo. 1.5 g was dissolved in 20 mL of tetrahydrofuran, 400 mg of succinic acid was added thereto, and the solution was kept open to air for three days, and the precipitate was collected by filtration to obtain troglitazone succinate.
  • Fig. 1 The X-ray powder diffraction pattern of the obtained troglitin succinate sample is shown in Fig. 1, which is substantially the same as the X-ray powder diffraction pattern of troglitazone succinate Form A provided in the patent document WO2008067465A1.
  • the PLM map is shown in Figure 2 and is shown as: Fine particles.
  • the PSD spectrum is shown in Fig. 3, and 0 10 , D 50 , and D 90 are 8 ⁇ m, 22 ⁇ m, and 66 ⁇ m, respectively.
  • the content of impurity N was 0.23% by HPLC.
  • the troglitin hydrochloride was prepared according to the method described below.
  • the gretliptin succinate prepared in Preparation Example 1 was weighed, 300 mg of hydrochloric acid (concentration: 37 wt%) was added dropwise, and the mixture was stirred at 30 ° C for 24 hours, filtered under reduced pressure, and vacuum dried at 40 ° C for 12 hours to obtain a quatrain column. Ting hydrochloride
  • trozastatin hydrochloride Take 0.80 g of trozastatin hydrochloride, add 12.0 mL of water to dissolve ultrasonically; take 0.17 g of disodium succinate, add 2.0 mL of water to dissolve ultrasonically; and dilute the aqueous solution of troglitazone hydrochloride by stirring The mixture was stirred at 40 ° C for 2 hours in an aqueous solution of disodium succinate, and the solvent was removed by spinning at 60 ° C, and dried under vacuum at 40 ° C for 10 hours to obtain 0.82 g of troglitazone hemisuccinate in a yield of 93.9%.
  • the content of impurity N was 0.08% by HPLC.
  • trozastatin hydrochloride Take 0.80g of trozastatin hydrochloride, add 100.OmL of ethanol to dissolve ultrasonically; take 0.09g of disodium succinate, add 40.0mL of ethanol to dissolve ultrasonically; and mix the tresolide hydrochloride in ethanol solution Add dropwise to a solution of disodium succinate in ethanol, stir at 30 ° C for 4 hours, spin dry at 30 ° C to remove the solvent, and dry at 30 ° C for 16 hours under vacuum to obtain 0.40 g of troglitazone hemisuccinate. 86.5%.
  • Example 3 Take 0.80 g of trozastatin hydrochloride, add 150.0 mL of methanol to dissolve ultrasonically; take 0.04 g of disodium succinate, add 60.0 mL of methanol to dissolve ultrasonically; and dilute the methoxide solution of troglitazone hydrochloride Adding to a solution of disodium succinate in methanol, stirring at 20 ° C for 8 hours, removing the solvent by spinning at 10 ° C, and drying under vacuum at 15 ° C for 24 hours to obtain 0.15 g of troglitazone hemisuccinate, yield 73 %.
  • the samples of Examples 2 and 3 have the same or similar HPLC and ifi-NMR detection results (not shown), indicating that the samples of Examples 2 and 3 are the same as the samples of Example 1.
  • trozastatin hydrochloride Take 0.80 g of trozastatin hydrochloride, add 13.4 mL of water to dissolve ultrasonically (the concentration of aqueous solution of troglitazone hydrochloride is 0.9 times its solubility in water at the crystallization temperature); take disodium succinate O.
  • the PLM map is shown in Figure 5.
  • the TGA map is shown in Figure 7.
  • the PSD spectrum is shown in Fig. 9, and its 0 10 , D 50 , and D 90 are 55 ⁇ m, 114 ⁇ m, and 192 ⁇ m, respectively.
  • HPLC characterization showed that trozastatin and succinic acid were about 2:1 sesquisuccinate in a molar ratio.
  • troglitin hydrochloride 0.80 g was added, and 160 mL of isopropanol was added to dissolve ultrasonically (the concentration of the isopropyl alcohol solution of troglitazone hydrochloride was 1 time in the isopropanol at the crystallization temperature); Take 0.17g of disodium succinate and add 80mL of isopropanol to dissolve ultrasonically (the concentration of disodium succinate in isopropanol solution is 1 times the solubility in isopropanol at the crystallization temperature); An isopropanol solution of troglitazone hydrochloride was added dropwise to a solution of disodium succinate in isopropanol, and 0.04 g of crystals of the trozastatin hemisuccinate of the present invention as a seed crystal was added, and stirred at 30 ° C After 2 hours, it was filtered under reduced pressure and dried under vacuum at 60 ° C for 10 hours to obtain crystals of the treglistatin hem
  • trozastatin hydrochloride Take 0.80 g of trozastatin hydrochloride and dissolve it by ultrasonic in 200 mL of ethanol (the concentration of the ethanol solution of troglitazone hydrochloride is 0.5 times the solubility in ethanol at the crystallization temperature); take disodium succinate 0.09 g, ultrasonically dissolved by adding 80mL of ethanol (the concentration of disodium succinate in ethanol is 0.5 times the solubility in ethanol at the crystallization temperature); under stirring conditions, the ethanol solution of troglitazone hydrochloride is 16mL At a rate of /min, add dropwise to a solution of disodium succinate in ethanol, stir at 20 ° C for 3 hours, filter under reduced pressure, and dry at 40 ° C. After drying for 14 hours, crystals of the treglistatin hemisuccinate of the present invention were obtained. The yield was 0.37 g and the yield was 80.0%.
  • trozastatin hydrochloride 0.80 g was added, and ultrasonically dissolved in 500 mL of methanol was added (the concentration of the methanol solution of troglitazone hydrochloride was 0.3 times the solubility in methanol at the crystallization temperature); taking disodium succinate 0.06 g, ultrasonically dissolved by adding 200mL of methanol (the concentration of disodium succinate in methanol is 0.3 times of the solubility in methanol at the crystallization temperature); under stirring conditions, the methanol solution of troglitazone hydrochloride is 12mL The solution was added dropwise to a solution of disodium succinate in methanol at a rate of /min, and 0.016 g of crystals of the troxliptin hemisuccinate of the present invention as a seed crystal was added, and the mixture was stirred at 50 ° C for 1 hour, and filtered under reduced pressure, 13 °. C was dried under vacuum for 48 hours to obtain crystals of the
  • n-butanol 1.4 L n-butanol to dissolve ultrasonically (the concentration of n-butanol solution of troglitazone hydrochloride is the solubility in n-butanol at the crystallization temperature 0.1 times); taking 0.04g of disodium succinate, ultrasonically dissolved by adding 6mL of water (the concentration of the aqueous solution of disodium succinate is 0.1 times of the solubility in water at the crystallization temperature); trozastatin under stirring conditions The n-butanol solution of the hydrochloride was added dropwise to an aqueous solution of disodium succinate at a rate of 20 mL/min, stirred at 5 ° C for 24 hours, filtered under reduced pressure, and dried under vacuum at 10 ° C for 72 hours to obtain a grid of the present invention. Crystals of statin hemisuccinate. The yield was O.llg, and the yield was 53.
  • Examples 5 to 8 have the same or similar XRPD patterns, PLM patterns, DSC patterns, TGA patterns, IR patterns, PSD patterns, and HPLC detection results (not shown), and Examples 5-8 The sample was the same as the sample of Example 4.
  • the tablets (containing 12.5 mg of troglitazone per tablet) are formulated as follows:
  • Lactose monohydrate 226.9mg
  • Microcrystalline cellulose 120.1 mg
  • Croscone sodium 32.0 mg
  • the preparation steps of the tablet are as follows:
  • the crystals of the trozastatin hemisuccinate of the present invention are mixed with the lactose monohydrate by an equal amount of increasing methods, followed by microcrystalline cellulose, croscarmellose sodium, colloidal silica, and hard After the magnesium oleate was uniformly mixed, it was placed in a tableting machine to be tableted, and the tablet weight was adjusted to obtain a corresponding tablet. A total of 1,000 tablets were prepared.
  • the tablets (containing 25.0 mg of troglitazone per tablet) are formulated as follows: Crystals of troglitazone hemisuccinate of the invention: 29. lmg
  • Microcrystalline cellulose 120.1 mg
  • Croscarmellose sodium 32.0 mg
  • the tablets (containing 50.0 mg of troglitazone per tablet) are formulated as follows:
  • Microcrystalline cellulose 120.1 mg
  • Croscarmellose sodium 32.0 mg
  • Capsules (containing 12.5 mg of troglitazone per capsule) are formulated as follows:
  • the preparation steps of the capsule are as follows:
  • the crystal of the trozastatin hemisuccinate of the present invention is uniformly mixed with pregelatinized starch, lactose and magnesium stearate, and then placed in a dry granulator to be granulated, and the obtained dry granules are input into a capsule filling machine. After filling the capsule, the corresponding capsules were obtained, and a total of 1000 capsules were prepared.
  • Capsules (containing 25.0 mg of troglitazone per capsule) are formulated as follows:
  • the preparation procedure of the capsule was the same as the preparation procedure of Example 12.
  • Capsules (50.0 mg each of troglitazone) are formulated as follows:
  • the preparation procedure of the capsule was the same as the preparation procedure of Example 12.
  • the above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change or replace without thinking of the creative work within the technical scope of the present invention. All should be covered by the scope of the present invention.

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Abstract

A DPP-IV inhibitor trelagliptin semi-succinate and crystals thereof, preparation method for trelagliptin semi-succinate and crystals thereof, pharmaceutical composition thereof and use thereof in preparation of drugs treating diseases such as diabetes and the like.

Description

曲格列汀半琥珀酸盐的晶体及其制备方法和药物組合物 技术领域  Crystal of troglitazone hemisuccinate, preparation method thereof and pharmaceutical composition thereof
本发明涉及药物化学结晶技术领域。 具体而言， 涉及一种抗抑郁药曲格列汀 半琥珀酸盐的晶体， 还涉及所述晶体的制备方法、 其药物组合物及用途。 背景技术  The invention relates to the field of medicinal chemical crystallization technology. In particular, it relates to a crystal of an antidepressant troglitazone hemisuccinate, to a method for preparing the crystal, a pharmaceutical composition thereof, and use thereof. Background technique
曲格列汀琥珀酸盐是由武田制药公司 （Takeda)和 Furiex制药公司共同研发 的一种新颖的二肽基肽酶 -IV (DPP-IV) 抑制剂， 用于治疗 2型糖尿病， 目前该 药处于临床 III期。 其口服固体制剂是以曲格列汀琥珀酸盐作为药物活性成分， 剂型有片剂和胶囊剂， 规格 l~20mg， 口服每周一次。  Triglitastat succinate is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor developed by Takeda and Furiex Pharmaceuticals for the treatment of type 2 diabetes. The drug is in clinical phase III. The oral solid preparation is troglitazone succinate as a pharmaceutically active ingredient, and the dosage form is a tablet and a capsule, and the specification is 1-20 mg, once a week orally.
曲格列汀琥珀酸盐的化学名称为 2-[6-[(3R)-3-氨基 -哌啶 -1-基] -3-甲基 -2,4-二 氧代 -3,4-二氫 -2H-嘧啶 -1-基甲基 ]-4-氟-苄腈琥珀酸盐， 英文名为 Trelagliptin succinate或 SYR-472 succinate, 分子式为 C22H26FN506， 分子量 475.47， 化学结 构式 ^下所示： The chemical name of troglitazone succinate is 2-[6-[(3R)-3-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4- Dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate, English name: Trelagliptin succinate or SYR-472 succinate, molecular formula C 22 H 26 FN 5 0 6 , molecular weight 475.47, chemistry The structure ^ is shown below:
Figure imgf000002_0001
Figure imgf000002_0001
专利文献 WO2005/095381A1公开了曲格列汀及其制备方法。  The patent document WO2005/095381A1 discloses troglitin and a process for the preparation thereof.
专利文献 WO2007/035629A2公开了曲格列汀琥珀酸盐及其制备方法， 还公 开了曲格列汀的三氟乙酸盐、 盐酸盐、 苯甲酸盐、 甲苯磺酸盐、 甲磺酸盐、 苯磺 酸盐、 （R; -;>-扁桃酸盐及它们的制备方法。  Patent document WO2007/035629A2 discloses treglistatin succinate and a process for the preparation thereof, and also discloses triflurane salt, hydrochloride, benzoate, tosylate, methanesulfonic acid of troglitazone. Salt, besylate, (R; -; >-mandelic acid salt and methods for their preparation).
专利文献 WO2007/033350A1 及 WO2008/033851A2公开了曲格列汀琥珀酸 盐的药物组合物、 其用于治疗糖尿病、 癌症、 自身免疫障碍、 HIV感染的用途以 及给药方法。 上述文献还公开了曲格列汀半琥珀酸盐， 但没有公开该化合物或其 晶型的任何表征数据及其制备方法。  Patent documents WO2007/033350A1 and WO2008/033851A2 disclose pharmaceutical compositions of troglitazone succinate, their use for the treatment of diabetes, cancer, autoimmune disorders, HIV infection, and methods of administration. The above document also discloses statastatin hemisuccinate, but does not disclose any characterization data of the compound or its crystalline form and a process for its preparation.
专利文献 WO2008/067465A1公开了曲格列汀琥珀酸盐的多晶型形式及其制 备方法， 其中多晶型包括 A型、 B型、 C型、 D型、 E型、 F型、 G型及其无定 形形式。 根据该文献的描述： A型是无水的并且在环境条件下是稳定的， A型为 针晶或针晶 /球状晶体； B型是水合的固体形式， 制备时得到的是 B型与 A型的 混合物 （A+B型）， B型在脱水条件下会转化为 A型， A+B型经相对湿度应激实 验也会转化为 A型； C型是针晶并且制备需要约 8天的时间； D型是水合的固体 形式， 从 25°C加热到 85°C时有 >20%的重量损失； E型是水合的固体形式， 在脱 水条件下会转为 A型； 制备 F型时得到的是 A+F型混合物； 制备 G型时得到的 是 A+E+G型混合物； 无定形形式在 58%和 88%相对湿度下应激产生 A型， 在水 蒸气中应激产生 A型和 D型的混合物。 由该专利文献可知， 曲格列汀琥珀酸盐 有七种晶型， 这种多晶型现象使得结晶工艺不易获得单一晶型， 影响工艺的可重 复性和产品质量， 也会包含更多的杂质。 本发明人发现 A型的制备方法中使用了 多种应被限制使用的溶剂， 例如乙腈、 二氯甲烷、 甲醇、 甲苯、 己烷、 四氫呋喃。 本发明人研究还发现， A型颗粒小、流动性差，影响固体制剂生产中的可加工性。 The patent document WO 2008/067465 A1 discloses a polymorphic form of troglitazone succinate and a preparation method thereof, wherein the polymorphic type includes A type, B type, C type, D type, E type, F type, G type and Its amorphous form. According to the description of this document: Type A is anhydrous and stable under ambient conditions, Type A is needle crystal or needle crystal/spherical crystal; Type B is a hydrated solid form, which is obtained by Form B and A. Type mixture (A+B type), type B will be converted to type A under dehydration conditions, and type A+B will be stressed by relative humidity. The test will also be converted to Form A; Form C is needle crystal and preparation takes about 8 days; Type D is a hydrated solid form with >20% weight loss from 25 ° C to 85 ° C; It is a hydrated solid form which is converted to Form A under dehydration conditions; A+F type mixture is obtained when Form F is prepared; A+E+G type mixture is obtained when Form G; Amorphous form is at 58% Stress produces a type A at 88% relative humidity and stress in water vapor produces a mixture of type A and type D. It is known from the patent literature that there are seven crystal forms of troglitazone succinate, which makes the crystallization process difficult to obtain a single crystal form, affects process repeatability and product quality, and also contains more Impurities. The present inventors have found that a variety of solvents which should be restricted, such as acetonitrile, dichloromethane, methanol, toluene, hexane, tetrahydrofuran, are used in the preparation method of Form A. The inventors have also found that the type A particles are small and have poor fluidity, which affects the processability in the production of solid preparations.
专利文献 WO2009/147125A1公开了曲格列汀或其可药用盐治疗和 /或预防非 酒精性脂肪肝疾病 （NAFLD) 的新用途。  The patent document WO 2009/147125 A1 discloses a novel use of troglitazone or a pharmaceutically acceptable salt thereof for the treatment and/or prevention of nonalcoholic fatty liver disease (NAFLD).
因此， 本领域仍需要开发具有更多优势性能的新的曲格列汀盐及其晶型， 以 满足固体制剂对药物活性成分更严格的要求。 发明内容  Therefore, there is still a need in the art to develop new troglitazone salts and their crystal forms with more advantageous properties to meet the more stringent requirements of solid formulations for pharmaceutically active ingredients. Summary of the invention
针对现有技术的不足， 本发明的主要目的是通过提供新的曲格列汀盐及其晶 体， 解决已知盐及其晶体存在的问题。 同时， 本发明还涉及所述新的曲格列汀盐 及其晶体的制备方法、 其药物组合物和用途。  In view of the deficiencies of the prior art, the main object of the present invention is to solve the problems of the presence of known salts and their crystals by providing new troglitin salts and their crystals. At the same time, the present invention also relates to the novel method for preparing troglitazone salt and crystals thereof, a pharmaceutical composition thereof and use thereof.
所述新的曲格列汀盐及其晶体与已知的盐及其晶体相比， 具有至少一种如下 的有利性质： 稳定性好， 例如晶型稳定性、 热学稳定性、 化学稳定性、 机械稳定 性、 贮存稳定性等； 溶解性好； 溶出速度快； 结晶度高； 不易吸湿； 易于纯化和 处理； 化学纯度高； 低残留溶剂； 低毒性； 颗粒形貌佳； 适宜的制剂可加工性例 如流动性好、 有利的粉体粘度、 紧密度和可压实性； 改进制剂表观； 高载药量； 改善生物利用度、 药效； 延长制剂保存期； 适合新剂型应用等方面。  The novel troglitazone salt and its crystals have at least one of the following advantageous properties compared to known salts and crystals thereof: good stability, such as crystal form stability, thermal stability, chemical stability, Mechanical stability, storage stability, etc.; Good solubility; Fast dissolution rate; High crystallinity; Not easy to absorb moisture; Easy to purify and handle; High chemical purity; Low residual solvent; Low toxicity; Good particle morphology; Such as good fluidity, favorable powder viscosity, tightness and compactability; improved formulation appearance; high drug loading; improved bioavailability, efficacy; extended formulation shelf life; suitable for new dosage form applications.
根据本发 式（I)所示：  According to the present invention (I):
Figure imgf000003_0001
Figure imgf000003_0001
( I ) 。  (I).
HPLC表征显示， 所述曲格列汀半琥珀酸盐是曲格列汀和琥珀酸以摩尔比约 为 2:1形成的化合物。  HPLC characterization revealed that the statastatin hemisuccinate was a compound formed from trozastatin and succinic acid in a molar ratio of about 2:1.
根据本发明目的， 本发明提供所述曲格列汀半琥珀酸盐的制备方法， 其包括 以下步骤： 分別形成曲格列汀盐酸盐和琥珀酸二钠盐在可溶溶剂中的溶液体系， 两个溶液体系中曲格列汀盐酸盐和琥珀酸二钠的摩尔比为 10: 1~2:1， 混合两个溶 液体系进行反应， 反应完成后除去溶剂， 得到所述曲格列汀半琥珀酸盐。 According to the object of the present invention, the present invention provides a process for preparing treglistatin hemisuccinate, which comprises the steps of: respectively forming a solution system of troglitazone hydrochloride and disodium succinate in a soluble solvent; , The molar ratio of troglitazone hydrochloride to disodium succinate in the two solution systems is 10:1~2:1, and the two solution systems are mixed to carry out the reaction. After the reaction is completed, the solvent is removed to obtain the troglitazone. Semi-succinate.
优选地， 所述可溶溶剂选自水、 醇或其混合物。  Preferably, the soluble solvent is selected from the group consisting of water, alcohol or a mixture thereof.
优选地，所述制备方法的操作温度为 20~40°C，所述反应的时间为 1~8小时。 所述 "除去溶剂"， 可以采用本领域的常规技术完成， 例如过滤、 离心或旋 干。 所述 "过滤"一般是在室温条件下以小于大气压的压力进行抽滤， 优选压力 小于 0.09MPa。所述"离心 "的具体操作为：将欲分离的样品置于 2mL离心管中， 以 6000转 /分的速率进行离心， 直至固体全部沉至离心管底部。 所述 "旋干"， 一 般是以小于大气压的压力进行旋蒸， 优选压力小于 0.09MPa。  Preferably, the preparation method has an operating temperature of 20 to 40 ° C and a reaction time of 1 to 8 hours. The "removal of the solvent" can be accomplished by conventional techniques in the art, such as filtration, centrifugation or spin drying. The "filtration" is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa. The specific operation of the "centrifugation" is to place the sample to be separated in a 2 mL centrifuge tube and centrifuge at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube. The "spinning" is generally carried out by steaming at a pressure less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa.
优选地，采用旋干法除去溶剂；更优选地，所述旋干法的温度为 10°C~60°C。 根据本发明目的， 本发明提供一种曲格列汀半琥珀酸盐的晶体（以下称作"晶 体"）， 使用 Cu-Κα辐射， 所述晶体以 2Θ角度表示的 X-射线粉末衍射图在以下位 置具有特征峰： 12.3士 0.2。、 17.0士 0.2。、 18.4士 0.2。、 19.0士 0.2°、 20.1士 0.2°和 21.6士 0.2°。  Preferably, the solvent is removed by spin-drying; more preferably, the spin-drying method has a temperature of from 10 ° C to 60 ° C. In accordance with the purpose of the present invention, there is provided a crystal of troglitazone hemisuccinate (hereinafter referred to as "crystal") using Cu-Κα radiation, the crystal having an X-ray powder diffraction pattern expressed at an angle of 2 在The following locations have characteristic peaks: 12.3 ± 0.2. 17.0 ± 0.2. 18.4 士 0.2. , 19.0 ± 0.2 °, 20.1 ± 0.2 ° and 21.6 ± 0.2 °.
在本发明的一个优选实施方案中， 所述晶体以 2Θ角度表示的 X-射线粉末衍 射图在以下位置具有特征峰：4.8士 0.2。、 12.3士 0.2。、 14.9士 0.2。、 15.2士 0.2。、 17.0士 0.2。、 18.4±0.2ο、 19.0士 0.2ο、 20.1士 0.2ο、 21.6±0.2ο、 22.5±0.2ο、 23.1±0.2ο和 26.7±0.2ο。 In a preferred embodiment of the invention, the X-ray powder diffraction pattern of the crystal at a 2 Θ angle has a characteristic peak at 4.8 ± 0.2. 12.3 ± 0.2. 14.9±0.2. 15.2 ± 0.2. , 17.0 ± 0.2. , 18.4 ± 0.2 ο , 19.0 ± 0.2 ο , 20.1 ± 0.2 ο , 21.6 ± 0.2 ο , 22.5 ± 0.2 ο , 23.1 ± 0.2 ο and 26.7 ± 0.2 ο .
在进一步优选的实施方案中， 所述晶体以 2Θ角度表示的 X-射线粉末衍射图 在以下位置具有特征峰及相对强度：  In a further preferred embodiment, the X-ray powder diffraction pattern of the crystal at a 2 Θ angle has characteristic peaks and relative intensities at:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
4.8士 0.2° 18.1  4.8 ± 0.2° 18.1
9.6士 0.2° 22.8  9.6 士 0.2° 22.8
12.3士 0.2° 52.4  12.3 ± 0.2 ° 52.4
12.6士 0.2° 16.5  12.6 ± 0.2° 16.5
13.9士 0.2° 15.1  13.9 ± 0.2° 15.1
14.9士 0.2° 28.4  14.9士 0.2° 28.4
15.2±0.2° 30.2  15.2±0.2° 30.2
17.0士 0.2° 100.0  17.0 ± 0.2° 100.0
18.4±0.2° 73.3  18.4±0.2° 73.3
19.0士 0.2° 58.3  19.0 ± 0.2° 58.3
20.1士 0.2° 50.8  20.1 ± 0.2° 50.8
21.6±0.2° 82.7  21.6±0.2° 82.7
22.5士 0.2° 39.4  22.5 ± 0.2° 39.4
23.1士 0.2° 61.2  23.1 ± 0.2 ° 61.2
24.7士 0.2° 26.4  24.7 ± 0.2° 26.4
25.0±0.2° 26.4  25.0±0.2° 26.4
26.7士 0.2° 44.3 28.0士 0.2 24.4 26.7 ± 0.2 ° 44.3 28.0 ± 0.2 24.4
28.5±0.2C 30.5 28.5±0.2 C 30.5
28.8±0.2 27.9  28.8±0.2 27.9
非限制性地， 所述晶体的一个典型实例具有如图 4所示的 X-射线粉末衍射 (XRPD) 图谱。  Without limitation, a typical example of the crystal has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
所述晶体的傅里叶红外光谱在波数为 3374、 2925、 1701、 1658、 1611、 1559、 1438、 1364、 1273、 1213、 958、 882、 820、 758和 662 cm 处具有特征峰。  The Fourier infrared spectrum of the crystal has characteristic peaks at wavenumbers of 3374, 2925, 1701, 1658, 1611, 1559, 1438, 1364, 1273, 1213, 958, 882, 820, 758, and 662 cm.
HPLC表征显示， 所述晶体是曲格列汀和琥珀酸以摩尔比约为 2:1形成的曲 格列汀半琥珀酸盐。  HPLC characterization revealed that the crystals were treglistatin hemisuccinate formed from trozastatin and succinic acid at a molar ratio of about 2:1.
所述晶体的偏正光显微镜 （PLM) 图谱显示其颗粒形貌较好、 颗粒较大。 所述晶体的激光粒度仪 （PSD) 图谱显示， 占总颗粒体积 10%的晶体颗粒的 平均直径 D1Q至少大约为 ΙΟμπι, 例如大约 10~80μπι、 大约 20~70μπι 或大约 40~60μπι;该晶体颗粒的中值体积直径 D5Q至少大约为 60μπι，例如大约 60〜： 150μπι、 大约 80~130μπι或大约 90~120μπι; 和 /或占总颗粒体积 90%的晶体颗粒的平均直 径 D9Q至少大约为 140μπι， 例如大约 140~220μπι、 大约 160~210μπι 或大约 180~200μπι。 The polarized light microscopy (PLM) pattern of the crystal showed a good particle morphology and a large particle size. The crystal size analyzer (PSD) pattern of the crystal shows that the average diameter D 1Q of the crystal particles accounting for 10% of the total particle volume is at least about ΙΟμπι, for example, about 10 to 80 μπι, about 20 to 70 μπι or about 40 to 60 μπι; The median volume diameter D 5 Q of the particles is at least about 60 μm, such as about 60 to: 150 μm, about 80 to 130 μm, or about 90 to 120 μm; and/or the average diameter D 9Q of the crystal particles, which is 90% of the total particle volume, is at least about It is 140 μm, for example, about 140 to 220 μm, about 160 to 210 μm, or about 180 to 200 μm.
所述晶体的差热分析 （DSC) 图谱显示其在 40~148°C有一宽大的吸热峰。 所述晶体的热重分析（TGA)检测显示其在 150°C之前失重 4.1%， 说明所述 晶体为水合物， 且每摩尔晶体含有约 2摩尔水。  The differential thermal analysis (DSC) pattern of the crystal showed a broad endothermic peak at 40 to 148 °C. Thermogravimetric analysis (TGA) of the crystals showed a weight loss of 4.1% before 150 ° C, indicating that the crystals were hydrates and contained about 2 moles of water per mole of crystals.
根据本发明目的， 本发明提供所述曲格列汀半琥珀酸盐的晶体的制备方法， 包括如下步骤： 分別形成曲格列汀盐酸盐和琥珀酸二钠在溶剂中的溶液体系， 其 中所述溶剂选自水、 d~C4醇或其混合物， 两个溶液体系中曲格列汀盐酸盐和琥 珀酸二钠的摩尔比为 10:1~2:1， 混合两个溶液体系， 可选地加入作为晶种的曲格 列汀半琥珀酸盐的晶体， 搅袢析晶， 得到所述曲格列汀半琥珀酸盐的晶体。 According to the object of the present invention, the present invention provides a method for preparing crystals of statastine hemisuccinate, comprising the steps of: respectively forming a solution system of troglitazone hydrochloride and disodium succinate in a solvent, wherein The solvent is selected from the group consisting of water, d-C 4 alcohol or a mixture thereof, and the molar ratio of troglitazone hydrochloride to disodium succinate in the two solution systems is 10:1 to 2:1, and the two solution systems are mixed. Optionally, crystals of trozastatin hemisuccinate as a seed crystal are added, and the crystals are stirred and stirred to obtain crystals of the troglitazone hemisuccinate.
所述 C广 C4醇包括甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇和异丁醇。 The C-C 4 alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol.
优选地， 所述溶剂选自水、 乙醇或异丙醇。  Preferably, the solvent is selected from the group consisting of water, ethanol or isopropanol.
优选地， 所述曲格列汀盐酸盐和琥珀酸二钠的摩尔比为 4:1~2:1。  Preferably, the molar ratio of statastine hydrochloride to disodium succinate is from 4:1 to 2:1.
优选地， 所述制备方法的操作温度为 -10~50°C， 更优选为室温。  Preferably, the preparation method has an operating temperature of -10 to 50 ° C, more preferably room temperature.
优选地， 所述析晶的时间为 1 ~48小时， 更优选为 2~4小时。  Preferably, the crystallization time is from 1 to 48 hours, more preferably from 2 to 4 hours.
优选地， 所述曲格列汀盐酸盐溶液体系的浓度为操作温度下其在所述溶剂中 溶解度的 0.1~1倍， 更优选为 0.5~1倍。  Preferably, the concentration of the troglitin hydrochloride solution system is 0.1 to 1 times, more preferably 0.5 to 1 times, the solubility in the solvent at the operating temperature.
优选地， 所述琥珀酸二钠溶液体系的浓度为操作温度下其在所述溶剂中溶解 度的 0.1~1倍， 更优选为 0.5~1倍。  Preferably, the concentration of the disodium succinate solution system is 0.1 to 1 times, more preferably 0.5 to 1 times, the solubility in the solvent at the operating temperature.
所述混合两个溶液体系的方式为将曲格列汀盐酸盐的溶液体系滴加至琥珀 酸二钠的溶液体系中或将琥珀酸二钠的溶液体系滴加至曲格列汀盐酸盐的溶液 体系中或将两个溶液体系同时滴加； 优选将曲格列汀盐酸盐的溶液体系滴加至琥 珀酸二钠的溶液体系中； 更优选将曲格列汀盐酸盐的溶液体系以 10~20mL/分钟 的速度滴加至琥珀酸二钠的溶液体系中。 The two solution systems are mixed by adding a solution system of troglitazone hydrochloride to a solution system of disodium succinate or adding a solution system of disodium succinate to trozastatin hydrochloride. Salt solution In the system, the two solution systems may be simultaneously added dropwise; preferably, the solution system of troglitazone hydrochloride is added dropwise to the solution system of disodium succinate; more preferably, the solution system of troglitazone hydrochloride is The solution was added dropwise to a solution of disodium succinate at a rate of 10 to 20 mL/min.
优选地， 所述晶种的用量为曲格列汀盐酸盐重量的 1%~5%。  Preferably, the seed crystal is used in an amount of from 1% to 5% by weight based on the weight of troglitazone hydrochloride.
所述 "室温" 是指 10~30°C o  The "room temperature" means 10~30 °C o
所述 "搅袢"， 可以采用本领域的常规方法， 搅袢方式包括磁力搅袢、 机械 搅袢等， 搅袢速度为 50〜： 1800转 /分， 优选为 300~900转 /分。  The "stirring" can be carried out by a conventional method in the art, and the stirring method includes magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to: 1800 rpm, preferably 300 to 900 rpm.
本发明上述得到的曲格列汀半琥珀酸盐的晶体， 可以采用本领域的常规方法 进行分离和干燥。 分离方法可以是过滤或离心。 所述 "过滤"一般是在室温条件 下以小于大气压的压力进行抽滤， 优选压力小于 0.09MPa。 所述 "离心" 的具体 操作为： 将欲分离的样品置于 2mL离心管中， 以 6000转 /分的速率进行离心， 直 至固体全部沉至离心管底部。 干燥方法可以是常温干燥、 减压干燥或鼓风干燥， 干燥设备为通风橱、真空烘箱或鼓风烘箱。干燥温度为 10~60°C，优选为 10~40°C ; 干燥时间为 10~72小时， 优选为 10~48小时， 更优选为 10~24小时。 优选减压干 燥， 压力优选小于 0.09MPa。  The crystal of the above trestratatide hemisuccinate obtained by the present invention can be isolated and dried by a conventional method in the art. The separation method can be filtration or centrifugation. The "filtration" is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa. The specific operation of the "centrifugation" is as follows: The sample to be separated is placed in a 2 mL centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube. The drying method may be drying at room temperature, drying under reduced pressure or blast drying, and the drying device is a fume hood, a vacuum oven or a blast oven. The drying temperature is 10 to 60 ° C, preferably 10 to 40 ° C; and the drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours. It is preferred to dry under reduced pressure, and the pressure is preferably less than 0.09 MPa.
本发明中可以通过以下操作来获得较大颗粒的曲格列汀半琥珀酸盐晶体： 加 料顺序 （例如将曲格列汀盐酸盐的溶液体系滴加至琥珀酸二钠的溶液体系中。）、 加料速度（例如将曲格列汀盐酸盐的溶液体系以 10~20mL/分钟的速度滴加至琥珀 酸二钠的溶液体系中。）、 加入晶种（例如加入相当于曲格列汀盐酸盐重量的 1%~5% 的曲格列汀半琥珀酸盐晶体作为晶种， 例如在将曲格列汀盐酸盐的溶液体系滴加 至琥珀酸二钠的溶液体系中后加入上述晶种。）。  Larger particles of trozastatin hemisuccinate crystals can be obtained in the present invention by the following procedure: Addition sequence (e.g., a solution system of troglitazone hydrochloride is added dropwise to a solution system of disodium succinate). Feed rate (for example, adding a solution system of troglitazone hydrochloride to a solution system of disodium succinate at a rate of 10-20 mL/min.), adding seed crystals (for example, adding the equivalent of Qugrid column) Between 1% and 5% of statin hydrochloride weight of trozastatin hemisuccinate crystals, for example, after adding a solution system of troglitazone hydrochloride to a solution system of disodium succinate Add the above seed crystals.).
本发明曲格列汀半琥珀酸盐及其晶体的制备方法中， 起始原料曲格列汀盐酸 盐可根据专利文献 WO2007/033350A1实施例 1或 WO2007/035629A2合成方案 3 描述的方法制备得到， 也可采用形成酸加成盐的常规方法制备得到， 例如将已知 的曲格列汀琥珀酸盐与盐酸反应， 任选地对反应混合物进行搅袢、 过滤、 洗涤和 干燥， 得到曲格列汀盐酸盐， 其中所述已知的曲格列汀琥珀酸盐可根据专利文献 WO2008/067465A1实施例 1A 1E描述的方法制备得到。  In the preparation method of the treglistatin hemisuccinate of the present invention and crystals thereof, the starting material troglitazone hydrochloride can be prepared according to the method described in the synthesis scheme 3 of WO2007/033350A1 or the synthesis scheme 3 of WO2007/035629A2. It can also be prepared by a conventional method for forming an acid addition salt, for example, by reacting known troglitazone succinate with hydrochloric acid, optionally, stirring, filtering, washing and drying the reaction mixture to obtain a grid. The statin hydrochloride, wherein the known trozastatin succinate can be prepared according to the method described in the embodiment 1A 1E of the patent document WO2008/067465A1.
相比已知的曲格列汀琥珀酸盐 A型，本发明的曲格列汀半琥珀酸盐晶体具有 以下有益性质及效果：  The trozastatin hemisuccinate crystal of the present invention has the following beneficial properties and effects compared to the known trozastatin succinate form A:
①已知的曲格列汀琥珀酸盐 A型颗粒细小，其01()、05()、09()例如分別为 8μπι、 22μπι、 66μπι; 本发明曲格列汀半琥珀酸盐晶体的颗粒整体显著增大， 其 D10、 D50、 D9。分別至少为 10μπι、 60μπι、 140μπι， 例如分別为 55μπι、 114μπι、 192μπι。 相对而言， 大颗粒具有更好的流动性， 可以减少原料药的过滤时间、 制剂的过筛 时间， 有利于制剂生产中的准确计量和提高效率； 形貌较好的大颗粒具有更好的 制剂可加工性， 可用于粉末直接压片， 避免了湿法制粒溶剂对原料药的影响， 有 利于制剂质量的控制， 提高批次稳定性； 1 Known trozastatin succinate type A particles are fine, and 0 1 () , 0 5 () , 0 9 () are, for example, 8 μπι, 22 μπι, 66 μπι, respectively; the trozastatin hemisuccinate of the present invention The particles of the crystal increase significantly overall, with D 10 , D 50 , D 9 . They are at least 10 μm, 60 μm, 140 μm, respectively, for example, 55 μm, 114 μm, and 192 μm, respectively. Relatively speaking, large particles have better fluidity, can reduce the filtration time of the drug substance, and the screening time of the preparation, which is beneficial to the accurate measurement and improvement of efficiency in the preparation of the preparation; the large particles with better morphology have better The processability of the preparation can be used for direct compression of the powder, which avoids the influence of the wet granulation solvent on the raw material medicine, is beneficial to the control of the preparation quality, and improves the stability of the batch;
②本发明的曲格列汀半琥珀酸盐晶体的分子中含 0.5个琥珀酸分子， 比已知 曲格列汀琥珀酸盐 A型含有的药物有效成分高， 使得制剂应用具有更高载药量。  2 The quetiastatine hemi-succinate crystal of the present invention contains 0.5 succinic acid molecules in a molecule, which is higher than the known medicinal active ingredient of trozastatin succinate type A, so that the preparation application has a higher drug loading. the amount.
③已知曲格列汀琥珀酸盐 A型的制备方法中，使用了多种应被限制使用的溶 剂， 例如乙腈、 二氯甲烷、 甲醇、 甲苯、 己烷、 四氫呋喃； 本发明曲格列汀半琥 珀酸盐晶体的制备方法中所用溶剂可只用水或 C广 C4醇， 残留溶剂无毒或毒性更 低， 使得制剂应用更安全。 3 In the preparation method of the known trozastatin succinate form A, a plurality of solvents which should be restricted, such as acetonitrile, dichloromethane, methanol, toluene, hexane, tetrahydrofuran; The solvent used in the preparation method of the semi-succinate crystal can be only water or C-C 4 alcohol, and the residual solvent is non-toxic or less toxic, making the formulation safer.
④已知的曲格列汀琥珀酸盐存在多晶型现象， 本发明曲格列汀半琥珀酸盐晶 体的晶型单一， 其结晶工艺的重现性好， 有利于提高产品质量和降低杂质。  4 The known trozastatin succinate has a polymorphic phenomenon, and the crystal form of the treglistatin hemisuccinate crystal of the invention has a single crystal form, and the crystallization process has good reproducibility, which is favorable for improving product quality and reducing impurities. .
⑤已知的曲格列汀琥珀酸盐含有如下结构式的杂质 N，其 HPLC含量 0.2%；  5 The known trozastatin succinate contains an impurity N of the following structural formula, and its HPLC content is 0.2%;
Figure imgf000007_0001
杂质 N
Figure imgf000007_0001
Impurity N
本发明人惊奇地发现， 本发明通过增加粒径获得的曲格列汀半琥珀酸盐的晶 体中，杂质 N的含量下降了，其 HPLC含量 <0.1%， 因而本发明产品的质量更高， 更适合制剂应用， 降低了由杂质含量升高所带来的制剂的稳定性问题、 疗效下降 风险和安全风险。  The present inventors have surprisingly found that in the crystal of trexagliptin hemisuccinate obtained by increasing the particle size, the content of the impurity N is lowered, and the HPLC content is <0.1%, so that the quality of the product of the present invention is higher. It is more suitable for formulation application, which reduces the stability of the preparation, the risk of decreased efficacy and the safety risk caused by the increase of the impurity content.
本发明的晶体是纯的、 单一的， 基本没有混合任何其他晶体， 例如没有混合 曲格列汀琥珀酸盐的已知晶体， 包括其 A型、 B型、 C型、 D型、 E型、 F型、 G 型及其无定形形式。 本发明中， "基本没有" 当用来指新晶体时， 指这个新晶 体含有少于 20% (重量） 的其他晶体， 尤其指少于 10% (重量） 的其他晶体， 更 指少于 5% (重量） 的其他晶体， 更指少于 1% (重量） 的其他晶体。  The crystal of the present invention is pure, single, and substantially free of any other crystals, such as known crystals without the addition of troglitazone succinate, including its type A, type B, type C, type D, type E, Type F, Type G and its amorphous form. In the present invention, "substantially free" when used to refer to a new crystal means that the new crystal contains less than 20% by weight of other crystals, especially less than 10% by weight of other crystals, more preferably less than 5 % (by weight) of other crystals, more preferably less than 1% by weight of other crystals.
本发明中， "晶体 " 指的是被所示的 X射线衍射图表征所证实的。 本领域技 术人员能够理解，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。 本领域技术人员公知， X 射线衍射图通常会随着仪器条件而有所改变。 特別是， X射线衍射图的相对强度也可能随着实验条件的变化而变化， 所以峰强度的顺序 不能作为唯一或决定性因素。 另外， 峰角度的实验误差通常在 5%或更少， 通常 允许有 ±0.2°的误差。 另外， 由于样品高度等实验因素的影响， 会造成峰角度的整 体偏移， 通常允许一定的偏移。 因而， 本领域技术人员可以理解的是， 任何具有 和本发明图谱中的特征峰相同或相似的图谱的晶体均在本发明范畴之内。 所述 "单一晶体" 是指经 X-射线粉末衍射检测是单一晶体。 In the present invention, "crystal" refers to the characterization of the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. It is well known to those skilled in the art that X-ray diffraction patterns typically vary with instrumental conditions. In particular, the relative intensity of the X-ray diffraction pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, those skilled in the art will understand that any has Crystals of the same or similar patterns as the characteristic peaks in the map of the present invention are within the scope of the present invention. The "single crystal" means a single crystal by X-ray powder diffraction.
根据本发明目的， 本发明提供一种药物组合物， 其包含治疗和 /或预防有效量的 本发明的曲格列汀半琥珀酸盐或其晶体或者由本发明制备方法得到的曲格列汀半 琥珀酸盐或其晶体， 以及至少一种药学上可接受的载体。 任选地， 所述药物组合物 可以包含其它可药用的曲格列汀或其盐的晶体或无定形物， 例如包括但不限于已知 的曲格列汀琥珀酸盐的 A型、 B型、 C型、 D型、 E型、 F型、 G型或其无定形物。 任选地， 所述药物组合物可以包含一种或多种其它可药用的药物活性成分， 例如包 括但不限于其他的 DPP-IV抑制剂如西他列汀、 維格列汀、 沙格列汀， 降糖药如 二甲双胍、 阿卡波糖、 仗格列波糖、 吡格列酮、 罗格列酮， 免疫抑制剂， 治疗细 胞增殖药物等。  According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of troxliptin hemisuccinate of the present invention or a crystal thereof or troglitazone half obtained by the preparation method of the present invention Succinate or crystals thereof, and at least one pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition may comprise crystals or amorphous forms of other pharmaceutically acceptable troglitazone or a salt thereof, for example, including but not limited to the known type A, B of troglitazone succinate. Type, C type, D type, E type, F type, G type or its amorphous substance. Optionally, the pharmaceutical composition may comprise one or more other pharmaceutically acceptable pharmaceutically active ingredients such as, but not limited to, other DPP-IV inhibitors such as sitagliptin, vildagliptin, Shag Lenin, hypoglycemic agents such as metformin, acarbose, sputum glucosamine, pioglitazone, rosiglitazone, immunosuppressive agents, therapeutic cell proliferation drugs, etc.
所述药物组合物可以制成适当的药物制剂形式， 例如包含适当量的本发明曲 格列汀半琥珀酸盐或其晶体的片剂、 胶囊、 丸剂、 粉剂、 颗粒剂、 无菌的肠胃外 溶液或悬浮液、 口服溶液或悬浮液、 油-水乳液、 持续释放的制剂等。  The pharmaceutical composition may be in the form of a suitable pharmaceutical preparation, for example, a tablet, capsule, pill, powder, granule, sterile parenteral containing an appropriate amount of troglitin trisuccinate or a crystal thereof of the present invention. Solutions or suspensions, oral solutions or suspensions, oil-water emulsions, sustained release formulations, and the like.
所述药物组合物中药学上可接受的载体包括但不限于： 稀释剂； 润滑剂； 粘 合剂； 湿润剂； 崩解剂； 助流剂； 甜味剂； 调味剂； 乳化剂； 增溶剂； pH值緩冲 剂； 香味剂； 表面稳定剂； 悬浮剂； 及其它常规的、 药学上非活性的物质。 特別 是， 药物组合物可以包括乳糖， 蔗糖， 磷酸氫钠， 羧甲基纤維素， 硬脂酸镁， 硬 脂酸钙， 滑石粉， 淀粉， 天然树胶 （例如阿拉伯胶， 明胶， 葡萄糖， 糖蜜， 聚乙 烯吡咯烷， 纤維素和其衍生物）， 聚維酮， 乙酸交聚維酮， 柠檬酸钠， 环糊精衍生 物， 单月桂酸脱水山梨醇酯，三乙醇胺乙酸钠， 油酸三乙醇胺， 及其它这类物质。  The pharmaceutically acceptable carrier in the pharmaceutical composition includes, but is not limited to: a diluent; a lubricant; a binder; a wetting agent; a disintegrant; a glidant; a sweetener; a flavoring agent; an emulsifier; ; pH buffer; flavoring agent; surface stabilizer; suspending agent; and other conventional, pharmaceutically inactive substances. In particular, the pharmaceutical compositions may include lactose, sucrose, sodium hydrogen phosphate, carboxymethylcellulose, magnesium stearate, calcium stearate, talc, starch, natural gums such as acacia, gelatin, glucose, molasses, Polyvinylpyrrolidine, cellulose and its derivatives), povidone, crospovidone, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate , and other such substances.
所述药物组合物可以适合多种途径给药。 例如： 按照本发明的药物组合物可 以口服、 胃肠外、 腹膜内、 静脉内、 动脉内、 透皮、 舌下、 肌肉内、 直肠、 经肺、 透颊粘膜、 鼻内、 脂质体、 经吸入、 阴道、 眼内、 经局部递送 （例如， 通过导管 或支架）、 皮下、 脂肪内、 关节内或鞘内给药， 任选以緩慢释放剂型。 在特定的 实施方案中， 药物组合物是通过口服、 吸入或皮下注射、 肌肉内、 静脉内或直接 进入脑脊液中的方式给药的。  The pharmaceutical composition can be administered in a variety of ways. For example: The pharmaceutical composition according to the invention may be orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transpulmonarily, transmucosally, intranasally, liposomes, Inhalation, vaginal, intraocular, topical delivery (eg, via a catheter or stent), subcutaneous, intra-, intra-articular, or intrathecal administration, optionally in a slow release dosage form. In a particular embodiment, the pharmaceutical composition is administered by oral, inhalation or subcutaneous injection, intramuscularly, intravenously or directly into the cerebrospinal fluid.
所述药物组合物可以使用本领域技术人员公知的方法来制备。在制备药物组 合物时， 本发明的曲格列汀半琥珀酸盐或其晶体与一种或多种药学上可接受的载 体， 任选的一种或多种的其他活性成分相混合。 固体制剂可以通过直接混合、 制 粒等工艺来制备。  The pharmaceutical composition can be prepared using methods well known to those skilled in the art. In the preparation of a pharmaceutical composition, the troglitazone hemi-succinate of the present invention or a crystal thereof is mixed with one or more pharmaceutically acceptable carriers, optionally one or more other active ingredients. The solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
特別提及的是片剂或胶囊， 片剂或胶囊可以通过将活性组分与一种或多种前 述的药学上可接受的载体混合， 随后将所得的混合物在常规制片机中压制来制备 片剂或灌入胶囊壳来制备胶囊剂， 所述载体的实例包括： 无水磷酸氫钙、 PVP、 PVP-VA共聚物、 微晶纤維素、 羟基乙酸淀粉钠、 玉米淀粉、 甘露醇、 马铃薯淀 粉、 滑石、 硬脂酸镁、 明胶、 乳糖、 树胶等， 还可以使用为达到上述目的而经常 使用的载体， 例如着色剂、 调味剂、 防腐剂等。 Particular mention is made of tablets or capsules which can be prepared by mixing the active component with one or more of the aforementioned pharmaceutically acceptable carriers, and subsequently compressing the resulting mixture in a conventional tablet machine Capsules are prepared by tableting or filling into a capsule shell, examples of which include: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, corn starch, mannitol, potato starch, talc, magnesium stearate, gelatin, lactose, gum, etc., can also be used frequently for the above purposes. Carriers such as coloring agents, flavoring agents, preservatives, and the like.
根据本发明目的， 本发明提供了本发明所述曲格列汀半琥珀酸盐或其晶体或 者由本发明制备方法得到的曲格列汀半琥珀酸盐或其晶体在制备治疗和 /或预防 I 型糖尿病， II 型糖尿病， 糖尿病性脂血异常， 葡萄糖耐量降低 （IGT) 的病况， 空腹血浆葡萄糖受损（IFG)的病况， 代谢性酸中毒、 酮症、食欲调节和肥胖症， 自身免疫障碍如炎性肠炎、 多发性硬化、 银屑病和类风湿性关节炎， 艾滋病或癌 症的药物中的用途。  According to the object of the present invention, the present invention provides the treglistatin hemisuccinate of the present invention or a crystal thereof or the treglistatin hemisuccinate obtained by the preparation method of the present invention or a crystal thereof for the preparation of a treatment and/or prevention I Type 2 diabetes, type 2 diabetes, diabetic lipemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolic acidosis, ketosis, appetite regulation and obesity, autoimmune disorders Uses in medicines such as inflammatory bowel disease, multiple sclerosis, psoriasis and rheumatoid arthritis, AIDS or cancer.
根据本发明目的， 本发明提供一种治疗和 /或预防 I型糖尿病， II型糖尿病， 糖尿病性脂血异常，葡萄糖耐量降低（IGT)的病况，空腹血浆葡萄糖受损（IFG) 的病况， 代谢性酸中毒、 酮症、 食欲调节和肥胖症， 自身免疫障碍如炎性肠炎、 多发性硬化、 银屑病和类风湿性关节炎， 艾滋病或癌症的方法， 所述方法包括给 予需要的患者治疗和 /或预防有效量的选自本发明的曲格列汀半琥珀酸盐或其晶 体、 由本发明制备方法得到的曲格列汀半琥珀酸盐或其晶体或者含本发明曲格列 汀半琥珀酸盐或其晶体的前述药物组合物。 在任何情况下， 所给予的药物组合物 应该含有足够数量的曲格列汀， 以充分降低体内二肽基肽酶活性， 提供期望的治 疗效果。 其中所述患者为包括人在内的哺乳动物。 方便地， 本发明曲格列汀半琥 珀酸盐或其晶体以单剂量给药， 所述单剂量中含有曲格列汀半琥珀酸盐或其晶体 (以曲格列汀游离碱计） 的量约 1~250 mg， 任选地， 2.5mg至 200mg， 任选地， 2.5mg 至 150mg， 任选地， 5mg 至 lOOmg; 其中每周进行 1次给药， 任选地， 持续至少 30天的时间段， 任选地持续至少 60天的时间段。 附图说明  According to the present invention, the present invention provides a condition for treating and/or preventing type I diabetes, type II diabetes, diabetic lipemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolism Acidosis, ketosis, appetite regulation and obesity, autoimmune disorders such as inflammatory bowel disease, multiple sclerosis, psoriasis and rheumatoid arthritis, AIDS or cancer, the method comprising administering to a patient in need thereof And/or a prophylactically effective amount of trozastatin hemi-succinate or a crystal thereof selected from the present invention, troglitazone hemi-succinate obtained by the preparation method of the present invention or a crystal thereof or containing the trozastatin of the present invention The aforementioned pharmaceutical composition of succinate or its crystals. In any event, the pharmaceutical composition administered should contain a sufficient amount of troglitazone to substantially reduce dipeptidyl peptidase activity in the body to provide the desired therapeutic effect. Wherein the patient is a mammal including a human. Conveniently, the treglistatin hemi-succinate of the present invention or a crystal thereof is administered in a single dose comprising troglitazone hemi-succinate or a crystal thereof (calculated as trozastatin free base) Amounts of from about 1 to 250 mg, optionally from 2.5 mg to 200 mg, optionally from 2.5 mg to 150 mg, optionally from 5 mg to 100 mg; wherein administration is administered once a week, optionally for at least 30 days The time period, optionally for a period of at least 60 days. DRAWINGS
图 1是已知的曲格列汀琥珀酸盐 A型的 XRPD图谱。  Figure 1 is a XRPD pattern of the known trozastatin succinate Form A.
图 2是已知的曲格列汀琥珀酸盐 A型的 PLM图谱。  Figure 2 is a PLM map of the known trozastatin succinate Form A.
图 3是已知的曲格列汀琥珀酸盐 A型的 PSD图谱。  Figure 3 is a PSD map of the known trozastatin succinate Form A.
图 4是本发明曲格列汀半琥珀酸盐的晶体的 XRPD图谱。  Figure 4 is an XRPD pattern of the crystal of troxliptin hemisuccinate of the present invention.
图 5是本发明曲格列汀半琥珀酸盐的晶体的 PLM图谱。  Figure 5 is a PLM map of crystals of troxliptin hemisuccinate of the present invention.
图 6是本发明曲格列汀半琥珀酸盐的晶体的 DSC图谱。  Figure 6 is a DSC spectrum of the crystal of troxliptin hemisuccinate of the present invention.
图 7是本发明曲格列汀半琥珀酸盐的晶体的 TGA图谱。  Figure 7 is a TGA spectrum of crystals of troglitinine hemisuccinate of the present invention.
图 8是本发明曲格列汀半琥珀酸盐的晶体的 IR图谱。  Figure 8 is an IR spectrum of the crystal of trozastatin hemisuccinate of the present invention.
图 9是本发明曲格列汀半琥珀酸盐的晶体的 PSD图谱。 具体实施方式 Figure 9 is a PSD spectrum of the crystal of troxliptin hemisuccinate of the present invention. detailed description
通过下述实施例将有助于进一步理解本发明， 但是不用于限制本发明。 所述 实施例详细描述本发明盐及其晶体的制备方法和应用。对本领域技术人员显而易 见的是， 对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。  The invention will be further understood by the following examples, which are not intended to limit the invention. The examples describe in detail the preparation methods and applications of the salts of the invention and their crystals. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.
采集数据所用的仪器及方法：  Instruments and methods used to collect data:
X射线粉末衍射 （XRPD) 所使用的仪器为 Bruker D8 Advance Diffractometer, 配置有 Θ-2Θ测角仪、 Mo单色仪、 Lynxeye探测器。 采集软件是 Diffiac Plus XRPD Commanded仪器在使用前用仪器自带的标准品（一般为刚玉）校准。检测条件为： 2Θ扫描角度范围 3~40°， 步长 0.02°， 速度 0.2秒 /步。 检测过程： 采用铜靶波长为 1.54nm的 Ka X-射线， 在 40kV和 40mA的操作条件下， 样品在室温条件下测试， 把需要检测的样品放在无反射板上。  The XRD powder diffraction (XRPD) instrument used was a Bruker D8 Advance Diffractometer equipped with a Θ-2Θ goniometer, a Mo monochromator, and a Lynxeye detector. The acquisition software is a Diffiac Plus XRPD Commanded instrument that is calibrated with the standard (usually corundum) supplied with the instrument before use. The detection conditions are: 2Θ scanning angle range 3~40°, step size 0.02°, speed 0.2 sec/step. Detection process: Ka X-ray with a copper target wavelength of 1.54 nm was used. Under the operating conditions of 40 kV and 40 mA, the sample was tested at room temperature, and the sample to be tested was placed on a non-reflecting plate.
偏振光显微镜（PLM) 图谱采自于 XP-500E偏振光显微镜（上海长方光学仪 器有限公司）。 取少量粉末样品置于载玻片上， 滴加少量矿物油以更好地分散粉 末样品， 盖上盖玻片， 然后将样品放置在载物台上， 选择合适的放大倍数观测样 品的形貌并拍照。  The polarized light microscope (PLM) pattern was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on a glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, then place the sample on the stage, select the appropriate magnification to observe the shape of the sample and Take a photo.
差热分析 （DSC) 数据采自于 TA Instruments Q200 MDSC, 仪器控制软件是 Thermal Advantage, 分析软件是 Universal Analysis o 通常取 l~10mg的样品放置 于铝坩埚内，以 10°C/min的升温速度在 40mL/min干燥 N2的保护下将样品从 0°C 升至 250 °C o The differential thermal analysis (DSC) data is taken from the TA Instruments Q200 MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually, a sample of 1~10mg is placed in the aluminum crucible at a heating rate of 10 °C/min. The sample was raised from 0 ° C to 250 ° C under the protection of 40 mL / min dry N 2 o
热重分析 （TGA) 数据采自于 TA Instruments Q500 TGA， 仪器控制软件是 Thermal Advantage, 分析软件是 Universal Analysis o 通常取 5~15mg样品放置于白 金坩埚内， 采用分段高分辨检测方式， 以 10°C/min的升温速度在 40mL/min干燥 N2保护下将样品从室温升至 300°C。 Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis o. Usually 5 to 15 mg of the sample was placed in a platinum crucible, using a segmented high-resolution detection method to 10 The temperature rise rate of ° C/min was raised from room temperature to 300 ° C under a dry N 2 protection of 40 mL/min.
红外光谱分析 （IR) 数据采自于 BmkerTensor 27， 仪器控制软件和数据分析 软件都是 OPUS，通常采用 ATR设备，在 όΟΟ^ΟΟΟ^η-1范围内采集红外吸收光谱， 样品和空白背景的扫描时间均为 16秒， 仪器分辨率为 ^πιΛ Infrared spectroscopy (IR) data is taken from BmkerTensor 27, instrument control software and data analysis software are OPUS, usually using ATR equipment, infrared absorption spectrum is collected in the range of όΟΟ^ΟΟΟ^η- 1 , scanning of samples and blank background The time is 16 seconds, the resolution of the instrument is ^πιΛ
激光粒度仪 （PSD) 数据采自于 Microtrac FLEX S3500, 来测量标准的粒度 分布。 其中： D10代表在该直径以下的占总颗粒体积 10%的颗粒的平均直径， D50 为中值体积直径， 即占总颗粒体积 50%的颗粒的平均直径， D9()为在该直径以下 的占总颗粒体积 90%的颗粒的平均直径。 The laser particle size analyzer (PSD) data was taken from the Microtrac FLEX S3500 to measure the standard particle size distribution. Wherein: D 10 represents the average diameter of the particles below the diameter of 10% of the total particle volume, and D 50 is the median volume diameter, that is, the average diameter of the particles of 50% of the total particle volume, D 9 () is The average diameter of the particles below the diameter of 90% of the total particle volume.
核磁氫谱 (^HNMR)数据采自于 BmkerAvance II DMX 400MHZ核磁共振波谱 仪。 称量 l-5mg样品， 用 0.5mL氘代二甲亚砜溶解， 配成 2-10mg/mL的溶液。  The nuclear magnetic resonance spectrum (^HNMR) data was obtained from a Bmker Avance II DMX 400 MHz magnetic resonance spectrometer. A sample of l-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
高效液相分析 （HPLC ) 数据采自于 Agilent 1260。 采用 C18 色谱柱， 150mmx4.6mm, 柱温 30°C， 波长 220nm， 流速 1.0mL/min， 进样量 5 L， 运行 时间 15min。 溶剂为 50%的乙腈和 50%的水， 流动相 A为 0.05%的三氟乙酸， 流 动相 B为乙腈， 梯度如下表： High performance liquid phase analysis (HPLC) data was taken from Agilent 1260. Using C18 column, 150mmx4.6mm, column temperature 30°C, wavelength 220nm, flow rate 1.0mL/min, injection volume 5 L, operation Time 15min. The solvent is 50% acetonitrile and 50% water, the mobile phase A is 0.05% trifluoroacetic acid, and the mobile phase B is acetonitrile. The gradient is as follows:
Figure imgf000011_0001
Figure imgf000011_0001
除非特殊注明， 实施例均在室温下操作。  The examples were operated at room temperature unless otherwise noted.
实施例中所用的各种试剂如无特別说明均为市售购买。  The various reagents used in the examples were commercially available unless otherwise specified.
实施例中的超声操作有利于样品的溶解， 设备为超声波清洗器， 一般采用 The ultrasonic operation in the embodiment is beneficial to the dissolution of the sample, and the device is an ultrasonic cleaner, generally adopted
40Khz功率超声 5分钟。 40Khz power ultrasound for 5 minutes.
制备例 1已知的曲格列汀琥珀酸盐 A型的制备 Preparation Example 1 Preparation of known statastatin succinate Form A
已知的曲格列汀琥珀酸盐 A型可根据专利文献 WO2008/067465A1 实施例 1A~1E描述的方法制备。 具体为：  The known trozastatin succinate Form A can be prepared according to the method described in Examples 1A to 1E of the patent document WO2008/067465A1. Specifically:
将 35g 2-溴 -5-氟-甲苯和 20gCuCN混合， 然后在 1L的 Ν,Ν-二甲基甲酰胺中 回流 24 小时， 反应物用水稀释并用己烷提取， 有机物用疏酸镁干燥并且除去溶 剂， 得到 4-氟 -2-甲基苄腈； 35 g of 2-bromo-5-fluoro-toluene and 20 g of CuCN were mixed, and then refluxed in 1 L of hydrazine, hydrazine-dimethylformamide for 24 hours. The reaction was diluted with water and extracted with hexane. Drying and removing the solvent to give 4-fluoro-2-methylbenzonitrile;
将 20g4-氟 -2-甲基苄腈， 26.4gN-溴琥珀酰亚胺和 lg偶氮双异丁腈在 800mL 的氯仿中混合， 然后在氮气下回流 2小时， 将反应冷却到室温， 通过过滤除去固 体， 将有机溶液浓缩， 得到油状物的 2-溴甲基 -4-氟苄腈； 20 g of 4-fluoro-2-methylbenzonitrile, 26.4 g of N-bromosuccinimide and lg azobisisobutyronitrile were mixed in 800 mL of chloroform, and then refluxed under nitrogen for 2 hours, and the reaction was cooled to The solid was removed by filtration at room temperature, and the organic solution was concentrated to give 2-bromomethyl-4-fluorobenzonitrile as an oil;
将 8.6g2-溴甲基 -4-氟苄腈， 6g粗的 3-甲基 -6-氯尿嘧啶 D和 5g碳酸鉀在 lOOmL二甲亚砜中混合， 60°C搅袢 2小时， 反应物用水稀释并用乙酸乙酯提取， 有机物用 MgS04干燥并且除去溶剂， 残余物通过柱色谱法纯化， 得到 6.4g2-(6- 氯 _3_甲基 -2,4-二氧代 -3,4-二氫 -2H-嘧啶 -1-基甲基 )-4_氟 -苄腈； 8.6 g of 2-bromomethyl-4-fluorobenzonitrile, 6 g of crude 3-methyl-6-chlorouracil D and 5 g of potassium carbonate were mixed in 100 mL of dimethyl sulfoxide, and stirred at 60 ° C for 2 hours. The reaction was diluted with water and extracted with ethyl acetate, dried organics with M g S04 and purified by column chromatography to remove solvent, the residue, to give 6.4 g 2- (6- chloro-3 _ _ methyl-2,4-dioxo -3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4_fluoro-benzonitrile;
将 3.0g2-(6-氯 -3-甲基 -2,4-二氧代 -3,4-二氫 -2H-嘧啶 -1-基甲基 )-4-氟-苄腈， 2.66g(R)-3-氨基-哌啶二盐酸盐和 5.0g碳酸氫钠在密封管中混合在 30mL乙醇中并 且在 100°C搅袢 2小时，通过硅藻土过滤反应，真空浓缩，然后用三氯甲烷稀释， 并且用水洗涤， 用三氯甲烷萃取水相并且用水洗涤合并的有机相， 用疏酸镁干燥 并且过滤， 将 10mL三氟乙酸添加到溶液中， 然后真空浓缩该溶液， 将残余物溶 于少量的甲醇中， 并且添加乙醚促进沉淀， 让混合物在室温下静置过夜， 除去溶 剂并用乙醚洗涤固体两次， 得到 2-(6-[(3R)-3-氨基 -哌啶 -1-基] -3-甲基 -2,4-二氧代 -3,4-二氫 -2H-嘧啶 -1-基甲基 )-4-氟 -苄腈 （即曲格列汀） 的三氟乙酸盐 2.5g; 3.0 g 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile, 2.66 g (R)-3-Amino-piperidine dihydrochloride and 5.0 g of sodium bicarbonate were mixed in a sealed tube in 30 mL of ethanol and stirred at 100 ° C for 2 hours, filtered through celite, concentrated in vacuo, then Dilute with chloroform and wash with water, extract the aqueous phase with chloroform and wash the combined organic phase with water, dry with magnesium sulfate and filter, add 10 mL of trifluoroacetic acid to the solution, then concentrate the solution in vacuo, The residue was dissolved in a small amount of methanol, and diethyl ether was added to evaporate, and the mixture was allowed to stand at room temperature overnight, solvent was removed and the solid was washed twice with diethyl ether to give 2-(6-[(3R)-3-amino-piperidine. -1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (ie, troglitazone) Trifluoroacetate salt 2.5g;
将上述制备得到的曲格列汀三氟乙酸盐悬浮在 50mL二氯甲烷中， 然后用饱 和碳酸钠调至 pH9， 水洗有机层 3次， 将有机层干燥并且真空除去溶剂， 将产物 1.5g溶于 20mL四氫呋喃中， 向其中加入 400mg琥珀酸， 使溶液保持对空气开放 静置三天，过滤收集沉淀物，得到曲格列汀琥珀酸盐。 JH-NMR (500MHz,CD3OD)： 1.45-1.57 (m, IH), 1.62-1.75 (m, 1H),1.80-1.90 (m, IH), 2.01-2.10 (m, IH), 2.51 (s, 4H), 2.65-2.80 (m, 2H),3.01-3.10 (m, IH), 3.23 (s, 3H), 3.23-3.35 (m, 2H), 5.18-5.35 (m, 2H), 5.45 (s, 1H),7.10-7.20 (m, IH), 7.20-7.30 (m, IH), 7.75-7.88 (m, 1H)。 The above prepared troglitazone trifluoroacetate was suspended in 50 mL of dichloromethane, then adjusted to pH 9 with saturated sodium carbonate, and the organic layer was washed three times with water, the organic layer was dried and solvent was evaporated in vacuo. 1.5 g was dissolved in 20 mL of tetrahydrofuran, 400 mg of succinic acid was added thereto, and the solution was kept open to air for three days, and the precipitate was collected by filtration to obtain troglitazone succinate. J H-NMR (500MHz, CD 3 OD): 1.45-1.57 (m, IH), 1.62-1.75 (m, 1H), 1.80-1.90 (m, IH), 2.01-2.10 (m, IH), 2.51 ( s, 4H), 2.65-2.80 (m, 2H), 3.01-3.10 (m, IH), 3.23 (s, 3H), 3.23-3.35 (m, 2H), 5.18-5.35 (m, 2H), 5.45 ( s, 1H), 7.10-7.20 (m, IH), 7.20-7.30 (m, IH), 7.75-7.88 (m, 1H).
所得曲格列汀琥珀酸盐样品的 X射线粉末衍射图谱如图 1 所示， 与专利文献 WO2008067465A1提供的曲格列汀琥珀酸盐 A型的 X射线粉末衍射图谱基本相同。  The X-ray powder diffraction pattern of the obtained troglitin succinate sample is shown in Fig. 1, which is substantially the same as the X-ray powder diffraction pattern of troglitazone succinate Form A provided in the patent document WO2008067465A1.
PLM图谱如图 2所示， 显示为： 颗粒细小。  The PLM map is shown in Figure 2 and is shown as: Fine particles.
PSD图谱如图 3所示， 其010、 D50、 D90分別为 8μπι、 22μπι、 66μπι。 The PSD spectrum is shown in Fig. 3, and 0 10 , D 50 , and D 90 are 8 μm, 22 μm, and 66 μm, respectively.
HPLC检测， 杂质 N的含量为 0.23%。  The content of impurity N was 0.23% by HPLC.
制备例 2曲格列汀盐酸盐的制备 Preparation Example 2 Preparation of troglitazone hydrochloride
曲格列汀盐酸盐根据下述方法制备。  The troglitin hydrochloride was prepared according to the method described below.
称取 lg制备例 1制备的曲格列汀琥珀酸盐，滴加 300mg盐酸（浓度 37wt%)， 30°C搅袢 24小时，减压过滤， 40°C真空干燥 12小时，得到曲格列汀盐酸盐  The gretliptin succinate prepared in Preparation Example 1 was weighed, 300 mg of hydrochloric acid (concentration: 37 wt%) was added dropwise, and the mixture was stirred at 30 ° C for 24 hours, filtered under reduced pressure, and vacuum dried at 40 ° C for 12 hours to obtain a quatrain column. Ting hydrochloride
(500MHz,i 6-DMSO): 1.45-1.60(m, IH), 1.65-1.75(m, IH), 1.78-2.0(m, 1Η),2.65-2.95 (m, 3H), 3.08 (s, 3H),3.20-3.35 (m, 2H), 5.05-5.12 (m, IH), 5.18-5.26 (m, IH), 5.42 (s, IH), 7.18 (m, 1H),7.35 (m, IH), 7.96 (m, 11 Hz, IH), 8.10-8.22 (m, 3H)。 (500MHz, i 6 -DMSO): 1.45-1.60 (m, IH), 1.65-1.75 (m, IH), 1.78-2.0 (m, 1 Η), 2.65-2.95 (m, 3H), 3.08 (s, 3H) ), 3.20-3.35 (m, 2H), 5.05-5.12 (m, IH), 5.18-5.26 (m, IH), 5.42 (s, IH), 7.18 (m, 1H), 7.35 (m, IH), 7.96 (m, 11 Hz, IH), 8.10-8.22 (m, 3H).
实施例 1 Example 1
取 0.80g曲格列汀盐酸盐， 加入 12.0mL水超声溶解； 取琥珀酸二钠 0.17g， 加入 2.0mL水超声溶解；搅袢条件下， 将曲格列汀盐酸盐的水溶液滴加至琥珀酸 二钠的水溶液中， 40°C搅袢 2小时， 60°C旋干除去溶剂， 40°C真空干燥 10小时， 得到 0.82g曲格列汀半琥珀酸盐， 产率 93.9%。  Take 0.80 g of trozastatin hydrochloride, add 12.0 mL of water to dissolve ultrasonically; take 0.17 g of disodium succinate, add 2.0 mL of water to dissolve ultrasonically; and dilute the aqueous solution of troglitazone hydrochloride by stirring The mixture was stirred at 40 ° C for 2 hours in an aqueous solution of disodium succinate, and the solvent was removed by spinning at 60 ° C, and dried under vacuum at 40 ° C for 10 hours to obtain 0.82 g of troglitazone hemisuccinate in a yield of 93.9%.
HPLC表征显示， 曲格列汀和琥珀酸以摩尔比约为 2:1成半琥珀酸盐。  HPLC characterization showed that trozastatin and succinic acid were about 2:1 hemi-succinate in a molar ratio.
JH-NMR (500MHz,CD3OD) 1.40-1.55 (m, 2H), 1.62-1.75 (m, 2H),1.78-1.86 (m, 2H), 2.01-2.09 (m, 2H), 2.43-2.51 (m, 6H), 2.60-2.80 (m, 4H),3.01-3.10 (m, 2H), 3.12-3.20 (m, 2H), 3.23 (s, 6H), 5.20-5.35 (m, 4H), 5.45 (s, 2H),7.12-7.20 (m, 2H), 7.20-7.28 (m, 2H), 7.78-7.83 (m, 2H)。 J H-NMR (500MHz, CD 3 OD) 1.40-1.55 (m, 2H), 1.62-1.75 (m, 2H), 1.78-1.86 (m, 2H), 2.01-2.09 (m, 2H), 2.43-2.51 (m, 6H), 2.60-2.80 (m, 4H), 3.01-3.10 (m, 2H), 3.12-3.20 (m, 2H), 3.23 (s, 6H), 5.20-5.35 (m, 4H), 5.45 (s, 2H), 7.12-7.20 (m, 2H), 7.20-7.28 (m, 2H), 7.78-7.83 (m, 2H).
HPLC检测， 杂质 N的含量为 0.08%。  The content of impurity N was 0.08% by HPLC.
实施例 2 Example 2
取 0.80g曲格列汀盐酸盐，加入 lOO.OmL乙醇超声溶解；取琥珀酸二钠 0.09g， 加入 40.0mL乙醇超声溶解； 搅袢条件下， 将曲格列汀盐酸盐的乙醇溶液滴加至 琥珀酸二钠的乙醇溶液中， 30°C搅袢 4小时， 30°C旋干除去溶剂， 30°C真空干燥 16小时， 得到 0.40g曲格列汀半琥珀酸盐， 产率 86.5%。  Take 0.80g of trozastatin hydrochloride, add 100.OmL of ethanol to dissolve ultrasonically; take 0.09g of disodium succinate, add 40.0mL of ethanol to dissolve ultrasonically; and mix the tresolide hydrochloride in ethanol solution Add dropwise to a solution of disodium succinate in ethanol, stir at 30 ° C for 4 hours, spin dry at 30 ° C to remove the solvent, and dry at 30 ° C for 16 hours under vacuum to obtain 0.40 g of troglitazone hemisuccinate. 86.5%.
实施例 3 取 0.80g曲格列汀盐酸盐，加入 150.0mL甲醇超声溶解；取琥珀酸二钠 0.04g， 加入 60.0mL甲醇超声溶解； 搅袢条件下， 将曲格列汀盐酸盐的甲醇溶液滴加至 琥珀酸二钠的甲醇溶液中， 20°C搅袢 8小时， 10°C旋干除去溶剂， 15°C真空干燥 24小时， 得到 0.15g曲格列汀半琥珀酸盐， 产率 73%。 Example 3 Take 0.80 g of trozastatin hydrochloride, add 150.0 mL of methanol to dissolve ultrasonically; take 0.04 g of disodium succinate, add 60.0 mL of methanol to dissolve ultrasonically; and dilute the methoxide solution of troglitazone hydrochloride Adding to a solution of disodium succinate in methanol, stirring at 20 ° C for 8 hours, removing the solvent by spinning at 10 ° C, and drying under vacuum at 15 ° C for 24 hours to obtain 0.15 g of troglitazone hemisuccinate, yield 73 %.
实施例 2、 3的样品与实施例 1样品具有相同或相似的 HPLC和 ifi-NMR检 测结果 （未示出）， 说明实施例 2、 3样品与实施例 1样品是相同的物质。  The samples of Examples 2 and 3 have the same or similar HPLC and ifi-NMR detection results (not shown), indicating that the samples of Examples 2 and 3 are the same as the samples of Example 1.
实施例 4 Example 4
取 0.80g曲格列汀盐酸盐， 加入 13.4mL水超声溶解 （曲格列汀盐酸盐的水 溶液的浓度为析晶温度下其在水中溶解度的 0.9倍）； 取琥珀酸二钠 O.llg, 加入 2.3mL水超声溶解 （琥珀酸二钠的水溶液的浓度为析晶温度下其在水中溶解度的 0.9倍）； 搅袢条件下， 将曲格列汀盐酸盐的水溶液以 10mL/分钟的速度滴加至琥 珀酸二钠的水溶液中， 15°C搅袢 4小时， 减压过滤， 40°C真空干燥 10小时， 得 到本发明曲格列汀半琥珀酸盐的晶体。 产量为 0.53g， 产率 93.8%。  Take 0.80 g of trozastatin hydrochloride, add 13.4 mL of water to dissolve ultrasonically (the concentration of aqueous solution of troglitazone hydrochloride is 0.9 times its solubility in water at the crystallization temperature); take disodium succinate O. Llg, ultrasonically dissolved by adding 2.3 mL of water (the concentration of the aqueous solution of disodium succinate is 0.9 times the solubility in water at the crystallization temperature); the aqueous solution of troglitazone hydrochloride is 10 mL/min under stirring conditions The mixture was added dropwise to an aqueous solution of disodium succinate, stirred at 15 ° C for 4 hours, filtered under reduced pressure, and dried under vacuum at 40 ° C for 10 hours to obtain crystals of the treglistatin hemisuccinate of the present invention. The yield was 0.53 g and the yield was 93.8%.
XRPD图谱如图 4所示。  The XRPD pattern is shown in Figure 4.
PLM图谱如图 5所示。  The PLM map is shown in Figure 5.
DSC图谱如图 6所示。  The DSC spectrum is shown in Figure 6.
TGA图谱如图 7所示。  The TGA map is shown in Figure 7.
IR图谱如图 8所示。  The IR spectrum is shown in Figure 8.
PSD图谱如图 9所示， 其010、 D50、 D90分別为 55μπι、 114μπι、 192μπι。 HPLC表征显示， 曲格列汀和琥珀酸以摩尔比约为 2:1成半琥珀酸盐。 The PSD spectrum is shown in Fig. 9, and its 0 10 , D 50 , and D 90 are 55 μm, 114 μm, and 192 μm, respectively. HPLC characterization showed that trozastatin and succinic acid were about 2:1 sesquisuccinate in a molar ratio.
实施例 5 Example 5
取 0.80g曲格列汀盐酸盐， 加入 160mL异丙醇超声溶解（曲格列汀盐酸盐的 异丙醇溶液的浓度为析晶温度下其在异丙醇中溶解度的 1 倍）； 取琥珀酸二钠 0.17g， 加入 80mL异丙醇超声溶解（琥珀酸二钠的异丙醇溶液的浓度为析晶温度 下其在异丙醇中溶解度的 1倍）； 搅袢条件下， 将曲格列汀盐酸盐的异丙醇溶液 滴加至琥珀酸二钠的异丙醇溶液中， 加入 0.04g作为晶种的本发明曲格列汀半琥 珀酸盐的晶体， 30°C搅袢 2小时， 减压过滤， 60°C真空干燥 10小时， 得到本发 明曲格列汀半琥珀酸盐的晶体。 产量为 0.79g， 产率 90.5%。  0.80 g of troglitin hydrochloride was added, and 160 mL of isopropanol was added to dissolve ultrasonically (the concentration of the isopropyl alcohol solution of troglitazone hydrochloride was 1 time in the isopropanol at the crystallization temperature); Take 0.17g of disodium succinate and add 80mL of isopropanol to dissolve ultrasonically (the concentration of disodium succinate in isopropanol solution is 1 times the solubility in isopropanol at the crystallization temperature); An isopropanol solution of troglitazone hydrochloride was added dropwise to a solution of disodium succinate in isopropanol, and 0.04 g of crystals of the trozastatin hemisuccinate of the present invention as a seed crystal was added, and stirred at 30 ° C After 2 hours, it was filtered under reduced pressure and dried under vacuum at 60 ° C for 10 hours to obtain crystals of the treglistatin hemisuccinate of the present invention. The yield was 0.79 g and the yield was 90.5%.
实施例 6 Example 6
取 0.80g曲格列汀盐酸盐， 加入 200mL乙醇超声溶解（曲格列汀盐酸盐的乙 醇溶液的浓度为析晶温度下其在乙醇中溶解度的 0.5倍）； 取琥珀酸二钠 0.09g， 加入 80mL乙醇超声溶解 （琥珀酸二钠的乙醇溶液的浓度为析晶温度下其在乙醇 中溶解度的 0.5倍）；搅袢条件下， 将曲格列汀盐酸盐的乙醇溶液以 16mL/分钟的 速度滴加至琥珀酸二钠的乙醇溶液中， 20°C搅袢 3小时， 减压过滤， 40°C真空干 燥 14小时，得到本发明曲格列汀半琥珀酸盐的晶体。产量为 0.37g，产率 80.0%。 实施例 7 Take 0.80 g of trozastatin hydrochloride and dissolve it by ultrasonic in 200 mL of ethanol (the concentration of the ethanol solution of troglitazone hydrochloride is 0.5 times the solubility in ethanol at the crystallization temperature); take disodium succinate 0.09 g, ultrasonically dissolved by adding 80mL of ethanol (the concentration of disodium succinate in ethanol is 0.5 times the solubility in ethanol at the crystallization temperature); under stirring conditions, the ethanol solution of troglitazone hydrochloride is 16mL At a rate of /min, add dropwise to a solution of disodium succinate in ethanol, stir at 20 ° C for 3 hours, filter under reduced pressure, and dry at 40 ° C. After drying for 14 hours, crystals of the treglistatin hemisuccinate of the present invention were obtained. The yield was 0.37 g and the yield was 80.0%. Example 7
取 0.80g曲格列汀盐酸盐， 加入 500mL甲醇超声溶解（曲格列汀盐酸盐的甲 醇溶液的浓度为析晶温度下其在甲醇中溶解度的 0.3倍）； 取琥珀酸二钠 0.06g， 加入 200mL 甲醇超声溶解 （琥珀酸二钠的甲醇溶液的浓度为析晶温度下其在甲 醇中溶解度的 0.3倍）；搅袢条件下， 将曲格列汀盐酸盐的甲醇溶液以 12mL/分钟 的速度滴加至琥珀酸二钠的甲醇溶液中，加入 0.016g作为晶种的本发明曲格列汀 半琥珀酸盐的晶体， 50°C搅袢 1 小时， 减压过滤， 13°C真空干燥 48小时， 得到 本发明曲格列汀半琥珀酸盐的晶体。 产量为 0.22g， 产率 71.4%。  0.80 g of trozastatin hydrochloride was added, and ultrasonically dissolved in 500 mL of methanol was added (the concentration of the methanol solution of troglitazone hydrochloride was 0.3 times the solubility in methanol at the crystallization temperature); taking disodium succinate 0.06 g, ultrasonically dissolved by adding 200mL of methanol (the concentration of disodium succinate in methanol is 0.3 times of the solubility in methanol at the crystallization temperature); under stirring conditions, the methanol solution of troglitazone hydrochloride is 12mL The solution was added dropwise to a solution of disodium succinate in methanol at a rate of /min, and 0.016 g of crystals of the troxliptin hemisuccinate of the present invention as a seed crystal was added, and the mixture was stirred at 50 ° C for 1 hour, and filtered under reduced pressure, 13 °. C was dried under vacuum for 48 hours to obtain crystals of the treglistatin hemisuccinate of the present invention. The yield was 0.22 g, and the yield was 71.4%.
实施例 8 Example 8
取 0.80g曲格列汀盐酸盐， 加入正丁醇 1.4L正丁醇超声溶解（曲格列汀盐酸 盐的正丁醇溶液的浓度为析晶温度下其在正丁醇中溶解度的 0.1倍）；取琥珀酸二 钠 0.04g， 加入 6mL水超声溶解 （琥珀酸二钠的水溶液的浓度为析晶温度下其在 水中溶解度的 0.1 倍）； 搅袢条件下， 将曲格列汀盐酸盐的正丁醇溶液以 20mL/ 分钟的速度滴加至琥珀酸二钠的水溶液中， 5°C搅袢 24小时， 减压过滤， 10°C真 空干燥 72小时，得到本发明曲格列汀半琥珀酸盐的晶体。产量为 O.llg，产率 53.5%。  Take 0.80 g of trozastatin hydrochloride, add n-butanol 1.4 L n-butanol to dissolve ultrasonically (the concentration of n-butanol solution of troglitazone hydrochloride is the solubility in n-butanol at the crystallization temperature 0.1 times); taking 0.04g of disodium succinate, ultrasonically dissolved by adding 6mL of water (the concentration of the aqueous solution of disodium succinate is 0.1 times of the solubility in water at the crystallization temperature); trozastatin under stirring conditions The n-butanol solution of the hydrochloride was added dropwise to an aqueous solution of disodium succinate at a rate of 20 mL/min, stirred at 5 ° C for 24 hours, filtered under reduced pressure, and dried under vacuum at 10 ° C for 72 hours to obtain a grid of the present invention. Crystals of statin hemisuccinate. The yield was O.llg, and the yield was 53.5%.
实施例 5~8的样品与实施例 4样品具有相同或相似的 XRPD图谱、 PLM图 谱、 DSC图谱、 TGA图谱、 IR图谱、 PSD图谱和 HPLC检测结果 （未示出）， 说明实施例 5~8样品与实施例 4样品是相同的物质。  The samples of Examples 5 to 8 have the same or similar XRPD patterns, PLM patterns, DSC patterns, TGA patterns, IR patterns, PSD patterns, and HPLC detection results (not shown), and Examples 5-8 The sample was the same as the sample of Example 4.
实施例 9 Example 9
片剂 （每片含 12.5mg的曲格列汀） 配方如下：  The tablets (containing 12.5 mg of troglitazone per tablet) are formulated as follows:
本发明的曲格列汀半琥珀酸盐的晶体： 14.6mg  Crystals of troglitazone hemisuccinate of the invention: 14.6 mg
乳糖一水合物： 226.9mg  Lactose monohydrate: 226.9mg
微晶纤維素： 120.1 mg  Microcrystalline cellulose: 120.1 mg
交联羧甲基纤維素钠： 32.0 mg  Croscone sodium: 32.0 mg
胶体二氧化硅： 3.2 mg  Colloidal silica: 3.2 mg
硬脂酸镁: 3.2 mg  Magnesium stearate: 3.2 mg
总计： 400.0 mg  Total: 400.0 mg
片剂的制备步骤如下：  The preparation steps of the tablet are as follows:
将本发明的曲格列汀半琥珀酸盐的晶体与乳糖一水合物采用等量递增方法 混合均勾， 再与微晶纤維素、 交联羧甲基纤維素钠、 胶体二氧化硅、 硬脂酸镁混 合均匀后， 置于压片机中压片， 调节片重， 即得相应片剂， 共制备 1000片。  The crystals of the trozastatin hemisuccinate of the present invention are mixed with the lactose monohydrate by an equal amount of increasing methods, followed by microcrystalline cellulose, croscarmellose sodium, colloidal silica, and hard After the magnesium oleate was uniformly mixed, it was placed in a tableting machine to be tableted, and the tablet weight was adjusted to obtain a corresponding tablet. A total of 1,000 tablets were prepared.
实施例 10 Example 10
片剂 （每片含 25.0mg的曲格列汀） 配方如下： 本发明的曲格列汀半琥珀酸盐的晶体： 29. lmg The tablets (containing 25.0 mg of troglitazone per tablet) are formulated as follows: Crystals of troglitazone hemisuccinate of the invention: 29. lmg
乳糖一水合物： 212.4mg  Lactose monohydrate: 212.4mg
微晶纤維素： 120.1 mg  Microcrystalline cellulose: 120.1 mg
交联羧甲纤维素钠： 32.0 mg  Croscarmellose sodium: 32.0 mg
胶体二氧化硅： 3.2 mg  Colloidal silica: 3.2 mg
硬脂酸镁: 3.2 mg  Magnesium stearate: 3.2 mg
总计： 400.0 mg  Total: 400.0 mg
该片剂的制备步骤与实施例 9的制备步骤相同。  The preparation steps of this tablet were the same as those of Example 9.
实施例 11 Example 11
片剂 （每片含 50.0mg的曲格列汀） 配方如下：  The tablets (containing 50.0 mg of troglitazone per tablet) are formulated as follows:
本发明的曲格列汀半琥珀酸盐的晶体： 58.3mg  Crystal of trozastatin hemisuccinate of the invention: 58.3 mg
乳糖一水合物： 183.2mg  Lactose monohydrate: 183.2mg
微晶纤维素： 120.1 mg  Microcrystalline cellulose: 120.1 mg
交联羧甲纤維素钠： 32.0 mg  Croscarmellose sodium: 32.0 mg
胶体二氧化硅： 3.2 mg  Colloidal silica: 3.2 mg
硬脂酸镁: 3.2 mg  Magnesium stearate: 3.2 mg
总计： 400.0 mg  Total: 400.0 mg
该片剂的制备步骤与实施例 9的制备步骤相同。  The preparation steps of this tablet were the same as those of Example 9.
实施例 12 Example 12
胶囊剂 （每粒含 12.5 mg的曲格列汀） 配方如下：  Capsules (containing 12.5 mg of troglitazone per capsule) are formulated as follows:
本发明的曲格列汀半琥珀酸盐的晶体： 14.6 mg  Crystals of troglitazone hemisuccinate of the invention: 14.6 mg
预胶化淀粉： 232.4 mg  Pregelatinized starch: 232.4 mg
乳糖： 150.0 mg  Lactose: 150.0 mg
硬脂酸镁： 3.0mg  Magnesium stearate: 3.0mg
总计： 400.0 mg  Total: 400.0 mg
胶囊剂的制备步骤如下：  The preparation steps of the capsule are as follows:
将本发明的曲格列汀半琥珀酸盐的晶体与预胶化淀粉、 乳糖、 硬脂酸镁混合 均匀后置于干法制粒机中制粒， 将制得的干颗粒输入胶囊填充机中灌入胶囊， 即 得相应胶囊剂， 共制备 1000粒。  The crystal of the trozastatin hemisuccinate of the present invention is uniformly mixed with pregelatinized starch, lactose and magnesium stearate, and then placed in a dry granulator to be granulated, and the obtained dry granules are input into a capsule filling machine. After filling the capsule, the corresponding capsules were obtained, and a total of 1000 capsules were prepared.
实施例 13 Example 13
胶囊剂 （每粒含 25.0 mg的曲格列汀） 配方如下：  Capsules (containing 25.0 mg of troglitazone per capsule) are formulated as follows:
本发明的曲格列汀半琥珀酸盐的晶体： 29.1 mg  Crystals of troglitazone hemisuccinate of the invention: 29.1 mg
预胶化淀粉： 217.9mg  Pregelatinized starch: 217.9mg
乳糖： 150.0 mg 硬脂酸镁： 3.0mg Lactose: 150.0 mg Magnesium stearate: 3.0mg
总计： 400.0 mg  Total: 400.0 mg
该胶囊剂的制备步骤与实施例 12的制备步骤相同。  The preparation procedure of the capsule was the same as the preparation procedure of Example 12.
实施例 14 Example 14
胶囊剂 （每粒含 50.0 mg的曲格列汀） 配方如下：  Capsules (50.0 mg each of troglitazone) are formulated as follows:
本发明的曲格列汀半琥珀酸盐的晶体： 58.3 mg  Crystals of troglitazone hemisuccinate of the invention: 58.3 mg
预胶化淀粉： 188.7mg  Pregelatinized starch: 188.7mg
乳糖： 150.0 mg  Lactose: 150.0 mg
硬脂酸镁： 3.0mg  Magnesium stearate: 3.0mg
总计： 400.0 mg  Total: 400.0 mg
该胶囊剂的制备步骤与实施例 12的制备步骤相同。 以上所述， 仅为本发明具体实施方式， 但本发明保护范围并不局限于此， 任 何熟悉本领域的技术人员在本发明所揭露的技术范围内， 可不经过创造性劳动想 到的变化或替换， 都应涵盖在本发明保护范围之内。  The preparation procedure of the capsule was the same as the preparation procedure of Example 12. The above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change or replace without thinking of the creative work within the technical scope of the present invention. All should be covered by the scope of the present invention.

Claims

权利要求 Rights request
1. 结构式如 （I) 所示的曲格列汀半琥珀酸盐 1. The trozastatin hemisuccinate of the formula (I)
Figure imgf000017_0001
Figure imgf000017_0001
2、一种权利要求 1所述曲格列汀半琥珀酸盐的制备方法，其包括以下步骤： 分別形成曲格列汀盐酸盐和琥珀酸二钠在可溶溶剂中的溶液体系， 两个溶液体系 中曲格列汀盐酸盐和琥珀酸二钠的摩尔比为 10:1~2:1， 混合两个溶液体系进行反 应， 反应完成后除去溶剂， 得到所述曲格列汀半琥珀酸盐； 2. A process for the preparation of troglitazone hemisuccinate according to claim 1, comprising the steps of: respectively forming a solution system of troglitazone hydrochloride and disodium succinate in a soluble solvent, In a solution system, the molar ratio of troglitazone hydrochloride to disodium succinate is 10:1 to 2:1, and the two solution systems are mixed to carry out the reaction, and after the reaction is completed, the solvent is removed to obtain the troglitazone half. Succinate
优选地， 所述可溶溶剂选自水、 醇或其混合物；  Preferably, the soluble solvent is selected from the group consisting of water, alcohol or a mixture thereof;
优选地，所述制备方法的操作温度为 20~40°C，所述反应的时间为 1~8小时； 优选地，采用旋干法除去溶剂；更优选地，所述旋干法的温度为 10°C~60°C。 Preferably, the preparation method has an operating temperature of 20 to 40 ° C, and the reaction time is 1 to 8 hours; preferably, the solvent is removed by spin-drying; more preferably, the temperature of the spin-drying method is 10 ° C ~ 60 ° C.
3、一种权利要求 1所述曲格列汀半琥珀酸盐的晶体，其特征在于，使用 Cu-Ka 辐射， 所述晶体以 2Θ 角度表示的 X-射线粉末衍射图在以下位置具有特征峰： 12.3士 0.2。、 17.0士 0.2。、 18.4±0.2。、 19.0士 0.2°、 20.1士 0.2。和 21.6士 0.2。。 A crystal of troglitazone hemisuccinate according to claim 1, characterized in that, by Cu-Ka radiation, the crystal has an X-ray powder diffraction pattern represented by an angle of 2 具有 having a characteristic peak at the following position : 12.3 ± 0.2. 17.0 ± 0.2. , 18.4 ± 0.2. , 19.0 ± 0.2 °, 20.1 ± 0.2. And 21.6 ± 0.2. .
4、 根据权利要求 3 所述曲格列汀半琥珀酸盐的晶体， 其特征在于， 所述晶 体以 2Θ角度表示的 X-射线粉末衍射图在以下位置具有特征峰： 4.8±0.2°、12.3±0.2°、 14.9士 0.2ο、 15.2±0.2ο、 17.0士 0.2ο、 18.4±0.2ο、 19.0士 0.2ο、 20.1士 0.2ο、 21.6±0.2ο、 22.5士 0.2°、 23.1士 0.2°和 26.7士 0.2。。 4. The crystal of trozastatin hemisuccinate according to claim 3, wherein the crystal has an X-ray powder diffraction pattern represented by a 2 Θ angle having characteristic peaks at the following positions: 4.8 ± 0.2°, 12.3 ±0.2°, 14.9±0.2 ο , 15.2±0.2 ο , 17.0 ± 0.2 ο , 18.4±0.2 ο , 19.0 ± 0.2 ο , 20.1 ± 0.2 ο , 21.6 ± 0.2 ο , 22.5 ± 0.2 ° , 23.1 ± 0.2 ° and 26.7 Division 0.2. .
5、 根据权利要求 4 所述曲格列汀半琥珀酸盐的晶体， 其特征在于， 所述晶 体以 2Θ角度表示的 X-射线粉末衍射图在以下位置具有特征峰及其相对强度： 衍射角 2Θ 相对强度％  5. The crystal of troglitazone hemi-succinate according to claim 4, wherein the crystal has an X-ray powder diffraction pattern represented by a 2 Θ angle having characteristic peaks and relative intensities at the following positions: diffraction angle 2Θ Relative strength%
4.8士 0.2° 18.1  4.8 ± 0.2° 18.1
9.6士 0.2° 22.8  9.6 士 0.2° 22.8
12.3士 0.2° 52.4  12.3 ± 0.2 ° 52.4
12.6士 0.2° 16.5  12.6 ± 0.2° 16.5
13.9士 0.2° 15.1  13.9 ± 0.2° 15.1
14.9士 0.2° 28.4  14.9士 0.2° 28.4
15.2±0.2° 30.2 15.2±0.2° 30.2
17.0士 0.2 100.0 17.0士 0.2 100.0
18.4±0.2 73.3  18.4±0.2 73.3
19.0士 0.2 58.3  19.0 ± 0.2 58.3
20.1±0.2 50.8  20.1±0.2 50.8
21.6士 0.2 82.7  21.6 ± 0.2 82.7
22.5士 0.2 39.4  22.5 ± 0.2 39.4
23.1±0.2 61.2  23.1±0.2 61.2
24.7士 0.2 26.4  24.7 ± 0.2 26.4
25.0士 0.2 26.4  25.0 士 0.2 26.4
26.7士 0.2 44.3  26.7 ± 0.2 44.3
28.0士 0.2 24.4  28.0 ± 0.2 24.4
28.5±0.2 30.5  28.5±0.2 30.5
28.8±0.2 27.9 ο  28.8±0.2 27.9 ο
6、 根据权利要求 3~5 中任一项所述曲格列汀半琥珀酸盐的晶体， 其特征在 于，所述晶体的傅里叶红外光谱在波数为 3374、 2925、 1701、 1658、 1611、 1559、 1438、 1364、 1273、 1213、 958、 882、 820、 758和 662 cm 处具有特征峰。  6. The crystal of troglitazone hemisuccinate according to any one of claims 3 to 5, wherein the Fourier transform infrared spectrum of the crystal is 3374, 2925, 1701, 1658, 1611 , 1559, 1438, 1364, 1273, 1213, 958, 882, 820, 758, and 662 cm have characteristic peaks.
7、 根据权利要求 6所述曲格列汀半琥珀酸盐的晶体， 其特征在于， 所述晶 体颗粒的中值体积直径 D5()至少为 60μπι， 占总颗粒体积 10%的晶体颗粒的平均 直径 D5Q至少为 ΙΟμπι, 和 /或占总颗粒体积 90%的晶体颗粒的平均直径 D9Q至少 为 140μπι。 7. The crystal of troglitazone hemisuccinate according to claim 6, wherein the crystal particles have a median volume diameter D 5 () of at least 60 μm, and 10% of the total particle volume of the crystal particles. The average diameter D 5Q is at least ΙΟμπι, and/or the average diameter D 9Q of the crystal particles which is 90% of the total particle volume is at least 140 μm.
8、 根据权利要求 7所述曲格列汀半琥珀酸盐的晶体， 其特征在于， 所述晶 体中具有如下结构式的杂质 Ν的重量含量小于 0.1%  The crystal of troglitazone hemisuccinate according to claim 7, wherein the impurity having the following structural formula in the crystal has a weight content of less than 0.1%.
Figure imgf000018_0001
Figure imgf000018_0001
杂质 N  Impurity N
9、一种权利要求 3~8中任一项所述曲格列汀半琥珀酸盐的晶体的制备方法， 其包括以下步骤： 分別形成曲格列汀盐酸盐和琥珀酸二钠在溶剂中的溶液体系， 其中所述溶剂选自水、 d~C4醇或其混合物， 两个溶液体系中曲格列汀盐酸盐和 琥珀酸二钠的摩尔比为 10: 1~2: 1， 混合两个溶液体系， 可选地加入作为晶种的曲 格列汀半琥珀酸盐的晶体， 搅袢析晶， 得到所述曲格列汀半琥珀酸盐的晶体。 10、 根据权利要求 9所述曲格列汀半琥珀酸盐的晶体的制备方法， 其特征在 于， 所述溶剂选自水、 乙醇或异丙醇； 所述曲格列汀盐酸盐和琥珀酸二钠的摩尔 比为 4:1~2:1。 A process for producing crystals of troglitazone hemisuccinate according to any one of claims 3 to 8, which comprises the steps of: respectively forming troglitazone hydrochloride and disodium succinate in a solvent a solution system, wherein the solvent is selected from the group consisting of water, d-C 4 alcohol or a mixture thereof, and the molar ratio of troglitazone hydrochloride to disodium succinate in the two solution systems is 10:1~2:1 The two solution systems are mixed, and crystals of trozastatin hemisuccinate as a seed crystal are optionally added, and the crystals are stirred and pulverized to obtain crystals of the trozastatin hemisuccinate. The method for preparing crystals of troglitazone hemisuccinate according to claim 9, wherein the solvent is selected from the group consisting of water, ethanol or isopropanol; the troglitazone hydrochloride and amber The molar ratio of disodium acid is 4:1 to 2:1.
11、 根据权利要求 9所述曲格列汀半琥珀酸盐的晶体的制备方法， 其特征在 于， 所述混合两个溶液体系的方式为将曲格列汀盐酸盐的溶液体系滴加至琥珀酸 二钠的溶液体系中或将琥珀酸二钠的溶液体系滴加至曲格列汀盐酸盐的溶液体 系中或将两个溶液体系同时滴加； 优选地， 将曲格列汀盐酸盐的溶液体系滴加至 琥珀酸二钠的溶液体系中；更优选地，将曲格列汀盐酸盐的溶液体系以 10~20mL/ 分钟的速度滴加至琥珀酸二钠的溶液体系中。  11. The method for preparing crystals of troglitazone hemisuccinate according to claim 9, wherein the two solution systems are mixed by adding a solution system of troglitazone hydrochloride to the solution system. In a solution system of disodium succinate or a solution system of disodium succinate or a solution system of troglinate hydrochloride or a solution of two solutions simultaneously; preferably, troglitazone salt The solution system of the acid salt is added dropwise to the solution system of disodium succinate; more preferably, the solution system of troglitazone hydrochloride is added dropwise to the solution system of disodium succinate at a rate of 10-20 mL/min. in.
12、 根据权利要求 11 所述曲格列汀半琥珀酸盐的晶体的制备方法， 其特征 在于， 将曲格列汀盐酸盐的溶液体系滴加至琥珀酸二钠的溶液体系中后， 加入作 为晶种的曲格列汀半琥珀酸盐的晶体， 晶种的用量为曲格列汀盐酸盐重量的 1%~5%。  12. The method for preparing crystals of trozastatin hemisuccinate according to claim 11, wherein after the solution system of troglitazone hydrochloride is added dropwise to a solution system of disodium succinate, Crystals of trozastatin hemisuccinate as a seed crystal are added in an amount of from 1% to 5% by weight based on the weight of troglitazone hydrochloride.
13、 根据权利要求 9~12 中任一项所述曲格列汀半琥珀酸盐的晶体的制备方 法， 其特征在于， 所述曲格列汀盐酸盐溶液体系的浓度为操作温度下其在所述溶 剂中溶解度的 0.1~1倍， 优选为 0.5~1倍； 所述琥珀酸二钠溶液体系的浓度为操 作温度下其在所述溶剂中溶解度的 0.1~1倍， 优选为 0.5~1倍。  The method for preparing crystals of troglitazone hemisuccinate according to any one of claims 9 to 12, wherein the concentration of the troglitin hydrochloride solution system is at an operating temperature The solubility in the solvent is 0.1 to 1 time, preferably 0.5 to 1 time; the concentration of the disodium succinate solution system is 0.1 to 1 times, preferably 0.5 to the solubility in the solvent at the operating temperature. 1 times.
14、 根据权利要求 9~12 中任一项所述曲格列汀半琥珀酸盐的晶体的制备方 法， 其特征在于， 所述制备方法的操作温度为 -10~50°C， 优选为室温； 所述析晶 的时间为 1~48小时， 优选为 2~4小时。  The method for preparing crystals of trozastatin hemisuccinate according to any one of claims 9 to 12, wherein the preparation method has an operating temperature of -10 to 50 ° C, preferably room temperature. The crystallization time is from 1 to 48 hours, preferably from 2 to 4 hours.
15、一种药物组合物，其包含治疗和 /或预防有效量的选自权利要求 1所述曲 格列汀半琥珀酸盐、 根据权利要求 2所述制备方法得到的曲格列汀半琥珀酸盐、 权利要求 3~8中任一项所述曲格列汀半琥珀酸盐的晶体或根据权利要求 9~14中 任一项所述制备方法得到的曲格列汀半琥珀酸盐的晶体， 以及至少一种药学上可 接受的载体。  15. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of troxliptin semi-succinimide selected from the method of claim 2, wherein the trozastatin hemisuccinate of claim 1 is prepared according to the method of claim 2. The acid salt, the crystal of troglitazone hemisuccinate according to any one of claims 3 to 8, or the trozastatin hemisuccinate obtained by the preparation method according to any one of claims 9 to 14. Crystals, and at least one pharmaceutically acceptable carrier.
16、 根据权利要求 15所述药物组合物， 其特征在于， 所述药物组合物为片 剂或胶囊剂。  The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is a tablet or a capsule.
17、 权利要求 1所述曲格列汀半琥珀酸盐、 根据权利要求 2所述制备方法得 到的曲格列汀半琥珀酸盐、权利要求 3~8中任一项所述曲格列汀半琥珀酸盐的晶 体或根据权利要求 9~14 中任一项所述制备方法得到的曲格列汀半琥珀酸盐的晶 体在制备治疗和 /或预防 I型糖尿病， II型糖尿病， 糖尿病性脂血异常， 葡萄糖耐 量降低的病况， 空腹血浆葡萄糖受损的病况， 代谢性酸中毒、 酮症、 食欲调节和 肥胖症， 自身免疫障碍如炎性肠炎、 多发性硬化、 银屑病和类风湿性关节炎， 艾 滋病或癌症的药物中的用途。 The trozastatin hemisuccinate according to claim 1, the trozastatin hemisuccinate obtained by the preparation method according to claim 2, and the troglitazone according to any one of claims 3 to 8. Crystals of succinate or the crystal of trozastatin hemisuccinate obtained by the preparation method according to any one of claims 9 to 14 for the treatment and/or prevention of type I diabetes, type II diabetes, diabetes Abnormal lipemia, glucose tolerance Reduced conditions, impaired fasting plasma glucose, metabolic acidosis, ketosis, appetite regulation and obesity, autoimmune disorders such as inflammatory bowel disease, multiple sclerosis, psoriasis and rheumatoid arthritis, AIDS Or use in drugs for cancer.
18、 一种治疗和 /或预防 I型糖尿病， II型糖尿病， 糖尿病性脂血异常， 葡萄 糖耐量降低的病况， 空腹血浆葡萄糖受损的病况， 代谢性酸中毒、 酮症、 食欲调 节和肥胖症， 自身免疫障碍如炎性肠炎、多发性硬化、银屑病和类风湿性关节炎， 艾滋病或癌症的方法，所述方法包括给予需要的患者治疗和 /或预防有效量的选自 权利要求 1所述曲格列汀半琥珀酸盐、 根据权利要求 2所述制备方法得到的曲格 列汀半琥珀酸盐、 权利要求 3~8中任一项所述曲格列汀半琥珀酸盐的晶体、 根据 权利要求 9~14 中任一项所述制备方法得到的曲格列汀半琥珀酸盐的晶体或者权 利要求 15或 16所述的药物组合物。  18. A treatment and/or prevention of type 1 diabetes, type II diabetes, diabetic lipemia, a condition of impaired glucose tolerance, a condition of impaired fasting plasma glucose, metabolic acidosis, ketosis, appetite regulation and obesity A method of autoimmune disorders such as inflammatory bowel disease, multiple sclerosis, psoriasis and rheumatoid arthritis, AIDS or cancer, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount selected from claim 1 The trozastatin hemisuccinate, the treglistatin hemisuccinate obtained by the preparation method according to claim 2, the trozastatin hemisuccinate according to any one of claims 3 to 8. Crystals, crystals of troglitazone hemisuccinate obtained by the preparation method according to any one of claims 9 to 14 or the pharmaceutical composition according to claim 15 or 16.
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