WO2021136491A1 - Forme cristalline d'inhibiteur de la dipeptidyl-peptidase iv, son procédé de préparation et son application - Google Patents

Forme cristalline d'inhibiteur de la dipeptidyl-peptidase iv, son procédé de préparation et son application Download PDF

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Publication number
WO2021136491A1
WO2021136491A1 PCT/CN2020/142058 CN2020142058W WO2021136491A1 WO 2021136491 A1 WO2021136491 A1 WO 2021136491A1 CN 2020142058 W CN2020142058 W CN 2020142058W WO 2021136491 A1 WO2021136491 A1 WO 2021136491A1
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dpp
inhibitor
crystal form
preparation
volume
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PCT/CN2020/142058
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English (en)
Chinese (zh)
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齐珊
王珍
郑利刚
李海霞
刘静媛
李鹏飞
彭肖石
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石药集团中奇制药技术（石家庄）有限公司
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Priority to CN202410179029.4A priority Critical patent/CN118047708A/zh
Priority to CN202080075230.8A priority patent/CN114616223A/zh
Publication of WO2021136491A1 publication Critical patent/WO2021136491A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a crystal form of a dipeptidyl peptidase IV (DPP-IV) inhibitor, and a preparation method and application thereof.
  • DPP-IV dipeptidyl peptidase IV
  • Compound I is a dipeptidyl peptidase IV (DPP-IV) inhibitor, which can inhibit DPP-IV and DPP-VIII, causing DPP-IV and DPP-VIII not to degrade glucagon-like peptide 1 (glucagon-like peptide-1, GLP-1), thereby promoting insulin secretion, reducing plasma glucose concentration and enhancing the function of pancreatic ⁇ -cells, and can be used clinically to treat type II diabetes.
  • DPP-IV dipeptidyl peptidase IV
  • Patent CN101970402B discloses compound I and its preparation method. The crude reaction product is separated by column chromatography to obtain a white solid, and its purity is not disclosed.
  • Jiang Guoyou et al. [Chinese Journal of New Drugs, 2016, Volume 25, Issue 13, Pages 1531-1534] made a new exploration of the synthetic route of compound I, using acetone recrystallization instead of column chromatography to obtain a white solid with purity 99.5%.
  • Neither of the two prior art studies explored the existence of other crystal forms and the properties of the crystal forms after synthesis and purification, nor did they conduct in-depth research on the possible defects of compound I in the subsequent drug development process.
  • seeking a crystal form of compound I with excellent properties has become an urgent problem for those skilled in the art.
  • This application prepared compound I according to the method in CN101970402B and evaluated its properties. It was found that, on the one hand, the product prepared by CN101970402B had the defects of irregular crystal particle appearance, small particle size, and poor fluidity, which made the formulation development process limited by raw materials. On the other hand, the separation method of column chromatography cannot be scaled up and used in industry.
  • the compound I samples prepared according to the method disclosed in the article by Jiang Guoyou et al. [Chinese Journal of New Drugs, 2016, Volume 25, Issue 13, Pages 1531-1534] also have the defects of small particle size and poor fluidity.
  • a technical problem to be solved by the present invention is to provide a new crystal form of Compound I that can be directly used and stored as a raw material medicine and is suitable for industrial scale-up production.
  • Another technical problem to be solved by the present invention is to provide a crystal particle with a more regular microscopic morphology and a larger particle size value (D 90 ), which can be directly used as a raw material medicine and long-term storage, suitable for preparation process operation, and suitable for industrial scale-up.
  • D 90 particle size value
  • DPP-IV inhibitor compound I crystal form, the structural formula of which is shown in the following formula I:
  • the relative intensity of the above-mentioned characteristic peak is:
  • the relative intensity of the above characteristic peak is:
  • the relative intensity of the above-mentioned characteristic peak is:
  • the DPP-IV inhibitor compound I crystal form is characterized in that, using Cu-K ⁇ radiation, powder X-ray diffraction expressed in 2 ⁇ angles (°) has characteristic peaks at the following positions: 8.0 ⁇ 0.2°, 8.8 ⁇ 0.2°, 14.0 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.8 ⁇ 0.2°.
  • the relative intensity of the above-mentioned characteristic peak is:
  • the relative intensity of the above characteristic peak is:
  • the relative intensity of the above-mentioned characteristic peak is:
  • the DPP-IV inhibitor compound I crystal form uses Cu-K ⁇ radiation, which has a powder X-ray diffraction pattern substantially as shown in FIG. 2.
  • substantially as shown in the drawings means that a certain crystal form that is substantially pure has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of its powder X-ray diffraction pattern. %, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern.
  • the content of a certain crystal form in the sample gradually decreases, some diffraction peaks in the powder X-ray diffraction pattern attributable to the crystal form may be reduced due to the detection sensitivity of the instrument.
  • the melting point of the DPP-IV inhibitor compound I crystal form is 160-170°C, preferably 166-169°C.
  • the crystal particles of the DPP-IV inhibitor compound I have a columnar shape.
  • the crystal size D 90 of the DPP-IV inhibitor compound I is ⁇ 165 ⁇ m, preferably ⁇ 170 ⁇ m, more preferably ⁇ 180 ⁇ m, further preferably ⁇ 220 ⁇ m, and even more preferably ⁇ 300 ⁇ m.
  • the diameter distribution range is 0.9 ⁇ 600 ⁇ m.
  • the present invention also provides a method for preparing the above-mentioned DPP-IV inhibitor compound I crystal form, which comprises: (1) adding the crude product to a single solvent system, heating and stirring to dissolve, cooling and stirring for crystallization, and filtering to obtain The crystal form of the DPP-IV inhibitor compound I; or (2) the crude product is added to solvent A and heated to dissolve, concentrated under reduced pressure, ethyl acetate is added, and the crystal form of the DPP-IV inhibitor compound I is filtered to obtain the crystal form of the DPP-IV compound I inhibitor; or ( 3) After adding the crude product to solvent A for heating and dissolving, it is concentrated under reduced pressure to remove part of the solvent and filtered to obtain the crystal form of the DPP-IV compound I inhibitor.
  • the single solvent in method (1) is selected from ethanol, isopropanol, tetrahydrofuran, preferably ethanol; preferably, the heating temperature is 20°C to reflux temperature, It is preferably 50°C to reflux temperature; preferably, the crystallization temperature is -10 to 50°C, preferably 0 to 50°C, and more preferably 30 to 50°C; preferably, between the crude product and the single solvent
  • the mass-volume ratio is 1:5-50, preferably 1:5-30.
  • the single solvent in the method (1) is selected from ethanol, anhydrous ethanol, isopropanol, and tetrahydrofuran, preferably ethanol, more preferably anhydrous ethanol; preferably, the heating The temperature is 20°C to reflux temperature, preferably 50°C to reflux temperature; preferably, the crystallization temperature is -10 to 50°C, preferably 0 to 50°C, more preferably 30 to 50°C; preferably The mass-volume ratio between the crude product and the single solvent is 1:5-50, preferably 1:5-30.
  • the solvent A in the method (2) and the method (3) is selected from methanol, dichloromethane, and acetonitrile, preferably methanol, dichloromethane; preferably, the crude product
  • the mass-volume ratio with solvent A is 1:1-10, preferably 1:2-5; preferably, the heating temperature is 20°C to reflux temperature, preferably 20-40°C; preferably, it is concentrated under reduced pressure to 2/3 volume to 1/6 volume, preferably 1/2 volume to 1/6 volume, more preferably 1/3 volume to 1/6 volume, still more preferably 1/4 volume to 1/6 volume, and further It is preferably 1/5 volume, specifically, the degree of concentration under reduced pressure is concentrated until the volume of the remaining solution in the bottle is 2/3 to 1/6 volume of the volume of the originally added solvent A, preferably 1/2 volume ⁇ 1/6 volume, more preferably 1/3 volume to 1/6 volume, still more preferably 1/4 volume to 1/6 volume, still more preferably 1/5 volume.
  • the above preparation method further includes a separation step before obtaining the DPP-IV inhibitor compound I crystals.
  • the separation step includes filtering, centrifugation and other suitable methods to remove the obtained compound I crystals from the crystal solution. separate from.
  • the drying method can be any suitable A known method is preferably drying under reduced pressure (vacuum).
  • the specific drying conditions are, for example, the temperature is preferably 40-60°C, more preferably 50-60°C; the pressure is preferably vacuum>0.090MPa; the drying time is preferably 5-20h, more preferably 5-8h. Regardless of the drying method used, it is advisable that the solvent residue in the product obtained meets the quality standard.
  • the crude DPP-IV inhibitor compound I described in the present invention is prepared by the known method disclosed in CN101970402B, and can also be prepared by any known method disclosed in other prior art.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned DPP-IV inhibitor compound I crystal form.
  • the pharmaceutical composition may further comprise other therapeutic components, and the other therapeutic components refer to Other active ingredients or drugs for the treatment of diabetes, such as insulin, metformin or a pharmaceutically acceptable salt thereof, and sulfonylurea and/or thiazolidinedione hypoglycemic agents, preferably metformin or a pharmaceutically acceptable salt thereof, More preferably, it is metformin hydrochloride.
  • the other therapeutic components can have a synergistic effect with the DPP-IV inhibitor compound I.
  • the compound I crystal form and other therapeutic components are administered in the form of a single preparation or a combined preparation.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned DPP-IV inhibitor compound I crystal form and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may also include other therapeutic components, so
  • the other therapeutic components refer to other active ingredients or drugs for the treatment of diabetes, such as insulin, metformin or a pharmaceutically acceptable salt thereof, and sulfonylureas and/or thiazolidinedione hypoglycemic agents, preferably metformin or its
  • the pharmaceutically acceptable salt is more preferably metformin hydrochloride.
  • the other therapeutic components can have a synergistic effect with the DPP-IV inhibitor compound I.
  • the compound I crystal form and other therapeutic components are administered in the form of a single preparation or a combined preparation.
  • the above-mentioned pharmaceutical composition is prepared into clinically accepted preparations, such as oral preparations, injection preparations, topical administration preparations, topical preparations and the like.
  • the oral preparations are preferably solid preparations, such as tablets, capsules, granules and the like. These preparations can be prepared by using adjuvants known to those of ordinary skill in the art and using conventional pharmaceutical preparation techniques.
  • Another aspect of the present invention also provides the application of the above-mentioned DPP-IV inhibitor compound I crystal form or a pharmaceutical composition containing the same in the preparation of DPP-IV inhibitor drugs, especially for the treatment of type II diabetes drugs.
  • Another aspect of the present invention also provides the above-mentioned DPP-IV inhibitor compound I crystal form or a pharmaceutical composition containing the same for the treatment of type II diabetes.
  • a method for treating type II diabetes which comprises administering the above-mentioned DPP-IV inhibitor compound I crystal form or a pharmaceutical composition containing the same to a patient or subject in need.
  • subject and patient include all members of the animal kingdom, including, but not limited to, mammals (for example, mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans.
  • the beneficial effects of the crystal form of the DPP-IV inhibitor compound I of the present invention are: (1) The crystal form of the DPP-IV inhibitor compound I of the present invention can be directly used as a raw material medicine, and the instruments, equipment and operations used in the preparation process There are no special and harsh requirements, and it is more suitable for industrial scale-up production; (2) The crystal particles of the crystal form of the DPP-IV inhibitor compound I of the present invention have a more regular microscopic morphology and a larger particle size value (D 90 ). The preparation process operation, especially the direct compression tableting process, can greatly simplify the preparation process of the preparation; (3) The crystal form of the DPP-IV inhibitor compound I of the present invention also has excellent stability. In the accelerated experiment and long-term stability test, the investigated crystal form did not undergo a crystal form transformation, and the maximum single impurities, content, moisture, etc. have no obvious changes, and it is more suitable for storage as a raw material drug.
  • Figure 1 Appearance of the crystal particles of the compound I sample obtained in Preparation Example 1.
  • Figure 3 Appearance morphology of the crystal particles of the compound I crystal form obtained in Example 1.
  • Figure 4 Appearance of the crystal particles of the compound I crystal form obtained in Example 3.
  • Figure 5 Appearance morphology of the crystal particles of the compound I sample obtained in Comparative Example 1.
  • Scan range: 1.5 ⁇ 40.0°.
  • Measurement time background measurement time 10s, sample measurement time 7s.
  • the crude compound I of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and those skilled in the art. Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the crude compound I (10 g, 30.83 mmol) prepared according to the method of Preparation Example 1 was added to 50 mL of dichloromethane, and dissolved under stirring at room temperature. Concentrate under reduced pressure to obtain 40 mL of dichloromethane, add 50 mL of ethyl acetate, filter, and wash the solid with ethyl acetate. After vacuum drying, 7.30 g of white crystalline powder was obtained. The yield is 73.0%, the purity of the liquid phase is 99.7%, and the melting point is 167.0-168.2°C. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 3. The appearance of the crystal particles is columnar crystals.
  • the crude compound I (20 g, 61.65 mmol) prepared according to the method of Preparation Example 1 was added to 160 mL of absolute ethanol, heated to reflux to dissolve, and the temperature was lowered to 30° C., and stirring was continued for 1 h. After filtration, the solid was washed with ethyl acetate and dried in vacuum to obtain 11.56 g of white crystalline powder with a yield of 57.8%, a liquid phase purity of 99.9%, and a melting point of 166.7-167.9°C.
  • a sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid. The results are shown in Table 4. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 5. The appearance of the crystal particles is shown in Figure 4, showing columnar crystals.
  • the crude compound I (20 g, 61.65 mmol) prepared according to the method of Preparation Example 1 was added to 160 mL of absolute ethanol, heated to reflux and dissolved, cooled to 0° C., and stirring was continued for 1 h. After filtration, the solid was washed with ethyl acetate, and dried in vacuum to obtain 16.04 g of white crystalline powder with a yield of 80.2%, a liquid phase purity of 99.8%, a melting point of 168.1-169.4°C, and all single impurities below 0.1%. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 6. The appearance of the crystal particles showed columnar crystals.
  • Example 5 The influence of different samples on the preparation process
  • microcrystalline cellulose (66.55%), sodium starch glycolate (1.0%), magnesium stearate (1.2%), the balance is compound I crystals; premix: compound I Mix with microcrystalline cellulose and sodium starch glycolate to obtain a premix; total mixing: mix the premix with magnesium stearate.
  • the crystal form (particle size ⁇ 165 ⁇ m) obtained in Examples 1-4 meets the requirements of the preparation direct compression process, while the preparation example 1 and comparative example 1 (particle size ⁇ 150 ⁇ m) It cannot meet the preparation process requirements.
  • test results of influencing factors show that, compared with the samples of Preparation Example 1 and Comparative Example 1, the maximum single impurity and total impurity content of the samples of the compound I crystal form obtained in Example 1 and Example 3 of the present invention at day 0 are both lower. That is, the sample has higher purity and is more suitable for direct use as an API; the samples obtained in Example 1 and Example 3 are at high temperature (40°C ⁇ 2°C, 60°C ⁇ 2°C) and high humidity (92.5%RH, 75%RH).
  • the accelerated test results show that the crystal form samples of Example 1 and Example 3 have been placed for 6 months at a temperature of 40°C ⁇ 2°C and a relative humidity of 75% ⁇ 5%, the appearance of the samples has not changed, and the related substances have no significant growth. , And the crystal form has not changed, the stability of the sample is good, and the packaging used has no obvious influence on the stability of the product, and it is suitable for storage as a bulk drug.
  • the long-term test results show that the crystal form samples of Example 1 and Example 3 have been placed for 36 months at a temperature of 25°C ⁇ 2°C and a relative humidity of 60% ⁇ 5%, and the appearance of the samples has no significant change, and there is no significant related substance. Growth, and the crystal form has not changed, the stability of the sample is good, the packaging used has no obvious effect on the stability of the product, and it is suitable for long-term storage as a bulk drug.
  • the compound I of the present invention has good crystal form stability, can be used directly as a raw material drug and stored for a long time.
  • the crystal particles have regular appearance and a larger particle size value (D 90 ), which is suitable for the preparation process operation, and the purification process is suitable for industry.
  • D 90 particle size value
  • the scale-up production provides a new way for the preparation of compound I drugs.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline d'un inhibiteur de la dipeptidyl-peptidase IV, son procédé de préparation et son utilisation. La forme cristalline obtenue présente les caractéristiques de pureté élevée, une morphologie de particule cristalline régulière, une taille de particule importante, une bonne stabilité, etc., et est appropriée pour un procédé de formulation à compression directe, facilite la préparation d'une formulation pharmaceutique, le procédé de préparation est simple et pratique et est approprié pour une production industrielle à grande échelle.
PCT/CN2020/142058 2019-12-31 2020-12-31 Forme cristalline d'inhibiteur de la dipeptidyl-peptidase iv, son procédé de préparation et son application WO2021136491A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202410179029.4A CN118047708A (zh) 2019-12-31 2020-12-31 一种二肽基肽酶iv抑制剂的晶型及其制备方法和用途
CN202080075230.8A CN114616223A (zh) 2019-12-31 2020-12-31 一种二肽基肽酶iv抑制剂的晶型及其制备方法和用途

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CN201911411550 2019-12-31

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Citations (5)

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WO2004092128A1 (fr) * 2003-04-10 2004-10-28 Smithkline Beecham Corporation Formes cristallines anhydres de (2s, 4s)-1-{(2r)-2-amino-3-'4-methoxybenzyl)sulfonyl!-3-methylbutanoyl}-4-fluoropyrrolindine-2-carbonitrile
CN101238099A (zh) * 2005-08-04 2008-08-06 诺瓦提斯公司 维格列汀的盐
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WO2004092128A1 (fr) * 2003-04-10 2004-10-28 Smithkline Beecham Corporation Formes cristallines anhydres de (2s, 4s)-1-{(2r)-2-amino-3-'4-methoxybenzyl)sulfonyl!-3-methylbutanoyl}-4-fluoropyrrolindine-2-carbonitrile
CN101238099A (zh) * 2005-08-04 2008-08-06 诺瓦提斯公司 维格列汀的盐
CN101970402A (zh) * 2008-03-05 2011-02-09 财团法人国家卫生研究院 吡咯烷化合物
CN102432599A (zh) * 2011-10-31 2012-05-02 成都地奥制药集团有限公司 一种二肽基肽酶抑制剂的草酸盐晶型及其制备方法和用途
WO2014147640A2 (fr) * 2013-03-19 2014-09-25 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Procédé de préparation d'anagliptine

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JIANG GUOYOU, ZHANG YONG;CAO WEN-TING: "Synthesis of the DPP-Ⅳ inhibitor DBPＲ108", CHINESE JOURNAL OF NEW DRUGS, GAI-KAN BIANJIBU, BEIJING, CN, vol. 25, no. 13, 1 January 2016 (2016-01-01), CN, pages 1531 - 1534, XP055827957, ISSN: 1003-3734 *
YEH TENG-KUANG; TSAI TING-YUEH; HSU TSU; CHENG JAI-HONG; CHEN XIN; SONG JEN-SHIN; SHY HORNG-SHING; CHIOU MEI-CHUN; CHIEN CHIA-HUI;: "(2S,4S)-1-[2-(1,1-Dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: A potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 20, no. 12, 1 January 1900 (1900-01-01), AMSTERDAM, NL, pages 3596 - 3600, XP029212999, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2010.04.124 *

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CN118047708A (zh) 2024-05-17

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