WO2022078269A1 - Forme cristalline d'avacopan, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'avacopan, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022078269A1
WO2022078269A1 PCT/CN2021/122947 CN2021122947W WO2022078269A1 WO 2022078269 A1 WO2022078269 A1 WO 2022078269A1 CN 2021122947 W CN2021122947 W CN 2021122947W WO 2022078269 A1 WO2022078269 A1 WO 2022078269A1
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csiii
crystal form
preparation
present
compound
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PCT/CN2021/122947
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English (en)
Chinese (zh)
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陈敏华
施文睿
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苏州科睿思制药有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention generally relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Avacopan and its preparation method and use.
  • Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a rare, serious and often fatal autoimmune disease caused by autoantibodies called antineutrophil cytoplasmic antibodies, It is characterized by inflammation that affects many different organ systems, usually involving the kidneys. C5a is thought to play a pro-inflammatory role in AAV by interacting with its receptor (C5aR). The C5aR pathway is an important part of pathogenic pathology.
  • C3 glomerulopathy is an extremely rare kidney disease characterized by the deposition of C3 protein in the glomerulus, or the filtering unit of the kidney, leading to kidney damage.
  • Hidradenitis suppurativa is a neutrophil-driven chronic disabling skin disease that often results in keloids, contractures, and immobility.
  • C5a promotes inflammatory mediators and is a strong activator of neutrophils.
  • Avacopan is an oral antagonist that inhibits C5aR and is being developed for the treatment of inflammatory and autoimmune diseases.
  • the chemical name for Avacopan is (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methyl-benzoyl)-N-(4-methyl) -3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (hereinafter referred to as "Compound I”), its structural formula is as follows:
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • Amorphous is an amorphous material without long-range order, and its XRPD (X-ray powder diffraction) pattern usually shows a broad "steamed bread peak".
  • XRPD X-ray powder diffraction
  • amorphous drugs are less thermodynamically stable, so amorphous drugs tend to crystallize during production and storage.
  • the poor stability of amorphous form may change the bioavailability and dissolution rate of the drug, and ultimately lead to changes in the clinical efficacy of the drug.
  • WO2021092286A1 discloses Compound I free crystalline form (hereinafter referred to as "prior art form A") and amorphous.
  • Prior art WO2016053890A1 discloses various methods for preparing solid compound I. The inventor of the present application repeats the method disclosed in WO2016053890A1, and the obtained solids are all the prior art crystal form A disclosed in WO2021092286A1, which is different from the crystal form CSIII of the present application.
  • the identification limit 0.10% or 1.0mg daily intake, whichever is lower.
  • the impurity limit of Compound I amorphous during storage exceeds the identification limit, which is not suitable for the development of Compound I-containing drugs.
  • WO2021092286A1 discloses solubility data for amorphous, whose solubility in FaSSGF (pH 1.64) and FeSSIF (pH 4.90) is only 9.9 ⁇ g/mL at maximum.
  • WO2021092286A1 discloses the solubility data of the prior art crystal form A, the solubility in FaSSGF (pH 1.64) and FeSSIF (pH 4.90) is very low, both below the detection limit. It can be seen from this that the solid disclosed in WO2016053890A1, namely the prior art crystal form A, is almost insoluble in FaSSGF and FeSSIF media.
  • the inventors of the present application found that the amorphous compound I has defects such as poor stability, high impurity content, and poor compressibility. There is a defect of extremely poor solubility, therefore, neither the amorphous nor the prior art Form A is suitable for pharmaceutical development.
  • the crystal form of Compound I has the advantages of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc.
  • At least one aspect of it has advantages, especially high solubility, good purification effect, good physical and chemical stability, good mechanical stability, and good compressibility, which solves the problems existing in the prior art, and has great advantages for the development of drugs containing compound I. Significance.
  • the present invention provides a new crystal form of compound I, a preparation method thereof, and a pharmaceutical composition comprising the new crystal form.
  • the present invention provides the crystal form CSIII of compound I (hereinafter referred to as "crystal form CSIII").
  • the X-ray powder diffraction of the crystalline form CSIII has characteristic peaks at diffraction angle 2 ⁇ values of 6.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CSIII has a diffraction angle 2 ⁇ value of 11.0° ⁇ 0.2°, 12.1° ⁇ 0.2°, 14.8° ⁇ 0.2° at 1 place, or at 2 places , or 3 places have characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at 3 places in the diffraction angle 2 ⁇ of 11.0° ⁇ 0.2°, 12.1° ⁇ 0.2°, 14.8° ⁇ 0.2° .
  • the X-ray powder diffraction of the crystal form CSIII has a diffraction angle 2 ⁇ value of 16.5° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.5° ⁇ 0.2° at 1 place, or at 2 places , or 3 places have characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at 3 places in the diffraction angle 2 ⁇ of 16.5° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.5° ⁇ 0.2° .
  • the X-ray powder diffraction of the crystalline form CSIII has diffraction angle 2 ⁇ values of 6.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.8° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.1° ⁇ 0.2°, 14.8° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.5° ⁇ 0.2° any 3 places, or 4 places, or 5 places, or 6 places, or 7 places , or 8, or 9 with characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSIII is substantially as shown in FIG. 1 .
  • thermogravimetric analysis diagram of the crystalline form CSIII is substantially as shown in FIG. 2 , which has a mass loss of about 2.6% when heated to 115°C.
  • the present invention also provides a preparation method of the crystal form CSIII, the preparation method comprising:
  • the present invention provides the use of crystal form CSIII in preparing other crystal forms or salts of compound I.
  • the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSIII and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSIII in the preparation of C5aR inhibitor medicines.
  • the present invention provides the use of crystal form CSIII in the preparation of anti-neutrophil cytoplasmic antibody-related vasculitis drugs.
  • the crystal form CSIII provided by the present invention has higher solubility.
  • Compound I is a poorly water-soluble drug belonging to BCS II or BCS IV.
  • the crystal form CSIII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystal form CSIII provided by the present invention has better purification effect.
  • the purity is significantly improved and the types of impurities are reduced.
  • the purity of the crystal form CSIII of the present invention is prepared by using raw materials with a purity of 99.23%, the purity is increased to 99.46%.
  • the chemical purity of the drug is of great significance to ensure the efficacy and safety of the drug and prevent the occurrence of adverse drug reactions.
  • Different pharmaceutical regulations have strict requirements on impurity content.
  • the crystal form CSIII provided by the invention has good purification effect and strong impurity removal ability.
  • the crude drug with higher purity can be obtained by crystallization, which effectively overcomes the disadvantages of low drug stability, poor efficacy and high toxicity caused by low drug purity.
  • the crystal form CSIII provided by the present invention has better compressibility.
  • the good compressibility of crystal form CSIII can effectively improve the unqualified hardness/brittleness, splits and other problems in the tableting process, make the formulation process more reliable, improve product appearance, and improve product quality and production efficiency.
  • the crystalline form CSIII bulk drug provided by the present invention has good physical and chemical stability.
  • the bulk drug of crystal form CSIII is placed under closed and open conditions at 25°C/60% RH, and the crystal form has not changed for at least 3 months, and the purity remains basically unchanged during storage.
  • the crystal form CSIII is mixed with excipients to make a pharmaceutical preparation, and placed under the condition of 25°C/60% RH, the crystal form does not change for at least 1 month, and the purity basically remains unchanged during the storage process. It shows that the crystalline form CSIII API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form CSIII bulk drug was placed under the closed and open conditions of 40°C/75%RH for at least 3 months, and the crystalline form did not change, and the purity remained basically unchanged during the storage process.
  • the crystal form of the bulk drug of crystal form CSIII did not change for at least one month under the closed condition of 60°C/75%RH, and the crystal form did not change for at least one week under the open condition of 60°C/75%RH.
  • the prior art amorphous crystallized in only one week under 60°C/75%RH open conditions. It shows that the crystalline form CSIII API has better stability under accelerated conditions and more severe conditions.
  • the crystalline form CSIII API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • the crystalline form CSIII has good humidity stability. After the crystal form CSIII of the present invention is cycled once under a relative humidity of 50%-95%-0%-95%, the crystal form does not change.
  • Crystal form CSIII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSIII provided by the present invention has good mechanical stability.
  • the crystal form CSIII API has good physical stability after grinding. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process. Under different pressures, the crystalline form CSIII API has good physical stability, which is conducive to maintaining the crystal form stability in the preparation and tableting process.
  • Figure 3 XRPD comparison chart of crystal form CSIII before and after placing under different conditions (from bottom to top: before placing, 25°C/60%RH closed for 3 months, 25°C/60%RH open for 3 months, 40 °C/75%RH closed for 3 months, 40°C/75%RH open for 3 months, 60°C/75%RH closed for 1 month, 60°C/75%RH open for 1 week)
  • Figure 4 XRPD comparison diagram of crystal form CSIII before and after DVS (top: before DVS, bottom: after DVS)
  • Figure 7 XRPD comparison diagram of crystal form CSIII before and after preparation (from top to bottom: blank mixed powder, after preparation process, crystal form CSIII)
  • Figure 8 XRPD comparison chart of crystal form CSIII preparation under 25°C/60%RH closed condition plus 1g desiccant for 1 month (top: before placing; bottom: after placing)
  • the X-ray powder diffraction pattern of Example 6 of the present invention was collected on a Bruker D8DISCOVER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • X-ray powder diffraction patterns of other examples described herein were collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the TGA map of the present invention was collected on a TA Q500.
  • the method parameters of TGA of the present invention are as follows:
  • test parameters of the related substance detection of the present invention are shown in Table 2 and Table 3:
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring speed is preferably 300-900 rev/min, and the mechanical stirring The speed is preferably 100-300 revolutions per minute.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: put the sample to be separated into a centrifuge tube, and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural drying.
  • the drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the "volatilization” is accomplished by conventional methods in the art, such as slow volatilization or rapid volatilization. Slow volatilization is to seal the container with sealing film, poke holes, and stand to volatilize; rapid volatilization is to leave the container open to volatilize.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. A person skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form CSIII of the present invention is pure, substantially free from admixture with any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • the compound I as a starting material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as starting material is in solid form.
  • Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2010075257A1 patent.
  • TGA has a mass loss of about 2.6% when the crystalline form CSIII is heated to 115 °C.
  • Example 4 Purification effect of crystal form CSIII and amorphous
  • the crystalline form CSIII and amorphous of the present invention are prepared from the same starting materials. HPLC was used to determine the chemical purity of the raw material, the crystal form CSIII of the present invention and the amorphous form, and the test results are shown in Table 6.
  • Table 7 shows the stability results of crystal form CSIII under the conditions of 25°C/60%RH and 40°C/75%RH.
  • the stability results of the crystal form CSIII under the conditions of 60° C./75% RH are shown in Table 8, and the XRPD comparison diagram is shown in FIG. 3 .
  • the stability results of the amorphous form are shown in Table 9.
  • Placement conditions put time Crystal form Purity change (area %) start N/A Form CSIII N/A 25°C/60%RH (closed) 3 months Form CSIII 0.06 25°C/60%RH(open) 3 months Form CSIII 0.01 40°C/75%RH (closed) 3 months Form CSIII 0.03 40°C/75%RH(open) 3 months Form CSIII 0.06
  • Placement conditions put time Crystal form start N/A Form CSIII 60°C/75%RH (closed) 1 month Form CSIII 60°C/75%RH(open) 1 week Form CSIII
  • Form CSIII is stable for at least one week under 60°C/75%RH opening conditions, and also has good physical stability under more severe conditions.
  • the state-of-the-art amorphous is partially crystallized after being placed for one week under the open condition of 60°C/75%RH.
  • Example 8 Compressibility of Form CSIII and Amorphous
  • the ENERPAC manual tablet press was used for tablet compression.
  • select a ⁇ 6mm circular flat punch add 80 mg of the present invention's crystal form CSIII and amorphous respectively, and use a pressure of 10 kN to compress into circular tablets, which are placed at room temperature for 24 hours until complete.
  • the diameter (D) and thickness (L) of the tablet were measured with a vernier caliper, and its radial breaking force (hardness, H) was measured with a tablet hardness tester.
  • the compressibility results of crystalline form CSIII and amorphous are shown in Table 10. The results show that the crystalline form CSIII has better compressibility compared to the amorphous form.
  • the formulation formula and formulation process of crystal form CSIII are shown in Table 11 and Table 12, respectively.
  • the XRPD comparison chart of the crystalline form CSIII before and after the preparation is shown in FIG. 7 .
  • Example 10 Formulation stability of Form CSIII
  • the preparation made of crystal form CSIII was placed for 1 month at 25°C/60% RH with 1 g of desiccant.

Abstract

L'invention concerne une nouvelle forme cristalline d'avacopan (appelée " composé I ") et son procédé de préparation, une composition pharmaceutique contenant la forme cristalline, et l'utilisation de la forme cristalline dans la préparation d'un médicament inhibiteur de C5aR et d'un médicament pour le traitement de la vascularite associée aux anticorps cytoplasmiques antineutrophiles. Par comparaison avec l'état de la technique, la nouvelle forme cristalline du composé I, selon l'invention a une ou plusieurs propriétés améliorées, résout les problèmes existant dans l'état de la technique, et a une grande valeur pour l'optimisation et le développement de médicaments contenant le composé I
PCT/CN2021/122947 2020-10-16 2021-10-11 Forme cristalline d'avacopan, son procédé de préparation et son utilisation WO2022078269A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113957106A (zh) * 2021-11-03 2022-01-21 暨明医药科技（苏州）有限公司 一种Avacopan及其中间体的制备方法
EP4054577A4 (fr) * 2019-11-08 2023-11-29 ChemoCentryx, Inc. Forme cristalline de base libre d'un récepteur de composant c5a du complément

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CN103068385A (zh) * 2010-06-24 2013-04-24 凯莫森特里克斯股份有限公司 C5aR拮抗剂
CN106999481A (zh) * 2014-09-29 2017-08-01 凯莫森特里克斯股份有限公司 制备C5aR拮抗剂的方法和中间体
US20210139426A1 (en) * 2019-11-08 2021-05-13 Chemocentryx, Inc. AMORPHOUS FORM OF A COMPLEMENT COMPONENT C5a RECEPTOR
US20210137907A1 (en) * 2019-11-08 2021-05-13 Chemocentryx, Inc. FREE BASE CRYSTALLINE FORM OF A COMPLEMENT COMPONENT C5a RECEPTOR
US20210139427A1 (en) * 2019-11-08 2021-05-13 Chemocentryx, Inc. Salt forms of a complement component c5a receptor

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CN102264227A (zh) * 2008-12-22 2011-11-30 凯莫森特里克斯股份有限公司 C5aR拮抗剂
CN103068385A (zh) * 2010-06-24 2013-04-24 凯莫森特里克斯股份有限公司 C5aR拮抗剂
CN106999481A (zh) * 2014-09-29 2017-08-01 凯莫森特里克斯股份有限公司 制备C5aR拮抗剂的方法和中间体
US20210139426A1 (en) * 2019-11-08 2021-05-13 Chemocentryx, Inc. AMORPHOUS FORM OF A COMPLEMENT COMPONENT C5a RECEPTOR
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4054577A4 (fr) * 2019-11-08 2023-11-29 ChemoCentryx, Inc. Forme cristalline de base libre d'un récepteur de composant c5a du complément
CN113957106A (zh) * 2021-11-03 2022-01-21 暨明医药科技（苏州）有限公司 一种Avacopan及其中间体的制备方法
CN113957106B (zh) * 2021-11-03 2024-04-19 暨明医药科技（苏州）有限公司 一种Avacopan及其中间体的制备方法

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