WO2023160579A1 - 一种二肽基肽酶1抑制剂多晶型物及其制备方法和用途 - Google Patents

一种二肽基肽酶1抑制剂多晶型物及其制备方法和用途 Download PDF

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WO2023160579A1
WO2023160579A1 PCT/CN2023/077649 CN2023077649W WO2023160579A1 WO 2023160579 A1 WO2023160579 A1 WO 2023160579A1 CN 2023077649 W CN2023077649 W CN 2023077649W WO 2023160579 A1 WO2023160579 A1 WO 2023160579A1
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polymorph
crystal form
ray powder
powder diffraction
compound
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PCT/CN2023/077649
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English (en)
French (fr)
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范江
窦赢
宫正
朱凤飞
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四川海思科制药有限公司
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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicines, and in particular relates to a dipeptidyl peptidase 1 inhibitor polymorph, its preparation method and application.
  • DPP1 Dipeptidyl peptidase 1
  • cathepsin C Dipeptidyl peptidase 1
  • NSPs neutrophil serine proteases
  • NE neutrophil elastase
  • proteinase 3 proteinase 3, Pr3
  • cathepsin G cathepsin G, CatG
  • DPP1 is associated with a variety of inflammatory diseases, including: Wegener's granulomatosis, rheumatoid arthritis, lung inflammation and viral infection.
  • DPP1 can have a good therapeutic effect on highly inflammatory lung diseases caused by neutrophils, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), acute lung injury, etc. Therefore, inhibiting the hyperactivation of NSPs by targeting DPP1 may have a potential therapeutic effect on bronchiectasis.
  • neutrophils such as bronchiectasis, chronic obstructive pulmonary disease (COPD), acute lung injury, etc. Therefore, inhibiting the hyperactivation of NSPs by targeting DPP1 may have a potential therapeutic effect on bronchiectasis.
  • COPD chronic obstructive pulmonary disease
  • the patent application PCT/CN2020/114500 prepared a DPP1 small molecule inhibitor of the following formula.
  • This compound shows high DPP1 inhibitory activity, has excellent bioavailability and pharmacokinetic characteristics, and has low toxicity and high safety. Intended for the treatment of lung diseases such as non-cystic fibrosis bronchiectasis, chronic obstructive pulmonary disease (COPD), acute lung injury and cystic fibrosis bronchiectasis.
  • COPD chronic obstructive pulmonary disease
  • the present invention provides a polymorphic form of the compound of formula I with high applicability as a medicine, said polymorphic form It has excellent characteristics such as high purity, good solubility, stable physical and chemical properties, high temperature resistance, high humidity and strong light, and low moisture absorption.
  • n 0 or 1.
  • the polymorphic form of the compound of formula I is an anhydrous crystal form, that is, n is 0, and the polymorphic form is described as crystal form B, using Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is in The following 2 ⁇ positions have characteristic diffraction peaks: 12.32 ⁇ 0.2°, 14.30 ⁇ 0.2°, 15.43 ⁇ 0.2°, 16.38 ⁇ 0.2°, 18.56 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B also has characteristic diffraction peaks at the following 2 ⁇ positions: 17.06 ⁇ 0.2°, 18.21 ⁇ 0.2°, 18.94 ⁇ 0.2°, 19.59 ⁇ 0.2° , 20.79 ⁇ 0.2°, 21.19 ⁇ 0.2°, 22.55 ⁇ 0.2°, 22.97 ⁇ 0.2°, 23.37 ⁇ 0.2°, 24.25 ⁇ 0.2°, 25.46 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B has characteristic diffraction peaks at the following 2 ⁇ positions:
  • the X-ray powder diffraction pattern of the crystal form B is basically as shown in FIG. 1 .
  • the crystalline form B has a DSC chart in FIG. 2 and/or a TGA chart in FIG. 3 .
  • the polymorphic form of the compound of formula I is a monohydrate crystal form, that is, n is 1, and the polymorphic form is described as crystal form C, using Cu-K ⁇ radiation, and its X-ray powder diffraction
  • the spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 8.93 ⁇ 0.2°, 12.10 ⁇ 0.2°, 14.14 ⁇ 0.2°, 20.38 ⁇ 0.2°, 23.86 ⁇ 0.2°, 25.07 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C also has characteristic diffraction peaks at the following 2 ⁇ positions: 15.19 ⁇ 0.2°, 15.92 ⁇ 0.2°, 16.06 ⁇ 0.2°, 17.55 ⁇ 0.2° , 17.90 ⁇ 0.2°, 18.90 ⁇ 0.2°, 19.10 ⁇ 0.2°, 20.81 ⁇ 0.2°, 24.33 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2 ⁇ positions:
  • the X-ray powder diffraction pattern of the crystal form C is basically as shown in FIG. 6 .
  • the crystal form C has the DSC diagram of Figure 7 and/or the TGA of Figure 8 picture.
  • the polymorphic form of the compound of formula I is an anhydrous crystal form, that is, n is 0, and the polymorphic form is described as crystal form D, using Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is in The following 2 ⁇ positions have characteristic diffraction peaks: 8.68 ⁇ 0.2°, 11.74 ⁇ 0.2°, 13.64 ⁇ 0.2°, 17.40 ⁇ 0.2°, 18.23 ⁇ 0.2°, 20.12 ⁇ 0.2°, 26.21 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form D also has characteristic diffraction peaks at the following 2 ⁇ positions: 8.99 ⁇ 0.2°, 13.51 ⁇ 0.2°, 27.49 ⁇ 0.2°, 32.19 ⁇ 0.2° , 32.97 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2 ⁇ positions:
  • the X-ray powder diffraction pattern of the crystal form D is basically as shown in FIG. 9 .
  • the crystalline form B, crystalline form C or crystalline form D of the present invention has a crystal particle size of less than 100 ⁇ m; in some embodiments, the crystal particle size is less than 90 ⁇ m; in some embodiments, the particle size of the crystals is less than 80 ⁇ m; in some embodiments, the particle size of the crystals is less than 70 ⁇ m; in some embodiments, the particle size of the crystals is less than 60 ⁇ m; in some embodiments, the particle size of the crystals is less than 50 ⁇ m; In some embodiments, the particle size of the crystals is less than 40 ⁇ m; in some embodiments, the particle size of the crystals is less than 30 ⁇ m; in some embodiments, the particle size of the crystals is less than 20 ⁇ m.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of crystalline form B, crystalline form C or crystalline form D, and a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also provides the use of crystal form B, crystal form C or crystal form D, or a pharmaceutical composition containing them in the preparation of medicines for treating diseases mediated by DPP1.
  • DPP1-mediated diseases include, but are not limited to, non-cystic fibrosis bronchiectasis, cystic fibrosis bronchiectasis, acute lung injury, airway obstructive disease, bronchiectasis, cystic fibrosis, asthma, pulmonary Emphysema and chronic obstructive pulmonary disease.
  • the crystalline form B, crystalline form C or crystalline form D of the present invention is present at about 5% to about 100% by weight of the raw drug; in some embodiments, at about 10% to about 100% by weight of the raw drug % by weight present; in certain embodiments, present from about 15% by weight to about 100% by weight of the drug substance; in certain embodiments, present from about 20% by weight to about 100% by weight of the drug substance; In some embodiments, it is present at about 25% to about 100% by weight of the drug substance; in some embodiments, it is present at about 30% to about 100% by weight of the drug substance; in some embodiments, it is present at present at about 35% to about 100% by weight of the drug substance; in certain embodiments, at about 40% to about 100% by weight of the drug substance; in certain embodiments, at about 45% by weight of the drug substance % to about 100% by weight; in certain embodiments, from about 50% to about 100% by weight of the drug substance; in certain embodiments, from about 55% to about 100% by weight of the drug substance present; in certain embodiments, from about 60% to
  • the present invention also provides a preparation method of the crystal form B, crystal form C or crystal form D, comprising:
  • Form B is obtained by suspending and stirring the free base of Compound I in IPAc solvent for 2-5 days.
  • crystal form B is obtained by dissolving the free base of compound I in a mixed solvent of nitrile solvent and alcohol solvent, and then cooling down to crystallize.
  • the nitrile solvent is selected from acetonitrile
  • the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or combinations thereof.
  • the solvent is a mixed solvent of acetonitrile and ethanol.
  • the volume ratio of nitrile solvent and alcohol solvent is (1-3):(1-3); In some embodiments, the volume ratio of nitrile solvent and alcohol solvent is (1-2 ):(1-2); In some embodiments, the volume ratio of nitrile solvent and alcoholic solvent is 1:1.
  • first cool the solution to 50-60°C then add seed crystals (which can be obtained from other methods, such as the method described in the previous scheme), and then continue to cool down and crystallize.
  • Form C is obtained by suspending and stirring the free base of Compound I in H 2 O for 2-5 days.
  • crystal form D is obtained by dissolving the free base of compound I in an alcoholic solvent, and then slowly cooling down to crystallize.
  • the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, or combinations thereof.
  • the solvent is methanol.
  • the crystal form of the present invention has excellent physical and chemical properties, such as good fluidity and significantly improved viscosity, etc., so that the crystal form of the present invention can significantly reduce the filtration time during the preparation process, shorten the production cycle, and save costs; good Light stability, heat stability and moisture stability can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation and the effectiveness after long-term storage, and the crystal form does not need to be used to prevent Affected by light, temperature and humidity, special packaging is adopted to reduce costs; the crystal form will not be degraded by light, high temperature and high humidity, and patients who take the crystal form will not worry about the preparation being exposed to sunlight. Photosensitivity reaction is generated under the condition; the crystal form also has higher solubility, which is beneficial to the dissolution of the drug and improves the bioavailability.
  • the crystal form of the present invention also has good stability.
  • the crystal form of the present invention is tested in DVS ((60%RH-95%RH-0%RH-95%RH or 0%RH-95%RH-0%RH )), or placed under the conditions of 25°C/60%RH and 40°C/75%RH for 1 week to 1 month, the crystal form does not change, and it also has grinding stability.
  • the preparation method of the crystal form of the present invention is simple and effective, and is easy to scale up production.
  • the crystal form has good fluidity, good compressibility, high bulk density, low hygroscopicity, uniform particle size distribution, and is convenient for the production of preparations.
  • the preparation prepared by using the crystal form of the present invention can reduce irritation and improve absorption, making the problem of metabolic rate It is solved, the toxicity is significantly reduced, the safety is improved, and the quality and efficacy of the preparation are effectively guaranteed.
  • thermogravimetric analysis TGA
  • DSC differential scanning calorimetry
  • the crystal form of the present invention is not limited to the characteristic spectra that are exactly the same as those described in the accompanying drawings disclosed in the present invention, such as XRPD, DSC, TGA, DVS, and isotherm adsorption curves, which have the same characteristics as those described in the accompanying drawings. Any crystalline form with substantially the same or essentially the same characteristic profiles as those profiles falls within the scope of the present invention.
  • “Therapeutically effective amount” means that amount of a compound that elicits a physiological or medical response in a tissue, system, or subject that is sought, including one or more that, when administered in a subject, is sufficient to prevent the disorder or condition being treated. The amount of compound at which several symptoms occur or are alleviated to some extent.
  • Carrier refers to: does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the body and its distribution in the body, controls the release rate of the drug and releases the drug.
  • Non-limiting examples of systems for delivery to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.
  • Excipient means: not itself a therapeutic agent, used as a diluent, adjuvant, binder and/or vehicle, added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate The compound or pharmaceutical composition is presented in unit dosage form for administration.
  • pharmaceutical excipients can serve various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrating agents, absorbing agents, preservatives , surfactants, coloring agents, flavoring agents and sweeteners.
  • Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (such as croscarmellose sodium) (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as oil (13) a
  • Crystal form or “crystal” or “polymorph” refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • Seed crystal means that in the crystallization method, by adding insoluble additives, crystal nuclei are formed to accelerate or promote the growth of enantiomer crystals with the same crystal form or stereo configuration.
  • X-ray powder diffraction pattern means an experimentally observed diffraction pattern or a parameter, data or value derived therefrom.
  • XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • 2 ⁇ refers to the peak position expressed in degrees (°) based on the settings in the X-ray diffraction experiment, and is usually the unit of abscissa in the diffraction pattern. If reflections are diffracted when the incident beam forms an angle ⁇ with a lattice plane, the experimental setup requires recording the reflected beam at 2 ⁇ angles. It should be understood that reference herein to a particular 2 ⁇ value for a particular crystalline form is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • Fig. XX X-ray diffraction peaks
  • peak position (2 ⁇ ) will show some variation, typically by as much as 0.1-0.2°, and that the instrumentation used to measure diffraction will also cause some variation.
  • relative peak intensities will vary due to instrument-to-instrument variation as well as degree of crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be considered only for qualitative measurement.
  • Figure 1 is the X-ray powder diffraction pattern of crystal form B.
  • Fig. 2 is a differential scanning calorimetry curve diagram of crystal form B.
  • Fig. 3 is the thermogravimetric analysis spectrum of crystal form B.
  • Figure 4 is the nuclear magnetic spectrum of crystal form B.
  • Fig. 5 is the variable temperature XRPD test pattern of crystal form B.
  • Figure 6 is the X-ray powder diffraction pattern of Form C.
  • Fig. 7 is a differential scanning calorimetry curve diagram of crystal form C.
  • Figure 8 is a thermogravimetric analysis spectrum of Form C.
  • Figure 9 is the X-ray powder diffraction pattern of Form D.
  • Figure 10 is the PLM diagram of Form B.
  • Figure 11 is the PLM diagram of Form C.
  • Figure 12 is the DVS diagram of Form B.
  • Figure 13 is the DVS diagram of Form C.
  • TGA and DSC were collected on TA Q5000/5500 thermogravimetric analyzer and TA 2500 differential scanning calorimeter respectively, and the test parameters are shown in Table 3:
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology Waiting for the company.
  • the solution refers to an aqueous solution.
  • Reaction In a 50L reactor, add 10.005kg of 1,4-dioxane, 1.600kg of compound a-1 (refer to the method of patent WO2015110826A1) and 2.000kg of compound a-2 (refer to the method of patent WO2016139355A1) under stirring, and then Add 6.605 kg of potassium carbonate aqueous solution (1.600 kg of potassium carbonate dissolved in 5.005 kg of purified water). After addition, nitrogen replacement was performed three times. Add 100.0 g of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, and replace with nitrogen once. Under the protection of nitrogen, the temperature of the reaction solution was raised to 80 ⁇ 5°C and reacted for about 2 hours, and the sample was monitored by HPLC. If the content of the target compound a-2 in the middle control was ⁇ 1.0%, the reaction was stopped.
  • Post-processing Add 5.000kg of purified water to the reaction solution, cool down to 10 ⁇ 5°C, add 10.005kg of purified water, stir and crystallize at 10 ⁇ 5°C for about 1 hour, filter, and wash the filter cake twice with 2.500kg of purified water/time Once, the filter cake was collected. Add 12.605kg of absolute ethanol and filter cake into a 50L reactor, stir at 20 ⁇ 5°C for about 0.5 hours, filter, wash the filter cake twice with 1.000kg of absolute ethanol/time, and collect the filter cake.
  • Reaction In a 50L glass reactor, add 16.785kg of acetonitrile, 2.1381kg of compound a and 2.950kg of p-toluenesulfonic acid monohydrate under stirring. After the addition is completed, the temperature is controlled at 25 ⁇ 5°C for about 2 hours, and then the sample is monitored by HPLC. If the content of the target compound a in the middle control is ⁇ 1.0%, the reaction is stopped.
  • Post-processing filter, wash the filter cake with 1.670 kg of acetonitrile, and collect the filter cake. Add 2.1381kg of acetonitrile and filter cake into the reaction kettle, raise the temperature to 80 ⁇ 5°C, and stir for 3 hours. Then lower the temperature to 20 ⁇ 5°C and stir for 1 hour. After filtering, the filter cake was washed with 1.670 kg of acetonitrile, and the filter cake was collected.
  • the reaction solution is successively washed with sodium bicarbonate solution (1.070kg sodium bicarbonate dissolved in 20.350kg water), lemon Acid solution (2.150kg citric acid monohydrate dissolved in 19.275kg water), sodium chloride wash (4.300kg sodium chloride dissolved in 17.135kg water).
  • sodium bicarbonate solution 1.070kg sodium bicarbonate dissolved in 20.350kg water
  • lemon Acid solution (2.150kg citric acid monohydrate dissolved in 19.275kg water
  • sodium chloride wash (4.300kg sodium chloride dissolved in 17.135kg water).
  • Pad 0.540 kg of diatomaceous earth to filter, and the filter cake is washed with 1.905 kg of ethyl acetate.
  • Post-treatment Cool the reaction solution to 10 ⁇ 5°C, add dilute ammonia water (1.075kg ammonia water mixed with 36.000kg purified water) dropwise, and control the material temperature below 25°C during the dropwise addition. After the addition, the temperature was lowered to 10 ⁇ 5°C for 2 hours for crystallization. Filter and wash the filter cake with 11.930kg of purified water. Add the filter cake and 14.890kg of ethanol into a 50L double-layer glass reactor, stir at 20 ⁇ 5°C for 0.5 hours, filter, wash the filter cake with 1.860kg of ethanol, and collect the filter cake. The filter cake was dried at 55 ⁇ 5°C and vacuum degree ⁇ -0.07MPa for about 13 hours to obtain 1.6627kg of crude compound 1 with a molar yield of 85.6%.
  • Refining In a 100L reactor, add 9.100kg of acetonitrile, 9.220kg of absolute ethanol and 1.6627kg of compound (1 crude product) under stirring, heat to an internal temperature of 75 ⁇ 5°C, stir until dissolved, and filter while hot. Transfer the filtrate to 100L for reaction In the kettle (if the filtrate has product precipitation, it should be heated to dissolve), stir and cool down to 35 ⁇ 5°C, keep warm until obvious solids are precipitated, keep warm and stir for about 0.5 hours. Then cool down to 5 ⁇ 5°C and keep warm for 2 hours for crystallization. Filter, wash the filter cake with 1.300kg ethanol, and collect the filter cake.
  • Example 2 Weigh 1.0 g of the compound prepared in Example 1, add 5 ml of acetonitrile and 5 ml of ethanol. Heat up to dissolve, then slowly Warm to 50-60°C, add seed crystals (Example 2), continue cooling down to room temperature, and filter and dry. The sample was characterized by XRPD, DSC and TGA, and it was Form B.
  • the DSC/TGA results are shown in Figures 7 and 8, and the results show that the sample has a weight loss of 4.5% when heated to 150 °C, and there are 3 endothermic peaks at 103.5, 113.4 and 183.0 °C (peak temperature). After heating it to 120°C and cooling to room temperature, XRPD was tested, and the results showed that Form C transformed into Form B after heating. Due to the crystal transformation of the sample after heating, combined with the TGA step weight loss, it is speculated that the crystal form C is a monohydrate.
  • Form B and Form C were characterized by PLM, and the results (Figure 10 to Figure 11) showed that the particle size of each sample was less than 20 ⁇ m.
  • Forms B and C The hygroscopicity of Forms B and C was evaluated by a dynamic moisture sorption instrument (DVS).
  • Form C starts with ambient humidity ( ⁇ 60%RH)
  • Form B starts with 0% relative humidity (0%RH).
  • 95%RH-0%RH-95%RH or 0%RH-95%RH-0%RH the percent change in mass of the sample.
  • the test results are shown in Figures 12 and 13, respectively.
  • the results showed that the moisture adsorption of Form B and Form C at 25°C/80%RH was 0.19% and 0.97%, respectively, and the crystal forms of all samples remained unchanged after the DVS test. It shows that the crystal form of the present invention has low hygroscopicity and has low requirements on pharmaceutical packaging and storage conditions.
  • crystal form B is from Example 3
  • crystal form C is from Example 5
  • the inner packaging material is a double-layer pharmaceutical low-density polyethylene bag
  • the outer packaging material is a polyester/aluminum/polyethylene pharmaceutical composite bag.
  • the inner packaging material is a double-layer pharmaceutical low-density polyethylene bag
  • the outer packaging material is a polyester/aluminum/polyethylene pharmaceutical composite bag.
  • the inner packaging material is a double-layer pharmaceutical low-density polyethylene bag
  • the outer packaging material is a polyester/aluminum/polyethylene pharmaceutical composite bag.
  • the inner packaging material is a double-layer pharmaceutical low-density polyethylene bag
  • the outer packaging material is a polyester/aluminum/polyethylene pharmaceutical composite bag.
  • Test animals male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Vehicle for intravenous administration 5% DMA + 5% Solutol + 90% Saline; vehicle for intragastric administration: 0.5% MC; the reference compound INS1007, which is compound 2 in patent WO2015110826A1, was prepared according to the patent method.
  • the compound of the present invention has good bioavailability and pharmacokinetic characteristics.
  • the SD rats were randomly divided into groups according to body weight, respectively vehicle control group (0.5% MC), INS1007 (30, 100, 300mg/kg) group, compound I (30, 100, 300mg/kg) group, each group of administration group 16 rats, 10 rats in the vehicle control group, half male and half male.
  • Drugs or vehicles of corresponding concentrations were given by oral gavage every day for 14 consecutive days, and the recovery period was 7 days.
  • the dosing period the general symptoms, body weight and food intake of each group were observed, and at the end of the dosing period and the recovery period, hematology, serum biochemistry and gross anatomy tests were carried out for each group.
  • the toxicity of the compound of the present invention is less than that of INS1007, and the safety is higher.

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Abstract

本发明公开了式I化合物的多晶型物、其制备方法及用途。本发明的多晶型物包括晶型B、晶型C和晶型D，所述多晶型物具有纯度高、溶解性好、物理和化学性质稳定、能耐高温、高湿及强光照、引湿性低等优异特性。

Description

一种二肽基肽酶1抑制剂多晶型物及其制备方法和用途 技术领域
本发明属于药物领域，具体涉及一种二肽基肽酶1抑制剂多晶型物，及其制备方法和用途。
背景技术
二肽基肽酶1(Dipeptidyl peptidase 1,DPP1)，又名组织蛋白酶C，是溶酶体木瓜蛋白酶家族的一种半胱氨酰蛋白酶，参与细胞内蛋白质降解。在中性粒细胞成熟过程中，DPP1通过切割目标蛋白N末端二肽从而激活中性粒细胞丝氨酸蛋白酶(NSPs)，包括中性粒细胞弹性蛋白酶(neutrophil elastase，NE)，蛋白酶3(proteinase 3，Pr3)和组织蛋白酶G(cathepsin G，CatG)。DPP1与多种炎症性疾病相关，包括：Wegener肉芽肿病，类风湿性关节炎，肺部炎症和病毒感染等疾病。研究显示抑制DPP1可对中性粒细胞引起的高度炎症性肺部疾病具有很好的治疗效果，如支气管扩张症，慢性阻塞性肺病(COPD)，急性肺损伤等。因此，通过靶向DPP1，抑制NSPs的过度活化，可能对支气管扩张症具有潜在的治疗作用。
专利申请PCT/CN2020/114500制备了下式的DPP1小分子抑制剂，该化合物显示了很高的DPP1抑制活性，具有优异的生物利用度和药代动力学特征，并且毒性小、安全性高，拟用于治疗非囊性纤维化支气管扩张症、慢性阻塞性肺疾病(COPD)、急性肺损伤和囊性纤维化支气管扩张症等肺部疾病。开发化合物更适于成药的药物晶型，特别是使稳定性、吸湿性、保存性和/或药效等得到改善的晶型，从而在制药中取得良好效果，成为亟待解决的问题。
发明内容
本发明提供了一种作为医药品的适用性高的式I化合物的多晶型物，所述多晶型物 具有纯度高、溶解性好、物理和化学性质稳定、能耐高温、高湿及强光照、引湿性低等优异特性。
式I化合物的多晶型物，
其中，n为0或1。
在一些实施方式中，式I化合物的多晶型物为无水晶型，即n为0，所述多晶型物描述为晶型B，采用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：12.32±0.2°、14.30±0.2°、15.43±0.2°、16.38±0.2°、18.56±0.2°。
进一步地，在一些实施方式中，所述晶型B的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：17.06±0.2°、18.21±0.2°、18.94±0.2°、19.59±0.2°、20.79±0.2°、21.19±0.2°、22.55±0.2°、22.97±0.2°、23.37±0.2°、24.25±0.2°、25.46±0.2°。
进一步地，在一些实施方式中，晶型B的X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：
进一步地，在一些实施方式中，所述晶型B的X-射线粉末衍射图谱基本如图1所示。
进一步地，在一些实施方式中，所述晶型B具有图2的DSC图和/或图3的TGA图。
在一些实施方式中，式I化合物的多晶型物为一水合物晶型，即n为1，所述多晶型物描述为晶型C，采用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：8.93±0.2°、12.10±0.2°、14.14±0.2°、20.38±0.2°、23.86±0.2°、25.07±0.2°。
进一步地，在一些实施方式中，所述晶型C的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：15.19±0.2°、15.92±0.2°、16.06±0.2°、17.55±0.2°、17.90±0.2°、18.90±0.2°、19.10±0.2°、20.81±0.2°、24.33±0.2°。
进一步地，在一些实施方式中，所述晶型C的X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：
进一步地，在一些实施方式中，所述晶型C的X-射线粉末衍射图谱基本如图6所示。
进一步地，在一些实施方式中，所述晶型C具有图7的DSC图和/或图8的TGA 图。
在一些实施方式中，式I化合物的多晶型物为无水晶型，即n为0，所述多晶型物描述为晶型D，采用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：8.68±0.2°、11.74±0.2°、13.64±0.2°、17.40±0.2°、18.23±0.2°、20.12±0.2°、26.21±0.2°。
进一步地，在一些实施方式中，所述晶型D的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：8.99±0.2°、13.51±0.2°、27.49±0.2°、32.19±0.2°、32.97±0.2°。
进一步地，在一些实施方式中，所述晶型D的X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：
进一步地，在一些实施方式中，所述晶型D的X-射线粉末衍射图谱基本如图9所示。
进一步地，在一些实施方式中，本发明所述的晶型B、晶型C或晶型D，其晶体的粒径小于100μm；在一些实施方式中，晶体的粒径小于90μm；在一些实施方式中，晶体的粒径小于80μm；在一些实施方式中，晶体的粒径小于70μm；在一些实施方式中，晶体的粒径小于60μm；在一些实施方式中，晶体的粒径小于50μm；在一些实施方式中，晶体的粒径小于40μm；在一些实施方式中，晶体的粒径小于30μm；在一些实施方式中，晶体的粒径小于20μm。
本发明还提供了一种药物组合物，其含有治疗有效量的晶型B、晶型C或晶型D，以及药学上可接受的载体和/或赋形剂。
本发明还提供了晶型B、晶型C或晶型D，或者含有它们的药物组合物在制备治疗DPP1介导的疾病的药物中的用途。
进一步地，DPP1介导的疾病包括但不限于非囊性纤维化支气管扩张症、囊性纤维化支气管扩张症、急性肺损伤、气道阻塞性疾病、支气管扩张、囊性纤维化、哮喘、肺气肿和慢性阻塞性肺病。
本发明所述的晶型B、晶型C或晶型D，以原料药的约5重量％至约100重量％存在；在某些实施方案中，以原料药的约10重量％至约100重量％存在；在某些实施方案中，以原料药的约15重量％至约100重量％存在；在某些实施方案中，以原料药的约20重量％至约100重量％存在；在某些实施方案中，以原料药的约25重量％至约100重量％存在；在某些实施方案中，以原料药的约30重量％至约100重量％存在；在某些实施方案中，以原料药的约35重量％至约100重量％存在；在某些实施方案中，以原料药的约40重量％至约100重量％存在；在某些实施方案中，以原料药的约45重量％至约100重量％存在；在某些实施方案中，以原料药的约50重量％至约100重量％存在；在某些实施方案中，以原料药的约55重量％至约100重量％存在；在某些实施方案中，以原料药的约60重量％至约100重量％存在；在某些实施方案中，以原料药的约65重量％至约100重量％存在；在某些实施方案中，以原料药的约70重量％至约100重量％存在；在某些实施方案中，以原料药的约75重量％至约100重量％存在；在某些实施方案中，以原料药的约80重量％至约100重量％存在；在某些实施方案中，以原料药的约85重量％至约100重量％存在；在某些实施方案中，以原料药的约90重量％至约100重量％存在；在某些实施方案中，以原料药的约95重量％至约100重量％存在；在某些实施方案中，以原料药的约98重量％至约100重量％存在；在某些实施方案中，以原料药的约99重量％至约100重量％存在；在某些实施方案中，基本上所有的原料药都是晶型B、晶型C或晶型D，即原料药是基本纯的晶体。
本发明还提供了所述晶型B、晶型C或晶型D的制备方法，包括：
(1)将式I化合物的游离碱粗品置于溶剂中悬浮搅拌，过滤，即得；或者
(2)将式I化合物的游离碱粗品置于溶剂中，升温溶清，降温析晶，过滤，即得。
在一些实施方案中，晶型B通过将化合物I的游离碱在IPAc溶剂中悬浮搅拌2-5天得到。
在一些实施方案中，晶型B通过将化合物I的游离碱在腈类溶剂和醇类溶剂的混合溶剂中升温溶清，再降温析晶得到。
在一些实施方案中，腈类溶剂选自乙腈，醇类溶剂选自甲醇、乙醇、丙醇、异丙醇或者它们的组合。
在一些实施方案中，溶剂为乙腈和乙醇的混合溶剂。
在一些实施方案中，腈类溶剂和醇类溶剂的体积比为(1-3):(1-3)；在一些实施方案中，腈类溶剂和醇类溶剂的体积比为(1-2):(1-2)；在一些实施方案中，腈类溶剂和醇类溶剂的体积比为1:1。
在一些实施方案中，先将溶清溶液降温到50～60℃，然后加入晶种(可来自其他方法，如前一方案所述的方法制备得到)，再继续降温析晶得到。
在一些实施方案中，晶型C通过将化合物I的游离碱在H2O中悬浮搅拌2-5天得到。
在一些实施方案中，晶型D通过将化合物I的游离碱在醇类溶剂中升温溶清，再缓慢降温析晶得到。在一些实施方案中，醇类溶剂选自甲醇、乙醇、丙醇、异丙醇或者它们的组合。在一些实施方案中，溶剂为甲醇。
本发明具有如下的有益效果：
本发明的晶型具有优良的理化性质，例如，好的流动性和明显改善的粘黏性等使得本发明的晶型在制剂过程中可明显降低过滤时间，缩短生产周期，节约成本；良好的光稳定性、热稳定性和湿稳定性，可保证所述晶型在储存和运输时的可靠性，从而保证制剂的安全性和长期贮藏后的有效性，并且所述晶型不需要为防止受光照、温度和湿度的影响而采取特殊包装处理，从而降低了成本；所述晶型不会因光照、高温和高湿产生降解，服用所述晶型的患者不会担忧制剂因暴露于日光下产生光敏反应；所述晶型还具有较高的溶解度，有利于药物的溶出，提高生物利用度。
本发明的晶型还具有良好的稳定性，例如，本发明晶型在DVS测试((60％RH-95％RH-0％RH-95％RH或0％RH-95％RH-0％RH))后、或在25℃/60％RH和在40℃/75％RH条件下放置1周至1月后，晶型均不发生改变，以及还具有研磨稳定性。
此外，本发明晶型的制备方法简单有效，易于放大生产。晶型流动性好，可压缩性好，堆密度大，吸湿性低，粒度分布均匀，便于用于制剂生产。
用本发明晶型制备得到的制剂可减少刺激性并提高吸收，使得代谢速度方面的问题 得以解决，毒性得以显著降低，安全性得以提高，有效地保证了制剂的质量和效能。
可以理解的是，热重分析(TGA)和差示扫描量热(DSC)为本领域中所熟知的，TGA曲线和DSC曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物具有特征峰位置的TGA图和DSC图，具有与本发明附图中提供的TGA图和DSC图实质上相同的性质，测量值误差容限为±5℃内，一般要求在±3℃内。
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。
可以理解的是，本发明的晶型不限于与本发明公开的附图中描述的特征图谱完全相同的特征图谱，比如XRPD、DSC、TGA、DVS、等温吸附曲线图，具有与附图中描述的那些图谱基本上相同或本质上相同的特征图谱的任何晶型均落入本发明的范围内。
“治疗有效量”指引起组织、系统或受试者生理或医学反应的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“室温”：10℃-30℃。
“载体”指的是：不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性，并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系，非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是：其本身并非治疗剂，用作稀释剂、辅料、粘合剂和/或媒介物，用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的，药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠)；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水； (18)林格溶液(Ringer’s solution)；(19)乙醇；(20)pH缓冲溶液；(21)聚酯、聚碳酸酯和/或聚酐；及(22)其他用于药物制剂中的无毒相容物质。
“晶型”或“晶体”或“多晶型物”是指呈现三维排序的任意固体物质，与无定型固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
“晶种”是指在结晶法中，通过加入不溶的添加物，形成晶核，加快或促进与其晶型或立体构型相同的对映异构体结晶的生长。
“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数、数据或值。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。
“2θ”是指基于X射线衍射实验中设置的以度数(°)表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶型的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。
对于X射线衍射峰的术语“基本上相同”或“基本如图XX所示”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2°，并且用于测量衍射的仪器也会导致一些变化。另外，本领域技术人员会理解相对峰强度会因仪器间的差异以及结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素而出现变化，并应将其看作仅为定性测量。
附图说明
图1为晶型B的X-射线粉末衍射图谱。
图2为晶型B的差示扫描量热分析曲线图谱。
图3为晶型B的热重分析图谱。
图4为晶型B的核磁图谱。
图5为晶型B的变温XRPD测试图谱。
图6为晶型C的X-射线粉末衍射图谱。
图7为晶型C的差示扫描量热分析曲线图谱。
图8为晶型C的热重分析图谱。
图9为晶型D的X-射线粉末衍射图谱。
图10为晶型B的PLM图。
图11为晶型C的PLM图。
图12为晶型B的DVS图。
图13为晶型C的DVS图。
具体实施方式
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的，按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明，但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
表1试验中选用试剂的中英文名称对照表
XRPD的测定使用X射线粉末衍射仪Panalytical EMPYREAN进行分析。扫描参数如表2所示：
表2 XRPD测试参数
TGA和DSC的测定分别在TA Q5000/5500热重分析仪和TA 2500差示扫描量热仪上采集，测试参数如表3所示：
表3 DSC和TGA测试参数
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明时，溶液是指水溶液。
实施例1化合物1的制备
(S)-N-((S)-1-氰基-2-(2-氟-4-(3-甲基-2-氧代-2,3-二氢苯并[d]恶唑-5-基)苯基)乙基)-1,4-氧杂氮杂环庚烷-2-甲酰胺(化合物1)
(S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide(compound 1)
第一步：
反应：50L反应釜中，搅拌下加入10.005kg 1,4-二氧六环、1.600kg化合物a-1(参考专利WO2015110826A1的方法)和2.000kg化合物a-2(参考专利WO2016139355A1的方法)，再加入6.605kg碳酸钾水溶液(1.600kg碳酸钾溶于5.005kg纯化水中)。加毕，氮气置换三次。加入100.0g[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，氮气置换一次。氮气保护下，将反应液升温至80±5℃反应约2小时后，取样HPLC监控，中控目标值化合物a-2含量≤1.0％，停止反应。
后处理：向反应液中加入5.000kg纯化水，降温至10±5℃，加入10.005kg纯化水，10±5℃搅拌析晶约1小时，过滤，滤饼用2.500kg纯化水/次洗涤两次，收集滤饼。将12.605kg无水乙醇及滤饼加入到50L反应釜中，于20±5℃搅拌约0.5小时，过滤，滤饼用1.000kg无水乙醇/次洗涤两次，收集滤饼。
干燥：滤饼于55±5℃、真空≤-0.07MPa干燥约16小时，收料得2.143kg化合物a， 摩尔收率为89.4％。
1H NMR(400MHz,DMSO)δ7.90(s,1H),7.72–7.30(m,6H),4.72(s,1H),3.41(d,3H),3.09-3.21(m,2H),1.37(s,9H)。
LCMS m/z＝356.1[M-56+H]+。
第二步：
反应：50L玻璃反应釜中，搅拌下加入16.785kg乙腈、2.1381kg化合物a和2.950kg对甲苯磺酸一水合物。加毕，控温25±5℃反应约2小时后取样HPLC监控，中控目标值化合物a含量≤1.0％，停止反应。
后处理：过滤，滤饼用1.670kg乙腈洗涤，收集滤饼。将2.1381kg乙腈及滤饼加入到反应釜中，升温至80±5℃，搅拌3小时。再降温至20±5℃，搅拌1小时。过滤，滤饼用1.670kg乙腈洗涤，收集滤饼。
干燥：滤饼于55±5℃、真空≤-0.07MPa干燥约16小时。收料得2.141kg化合物b，收率为85.5％。
1H NMR(400MHz,DMSO)δ9.04(s,3H),7.70–7.37(m,8H),7.13(d,2H),4.90(dd,1H),3.41(s,3H),3.29(t,2H),2.29(s,3H)。
LCMS m/z＝312.2[M-172+H]+。
第三步：
反应：100L反应釜中，搅拌下加入19.060kg乙酸乙酯、2.1413kg化合物b和1.1300kg化合物b-1(购买于南京药石科技股份有限公司)，再加入1.725kg N,N-二异丙基乙胺。加毕，氮气保护下，将反应液降温到5±5℃，控温10±5℃滴加4.240kg丙基磷酸酐，加毕，保温25±5℃反应约3～8小时。
后处理：将反应液依次用碳酸氢钠溶液(1.070kg碳酸氢钠溶于20.350kg水)、柠檬 酸溶液(2.150kg柠檬酸一水合物溶于19.275kg水)、氯化钠洗涤(4.300kg氯化钠溶于17.135kg水)。有机相中加入0.210kg药用炭，搅拌约0.5小时。垫0.540kg硅藻土过滤，滤饼用乙酸乙酯1.905kg洗涤。向有机相加入1.070kg无水硫酸钠，干燥约0.5小时。过滤，用乙酸乙酯1.905kg洗涤滤饼，合并滤液。
浓缩：滤液在50±5℃减压浓缩至无明显馏分流出，得到2.385kg化合物c(超重、按照收率100％计算此量)。直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ7.54–7.01(m,7H),5.18(s,1H),4.25–3.94(m,3H),3.54(dd,2H),3.46(s,3H),3.39–3.04(m,4H),1.99(d,2H),1.54–1.39(m,9H)。
LCMS m/z＝483.2[M-56+1]+。
第四步：
反应：向装有化合物c浓缩物的50L双层玻璃反应釜中，搅拌下加入9.305kg乙腈、2.530kg对甲苯磺酸一水合物。加毕，保温25±5℃反应约2小时后取样HPLC监控，中控目标值化合物c含量≤1.0％，停止反应。
后处理：将反应液降温到10±5℃，滴加稀氨水(1.075kg氨水与36.000kg纯化水混合)，滴加过程中控制料温25℃以下。加毕，再降温至10±5℃析晶2小时。过滤，滤饼用11.930kg纯化水洗涤。将滤饼和14.890kg乙醇加入至50L双层玻璃反应釜中，于20±5℃搅拌0.5小时，过滤，滤饼用1.860kg乙醇洗涤，收集滤饼。滤饼于55±5℃、真空度≤-0.07MPa干燥约13小时，收料得1.6627kg化合物1粗品，摩尔收率为85.6％。
精制：100L反应釜中，搅拌下加入9.100kg乙腈、9.220kg无水乙醇和1.6627kg化合物(1粗品，加热至内温75±5℃，搅拌至溶清，趁热过滤。滤液转入100L反应釜中(滤液若有产品析出，应加热溶清)，搅拌下降温至35±5℃，保温至析出明显固体，再保温搅拌约0.5小时。再降温至5±5℃保温析晶2小时。过滤，滤饼用1.300kg乙醇洗涤，收集滤饼。
干燥：滤饼于55±5℃、真空度≤-0.07MPa干燥约25小时，得1.4060kg化合物式1游离碱，收率84.6％。
1H NMR(400MHz,DMSO)δ8.69(d,1H),7.64(d,1H),7.61–7.51(m,2H),7.46(t, 2H),7.39(d,1H),5.06(q,1H),4.01(dd,1H),3.87(ddd,1H),3.73(ddd,1H),3.40(s,3H),3.34–3.28(m,1H),3.20(dd,1H),3.06(dd,1H),2.78(ddd,1H),2.69–2.54(m,2H),2.21(s,1H),1.84–1.63(m,2H)。
LCMS m/z＝439.2[M+1]+。
实施例2化合物1晶型B的制备
称取实施例1制得的化合物200mg在IPAc溶剂中室温悬浮搅拌3天，过滤，干燥。样品经XRPD测试，描述该游离碱晶型为晶型B。
其XRPD图如图1所示，XRPD衍射峰出峰列于表4。
表4
DSC/TGA结果列于图2和3，显示样品加热至150℃时样品有2.3％的失重，并在181.9℃(起始温度)处有1个吸热峰。核磁结果(图4)显示样品中残留溶剂IPAc与API摩尔比为0.01(对应失重0.1wt％)。为对晶型B的TGA失重进行研究，对其进行变温XRPD测试，结果(图5)显示游离碱晶型B在氮气吹扫20分钟，加热至120℃和降温至30℃，晶型均未发生改变(120℃下有部分衍射峰偏移，推测可能是高温下晶格膨胀导致)，因此推测游离碱晶型B为无水晶型。
实施例3化合物1晶型B的制备
称取实施例1制得的化合物1.0g，加入5ml乙腈、5ml乙醇。升温至溶清，缓慢降 温至50～60℃，加入晶种(实施例2)，继续降温至室温，过滤干燥。样品通过XRPD、DSC和TGA表征，为晶型B。
实施例4化合物1晶型B的制备
称取实施例1制得的化合物4.0g，加入15ml二甲亚砜；升温至75℃溶清。溶清后加入70ml乙醇，保温搅拌30min；加入实施例3所得晶种，降温至室温，过滤干燥得3.36g晶型B，收率84.0％。
实施例5化合物1一水合物晶型C的制备
称取实施例1制得的化合物200mg在H2O中室温悬浮搅拌3天过滤，干燥。样品经XRPD测试，描述该晶型为晶型C。
其XRPD图如图6所示，XRPD衍射峰出峰列于表5。
表5

DSC/TGA结果列于图7和8，结果显示样品加热至150℃时有4.5％的失重，并在103.5,113.4和183.0℃(峰值温度)有3个吸热峰。将其加热至120℃并冷却至室温后测试XRPD，结果显示晶型C在加热后转为晶型B。由于样品加热后转晶，结合TGA台阶式失重，推测晶型C为一水合物。
实施例6化合物1晶型D的制备
称取实施例1制得的化合物200mg，加入20mg甲醇中。升温至回流，趁热过滤。缓慢降温至室温，析晶，过滤，干燥。通过XRPD表征，描述该晶型为晶型D。
其XRPD图如图9所示，XRPD衍射峰出峰列于表6。
表6
晶型评估试验
1、晶型转化
为研究水合物晶型C和无水晶型B之间的转化关系，对其进行混悬竞争试验。称 取一定量的游离碱，加入对应溶剂在室温下混悬搅拌约2小时后，用0.45μm PTFE滤膜过滤得到饱和溶液。称取5～7mg游离碱晶型B和晶型C样品至HPLC小瓶中，加入1.0mL饱和溶液，置于室温混悬搅拌后测试固体XRPD。结果汇总于表7，结果显示，在水活度0～0.2体系中得到游离碱晶型B，在水活度0.4～1体系中得到晶型C。
表7
2、PLM
对晶型B和晶型C进行PLM表征，结果(图10至图11)显示各样品的粒径均小于20μm。
3、引湿性
通过动态水分吸附仪(DVS)对晶型B和C进行引湿性评估。晶型C以环境湿度(～60％RH)为起始，晶型B以0％相对湿度(0％RH)为起始，测试收集了25℃恒温条件下，随湿度变化(60％RH-95％RH-0％RH-95％RH或0％RH-95％RH-0％RH)时，样品的质量变化百分比。测试结果分别如图12和13所示，结果显示晶型B和晶型C在25℃/80％RH时水分吸附分别为0.19％和0.97％，所有样品在DVS测试后晶型均未改变。说明本发明晶型引湿性低，对药品包装和贮存条件要求低。
4、固体稳定性
本实验所用化合物中，晶型B来自实施例3，晶型C来自实施例5
将晶型B和C在25℃/60％RH和在40℃/75％RH条件下裸放后，分别通过XRPD和UPLC测试其物理和化学稳定性。结果汇总于表8。结果显示各样品在25℃/60％RH和在40℃/75％RH条件下放置1周至1月后，晶型均未发生改变，且纯度无明显下降，稳定性好。
表8

5、稳定性数据
本实验所用化合物来自实施例4。
5.1加速试验
考察条件：40℃±2℃，75％RH±5％RH。
包装：内包材为双层药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药用复合袋。
表9加速试验结果
5.2长期试验1
考察条件：25℃±2℃，60％RH±5％RH。
包装：内包材为双层药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药用复合袋。
表10长期试验1结果

5.3长期试验2
考察条件：30℃±2℃，65％RH±5％RH。
包装：内包材为双层药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药用复合袋。
表11长期试验2结果
5.4长期试验3
考察条件：2-8℃。
包装：内包材为双层药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药用复合袋。
表12长期试验3结果
其中纯度的分析方法如下：

生物实验
1、体外DPP1酶活检测实验
终浓度100μg/mL的重组人DPP1酶(R&D Systems,Cat.No 1071-CY)与终浓度20μg/mL重组人组织蛋白酶L(R&D System，Cat.No 952-CY)混合后于室温孵育1小时，使DPP1酶活化。活化后的DPP1酶稀释100倍，于384孔板中加入5μL不同浓度的化合物和5μL稀释后的DPP1酶，室温孵育30分钟。加入10μL浓度为20μM的底物Gly--Arg-AMC(bachem，Cat.No I-1215)后，继续室温孵育60分钟，酶标仪检测荧光强度，其中激发光为380nm，发射光为460nm。运用Origin2019软件DosResp函数计算IC50值。
表13 DPP1抑制活性
结论:化合物1对于DPP1受体显示出很高的抑制活性。
2、大鼠药代动力学测试
1.1试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。
1.2试验设计：试验当天，6只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表14给药信息

静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC；对照化合物INS1007即专利WO2015110826A1中的化合物2，按照专利方法制备。
于给药前及给药后异氟烷麻醉经眼眶取血0.1ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组采血时间点：0,5,15,30min,1,2,4,6,8,24h；灌胃组采血时间点：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃。
表15测试化合物在大鼠血浆中的药代动力学参数
结论：本发明化合物具有良好的生物利用度和药代动力学特征。
3.大鼠14天口服重复给药毒性试验测试
将SD大鼠按体重随机分组，分别为溶媒对照组(0.5％MC)、INS1007(30、100、300mg/kg)组、化合物I(30、100、300mg/kg)组，给药组每组16只，溶媒对照组10只，雌雄各半。每天经口灌胃给予相应浓度药物或溶媒，连续给药14天，恢复期7天。给药期间对各组进行一般症状观察，体重和摄食量的检测，给药期结束和恢复期结束，分别对各组进行血液学、血清生化和大体解剖检测。
结论：同等剂量下，本发明化合物的毒性小于INS1007，安全性更高。

Claims (15)

  1. 一种式I化合物的多晶型物：
    其中，n为0或1。
  2. 根据权利要求1所述的多晶型物，其中，n为0，所述多晶型物为晶型B，采用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：12.32±0.2°、14.30±0.2°、15.43±0.2°、16.38±0.2°、18.56±0.2°。
  3. 根据权利要求2所述的多晶型物，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：17.06±0.2°、18.21±0.2°、18.94±0.2°、19.59±0.2°、20.79±0.2°、21.19±0.2°、22.55±0.2°、22.97±0.2°、23.37±0.2°、24.25±0.2°、25.46±0.2°。
  4. 根据权利要求2或3所述的多晶型物，其X-射线粉末衍射图谱基本如图1所示。
  5. 根据权利要求2或3所述的多晶型物，所述晶型B具有图2的DSC图和/或图3的TGA图。
  6. 根据权利要求1所述的多晶型物，其中，n为1，所述多晶型物为晶型C，采用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：8.93±0.2°、12.10±0.2°、14.14±0.2°、20.38±0.2°、23.86±0.2°、25.07±0.2°。
  7. 根据权利要求6所述的多晶型物，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：15.19±0.2°、15.92±0.2°、16.06±0.2°、17.55±0.2°、17.90±0.2°、18.90±0.2°、19.10±0.2°、20.81±0.2°、24.33±0.2°。
  8. 根据权利要求6或7所述的多晶型物，其X-射线粉末衍射图谱基本如图6所示。
  9. 根据权利要求6或7所述的多晶型物，所述晶型C具有图7的DSC图和/或图8的TGA图。
  10. 根据权利要求1所述的多晶型物，其中，n为0，所述多晶型物为晶型D，采用 Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：8.68±0.2°、11.74±0.2°、13.64±0.2°、17.40±0.2°、18.23±0.2°、20.12±0.2°、26.21±0.2°。
  11. 根据权利要求10所述的多晶型物，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：8.99±0.2°、13.51±0.2°、27.49±0.2°、32.19±0.2°、32.97±0.2°。
  12. 根据权利要求10或11所述的多晶型物，其X-射线粉末衍射图谱基本如图9所示。
  13. 一种药物组合物，其含有治疗有效量的权利要求1～12中任意一项所述的多晶型物，以及药学上可接受的载体和/或赋形剂。
  14. 权利要求1～12中任意一项所述的多晶型物或者权利要求13所述的药物组合物在制备治疗DPP1介导的疾病的药物中的用途。
  15. 根据权利要求14所述的用途，其中，所述DPP1介导的疾病选自非囊性纤维化支气管扩张症、囊性纤维化支气管扩张症、急性肺损伤、气道阻塞性疾病、支气管扩张、囊性纤维化、哮喘、肺气肿和慢性阻塞性肺病。
PCT/CN2023/077649 2022-02-22 2023-02-22 一种二肽基肽酶1抑制剂多晶型物及其制备方法和用途 WO2023160579A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105980367A (zh) * 2014-01-24 2016-09-28 阿斯利康(瑞典)有限公司 (2s)-n-[(1s)-1-氰基-2-苯基乙基]-1，4-氧杂氮杂环庚烷-2-甲酰胺作为二肽基肽酶i抑制剂
CN114591315A (zh) * 2020-12-04 2022-06-07 瑞石生物医药有限公司 一种组织蛋白酶c小分子抑制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105980367A (zh) * 2014-01-24 2016-09-28 阿斯利康(瑞典)有限公司 (2s)-n-[(1s)-1-氰基-2-苯基乙基]-1，4-氧杂氮杂环庚烷-2-甲酰胺作为二肽基肽酶i抑制剂
CN114591315A (zh) * 2020-12-04 2022-06-07 瑞石生物医药有限公司 一种组织蛋白酶c小分子抑制剂

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