WO2023246854A1 - 一种硼酸酯衍生物的结晶、其制备方法及用途 - Google Patents
一种硼酸酯衍生物的结晶、其制备方法及用途 Download PDFInfo
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- WO2023246854A1 WO2023246854A1 PCT/CN2023/101645 CN2023101645W WO2023246854A1 WO 2023246854 A1 WO2023246854 A1 WO 2023246854A1 CN 2023101645 W CN2023101645 W CN 2023101645W WO 2023246854 A1 WO2023246854 A1 WO 2023246854A1
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- acetone
- toluene
- acetonitrile
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- methanol
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- 230000007547 defect Effects 0.000 description 1
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- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
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- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
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- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
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- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
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- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Definitions
- the present disclosure belongs to the field of pharmacy and relates to the crystallization of a borate derivative, its preparation method and use.
- Phosphodiesterases are a class of phosphodiesters that cleave the second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) key intracellular enzymes.
- the cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways.
- PDE4 is highly specific for cAMP and has 4 subtypes: PDE4A, PDE4B, PDE4C and PDE4D.
- PDE4 is involved in promoting monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, myocardial contraction and other related physiological and pathological processes. It has important effects on central nervous system function, cardiovascular function, inflammation/immune system, Cell adhesion, etc. are all affected. PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.
- PDE4 inhibitors have been discovered in recent years. For example, roflumilast is approved for use in severe chronic obstructive pulmonary disease (COPD) to reduce the number of flare-ups or prevent worsening of COPD symptoms; apremilast is approved for the treatment of adults with active psoriatic arthritis.
- COPD severe chronic obstructive pulmonary disease
- apremilast is approved for the treatment of adults with active psoriatic arthritis.
- PDE4 inhibitors show good pharmacological activity, these PDE inhibitors can cause side effects, such as induced gastrointestinal symptoms such as vomiting and diarrhea.
- the crystal form A of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 7.537°, 11.366°, 14.297°, 15.219°, 16.190°, 17.623 There are characteristic peaks at 19.134°, 21.798°, 22.911°, and 24.735°.
- the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ of the crystal form A of the compound represented by Formula I is shown in Figure 7.
- the present disclosure also provides a method for preparing crystal form A of the compound represented by formula I as described above, which is method one or method two:
- Method one includes the following steps:
- the solvent (1) is selected from water, nitromethane, N,N-dimethylformamide (DMF), acetonitrile, methanol, ethanol, acetone, isopropyl alcohol (IPA), methyl ethyl ketone ( One of MEK), tetrahydrofuran (THF), 1,2-dimethoxyethane, chloroform, methyl tert-butyl ether (MTBE), 1,2-xylene, toluene, dioxane and hexane or more;
- DMF N,N-dimethylformamide
- IPA isopropyl alcohol
- MEK methyl ethyl ketone
- THF tetrahydrofuran
- MTBE methyl tert-butyl ether
- 1,2-xylene 1,2-xylene, toluene, dioxane and hexane or more
- Method two includes the following steps:
- the solvent (2) is selected from acetone, acetonitrile, dichloromethane (DCM), dioxane, ethanol, ethyl acetate, heptane, isopropyl alcohol, methanol, methyl ethyl ketone, methyl tert.
- DCM dichloromethane
- dioxane ethanol
- ethyl acetate ethyl acetate
- heptane isopropyl alcohol
- methanol methyl ethyl ketone
- methyl tert methyl tert.
- One or more of butyl ether, toluene and water is selected from acetone, acetonitrile, dichloromethane (DCM), dioxane, ethanol, ethyl acetate, heptane, isopropyl alcohol, methanol, methyl ethyl ketone, methyl tert.
- the solvent (1) is water, nitromethane, N,N-dimethylformamide, acetonitrile, ethanol, acetone, isopropyl alcohol, methyl ethyl ketone, tetrahydrofuran, 1,2 -Dimethoxyethane, chloroform, methyl tert-butyl ether, 1,2-xylene, toluene, dioxane, hexane, or a mixed solvent of water and methanol.
- the stirring crystallization is beating crystallization.
- the volume ratio of the two is 1:3-3:1, preferably 1:1.
- the volume ( ⁇ l) used in the solvents (1) and (2) can be 1-200 times the mass (mg) of the compound represented by Formula I, and in non-limiting embodiments can be 1 ,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125 , 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
- the present disclosure also provides a pharmaceutical composition, which includes the above-mentioned crystalline form A or the crystalline form A prepared by the above-mentioned preparation method, and optionally pharmaceutically acceptable excipients.
- the present disclosure also provides a method for preparing the above-mentioned pharmaceutical composition, which includes the step of mixing the above-mentioned crystalline form A or the crystalline form A prepared by the above-mentioned method and a pharmaceutically acceptable excipient.
- the present disclosure also provides the use of the above crystalline form A or the crystalline form A prepared by the above preparation method or the above pharmaceutical composition in the preparation of drugs for preventing and/or treating diseases related to PDE.
- the disease associated with PDE is asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatic disease.
- Deliquescence Absorbing enough water to form a liquid
- the weight gain by attracting moisture is not less than 15%;
- the weight gain by attracting moisture is less than 15% but not less than 2%;
- weight gain due to moisture absorption is less than 0.2%.
- Differential scanning calorimetry or DSC refers to measuring the temperature difference and heat flow difference between the sample and the reference during the process of heating or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical changes to obtain phase change information of the sample.
- HPLC high-performance liquid chromatography
- MS was measured using Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, Waters Xbridge C18 4.6 ⁇ 50mm, 5 ⁇ M chromatographic column, scanning in positive/negative ion mode, and the mass scanning range was 80 ⁇ 1200.
- Forward column chromatography generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh or 300 ⁇ 400 mesh silica gel as the carrier, or uses Changzhou Santai prefilled ultra-pure normal phase silica gel column (40-63 ⁇ m, 60g, 24g, 40g, 120g or other specifications).
- Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1L.
- Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.
- Step 5) At room temperature, add compound c (10.0g, 36.9mmol) and diethylaniline (10mL, 62.5mmol) in sequence to a 50mL single-mouth bottle. Stir at 210°C for 1 hour. Cool to room temperature, adjust the pH to neutral with 1M HCl solution, extract with ethyl acetate (200mL ⁇ 3), and wash with water (200mL ⁇ 3). Concentrate under reduced pressure to obtain compound d (9.1g).
- Step 7) At room temperature, add compound e (28.4g, 105mmol), dioxane (300mL), pinacol diborate (31.9g, 126mmol), and potassium acetate (20.6g) into a 500mL single-mouth bottle in sequence. 209mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.66g, 10.5mmol). Under nitrogen atmosphere, stir at 105°C for 16 hours. Cool to room temperature and filter. It was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound f (28.4g).
- Step 9) At room temperature, add compound g (35.0g, 115mmol), compound 1c (44.5g, 149mmol), potassium carbonate (23.8g, 172mmol), potassium acetate (16.9g, 172mmol) and [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.41g, 11.5mmol) in a mixed solvent of 1,4-dioxane (250mL) and water (5mL). Stir until dissolved, replace with nitrogen three times, and stir at 110°C for 16 hours. Cool to room temperature, add water (500 mL), extract with ethyl acetate (300 mL ⁇ 3), and dry over anhydrous sodium sulfate. filter, reduce pressure After concentration, the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound h (37g).
- N/A means not detected
- the solids obtained in Examples 3 and 4 were detected by X-ray powder diffraction, and the product was defined as crystal form A.
- the XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 3.
- the DSC spectrum is shown in Figure 8, showing the endothermic peak at 140.43°C.
- the TGA spectrum is shown in Figure 9, showing a weight loss of 1.53% between 25°C and 100°C.
- the DVS test is shown in Figure 10, which shows that under normal storage conditions (i.e., 25°C, 60% RH), the hygroscopic weight gain of the sample is approximately 0.08%; under accelerated experimental conditions (i.e., 70% RH), the hygroscopic weight gain is approximately 0.15%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is approximately 0.70%.
- the humidity change process from 0% to 90% RH, the desorption and adsorption processes of this sample coincided.
- the crystal form was retested after the DVS test, and the XRPD test showed that the crystal form did not change before and after the DVS test.
- Crystal Form A was placed in a stable box and an accelerated stability experiment was conducted using a series of temperature and humidity combination conditions. After being placed under various temperature and humidity conditions for different days, the samples were taken out, and the obtained solids were compared with the initial crystal form A.
- the content of the compound represented by formula I was determined by high-performance liquid chromatography and detected by XRPD. The experimental results are shown in Table 4 below.
- Compound A was prepared using the method disclosed in the patent application "Example 4 on page 181 of the specification in WO2020070651A”.
- the RLU data After the incubation, read the RLU data and calculate the inhibition rate. Calculate the IC 50 value based on the concentration and inhibition rate fitting curve.
- the maximum value refers to the reading value of the DMSO control, and the minimum value refers to the reading value of the no enzyme activity control.
- Test Example 2 Inhibitory effect of compounds on the release of pro-inflammatory cytokines from peripheral blood mononuclear cells (PBMC)
- PBMC frozen PBMC and detect cell viability and number by trypan blue staining. Wash the thawed PBMC with RPMI1640 complete medium (RPMI1640+10% FBS+1% PS), centrifuge and discard the supernatant. Resuspend PBMC in RPMI1640 complete medium and adjust the cell density to 2 ⁇ 10 6 cells/mL. Spread 2 ⁇ 10 5 PBMC cells in a 96-well cell culture plate, add different concentrations of the compound to be tested, starting from the maximum compound concentration of 100 ⁇ M, make 9 concentration gradient dilutions at a ratio of 1:5, and detect in duplicate wells. Add LPS with a final concentration of 0.1ng/mL to a total volume of 200 ⁇ L. Set negative and positive controls.
- Test Example 3 In vitro experiment of compounds inhibiting the secretion of IL-23 by DC cells differentiated from human monocytes
- Day 0 Isolate and purify monocytes from fresh human peripheral blood and resuspend them in complete RPMI-1640 culture medium.
- IL-4 at a concentration of 50ng/ml and 100ng/ml to the culture medium.
- GM-CSF was cultured in a culture dish with a diameter of 100 mm at a density of 1 ⁇ 10 6 cells/mL.
- the incubator temperature was 37°C and the carbon dioxide concentration was 5%.
- Day 3 Replace half the volume of complete RPMI culture medium with fresh complete RPMI culture medium, keeping the concentration of IL-4 at 50ng/ml and the concentration of GM-CSF at 100ng/ml.
- DC cells non-adherent cells
- the washed DC cells were resuspended in complete RPMI culture medium, and the resuspended cell density was 1 ⁇ 10 6 cells/mL. Then add 1 ⁇ 10 5 DC cells to each well of the 96-well cell culture plate, and add different concentration gradients of the test compound (or DMSO blank negative control of the same concentration) for pretreatment and incubation for 1 hour, and then add 200ug/ml TLR2
- the agonist Zymosan stimulates DC cells for 24 hours.
- Day 7 After zymosan stimulates DC cells for 24 hours, collect the supernatant from each well in the 96-well plate, and detect the concentration of IL-23 by ELISA.
- mice Seven-week-old Balb/c female mice were used. The backs were shaved the day before the experiment, and the shaved area was 2 cm ⁇ 3 cm.
- imiquimod (IMQ) ointment (Aldara (5%)) was continuously applied to the back skin of mice for 7 days to construct a psoriasis mouse model.
- the control group was given the same dose of Vaseline ointment.
- the severity of skin inflammation was evaluated on days 3, 5, and 7, including measuring skin thickness, scabs, and erythema, and scoring each on a 5-point scale (0-5). The total score is used to assess the severity of skin inflammation.
- the spleen was taken and weighed, and the percentage of spleen in body weight was calculated to evaluate the degree of drug immunosuppression.
- This experiment consists of a normal control group, a model control group, low, medium and high dose groups of compound I (0.01%, 0.03% and 0.1%), and a 0.03% reference compound A group.
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本公开涉及一种硼酸酯衍生物的结晶、其制备方法及用途。具体而言,本公开提供了式I所示化合物的结晶、其制备方法及用途。
Description
本公开属于药学领域,涉及一种硼酸酯衍生物的结晶、其制备方法及用途。
磷酸二酯酶(PDEs)为一类裂解在第二信使分子3',5'-环腺苷单磷酸(cAMP)和3',5'-环鸟苷单磷酸(cGMP)上的磷酸二酯键的细胞内酶。环核苷酸cAMP和cGMP在各种细胞途径中充当第二信使。其中,PDE4对cAMP具有高度特异性,有4种亚型:PDE4A、PDE4B、PDE4C和PDE4D。PDE4参与了促进单核细胞与巨噬细胞活化、中性粒细胞浸润、血管平滑肌的增殖、血管扩张以及心肌收缩等相关生理病理过程,对中枢神经系统功能、心血管功能、炎症/免疫系统、细胞黏附等都有影响。PDE4在促炎介质和抗炎介质的表达中起主要调节作用,PDE4抑制剂能够抑制炎症细胞释放有害介质。
近年发现许多PDE4抑制剂。例如,罗氟司特获准用于严重慢性阻塞性肺病(COPD)以减少突然发作的次数或防止COPD症状恶化;阿普司特获批用于治疗患有活动性牛皮癣性关节炎的成人。虽然PDE4抑制剂显示良好药理活性,但这些PDE抑制剂会出现副作用,诸如诱发性胃肠症状如呕吐及腹泻。仍需要开发选择性PDE4抑制剂,尤其对PDE4B和PDE4D具有亲和力的选择性PDE4抑制剂。
含硼(B)药物克立硼罗于2016年12月14日经FDA批准为一种轻度至中度特应性皮炎的局部治疗药物。该硼原子有助于皮肤渗透并与磷酸二酯酶4(PDE4)的双金属中心结合。另外,其他含硼的PDEs抑制剂小分子已有报道,诸如CN102014927A、WO2020070651。然而本公开的化合物并没有在任何文献中公开,且该类化合物展现特异性PDE4抑制效果。
PCT/CN2021/141010提供了一类新型的PDE4抑制剂,其化学名为(R)-4-(6-(8-甲氧基-2,2-二甲基苯并二氢吡喃-5-基)吡嗪-2-基)-1,2-氧杂硼杂环戊烷-2-醇,具有式I所示的结构,
作为药用活性成分的晶型往往影响到药物的化学稳定性,结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化,有时还会伴随着产生其他形态的晶型。一般来说,无定形的药物产品没有规则的晶型结构,往往具有其它缺陷,
比如产物稳定性较差,析晶较细,过滤较难,易结块,流动性差等。药物的多晶型对产品储存、生产及放大有不同的要求。因此,深入研究前述化合物的晶型,改善前述化合物的各方面性质是很有必要的。
发明内容
本公开提供了一种式I所示化合物的晶型A,其以衍射角2θ角度表示的X-射线粉末衍射图,在7.537°、15.219°、21.798°、22.911°处有特征峰,
在一些实施方案中,所述式I所示化合物的晶型A,其以衍射角2θ角度表示的X-射线粉末衍射图,在7.537°、11.366°、14.297°、15.219°、16.190°、17.623°、19.134°、21.798°、22.911°、24.735°处有特征峰。
在一些实施方案中,所述式I所示化合物的晶型A,其以衍射角2θ角度表示的X-射线粉末衍射图,在7.537°、11.366°、14.018°、14.297°、15.219°、16.190°、17.623°、19.134°、21.062°、21.798°、22.911°、24.735°、25.123°、26.884°处有特征峰。
在一些实施方案中,所述式I所示化合物的晶型A,其以衍射角2θ角度表示的X-射线粉末衍射图,在7.537°、11.366°、14.018°、14.297°、15.219°、16.190°、17.623°、18.412°、19.134°、20.010°、21.062°、21.798°、22.911°、23.889°、24.735°、25.123°、26.884°、28.343°、29.645°、33.499°、36.362°处有特征峰。
在一些实施方案中,所述式I所示化合物的晶型A,其以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
在一些实施方案中,本公开所述的式I所示化合物的晶型A,其中所述2θ角度值误差范围为±0.2°。
本公开还提供了一种如上所述的式I所示化合物的晶型A的制备方法,其为方法一或方法二:
方法一包括以下步骤:
(a1)将式I所示化合物与溶剂(1)混合;
(b1)搅拌析晶;
其中,所述溶剂(1)选自水、硝基甲烷、N,N-二甲基甲酰胺(DMF)、乙腈、甲醇、乙醇、丙酮、异丙醇(IPA)、甲基乙基酮(MEK)、四氢呋喃(THF)、1,2-二甲氧基乙烷、氯仿、甲基叔丁基醚(MTBE)、1,2-二甲苯、甲苯、二氧六环和己烷中的一种或多种;
方法二包括以下步骤:
(a2)将式I所示化合物与溶剂(2)混合;
(b2)挥发析晶;
其中,所述溶剂(2)选自丙酮、乙腈、二氯甲烷(DCM)、二氧六环、乙醇、乙酸乙酯、庚烷、异丙醇、甲醇、甲基乙基酮、甲基叔丁基醚、甲苯和水中的一种或多种。
在一些实施方案中,所述溶剂(1)为水、硝基甲烷、N,N-二甲基甲酰胺、乙腈、乙醇、丙酮、异丙醇、甲基乙基酮、四氢呋喃、1,2-二甲氧基乙烷、氯仿、甲基叔丁基醚、1,2-二甲苯、甲苯、二氧六环、己烷、或水和甲醇的混合溶剂。
在一些实施方案中,当所述溶剂(1)为水和甲醇的混合溶剂时,所述水和所述甲醇的摩尔比为0.37-0.90,在非限制性实施方案中可为0.37、0.40、0.47、0.50、0.57、0.60、0.66、0.70、0.74、0.80、0.82、0.90。
在一些实施方案中,所述搅拌析晶时的温度为10-60℃,在非限制性实施方案中可为10℃、20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃。
在一些实施方案中,所述搅拌析晶时的温度为室温。
在一些实施方案中,当所述搅拌析晶时的温度为10-40℃(例如室温)时,所述溶剂(1)为水、硝基甲烷、乙腈、乙醇、丙酮、异丙醇、甲基乙基酮、四氢呋喃、1,2-二甲氧基乙烷、氯仿、甲基叔丁基醚、1,2-二甲苯、甲苯、二氧六环、己烷、或水和甲醇的混合溶剂。
在一些实施方案中,当所述搅拌析晶时的温度为41-60℃(例如50℃)时,所述溶剂(1)为水、N,N-二甲基甲酰胺、乙腈、丙酮、甲基乙基酮、1,2-二甲氧基乙烷、氯仿、甲基叔丁基醚、1,2-二甲苯、甲苯、己烷、或水和甲醇的混合溶剂。
在一些实施方案中,所述搅拌析晶为打浆析晶。
在一些实施方案中,所述溶剂(2)为丙酮、乙腈、二氯甲烷、二氧六环、乙酸乙酯、庚烷、异丙醇、甲基乙基酮、甲基叔丁基醚、甲苯、水或以下任一组混合溶剂:丙酮和乙腈、丙酮和二氯甲烷、丙酮和二氧六环、丙酮和乙醇、丙酮和乙酸乙酯、丙酮和庚烷、丙酮和异丙醇、丙酮和甲醇、丙酮和甲基乙基酮、丙酮和甲基叔丁基醚、丙酮和四氢呋喃、丙酮和甲苯、丙酮和水、乙腈和二氯甲烷、乙腈和二氧六环、乙腈和乙醇、乙腈和乙酸乙酯、乙腈和异丙醇、乙腈和甲基乙基酮、乙腈和甲基叔丁基醚、乙腈和四氢呋喃、乙腈和甲苯、二氯甲烷和二氧六环、二氯甲烷和乙醇、二氯甲烷和乙酸乙酯、二氯甲烷和庚烷、二氯甲烷和异丙
醇、二氯甲烷和甲基乙基酮、二氯甲烷和甲基叔丁基醚、二氯甲烷和四氢呋喃、二氯甲烷和甲苯、二氧六环和甲基乙基酮、二氧六环和四氢呋喃、二氧六环和甲苯、乙醇和乙酸乙酯、乙醇和甲醇、乙醇和四氢呋喃、乙醇和甲苯、乙醇和水、乙酸乙酯和庚烷、乙酸乙酯和异丙醇、乙酸乙酯和甲醇、乙酸乙酯和甲基乙基酮、乙酸乙酯和甲基叔丁基醚、乙酸乙酯和甲苯、庚烷和甲基乙基酮、庚烷和甲基叔丁基醚、庚烷和四氢呋喃、庚烷和甲苯、甲醇和甲基乙基酮、甲醇和甲基叔丁基醚、甲醇和甲苯、甲醇和水、甲基乙基酮和甲基叔丁基醚、甲基乙基酮和四氢呋喃、甲基乙基酮和甲苯、甲基叔丁基醚和四氢呋喃、甲基叔丁基醚和甲苯、四氢呋喃和甲苯、四氢呋喃和水。
在一些实施方案中,当所述溶剂(2)为混合溶剂时,两者的体积比为1:3-3:1,优选1:1。
在一些实施方案中,所述挥发析晶时的温度为10-40℃,在非限制性实施方案中可为10℃、20℃、25℃、30℃、35℃、40℃。
在一些实施方案中,所述挥发析晶时的温度为室温。
在一些实施方案中,所述溶剂(1)和(2)所用体积(μl)可以为所述式I所示化合物质量(mg)的1-200倍,在非限制性实施方案中可为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200或任意两数之间的值。
在某些实施方案中,所述的搅拌析晶或挥发析晶之后,还包括过滤、洗涤或干燥步骤。
本公开还提供了一种药物组合物,其包括上述晶型A或由上述制备方法制得的晶型A,和任选地药学上可接受的赋形剂。
本公开还提供了一种上述药物组合物的制备方法,其包括将上述晶型A或由上述方法制备的晶型A与药学上可接受的赋形剂混合的步骤。
本公开还提供了一种上述晶型A或由上述制备方法制得的晶型A或上述药物组合物在制备用于预防和/或治疗与PDE相关的疾病的药物中的用途。在一些实施方案中,所述与PDE相关的疾病为气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病。
本公开还提供了一种上述晶型A或由上述制备方法制得的晶型A或上述药物组合物在制备用于预防和/或治疗气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病的药物中的用途。
本公开所述的“2θ或2θ角度”是指衍射角,θ为布拉格角,单位为°或度;每个特征峰2θ的误差范围为±0.2(包括超过1位小数的数字经过四舍五入后的情况),可以为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、
0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定,
潮解:吸收足量水分形成液体;
极具引湿性:引湿增重不小于15%;
有引湿性:引湿增重小于15%但不小于2%;
略有引湿性:引湿增重小于2%但不小于0.2%;
无或几乎无引湿性:引湿增重小于0.2%。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中,测量样品与参考物之间的温度差、热流差,以表征所有与热效应有关的物理变化和化学变化,得到样品的相变信息。
本公开中所述干燥温度一般为25℃~100℃,优选40℃~70℃,可以常压干燥,也可以减压干燥,压强<-0.08MPa。
本公开中所述的“室温”为25℃±5℃。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开所述的“打浆”是指利用物质在溶剂中溶解性差,但杂质在溶剂中溶解性好的特性进行纯化的方法,打浆提纯可以去色、改变晶型或去除少量杂质。
本公开晶型制备方法中所用的起始原料可以是任意形式化合物,具体形式包括但不限于:无定形、任意晶型、水合物、溶剂合物等。
本公开中数值,例如,有关物质含量测定计算的数据,不可避免存在一定程度的误差。一般而言,±10%均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化,该误差变化不超过±10%,可以为±9%、±8%、±7%、±6%、±5%、±4%、±3%、±2%或±1%,优选±5%。
本公开式I化合物(R)-4-(6-(8-甲氧基-2,2-二甲基苯并二氢吡喃-5-基)吡嗪-2-基)-1,2-氧杂硼杂环戊烷-2-醇(无定型,以下简称化合物I)参照PCT/CN2021/141010中方法制备获得,本文本引用相关内容以示说明。
图1:化合物I无定型的XRPD谱图。
图2:测试例4中各组化合物在疾病模型的临床评分比对图。
图3:测试例4中各组化合物在红斑疾病模型的临床评分比对图。
图4:测试例4中各组化合物在银屑疾病模型的临床评分比对图。
图5:测试例4中各组化合物对皮肤厚度增加的抑制作用比对图。
图6:测试例4中各组化合物对脾脏体重占比影响的比对图。
图7:晶型A的XRPD谱图。
图8:晶型A的DSC谱图。
图9:晶型A的TGA谱图。
图10:晶型A的DVS谱图。
在图1-图6中,*表示同模型组相比p<0.05,**表示同模型组相比p<0.01,***表示同模型组相比p<0.001,▼、●、◆、和#这些符号仅用于区分组别,无实际意义。
以下将结合实施例更详细地说明本公开内容,本公开中的实施例或实验例仅用于说明本公开中的技术方案,并非限定本公开中的实质和范围。
本公开所用到的缩写的解释如下:
XRPD X-射线粉末衍射
DSC 示差扫描量热法
TGA 热重分析
DVS 动态水分吸附
1H-NMR 液态核磁氢谱
DMF N,N-二甲基甲酰胺
MEK 甲基乙基酮
MTBE 甲基叔丁基醚
THF 四氢呋喃
IPA 异丙醇
DCM 二氯甲烷
ACN 乙腈
本公开中实验所用仪器的测试条件:
1、X-射线粉末衍射仪(X-ray Powder Diffraction,XRPD)
仪器型号:Malver Panalytical Aeris X-射线粉末衍射仪
射线:单色Cu-Kα射线(λ=1.54188)
扫描方式:θ/2θ,扫描范围(2θ范围):3.5~50°
电压:40kV,电流:15mA。
2、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号:TA DSC250
吹扫气:氮气;氮气吹扫速度:50mL/min
升温速率:10℃/min
温度范围:25℃-300℃。
3、热重分析仪(Thermogravimetric Analysis,TGA)
仪器型号:TA TGA550
吹扫气:氮气;氮气吹扫速度:20ml/min
升温速率:10℃/min
温度范围:30℃-350℃。
4、动态水分吸附(DVS)
检测采用SMS Intrinsic PLUS,在25℃,湿度从50%-0%-90%,步进为10%,判断标准为每个梯度质量变化dM/dT小于0.0002%,TMAX 360min,循环两圈。
5、本发明晶型A稳定性测试中所述的高效液相色谱法(HPLC)在Agilent 1260 Infinity II上采集,HPLC条件:色谱柱:Agilen XDB C18 5μm 4.6×250mm;流动相:A-0.05%TFA(水中),B-ACN;流速:1.0ml/min;波长:220nm。
6、化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(Methanol-d4),内标为四甲基硅烷(TMS)。
7、化合物I制备实施例中HPLC的测定使用Agilent1100高压液相色谱仪,GAS15B DAD紫外检测器,Water Vbridge C18 150×4.6mm 5μM色谱柱。
8、MS的测定用Agilent6120三重四级杆质谱仪,G1315D DAD检测器,Waters Xbridge C18 4.6×50mm,5μM色谱柱,以正/负离子模式扫描,质量扫描范围为80~1200。
9、制备HPLC条件:水;柱子:Sunfire(Prep C18 OBD 19×250mm 10μm)。
10、手性柱拆分条件:柱子:Chiralpak IG 5μm 30×250mm;流动相:Hex:EtOH=35:65,15mL/min;温度:30℃;波长:254nm。
11、薄层层析硅胶板使用烟台黄海HSGF254硅胶板,薄层色谱法(TLC)使用硅胶板采用规格是0.2mm±0.03mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
12、快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
13、正向柱层析色谱法一般使用烟台黄海硅胶200~300目或300~400目硅胶为载体,或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm,60g,24g,40g,120g或其它规格)。
本公开中的已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
购买自上海泰坦科技、ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、毕得医药等公司。
实施例中无特殊说明,反应能够均在氮气氛下进行。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢气是由上海全浦科学仪器公司QPH-1L型氢气发生仪制得。
氮气氛或氢气氛通常抽真空,充入氮气或氢气,反复操作3次。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂,纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1:化合物I的制备
步骤1):化合物1a(2.0g,14.6mmol)和三乙胺(1.8g,17.8mmol)溶于N,N-二甲基甲酰胺(30mL),溶液冷却至0℃。氮气氛下,将叔丁基二苯基氯硅烷(4.0g,14.6mmol)滴加至反应体系。升至室温继续搅拌至TLC检测反应完成,将反应液倒入水中,乙酸乙酯萃取(100mL×3)。有机相用水洗(50mL×2),无水硫酸钠干燥,浓缩,残余物经硅胶柱层析色谱法纯化(乙酸乙酯/石油醚),得到化合物1b(5.1g),直接用于下一步反应。
步骤2):氮气氛下,将化合物1b(5.1g,13.6mmol)、联硼酸频那醇酯(4.2g,16.3mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(512mg,0.7mmol)、乙酸钾(2.0g,20.4mmol)和二氧六环(100mL)混合物升温至80℃,并且搅拌过夜。将反应液倒入水中,乙酸乙酯萃取(100mL×2)。用水洗涤(30mL×2),无水硫酸钠干燥,浓缩,残余物经硅胶柱层析色谱法纯化(石油醚/乙酸乙酯),得到化合物1c(2.0g),LCMS:m/z 423.2(M+H)+。
步骤3):室温下,向2000mL单口瓶中依次加入化合物a(100g,492mmol)、DMF(1000mL)、碘化钾(92.6g,837mmol)、碘化亚铜(3.13g,9.85mmol)、碳酸钾(136g,985mmol)。氮气氛下,滴加3-氯-3-甲基-1-丁炔(100mL,886mmol)。70℃搅拌16小时。冷却至室温,加入水(1000mL),石油醚(1000mL×3)萃取。无水硫酸钠干燥,过滤。减压浓缩,残余物经柱层析色谱法(石油醚/乙酸乙酯)纯化,得到化合物b(50g)。
1H NMR(400MHz,CDCl3)δ7.57(d,J=2.4Hz,1H),7.15(dd,J=8.8,2.4Hz,1H),6.76(d,J=8.8Hz,1H),3.79(s,3H),2.58(s,1H),1.65(s,6H)。
步骤4):室温下,向500mL单口瓶中依次加入化合物b(20.0g,74.4mmol)、正己烷(200mL)、钯碳酸钙(1.95g,18.8mmol)。氢气氛下,室温搅拌16小时。过滤,减压浓缩,得到化合物c(19g)。
1H NMR(400MHz,CDCl3)δ7.15(d,J=2.4Hz,1H),7.09(dd,J=8.8,2.4Hz,1H),6.73(d,J=8.8Hz,1H),6.12(dd,J=17.6,10.8Hz,1H),5.14(dd,J=20.0,9.2Hz,2H),3.79(s,3H),1.46(s,6H)。
步骤5):室温下,向50mL单口瓶中依次加入化合物c(10.0g,36.9mmol)、二乙基苯胺(10mL,62.5mmol)。210℃搅拌1小时。冷却至室温,用1M HCl溶液调节pH调至中性,乙酸乙酯萃取(200mL×3),水洗(200mL×3)。减压浓缩,得到化合物d(9.1g)。
1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),6.97(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),5.14-5.01(m,1H),3.78(s,3H),3.40(d,J=6.8Hz,2H),1.74(s,3H),1.63(s,3H)。
步骤6):室温下,向100mL单口瓶中依次加入化合物d(5.00g,18.5mmol)、甲苯(25mL)、15(5.00g,15.9mmol)。氮气氛下,100℃搅拌2小时。冷却至室温,过滤。减压浓缩,得到化合物e(3.89g)。
1H NMR(400MHz,DMSO-d6)δ7.04(d,J=8.8Hz,1H),6.75(d,J=8.8Hz,1H),3.71(s,3H),2.63(t,J=6.8Hz,2H),1.78(t,J=6.8Hz,2H),1.26(s,6H)。
步骤7):室温下,向500mL单口瓶中依次加入化合物e(28.4g,105mmol)、二氧六环(300mL)、联硼酸频那醇酯(31.9g,126mmol)、醋酸钾(20.6g,209mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(7.66g,10.5mmol)。氮气氛下,105℃搅拌16时。冷却至室温,过滤。减压浓缩,残余物经柱层析色谱法(石油醚/乙酸乙酯)纯化,得到化合物f(28.4g)。
LCMS:m/z 319(M+H)+。
步骤8):室温下,向250mL单口瓶中依次加入化合物f(6.20g,19.5mmol)、1,4-二氧六环(80mL)、水(16mL)、2,6-二氯吡嗪(2.90g,39.0mmol)、碳酸钾(5.39g,39.0mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(1.43g,1.95mmol)。氮气氛下,110℃搅拌16小时。冷却至室温,过滤。减压浓缩,残余物经柱层析色谱法(石油醚/乙酸乙酯)纯化,得到化合物g(5.7g)。
LCMS:m/z 305(M+H)+。
步骤9):室温下,向100mL单口瓶中加入化合物g(35.0g,115mmol)、化合物1c(44.5g,149mmol)、碳酸钾(23.8g,172mmol)、醋酸钾(16.9g,172mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(8.41g,11.5mmol)于1,4-二氧六环(250mL)与水(5mL)混合溶剂中。搅拌至溶解,氮气置换3次,110℃搅拌16小时。冷却至室温,加水(500mL),乙酸乙酯(300mL×3)萃取,无水硫酸钠干燥。过滤,减压
浓缩,残余物经柱层析色谱法(石油醚/乙酸乙酯)纯化,得到化合物h(37g)。
LCMS:m/z 441.1(M+H)+。
步骤10):室温下,向250mL三口瓶中加入1,2-双(二苯基膦)乙烷(1.81g,4.54mmol)、(1,5-环辛二烯)甲氧基铱(I)二聚体(1.50g,2.27mmol)和无水1,2-二氯乙烷(100mL)。室温搅拌10分钟,加入化合物h(10.0g,22.7mmol)。升温至70℃,滴加频那醇硼烷(20.3g,159mmol)。95℃反应4小时。降温到0℃,滴加甲醇(50mL)淬灭。浓缩,残余物经柱层析色谱法(石油醚/乙酸乙酯)纯化,得到化合物i(1.4g)。
LCMS:m/z 569.3(M+H)+。
步骤11):室温下,在50ml单口瓶中加入化合物i(9.00g,15.8mmol)和四氢呋喃(30mL)。冷却至0℃,加入2M盐酸(50mL)。50℃搅拌16小时。减压浓缩,加入乙酸乙酯(300mL X 3)萃取,无水硫酸钠干燥,过滤。减压浓缩,残余物经反相柱层析色谱法(乙腈/水/三氟乙酸)纯化,得化合物I-A(3.82g)。
利用手性分离(柱子:Chiralpak IG 5μm 30*250mm;流动相:Hex:EtOH=35:65;流速:15mL/min;温度:30℃;波长:254nm),得到化合物I(保留时间较短的)。
化合物I
将化合物I经XRPD测定,结果显示该产物为无定型,其XRPD谱图见图1。
LCMS:m/z 355.0(M+H)+。
1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.48(s,1H),6.98(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),4.29(dd,J=8.8,7.6Hz,1H),3.96(dd,J=8.8,6.8Hz,1H),3.77(s,3H),3.74-3.62(m,1H),2.93-2.67(m,2H),1.68(t,J=6.8Hz,2H),1.38-1.24(m,7H),1.21-1.08(m,1H)。
实施例2:化合物I的晶型A的制备
将10mg化合物I加入到0.2ml溶剂中,如下表1所示,保持化合物在溶剂中成浆,室温(25℃)或50℃搅拌7天,迅速使用滤纸去除溶剂,所得固体经XRPD检测为晶型A。
表1、搅拌析晶制备晶型A选择的溶剂及XRPD检测结果
注:N/A为未检测
实施例3:化合物I的晶型A的制备
将5mg的化合物I加入到溶剂中,如下表2所示。室温下挥发,7天后置于50℃真空干燥箱中去除溶剂,所得固体经XRPD检测为晶型A。
表2、挥发析晶制备晶型A选择的溶剂及XRPD检测结果
实施例3和4所得固体经X-射线粉末衍射检测,将该产物定义为晶型A,XRPD谱图如图7所示,其特征峰位置如表3所示。DSC谱图如图8所示,显示吸热峰峰值140.43℃。TGA谱图如图9所示,显示25℃-100℃失重1.53%。
DVS检测如图10所示,显示在正常储存条件下(即25℃,60%RH),该样品吸湿增重约为0.08%;在加速实验条件(即70%RH),吸湿增重约为0.15%;在极端条件下(即90%RH),吸湿增重约为0.70%。在0%-90%RH湿度变化过程中,该样品的解吸附与吸附过程重合。且DVS检测后复测晶型,XRPD检测显示DVS检测前后晶型未转变。
表3、晶型A的XRPD特征衍射峰数据
实施例4:晶型A的稳定性实验一
测定温度和湿度对式I所示化合物晶型A的稳定性是否有影响。
将晶型A置于稳定箱中,使用一系列温湿度组合条件进行加速稳定性实验。在各个温湿度条件下放置不同天数后取出样品,将所得固体与初始晶型A比较,高效液相色谱法测定式I所示化合物的含量并进行XRPD检测。实验结果如下表4所示。
结果显示晶型A无变化,具有良好的稳定性。
表4、晶型A稳定性实验温/湿度条件、含量及有关物质测定结果
实施例5:晶型A的稳定性实验二
测定光照对式I所示化合物晶型A的稳定性是否有影响。
将晶型A置于光照稳定箱中,达到ICH强度后,取出,将所得固体与初始晶型A比较,高效液相色谱法测定式I所示化合物的含量并进行XRPD检测。实验结果如下表5所示。
表5、晶型A光照稳定性
生物学评价
以下结合测试例进一步描述本公开,但这些测试例并非意味着限制本公开的范围。
化合物A的结构为:
化合物A是采用专利申请“WO2020070651A中说明书第181页的实施例4”公开的方法制备而得的。
测试例1、体外PDE4B酶活性检测实验
1、实验材料
2、实验步骤
先在试管中以90%的DMSO(10%的水)配制浓度为10mM的化合物储备溶液,并用其制备稀释梯度为1:5的系列稀释液,终浓度从100μM开始,低至0.05nM。
将0.2μL化合物溶液转入384孔反应板中,阴性对照和阳性对照均转入0.2μL的100%DMSO。然后向孔中加入10μL的2倍浓度PDE4B1酶溶液(终浓度为0.04nM),对于无酶活对照孔,用10μL的1倍反应缓冲液(50mM HEPES,pH 7.5,0.0015%Brij-35)替代酶溶液。1000rpm离心1min,室温孵育15分钟。接着向384孔反应板每孔中加入10μL的2倍FAM-cAMP底物溶液(底物终浓度为0.1μM),1000rpm离心1min,25℃反应30分钟。反应结束后向384孔反应板每孔中加入
60μL的反应终止液终止反应,室温下摇床600rpm振荡避光孵育60分钟。
孵育结束后读取RLU数据并计算抑制率,根据浓度和抑制率拟合曲线计算出IC50值,其中最大值是指DMSO对照的读值,最小值是指无酶活对照的读值。
本公开的化合物I在体外对PDE4B1酶活性抑制通过以上的试验进行测定,测得的IC50值见表6。
表6
测试例2、化合物对外周血单核细胞(PBMC)促炎细胞因子的释放的抑制作用
解冻冻存的PBMC,台盼蓝染色检测细胞活率和数目。用RPMI1640完全培养基(RPMI1640+10%FBS+1%PS)清洗解冻后的PBMC,离心后弃去上清。用RPMI1640完全培养基重悬PBMC,将细胞密度调至2×106个细胞/mL。铺2×105PBMC细胞于96孔细胞培养板中,加入不同浓度的待测化合物,从化合物最大浓度100μM开始,按照1:5的比例做9个浓度的梯度稀释,双复孔检测。加入终浓度为0.1ng/mL的LPS,总体积为200μL。设置阴性和阳性对照,阴性对照孔内只加LPS和终浓度为DMSO,阳性对照孔内除细胞和LPS之外,还加入1μg/mL的地塞米松作为阳性对照。将细胞于37℃培养箱孵育24小时。孵育完成后,收集100μL细胞培养上清,用ELISA检测TNF-α的水平。向每孔剩余的细胞中加入100μL CellTiter-Glo,检测细胞活力水平。计算化合物抑制TNF-α释放的IC50值。
本公开的化合物I在体外对PBMC促炎细胞因子释放的抑制通过以上的试验进行测定,测得的IC50值见表7。
表7
测试例3、化合物体外抑制人单核细胞分化的DC细胞分泌IL-23实验
第0天:从新鲜人外周血中分离纯化单核细胞并重悬于完全的RPMI-1640培养液内,分化DC细胞时,在培养液内加入浓度为50ng/ml的IL-4和100ng/ml的GM-CSF,以1×106个细胞/mL的密度在直径为100mm的培养皿中进行分化培养,培养箱温度37℃,二氧化碳浓度为5%。第3天:将一半体积的完全RPMI培养液替换为新鲜的完全RPMI培养液,保持IL-4的浓度为50ng/ml,GM-CSF的浓度为100ng/ml。第6天:收集培养皿内未贴壁的细胞(为DC细胞)并用PBS清洗,
清洗后的DC细胞用完全RPMI培养液进行重悬,重悬细胞密为1×106个细胞/mL。然后向96孔细胞培养板中每孔加入1×105个DC细胞,并加入不同浓度梯度的待测化合物(或同等浓度的DMSO空白阴性对照)预处理孵育1小时,而后加入200ug/ml TLR2激动剂酵母聚糖(Zymosan)刺激DC细胞24小时。第7天:酵母聚糖刺激DC细胞24小时后,收集96孔板中各孔的上清,用ELISA检测IL-23的浓度。
本公开的化合物在体外对人单核细胞分化的DC细胞分泌IL-23的抑制通过以上的试验进行测定,测得的IC50值见表8。
表8
测试例4、咪喹莫特诱导的银屑病抑制实验
取适量化合物I配制成下述成分的软膏:0.1%的化合物I,9%的己二醇,78.8%的白凡士林,5%的石蜡,7%的单双硬脂酸甘油酯,0.1%的二羟基丁基甲苯,机械搅拌至软膏。
1)造模和给药
选用7周龄Balb/c雌性小鼠,实验前一天进行背部剃毛,剃毛面积为2cm×3cm。实验第1-7天在皮肤涂抹受试物6小时后,将咪喹莫特(IMQ)软膏(Aldara(5%))连续涂抹于小鼠背部皮肤7天,构建银屑病小鼠模型,对照组给予同等剂量的凡士林软膏。第3、5、7天评估皮肤炎症的严重程度,包括测量皮肤厚度,结痂,红斑情况,采用5分制(0-5)分别进行打分。总评分用于评估皮肤炎症严重程度。实验第7天取脾脏称重,计算脾脏占体重百分比用于评估药物免疫抑制作用程度。
本实验设正常对照组,模型对照组,化合物I的低、中、高剂量组(0.01%,0.03%和0.1%),以及0.03%参比化合物A组。
2)评价指标
皮肤炎症程度的总评分为临床评分,指标相对主观,评分越高代表疾病越严重。皮肤厚度增加程度为客观评价指标,厚度增加越大代表疾病越严重。脾脏占体重比重为客观评价指标,脾脏体重占比越小代表药物免疫抑制作用越强。
3)实验结果
3.1)临床评分
化合物A以及化合物I各剂量在实验终点显著降低了临床评分。(图2-图5)。从单项评分看,化合物I各剂量组主要改善模型银屑结痂情况以及减少皮肤厚度。在皮肤厚度评分中,化合物I低、高剂量组均显著抑制皮肤厚度增加,化合物A
无显著作用。0.03%的化合物I对皮肤厚度增加的抑制作用显著高于相同剂量的化合物A(图5)。结果显示化合物I在改善银屑病表征上显著优于参比化合物A。各具体评分数据见下表9。
表9
3.2)脾脏体重占比
在IMQ作用下,模型组及各给药组动物体重无显著区别,而模型组脾脏占总体积比显著增加(图6),提示脾肿大。化合物A对脾脏体重占比无显著影响,化合物I三个剂量组显著降低脾脏体重占比。提示化合物有免疫抑制作用,且化合物I作用呈量效关系。同剂量下(0.03%),化合物I对脾脏占体重比作用与化合物A有显著差异,结果提示化合物I免疫作用强于化合物A。具体数据见下表10。
表10
Claims (10)
- 一种式I所示化合物的晶型A,其以衍射角2θ角度表示的X-射线粉末衍射图,在7.537°、15.219°、21.798°、22.911°处有特征峰;优选在7.537°、11.366°、14.297°、15.219°、16.190°、17.623°、19.134°、21.798°、22.911°、24.735°处有特征峰;更优选在7.537°、11.366°、14.018°、14.297°、15.219°、16.190°、17.623°、19.134°、21.062°、21.798°、22.911°、24.735°、25.123°、26.884°处有特征峰;进一步优选在7.537°、11.366°、14.018°、14.297°、15.219°、16.190°、17.623°、18.412°、19.134°、20.010°、21.062°、21.798°、22.911°、23.889°、24.735°、25.123°、26.884°、28.343°、29.645°、33.499°、36.362°处有特征峰;更进一步优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示,
- 根据权利要求1所述的晶型A,其中所述2θ角度值误差范围为±0.2°。
- 一种根据权利要求1或2所述的晶型A的制备方法,其为方法一或方法二:方法一包括以下步骤:(a1)将式I所示化合物与溶剂(1)混合;(b1)搅拌析晶;
其中,所述溶剂(1)选自水、硝基甲烷、N,N-二甲基甲酰胺、乙腈、甲醇、乙醇、丙酮、异丙醇、甲基乙基酮、四氢呋喃、1,2-二甲氧基乙烷、氯仿、甲基叔丁基醚、1,2-二甲苯、甲苯、二氧六环和己烷中的一种或多种;方法二包括以下步骤:(a2)将式I所示化合物与溶剂(2)混合;(b2)挥发析晶;其中,所述溶剂(2)选自丙酮、乙腈、二氯甲烷、二氧六环、乙醇、乙酸乙酯、庚烷、异丙醇、甲醇、甲基乙基酮、甲基叔丁基醚、四氢呋喃、甲苯和水中的一种或多种。 - 根据权利要求3所述的制备方法,其中所述溶剂(1)为水、硝基甲烷、N,N-二甲基甲酰胺、乙腈、乙醇、丙酮、异丙醇、甲基乙基酮、四氢呋喃、1,2-二甲氧基乙烷、氯仿、甲基叔丁基醚、1,2-二甲苯、甲苯、二氧六环、己烷、或水和甲醇的混合溶剂。
- 根据权利要求4所述的制备方法,其中当所述溶剂(1)为水和甲醇的混合溶剂时,所述水和所述甲醇的摩尔比为0.37-0.90,优选0.37、0.40、0.47、0.50、0.57、0.60、0.66、0.70、0.74、0.80、0.82、0.90。
- 根据权利要求3所述的制备方法,其中所述溶剂(2)为丙酮、乙腈、二氯甲烷、二氧六环、乙酸乙酯、庚烷、异丙醇、甲基乙基酮、甲基叔丁基醚、甲苯、水或以下任一组混合溶剂:丙酮和乙腈、丙酮和二氯甲烷、丙酮和二氧六环、丙酮和乙醇、丙酮和乙酸乙酯、丙酮和庚烷、丙酮和异丙醇、丙酮和甲醇、丙酮和甲基乙基酮、丙酮和甲基叔丁基醚、丙酮和四氢呋喃、丙酮和甲苯、丙酮和水、乙腈和二氯甲烷、乙腈和二氧六环、乙腈和乙醇、乙腈和乙酸乙酯、乙腈和异丙醇、乙腈和甲基乙基酮、乙腈和甲基叔丁基醚、乙腈和四氢呋喃、乙腈和甲苯、二氯甲烷和二氧六环、二氯甲烷和乙醇、二氯甲烷和乙酸乙酯、二氯甲烷和庚烷、二氯甲烷和异丙醇、二氯甲烷和甲基乙基酮、二氯甲烷和甲基叔丁基醚、二氯甲烷和四氢呋喃、二氯甲烷和甲苯、二氧六环和甲基乙基酮、二氧六环和四氢呋喃、二氧六环和甲苯、乙醇和乙酸乙酯、乙醇和甲醇、乙醇和四氢呋喃、乙醇和甲苯、乙醇和水、乙酸乙酯和庚烷、乙酸乙酯和异丙醇、乙酸乙酯和甲醇、乙酸乙酯和甲基乙基酮、乙酸乙酯和甲基叔丁基醚、乙酸乙酯和甲苯、庚烷和甲基乙基酮、庚烷和甲基叔丁基醚、庚烷和四氢呋喃、庚烷和甲苯、甲醇和甲基乙基酮、甲醇和甲基叔丁基醚、甲醇和甲苯、甲醇和水、甲基乙基酮和甲基叔丁基醚、甲基乙基酮和四氢呋喃、甲基乙基酮和甲苯、甲基叔丁基醚和四氢呋喃、甲基叔丁基醚和甲苯、四氢呋喃和甲苯、四氢呋喃和水;优选地,当所述溶剂(2)为混合溶剂时,两者的体积比为1:3-3:1,优选1:1。
- 一种药物组合物,其包含根据权利要求1或2所述的晶型A或由根据权利要求3至6中任一项所述的制备方法制得的晶型A,和任选地药学上可接受的赋形剂。
- 一种根据权利要求7所述的药物组合物的制备方法,其包括将根据权利要求1或2所述的晶型A或由根据权利要求3至6中任一项所述的制备方法制得的晶型A与药学上可接受的赋形剂混合的步骤。
- 一种根据权利要求1或2所述的晶型A或由根据权利要求3至6中任一项所述的制备方法制得的晶型A或根据权利要求7所述的药物组合物在制备用于预防和/或治疗与PDE相关的疾病的药物中的用途;优选地,所述与PDE相关的疾病为气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病。
- 一种根据权利要求1或2所述的晶型A或由根据权利要求3至6中任一项所述的制备方法制得的晶型A或根据权利要求7所述的药物组合物在制备用于预防和/或治疗气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病的药物中的用途。
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WO2020070651A1 (en) * | 2018-10-05 | 2020-04-09 | Pfizer Inc. | Boron containing pde4 inhibitors |
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WO2022135550A1 (zh) * | 2020-12-25 | 2022-06-30 | 瑞石生物医药有限公司 | 一种硼酸酯衍生物及其用途 |
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WO2019204419A1 (en) * | 2018-04-20 | 2019-10-24 | The Medicines Company (San Diego), Llc | Boronic acid derivatives and therapeutic uses thereof |
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