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WO2017050224A1 - Forme saline et forme cristalline d'un dérivé de quinoléine, procédé de préparation et intermédiaire de celui-ci - Google Patents

Forme saline et forme cristalline d'un dérivé de quinoléine, procédé de préparation et intermédiaire de celui-ci Download PDF

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Publication number
WO2017050224A1
WO2017050224A1 PCT/CN2016/099537 CN2016099537W WO2017050224A1 WO 2017050224 A1 WO2017050224 A1 WO 2017050224A1 CN 2016099537 W CN2016099537 W CN 2016099537W WO 2017050224 A1 WO2017050224 A1 WO 2017050224A1
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Prior art keywords
compound
crystal form
solvent
crystalline form
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/CN2016/099537
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English (en)
Chinese (zh)
Inventor
吴颢
龙超峰
林军
陈小新
廖勇刚
刘卓伟
韦昌青
陈俐娟
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Zhongsheng Pharmaceutical Co Ltd
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Guangdong Zhongsheng Pharmaceutical Co Ltd
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Priority to CN201680054765.0A priority Critical patent/CN108290859B/zh
Publication of WO2017050224A1 publication Critical patent/WO2017050224A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D413/10—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 carbon chain containing aromatic rings

Definitions

  • the present invention relates to a crystalline form, a salt form, a salt form of a quinoline derivative, and a process for the preparation thereof.
  • the Hedgehog protein was originally a secreted signaling protein found in Drosophila, a highly hydrophobic protein that plays a crucial role in embryonic development.
  • Three homologous hedgehog proteins have been identified in humans, namely Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh).
  • Shh is not only important in embryonic development, but also has many evidences that it plays an important role in the carcinogenic mechanisms of some cancers including basal cell carcinoma (Caro, I. and Jalow, Clin Cancer Res, 2010. 16(13): 3335 -9).
  • Shh synthesizes a 45kDa precursor protein in vivo and produces a 20kDa N-terminal fragment by self-resection.
  • This N-terminal fragment has all the biological activities known in the body, including activation of intracellular hedgehog information pathway.
  • the major members of the pathway include patched (PTCH), G-like protein and receptor oncogene smoothened (SMO), and transcription factor Gli (Bale, AE and KPYu, Hum Mol Genet, 2001.10(7): 757-62) .
  • PTCH-1 is a membrane protein with 12 transmembrane structures that is a direct acting receptor for Shh.
  • PTCH-1 In the absence of Shh, PTCH-1 interacts with SMO, which is a 7-transmembrane structural protein that inhibits the biological viability of SMO.
  • SMO which is a 7-transmembrane structural protein that inhibits the biological viability of SMO.
  • the combination of Shh and PTCH-1 causes PTCH-1 to detach from SMO, freeing SMO from the suppressed state.
  • the Gli transcription factor is controlled by SMO, which acts as a switch for gene transcription, with the major members including Glil, Gli2 and Gli3.
  • the entire hedgehog pathway plays an important role in the normal development of the embryo. Disturbing this information pathway will lead to severe malformations, such as the natural teratogenic compound cyclopamine is a hedgehog inhibitor. Under normal conditions, the concentration of hedgehog protein in adults is very low.
  • PTCH-1 In the case of a low concentration of hedgehog protein, PTCH-1 binds to SMO and inhibits its biological activity, so the entire pathway is in an inactive or low-activity state.
  • the binding of the hedgehog protein to the PTCH-1 receptor causes it to detach from the SMO, thereby losing the inhibition of SMO.
  • SMO further activates the transcription factor Gli-1 to regulate gene transcription and cell growth.
  • the cause of most basal cell carcinomas is the excessive activity of the hedgehog signaling pathway due to mutations or other causes. Therefore, the activity of the excessively high hedgehog information transduction pathway is inhibited, and the growth of cancer cells can be inhibited to achieve treatment of basal cell carcinoma or other cancers caused by the same mechanism.
  • SMO inhibitors already exist in the prior art, they need to be improved in terms of activity, solubility, pharmacokinetics, drug-forming properties and the like.
  • CN201410110890.1 describes a new class of quinoline derivatives which act as inhibitors of the hedgehog pathway, particularly as SMO inhibitors. It can be used to treat conditions related to the hedgehog pathway including cancer.
  • the present invention provides Form A of Compound 1, the XRPD pattern of which is shown in Figure 1.
  • the A crystal form XRPD analytical data is shown in Table 1.
  • the A crystalline form of Compound 1 above has a differential scanning calorimetry curve having an end point of endothermic peak at 111.41 °C ⁇ 2 °C, 126.08 °C ⁇ 2 °C, and 146.06 °C ⁇ 2 °C.
  • the A crystal form of the above compound 1 has a DSC pattern as shown in FIG.
  • the A crystal form of the above compound 1 has a thermogravimetric analysis curve weight loss of 0.7658% ⁇ 0.2% at 135.65 ⁇ 2 °C.
  • the T crystal of Form A of Compound 1 above is shown in Figure 3.
  • the present invention also provides Form B of Compound 1, the XRPD pattern of which is shown in Figure 4.
  • the B-form XRPD analytical data is shown in Table 2.
  • the B crystal form of Compound 1 above has a differential scanning calorimetry curve having a starting point of endothermic peak at 165.73 °C ⁇ 2 °C.
  • the B crystal form of the above Compound 1 has a DSC pattern as shown in FIG.
  • the B crystal form of the above compound 1 has a thermogravimetric analysis curve having a weight loss of 0.2383% ⁇ 0.2% at 120.00 ⁇ 2 ° C and a loss of 0.2005% ⁇ 0.2% at 247.60 ⁇ 2 ° C.
  • the T crystal of Form B of Compound 1 above is shown in Figure 6.
  • the invention also provides a preparation method of the B crystal form, which comprises adding the crystal form of the compound A to the solvent of the ester solvent, the solvent of the alcohol or the solvent of the ester and the solvent of the alcohol solvent, heating to reflux to dissolve, and then slowly Cooled and crystallized.
  • the ester is dissolved in the group consisting of propyl formate, isopropyl formate, butyl formate, isobutyl formate, ethyl acetate, isopropyl acetate, and isopropyl acetate.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol.
  • the volume ratio of the ester solvent to the alcohol solvent is from 0.1:1 to 12.
  • the volume ratio of the ester solvent to the alcohol solvent is 1:2 to 8.
  • the present invention provides a compound 2 of the following formula,
  • the present invention provides a crystalline form C of Compound 2, the XRPD pattern of which is shown in FIG.
  • the C-form XRPD pattern analysis data is shown in Table 3.
  • the C crystal form of Compound 2 above has a differential scanning calorimetry curve having an end point of endothermic peak at 57.33 ° C ⁇ 5 ° C and 212.56 ° C ⁇ 5 ° C.
  • the C crystal form of the above Compound 2 has a DSC spectrum as shown in FIG.
  • the C crystal form of the above compound 2 has a thermogravimetric analysis curve having a weight loss of 5.10% ⁇ 0.5% at 120.00 ⁇ 3 °C.
  • the C crystal form of the above compound 2 has a TGA pattern as shown in FIG.
  • the invention provides a preparation method of the C crystal form, which comprises the compound 1 dissolved in an organic solvent, slowly adding a sulfuric acid aqueous solution, and stirring and crystallization.
  • the organic solvent is selected from the group consisting of acetone, methyl ethyl ketone, and cyclohexanone.
  • the molar ratio of Compound 1 to sulfuric acid is selected from 1:2 to 4.
  • the invention also provides the use of the above A crystal form, B crystal form, compound 2 and C crystal form in the preparation of a medicament for treating diseases related to SMO receptors.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • DCM dichloromethane
  • PE petroleum ether
  • EA ethyl acetate
  • DMF N,N-dimethylformamide
  • DMAC N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • EtOAc ethyl acetate
  • tol stands for toluene
  • THF tetrahydrofuran
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • NMP stands for N-methylpyrrolidone
  • 2-METHF stands for 2-methyltetrahydrofuran
  • Bn stands for benzyl
  • Cbz stands for benzyloxycarbonyl and is an amine protecting group
  • Boc stands for t-butylcarbonyl which is an amine protecting group
  • Fmoc fluorenylmethoxycarbonyl and is an amine a protecting group
  • XRPD X-ray powder diffractometer
  • Tube voltage 40kV
  • tube current 40mA
  • DSC Differential Scanning Calorimeter
  • Test conditions The sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing at 25 ° C - 350 ° C and a heating rate of 10 ° C / min.
  • TGA Thermal Gravimetric Analyzer
  • Test conditions Samples (2 to 5 mg) were placed in a TGA platinum pot for testing at room temperature - 350 ° C and a heating rate of 10 ° C / min.
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A.
  • Figure 2 is a DSC pattern of Form A.
  • Figure 3 is a TGA pattern of Form A.
  • Figure 4 is an XRPD spectrum of Cu-K ⁇ radiation of Form B.
  • Figure 5 is a DSC pattern of Form B.
  • Figure 6 is a TGA pattern of Form B.
  • Figure 7 is an XRPD spectrum of Cu-K ⁇ radiation of Form C.
  • Figure 8 is a DSC pattern of Form C.
  • Figure 9 is a TGA pattern of Form C.
  • the third step 8-bromo-4-hydroxyquinoline (2 kg, 8.93 mol), (4-cyanophenyl)boronic acid (1.31 kg, 8.93 mol), Pd(dppf)Cl 2 (130.68 g, 178.60 m
  • tetrahydrofuran 10 L
  • DMF 2 L
  • water 2 L
  • the mixture was heated to 78 °C. After 3 hours, 4 liters of water was added and the mixture was filtered.
  • Step 4 In a 30 L reactor, add DMF (10 L) and 4-(4-hydroxyquinolin-8-yl)benzonitrile (2.2 kg, 8.93 mol), stir at room temperature, then slowly in 5 minutes. NIS (2.01 kg, 8.93 mol) was added. After half an hour, the samples were detected by LCMS and the reaction was completed. Add 20 L of ice water and stir and filter. The solid was washed with water (5 L x 3). The product was dried in a vacuum oven at 50 ° C for three days to give 4-(4-hydroxy-3-iodo-8-quinolinyl)benzonitrile (2.55 kg, yield 76.73%) as a yellow solid.
  • Step 6 4-(4-Bromo-3-iodo-8-quinoline)benzonitrile (3.5 kg, 8.04 mol), (2S,6R)-2,6-dimethyl-4-(5(5) 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]morpholine (3.07 kg, 9.65 mol) in tetrahydrofuran (30.00 L) Heat to 65 ° C. After all the reactants were dissolved, add Na 2 CO 3 (1.70 kg, 16.08 mol) and Pd (dppf) Cl 2 (294.14 g, 402.00 mmol, 0.05 eq), then add DMF (5 L) and water (L). 4) mixture.
  • Step 7 4-(4-Bromo-3-(6-((2S,6R)-2,6-dimethylmorphinolin-4-yl)-3-pyridyl)-8-quinoline)
  • the benzonitrile (2.68 kg, 5.37 mol) solvent was heated to 60 ° C in toluene (25 L) to be completely dissolved.
  • the free base compound 1 (1.19 kg, 2.58 mol, 1 eq.) was dissolved in acetone (12 L), sulfuric acid (3M, 1.72 liters, 2 eq) was slowly added for about 30 minutes, and then the mixture was stirred at 25 ° C for 1.5 hours. The mixture was filtered, dried and dried under vacuum at 35 ° C.
  • the target product salt (1.56 kg, yield 92.07%) in 48 hours was a yellow solid, which was crystal form.
  • the prepared samples were placed at 60 ° C, 92.5% RH (relative humidity), 25 ° C / 60% RH and 40 ° C / 75% RH, respectively, and the physical stability of the samples was examined for 10 days. On day 10, all samples were taken, returned to room temperature, the appearance change of the samples was observed, and the crystal form of the samples was examined by XRPD. The solid physical stability of the C crystal form was judged by comparison with the crystal form of the 0 day sample. Table 8 shows the results of solid physical stability experiments of Form C.
  • the luciferase (Gli-Luc) reporter gene with Gli response element was stably transfected into C3H10T1/2 cells, and the expression of Hedgehog signaling pathway inhibitor was determined by detecting the expression of intracellular reporter gene under Shh-N stimulation conditions. active.
  • the IC50 value of the compound was used as an indicator to evaluate the inhibitory effect of the compound on the Hedgehog signaling pathway.
  • C3H10T1/2/Gli-Luc cell culture medium (DMEM/high glucose HyClone, #SH30022.01B; 10% serum Hyclone, #SV30087;
  • the logarithmic growth phase C3H10T1/2/Gli-Luc cells were plated in a 96-well plate at 20,000 cells per well, and the cells were cultured overnight at 37 ° C in a 5% CO 2 incubator. On the next day, the compounds were diluted as follows: the positive compound GDC0449 (1 mM) and the test compound (1 mM) were serially diluted to a concentration of 7 compounds in DMSO at 1:3 and 1:10, respectively, and the 8th was DMSO. Control, and then diluted 100 times with fresh medium.
  • the cells were cultured overnight, the medium was removed, 80 ⁇ L of fresh medium was added to each well, and then 20 ⁇ L of the gradient-diluted positive compound and the test compound were added, and 100 ⁇ L of conditioned medium containing 30 nM Shh-N, 2 for each concentration.
  • Double wells, set both positive and negative reference wells ie Shh Ctrl: 80 ⁇ L fresh medium + 20 ⁇ L containing 1% DMSO medium + 100 ⁇ L conditioned medium containing 30 nM Shh-N; Unstimulated Ctrl: 180 ⁇ L fresh medium + 20 ⁇ L containing 1
  • the cells were cultured for 24 hours in a CO 2 incubator.
  • luciferase activity 96-well plate cells were removed, the medium was discarded, and the cells were washed twice with PBS, followed by addition of 20 ⁇ L of lysate (Promega E1531) per well, and cleavage at room temperature for 30 min. Transfer 5 ⁇ L of cell lysate to a 384-well plate (Greiner 781074), then add 25 ⁇ L of luciferase reaction solution (Promega E1501) to each well, and mix it immediately into the VarioSkan Flash multi-reader to read the relative light unit. (RLU) value.
  • RLU relative light unit.

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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une forme cristalline et une forme saline d'un dérivé de quinoléine, une forme cristalline de la forme saline, et un procédé de préparation associé.
PCT/CN2016/099537 2015-09-21 2016-09-21 Forme saline et forme cristalline d'un dérivé de quinoléine, procédé de préparation et intermédiaire de celui-ci Ceased WO2017050224A1 (fr)

Priority Applications (1)

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CN201680054765.0A CN108290859B (zh) 2015-09-21 2016-09-21 喹啉衍生物的盐型、晶型及其制备方法和中间体

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CN201510605455.0 2015-09-21
CN201510605455 2015-09-21

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WO2017050224A1 true WO2017050224A1 (fr) 2017-03-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021190337A1 (fr) * 2020-03-27 2021-09-30 广东众生药业股份有限公司 Forme de sel et forme cristalline d'un composé en tant qu'inhibiteur de smo, et procédé de préparation associé

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104470902A (zh) * 2012-07-19 2015-03-25 南京英派药业有限公司 N-(3-杂芳基芳基)-4-芳基芳基甲酰胺和类似物作为Hedgehog通路抑制剂及其应用
CN104945377A (zh) * 2014-03-24 2015-09-30 南京明德新药研发股份有限公司 作为smo抑制剂的喹啉衍生物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160058972A (ko) * 2004-09-02 2016-05-25 제넨테크, 인크. 헤지호그 신호전달에 대한 피리딜 억제제

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104470902A (zh) * 2012-07-19 2015-03-25 南京英派药业有限公司 N-(3-杂芳基芳基)-4-芳基芳基甲酰胺和类似物作为Hedgehog通路抑制剂及其应用
CN104945377A (zh) * 2014-03-24 2015-09-30 南京明德新药研发股份有限公司 作为smo抑制剂的喹啉衍生物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021190337A1 (fr) * 2020-03-27 2021-09-30 广东众生药业股份有限公司 Forme de sel et forme cristalline d'un composé en tant qu'inhibiteur de smo, et procédé de préparation associé
CN115298172A (zh) * 2020-03-27 2022-11-04 广东众生药业股份有限公司 一种作为smo抑制剂化合物的盐型、晶型及其制备方法
CN115298172B (zh) * 2020-03-27 2023-11-14 广东众生药业股份有限公司 一种作为smo抑制剂化合物的盐型、晶型及其制备方法

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TWI694999B (zh) 2020-06-01
TW201718564A (zh) 2017-06-01
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