WO2023143112A1 - Salt form and crystal form of azabenzo eight-membered ring compound and application thereof - Google Patents

Salt form and crystal form of azabenzo eight-membered ring compound and application thereof Download PDF

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WO2023143112A1
WO2023143112A1 PCT/CN2023/072025 CN2023072025W WO2023143112A1 WO 2023143112 A1 WO2023143112 A1 WO 2023143112A1 CN 2023072025 W CN2023072025 W CN 2023072025W WO 2023143112 A1 WO2023143112 A1 WO 2023143112A1
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crystal form
angles
ray powder
following
diffraction pattern
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Chinese (zh)
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周建光
李不鱼
丁施敏
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无锡瓴方生物医药科技有限公司
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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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to the field of medicine, in particular to the methanesulfonate, hydrochloride or fumarate of azabenzo eight-membered ring compounds, and the crystal forms of the salts.
  • Chemokines are a family of small, secreted pro-inflammatory cytokines that act as leukocyte chemoattractants. They facilitate the transport of leukocytes from vascular beds to surrounding tissues in response to inflammatory signals. Chemotaxis is initiated upon binding of chemokines to receptors (GPCRs) by initiating signals involving increased calcium flux, inhibition of cyclic AMP production, rearrangements of the cytoskeleton, activation of integrins, and cellular motility processes transduction pathways and increased expression of adhesion proteins.
  • GPCRs chemokines to receptors
  • Cytokines are relatively small proteins (8-10 kD) that stimulate the migration of cells.
  • the chemokine family is divided into four subfamilies based on the number of amino acid residues between the first and second highly conserved cysteines.
  • Monocyte chemoattractant protein-1 MCP-1
  • MCP-1 is a member of the CC chemokine subfamily (where CC stands for the subfamily with adjacent first and second cysteines) and binds cell surface chemokines receptor 2 (CCR2).
  • MCP-1 is a potent chemokine that, upon binding to CCR2, mediates the migration of monocytes and lymphocytes to sites of inflammation (ie, chemotaxis).
  • MCP-1 is also expressed by cardiomyocytes, vascular endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, glomerular mesangial cells, alveolar cells, T lymphocytes, esophageal carcinoma, etc.
  • monocytes After entering inflamed tissues, monocytes differentiate into CCR5-expressing macrophages, which provide a secondary source of several pro-inflammatory regulators, including tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 (IL-1 ), IL-8CXC chemokine subfamily, where CXC represents an amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (such as PGE 2 and LTB 4) , oxygen-derived free radicals, matrix metalloproteinases and complement components.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-1 interleukin-1
  • IL-8CXC chemokine subfamily where CXC represents an amino acid residue between the first and second cysteines
  • IL-12 arachidonic acid metabolites
  • oxygen-derived free radicals such as PGE 2 and LTB 4
  • CCR2 (also known as CKR-2, MCP-1RA or MCIRB) is predominantly expressed on monocytes and macrophages and is essential for macrophage-dependent inflammation.
  • CCR2 is a G protein-coupled receptor (GPCR) that binds with high affinity to several members of the chemokine MCP family (CCL2, CCL7, CCL8, etc.), triggering chemotactic signals that lead to migration of directed receptor-carrying cells.
  • GPCR G protein-coupled receptor
  • CCR5 is a G protein-coupled receptor that binds several CC chemokine ligands, including CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL11 and CCL13.
  • the in vivo function of CCR5 is less clear than that of CCR2.
  • CCR5 In contrast to CCR2, CCR5 is predominantly expressed in activated Th1 cells and tissue macrophages differentiated from blood monocytes, which concomitantly downregulates CCR2 expression.
  • CCR5 has been shown to contribute to the survival of macrophages during inflammation and infection, and may also function to retain macrophages within inflamed tissues. Furthermore, CCR5 mediates the recruitment and activation of Th1 cells in inflammation.
  • CCR5 is also expressed on osteoclasts and is important for osteoclastogenesis, suggesting a contributing role for CCR5 in the pathology of rheumatoid arthritis.
  • Activation of vascular smooth cells through CCL4/CCR5 involvement may also contribute to the pathology of atherosclerosis and AIH (accelerated intimal hyperplasia).
  • CCR2/5 dual antagonists At present, there are few types of CCR2/5 dual antagonists. At the same time, studies have shown that different drug crystal forms will directly affect the blood drug concentration in the body and the degree of toxic and side effects. In view of this, the present invention studies the salt form, crystal form and application of the azabenzo eight-membered ring compound.
  • the present invention specifically discloses crystal forms A, B, C and D of methanesulfonate, hydrochloride or fumarate of compound 1 and applications thereof.
  • the present invention provides the methanesulfonate, hydrochloride or fumarate of compound 1,
  • the above-mentioned pharmaceutically acceptable salts are methanesulfonate salts shown in formula (I), hydrochloride salts shown in formula (II) or fumarate salts shown in formula (III) ,
  • the present invention also provides the A crystal form of the compound of formula (I),
  • X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.536 ⁇ 0.200°, 17.608 ⁇ 0.200°, 21.702 ⁇ 0.200°.
  • X-ray powder diffraction adopts Cu-k ⁇ radiation, the same below.
  • its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.536 ⁇ 0.200°, 15.382 ⁇ 0.200°, 17.608 ⁇ 0.200°, 20.401 ⁇ 0.200°, 21.702 ⁇ 0.200°, 23.326 ⁇ 0.200°, 27.143 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.536 ⁇ 0.200°, 15.382 ⁇ 0.200°, 16.949 ⁇ 0.200°, 17.608 ⁇ 0.200°, 18.628 ⁇ 0.200°, 20.401 ⁇ 0.200°, 21.702 ⁇ 0.200°, 23.326 ⁇ 0.200°, 27.143 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.536 ⁇ 0.200°, 15.382 ⁇ 0.200°, 16.949 ⁇ 0.200°, 17.608 ⁇ 0.200°, 18.628 ⁇ 0.200°, 20.401 ⁇ 0.200°, 21.066 ⁇ 0.200°, 21.702 ⁇ 0.200°, 23.326 ⁇ 0.200°, 23.956 ⁇ 0.200°, 27.143 ⁇ 0.200°.
  • the ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.536 ⁇ 0.200°, 10.096 ⁇ 0.200°, 14.412 ⁇ 0.200°, 15.382 ⁇ 0.200°, 16.949 ⁇ 0.200 °, 17.608 ⁇ 0.200°, 18.628 ⁇ 0.200°, 19.520 ⁇ 0.200°, 20.401 ⁇ 0.200°, 21.066 ⁇ 0.200°, 21.702 ⁇ 0.200°, 22.347 ⁇ 0.200°, 23.326 ⁇ 0.200°, 23.956 ⁇ 0.200°, 25.000 ⁇ 0.200 °, 27.143 ⁇ 0.200°.
  • the ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.536°, 10.096°, 10.763°, 13.126°, 13.586°, 14.412°, 15.382°, 16.009° , 16.949°, 17.608°, 17.984°, 18.628°, 19.520°, 20.401°, 21.066°, 21.702°, 22.347°, 23.326°, 23.956°, 25.000°, 26.648°, 27.143°, 27.942°, 28.520°, 29.350 °, 30.752°, 31.429°, 34.439°, 35.134°.
  • the present invention also provides the above crystal form A, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles and also includes 17.608 ⁇ 0.200°, 9.536 ⁇ 0.200°, and/or 21.702 ⁇ 0.200°, 20.401 ⁇ 0.200°, and/or 23.326 ⁇ 0.200°, and/or 15.382 ⁇ 0.200°, and/or 27.143 ⁇ 0.200°, and/or 18.628 ⁇ 0.200°, and/or 23.956 ⁇ 0.200°, and/or 16.949 ⁇ 0.200°, and/or or 21.066 ⁇ 0.200°, and/or 22.347 ⁇ 0.200°, and/or 25.000 ⁇ 0.200°, and/or 19.520 ⁇ 0.200°, and/or 10.096 ⁇ 0.200°, and/or 13.126 ⁇ 0.200°, and/or 31.429 ⁇ 0.200°, and/or 16.009 ⁇ 0.200°, and/or 28.520 ⁇ 0.200°, and/or 25.526 ⁇ 0.200°, and/or 29
  • the XRPD pattern of the above crystal form A is shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 164.38°C ⁇ 3.0°C.
  • the DSC spectrum of the above crystal form A is shown in FIG. 2 .
  • the weight loss of the thermogravimetric analysis curve of the above crystal form A is 0.588% at 150.0°C ⁇ 3.0°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 3 .
  • the preparation method of crystal form A includes: dissolving compound 1 in a mixed solvent of EtOAc and MeCN under heating conditions, adding CH 3 SO 3 H, cooling down, and crystallizing.
  • the present invention also provides the B crystal form of the compound of formula (I),
  • Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.660 ⁇ 0.200°, 16.740 ⁇ 0.200°, 22.020 ⁇ 0.200°.
  • its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.660 ⁇ 0.200°, 16.740 ⁇ 0.200°, 17.970 ⁇ 0.200°, 18.620 ⁇ 0.200°, 20.890 ⁇ 0.200°, 22.020 ⁇ 0.200°, 23.270 ⁇ 0.200°, 24.380 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.660 ⁇ 0.200°, 9.220 ⁇ 0.200°, 16.740 ⁇ 0.200°, 17.970 ⁇ 0.200°, 18.620 ⁇ 0.200°, 20.890 ⁇ 0.200°, 22.020 ⁇ 0.200°, 22.740 ⁇ 0.200°, 23.270 ⁇ 0.200°, 24.380 ⁇ 0.200°, 26.930 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.660 ⁇ 0.200°, 9.220 ⁇ 0.200°, 14.570 ⁇ 0.200°, 16.740 ⁇ 0.200°, 17.970 ⁇ 0.200°, 18.620 ⁇ 0.200°, 20.890 ⁇ 0.200°, 22.020 ⁇ 0.200°, 22.740 ⁇ 0.200°, 23.270 ⁇ 0.200°, 24.380 ⁇ 0.200°, 26.930 ⁇ 0.200°.
  • the ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.660°, 5.240°, 9.220°, 10.450°, 11.650°, 14.570°, 15.670°, 16.740° , 17.970°, 18.620°, 19.880°, 20.890°, 21.310°, 22.020°, 22.740°, 23.040°, 23.270°, 24.380°, 25.220°, 25.780°, 26.930°.
  • the present invention also provides the above crystal form B, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles and also includes 18.620 ⁇ 0.200°, 4.660 ⁇ 0.200°, and/or 16.740 ⁇ 0.200°, and/or 23.270 ⁇ 0.200°, and/or 24.380 ⁇ 0.200°, and/or 22.020 ⁇ 0.200°, and/or 20.890 ⁇ 0.200°, and/or 9.220 ⁇ 0.200°, and/or 26.930 ⁇ 0.200°, and/or 14.570 ⁇ 0.200° , and/or 22.740 ⁇ 0.200°, and/or 11.650 ⁇ 0.200°, and/or 21.310 ⁇ 0.200°, and/or 15.670 ⁇ 0.200°, and/or 10.450 ⁇ 0.200°, and/or 25.220 ⁇ 0.200°, and /or 19.880 ⁇ 0.200°, and/or 5.240 ⁇ 0.200°, and/or 25.780 ⁇ 0.200°.
  • the XRPD spectrum of the above crystal form B is shown in FIG. 4 .
  • the differential scanning calorimetry curve of the above crystal form B has an endothermic peak at 166.7°C ⁇ 3.0°C.
  • the DSC spectrum of the above crystal form B is shown in FIG. 5 .
  • the weight loss of the thermogravimetric analysis curve of the above crystal form B is 0.25% at 130.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form B is shown in FIG. 6 .
  • the preparation method of crystal form B comprises: dissolving compound 1 in a mixed solvent of EtOAc and IPA under heating conditions, adding CH 3 SO 3 H, cooling down, and crystallizing.
  • the present invention also provides the C crystal form of the compound of formula (II),
  • Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 16.700 ⁇ 0.200°, 20.150 ⁇ 0.200°, 24.720 ⁇ 0.200°.
  • its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.380 ⁇ 0.200°, 16.700 ⁇ 0.200°, 18.640 ⁇ 0.200°, 19.580 ⁇ 0.200°, 23.520 ⁇ 0.200°, 24.720 ⁇ 0.200°, 24.720 ⁇ 0.200°, 26.090 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 12.380 ⁇ 0.200°, 15.350 ⁇ 0.200°, 16.700 ⁇ 0.200°, 18.640 ⁇ 0.200°, 19.580 ⁇ 0.200°, 21.310 ⁇ 0.200°, 23.520 ⁇ 0.200°, 24.720 ⁇ 0.200°, 24.720 ⁇ 0.200°, 26.090 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 7.980 ⁇ 0.200°, 12.380 ⁇ 0.200°, 15.350 ⁇ 0.200°, 16.700 ⁇ 0.200°, 18.640 ⁇ 0.200°, 19.580 ⁇ 0.200°, 19.990 ⁇ 0.200°, 20.150 ⁇ 0.200°, 21.310 ⁇ 0.200°, 23.520 ⁇ 0.200°, 24.720 ⁇ 0.200°, 26.090 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 6.760°, 7.980°, 10.140°, 11.180°, 12.380°, 13.050°, 15.350°, 16.450 °, 16.700°, 17.050°, 18.640°, 19.110°, 19.580°, 19.990°, 20.150°, 21.310°, 22.980°, 23.520°, 23.710°, 24.720°, 26.090°, 26.330°, 27.380° .
  • the present invention also provides the above crystal form C, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles and also includes 24.720 ⁇ 0.200°, 20.150 ⁇ 0.200°, and/or 16.700 ⁇ 0.200°, and/or 23.520 ⁇ 0.200°, and/or 19.990 ⁇ 0.200°, and/or 19.580 ⁇ 0.200°, and/or 18.640 ⁇ 0.200°, and/or 12.380 ⁇ 0.200°, and/or 26.090 ⁇ 0.200°, and/or 21.310 ⁇ 0.200° , and/or 15.350 ⁇ 0.200°, and/or 7.980 ⁇ 0.200°, and/or 22.980 ⁇ 0.200°, and/or 19.110 ⁇ 0.200°, and/or 11.180 ⁇ 0.200°, and/or 6.760 ⁇ 0.200°, and /or 13.050 ⁇ 0.200°, and/or 27.380 ⁇ 0.200°, and/or 10.140 ⁇ 0.200°.
  • the XRPD spectrum of the above crystal form C is shown in FIG. 7 .
  • the differential scanning calorimetry curve of the above crystal form C has an endothermic peak at 153.3°C ⁇ 3.0°C.
  • the DSC spectrum of the above crystal form C is shown in FIG. 8 .
  • the weight loss of the thermogravimetric analysis curve of the above crystal form C is 4.89% at 130.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form C is shown in FIG. 9 .
  • the preparation method of crystal form C comprises: dissolving compound 1 in MeCN, adding HCl/dioxane, stirring and reacting under heating conditions, cooling down and crystallizing.
  • the present invention also provides the D crystal form of the compound of formula (III),
  • Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.420° ⁇ 0.200°, 17.680 ⁇ 0.200°, 22.693 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.420° ⁇ 0.200°, 12.989 ⁇ 0.200°, 17.680 ⁇ 0.200°, 18.236 ⁇ 0.200°, 18.866 ⁇ 0.200°, 19.195 ⁇ 0.200°, 22.693 ⁇ 0.200°, 25.237 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.420° ⁇ 0.200°, 12.989 ⁇ 0.200°, 15.124 ⁇ 0.200°, 16.486 ⁇ 0.200°, 17.680 ⁇ 0.200°, 18.236 ⁇ 0.200°, 18.866 ⁇ 0.200°, 19.195 ⁇ 0.200°, 20.491 ⁇ 0.200°, 21.505 ⁇ 0.200°, 22.693 ⁇ 0.200°, 25.237 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.420°, 6.199°, 8.651°, 11.334°, 12.344°, 12.989°, 13.705°, 15.124 °, 15.699°, 16.486°, 17.680°, 18.236°, 18.866°, 19.195°, 20.491°, 21.505°, 22.693°, 24.100°, 25.237°, 30.453°.
  • the present invention also provides the above crystal form D, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles and also includes 4.420° ⁇ 0.200°, 22.693 ⁇ 0.200°, and/or 17.680 ⁇ 0.200°, and/or 19.195 ⁇ 0.200°, and/or 25.237 ⁇ 0.200°, and/or 12.989 ⁇ 0.200°, and/or 18.236 ⁇ 0.200°, and/or 16.486 ⁇ 0.200°, and/or 20.491 ⁇ 0.200°, and/or 15.124 ⁇ 0.200 °, and/or 21.505 ⁇ 0.200°, and/or 13.705 ⁇ 0.200°, and/or 24.100 ⁇ 0.200°, and/or 12.344 ⁇ 0.200°, and/or 15.699 ⁇ 0.200°, and/or 6.199 ⁇ 0.200°, And/or 30.453 ⁇ 0.200°, and/or 11.334 ⁇ 0.200°, and/or 8.651 ⁇ 0.200°.
  • the XRPD pattern of the above crystal form D is shown in FIG. 10 .
  • the differential scanning calorimetry curve of the above crystal form D has an endothermic peak at 160.35°C ⁇ 3.0°C.
  • the DSC spectrum of the above crystal form D is shown in FIG. 11 .
  • the weight loss of the thermogravimetric analysis curve of the above crystal form D is 0.3823% at 121.75°C ⁇ 3.0°C.
  • the TGA spectrum of the above crystal form D is shown in FIG. 12 .
  • the preparation method of D crystal form comprises: dissolving compound 1 in EtOAc, adding fumaric acid under heating conditions, keeping the temperature for reaction after adding, cooling down and crystallizing.
  • the "lower temperature” in the present invention means that the solubility is reduced by lowering the temperature, but the crystals are precipitated. In the present invention, it is generally selected to reduce to 20-30°C.
  • the present invention also provides the application of A crystal form, B crystal form, C crystal form or D crystal form in the preparation of drugs for treating advanced solid tumors and lymphomas and CCR2/5 dual antagonists.
  • Antagonists upon binding to a receptor, block the agonist-mediated action of that receptor.
  • crystal form A, crystal form B of the compound of formula (I), crystal form C of the compound of formula (II), and crystal form D of the compound of formula (III) provided by the present invention have stable properties, good solubility, poor hygroscopicity, and have Good drug prospects.
  • each crystal form of the present invention is simple, does not require harsh conditions and highly toxic solvents, has high crystal purity and good yield, and is beneficial to industrial scale-up.
  • the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the CCR2/5 antagonist BMS-813160 was selected as the reference compound, which has been used in the development and treatment of liver cancer, pancreatic cancer, non-small cell lung cancer, colorectal cancer and other cancers, and is currently in the second phase of clinical development. Its structure is as follows:
  • IPA isopropanol
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Light tube voltage 30kV
  • light tube current 40mA
  • Step size 0.5 seconds
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 , heat the sample from 30°C to 300°C (or 350°C) at a heating rate of 10°C/min.
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 , at a heating rate of 10°C/min, heat the sample from room temperature to 350°C or lose 20% of its weight.
  • Test conditions Take a sample (10-15 mg) and place it in a DVS sample tray for testing.
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Fig. 1 is the Cu-K ⁇ radiation XRPD spectrogram of formula (I) compound A crystal form
  • Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form
  • Fig. 3 is the TGA spectrogram of formula (I) compound A crystal form
  • Fig. 4 is the Cu-K ⁇ radiation XRPD spectrogram of formula (I) compound B crystal form
  • Fig. 5 is the DSC spectrogram of formula (I) compound B crystal form
  • Fig. 6 is the TGA spectrogram of formula (I) compound B crystal form
  • Fig. 7 is the Cu-K ⁇ radiation XRPD spectrogram of formula (II) compound C crystal form
  • Fig. 8 is the DSC spectrogram of formula (II) compound C crystal form
  • Fig. 9 is the TGA spectrogram of formula (II) compound C crystal form
  • Figure 10 is the Cu-K ⁇ radiation XRPD spectrum of the D crystal form of the compound of formula (III);
  • Fig. 11 is the DSC spectrogram of formula (III) compound D crystal form
  • Fig. 12 is the TGA spectrogram of formula (III) compound D crystal form
  • Fig. 17 DVS diagram of the D crystal form of the compound of formula (III).
  • Table 5 shows the melting point and solubility of Compound 1 and its mesylate salt form A, mesylate salt form B, hydrochloride form C, and fumarate form D.
  • the melting points of compound 1 and each crystal form are obtained by differential thermal analysis (Differential Scanning Calorimeter, DSC) method, and the measurement method of solubility is: take a certain mass (ranging from 1 mg to 200 mg) of the compound and add it to 1 mL of pure water, Vibrate, ultrasonically aid in dissolution, and observe the dissolution with the naked eye.
  • the experimental results show that the free base has a low melting point and is very easy to vitrify, which poses a high risk for the stability of subsequent formulation development and long-term storage shape stability.
  • the melting point of the four crystal forms disclosed in the present invention has been greatly improved, the melting point has been increased by about 65°C, and the solubility has been increased by 200 mg/mL.
  • the free base has low osmosis and low solubility, which belongs to BCS4 category, which is not conducive to the development of later dosage forms. Crystal forms A, B, and D are easily soluble in water and belong to the BCS3 category, which can significantly increase the dissolution efficiency of compounds and preparations.
  • Table 6 shows the difficulty of compound 1 and its salts in preparing crystals.
  • the mesylate crystal form A has the smallest ⁇ W% value and is slightly hygroscopic. Between ⁇ 6%, less than 15%, it has certain hygroscopicity.
  • Transwell is an experimental device widely used to study cell migration and invasion. It consists of two detachable upper and lower chambers, and the bottom of the upper chamber is a perforated membrane that cells can pass through.
  • THP1 cell suspension in the upper chamber of Transwell, and added the culture medium containing MCP-1 into the lower chamber of Transwell, because THP1 cells express the MCP-1 receptor CCR2, so the chemotaxis effect of the concentration difference in the upper and lower chambers of MCP-1
  • THP1 cells migrate to the lower chamber through the holes in the bottom of the upper chamber. Therefore, in the case of adding the compound to be tested, the inhibitory effect of the compound on MCP-1 chemotactic THP1 cell migration can be evaluated by detecting the number of cells in the lower chamber after a certain period of time after the start of cell migration.
  • the number of cells in the lower chamber of Transwell is detected by CTG method: the components in this reagent can react with ATP in the cell lysate and produce Fluorescence, the ATP content can be detected by measuring the fluorescence intensity, which in turn reflects the number of cells.
  • THP1 (sourced from ATCC, product number TIB-202)
  • THP1 cells The concentration of THP1 cells was adjusted to 2 ⁇ 10 6 cells/mL with culture medium, and 200 ⁇ L/well was inoculated into a 96-well round bottom plate.
  • step 6) Take 150 ⁇ L of the solution prepared in step 4) to the corresponding lower chamber, and incubate at 37° C. for 60 min (cell migration).
  • Both compounds have inhibitory activity on MCP-1 chemotactic THP1 migration, and Compound 1 of the present invention has stronger inhibitory activity on MCP-1-mediated THP1 chemotaxis than BMS-813160.
  • Table 12 is the oral bioavailability test of compound 1 and its salts in rats.
  • the experimental results showed that the hydrochloride crystal form C significantly improved the oral bioavailability in rats, and its bioavailability was increased by 19.7% compared with the free base form of compound 1.
  • the present invention has only tested the hydrochloride crystal form C of compound 1, and its phase crystal forms (mesylate crystal form A, mesylate salt crystal form B, fumarate salt crystal form D) have yet to be further developed.

Abstract

Disclosed are a salt form and a crystal form of an azabenzo eight-membered ring compound and an application thereof. Specifically disclosed are a crystal form A, crystal form B, crystal form C, and crystal form D of fumarate salt, hydrochloride salt, or methane sulfonate of compound 1, and an application thereof.

Description

氮杂苯并八元环化合物的盐型、晶型及其应用Salt form, crystal form and application of azabenzo eight-membered ring compound 技术领域technical field
本发明涉及医药领域，具体涉及涉及氮杂苯并八元环化合物的甲烷磺酸盐、盐酸盐或富马酸盐，及上述盐的晶型。The invention relates to the field of medicine, in particular to the methanesulfonate, hydrochloride or fumarate of azabenzo eight-membered ring compounds, and the crystal forms of the salts.
背景技术Background technique
趋化因子是一种小的，分泌促炎细胞因子的家族，起到白细胞化学引诱物的作用。它们促进白细胞从血管床到响应炎症信号的周围组织的运输。趋化性起始于趋化因子与受体结合(GPCR)，通过启动涉及增加的钙流量，环磷酸腺苷产生的抑制，细胞骨架的重排，整联蛋白的活化和细胞运动过程的信号传导途径以及增加粘附蛋白的表达。Chemokines are a family of small, secreted pro-inflammatory cytokines that act as leukocyte chemoattractants. They facilitate the transport of leukocytes from vascular beds to surrounding tissues in response to inflammatory signals. Chemotaxis is initiated upon binding of chemokines to receptors (GPCRs) by initiating signals involving increased calcium flux, inhibition of cyclic AMP production, rearrangements of the cytoskeleton, activation of integrins, and cellular motility processes transduction pathways and increased expression of adhesion proteins.
化学诱导剂细胞因子(即趋化因子)是相对小的蛋白质(8-10kD)，其刺激细胞的迁移。基于第一和第二高度保守的半胱氨酸之间的氨基酸残基的数目，将趋化因子家族分成四个亚家族。单核细胞趋化蛋白-1(MCP-1)是CC趋化因子亚家族(其中CC代表具有相邻的第一和第二半胱氨酸的亚家族)的成员并且结合细胞表面趋化因子受体2(CCR2)。MCP-1是有效的趋化因子，其在结合CCR2后介导单核细胞和淋巴细胞向炎症位点的迁移(即趋化性)。MCP-1也由心肌细胞，血管内皮细胞，成纤维细胞，软骨细胞，平滑肌细胞，肾小球系膜细胞，肺泡细胞，T淋巴细胞，食管癌等表达。单核细胞进入炎症组织后，分化成表达CCR5的巨噬细胞，提供几种促炎调节剂的次级来源，包括肿瘤坏死因子-α(TNF-α)，白细胞介素-1(IL-1)，IL-8CXC趋化因子亚家族，其中CXC代表第一和第二半胱氨酸之间的一个氨基酸残基)，IL-12，花生四烯酸代谢物(例如PGE 2和LTB 4)，氧衍生的自由基，基质金属蛋白酶和补体成分。Chemoinducers Cytokines (ie, chemokines) are relatively small proteins (8-10 kD) that stimulate the migration of cells. The chemokine family is divided into four subfamilies based on the number of amino acid residues between the first and second highly conserved cysteines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine subfamily (where CC stands for the subfamily with adjacent first and second cysteines) and binds cell surface chemokines receptor 2 (CCR2). MCP-1 is a potent chemokine that, upon binding to CCR2, mediates the migration of monocytes and lymphocytes to sites of inflammation (ie, chemotaxis). MCP-1 is also expressed by cardiomyocytes, vascular endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, glomerular mesangial cells, alveolar cells, T lymphocytes, esophageal carcinoma, etc. After entering inflamed tissues, monocytes differentiate into CCR5-expressing macrophages, which provide a secondary source of several pro-inflammatory regulators, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1 ), IL-8CXC chemokine subfamily, where CXC represents an amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (such as PGE 2 and LTB 4) , oxygen-derived free radicals, matrix metalloproteinases and complement components.
CCR2(也称为CKR-2，MCP-1RA或MCIRB)主要在单核细胞和巨噬细胞上表达，并且对于巨噬细胞依赖性炎症是必需的。CCR2是以高亲和力结合趋化因子MCP家族(CCL2，CCL7，CCL8等)的几个成员的G蛋白偶联受体(GPCR)，引发趋化信号，导致定向受体携带细胞的迁移。慢性炎性疾病的动物模型研究已经证明，拮抗剂抑制MCP-1和CCR2之间的结合抑制炎症反应。CCR2 (also known as CKR-2, MCP-1RA or MCIRB) is predominantly expressed on monocytes and macrophages and is essential for macrophage-dependent inflammation. CCR2 is a G protein-coupled receptor (GPCR) that binds with high affinity to several members of the chemokine MCP family (CCL2, CCL7, CCL8, etc.), triggering chemotactic signals that lead to migration of directed receptor-carrying cells. Studies in animal models of chronic inflammatory diseases have demonstrated that antagonist inhibition of the binding between MCP-1 and CCR2 inhibits the inflammatory response.
CCR5是结合多种CC趋化因子配体的G蛋白偶联受体，包括CCL3，CCL3L1，CCL4，CCL5，CCL7，CCL11和CCL13。相对于CCR2，CCR5的体内功能较不明确。与CCR2相比，CCR5主要表达在活化的Th1细胞和从血液单核细胞分化的组织巨噬细胞，其伴随地下调CCR2表达。已经显示CCR5在炎症和感染过程中有助于巨噬细胞的存活，并且还可以起到在发炎组织内保留巨噬细胞的作用。此外，CCR5介导Th1细胞在炎症中的募集和激活。CCR5也在破骨细胞上表达，并且对于破骨细胞形成是重要的，这表明CCR5在类风湿性关节炎病理学中的贡献作用。通过CCL4/CCR5参与的血管平滑细胞的活化也可以促成动脉粥样硬化和AIH的病理学(加速的内膜增生)。CCR5 is a G protein-coupled receptor that binds several CC chemokine ligands, including CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL11 and CCL13. The in vivo function of CCR5 is less clear than that of CCR2. In contrast to CCR2, CCR5 is predominantly expressed in activated Th1 cells and tissue macrophages differentiated from blood monocytes, which concomitantly downregulates CCR2 expression. CCR5 has been shown to contribute to the survival of macrophages during inflammation and infection, and may also function to retain macrophages within inflamed tissues. Furthermore, CCR5 mediates the recruitment and activation of Th1 cells in inflammation. CCR5 is also expressed on osteoclasts and is important for osteoclastogenesis, suggesting a contributing role for CCR5 in the pathology of rheumatoid arthritis. Activation of vascular smooth cells through CCL4/CCR5 involvement may also contribute to the pathology of atherosclerosis and AIH (accelerated intimal hyperplasia).
目前对CCR2/5双重拮抗剂种类较少，同时有研究表明不同药物晶型，会直接影响体内血药浓度高低及毒副作用大小。鉴于此，本发明研究了氮杂苯并八元环化合物的盐型、晶型及其应用。At present, there are few types of CCR2/5 dual antagonists. At the same time, studies have shown that different drug crystal forms will directly affect the blood drug concentration in the body and the degree of toxic and side effects. In view of this, the present invention studies the salt form, crystal form and application of the azabenzo eight-membered ring compound.
发明内容Contents of the invention
本发明，具体公开了化合物1的甲烷磺酸盐、盐酸盐或富马酸盐的A晶型、B晶型、C晶型和D晶型及其应用。The present invention specifically discloses crystal forms A, B, C and D of methanesulfonate, hydrochloride or fumarate of compound 1 and applications thereof.
本发明提供了化合物1的甲烷磺酸盐、盐酸盐或富马酸盐，
The present invention provides the methanesulfonate, hydrochloride or fumarate of compound 1,
在本发明的一些方案中，上述药学上可接受的盐为式(I)所示的甲烷磺酸盐、式(II)所示的盐酸盐或式(III)所示的富马酸盐，
In some schemes of the present invention, the above-mentioned pharmaceutically acceptable salts are methanesulfonate salts shown in formula (I), hydrochloride salts shown in formula (II) or fumarate salts shown in formula (III) ,
本发明还提供了式(I)化合物的A晶型，
The present invention also provides the A crystal form of the compound of formula (I),
其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536±0.200°，17.608±0.200°，21.702±0.200°。 本发明中X射线粉末衍射均采用Cu-kα辐射，下同。Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 17.608±0.200°, 21.702±0.200°. In the present invention, X-ray powder diffraction adopts Cu-kα radiation, the same below.
在本发明的一些方案中，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536±0.200°，15.382±0.200°，17.608±0.200°，20.401±0.200°，21.702±0.200°，23.326±0.200°，27.143±0.200°。In some solutions of the present invention, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 15.382±0.200°, 17.608±0.200°, 20.401±0.200°, 21.702±0.200°, 23.326 ±0.200°, 27.143±0.200°.
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536±0.200°，15.382±0.200°，16.949±0.200°，17.608±0.200°，18.628±0.200°，20.401±0.200°，21.702±0.200°，23.326±0.200°，27.143±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 15.382±0.200°, 16.949±0.200°, 17.608±0.200°, 18.628± 0.200°, 20.401±0.200°, 21.702±0.200°, 23.326±0.200°, 27.143±0.200°.
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536±0.200°，15.382±0.200°，16.949±0.200°，17.608±0.200°，18.628±0.200°，20.401±0.200°，21.066±0.200°，21.702±0.200°，23.326±0.200°，23.956±0.200°，27.143±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 15.382±0.200°, 16.949±0.200°, 17.608±0.200°, 18.628± 0.200°, 20.401±0.200°, 21.066±0.200°, 21.702±0.200°, 23.326±0.200°, 23.956±0.200°, 27.143±0.200°.
在本发明的一些方案中，上述A晶型的射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536±0.200°，10.096±0.200°，14.412±0.200°，15.382±0.200°，16.949±0.200°，17.608±0.200°，18.628±0.200°，19.520±0.200°，20.401±0.200°，21.066±0.200°，21.702±0.200°，22.347±0.200°，23.326±0.200°，23.956±0.200°，25.000±0.200°，27.143±0.200°。In some solutions of the present invention, the ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 10.096±0.200°, 14.412±0.200°, 15.382±0.200°, 16.949±0.200 °, 17.608±0.200°, 18.628±0.200°, 19.520±0.200°, 20.401±0.200°, 21.066±0.200°, 21.702±0.200°, 22.347±0.200°, 23.326±0.200°, 23.956± 0.200°, 25.000±0.200 °, 27.143±0.200°.
在本发明的一些方案中，上述A晶型的射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536°，10.096°，10.763°，13.126°，13.586°，14.412°，15.382°，16.009°，16.949°，17.608°，17.984°，18.628°，19.520°，20.401°，21.066°，21.702°，22.347°，23.326°，23.956°，25.000°，26.648°，27.143°，27.942°，28.520°，29.350°，30.752°，31.429°，34.439°，35.134°。In some solutions of the present invention, the ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 9.536°, 10.096°, 10.763°, 13.126°, 13.586°, 14.412°, 15.382°, 16.009° , 16.949°, 17.608°, 17.984°, 18.628°, 19.520°, 20.401°, 21.066°, 21.702°, 22.347°, 23.326°, 23.956°, 25.000°, 26.648°, 27.143°, 27.942°, 28.520°, 29.350 °, 30.752°, 31.429°, 34.439°, 35.134°.
本发明还提供了上述A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰还包含17.608±0.200°，9.536±0.200°，和/或21.702±0.200°，20.401±0.200°，和/或23.326±0.200°，和/或15.382±0.200°，和/或27.143±0.200°，和/或18.628±0.200°，和/或23.956±0.200°，和/或16.949±0.200°，和/或21.066±0.200°，和/或22.347±0.200°，和/或25.000±0.200°，和/或19.520±0.200°，和/或10.096±0.200°，和/或13.126±0.200°，和/或31.429±0.200°，和/或16.009±0.200°，和/或28.520±0.200°，和/或25.526±0.200°，和/或29.350±0.200°，和/或30.752±0.200°，和/或12.303±0.200°，和/或27.942±0.200°，和/或35.134±0.200°，和/或4.825±0.200°，和/或34.439±0.200°，和/或41.188±0.200°，和/或7.975±0.200°。The present invention also provides the above crystal form A, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles and also includes 17.608±0.200°, 9.536±0.200°, and/or 21.702±0.200°, 20.401±0.200°, and/or 23.326±0.200°, and/or 15.382±0.200°, and/or 27.143±0.200°, and/or 18.628±0.200°, and/or 23.956±0.200°, and/or 16.949±0.200°, and/or or 21.066±0.200°, and/or 22.347±0.200°, and/or 25.000±0.200°, and/or 19.520±0.200°, and/or 10.096±0.200°, and/or 13.126±0.200°, and/or 31.429 ±0.200°, and/or 16.009±0.200°, and/or 28.520±0.200°, and/or 25.526±0.200°, and/or 29.350±0.200°, and/or 30.752±0.200°, and/or 12.303±0.200 °, and/or 27.942±0.200°, and/or 35.134±0.200°, and/or 4.825±0.200°, and/or 34.439±0.200°, and/or 41.188±0.200°, and/or 7.975±0.200°.
在本发明的一些方案中，上述A晶型的XRPD图谱如图1所示。In some solutions of the present invention, the XRPD pattern of the above crystal form A is shown in FIG. 1 .
在本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示：In some solutions of the present invention, the XRPD spectrum analysis data of the above crystal form A are shown in Table 1:
表1 A晶型的XRPD图谱解析数据

Table 1 XRPD analysis data of crystal form A

在本发明的一些方案中，上述A晶型的差示扫描量热曲线在164.38℃±3.0℃处具有一个吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 164.38°C±3.0°C.
在本发明的一些方案中，上述A晶型的DSC图谱如图2所示。In some solutions of the present invention, the DSC spectrum of the above crystal form A is shown in FIG. 2 .
在本发明的一些方案中，上述A晶型的热重分析曲线在150.0℃±3.0℃时失重为0.588％。In some solutions of the present invention, the weight loss of the thermogravimetric analysis curve of the above crystal form A is 0.588% at 150.0°C±3.0°C.
在本发明的一些方案中，上述A晶型的TGA图谱如图3所示。In some solutions of the present invention, the TGA spectrum of the above crystal form A is shown in FIG. 3 .
A晶型的制备方法包括：化合物1，在加热条件下，溶解于EtOAc、MeCN混合溶剂，加入CH3SO3H，降温，析晶。The preparation method of crystal form A includes: dissolving compound 1 in a mixed solvent of EtOAc and MeCN under heating conditions, adding CH 3 SO 3 H, cooling down, and crystallizing.
本发明还提供了式(I)化合物的B晶型，
The present invention also provides the B crystal form of the compound of formula (I),
其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660±0.200°，16.740±0.200°，22.020±0.200°。Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.660±0.200°, 16.740±0.200°, 22.020±0.200°.
在本发明的一些方案中，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660±0.200°，16.740±0.200°，17.970±0.200°，18.620±0.200°，20.890±0.200°，22.020±0.200°，23.270±0.200°，24.380±0.200°。In some solutions of the present invention, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.660±0.200°, 16.740±0.200°, 17.970±0.200°, 18.620±0.200°, 20.890±0.200°, 22.020 ±0.200°, 23.270±0.200°, 24.380±0.200°.
在本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660±0.200°，9.220±0.200°，16.740±0.200°，17.970±0.200°，18.620±0.200°，20.890±0.200°，22.020±0.200°，22.740±0.200°，23.270±0.200°，24.380±0.200°，26.930±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 4.660±0.200°, 9.220±0.200°, 16.740±0.200°, 17.970±0.200°, 18.620± 0.200°, 20.890±0.200°, 22.020±0.200°, 22.740±0.200°, 23.270±0.200°, 24.380±0.200°, 26.930±0.200°.
在本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660±0.200°，9.220±0.200°，14.570±0.200°，16.740±0.200°，17.970±0.200°，18.620±0.200°，20.890±0.200°，22.020±0.200°，22.740±0.200°，23.270±0.200°，24.380±0.200°，26.930±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 4.660±0.200°, 9.220±0.200°, 14.570±0.200°, 16.740±0.200°, 17.970± 0.200°, 18.620±0.200°, 20.890±0.200°, 22.020±0.200°, 22.740±0.200°, 23.270±0.200°, 24.380±0.200°, 26.930±0.200°.
在本发明的一些方案中，上述B晶型的射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660°，5.240°，9.220°，10.450°，11.650°，14.570°，15.670°，16.740°，17.970°，18.620°，19.880°，20.890°，21.310°，22.020°，22.740°，23.040°，23.270°，24.380°，25.220°，25.780°，26.930°。In some solutions of the present invention, the ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.660°, 5.240°, 9.220°, 10.450°, 11.650°, 14.570°, 15.670°, 16.740° , 17.970°, 18.620°, 19.880°, 20.890°, 21.310°, 22.020°, 22.740°, 23.040°, 23.270°, 24.380°, 25.220°, 25.780°, 26.930°.
本发明还提供了上述B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰还包含18.620±0.200°，4.660±0.200°，和/或16.740±0.200°，和/或23.270±0.200°，和/或24.380±0.200°，和/或22.020±0.200°，和/或20.890±0.200°，和/或9.220±0.200°，和/或26.930±0.200°，和/或14.570±0.200°，和/或22.740±0.200°，和/或11.650±0.200°，和/或21.310±0.200°，和/或15.670±0.200°，和/或10.450±0.200°，和/或25.220±0.200°，和/或19.880±0.200°，和/或5.240±0.200°，和/或25.780±0.200°。The present invention also provides the above crystal form B, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles and also includes 18.620±0.200°, 4.660±0.200°, and/or 16.740±0.200°, and/or 23.270± 0.200°, and/or 24.380±0.200°, and/or 22.020±0.200°, and/or 20.890±0.200°, and/or 9.220±0.200°, and/or 26.930±0.200°, and/or 14.570±0.200° , and/or 22.740±0.200°, and/or 11.650±0.200°, and/or 21.310±0.200°, and/or 15.670±0.200°, and/or 10.450±0.200°, and/or 25.220±0.200°, and /or 19.880±0.200°, and/or 5.240±0.200°, and/or 25.780±0.200°.
在本发明的一些方案中，上述B晶型的XRPD图谱如图4所示。In some solutions of the present invention, the XRPD spectrum of the above crystal form B is shown in FIG. 4 .
在本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示：In some solutions of the present invention, the XRPD spectrum analysis data of the above crystal form B are shown in Table 2:
表2 B晶型的XRPD图谱解析数据
Table 2 XRPD analysis data of crystal form B
在本发明的一些方案中，上述B晶型的差示扫描量热曲线在166.7℃±3.0℃具有一个吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry curve of the above crystal form B has an endothermic peak at 166.7°C±3.0°C.
在本发明的一些方案中，上述B晶型的DSC图谱如图5所示。In some solutions of the present invention, the DSC spectrum of the above crystal form B is shown in FIG. 5 .
在本发明的一些方案中，上述B晶型的热重分析曲线在130.0℃±3℃时失重为0.25％。In some solutions of the present invention, the weight loss of the thermogravimetric analysis curve of the above crystal form B is 0.25% at 130.0°C±3°C.
在本发明的一些方案中，上述B晶型的TGA图谱如图6所示。In some solutions of the present invention, the TGA spectrum of the above crystal form B is shown in FIG. 6 .
B晶型的制备方法包括：化合物1，在加热条件下，溶解于EtOAc、IPA混合溶剂，加入CH3SO3H，降温，析晶。The preparation method of crystal form B comprises: dissolving compound 1 in a mixed solvent of EtOAc and IPA under heating conditions, adding CH 3 SO 3 H, cooling down, and crystallizing.
本发明还提供了式(II)化合物的C晶型，
The present invention also provides the C crystal form of the compound of formula (II),
其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：16.700±0.200°，20.150±0.200°，24.720±0.200°。Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 16.700±0.200°, 20.150±0.200°, 24.720±0.200°.
在本发明的一些方案中，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.380±0.200°，16.700±0.200°，18.640±0.200°，19.580±0.200°，23.520±0.200°，24.720±0.200°，24.720±0.200°，26.090±0.200°。 In some solutions of the present invention, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.380±0.200°, 16.700±0.200°, 18.640±0.200°, 19.580±0.200°, 23.520±0.200°, 24.720 ±0.200°, 24.720±0.200°, 26.090±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.380±0.200°，15.350±0.200°，16.700±0.200°，18.640±0.200°，19.580±0.200°，21.310±0.200°，23.520±0.200°，24.720±0.200°，24.720±0.200°，26.090±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 12.380±0.200°, 15.350±0.200°, 16.700±0.200°, 18.640±0.200°, 19.580± 0.200°, 21.310±0.200°, 23.520±0.200°, 24.720±0.200°, 24.720±0.200°, 26.090±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.980±0.200°，12.380±0.200°，15.350±0.200°，16.700±0.200°，18.640±0.200°，19.580±0.200°，19.990±0.200°，20.150±0.200°，21.310±0.200°，23.520±0.200°，24.720±0.200°，26.090±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.980±0.200°, 12.380±0.200°, 15.350±0.200°, 16.700±0.200°, 18.640± 0.200°, 19.580±0.200°, 19.990±0.200°, 20.150±0.200°, 21.310±0.200°, 23.520±0.200°, 24.720±0.200°, 26.090±0.200°.
在本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.760°，7.980°，10.140°，11.180°，12.380°，13.050°，15.350°，16.450°，16.700°，17.050°，18.640°，19.110°，19.580°，19.990°，20.150°，21.310°，22.980°，23.520°，23.710°，24.720°，26.090°，26.330°，27.380°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 6.760°, 7.980°, 10.140°, 11.180°, 12.380°, 13.050°, 15.350°, 16.450 °, 16.700°, 17.050°, 18.640°, 19.110°, 19.580°, 19.990°, 20.150°, 21.310°, 22.980°, 23.520°, 23.710°, 24.720°, 26.090°, 26.330°, 27.380° .
本发明还提供了上述C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰还包含24.720±0.200°，20.150±0.200°，和/或16.700±0.200°，和/或23.520±0.200°，和/或19.990±0.200°，和/或19.580±0.200°，和/或18.640±0.200°，和/或12.380±0.200°，和/或26.090±0.200°，和/或21.310±0.200°，和/或15.350±0.200°，和/或7.980±0.200°，和/或22.980±0.200°，和/或19.110±0.200°，和/或11.180±0.200°，和/或6.760±0.200°，和/或13.050±0.200°，和/或27.380±0.200°，和/或10.140±0.200°。The present invention also provides the above crystal form C, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles and also includes 24.720±0.200°, 20.150±0.200°, and/or 16.700±0.200°, and/or 23.520± 0.200°, and/or 19.990±0.200°, and/or 19.580±0.200°, and/or 18.640±0.200°, and/or 12.380±0.200°, and/or 26.090±0.200°, and/or 21.310±0.200° , and/or 15.350±0.200°, and/or 7.980±0.200°, and/or 22.980±0.200°, and/or 19.110±0.200°, and/or 11.180±0.200°, and/or 6.760±0.200°, and /or 13.050±0.200°, and/or 27.380±0.200°, and/or 10.140±0.200°.
在本发明的一些方案中，上述C晶型的XRPD图谱如图7所示。In some solutions of the present invention, the XRPD spectrum of the above crystal form C is shown in FIG. 7 .
在本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表3所示：In some solutions of the present invention, the XRPD spectrum analysis data of the above crystal form C are shown in Table 3:
表3 C晶型的XRPD图谱解析数据
Table 3 XRPD analysis data of crystal form C
在本发明的一些方案中，上述C晶型的差示扫描量热曲线在153.3℃±3.0℃具有一个吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry curve of the above crystal form C has an endothermic peak at 153.3°C±3.0°C.
在本发明的一些方案中，上述C晶型的DSC图谱如图8所示。In some solutions of the present invention, the DSC spectrum of the above crystal form C is shown in FIG. 8 .
在本发明的一些方案中，上述C晶型的热重分析曲线在130.0℃±3℃时失重为4.89％。 In some solutions of the present invention, the weight loss of the thermogravimetric analysis curve of the above crystal form C is 4.89% at 130.0°C±3°C.
在本发明的一些方案中，上述C晶型的TGA图谱如图9所示。In some solutions of the present invention, the TGA spectrum of the above crystal form C is shown in FIG. 9 .
C晶型的制备方法包括：化合物1溶解到MeCN中，加入HCl/二氧六环，加热条件下搅拌反应后，降温，析晶。The preparation method of crystal form C comprises: dissolving compound 1 in MeCN, adding HCl/dioxane, stirring and reacting under heating conditions, cooling down and crystallizing.
本发明还提供了式(III)化合物的D晶型，
The present invention also provides the D crystal form of the compound of formula (III),
其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.420°±0.200°，17.680±0.200°，22.693±0.200°。Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.420°±0.200°, 17.680±0.200°, 22.693±0.200°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.420°±0.200°，12.989±0.200°，17.680±0.200°，18.236±0.200°，18.866±0.200°，19.195±0.200°，22.693±0.200°，25.237±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 4.420°±0.200°, 12.989±0.200°, 17.680±0.200°, 18.236±0.200°, 18.866 ±0.200°, 19.195±0.200°, 22.693±0.200°, 25.237±0.200°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.420°±0.200°，12.989±0.200°，15.124±0.200°，16.486±0.200°，17.680±0.200°，18.236±0.200°，18.866±0.200°，19.195±0.200°，20.491±0.200°，21.505±0.200°，22.693±0.200°，25.237±0.200°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 4.420°±0.200°, 12.989±0.200°, 15.124±0.200°, 16.486±0.200°, 17.680 ±0.200°, 18.236±0.200°, 18.866±0.200°, 19.195±0.200°, 20.491±0.200°, 21.505±0.200°, 22.693±0.200°, 25.237±0.200°.
在本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.420°，6.199°，8.651°，11.334°，12.344°，12.989°，13.705°，15.124°，15.699°，16.486°，17.680°，18.236°，18.866°，19.195°，20.491°，21.505°，22.693°，24.100°，25.237°，30.453°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 4.420°, 6.199°, 8.651°, 11.334°, 12.344°, 12.989°, 13.705°, 15.124 °, 15.699°, 16.486°, 17.680°, 18.236°, 18.866°, 19.195°, 20.491°, 21.505°, 22.693°, 24.100°, 25.237°, 30.453°.
本发明还提供了上述D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰还包含4.420°±0.200°，22.693±0.200°，和/或17.680±0.200°，和/或19.195±0.200°，和/或25.237±0.200°，和/或12.989±0.200°，和/或18.236±0.200°，和/或16.486±0.200°，和/或20.491±0.200°，和/或15.124±0.200°，和/或21.505±0.200°，和/或13.705±0.200°，和/或24.100±0.200°，和/或12.344±0.200°，和/或15.699±0.200°，和/或6.199±0.200°，和/或30.453±0.200°，和/或11.334±0.200°，和/或8.651±0.200°。The present invention also provides the above crystal form D, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles and also includes 4.420°±0.200°, 22.693±0.200°, and/or 17.680±0.200°, and/or 19.195 ±0.200°, and/or 25.237±0.200°, and/or 12.989±0.200°, and/or 18.236±0.200°, and/or 16.486±0.200°, and/or 20.491±0.200°, and/or 15.124±0.200 °, and/or 21.505±0.200°, and/or 13.705±0.200°, and/or 24.100±0.200°, and/or 12.344±0.200°, and/or 15.699±0.200°, and/or 6.199±0.200°, And/or 30.453±0.200°, and/or 11.334±0.200°, and/or 8.651±0.200°.
在本发明的一些方案中，上述D晶型的XRPD图谱如图10所示。In some solutions of the present invention, the XRPD pattern of the above crystal form D is shown in FIG. 10 .
在本发明的一些方案中，上述D晶型的XRPD图谱解析数据如表4所示：In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned D crystal form are shown in Table 4:
表4 D晶型的XRPD图谱解析数据
Table 4 XRPD analysis data of crystal form D
在本发明的一些方案中，上述D晶型的差示扫描量热曲线在160.35℃±3.0℃具有一个吸热峰的峰值。In some solutions of the present invention, the differential scanning calorimetry curve of the above crystal form D has an endothermic peak at 160.35°C±3.0°C.
在本发明的一些方案中，上述D晶型的DSC图谱如图11所示。In some solutions of the present invention, the DSC spectrum of the above crystal form D is shown in FIG. 11 .
在本发明的一些方案中，上述D晶型的热重分析曲线在121.75℃±3.0℃时失重为0.3823％。In some solutions of the present invention, the weight loss of the thermogravimetric analysis curve of the above crystal form D is 0.3823% at 121.75°C±3.0°C.
在本发明的一些方案中，上述D晶型的TGA图谱如图12所示。In some solutions of the present invention, the TGA spectrum of the above crystal form D is shown in FIG. 12 .
D晶型的制备方法包括：化合物1溶于EtOAc，加热条件下加入富马酸，加完保持该温度反应，再降温，析晶。The preparation method of D crystal form comprises: dissolving compound 1 in EtOAc, adding fumaric acid under heating conditions, keeping the temperature for reaction after adding, cooling down and crystallizing.
本发明中所述“降温”，是指通过降低温度从而降低溶解度，而是晶体析出。本发明中一般选择降低至20-30℃。The "lower temperature" in the present invention means that the solubility is reduced by lowering the temperature, but the crystals are precipitated. In the present invention, it is generally selected to reduce to 20-30°C.
本发明还提供A晶型，B晶型，C晶型或D晶型在制备治疗晚期实体瘤及淋巴瘤的药物及CCR2/5双重拮抗剂中的应用。The present invention also provides the application of A crystal form, B crystal form, C crystal form or D crystal form in the preparation of drugs for treating advanced solid tumors and lymphomas and CCR2/5 dual antagonists.
拮抗剂，与受体结合后，阻断该受体激动剂介导作用。Antagonists, upon binding to a receptor, block the agonist-mediated action of that receptor.
技术效果technical effect
本发明所提供的式(I)化合物的A晶型，B晶型，式(Ⅱ)化合物的C晶型，式(Ⅲ)化合物的D晶型，性质稳定，溶解度好，引湿性差，具有良好的成药前景。The crystal form A, crystal form B of the compound of formula (I), crystal form C of the compound of formula (II), and crystal form D of the compound of formula (III) provided by the present invention have stable properties, good solubility, poor hygroscopicity, and have Good drug prospects.
本发明的各个晶型的制备方法简单，无需苛刻条件及剧毒溶剂，晶型纯度高，收率好，利于工业化放大。The preparation method of each crystal form of the present invention is simple, does not require harsh conditions and highly toxic solvents, has high crystal purity and good yield, and is beneficial to industrial scale-up.
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及 其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reaction of the specific embodiment of the present invention is to be finished in suitable solvent, and described solvent must be suitable for the chemical change of the present invention and Reagents and materials required for it. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
本研究选取CCR2/5拮抗剂BMS-813160作为参比化合物，其被用于开发治疗肝癌、胰腺癌、非小细胞肺癌、结直肠癌等癌症，目前已处于临床二期开发阶段。其结构如下：
In this study, the CCR2/5 antagonist BMS-813160 was selected as the reference compound, which has been used in the development and treatment of liver cancer, pancreatic cancer, non-small cell lung cancer, colorectal cancer and other cancers, and is currently in the second phase of clinical development. Its structure is as follows:
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be specifically described by examples below, and these examples do not imply any limitation to the present invention.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
本发明采用下述缩略词：IPA代表异丙醇。The following abbreviations are used herein: IPA stands for isopropanol.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to the conventional naming principles in this field or using The software is named, and the commercially available compounds adopt the supplier catalog name.
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法Powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：BRUKER D2 PHASER X射线衍射仪Instrument model: BRUKER D2 PHASER X-ray diffractometer
测试方法：大约10～20mg样品用于XRPD检测。Test method: About 10-20 mg of sample is used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
光管：Cu,kα, Light pipe: Cu, kα,
光管电压：30kV，光管电流：40mALight tube voltage: 30kV, light tube current: 40mA
发散狭缝：0.60mmDivergence slit: 0.60mm
探测器狭缝：10.50mmDetector slit: 10.50mm
防散射狭缝：7.10mmAnti-scatter slit: 7.10mm
扫描范围：3-45°Scanning range: 3-45°
步径：0.02°Step diameter: 0.02°
步长：0.5秒Step size: 0.5 seconds
样品盘转速：15rpmSample disk speed: 15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法The present invention's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
仪器型号：TA Q2000差示扫描量热仪Instrument Model: TA Q2000 Differential Scanning Calorimeter
测试方法：取样品(～1mg)置于DSC铝锅内进行测试，在50mL/min N2条件下，以10℃/min的升温速率，加热样品从30℃到300℃(或350℃)。Test method: Take a sample (~1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 , heat the sample from 30°C to 300°C (or 350°C) at a heating rate of 10°C/min.
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
仪器型号：TA Q5000IR热重分析仪Instrument Model: TA Q5000IR Thermogravimetric Analyzer
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N2条件下，以10℃/min的升温速率，加热样品从室温到350℃或失重20％。Test method: Take a sample (2~5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 , at a heating rate of 10°C/min, heat the sample from room temperature to 350°C or lose 20% of its weight.
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法Dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention
仪器型号：SMS DVS Advantage动态蒸汽吸附仪Instrument model: SMS DVS Advantage dynamic vapor adsorption instrument
测试条件：取样品(10～15mg)置于DVS样品盘内进行测试。Test conditions: Take a sample (10-15 mg) and place it in a DVS sample tray for testing.
详细的DVS参数如下： The detailed DVS parameters are as follows:
温度：25℃Temperature: 25°C
平衡：dm/dt＝0.01％/min(最短：10min，最长：180min)Balance: dm/dt=0.01%/min (shortest: 10min, longest: 180min)
干燥：0％RH下干燥120minDrying: 120min at 0% RH
RH(％)测试梯级：10％RH(%) test rung: 10%
RH(％)测试梯级范围：0％-90％-0％RH (%) test step range: 0%-90%-0%
引湿性评价分类如下：
The classification of hygroscopicity evaluation is as follows:
注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Note: ΔW% represents the moisture absorption weight gain of the test product at 25±1°C and 80±2%RH.
附图说明Description of drawings
图1为式(I)化合物A晶型的Cu-Kα辐射XRPD谱图；Fig. 1 is the Cu-Kα radiation XRPD spectrogram of formula (I) compound A crystal form;
图2为式(I)化合物A晶型的DSC谱图；Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form;
图3为式(I)化合物A晶型的TGA谱图；Fig. 3 is the TGA spectrogram of formula (I) compound A crystal form;
图4为式(I)化合物B晶型的Cu-Kα辐射XRPD谱图；Fig. 4 is the Cu-Kα radiation XRPD spectrogram of formula (I) compound B crystal form;
图5为式(I)化合物B晶型的DSC谱图；Fig. 5 is the DSC spectrogram of formula (I) compound B crystal form;
图6为式(I)化合物B晶型的TGA谱图；Fig. 6 is the TGA spectrogram of formula (I) compound B crystal form;
图7为式(II)化合物C晶型的Cu-Kα辐射XRPD谱图；Fig. 7 is the Cu-Kα radiation XRPD spectrogram of formula (II) compound C crystal form;
图8为式(II)化合物C晶型的DSC谱图；Fig. 8 is the DSC spectrogram of formula (II) compound C crystal form;
图9为式(II)化合物C晶型的TGA谱图；Fig. 9 is the TGA spectrogram of formula (II) compound C crystal form;
图10为式(III)化合物D晶型的Cu-Kα辐射XRPD谱图；Figure 10 is the Cu-Kα radiation XRPD spectrum of the D crystal form of the compound of formula (III);
图11为式(III)化合物D晶型的DSC谱图；Fig. 11 is the DSC spectrogram of formula (III) compound D crystal form;
图12为式(III)化合物D晶型的TGA谱图；Fig. 12 is the TGA spectrogram of formula (III) compound D crystal form;
图13游离碱(化合物1)DSC与TGA叠图；Figure 13 free base (compound 1) DSC and TGA overlay;
图14式(I)化合物的A晶型的DVS图；The DVS figure of the A crystal form of Fig. 14 formula (I) compound;
图15式(I)化合物的B晶型的DVS图；The DVS figure of the B crystal form of Fig. 15 formula (I) compound;
图16式(Ⅱ)化合物的C晶型的DVS图；Figure 16 The DVS diagram of the C crystal form of the compound of formula (II);
图17式(III)化合物的D晶型的DVS图。Fig. 17 DVS diagram of the D crystal form of the compound of formula (III).
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1式(I)化合物的A晶型的制备
The preparation of the A crystal form of embodiment 1 formula (I) compound
80℃将化合物1(50.92g,68.91mmol,1eq)与EtOAc(350mL)，MeCN(700mL)混合溶解，再滴加CH3SO3H(6.62g,68.91mmol,4.91mL,1eq)，降温至25℃搅拌12hr，有黄色固体析出，过滤，滤饼真空干燥得到黄色固体为式(I)化合物的A晶型。Mix and dissolve compound 1 (50.92g, 68.91mmol, 1eq) with EtOAc (350mL), MeCN (700mL) at 80°C, then add CH 3 SO 3 H (6.62g, 68.91mmol, 4.91mL, 1eq) dropwise, and cool down to After stirring at 25°C for 12 hrs, a yellow solid precipitated out, filtered, and the filter cake was vacuum-dried to obtain a yellow solid which was Form A of the compound of formula (I).
1H NMR(400MHz,CD3OD)δ＝14.35(s,1H),10.19(s,1H),9.08(s,1H),7.92(d,J＝8.4Hz,2H),7.62(s,1H),7.53-7.43(m,6H),6.98(d,J＝8.4Hz,2H),6.88(d,J＝9.2Hz,1H),4.73(d,J＝14.8Hz,1H),4.33(d,J＝14.8Hz,1H),4.17-4.09(m,4H),3.90-3.86(m,2H),3.70(t,J＝4.4Hz,2H),3.51(brs,2H),3.46(t,J＝6.4Hz,2H),3.28(t,J＝11.2Hz,2H),3.16(d,J＝6.8Hz,2H),2.44(brs,2H),2.32(s,3H),2.13-2.00(m,1H),1.69(s,3H),1.64-1.61(m,2H),1.54-1.45(m,4H),1.41(t,J＝7.2Hz,3H),1.36-1.28(m,4H),0.88(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD) δ=14.35(s,1H),10.19(s,1H),9.08(s,1H),7.92(d,J=8.4Hz,2H),7.62(s,1H ),7.53-7.43(m,6H),6.98(d,J=8.4Hz,2H),6.88(d,J=9.2Hz,1H),4.73(d,J=14.8Hz,1H),4.33(d ,J=14.8Hz,1H),4.17-4.09(m,4H),3.90-3.86(m,2H),3.70(t,J=4.4Hz,2H),3.51(brs,2H),3.46(t, J＝6.4Hz, 2H), 3.28(t, J＝11.2Hz, 2H), 3.16(d, J＝6.8Hz, 2H), 2.44(brs, 2H), 2.32(s, 3H), 2.13-2.00( m,1H),1.69(s,3H),1.64-1.61(m,2H),1.54-1.45(m,4H),1.41(t,J＝7.2Hz,3H),1.36-1.28(m,4H) ,0.88(t,J=7.2Hz,3H).
实施例2式(I)化合物的B晶型的制备
The preparation of the B crystal form of embodiment 2 formula (I) compound
80℃将化合物1(74.4g,100.68mmol,1eq)与EtOAc(520mL)，IPA(260mL)混合溶解，再滴加CH3SO3H(9.68g,100.68mmol,7.17mL,1eq)，降温至25℃搅拌12hr，有黄色固体析出，过滤，滤饼真空干燥得到黄色固体为式(I)化合物的B晶型。Mix and dissolve compound 1 (74.4g, 100.68mmol, 1eq) with EtOAc (520mL), IPA (260mL) at 80°C, then add CH 3 SO 3 H (9.68g, 100.68mmol, 7.17mL, 1eq) dropwise, and cool down to After stirring at 25°C for 12 hrs, a yellow solid precipitated out, filtered, and the filter cake was vacuum-dried to obtain a yellow solid which was the crystal form B of the compound of formula (I).
1H NMR(400MHz,DMSO-d6)δppm 14.27(s,1H),10.17(s,1H),9.07(s,1H),7.90(d,J＝8.8Hz,2H),7.61(s,1H),7.52-7.42(m,6H),6.97(d,J＝8.8Hz,2H),6.86(d,J＝9.2Hz,1H),4.73(d,J＝11.2Hz,1H),4.32(d,J＝11.2Hz,1H),4.16-4.08(m,4H),3.88-3.85(m,2H),3.69(t,J＝4.8Hz,2H),3.49(brs,2H),3.45(t,J＝6.4Hz,2H),3.27(t,J＝11.2Hz,2H),3.16(d,J＝6.4Hz,2H),2.48(brs,2H),2.32(s,3H),2.11-1.98(m,1H),1.68(s,3H),1.63-1.59(m,2H),1.53-1.46(m,4H),1.39(t,J＝7.2Hz,3H),1.37-1.27(m,4H),0.87(t,J＝0.72Hz,3H). 1 H NMR (400MHz,DMSO-d6)δppm 14.27(s,1H),10.17(s,1H),9.07(s,1H),7.90(d,J=8.8Hz,2H),7.61(s,1H) ,7.52-7.42(m,6H),6.97(d,J=8.8Hz,2H),6.86(d,J=9.2Hz,1H),4.73(d,J=11.2Hz,1H),4.32(d, J＝11.2Hz, 1H), 4.16-4.08(m, 4H), 3.88-3.85(m, 2H), 3.69(t, J＝4.8Hz, 2H), 3.49(brs, 2H), 3.45(t, J =6.4Hz, 2H), 3.27(t, J=11.2Hz, 2H), 3.16(d, J=6.4Hz, 2H), 2.48(brs, 2H), 2.32(s, 3H), 2.11-1.98(m ,1H),1.68(s,3H),1.63-1.59(m,2H),1.53-1.46(m,4H),1.39(t,J=7.2Hz,3H),1.37-1.27(m,4H), 0.87(t,J=0.72Hz,3H).
实施例3式(Ⅱ)化合物的C晶型的制备
The preparation of the C crystal form of embodiment 3 formula (II) compound
将化合物1(1g,1.35mmol,1eq)溶解到MeCN(20mL)中加入HCl/二氧六环(4M,338.31μL,1eq)50℃搅拌1hr后降温至25℃搅拌12hr。有固体析出，过滤，滤饼用乙腈(5mL)洗涤。滤饼真空干燥得到黄色固体为式(Ⅱ)化合物的C晶型。Compound 1 (1 g, 1.35 mmol, 1 eq) was dissolved in MeCN (20 mL) and HCl/dioxane (4M, 338.31 μL, 1 eq) was added and stirred at 50°C for 1 hr, then cooled to 25°C and stirred for 12 hr. A solid precipitated out and was filtered, and the filter cake was washed with acetonitrile (5 mL). The filter cake was dried in vacuo to obtain a yellow solid which is the crystal form C of the compound of formula (II).
1H NMR(400MHz,DMSO-d6)δppm 14.55(brs,1H),10.28(s,1H),9.09(s,1H),7.94(d,J＝8.8Hz,2H),7.66(s,1H),7.53-7.51(m,3H),7.46-7.42(m,3H),6.97(d,J＝8.8Hz,2H),6.86(d,J＝8.8Hz,1H),4.72(d,J＝14.8Hz,1H),4.32(d,J＝14.8Hz,1H),4.15-4.08(m,4H),3.89-3.85(m,2H),3.69(t,J＝4.4Hz,2H),3.50-3.43(m,4H),3.27(t,J＝11.2Hz,2H),3.16(d,J＝6.8Hz,2H),2.43(brs,2H),2.05-2.01(m,1H),1.67(s,3H),1.63-1.60(m,2H),1.53-1.46(m,4H),1.39(t,J＝7.2Hz,3H),1.37-1.28(m,4H),0.88(t,J＝0.72Hz,3H). 1 H NMR (400MHz,DMSO-d6)δppm 14.55(brs,1H),10.28(s,1H),9.09(s,1H),7.94(d,J=8.8Hz,2H),7.66(s,1H) ,7.53-7.51(m,3H),7.46-7.42(m,3H),6.97(d,J=8.8Hz,2H),6.86(d,J=8.8Hz,1H),4.72(d,J=14.8 Hz,1H),4.32(d,J=14.8Hz,1H),4.15-4.08(m,4H),3.89-3.85(m,2H),3.69(t,J=4.4Hz,2H),3.50-3.43 (m,4H),3.27(t,J=11.2Hz,2H),3.16(d,J=6.8Hz,2H),2.43(brs,2H),2.05-2.01(m,1H),1.67(s, 3H), 1.63-1.60(m, 2H), 1.53-1.46(m, 4H), 1.39(t, J=7.2Hz, 3H), 1.37-1.28(m, 4H), 0.88(t, J=0.72Hz ,3H).
实施例4式(III)化合物的D晶型的制备
The preparation of the D crystal form of embodiment 4 formula (III) compound
将化合物1(3.5g,4.74mmol,1eq)溶于EtOAc(50mL)中，搅拌至全溶，加热至70℃后向其中加入富马酸(700mg,6.03mmol,1.27eq)，加完保持该温度搅拌1小时，冷却至20℃继续搅拌11小时。反应液过滤得黄色滤饼，为式(III)化合物的D晶型。Compound 1 (3.5g, 4.74mmol, 1eq) was dissolved in EtOAc (50mL), stirred until completely dissolved, heated to 70°C, and fumaric acid (700mg, 6.03mmol, 1.27eq) was added thereto. Stir at high temperature for 1 hour, cool to 20°C and continue stirring for 11 hours. The reaction liquid was filtered to obtain a yellow filter cake, which was the D crystal form of the compound of formula (III).
1H NMR(400MHz,CD3OD)δppm：8.16(s,1H),7.87(d,J＝8.5Hz,2H),7.59(s,1H),7.50(br d,J＝8.5Hz,2H),7.46-7.39(m,4H),6.98(d,J＝8.5Hz,2H),6.95-6.89(m,1H),6.73(s,2H),4.50(br d,J＝14.8Hz,1H),4.24(d,J＝14.8Hz,1H),4.18-4.09(m,2H),4.07-3.92(m,4H),3.86-3.76(m,2H),3.62-3.52(m,4H),3.41(br t,J＝11.3Hz,2H),3.20(br d,J＝6.8Hz,2H),2.58(br d,J＝5.8Hz,2H),2.13(br s,1H),1.79-1.66(m,5H),1.64-1.54(m,4H),1.49-1.36(m,7H),0.95(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δppm: 8.16(s, 1H), 7.87(d, J=8.5Hz, 2H), 7.59(s, 1H), 7.50(br d, J=8.5Hz, 2H) ,7.46-7.39(m,4H),6.98(d,J=8.5Hz,2H),6.95-6.89(m,1H),6.73(s,2H),4.50(br d,J=14.8Hz,1H) ,4.24(d,J＝14.8Hz,1H),4.18-4.09(m,2H),4.07-3.92(m,4H),3.86-3.76(m,2H),3.62-3.52(m,4H),3.41 (br t, J = 11.3Hz, 2H), 3.20 (br d, J = 6.8Hz, 2H), 2.58 (br d, J = 5.8Hz, 2H), 2.13 (br s, 1H), 1.79-1.66 ( m, 5H), 1.64-1.54 (m, 4H), 1.49-1.36 (m, 7H), 0.95 (t, J=7.4Hz, 3H).
熔点及溶解性测试Melting point and solubility test
表5为化合物1及它的甲磺酸盐晶型A、甲磺酸盐晶型B、盐酸盐晶型C、富马酸盐晶型D的熔点及溶解度。本发明中化合物1及各晶型的熔点均通过差热分析(Differential Scanning Calorimeter,DSC)方法得到，溶解性的测量方法为：取一定质量(1mg～200mg不等)化合物加入1mL纯水中，震荡、超声助溶，肉眼观察溶解情况。Table 5 shows the melting point and solubility of Compound 1 and its mesylate salt form A, mesylate salt form B, hydrochloride form C, and fumarate form D. In the present invention, the melting points of compound 1 and each crystal form are obtained by differential thermal analysis (Differential Scanning Calorimeter, DSC) method, and the measurement method of solubility is: take a certain mass (ranging from 1 mg to 200 mg) of the compound and add it to 1 mL of pure water, Vibrate, ultrasonically aid in dissolution, and observe the dissolution with the naked eye.
表5各化合物熔点与溶解性
Table 5 Melting point and solubility of each compound
实验结果表明游离碱熔点低，极易玻璃化，后续制剂开发稳定性和长期放置形态稳定性风险大。本发明披露的四种晶型对于熔点均有大幅提升，熔点提高了65℃左右，溶解度增大了200mg/mL。游离碱低渗低溶，为BCS4类，不利于后期剂型开发。A、B、D晶型易溶于水，为BCS3类，能显著增加化合物和制剂的溶出效率。The experimental results show that the free base has a low melting point and is very easy to vitrify, which poses a high risk for the stability of subsequent formulation development and long-term storage shape stability. The melting point of the four crystal forms disclosed in the present invention has been greatly improved, the melting point has been increased by about 65°C, and the solubility has been increased by 200 mg/mL. The free base has low osmosis and low solubility, which belongs to BCS4 category, which is not conducive to the development of later dosage forms. Crystal forms A, B, and D are easily soluble in water and belong to the BCS3 category, which can significantly increase the dissolution efficiency of compounds and preparations.
制备工艺Preparation Process
表6展示了化合物1及其各盐在制备晶体时的难易程度。Table 6 shows the difficulty of compound 1 and its salts in preparing crystals.
表6制备晶体工艺难易程度
Table 6 Difficulty of preparing crystal technology
以上实验结果表明，化合物1的甲黄酸盐及富马酸盐成盐结晶工艺成熟，质量可控，便于工业化。而化合物1难以结晶，在工艺制备中无法通过结晶进一步纯化，在后续生物体利用中其质量无法保证。The above experimental results show that the salt-forming crystallization process of mesylate and fumarate of compound 1 is mature, the quality is controllable, and it is convenient for industrialization. However, compound 1 is difficult to crystallize, and cannot be further purified by crystallization in the process preparation, and its quality cannot be guaranteed in the subsequent utilization of organisms.
引湿性测试Humidity test
表7引湿性测试结果
Table 7 Humidity test results
以上结果表明甲磺酸盐晶型A的ΔW％值最小，略微有吸湿性，甲磺酸盐晶型B、盐酸盐晶型C、富马酸盐晶型D的引湿性值在2％～6％之间，小于15％，具有一定吸湿性。The above results show that the mesylate crystal form A has the smallest ΔW% value and is slightly hygroscopic. Between ~6%, less than 15%, it has certain hygroscopicity.
生物测试biological test
1.研究目的1. Research purpose
检测化合物对MCP-1趋化THP1细胞迁移的抑制作用。The inhibitory effect of compounds on MCP-1 chemotactic THP1 cell migration was detected.
2.实验原理2. Experimental principle
Transwell是一种被广泛用于研究细胞迁移和侵袭的实验装置，由上下两个可拆分的腔室构成，上室的底部为细胞可穿过的带孔的膜。我们将THP1细胞悬液接种于Transwell上室，将含有MCP-1的培养液加入Transwell下室，因为THP1细胞表达MCP-1受体CCR2，所以在MCP-1的上下室浓度差的趋化作用下，THP1细胞会通过上室底部的孔向下室迁移。因此，在加入待测化合物的情况下，通过检测细胞迁移开始一定时间之后下室的细胞数量，则可评估化合物对MCP-1趋化THP1细胞迁移的抑制作用。Transwell is an experimental device widely used to study cell migration and invasion. It consists of two detachable upper and lower chambers, and the bottom of the upper chamber is a perforated membrane that cells can pass through. We inoculated the THP1 cell suspension in the upper chamber of Transwell, and added the culture medium containing MCP-1 into the lower chamber of Transwell, because THP1 cells express the MCP-1 receptor CCR2, so the chemotaxis effect of the concentration difference in the upper and lower chambers of MCP-1 Next, THP1 cells migrate to the lower chamber through the holes in the bottom of the upper chamber. Therefore, in the case of adding the compound to be tested, the inhibitory effect of the compound on MCP-1 chemotactic THP1 cell migration can be evaluated by detecting the number of cells in the lower chamber after a certain period of time after the start of cell migration.
Transwell下室细胞数量通过CTG法检测：该试剂中的成分可与细胞裂解液中的ATP发生反应并产生 荧光，通过测定荧光强度可检测ATP含量，进而反映细胞数量。The number of cells in the lower chamber of Transwell is detected by CTG method: the components in this reagent can react with ATP in the cell lysate and produce Fluorescence, the ATP content can be detected by measuring the fluorescence intensity, which in turn reflects the number of cells.
3.实验材料3. Experimental materials
1.1细胞1.1 cells
THP1(来源于ATCC，货号TIB-202)THP1 (sourced from ATCC, product number TIB-202)
1.2主要试剂耗材1.2 Main reagent consumables
表8主要试剂
Table 8 Main Reagents
1.3主要仪器1.3 Main instruments
表9主要仪器
Table 9 Main Instruments
1.4化合物信息1.4 Compound information
表10化合物信息
Table 10 Compound information
4.实验方法4. Experimental method
1.5Transwell细胞迁移实验1.5 Transwell cell migration assay
1)配制培养液：1640培养基+1％胎牛血清+1％青/链霉素(百分比皆为体积比)。1) Preparation of culture medium: 1640 medium + 1% fetal bovine serum + 1% penicillin/streptomycin (all percentages are volume ratios).
2)用培养液将THP1细胞浓度调整为2×106个/mL，200μL/孔接种至96孔圆底板。2) The concentration of THP1 cells was adjusted to 2×10 6 cells/mL with culture medium, and 200 μL/well was inoculated into a 96-well round bottom plate.
3)在细胞中加入药物(具体见下方plate map)，37℃孵育30min。3) Add drugs to the cells (see the plate map below for details), and incubate at 37°C for 30min.
4)药物孵育过程中配制下室溶液：在培养液中加入MCP-1(终浓度100ng/mL)，再加入与步骤3)中对应位置相同的化合物。4) Prepare the lower chamber solution during drug incubation: add MCP-1 (final concentration 100 ng/mL) to the culture medium, and then add the same compound as the corresponding position in step 3).
5)从步骤3)中吸取50μL细胞悬液到对应的Transwell上室(上室细胞量为1×105)。5) Pipette 50 μL of the cell suspension from step 3) into the corresponding upper chamber of the Transwell (the cell volume in the upper chamber is 1×10 5 ).
6)取150μL步骤4)中配制的溶液到对应的下室，37℃孵育60min(细胞迁移)。6) Take 150 μL of the solution prepared in step 4) to the corresponding lower chamber, and incubate at 37° C. for 60 min (cell migration).
注：药物孵育时DMSO和Control组加入1/10000 DMSO；Control下室不加MCP-1。Note: 1/10000 DMSO was added to the DMSO and Control groups during drug incubation; MCP-1 was not added to the Control lower chamber.
1.6 CTG检测细胞数量1.6 CTG detection of cell number
1)孵育结束后将Transwell板子放在水平震荡器上500rpm震荡30s以使得粘附在上室下表面的细胞脱落进入下室。1) After the incubation, place the Transwell plate on a horizontal shaker at 500rpm for 30s so that the cells adhering to the lower surface of the upper chamber fall off and enter the lower chamber.
2)从Transwell下室吸取50μL细胞悬液进入96孔黑壁板。2) Pipette 50 μL of cell suspension from the lower chamber of the Transwell into a 96-well black-walled plate.
3)每孔加入50μL CTG溶液，避光400rpm水平震荡5min。3) Add 50 μL of CTG solution to each well, and shake horizontally at 400 rpm for 5 minutes in the dark.
4)避光静置10min后用酶标仪检测荧光强度。4) After standing in the dark for 10 minutes, detect the fluorescence intensity with a microplate reader.
5.数据处理5. Data processing
1)计算Inhibition％＝100-100×(加药样品孔荧光值-Control孔荧光均值)/(DMSO孔荧光均值-Control孔荧光均值)1) Calculation of Inhibition% = 100-100 × (fluorescence value of drug-dosed sample wells - average fluorescence value of Control wells) / (average fluorescence value of DMSO wells - average fluorescence value of Control wells)
注：原始数据(荧光值)及Inhibition％值见分别附录9.1和9.2Note: See Appendix 9.1 and 9.2 for raw data (fluorescence value) and Inhibition% value
2)将Inhibition％值带入Graphpadprism 8软件，使用log(inhibitor)vs.response--Variable slope(four parameters)方法绘制抑制曲线，并得到对应的绝对IC50值。2) Bring the Inhibition% value into Graphpadprism 8 software, use the log(inhibitor)vs.response--Variable slope(four parameters) method to draw the inhibition curve, and obtain the corresponding absolute IC 50 value.
6.实验结果6. Experimental results
表11化合物抑制MCP-1趋化作用的绝对IC50值(nM)
Absolute IC 50 values (nM) of compounds in table 11 inhibiting MCP-1 chemotaxis
结论in conclusion
两个化合物对MCP-1趋化THP1迁移均有抑制活性，本发明化合物1对MCP-1介导的THP1的趋化抑制强于BMS-813160。Both compounds have inhibitory activity on MCP-1 chemotactic THP1 migration, and Compound 1 of the present invention has stronger inhibitory activity on MCP-1-mediated THP1 chemotaxis than BMS-813160.
大鼠口服生物利用度Oral bioavailability in rats
表12为化合物1及其各盐的大鼠口服生物生物利用度实验。Table 12 is the oral bioavailability test of compound 1 and its salts in rats.
大鼠PK(注射剂量＝2mpk，口服剂量＝10mpk)口服生物利用度＝口服0～24小时暴露量/(注射0～24小时暴露量*5)Rat PK (injection dose = 2mpk, oral dose = 10mpk) oral bioavailability = oral exposure in 0-24 hours / (injection exposure in 0-24 hours * 5)
表12生物利用度
Table 12 Bioavailability
实验结果表明盐酸盐晶型C显著改善大鼠口服生物利用度，其生物利用度与化合物1的游离碱形态相比，生物利用度提高了19.7％。本发明目前仅对化合物1的盐酸盐晶型C做了测试，其相晶型(甲磺酸盐晶型A、甲磺酸盐晶型B、富马酸盐晶型D)还有待进一步实验研究。The experimental results showed that the hydrochloride crystal form C significantly improved the oral bioavailability in rats, and its bioavailability was increased by 19.7% compared with the free base form of compound 1. The present invention has only tested the hydrochloride crystal form C of compound 1, and its phase crystal forms (mesylate crystal form A, mesylate salt crystal form B, fumarate salt crystal form D) have yet to be further developed. Experimental Study.
以上研究结果表明，本发明中化合物1的各种晶型(甲磺酸盐晶型A、甲磺酸盐晶型B、盐酸盐晶型C、富马酸盐晶型D)不管是在工艺制备中的质量控制，还是药物稳定性以及生物利用度方面，都有优于化合物1的可能性，相比于化合物1，在制备治疗晚期实体瘤及淋巴瘤的药物及CCR2/5双重拮抗剂中具有更大的应用潜力。 The above research results show that the various crystal forms of compound 1 in the present invention (mesylate salt crystal form A, mesylate salt crystal form B, hydrochloride salt crystal form C, fumarate salt crystal form D) no matter in The quality control in the process preparation, or the drug stability and bioavailability, have the possibility of being superior to compound 1. Compared with compound 1, it is more effective in the preparation of drugs for the treatment of advanced solid tumors and lymphomas and CCR2/5 dual antagonists. agent has greater application potential.

Claims (28)

  1. 化合物1的甲烷磺酸盐、盐酸盐或富马酸盐，
    Methanesulfonate, hydrochloride or fumarate of compound 1,
  2. 根据权利要求1所述的盐，其选自，
    The salt according to claim 1, selected from the group consisting of,
  3. 式(I)化合物的A晶型，
    A crystal form of the compound of formula (I),
    其特征在于，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：9.536±0.200°，10.096±0.200°，14.412±0.200°，15.382±0.200°，16.949±0.200°，17.608±0.200°，20.401±0.200°。It is characterized in that its X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 10.096±0.200°, 14.412±0.200°, 15.382±0.200°, 16.949±0.200 °, 17.608±0.200°, 20.401±0.200°.
  4. 根据权利要求3所述的A晶型，其X射线粉末衍射图谱还包括下列2θ角处具有特征衍射峰之一或两种以上：18.628±0.200°，21.066±0.200°，21.702±0.200°，23.326±0.200°，23.956±0.200°，27.143±0.200°。The crystal form A according to claim 3, whose X-ray powder diffraction pattern also includes one or more than two characteristic diffraction peaks at the following 2θ angles: 18.628±0.200°, 21.066±0.200°, 21.702±0.200°, 23.326± 0.200°, 23.956±0.200°, 27.143±0.200°.
  5. 根据权利要求3所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536±0.200°，10.096±0.200°，14.412±0.200°，15.382±0.200°，16.949±0.200°，17.608±0.200°，18.628±0.200°，19.520±0.200°，20.401±0.200°，21.066±0.200°，21.702±0.200°，22.347±0.200°，23.326±0.200°，23.956±0.200°，25.000±0.200°，27.143±0.200°。The crystal form A according to claim 3, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.536±0.200°, 10.096±0.200°, 14.412±0.200°, 15.382±0.200°, 16.949±0.200 °, 17.608±0.200°, 18.628±0.200°, 19.520±0.200°, 20.401±0.200°, 21.066±0.200°, 21.702±0.200°, 22.347±0.200°, 23.326±0.200°, 23.956± 0.200°, 25.000±0.200 °, 27.143±0.200°.
  6. 根据权利要求5所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.536°，10.096°，10.763°，13.126°，13.586°，14.412°，15.382°，16.009°，16.949°，17.608°，17.984°，18.628°，19.520°，20.401°，21.066°，21.702°，22.347°，23.326°，23.956°，25.000°，26.648°，27.143°，27.942°，28.520°，29.350°，30.752°，31.429°，34.439°，35.134°。According to the crystal form A according to claim 5, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.536°, 10.096°, 10.763°, 13.126°, 13.586°, 14.412°, 15.382°, 16.009° , 16.949°, 17.608°, 17.984°, 18.628°, 19.520°, 20.401°, 21.066°, 21.702°, 22.347°, 23.326°, 23.956°, 25.000°, 26.648°, 27.143°, 27.942°, 28.520°, 29.350 °, 30.752°, 31.429°, 34.439°, 35.134°.
  7. 根据权利要求3～6任意一项所述的A晶型，其差示扫描量热曲线在164.38℃±3.0℃处有吸热峰。According to the crystal form A described in any one of claims 3-6, its differential scanning calorimetry curve has an endothermic peak at 164.38°C±3.0°C.
  8. 根据权利要求3～6任意一项所述的A晶型，其热重分析曲线在150.0℃±3.0℃时有失重。According to the crystal form A described in any one of claims 3-6, its thermogravimetric analysis curve has weight loss at 150.0°C±3.0°C.
  9. 式(I)化合物的B晶型，
    Form B of the compound of formula (I),
    其特征在于，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：4.660±0.200°，9.220±0.200°，11.650±0.200°，14.570±0.200°，16.740±0.200°，17.970±0.200°，18.620±0.200°，20.890±0.200°。It is characterized in that its X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 4.660±0.200°, 9.220±0.200°, 11.650±0.200°, 14.570±0.200°, 16.740±0.200 °, 17.970±0.200°, 18.620±0.200°, 20.890±0.200°.
  10. 根据权利要求9所述的B晶型，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：10.450±0.200°，15.670±0.200°，22.020±0.200°，22.740±0.200°，23.270±0.200°，24.380±0.200°，26.930±0.200°。The crystal form B according to claim 9, whose X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 10.450±0.200°, 15.670±0.200°, 22.020±0.200°, 22.740 ±0.200°, 23.270±0.200°, 24.380±0.200°, 26.930±0.200°.
  11. 根据权利要求9所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660±0.200°，9.220±0.200°，10.450±0.200°，11.650±0.200°，14.570±0.200°，15.670±0.200°，16.740±0.200°，17.970±0.200°，18.620±0.200°，20.890±0.200°，22.020±0.200°，22.740±0.200°，23.270±0.200°，24.380±0.200°，26.930±0.200°。The crystal form B according to claim 9, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.660±0.200°, 9.220±0.200°, 10.450±0.200°, 11.650±0.200°, 14.570±0.200 °, 15.670±0.200°, 16.740±0.200°, 17.970±0.200°, 18.620±0.200°, 20.890±0.200°, 22.020±0.200°, 22.740±0.200°, 23.270±0.200°, 24.380± 0.200°, 26.930±0.200 °.
  12. 根据权利要求9所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.660°，5.240°，9.220°，10.450°，11.650°，14.570°，15.670°，16.740°，17.970°，18.620°，19.880°，20.890°，21.310°，22.020°，22.740°，23.040°，23.270°，24.380°，25.220°，25.780°，26.930°。The B crystal form according to claim 9, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.660°, 5.240°, 9.220°, 10.450°, 11.650°, 14.570°, 15.670°, 16.740° , 17.970°, 18.620°, 19.880°, 20.890°, 21.310°, 22.020°, 22.740°, 23.040°, 23.270°, 24.380°, 25.220°, 25.780°, 26.930°.
  13. 根据权利要求9～12任意一项所述的B晶型，其差示扫描量热曲线在166.7℃±3.0℃处有吸热峰。According to any one of claims 9-12, the crystal form B has an endothermic peak at 166.7°C±3.0°C in its differential scanning calorimetry curve.
  14. 根据权利要求9～12任意一项所述的B晶型，其热重分析曲线在130.0℃±3.0℃时有失重。According to the crystal form B according to any one of claims 9-12, its thermogravimetric analysis curve has weight loss at 130.0°C±3.0°C.
  15. 式(II)化合物的C晶型，
    Form C of the compound of formula (II),
    其特征在于，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：7.980±0.200°，12.380±0.200°，15.350±0.200°，16.700±0.200°，18.640±0.200°，19.580±0.200°，20.150±0.200°。It is characterized in that its X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 7.980±0.200°, 12.380±0.200°, 15.350±0.200°, 16.700±0.200°, 18.640±0.200 °, 19.580±0.200°, 20.150±0.200°.
  16. 根据权利要求15所述的C晶型，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：6.760±0.200°，11.180±0.200°，21.310±0.200°，23.520±0.200°，24.720±0.200°，26.090±0.200°。The crystal form C according to claim 15, whose X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 6.760±0.200°, 11.180±0.200°, 21.310±0.200°, 23.520 ±0.200°, 24.720±0.200°, 26.090±0.200°.
  17. 根据权利要求15所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.760±0.200°，7.980±0.200°，11.180±0.200°，12.380±0.200°，15.350±0.200°，16.700±0.200°，18.640±0.200°，19.580±0.200°，20.150±0.200°，21.310±0.200°，23.520±0.200°，24.720±0.200°，26.090±0.200°。According to the crystal form C according to claim 15, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.760±0.200°, 7.980±0.200°, 11.180±0.200°, 12.380±0.200°, 15.350±0.200 °, 16.700±0.200°, 18.640±0.200°, 19.580±0.200°, 20.150±0.200°, 21.310±0.200°, 23.520±0.200°, 24.720±0.200°, 26.090±0.200°.
  18. 根据权利要求15所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.760°，7.980°，10.140°，11.180°，12.380°，13.050°，15.350°，16.450°，16.700°，17.050°，18.640°，19.110°，19.580°，19.990°，20.150°，21.310°，22.980°，23.520°，23.710°，24.720°，26.090°，26.330°，27.380°。The crystal form C according to claim 15, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.760°, 7.980°, 10.140°, 11.180°, 12.380°, 13.050°, 15.350°, 16.450° ，16.700°，17.050°，18.640°，19.110°，19.580°，19.990°，20.150°，21.310°，22.980°，23.520°，23.710°，24.720°，26.090°，26.330°，27.380°。
  19. 根据权利要求15～18任意一项所述的C晶型，其差示扫描量热曲线在153.3℃±3.0℃处有吸热峰。According to the crystal form C according to any one of claims 15-18, its differential scanning calorimetry curve has an endothermic peak at 153.3°C±3.0°C.
  20. 根据权利要求15～18任意一项所述的C晶型，其热重分析曲线在130.0℃±3.0℃时有失重。According to the crystal form C according to any one of claims 15-18, its thermogravimetric analysis curve has weight loss at 130.0°C±3.0°C.
  21. 式(III)化合物的D晶型，
    Form D of the compound of formula (III),
    其特征在于，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：4.420°±0.200°，6.199±0.200°，11.334±0.200°，12.989±0.200°，13.705±0.200°，15.124±0.200°，16.486±0.200°，17.680±0.200°，18.236±0.200°，19.195±0.200°。It is characterized in that its X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 4.420°±0.200°, 6.199±0.200°, 11.334±0.200°, 12.989±0.200°, 13.705± 0.200°, 15.124±0.200°, 16.486±0.200°, 17.680±0.200°, 18.236±0.200°, 19.195±0.200°.
  22. 根据权利要求21所述的D晶型，其X射线粉末衍射图谱至少包括在下列2θ角处具有特征衍射峰之一或两种以上：20.491±0.200°，21.505±0.200°，22.693±0.200°，25.237±0.200°。The crystal form D according to claim 21, whose X-ray powder diffraction pattern includes at least one or more than two characteristic diffraction peaks at the following 2θ angles: 20.491±0.200°, 21.505±0.200°, 22.693±0.200°, 25.237 ±0.200°.
  23. 根据权利要求21所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.420°，6.199°，8.651°，11.334°，12.344°，12.989°，13.705°，15.124°，15.699°，16.486°，17.680°，18.236°，18.866°，19.195°，20.491°，21.505°，22.693°，24.100°，25.237°，30.453°。According to the crystal form D according to claim 21, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.420°, 6.199°, 8.651°, 11.334°, 12.344°, 12.989°, 13.705°, 15.124° , 15.699°, 16.486°, 17.680°, 18.236°, 18.866°, 19.195°, 20.491°, 21.505°, 22.693°, 24.100°, 25.237°, 30.453°.
  24. 根据权利要求21～23任意一项所述的D晶型，其差示扫描量热曲线在160.35℃±3.0℃处有吸热峰。According to the crystal form D according to any one of claims 21-23, its differential scanning calorimetry curve has an endothermic peak at 160.35°C±3.0°C.
  25. 根据权利要求21～23任意一项所述的D晶型，其热重分析曲线在121.75℃±3.0℃时有失重。 According to the crystal form D according to any one of claims 21-23, its thermogravimetric analysis curve shows weight loss at 121.75°C±3.0°C.
  26. 根据权利要求1或2所述的盐型、权利要求3～8任意一项所述的A晶型或根据权利要求9～14任意一项所述的B晶型或根据权利要求15～20任意一项所述的C晶型或根据权利要求21～25任意一项所述的D晶型在制备CCR2或/和CCR5拮抗剂中的应用。The salt form according to claim 1 or 2, the A crystal form according to any one of claims 3-8, or the B crystal form according to any one of claims 9-14, or any one of claims 15-20. Use of one of the crystal forms C or the crystal form D according to any one of claims 21-25 in the preparation of CCR2 and/or CCR5 antagonists.
  27. 根据权利要求1或2所述的盐型、权利要求3～8任意一项所述的A晶型或根据权利要求9～14任意一项所述的B晶型或根据权利要求15～20任意一项所述的C晶型或根据权利要求21～25任意一项所述的D晶型在制备治疗晚期实体瘤、淋巴瘤或与非酒精性脂肪性肝炎相关疾病的药物上的应用。The salt form according to claim 1 or 2, the A crystal form according to any one of claims 3-8, or the B crystal form according to any one of claims 9-14, or any one of claims 15-20. Use of one of the crystal forms C or the crystal form D according to any one of claims 21-25 in the preparation of a medicament for treating advanced solid tumors, lymphomas or diseases related to non-alcoholic steatohepatitis.
  28. 据权利要求1或2所述的盐型、权利要求3～8任意一项所述的A晶型或根据权利要求9～14任意一项所述的B晶型或根据权利要求15～20任意一项所述的C晶型或根据权利要求21～25任意一项所述的D晶型在制备治疗肝癌、胰腺癌、非小细胞肺癌、结直肠癌的药物上的应用。 The salt form according to claim 1 or 2, the A crystal form according to any one of claims 3-8, or the B crystal form according to any one of claims 9-14, or any one of claims 15-20 Use of one of the crystal forms C or the crystal form D according to any one of claims 21-25 in the preparation of drugs for treating liver cancer, pancreatic cancer, non-small cell lung cancer, and colorectal cancer.
PCT/CN2023/072025 2022-01-26 2023-01-13 Salt form and crystal form of azabenzo eight-membered ring compound and application thereof WO2023143112A1 (en)

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JP2003119191A (en) * 2001-08-08 2003-04-23 Takeda Chem Ind Ltd Benzoazepine derivative, production method and use thereof
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