CN113754657A - 大环类化合物的晶型及其制备方法和应用 - Google Patents
大环类化合物的晶型及其制备方法和应用 Download PDFInfo
- Publication number
- CN113754657A CN113754657A CN202111111449.1A CN202111111449A CN113754657A CN 113754657 A CN113754657 A CN 113754657A CN 202111111449 A CN202111111449 A CN 202111111449A CN 113754657 A CN113754657 A CN 113754657A
- Authority
- CN
- China
- Prior art keywords
- macrocyclic compound
- crystalline form
- crystal form
- solvent
- filter residue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002678 macrocyclic compounds Chemical class 0.000 title claims abstract description 53
- 239000013078 crystal Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 14
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000036210 malignancy Effects 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- 239000000843 powder Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000003795 desorption Methods 0.000 description 8
- 238000001179 sorption measurement Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000007416 differential thermogravimetric analysis Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010011796 Cystitis interstitial Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 101150111783 NTRK1 gene Proteins 0.000 description 1
- 101150117329 NTRK3 gene Proteins 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
- 101150056950 Ntrk2 gene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 241000238711 Pyroglyphidae Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000013507 chronic prostatitis Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940046533 house dust mites Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 108010064892 trkC Receptor Proteins 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed 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
- A61K31/435—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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Transplantation (AREA)
- Psychology (AREA)
- Dermatology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明属于药物合成技术领域,公开了大环类化合物的晶型及其制备方法和应用。该大环类化合物为(6R,16R)‑9‑氟‑16‑甲基‑13‑氧杂‑2,17,21,25‑四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷‑1(25),7,9,11,18(26),19,21,23‑辛烷‑19‑腈,该晶型的X射线衍射图在2θ值为9.49±0.2、10.60±0.2、11.54±0.2、14.10±0.2、17.09±0.2、19.15±0.2、20.30±0.2、22.85±0.2、23.89±0.2和27.74±0.2处具有特征峰。该晶型无引湿性,具有良好稳定性和药代动力学性质。
Description
技术领域
本发明属于药物合成技术领域,具体涉及大环类化合物的晶型及其制备方法和应用。
背景技术
原肌球蛋白相关激酶(简称Trk激酶)是一类神经生长因子受体,其家族由高度同源性的TrkA、TrkB以及TrkC组成,分别由NTRK1、NTRK2和NTRK3基因编码。正常生理条件下,Trk蛋白是神经生长因子的高亲和力受体。在器官形成过程中,Trk蛋白在神经元组织中表达,它们在中枢和外周神经系统发育中起关键作用。当染色体变异发生NTRK基因融合,导致嵌合型Trk蛋白的高表达,致使Trk激酶下游信号通路调控失常,该通路的过度激活可导致癌症产生。
NTRK基因融合出现在多种成人和儿童实体瘤之中,包括乳腺癌、结直肠癌、非小细胞肺癌,以及各种肉瘤。目前靶向NTRK融合基因的临床在研新药有多种,它们都具有Trk激酶抑制活性,大多通过与ATP竞争结合位点实现抑制激酶催化活性。现有技术公开了一种大环类激酶抑制剂,该类化合物显示良好的Trk抑制活性和选择性,并且展示出良好的体内肿瘤生长抑制作用。经研究发现,其中的大环类化合物(6R,16R)-9-氟-16-甲基-13-氧杂 -2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷 -19-腈具有较佳的效果,大环类化合物的结构如下式所示。
现有技术虽然公开了大环类化合物的一般制备方法,但没有提供化合物的结晶形式以及结晶形式相应的制备方法。
众所周知,药物分子通常具有多种排列方式,不同的排列方式构成了不同的晶型,即药物的多晶型现象,其一般表现为药物原料在固体状态下的存在形式。一种药物可以有多种晶型,同一种药物的不同晶型,除了稳定性有差异以外,其在体内的溶解和吸收也可能有所不同,从而影响临床疗效和安全性。而目前并没有对大环类化合物(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19- 腈相关晶型的研究,无定型的化合物其引湿性、稳定性差,制备的药物不能发挥良好的作用。
因此,亟需提供一种大环类化合物的晶型,具有良好的物理、化学稳定性,且无引湿性,能够表现出良好的药代动力学性质。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出大环类化合物的晶型,具有良好的物理、化学稳定性,且无引湿性,能够表现出良好的药代动力学性质。
本发明第一方面提供了大环类化合物的晶型。
具体的,大环类化合物的晶型,所述大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂 -2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19- 腈,所述晶型的X射线衍射图在2θ值为9.49±0.2、10.60±0.2、11.54±0.2、14.10±0.2、17.09±0.2、 19.15±0.2、20.30±0.2、22.85±0.2、23.89±0.2和27.74±0.2处具有特征峰。
优选的,所述晶型的X射线衍射图还在2θ值为18.75±0.2、21.29±0.2、24.25±0.2、24.99±0.2、 28.74±0.2和31.35±0.2处具有特征峰。
进一步优选的,所述晶型的X射线衍射图还在2θ值为5.69±0.2、16.11±0.2、25.62±0.2、 26.34±0.2、27.26±0.2、29.91±0.2、32.19±0.2、33.86±0.2、34.70±0.2、35.59±0.2、36.95±0.2、 37.40±0.2、39.19±0.2、40.33±0.2、41.16±0.2、42.56±0.2、43.11±0.2、45.30±0.2、46.35±0.2 和49.80±0.2处具有特征峰。
优选的,所述晶型的差示扫描量热图在233±5℃处有吸热峰;进一步优选的,所述晶型的差示扫描量热图在233±3℃处有吸热峰。
本发明第二方面提供了上述大环类化合物的晶型的制备方法。
具体的,上述大环类化合物的晶型的制备方法,选自以下三种方式之一:
(1)向所述大环类化合物中加入溶剂至过饱和状态,然后搅拌,析晶,再经过滤得滤渣,将所述滤渣干燥即制得晶型;
或,
(2)将所述大环类化合物加热溶解于溶剂中,然后冷却析晶,再经过滤得滤渣,将所述滤渣干燥即制得晶型;
或,
(3)将所述大环类化合物溶解于溶剂中,然后加入抗溶剂,析晶,再经过滤得滤渣,将所述滤渣干燥即制得晶型。
在方式(1)-(3)中,所述大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25- 四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈,所述大环类化合物的晶型没有特别限定,可以使用其他结晶形式或无定型。
优选的,在方式(2)中,所述加热的温度为40-100℃;进一步优选的,在方式(2)中,所述加热的温度为50-80℃。
优选的,方式(1)-(3)中所述溶剂和方式(3)中所述抗溶剂选自C2-C7烃类物质、C2-C7醇类物质、C2-C7酮类物质、C2-C7腈类物质、C2-C7醚类物质、C2-C7酯类物质或水中的一种或几种。
优选的,所述C2-C7烃类物质包含二氯甲烷、正庚烷或甲苯。
优选的,所述C2-C7醇类物质包含甲醇、乙醇、三氟乙醇、正丙醇或异丙醇。
优选的,所述C2-C7酮类物质包含丙酮或丁酮。
优选的,所述C2-C7腈类物质包含乙腈。
优选的,所述C2-C7醚类物质包含异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二氧六环。
优选的,所述C2-C7酯类物质包含乙酸乙酯或乙酸异丙酯。
优选的,所述溶剂选自甲醇、乙醇、丙酮、二氯甲烷、四氢呋喃或水中的至少一种。
优选的,所述抗溶剂选自异丙醚、正庚烷或水中的至少一种。
本发明第三方面提供了上述大环类化合物的晶型的应用。
具体的,上述大环类化合物的晶型在制备Trk激酶相关疾病的药物中的应用。
优选的,所述Trk激酶相关疾病包括疼痛、恶性肿瘤、炎性疾病或神经退行性疾病中的一种。
优选的,所述疼痛包括慢性疼痛和急性疼痛,包括但不限于由癌症、外科手术、骨折、肿瘤转移等引起的骨痛、内脏痛、炎性痛、偏头痛、慢性腰背痛、膀胱疼痛综合征和神经性疼痛。
优选的,所述恶性肿瘤是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种,受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。所述恶性肿瘤包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌、纤维肉瘤、鳞状细胞癌、黑素瘤或卵巢癌。
优选的,所述炎性疾病包括以组织病理性炎症为特征的多种病症。所述炎性疾病包括寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球性肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症或间质性膀胱炎。炎性疾病与自身免疫性疾病之间存在显著重叠。
优选的,神经退休性疾病包括多发性硬化症、帕金森氏症和阿尔茨海默症。
相对于现有技术,本发明的有益效果如下:
本发明提供的大环类化合物的晶型无引湿性,且高温、高湿或光照条件对其纯度的影响小,该晶型具有良好的化学稳定性;该晶型在温度40℃±2℃,相对湿度75%±5%的加速条件下放置6个月,其晶型仍然保持一致,具有良好的物理稳定性;此外,该晶型具有良好的药代动力学性质。
附图说明
图1为本发明实施例1制备的晶型的PXRD谱图;
图2为本发明实施例1制备的晶型的DSC谱图;
图3为本发明实施例1制备的晶型的TGA谱图;
图4为本发明对比例1制备的无定型的PXRD谱图;
图5为本发明实施例1制备的晶型的DVS等温吸附、脱附图;
图6为本发明对比例1制备的无定型的DVS等温吸附、脱附图。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案,现列举以下实施例进行说明。需要指出的是,以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例或对比例中所用的原料、试剂如无特殊说明,均可从常规商业途径得到,或者可以通过现有已知方法得到。以下实施例或对比例中所用的主要测试仪器如表1所示。
表1
仪器名称 | 仪器型号 |
X-射线粉末衍射仪(PXRD) | Bruker D8 Advance Diffractometer |
差示扫描量热仪(DSC) | TA Instruments Q200 DSC |
热重分析仪(TGA) | TA Instruments Q500 TGA |
动态水分吸附仪(DVS) | TA Instruments Q5000 TGA |
高效液相色谱(HPLC) | Agilent 1260HPLC |
实施例1
一种大环类化合物的晶型的制备方法,包括以下步骤:
将1mg按专利CN110386945A实施例1制备得到的大环类化合物(6R,16R)-9-氟-16-甲基 -13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入1.0mL甲醇中,室温(25±5℃)下搅拌溶清后,缓慢滴加0.8mL水,析出固体后,继续搅拌一段时间,过滤,将滤渣干燥,得结晶性粉末。
对得到的结晶性粉末进行X-射线粉末衍射、差热扫描量热分析以及热重分析。该结晶样品经表征后,命名为晶型。其PXRD谱图(X射线粉末衍射谱图)见图1,图1表明样品在2θ值为5.69、9.49、10.60、11.54、14.10、16.11、17.09、18.75、19.15、20.30、21.29、22.85、23.89、24.25、24.99、25.62、26.34、27.26、27.74、28.74、29.91、31.35、32.19、33.86、34.70、 35.59、36.95、37.40、39.19、40.33、41.16、42.56、43.11、45.30、46.35和49.80处有特征峰,其中2θ角度的仪器测量误差值为±0.2。DSC谱图(差示扫描量热谱图)见图2,图2中横坐标为温度(Temperature),纵坐标为热流量(Heat Flow),图2显示样品在233℃处有吸热峰。TGA谱图(热重分析谱图)见图3,图3中横坐标为温度(Temperature),纵坐标为重量(Weight),图3显示样品在150℃前有约0.3%的缓慢失重,为无水物,分解温度约为295℃。
实施例2
一种大环类化合物的晶型的制备方法,包括以下步骤:
将15mg(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷 -1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入0.4mL甲醇中,室温搅拌溶清后,将溶液缓慢加入0.8mL水中,析出固体后,继续搅拌一段时间后,过滤,干燥,得浅黄色结晶性粉末。该结晶样品的PXRD谱图和DSC谱图经对比后,确定为与实施例1相同晶型。
实施例3
一种大环类化合物的晶型的制备方法,包括以下步骤:
将15mg(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02, 6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入0.2mL二氯甲烷中,室温搅拌溶清后,缓慢滴加3.6mL正庚烷,析出固体后,继续搅拌一段时间后,过滤,干燥,得结晶性粉末。该结晶样品的PXRD谱图和DSC谱图经对比后,确定为与实施例1相同晶型。
实施例4
一种大环类化合物的晶型的制备方法,包括以下步骤:
将15mg(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入1.8mL甲醇和0.2mL水的混合溶剂中,加热至65℃,搅拌溶清后,缓慢冷却,在4℃下保温搅拌,析出固体后,过滤,干燥,得结晶性粉末。该结晶样品的PXRD谱图和DSC谱图经对比后,确定为与实施例1相同晶型。
对比例1
一种无定型的大环类化合物的制备方法,包括以下步骤:
将15mg按专利CN110386945A所公开的方法制备得到的化合物(6R,16R)-9-氟-16-甲基 -13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈加入0.4mL二甲基亚砜中,室温搅拌溶清后,缓慢滴加0.6mL水,析出固体后,继续搅拌一段时间后,过滤,干燥,得结晶性粉末。对得到的结晶性粉末进行X-射线粉末衍射、差热扫描量热分析以及热重分析。该样品经X-射线粉末衍射表征,确定为无定型,PXRD谱图(X射线粉末衍射谱图)见图4,图4中横坐标为2θ(Two-theta),纵坐标为强度(Intensity)。
产品效果测试
(1)引湿性测试
对本发明提供的大环类化合物的晶型与无定型进行引湿性评价,引湿性数据利用动态水分吸附仪进行检测,引湿性特征描述与引湿性增重的界定参照《中国药典》2020年版四部通则9103,如表2所示。
表2
引湿性特征描述 | 引湿增重 |
潮解 | 吸收足量水分形成液体 |
极具引湿性 | 不小于15% |
有引湿性 | 小于15%但不小于2% |
略有引湿性 | 小于2%但不小于0.2% |
无或几乎无引湿性 | 小于0.2% |
实施例1制备的晶型的等温吸附、脱附图见图5,图5中横坐标为相对湿度(Relative Humidity),纵坐标为重量百分数(Weight/%),图5中两条曲线分别代表吸附与脱附曲线,由于脱附时可能存在滞后现象,导致两条曲线不重合。图5显示样品在相对湿度(RH) 为0%-80%之间,随着湿度增加,重量变化约为0.1%,表明样品不吸湿,无引湿性。对比例1制备的无定型的大环类化合物的等温吸附、脱附图见图6,图6中横坐标为相对湿度(Relative Humidity),纵坐标为重量百分数(Weight/%),图6中两条曲线分别代表吸附与脱附曲线,由于脱附时可能存在滞后现象,导致两条曲线不重合,图6显示样品在相对湿度为0%-80%之间,随着湿度增加,重量增加约为21.6%,表明样品极易吸湿,极具引湿性。实验结果表明,在引湿性方面,该晶型比无定型显示出更优良的性质。
(2)影响因素稳定性测试
对本发明提供的大环类化合物的晶型与无定型进行影响因素稳定性考察,考察条件参照《中国药典》2020年版四部通则9103。考察内容如下:将实施例制备的大环类化合物的晶型和对比例1制备的无定型的大环类化合物敞口放置,考察在高温(60℃±2℃)、高湿90%±5%RH、25℃±2℃)以及光照(4500±500Lx)条件下的稳定性,考察周期为30天,取样时间点为5天、10天和30天,对应时间点的样品纯度通过高效液相色谱检测,以面积归一化法计算,结果如表3所示。
表3
实验显示对比例1制备的无定型的大环类化合物在高温、高湿和光照条件下,考察周期内的纯度均有下降,尤其是在30天后,高温、光照使得化合物的纯度下降明显。而实施例1 制备的晶型的杂质含量仅在光照条件下略微增长,其余条件下无显著变化。
(3)加速稳定性试验
对本发明提供的大环类化合物的晶型进行加速稳定性考察,考察晶型的稳定性。考察条件参照《中国药典》2020年版四部通则9103。考察内容如下:将晶型样品密封放置,考察在温度40℃±2℃,相对湿度75%±5%条件下的晶型稳定性,考察周期为6个月,取样时间点为 1月、2月、3月和6月,对应时间点的样品晶型通过X-射线粉末衍射仪检测,结果如表4 所示。
表4
实验显示本发明提供的大环类化合物的晶型样品在加速试验条件下,放置6个月化合物的晶型仍然保持一致,本发明提供的大环类化合物的晶型具有更良好的物理稳定性。
(4)药代动力学试验
取雄性比格犬,3只为一组,单次经口灌胃给予本发明提供的大环类化合物的晶型样品,剂量为8mg/kg,采样时间点为0.25、0.5、1.0、2.0、4.0、6.0、8.0和24小时。根据样品浓度建立合适范围的标准曲线,并测定血浆样品中供试样品的浓度,进行定量分析和计算药代动力学参数,结果如表5所示。表5中,Cmax为药物的达峰浓度,AUC0-last是药时曲线下面积,Tmax为药物作用的达峰时间,T1/2为药物的消除半衰期。
表5
由表5可知,本发明提供的大环类化合物的晶型在比格犬体内吸收较快,血浆暴露量较大,表明其具有良好的药代动力学性质。
Claims (10)
1.一种大环类化合物的晶型,所述大环类化合物为(6R,16R)-9-氟-16-甲基-13-氧杂-2,17,21,25-四氮杂戊环[16.6.2.02,6.07,12.022,26]二十六烷-1(25),7,9,11,18(26),19,21,23-辛烷-19-腈,其特征在于,所述晶型的X射线衍射图在2θ值为9.49±0.2、10.60±0.2、11.54±0.2、14.10±0.2、17.09±0.2、19.15±0.2、20.30±0.2、22.85±0.2、23.89±0.2和27.74±0.2处具有特征峰。
2.根据权利要求1所述的大环类化合物的晶型,其特征在于,所述晶型的X射线衍射图还在2θ值为18.75±0.2、21.29±0.2、24.25±0.2、24.99±0.2、28.74±0.2和31.35±0.2处具有特征峰。
3.根据权利要求1或2所述的晶型,其特征在于,所述晶型的X射线衍射图还在2θ值为5.69±0.2、16.11±0.2、25.62±0.2、26.34±0.2、27.26±0.2、29.91±0.2、32.19±0.2、33.86±0.2、34.70±0.2、35.59±0.2、36.95±0.2、37.40±0.2、39.19±0.2、40.33±0.2、41.16±0.2、42.56±0.2、43.11±0.2、45.30±0.2、46.35±0.2和49.80±0.2处具有特征峰。
4.根据权利要求1所述的大环类化合物的晶型,其特征在于,所述晶型的差示扫描量热图在233±5℃处有吸热峰。
5.权利要求1-4中任一项所述的大环类化合物的晶型的制备方法,其特征在于,选自以下三种方式之一:
(1)向所述大环类化合物中加入溶剂至过饱和状态,然后搅拌,析晶,再经过滤得滤渣,将所述滤渣干燥即制得晶型;
或,
(2)将所述大环类化合物加热溶解于溶剂中,然后冷却析晶,再经过滤得滤渣,将所述滤渣干燥即制得晶型;
或,
(3)将所述大环类化合物溶解于溶剂中,然后加入抗溶剂,析晶,再经过滤得滤渣,将所述滤渣干燥即制得晶型。
6.根据权利要求5所述的制备方法,其特征在于,方式(1)-(3)中所述溶剂和方式(3)中所述抗溶剂选自C2-C7烃类物质、C2-C7醇类物质、C2-C7酮类物质、C2-C7腈类物质、C2-C7醚类物质、C2-C7酯类物质或水中的一种或几种。
7.根据权利要求6所述的制备方法,其特征在于,所述C2-C7烃类物质包含二氯甲烷、正庚烷或甲苯;所述C2-C7醇类物质包含甲醇、乙醇、三氟乙醇、正丙醇或异丙醇;所述C2-C7酮类物质包含丙酮或丁酮;所述C2-C7腈类物质包含乙腈;所述C2-C7醚类物质包含异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二氧六环;所述C2-C7酯类物质包含乙酸乙酯或乙酸异丙酯。
8.根据权利要求6所述的制备方法,其特征在于,所述溶剂选自甲醇、乙醇、丙酮、二氯甲烷、四氢呋喃或水中的至少一种;所述抗溶剂选自异丙醚、正庚烷或水中的至少一种。
9.权利要求1-4中任一项所述的大环类化合物的晶型在制备Trk激酶相关疾病的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述Trk激酶相关疾病包括疼痛、恶性肿瘤、炎性疾病或神经退行性疾病中的一种。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111111449.1A CN113754657B (zh) | 2021-09-22 | 2021-09-22 | 大环类化合物的晶型及其制备方法和应用 |
KR1020247012379A KR20240060655A (ko) | 2021-09-22 | 2022-05-17 | 거대고리 화합물의 결정형 및 제조 방법 및 그 용도 |
AU2022350240A AU2022350240A1 (en) | 2021-09-22 | 2022-05-17 | Crystal form of macrocyclic compound, and preparation method therefor and use thereof |
PCT/CN2022/093322 WO2023045360A1 (zh) | 2021-09-22 | 2022-05-17 | 大环类化合物的晶型及其制备方法和应用 |
CA3232913A CA3232913A1 (en) | 2021-09-22 | 2022-05-17 | Crystal form of macrocyclic compound, and preparation method therefor and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111111449.1A CN113754657B (zh) | 2021-09-22 | 2021-09-22 | 大环类化合物的晶型及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113754657A true CN113754657A (zh) | 2021-12-07 |
CN113754657B CN113754657B (zh) | 2023-01-17 |
Family
ID=78796888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111111449.1A Active CN113754657B (zh) | 2021-09-22 | 2021-09-22 | 大环类化合物的晶型及其制备方法和应用 |
Country Status (5)
Country | Link |
---|---|
KR (1) | KR20240060655A (zh) |
CN (1) | CN113754657B (zh) |
AU (1) | AU2022350240A1 (zh) |
CA (1) | CA3232913A1 (zh) |
WO (1) | WO2023045360A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023045360A1 (zh) * | 2021-09-22 | 2023-03-30 | 成都先导药物开发股份有限公司 | 大环类化合物的晶型及其制备方法和应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109956957A (zh) * | 2017-12-22 | 2019-07-02 | 成都先导药物开发股份有限公司 | 一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂 |
CN110386945A (zh) * | 2018-04-18 | 2019-10-29 | 成都先导药物开发股份有限公司 | 一种大环类激酶抑制剂 |
CN112174982A (zh) * | 2020-09-10 | 2021-01-05 | 上海希迈医药科技有限公司 | 一种洛普替尼晶型及其制备方法 |
CN113045587A (zh) * | 2019-12-27 | 2021-06-29 | 成都倍特药业股份有限公司 | 一种大环结构化合物的晶型及其制备方法 |
CN113121568A (zh) * | 2019-12-31 | 2021-07-16 | 成都倍特药业股份有限公司 | 一种大环结构化合物的盐及其制备方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8765727B2 (en) * | 2009-01-23 | 2014-07-01 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
CN113754657B (zh) * | 2021-09-22 | 2023-01-17 | 广州白云山医药集团股份有限公司白云山制药总厂 | 大环类化合物的晶型及其制备方法和应用 |
-
2021
- 2021-09-22 CN CN202111111449.1A patent/CN113754657B/zh active Active
-
2022
- 2022-05-17 AU AU2022350240A patent/AU2022350240A1/en active Pending
- 2022-05-17 CA CA3232913A patent/CA3232913A1/en active Pending
- 2022-05-17 KR KR1020247012379A patent/KR20240060655A/ko unknown
- 2022-05-17 WO PCT/CN2022/093322 patent/WO2023045360A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109956957A (zh) * | 2017-12-22 | 2019-07-02 | 成都先导药物开发股份有限公司 | 一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂 |
CN110386945A (zh) * | 2018-04-18 | 2019-10-29 | 成都先导药物开发股份有限公司 | 一种大环类激酶抑制剂 |
CN113045587A (zh) * | 2019-12-27 | 2021-06-29 | 成都倍特药业股份有限公司 | 一种大环结构化合物的晶型及其制备方法 |
CN113121568A (zh) * | 2019-12-31 | 2021-07-16 | 成都倍特药业股份有限公司 | 一种大环结构化合物的盐及其制备方法 |
CN112174982A (zh) * | 2020-09-10 | 2021-01-05 | 上海希迈医药科技有限公司 | 一种洛普替尼晶型及其制备方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023045360A1 (zh) * | 2021-09-22 | 2023-03-30 | 成都先导药物开发股份有限公司 | 大环类化合物的晶型及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
AU2022350240A1 (en) | 2024-04-04 |
CN113754657B (zh) | 2023-01-17 |
WO2023045360A1 (zh) | 2023-03-30 |
CA3232913A1 (en) | 2023-03-30 |
KR20240060655A (ko) | 2024-05-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3013835B1 (en) | Solid forms of a macrocyclic kinase inhibitor | |
CN111187253A (zh) | 一种阿昔替尼新晶型 | |
BR112015000045B1 (pt) | Crista de forma i de inibidor de dimaleato de tirosina quinase, seu uso e seu método de preparação, e composição farmacêutica | |
CN109640982A (zh) | 奥扎莫德盐酸盐的晶型及其制备方法 | |
CN112961120B (zh) | 一种萘基脲类化合物、其制备方法及应用 | |
CN109563059A (zh) | 奥扎莫德的晶型及其制备方法 | |
CN113754657B (zh) | 大环类化合物的晶型及其制备方法和应用 | |
KR102466958B1 (ko) | 단백질 키나제 활성을 억제하는 화합물의 결정 형태 및 이의 응용 | |
WO2020007219A1 (zh) | 一种egfr抑制剂的晶型及其制备方法 | |
WO2022194252A1 (zh) | 一种化合物的多晶型及其制备方法和应用 | |
CN112209884B (zh) | 1-h苯并咪唑衍生物、制备方法及其应用 | |
CN109705090B (zh) | 3,4-二取代的1h-吡唑化合物的酒石酸加成盐及其晶型 | |
JP2022517396A (ja) | Egfr阻害剤の塩、結晶形及びその製造方法 | |
CN112125910A (zh) | 一种阿伐普替尼晶型及其制备方法 | |
AU2021407012B2 (en) | CRYSTAL FORM OF CASEIN KINASE 1ε INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF | |
CN116120301A (zh) | 一种化合物的甲磺酸盐晶型、药物组合物及用途 | |
CN113784971B (zh) | 一种egfr抑制剂的晶型及其制备方法 | |
CN111848677B (zh) | 一种alk激酶抑制剂化合物的晶型、制备方法及应用 | |
CN113149998B (zh) | 2-吲哚啉螺环酮类化合物或其盐、溶剂合物的无定形形式或结晶形式 | |
WO2022247772A1 (zh) | 一种含氧杂环化合物的晶型、其制备方法及应用 | |
EP3912971B1 (en) | Cholinesterase inhibitor polymorph and application thereof | |
WO2022166774A1 (zh) | 3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途 | |
WO2023041061A1 (zh) | 一种稠合二环类衍生物的可药用盐、晶型及其制备方法 | |
WO2020216188A1 (zh) | 化合物晶型、其制备方法、药物组合物以及应用 | |
CN115710257A (zh) | 一种酰胺化合物的硫酸盐晶型、药物组合物及用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |