CN116675686A - Isoindolinyl-piperidine carboxamide compound, and preparation method and application thereof - Google Patents
Isoindolinyl-piperidine carboxamide compound, and preparation method and application thereof Download PDFInfo
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- CN116675686A CN116675686A CN202310534104.XA CN202310534104A CN116675686A CN 116675686 A CN116675686 A CN 116675686A CN 202310534104 A CN202310534104 A CN 202310534104A CN 116675686 A CN116675686 A CN 116675686A
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- isoindolinyl
- cancer
- piperidine
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- -1 Isoindolinyl-piperidine carboxamide compound Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 10
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 10
- 201000005202 lung cancer Diseases 0.000 claims abstract description 10
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 10
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 10
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 6
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 235000010338 boric acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- OZRNSSUDZOLUSN-LBPRGKRZSA-N dihydrofolic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OZRNSSUDZOLUSN-LBPRGKRZSA-N 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940093956 potassium carbonate Drugs 0.000 claims 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 claims 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 25
- 241000699670 Mus sp. Species 0.000 abstract description 8
- 230000035755 proliferation Effects 0.000 abstract description 6
- 238000011161 development Methods 0.000 abstract description 4
- 230000012010 growth Effects 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000011728 BALB/c nude (JAX™ mouse strain) Methods 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 235000009161 Espostoa lanata Nutrition 0.000 description 1
- 240000001624 Espostoa lanata Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides an isoindolinyl-piperidine formamide compound, a preparation method and application thereof, and the isoindolinyl-piperidine formamide compound contains the isoindolinyl-piperidine formamide mother nucleus group with biological activity, which is further chemically modified to generate a plurality of compounds with higher biological activity, so that the wide application of the compounds in biological medicine and the development prospect of pharmaceutical preparations are expanded. The compound can obviously inhibit proliferation of cells such as lung cancer, liver cancer, pancreatic cancer, gastric cancer and the like at low dose (nanomole), and can effectively inhibit growth of transplanted tumor in mice, so that the compound has a prospect of being developed into antitumor drugs.
Description
Technical Field
The application belongs to the field of tumor targeted therapy, and particularly relates to an isoindolinyl-piperidine carboxamide compound, a preparation method and application thereof.
Background
Cancer has high morbidity and mortality in China, and patients have a tendency to be younger. Because the early symptoms of most cancers are not specific, most patients are in middle and late stages when diagnosis is confirmed, the postoperative metastasis and recurrence rate is high, and the side effects of the traditional treatment modes such as combined chemotherapy and radiotherapy are large, and the clinical benefit rate is low. Although there has been great progress in the clinical diagnosis and treatment of some cancers, many drugs have problems of primary or secondary drug resistance due to inherent heterogeneity and phenotypic plasticity of cancer cells, resulting in a clinical lack of available effective drugs. Therefore, the development of new cancer therapeutic drugs is of great importance.
The application synthesizes an isoindolinyl-piperidine carboxamide compound with a brand new structural formula. Through analysis of some biological technologies, the compounds can obviously inhibit proliferation of lung cancer, liver cancer, pancreatic cancer and gastric cancer cells at very low dose, have good tumor inhibiting effect in animal bodies, and have no obvious toxic or side effect. Therefore, further development of such compounds would be of great significance in the application of tumor therapy.
Disclosure of Invention
The application aims to provide an isoindolinyl-piperidine carboxamide compound, a preparation method and application thereof.
Based on the above purpose, the application adopts the following technical scheme:
an isoindolinyl-piperidine carboxamide compound has a structural formula shown in a general formula I:
wherein R is 1 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、SO 2 NH 2 ；
R 2 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH、
R 3 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH；R 4 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH；R 5 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH, OH; w, X, G are each independently selected from C or N;
k is selected from O or NH.
The isoindolinyl-piperidine formamide compound is specifically a compound with the following structure:
。
a biologically acceptable salt of the isoindolinyl-piperidine carboxamide compound with at least one of acetic acid, dihydrofolate, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanilloid acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.
The preparation method of the isoindolinyl-piperidine carboxamide compound comprises the following synthetic route:
the specific synthesis steps are as follows:
(1) Dissolving a compound 1, a compound 2 and potassium carbonate in DMF, stirring at 65-75 ℃ for complete reaction, diluting the reaction solution with ethyl acetate, washing with saturated saline, and spin-drying an organic phase to obtain a compound 3;
(2) Dissolving the compound 3 in methanol, adding an ethyl acetate solution of hydrogen chloride, stirring at room temperature, and spin-drying the reaction solution to obtain a compound 4;
(3) Dissolving the compound 4, the compound 6, HBTU and DIEA in DMF, stirring at room temperature, completely reacting, spin-drying the reaction solution, and performing column chromatography to obtain the target compound.
Further, in the step (1), the molar ratio of the compound 1 to the compound 2 to the potassium carbonate is 1:1:1.2; in the step (2), the molar ratio of the compound 3 to the hydrogen chloride is 1:10; in step (3), the molar ratio of compound 4, compound 6, HBTU and DIEA is 1:1.2:1.2:3.
The isoindolinyl-piperidine carboxamide compounds and application of the biologically acceptable salts thereof in preparing antitumor drugs.
Preferably, the antitumor drug is a drug for treating lung cancer, liver cancer, pancreatic cancer, gastric cancer and the like.
Specifically, the isoindolinyl-piperidine formamide compounds with brand new structures, such as IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321C-1, IG230322A-1, IG230322B-1, IW230322A-1, IW230322B-1, IW230322C-1, IW230322A-1, IW 230322C-37C-1, and the like are synthesized. Detecting proliferation inhibition of the compound on various cancer cells by a CCK-8 method; and detecting the influence of the compound on the in-vivo growth of liver cancer by a nude mouse transplanted tumor model.
The results show that the compounds of the present application, IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321C-1, IG230322A-1, IG230322B-1, IG230322C-1, IW230322A-1, IW230322B-1, IW230322C-1, IW230323A-1, IW230323B-1 and IW230323C-1, can effectively inhibit liver cancer and lung cancer in vivo and inhibit cancer of the lung, and can significantly inhibit the growth of cancer cells in mice.
In summary, the present application provides a novel isoindolinyl-piperidine carboxamide compound and its derivatives for use in tumor therapy and potential molecular mechanisms.
Drawings
FIG. 1 is a graph showing the evaluation of antitumor effect of different doses of IG230308B-1 in mice against a blank solvent.
Detailed Description
In order to make the technical purpose, technical scheme and beneficial effect of the present application more clear, the technical scheme of the present application is further described below with reference to the accompanying drawings and specific embodiments.
In the process according to the application for the synthesis of the compounds of the formula I, the various starting materials used for the reaction are preparable by the person skilled in the art according to the prior art, or can be prepared by methods known from the literature, or can be obtained commercially. The intermediates, raw materials, reagents, reaction conditions and the like used in the above reaction schemes may be appropriately changed according to the knowledge already known to those skilled in the art.
In the present application, unless otherwise specified, wherein: (i) The temperature is expressed in degrees centigrade (DEG C), and the operation is performed in a room temperature environment; more specifically, the room temperature is 20-30 ℃; (ii) Drying the organic solvent by a common drying method, evaporating the solvent by a rotary evaporator under reduced pressure, wherein the bath temperature is not higher than 50 ℃; the volume ratio of the developing agent to the eluent is equal; (iii) the reaction process is followed by Thin Layer Chromatography (TLC); (iv) The final product has satisfactory proton nuclear magnetic resonance 1 H-NMR)。
EXAMPLE 1 Synthesis of all Compounds reference the following scheme
The specific synthesis method is exemplified by a compound IG230308B-1, and the structural formula is as follows:
the compound IG230308B-1, named (1- (4- (2, 2-trifluomethoxy) benzyl) piridin-4-yl) (5- ((5- (4- (trifluormethyl) phenyl) -1,2, 4-oxazo-5-yl) oxy) pyraziin-2-yl) oxy) isoidin-2-yl) methane, was synthesized as follows:
step 1.Tert-butyl 5- ((5- (3- (4- (trifluoromethyl) phenyl) -1,2, 4-oxazo l-5-yl) pyrazin-2-yl) oxy) isoindole-2-carbox-ylate (Compound 3)
Compound 1 (2.0 g,8.50mmol,1.0 eq), compound 2 (2.78 g,8.50mmol,1.0 eq) and potassium carbonate (1.41 g,10.2mmol,1.2 eq) were dissolved in 30 mM LDMF and reacted at 70℃for 3 hours, after which the reaction was monitored by TLC. The reaction was diluted with 200mL ethyl acetate, washed three times with saturated brine (200 mL x 3), the organic phase dried and spun-dried and the crude product purified by column (PE/ea=10/1 to 3/1) to give 3.5g of compound 3 as a white solid in 78.3% yield.
1 H NMR(CDCl 3 ,300MHz)δ:9.05(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.38(d,J＝8.2Hz,2H),7.84(d,J＝8.4Hz,2H),7.35(s,1H),6.95(d,J＝10.0Hz,2H),4.83(s,4H),1.59(s,9H).
Step 2. (4- (2- (piperidine-1-yl) ethoxy) phenyl) methane-nol (Compound 4)
Compound 3 (3.2 g,6.09mmol,1.0 eq) was dissolved in 20mL of methanol, cooled to 0deg.C, 4M hydrogen chloride in ethyl acetate (15.2 mL,60.9mmol,10 eq) was added, and the reaction was allowed to warm to room temperature naturally for 2 hours, and TLC monitoring showed complete reaction of starting material and new points had occurred. The reaction solution was directly dried by spin to obtain 2.75g of Compound 4 as a white solid in 97.8% yield.
1 H NMR(CDCl 3 ,300MHz)δ:9.05(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.38(d,J＝8.2Hz,2H),7.84(d,J＝8.4Hz,2H),7.35(s,1H),6.95(d,J＝10.0Hz,2H),4.83(s,4H)
Step 3. (4- (4- (2, 2-trifluothoxy) benzyl) piperazin-1-yl) (5- ((5- (3- (4- (trifluormethyl) phenyl) -1,2, 4-oxazo-5-yl) pyrazin-2-yl) oxy) isorack-2-yl) methane (IG 230308B-1)
Compound 4 (1.0 g,2.17mmol,1.0 eq), compound 6 (0.87 g,2.60mmol,1.2 eq), HBTU (1.84 g,2.60mmol,1.2 eq) and DIEA (0.84 g,6.50mmol,3.0 eq) were dissolved in 25mL DMF and reacted at room temperature for 4 hours, after which the reaction was monitored by TLC. The reaction was directly spin-dried over column (DCM/meoh=60:1 to 20:1) to give 1.53g of ig230308b-1 as a yellow solid in 75% yield.
1 H NMR(CDCl 3 ,300MHz)δ:9.11(d,J＝1.1Hz,1H),8.69(d,J＝1.1Hz,1H),8.40(d,J＝8.2Hz,2H),7.86(d,J＝8.4Hz,2H),7.40(d,J＝8.6Hz,2H),7.37(s,1H),7.18(d,J＝12.2Hz,2H),6.99(d,J＝10.0Hz,2H),4.85(s,4H),4.41(s,3H),3.70(m,2H),3.61(s,2H),3.45(s,4H),2.55(s,4H).
Examples 2, IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321B-1, IG230321C-1, IG230322A-1, IG230322B-1, IG230322C-1, IW230322A-1, IW230322B-1, IW230322C-1, IW230323A-1, IW230323B-1 and IW230323C-1 have inhibitory effect on proliferation of gastric cancer, lung cancer, liver cancer, pancreatic cancer, and other cancer cells
HGC827, hepG2, bxPC-3 and HGC-27 cells in logarithmic growth phase were collected, counted and the cell suspension concentration was adjusted to 5X 10 4 Each mL was added to a 96-well cell culture plate at a volume of 100uL per well. The compounds of the present application, IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321B-1, IG230322A-1, IG230322B-1, IW230322C-1, IW230322A-1, IW230322B-1 and IW230322C-1 were diluted to a final concentration of 100.0.3L and a final concentration of the mixture was used in a final culture system of 100.0.3.3 mol/1, respectively. After further culturing for 48h, 10 μl of CCK-8 solvent was added to each well, incubated at 37deg.C for 1h, and the OD value at an absorption wavelength of 450nm was measured, the results were recorded, and the cell growth curve was drawn with the dose of the compound as abscissa and the absorbance as ordinate. The statistics of half-maximal inhibition (IC 50 value) of tumor cells by the compounds are shown in table 1 below:
table 1.CCK-8 detection of IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321B-1, IG230321C-1, IG230322A-1, IG230322B-1, IG230322C-1, IW230322A-1, IW230322B-1, IW230322C-1, IW230323A-1, IW230323B-1 and IW230323C-1, inhibition of lung cancer, pancreatic cancer, proliferation and other cancers, and cell proliferation and the like
The table shows: the compounds of the present application have excellent inhibitory effects on lung cancer, pancreatic cancer, gastric cancer, pancreatic cancer and the like, and are preferably used in the treatment of lung cancer, pancreatic cancer, etc. IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321B-1, IG230321C-1, IG230322A-1, IG230322B-1, IG230322C-1, IW230322A-1, IW230322B-1, IW230322C-1, IW230323A-1, IW230323B-1, IW 230323C-1. The present application takes IG230308B-1 as an example to further study the in vivo anti-tumor effect of the compounds.
EXAMPLE 3 antitumor efficacy of IG230308B-1 in mice
SPF grade, 30 BALB/c-nude female nude mice of 6 week old and 18-22g in weight were purchased from St Bei Fu (Beijing) Biotechnology Co., ltd. Taking HepG2 cell transplanted tumor tissue which is successfully inoculated subcutaneously, washing blood stain by PBS, cutting into small blocks of 1.5 mm, sucking a small tumor block by a puncture needle, wiping the abdomen of an animal by an alcohol cotton ball, directly penetrating subcutaneously, and injecting the tumor block. The inoculated animals are put back into the original cage for feeding, so that the environment is kept clean, and the infection is avoided. After 1 week of tumor cell inoculation, the inoculation site was observed for the formation of milky white nodules. The major and minor diameters of the tumor were measured with a vernier caliper, and the volume of the tumor was calculated according to the formula (tumor volume=major diameter×minor diameter 2×0.5). The tumor volume reaches 100-150mm 3 Grouping and administration is performed at that time. The 20 mice meeting the experimental volume requirements were randomly divided into 4 groups of 5 mice each. By gastric administration, IG230308B-1 was administered 1 time per day at 5, 10 and 20mg/kg per mouse, with suspension solvent (SUS Control,2.5% CMC-Na aqueous solution) as Control100 mu L each time was administered for 11 days. Tumor volume and body weight of mice were measured every other day, and the results are shown in FIG. 1.
The results in FIG. 1A show that at the end of the trial, the morphology of the grafts in the IG 230308B-1-20 mg/kg group was significantly smaller than in the solvent control group. The results in FIG. 1B show that, from the third day of administration, the transplanted tumor volume in the IG 230308B-1-20 mg/kg group began to shrink, the later growth was slow, and the tumor volumes in the control group and the other dosed groups continued to grow larger.
Taken together, the results demonstrate that IG230308B-1, IG230309B-1, IG230310B-1, IG230308C-1, IG230309C-1, IG230310C-1, IW230307A-1, IW230308A-1, IW230309A-1, IW230309B-1, IW230310B-1, IW230312B-1, IW230313A-1, IW230313B-1, IW230313C-1, IG230320A-1, IG230320B-1, IG230320C-1, IG230321A-1, IG230321B-1, IG230321C-1, IG230320A-1, IG230320C-1, IW 230320A-1, IW 230320B-1, IW 230320C-1, IW 230320B-1 and IW 230320C-1 can significantly inhibit lung cancer, pancreatic cancer, and the like, and that can significantly inhibit the proliferation of tumors of the cells in mice and the body of the liver, and the like. Therefore, the medicine has good anticancer effect and development potential.
According to the general way of drug development (conventional anti-tumor in-vitro screening is carried out firstly and then targeted research is carried out), the compound can be applied to cancer treatment drugs related to abnormal cell proliferation, and the anti-tumor drugs can be prepared by salifying with human bodies or mixing with a medicinal carrier.
Finally, what should be said is: the above embodiments are only for illustrating the technical solution of the present application, and any equivalent replacement of the present application and modification or partial replacement without departing from the spirit and scope of the present application should be covered in the scope of the claims of the present application.
Claims (7)
1. An isoindolinyl-piperidine carboxamide compound is characterized by having a structural formula as shown in a general formula I:
wherein R is 1 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-SO 2 NH 2 ；
R 2 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH、
R 3 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH；
R 4 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH；
R 5 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH；
W, X, G are each independently selected from C or N;
k is selected from O or NH.
2. The isoindolinyl-piperidine carboxamide compound according to claim 1, characterized in that it is a compound of the following structure:
。
3. the biologically acceptable salt of an isoindolinyl-piperidine carboxamide compound of claim 1 or 2 with at least one of acetic acid, dihydrofolate, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.
4. The method for preparing the isoindolinyl-piperidine carboxamide compound according to claim 1, wherein the synthetic route is as follows:
the specific synthesis steps are as follows:
(1) Dissolving the compound 1, the compound 2 and potassium carbonate in DMF, stirring at 65-75 ℃ for complete reaction, diluting the reaction liquid with ethyl acetate, washing with saturated saline, spin-drying the organic phase, and performing column chromatography to obtain a compound 3;
(2) Dissolving the compound 3 in methanol, adding an ethyl acetate solution of hydrogen chloride, stirring at room temperature, and spin-drying the reaction solution to obtain a compound 4;
(3) Dissolving the compound 4, the compound 6, HBTU and DIEA in DMF, stirring at room temperature, completely reacting, spin-drying the reaction solution, and performing column chromatography to obtain the target compound.
5. The method for producing isoindolinyl-piperidine carboxamides according to claim 4, wherein in step (1), the molar ratio of compound 1, compound 2 and potassium carbonate is 1:1:1.2; in the step (2), the molar ratio of the compound 3 to the hydrogen chloride is 1:10; in step (3), the molar ratio of compound 4, compound 6, HBTU and DIEA is 1:1.2:1.2:3.
6. Use of the isoindolinyl-piperidine carboxamides and their biologically acceptable salts according to any one of claims 1 to 3 for the preparation of antitumor drugs.
7. The use according to claim 6, characterized in that: the antitumor drug is a drug for treating lung cancer, liver cancer, pancreatic cancer and gastric cancer.
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