CN114773424B - A bioactive androstanol derivative, and its preparation method and application - Google Patents
A bioactive androstanol derivative, and its preparation method and application Download PDFInfo
- Publication number
- CN114773424B CN114773424B CN202210651451.6A CN202210651451A CN114773424B CN 114773424 B CN114773424 B CN 114773424B CN 202210651451 A CN202210651451 A CN 202210651451A CN 114773424 B CN114773424 B CN 114773424B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- reaction
- preparation
- stirring
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- DJTOLSNIKJIDFF-LOVVWNRFSA-N 5alpha-Androstan-3beta-ol Chemical class C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 DJTOLSNIKJIDFF-LOVVWNRFSA-N 0.000 title abstract description 8
- 230000000975 bioactive effect Effects 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 239000012074 organic phase Substances 0.000 claims description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000012544 monitoring process Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 7
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 7
- 229960005055 sodium ascorbate Drugs 0.000 claims description 7
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 239000007791 liquid phase Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- NQPHMXWPDCSHTE-UHFFFAOYSA-N trifluoromethanesulfonyl azide Chemical compound FC(F)(F)S(=O)(=O)N=[N+]=[N-] NQPHMXWPDCSHTE-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- QVVZPIOQOKJWRD-UHFFFAOYSA-N tert-butyl n-(2-chloro-2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC(Cl)=O QVVZPIOQOKJWRD-UHFFFAOYSA-N 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 2
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 abstract description 6
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical class C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 6
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 229960004942 lenalidomide Drugs 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 102000001307 androgen receptors Human genes 0.000 description 3
- 108010080146 androgen receptors Proteins 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical class O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- NSKXMXGWANGSKK-UHFFFAOYSA-N 3-(7-amino-3-oxo-1h-isoindol-2-yl)-1-prop-2-ynylpiperidine-2,6-dione Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)N(CC#C)C1=O NSKXMXGWANGSKK-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- CWRYPZZKDGJXCA-UHFFFAOYSA-N acenaphthene Chemical compound C1=CC(CC2)=C3C2=CC=CC3=C1 CWRYPZZKDGJXCA-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- YRMODRRGEUGHTF-UHFFFAOYSA-N methyl 2-formylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C=O YRMODRRGEUGHTF-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- WGVYCXYGPNNUQA-UHFFFAOYSA-N 1-(bromomethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CBr WGVYCXYGPNNUQA-UHFFFAOYSA-N 0.000 description 1
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- RTDDSWLIZLMORY-UHFFFAOYSA-N 4-nitro-2,3-dihydroisoindol-1-one Chemical compound [O-][N+](=O)C1=CC=CC2=C1CNC2=O RTDDSWLIZLMORY-UHFFFAOYSA-N 0.000 description 1
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229940124011 Androgen receptor agonist Drugs 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HXGDTGSAIMULJN-UHFFFAOYSA-N acetnaphthylene Natural products C1=CC(C=C2)=C3C2=CC=CC3=C1 HXGDTGSAIMULJN-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229960004701 amonafide Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- XSBPYGDBXQXSCU-UHFFFAOYSA-N but-3-yn-1-amine Chemical compound NCCC#C XSBPYGDBXQXSCU-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 101150073818 gap gene Proteins 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 102000043557 human IFNG Human genes 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- KPQJSSLKKBKWEW-RKDOVGOJSA-N methanesulfonic acid;5-nitro-2-[(2r)-1-[2-[[(2r)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.[O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 KPQJSSLKKBKWEW-RKDOVGOJSA-N 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- IBMRTYCHDPMBFN-UHFFFAOYSA-N monomethyl glutaric acid Chemical compound COC(=O)CCCC(O)=O IBMRTYCHDPMBFN-UHFFFAOYSA-N 0.000 description 1
- 231100001096 no neurotoxicity Toxicity 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- -1 steroid compound Chemical class 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
The invention relates to a bioactive androstanol derivative, and a preparation method and application thereof, belonging to the technical field of antitumor drug preparation. A compound of formula (i):the molecular structure of the androstanol derivative contains the androstanol structure and the 1,2, 3-triazole structure, and different substituents are linked on the 1,2, 3-triazole structure, so that the molecular structure is novel; (2) The andrulon derivative obtained by the invention has good inhibition on the activity of IDO 1.
Description
Technical Field
The invention belongs to the technical field of preparation of antitumor drugs. In particular to a biological active andrulon derivative, a preparation method and application thereof.
Background
Androstane, also known as dihydrotestosterone, is a steroid compound with a chemical name of 17β -hydroxy-5α -androstan-3-one. It is an androgen produced by the hydrogenation of testosterone with 5α reductase in the human body, which is a metabolite of testosterone and widely exists in the whole body blood. The biological activity of the extract is 2-3 times of testosterone. The androstane is used as a protein androgen receptor agonist in human body, has stronger affinity and intrinsic activity to androgen receptor, has 2-5 times of the capacity of binding to receptor than testosterone, can bind to the corresponding androgen receptor in target cells and can excite the androgen receptor to exert maximum drug effect.
The 1, 8-naphthalimide derivative has a special planar rigid structure, so that the 1, 8-naphthalimide derivative has strong DNA embedding capability and is focused on the field of anti-tumor drug research and development. Some mononaphthalimides such as amonafide, mitonaphthylamine, and bisnaphthalimides have entered the clinical stage of research. Aminonaftides and mitoxantrone are not only capable of intercalating DNA, inhibiting DNA and RNA synthesis, but also inhibiting topoisomerase II activity and thus tumor cell division. In addition, the dinaphthoimide compound can be inserted into DNA, has specificity to G-C base sequences, shows stronger DNA binding force and greater cytotoxicity compared with mononaphthoimide, for example, DMP-840 can effectively inhibit two human solid tumors, namely DLD-2 colon cancer and MX-1 breast cancer, and has good water solubility; LU-79553 without any substituent can also have good inhibition effect on various tumor cells, so that the research prospect of anti-tumor activity of naphthalimide derivatives is good.
Lenalidomide, known by the chemical name 3- (4-amino-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) -2, 6-piperidinedione, is one of the structural analogues of thalidomide. A second generation of novel immunomodulators following thalidomide was developed by Celgene company in the united states. The product can activate T cells to produce interleukin-2 (IL-2), change the number and function of natural killer cells (NK cells), further enhance the cytotoxic activity of NK cells, and has almost no neurotoxicity and teratogenicity. The drug is approved by the FDA in the United states in 1 st 2006, and is mainly used for treating the subtype of myelodysplastic syndrome (MDS), multiple Myeloma (MM), lymphoma and the like of 5q deletion (the gap gene deletion of a chromosome long arm of the 5 th pair), and particularly has the most remarkable treatment effect on the Multiple Myeloma (MM).
By combining andrulon with pharmaceutically active 1, 8-naphthalimide and lenalidomide respectively, it is expected that the drug effect of each compound molecule can be enhanced, and the compound can have a certain effect in tumor immunotherapy, and the university of south-open is responsible for the design of the final target compound.
Disclosure of Invention
The invention modifies the structure of the andrulon and applies the structure to the anti-tumor activity research. The inventor uses the principle of structural splicing, and changes the substituent group on the 1,2, 3-triazole to make the 1,2, 3-triazole show excellent inhibition effect on prostate tumor.
In a first aspect of the present invention, there is provided a compound of formula (i):
wherein R is
In a second aspect, the present invention provides a process for preparing a compound of formula (I) as follows:
the preparation method comprises the following steps:
sequentially adding a compound shown in a formula (II), a compound shown in a formula (VIII), tertiary butanol, water, tetrahydrofuran, copper sulfate pentahydrate and sodium ascorbate into a reaction bottle, and reacting at 70 ℃ until the raw materials are completely reacted; then adding dichloromethane, filtering the reaction solution, separating out an organic phase, drying the organic phase through anhydrous magnesium sulfate, and evaporating the solvent to obtain a compound shown in a formula (I); wherein R in the compound of formula (VIII) is the same as the compound of formula (I).
The invention also provides another method for preparing the compound shown in the formula (I), wherein the reaction formula is as follows:
the preparation method comprises the following steps:
adding a compound of a formula (III) and trifluoromethanesulfonyl azide into 5mL of mixed solution of tertiary butanol, dichloromethane and water, adding triethylamine and copper sulfate, heating to 40 ℃ for stirring reaction, adding a compound of a formula (VIII) and sodium ascorbate for stirring reaction at 40 ℃, adding dichloromethane after the reaction is finished, filtering a reaction solution, separating an organic phase, drying the organic phase through anhydrous magnesium sulfate, and evaporating a solvent to obtain the compound of the formula (I); wherein R in the compound of formula (VIII) is the same as the compound of formula (I).
Further, a process for preparing the compound of formula (II) is described as follows:
the preparation method comprises the following steps:
adding a compound of the formula (III) into acetonitrile, adding p-toluenesulfonyl chloride, stirring for reacting for a period of time, adding sodium azide, heating to reflux under the protection of nitrogen, concentrating after the reaction is finished, adding dichloromethane, stirring, washing with water, drying by anhydrous magnesium sulfate, and concentrating again to obtain the compound of the formula (II).
Further, a process for preparing the compound of formula (III) is described as follows:
the preparation method comprises the following steps:
adding a compound (andrulon) of the formula (IV) into dichloromethane, completely dissolving, adding potassium carbonate, slowly dropwise adding N-Boc-aminoacetyl chloride, stirring for reaction at room temperature after dropwise adding, monitoring the raw materials for complete reaction by TLC, adding dilute hydrochloric acid into a reaction system, adding trifluoroacetic acid, stirring at room temperature, regulating the pH value to 7-8 by using triethylamine, separating an organic phase, and concentrating the organic phase to obtain the compound of the formula (III).
Further, a method for preparing the compound of formula (IV) comprises the following steps:
the preparation method comprises the following steps:
(1) Adding a compound of the formula (VII) into benzene, heating and refluxing, cooling to 60 ℃, adding ethylene glycol, heating and refluxing, cooling to 60 ℃, adding p-toluenesulfonic acid, heating and refluxing for reaction, cooling after the reaction is finished, adding triethylamine, separating a benzene layer, extracting the rest part by using benzene, mixing organic phases, washing twice by using water, rotationally evaporating and concentrating the organic phases, adding methanol, heating and dissolving, continuing concentrating, adding methanol, cooling and crystallizing, performing suction filtration and drying, and then preparing a liquid phase by medium pressure, separating and purifying to obtain the compound of the formula (VI);
(2) Adding a compound of formula (VI) into methanol, adding 5% of palladium/calcium carbonate, introducing hydrogen, controlling the pressure to be 0.2MPa and the temperature to be 35 ℃, monitoring the reaction of raw materials by TLC, filtering the reaction liquid, concentrating the reaction liquid, cooling and crystallizing, and then preparing a liquid phase by medium pressure to separate to obtain the compound of formula (V);
(3) Adding the compound of formula (V) into a mixed solution of glacial acetic acid and water, stirring at room temperature, monitoring the reaction completion of the raw materials by TLC, extracting the reaction solution by using chloroform, combining organic phases, and carrying out vacuum spin-drying to obtain the compound of formula (IV).
In a third aspect, the present invention provides the use of a compound of formula (I) for the preparation of a medicament for inhibiting IDO1
The beneficial effects of the invention are as follows:
(1) The molecular structure of the androstanol derivative contains a androstanol structure and a 1,2, 3-triazole structure, different substituents are linked on the 1,2, 3-triazole structure, the molecular structure is novel, the substituents are lenalidomide and naphthalimide, and the androstanol derivative has excellent bioactivity;
(2) The andrulon derivative obtained by the invention has good inhibition on IDO1 activity, can be applied to tumor immunotherapy, and has an activity effect far superior to that of andrulon, lenalidomide and 1, 8-naphthalimide structure.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the description of the embodiments or the prior art will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is a schematic illustration of the product of example 8 of the present invention 1 HNMR profile.
FIG. 2 is a schematic diagram of a D1 compound of the invention 1 HNMR profile.
FIG. 3 is a schematic diagram of a D2 compound of the invention 1 HNMR profile.
FIG. 4 is an MS spectrum of the D2 compound of the present invention.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
Example 1
Adding 60g of a compound of formula (VII) into 2000mL of benzene, heating and refluxing for 1h, cooling to 60 ℃, adding 170g of ethylene glycol, heating and refluxing for 2h, cooling to 60 ℃, adding 2g of p-toluenesulfonic acid, heating and refluxing for 8h, reacting overnight, monitoring the product point content by TLC to be about 90%, cooling, adding 30mL of triethylamine, separating a benzene layer, extracting the rest part with 300mL of benzene for 2 times, merging organic phases, washing twice with water, rotationally evaporating to concentrate the organic phase, adding 1000mL of methanol, heating and dissolving, continuing concentrating, adding 700mL of methanol, cooling and crystallizing, performing suction filtration and drying, and then preparing liquid phase by medium pressure, separating and purifying to obtain 45g of the compound of formula (VI).
1 H NMR(400MHz,CDCl 3 )δ5.71(s,1H),3.68-3.60(m,4H),3.27-3.05(m,2H),2.41-2.24(m,4H),2.01(d,J＝16.0Hz,2H),1.83(d,J＝12.0Hz,2H),1.67-1.50(m,4H),1.46-1.27(m,3H),1.17(s,3H),1.09-0.88(m,4H),0.77(s,3H).
Example 2
45g of the compound of formula (VI) was added to 2250mL of methanol, 9g of 5% palladium/calcium carbonate was added, hydrogen was introduced at a pressure of 0.2MPa and a temperature of 35℃for 24 hours, the TLC monitored the completion of the reaction, the reaction solution was suction-filtered, concentrated and then cooled to crystallize, and then a liquid phase was prepared by medium pressure separation to obtain 37g of the compound of formula (V).
Example 3
5g of the compound of formula (V) was added to a mixture of 200mL of glacial acetic acid and 50mL of water, stirred at room temperature, TLC monitored complete reaction of the starting materials, the reaction solution was extracted several times with 100mL of chloroform, the organic phases were combined and dried by vacuum spin to give 3.4g of the compound of formula (IV) (andrulon) with an ee value of 99.1%.
1 H NMR(400MHz,CDCl 3 )δ3.64(t,J＝8.6Hz,1H),2.43-2.23(m,3H),2.11-1.99(m,3H),1.84-1.79(m,1H),1.73-1.67(m,1H),1.63-1.23(m,11H),1.11-1.04(m,1H),1.02(s,3H),0.98-0.93(m,1H),0.90-0.83(m,1H),0.76(s,3H),0.74-0.70(m,1H).
Example 4
2.9g of a compound (andrulon) shown in the formula (IV) is added into 50mL of dichloromethane to be completely dissolved, 1.4g of potassium carbonate is added, 2.0g of N-Boc-aminoacetyl chloride is slowly added dropwise, the reaction is stirred for 1h under the condition of room temperature after the dropwise addition, TLC monitors that the raw materials are completely reacted, 100mL of diluted hydrochloric acid is added into a reaction system, 20mL of trifluoroacetic acid is added, the stirring is carried out for 8h at room temperature, the pH value is regulated to 7-8 by triethylamine, an organic phase is separated, an aqueous phase is extracted three times by 50mL of dichloromethane, the organic phases are combined, and 3.14g of the compound shown in the formula (III) is obtained after concentration.
LC-MS(ESI):m/z 348[M+H] + .
Example 5
3.7g of the compound of the formula (III) is added into 50mL of acetonitrile, 1.9g of p-toluenesulfonyl chloride is added, stirring is carried out for a period of time, 1g of sodium azide is added, heating is carried out under the protection of nitrogen until reflux, concentration is carried out after 2h of reaction, 100mL of dichloromethane is added, stirring is carried out for complete dissolution, 30mL of water is used for washing for a plurality of times, and 3.57g of the compound of the formula (II) is obtained after drying through anhydrous magnesium sulfate and concentrating again.
Example 6
In a reaction device with a stirrer, 16.5g of methyl 2-formylbenzoate and 8.5g of hydroxylamine hydrochloride are added into 1000mL of N, N-dimethylformamide to be completely dissolved, 38g of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 20g of N, N-diisopropylethylamine are sequentially added under the protection of nitrogen, stirring is carried out for 30min after the addition, the temperature is slowly raised to 50 ℃, then the reaction is carried out for 20h, after the reaction is monitored by TLC, the methyl 2-formylbenzoate is completely reacted, the mixture is poured into 1000mL of water, the mixture is stirred and is extracted for a plurality of times by 400mL of ethyl acetate, the organic phase is combined, the mixture is concentrated and then added into 700mL of benzene, 6.5g of zinc powder and 300mL of anhydrous acetic acid are added, the mixture is heated to reflux under the protection of nitrogen, the mixture is reacted for 4h, the reaction solution is filtered, 6.3g of nitric acid is slowly dripped into the mixture under the condition of-10 ℃, the mixture is stirred for 1h, the mixture is slowly dripped into room temperature, then the saturated potassium carbonate solution is slowly dripped into the mixture, the mixture is adjusted to be neutral, 300mL of dichloromethane is added, the mixture is extracted by a plurality of magnesium sulfate phase and the mixture is subjected to separation by a chromatography of 4-15 g of isoindoline and the phase and is separated by a silica gel column chromatography.
1 H NMR(400MHz,DMSO-d 6 ):8.97(s,1H),8.44(d,J＝8.0Hz,1H),8.12(d,J＝8.0Hz,1H),7.81(t,J1＝8.0Hz,J2＝8.0Hz,1H),4.80(s,2H)； 13 C NMR(100MHz,DMSO-d 6 ):168.1,143.9,139.9,136.3,130.3,129.9,127.1,46.4.
Example 7
In a reaction device with a stirrer, 16.5g of 2-methyl benzyl bromide and 8g of sodium azide are added into 1000mL of N, N-dimethylformamide, stirring is carried out for 3h at room temperature, then ammonia water is added, 38g of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 20g of N, N-diisopropylethylamine are sequentially added under the protection of nitrogen, stirring is carried out for 30min after the addition, the temperature is slowly increased to 75 ℃, then the reaction is carried out for 10h, the mixture is poured into 1000mL of water, 400mL of ethyl acetate is used for extraction for multiple times, the organic phase is combined, dried and concentrated through anhydrous sodium sulfate, then the mixture is added into 600mL of tetrahydrofuran, then 2g of dichloro tetracarbonyl rhodium, 26g of triphenylphosphine and 200mL of water are added, and the mixture is heated to reflux under the protection of nitrogen for 14h; filtering the reaction solution, concentrating in vacuum, adding a mixed solution of 700mL benzene and 300mL acetic acid, placing at-10 ℃, slowly dropwise adding 10g nitric acid, stirring for 1h, heating to room temperature, slowly dropwise adding a potassium carbonate solution, adjusting the reaction system to be neutral, adding 300mL dichloromethane, extracting for multiple times, drying by anhydrous magnesium sulfate, concentrating an organic phase, and separating by silica gel column chromatography to obtain 15.77g 4-nitroisoindoline-1-ketone.
Example 8
In a reaction bottle with a stirring device, 18g of 4-nitroisoindoline-1-one and 23g of 2-bromo-1, 5-methyl glutarate are added into 1000mL of N, N-dimethylformamide, 17g of barium hydroxide is added after stirring and dissolving, the reaction system is heated to 100 ℃, the reaction system is stirred and reacted for 3h, the reaction solution is filtered, then the reaction solution is transferred into a high-pressure reaction kettle, 8.3g of N, N-carbonyldiimidazole, 10g of triethylamine, 2.3g of palladium acetate and 8.3g of 3-aminopropyne are added into the reaction kettle, the reaction is slowly heated to 80 ℃, the reaction is carried out for 2h under stirring, the gas in the reaction system is removed under vacuum, hydrogen is introduced into the reaction kettle, the pressure in the reaction kettle reaches 1.5MPa, the temperature is kept for 8.5h under stirring, the reaction solution is filtered after the reaction is finished, the filtrate is poured into 1000mL of water, the reaction system is heated to be adjusted to 6 by dilute hydrochloric acid under stirring, then 400mL of dichloromethane is used for extracting the reaction system for multiple times, the organic phase is combined, and 3- (4-amino-1-oxo-1, 3-dihydro-1-2-dimethyl-1-2-1-2-dimethyl-1-alkyne is obtained after the mixed solution is dried and recrystallized through acetone and ethanol.
1 H NMR(400MHz,CDCl 3 )δ7.20(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),6.93(d,J＝4.0Hz,1H),6.81(d,J＝4.0Hz,1H),5.43(s,2H),5.24(dd,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),4.38(s,2H),4.24-4.21(m,1H),4.13-4.10(m,1H),3.10-3.04(m,2H),2.84-2.80(m,1H),2.35-2.27(m,1H),2.09-2.05(m,1H).
Example 9
To a mixed solution of 100mL of t-butanol, 10mL of methylene chloride, 5mL of water and 5mL of methyl t-butyl ether was added 1.9g of trifluoromethanesulfonyl azide, 3g of triethylamine and 0.32g of copper sulfate were added, the mixture was heated to 45℃and stirred for reaction for 8 hours, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -1-prop-2-ynyl piperidine-2, 6-dione 3g and sodium ascorbate 0.7g were added, the mixture was stirred at 40℃and reacted for 14 hours, 200mL of methylene chloride was added, the reaction solution was filtered, the organic phase was separated, the aqueous phase was extracted twice with 100mL of methylene chloride, the combined organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain a solid, and D1 (6.22 g) was purified by recrystallization from methanol.
1 H NMR(400MHz,CDCl 3 )δ8.62(s,1H),7.64(s,1H),7.31(t,J＝7.7Hz,1H),7.24(d,J＝7.5Hz,1H),6.82(d,J＝7.9Hz,1H),5.13(d,J＝2.5Hz,2H),4.68–4.62(m,1H),4.53(s,2H),4.25(d,J＝15.9Hz,1H),4.13(d,J＝15.9Hz,1H),2.78(d,J＝15.8Hz,2H),2.30(s,2H),2.24(d,J＝14.3Hz,2H),2.06(s,3H),2.02(s,1H),1.67(d,J＝34.7Hz,3H),1.55(s,3H),1.36(s,7H),1.11(d,J＝43.2Hz,2H),1.00(s,3H),0.85(s,2H),0.73(d,J＝22.7Hz,4H).
Example 10
In a reaction bottle, 1g of a compound of formula (II), 1g of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -1-prop-2-ynylpiperidine-2, 6-dione, 50mL of tertiary butanol, 100mL of water, 50mL of tetrahydrofuran, 0.5g of cupric sulfate pentahydrate and 1g of sodium ascorbate are sequentially added, the reaction is carried out until the raw materials are completely reacted at 70 ℃, 100mL of dichloromethane is added, the reaction solution is filtered to obtain a yellow liquid, an organic phase is separated, an aqueous phase is extracted twice with 100mL of dichloromethane, the organic phase is combined, the solvent is distilled off after being dried by anhydrous magnesium sulfate, and the solid is obtained, and D1 (0.917 g) is obtained through silica gel column chromatography.
Example 11
1.5g of acenaphthene is added into 100mL of glacial acetic acid, 7.5g of sodium dichromate is added, the temperature is slowly raised to 90 ℃ after stirring uniformly at room temperature, the reaction is kept for 3.5h, the reaction liquid is poured into 200mL of ice water while the reaction liquid is hot, the reaction liquid is stirred and filtered, the filter cake is dried and then added into 100mL of N, N-dimethylformamide, 0.84g of 4-amino-1-butyne and 0.6g of potassium hydroxide are added, the reaction is carried out for 3h after heating to 100 ℃, then the reaction liquid is poured into 150mL of water, the pH value of the system is regulated to be neutral by dilute hydrochloric acid, the reaction liquid is extracted for multiple times by 100mL of dichloromethane, and the N-butynyl-1, 8-naphthalimide is obtained after the organic phase is combined and concentrated; 3.5g of a compound of formula (III) and 1.9g of trifluoromethanesulfonyl azide are added into a mixed solution of 100mL of tertiary butanol, 10mL of dichloromethane, 5mL of water and 5mL of methyl tertiary butyl ether, 3g of triethylamine and 0.32g of copper sulfate are added, the mixture is heated to 45 ℃ and stirred for reaction for 8 hours, 0.7g of N-butynyl-1, 8-naphthalimide and sodium ascorbate are added, stirring is carried out for reaction for 4 hours at 40 ℃, 200mL of dichloromethane is added, the reaction solution is filtered, an organic phase is separated, an aqueous phase is extracted twice by 100mL of dichloromethane, the organic phase is combined, dried by anhydrous magnesium sulfate, a solvent is distilled off to obtain a solid, and D2 (2.52 g) is obtained through silica gel column chromatography separation and purification after methanol recrystallization.
1 H NMR(400MHz,CDCl 3 )δ8.60(d,J＝8.0Hz,2H),8.26-8.21(m,2H),7.76(t,J 1 ＝4.0Hz,J 2 ＝8.0Hz,2H),7.60(s,1H),5.12(s,1H),4.69-4.63(m,1H),4.56-4.38(m,2H),3.24(t,J 1 ＝8.0Hz,J 2 ＝8.0Hz,2H),2.37-2.01(m,6H),1.72-1.60(m,5H),1.37-1.30(m,4H),1.29-1.19(m,5H),1.00(s,3H),0.91-0.84(m,3H),0.75-0.69(m,3H).
Example 12
In a reaction flask, heating to 70 ℃, and melting 100g of 1, 4-dichlorobenzene into a liquid state; then adding 1.6g of aluminum trichloride and 1.52g of oxalyl chloride under the stirring state, keeping the temperature unchanged, adding 1.3g of naphthalene in two batches, keeping the temperature and stirring for 2 hours, then adding 1.38g of trimethylsilyl isocyanate and 1.2g of palladium acetate in three batches, and stirring and reacting for 4 hours at 140 ℃ under the oxygen atmosphere; filtering the reaction liquid while the reaction liquid is hot, adding 300mL of saturated sodium carbonate solution into the reaction system, heating to 100 ℃, stirring for 30min, slowly cooling to 35-45 ℃, wherein 1, 4-dichlorobenzene is solid, rapidly filtering the reaction liquid, removing 1, 4-dichlorobenzene, regulating the pH of the filtrate to about 6 by using dilute hydrochloric acid, extracting the filtrate for multiple times by using 100mL of dichloromethane, merging organic phases, concentrating, and recrystallizing by using 30mL of ethanol and 20mL of n-hexane; dissolving with 70mL of dichloromethane, placing in a reaction bottle, adding 1.6g of 4-bromo-N-butyne and 0.6g of potassium hydroxide, heating and refluxing for reaction for a period of time, washing the reaction liquid with water, and concentrating to obtain N-butyne-1, 8-naphthalimide; then, the compound (3.8 g) of the formula (II) is added into a mixed solution of 50mL of dichloromethane, 50mL of tertiary butanol and 50mL of water, 0.2g of concentrated N-butynyl-1, 8-naphthalimide and cuprous iodide are added, the mixture is heated to reflux for 9.5h, then an organic phase is separated, the aqueous phase is extracted for a plurality of times by using 40mL of dichloromethane, the organic phases are combined, and D2.09 g is obtained after concentration and separation by silica gel column chromatography.
Example 13
From CO 2 Taking out the human cervical cancer Hela cell culture dishes with activity from the incubator, and respectively performing the following operations: and (3) performing aseptic operation beside the alcohol lamp, opening a dish cover, sucking out the culture solution in a waste liquid jar, washing the culture solution in the culture bottle with 2mL of PBS twice, performing digestion with 0.25% trypsin, stopping digestion when the increase of cell gaps and the change of cells into a small circle shape are observed, blowing the bottom of the culture bottle by using a pipetting gun to make the cells fall off, transferring the obtained cell suspension into an aseptic centrifuge tube, setting the centrifuge to be 1000r/min, centrifuging for 3min, slowly pouring the supernatant in the centrifuge tube, adding 2-5 mL of culture solution, and performing cell counting under an inverted microscope. According to the counting result, human cervical cancer Hela cells with activity growing in logarithmic phase are spread in 96-well cell culture plate with 50000 cells per well, cultured for 5-6 hr with RPMI1640 containing 10% fetal bovine serum, and added with 100 μl for cultureTwo compounds to be tested diluted in medium and lenalidomide and androstane were used as controls (preparation concentrations of 0.1. Mu.M, 1.0. Mu.M, 10.0. Mu.M, 0.3. Mu.M, 3.0. Mu.M, 30.0. Mu.M, respectively) and recombinant human interferon gamma (final concentration of 100 ng/mg) to activate IDO1 expression in HeLa cells. After the completion of the operation, the 96-well cell culture plate was placed in a 37℃cell culture incubator rich in 5% carbon dioxide for 18 hours, and the reaction was terminated with a certain amount of 6.1N trichloroacetic acid, followed by incubation at 50℃for 30 minutes. After the cell culture solution is precipitated, supernatant is taken, and after the color development of the p-dimethylaminobenzaldehyde, absorbance at 480nm is detected by a multifunctional enzyme-labeled instrument. The group treated with IFNγ medium alone without drug was taken as 100% (At), and the group treated with DMSO medium alone At 0.1% was taken as blank 0% (Ab); the absorbance at different conditions was calculated according to the following formula: absorbance% = (a-Ab)/(At-Ab), a: drug treatment +100ng/mL ifnγ, ab: blank, at: no drug contained only 100ng/mL IFNγ; generating a memory with IC according to using Graph Pad Prism 8.0 software 50 Inhibition curves of values. The inhibition activity data for specific compounds are detailed in table 1. Wherein, the inhibitory activity of the compound D1 on IDO1 is best to reach 3.57 mu M, and the D2 also has certain inhibitory activity on IDO1 to reach 10.04 mu M.
TABLE 1 evaluation of cytotoxic Activity of Compounds
Although the present invention has been described in detail by way of preferred embodiments with reference to the accompanying drawings, the present invention is not limited thereto. Various equivalent modifications and substitutions may be made in the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and it is intended that all such modifications and substitutions be within the scope of the present invention/be within the scope of the present invention as defined by the appended claims. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (7)
1. A compound of formula (i):
；
wherein R isOr->。
2. A process for the preparation of a compound of formula (i) as claimed in claim 1, wherein the reaction is as follows:
；
the preparation method comprises the following steps:
sequentially adding a compound shown in a formula (II), a compound shown in a formula (VIII), tertiary butanol, water, tetrahydrofuran, copper sulfate pentahydrate and sodium ascorbate into a reaction bottle, and reacting at 70 ℃ until the raw materials are completely reacted; then adding dichloromethane, filtering the reaction solution, separating out an organic phase, drying the organic phase through anhydrous magnesium sulfate, and evaporating the solvent to obtain a compound shown in a formula (I); wherein R in the compound of formula (VIII) is the same as the compound of formula (I).
3. A process for the preparation of a compound of formula (i) as claimed in claim 1, wherein the reaction is as follows:
；
the preparation method comprises the following steps:
adding a compound of a formula (III) and trifluoromethanesulfonyl azide into 5mL of mixed solution of tertiary butanol, dichloromethane and water, adding triethylamine and copper sulfate, heating to 40 ℃ for stirring reaction, adding a compound of a formula (VIII) and sodium ascorbate for stirring reaction at 40 ℃, adding dichloromethane after the reaction is finished, filtering a reaction solution, separating an organic phase, drying the organic phase through anhydrous magnesium sulfate, and evaporating a solvent to obtain the compound of the formula (I); wherein R in the compound of formula (VIII) is the same as the compound of formula (I).
4. The process according to claim 2, wherein the compound of formula (ii) is prepared according to the following reaction scheme:
the preparation method comprises the following steps:
adding a compound of the formula (III) into acetonitrile, adding p-toluenesulfonyl chloride, stirring for reacting for a period of time, adding sodium azide, heating to reflux under the protection of nitrogen, concentrating after the reaction is finished, adding dichloromethane, stirring, washing with water, drying by anhydrous magnesium sulfate, and concentrating again to obtain the compound of the formula (II).
5. The process of claim 4, wherein the compound of formula (iii) is prepared according to the following reaction scheme:
the preparation method comprises the following steps:
adding a compound of the formula (IV) into dichloromethane to be completely dissolved, then adding potassium carbonate, slowly dropwise adding N-Boc-aminoacetyl chloride, stirring to react at room temperature after the dropwise adding, monitoring the raw materials to react completely by TLC, then adding dilute hydrochloric acid into a reaction system, adding trifluoroacetic acid, stirring at room temperature, then regulating the pH to 7-8 by using triethylamine, separating an organic phase, and concentrating the organic phase to obtain the compound of the formula (III).
6. The method of claim 5, wherein the compound of formula (iv) is prepared according to the following reaction scheme:
the preparation method comprises the following steps:
(1) Adding a compound of the formula (VII) into benzene, heating and refluxing, cooling to 60 ℃, adding ethylene glycol, heating and refluxing, cooling to 60 ℃, adding p-toluenesulfonic acid, heating and refluxing for reaction, cooling after the reaction is finished, adding triethylamine, separating a benzene layer, extracting the rest part by using benzene, mixing organic phases, washing twice by using water, rotationally evaporating and concentrating the organic phases, adding methanol, heating and dissolving, continuing concentrating, adding methanol, cooling and crystallizing, performing suction filtration and drying, and then preparing a liquid phase by medium pressure, separating and purifying to obtain the compound of the formula (VI);
(2) Adding a compound of formula (VI) into methanol, adding 5% of palladium/calcium carbonate, introducing hydrogen, controlling the pressure to be 0.2MPa and the temperature to be 35 ℃, monitoring the reaction of raw materials by TLC, filtering the reaction liquid, concentrating the reaction liquid, cooling and crystallizing, and then preparing a liquid phase by medium pressure to separate to obtain the compound of formula (V);
(3) Adding the compound of formula (V) into a mixed solution of glacial acetic acid and water, stirring at room temperature, monitoring the reaction completion of the raw materials by TLC, extracting the reaction solution by using chloroform, combining organic phases, and carrying out vacuum spin-drying to obtain the compound of formula (IV).
7. The use of a compound of formula (i) as defined in claim 1 for the preparation of a medicament for inhibiting IDO 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111538790 | 2021-12-15 | ||
| CN2021115387905 | 2021-12-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114773424A CN114773424A (en) | 2022-07-22 |
| CN114773424B true CN114773424B (en) | 2024-02-02 |
Family
ID=82420404
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210651446.5A Active CN114907437B (en) | 2021-12-15 | 2022-06-10 | Androstanol derivative with anti-tumor activity and preparation method and application thereof |
| CN202210652014.6A Active CN114940695B (en) | 2021-12-15 | 2022-06-10 | Androstanol derivative with anti-tumor activity and preparation method and application thereof |
| CN202210651451.6A Active CN114773424B (en) | 2021-12-15 | 2022-06-10 | A bioactive androstanol derivative, and its preparation method and application |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210651446.5A Active CN114907437B (en) | 2021-12-15 | 2022-06-10 | Androstanol derivative with anti-tumor activity and preparation method and application thereof |
| CN202210652014.6A Active CN114940695B (en) | 2021-12-15 | 2022-06-10 | Androstanol derivative with anti-tumor activity and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN114907437B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008109417A1 (en) * | 2007-03-02 | 2008-09-12 | Case Western Reserve University | Mgmt inhibitor combinations for the treatment of neoplastic disorders |
| CN106496297A (en) * | 2016-10-26 | 2017-03-15 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of stanolone |
| CN107098944A (en) * | 2017-06-10 | 2017-08-29 | 浙江圃瑞药业有限公司 | A kind of preparation method of allodihydrotestosterone |
| CN112566666A (en) * | 2018-05-14 | 2021-03-26 | 努瓦申生物公司 | Compounds targeting anti-cancer nuclear hormone receptors |
-
2022
- 2022-06-10 CN CN202210651446.5A patent/CN114907437B/en active Active
- 2022-06-10 CN CN202210652014.6A patent/CN114940695B/en active Active
- 2022-06-10 CN CN202210651451.6A patent/CN114773424B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| A.NTHONY E. PEGG 等.Increased killing of prostate, breast, colon, and lung tumor cells by the combination of inactivators of O6-alkylguanine-DNA alkyltransferase and N,N'-bis(2-chloroethyl)-N-nitrosourea.《Biochemical Pharmacology》.1995,第50卷(第8期),第1141-1148页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114907437A (en) | 2022-08-16 |
| CN114940695A (en) | 2022-08-26 |
| CN114907437B (en) | 2023-06-27 |
| CN114773424A (en) | 2022-07-22 |
| CN114940695B (en) | 2023-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11453662B2 (en) | Process for preparing modulators of p300 and/or CBP | |
| WO2008136010A1 (en) | A process for the preparation of highly pure imatinib base | |
| WO2017202365A1 (en) | Preparation method for trifluoromethyl-substituted pyran derivative | |
| US20180065958A1 (en) | Preparation method of pci-32765 crystal form a | |
| CN103664922A (en) | Novel crystal-form azilsartan and preparation method for same | |
| CN110642834A (en) | Method for synthesizing Lenalidomide | |
| CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
| CN114773424B (en) | A bioactive androstanol derivative, and its preparation method and application | |
| CN113717176A (en) | Method for preparing remazolam | |
| CN110759870B (en) | Synthesis method of oxalagogri intermediate | |
| CN112300050A (en) | Method for preparing N-methyl-5-hydroxytryptamine by taking 5-hydroxytryptamine hydrochloride as raw material | |
| CN110092786B (en) | Method for preparing evodiamine | |
| CN101429224B (en) | Synthesis of 1,4-diene-6-methylene steroids and intermediate thereof | |
| WO2021223425A1 (en) | Method for refining dabigatran crude product | |
| CN113527401A (en) | Abiraterone precursor compound and preparation method and application thereof | |
| CN110759961B (en) | Ursolic acid indolyquinone amide derivatives and preparation method and application thereof | |
| KR20090014225A (en) | Polymorphs of (r)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-thione hydrochloride | |
| CN111943959A (en) | Synthetic method of JAK inhibitor | |
| CN114989141B (en) | Lenalidomide derivative and preparation method and application thereof | |
| CN111170996B (en) | Pyrimidine derivative with ALK inhibitory activity and synthetic method and application thereof | |
| CN110655549A (en) | Preparation method of 6 beta-methylprednisolone | |
| CN113292556B (en) | Preparation method and intermediate of alkynyl-containing compound | |
| KR100633232B1 (en) | A novel method for purification of 6-[4-1-cyclohexyl-1h-tetrazol-5-ylbutoxy-3,4-dihydro-21h-quinolinone having high purity | |
| CN110194740A (en) | 4- tert-butoxycarbonyl-piperazine -1,8- naphthalimide derivative and its synthetic method and application | |
| CN115850158A (en) | Preparation method of high-purity key intermediate M2 of flat drugs |
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 |