CN112898190A - Cannabidiol derivative and preparation method thereof - Google Patents
Cannabidiol derivative and preparation method thereof Download PDFInfo
- Publication number
- CN112898190A CN112898190A CN202110177223.5A CN202110177223A CN112898190A CN 112898190 A CN112898190 A CN 112898190A CN 202110177223 A CN202110177223 A CN 202110177223A CN 112898190 A CN112898190 A CN 112898190A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- formula
- reacting
- molar ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical class OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 146
- 238000006243 chemical reaction Methods 0.000 claims description 79
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 31
- 230000035484 reaction time Effects 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- -1 nitrogen heterocyclic compound Chemical class 0.000 claims description 15
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 abstract description 24
- 229950011318 cannabidiol Drugs 0.000 abstract description 24
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 abstract description 24
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 17
- 230000001988 toxicity Effects 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- 239000012074 organic phase Substances 0.000 description 25
- 238000001035 drying Methods 0.000 description 24
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 23
- 238000005406 washing Methods 0.000 description 21
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000012071 phase Substances 0.000 description 18
- 239000007832 Na2SO4 Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 230000002757 inflammatory effect Effects 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000002158 endotoxin Substances 0.000 description 13
- 229920006008 lipopolysaccharide Polymers 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 238000010828 elution Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 210000000274 microglia Anatomy 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- VWVIOABMCXYUAS-UHFFFAOYSA-N 1-[3-[[3,5-dihydroxy-4-(3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl)phenyl]methyl]azetidin-1-yl]ethanone Chemical compound CC(=C)C1CCC(C)=CC1C1=C(O)C=C(CC2CN(C2)C(C)=O)C=C1O VWVIOABMCXYUAS-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 229940065144 cannabinoids Drugs 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 description 1
- HAQLHRYUDBKTJG-UHFFFAOYSA-N 3,5-dihydroxybenzaldehyde Chemical compound OC1=CC(O)=CC(C=O)=C1 HAQLHRYUDBKTJG-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000005911 anti-cytotoxic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- XTBLDMQMUSHDEN-UHFFFAOYSA-N naphthalene-2,3-diamine Chemical compound C1=CC=C2C=C(N)C(N)=CC2=C1 XTBLDMQMUSHDEN-UHFFFAOYSA-N 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a cannabidiol derivative and a preparation method thereof. The cannabidiol derivative provided by the invention forms a specific structure shown in a formula I by improving a benzyl substituent and a side chain on the basis of CBD, and can improve the anti-inflammatory effect and reduce the toxicity.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a cannabidiol derivative and a preparation method thereof.
Background
Of the 60 phytocannabinoids identified in cannabis extracts, the two most abundant major active ingredients are the psychoactive ingredient Δ 9-Tetrahydrocannabinol (THC) and the non-psychoactive ingredient Cannabidiol (CBD). Cannabinoids have shown a wide range of therapeutic effects, and many cannabinoids, especially CBD, have been shown to have potent anti-inflammatory and immunomodulatory activity. There are also studies in the prior art on the molecular design of CBD to improve the effect of CBD.
For example, the introduction of two methyl groups at the benzyl positions of the CBD carbon chains can obviously improve the anti-inflammatory activity of the CBD derivatives and reduce the expression of IL6 and TNF alpha mRNA (Jukant, A.J Basic clean physiological Pharmacol 2016,27(3), 289-96.). Again as CBD is more cytotoxic, LPS treated BV-2 cells showed significant death after 6h at 10. mu.M CBD concentration (Kozela, E.journal of biological chemistry2010,285(3), 1616-1626.). And Kinney, W.A. obtains KLS-13019(Kinney, W.A. ACS Med Chem Lett2016,7(4),424-8) by introducing a polar group into the carbon number 4 of the side chain, and the therapeutic index and the neuroprotective activity of the KLS-13019 are obviously improved.
However, the existing CBD and the derivatives thereof have poor anti-inflammatory effect and high toxicity, and the application of the CBD and the derivatives thereof is limited.
Disclosure of Invention
In view of the above, the present invention aims to provide a cannabidiol derivative and a preparation method thereof. The cannabidiol derivative provided by the invention can effectively improve the anti-inflammatory activity of CBD and reduce the cytotoxicity of CBD.
The invention provides a cannabidiol derivative which has a structure shown in a formula I:
wherein:
R1selected from the following structures:
R2selected from: h or C1-C4 alkyl;
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
n is 0 to 12.
Preferably, R2Selected from: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl;
the halogen is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
Preferably, the structure is selected from one or more of the structures shown in formula I-1 to formula I-9:
the invention also provides a preparation method of the cannabidiol derivative in the technical scheme, which comprises the following steps:
a) reacting compound X with benzyl bromide to form compound a;
b) reacting compound a with compound Y to form compound b;
c) reacting compound b with phosphorus tribromide to form compound c;
d) reacting compound c with a nitrogen heterocyclic compound to form compound d;
e) after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I;
or
Removing benzyl from compound d, reacting with trans-menthyl-2, 8-diene-1-ol, reacting with R3I reacting to form a compound of formula I;
wherein:
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
R4selected from: -COCH3or-CHO;
R1selected from the following structures:
the nitrogen heterocyclic compound is selected from one or more of the following compounds:
the compound Y is sodium borohydride or alkane of C1-C12.
Preferably, in the step a), the reaction temperature is 20-60 ℃ and the reaction time is 12-48 h;
the molar ratio of the compound X to the benzyl bromide is 1: 2-6.
Preferably, in step b):
the introduction temperature of the compound Y is-78 to-20 ℃,
the reaction temperature is 20-35 ℃, and the reaction time is 2-8 h;
the molar ratio of the compound a to the compound Y is 1: 1-3.
Preferably, in step c):
the reaction temperature is 20-120 ℃, and the reaction time is 4-12 h;
the molar ratio of the compound b to the phosphorus tribromide is 1: 1-3.
Preferably, in step d);
the reaction is carried out under the action of NaH;
the introduction temperature of the NaH is-40 to-20 ℃;
the reaction temperature is 20-100 ℃, and the reaction time is 12-48 h;
the molar ratio of the compound c to the nitrogen heterocyclic compound is 1: 1.5-3;
the molar ratio of the compound c to NaH is 1: 2-4.
Preferably, in step e):
the reaction temperature is 20-35 ℃, and the reaction time is 2-6 h.
Preferably, in step e):
R2is H, compound d is debenzylated and then reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in formula I;
or
R2Instead of H, compound d is debenzylated, reacted with trans-menthyl-2, 8-dien-1-ol and the resulting reaction mass is reacted with R2I reacting to form a compound of formula I;
the benzyl removal is carried out under the action of a Pd/C catalyst;
the molar ratio of the compound d to the Pd/C catalyst is 1: 0.5-1.5.
The cannabidiol derivative provided by the invention forms a specific structure shown in a formula I by improving a benzyl substituent and a side chain on the basis of CBD, and can improve the anti-inflammatory effect and reduce the toxicity. Experimental results show that the cannabidiol derivative provided by the invention can effectively reduce the concentration IC50 of NO generated by BV-2 cells treated by lipopolysaccharide, reduce the mRNA expression of inflammatory factors and reduce the Viability value in a cytotoxicity test, and shows better anti-inflammatory effect and lower cytotoxicity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product 1f obtained in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the product 1f obtained in example 1;
FIG. 3 is a mass spectrum of the product 1f obtained in example 1;
FIG. 4 is a graph of the effect of CBD derivatives in inhibiting NO production and cytotoxicity in lipopolysaccharide treated BV-2 cells;
FIG. 5 is a graph showing the effect of CIAC003 on the inhibition of the production of mRNA by the inflammatory factor in CBD and the compound obtained in example 3;
FIG. 6 is a graph showing the effect of the compound CIAC003 obtained in example 3 on the mechanism of inhibition of inflammatory factors.
Detailed Description
The invention provides a cannabidiol derivative which has a structure shown in a formula I:
wherein:
R1selected from the following structures:
R2selected from: h or C1-C4 alkyl; preferably: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
R3Selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group; among them, the halogen is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
n is an integer of 0 to 12.
More preferably, the cannabidiol derivative shown in the formula I is selected from one or more of the structures shown in the formulae I-1 to I-9:
the cannabidiol derivative provided by the invention forms a structure shown in a formula I by improving a benzyl substituent and a side chain on the basis of CBD, and can improve the anti-inflammatory effect and reduce the toxicity.
The invention also provides a preparation method of the cannabidiol derivative in the technical scheme, which comprises the following steps:
a) reacting compound X with benzyl bromide to form compound a;
b) reacting compound a with compound Y to form compound b;
c) reacting compound b with phosphorus tribromide to form compound c;
d) reacting compound c with a nitrogen heterocyclic compound to form compound d;
e) after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I;
or
Removing benzyl from compound d, reacting with trans-menthyl-2, 8-diene-1-ol, reacting with R3I reacting to form a compound of formula I;
wherein:
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
R4selected from: -COCH3or-CHO;
R1selected from the following structures:
the nitrogen heterocyclic compound is selected from one or more of the following compounds:
the compound Y is sodium borohydride or alkane of C1-C12.
With respect to step a): compound X is reacted with benzyl bromide to form compound a.
The structures of the compound X and benzyl bromide are respectively as follows:
wherein R is3The above technical solutions are the same, and are not described herein again. R4Selected from: -COCH3or-CHO.
The molar ratio of the compound X to the benzyl bromide is preferably 1 to (2-6).
The reaction is preferably carried out under weakly basic conditions, which provide weakly basic conditions that enable the phenolic hydroxyl groups on compound X to ionize, forcing the reaction to proceed in the forward direction. The alkaline substance providing the weakly alkaline condition is preferably one or more of potassium carbonate, sodium hydroxide and sodium carbonate. The molar ratio of the weakly basic substance to the compound X is preferably (0.1-1) to 1.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of acetone, tetrahydrofuran, acetonitrile and N, N-dimethylformamide. The dosage ratio of the compound X to the solvent is preferably 1mmol to (5-20) mL.
The reaction temperature is preferably 20-60 ℃; the reaction time is preferably 12-48 h. After the above reaction, the compound a is produced in the system.
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-processing comprises: diluting the reaction system with water, extracting with ethyl acetate, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, and then, using dichloromethane and methanol as mobile phases, and performing gradient elution separation by using a silica gel column to obtain a product a.
Wherein R is3、R4The above technical solutions are the same, and are not described herein again. Bn represents benzyl, also known as benzyl.
With respect to step b): compound a is reacted with compound Y to form compound b.
The compound Y is sodium borohydride or alkane of C1-C12. The molar ratio of the compound a to the compound Y is preferably 1: 1-3. The introduction temperature of the compound Y is preferably-78 to-20 ℃.
The reaction is preferably carried out in an organic solvent medium. The organic solvent is preferably one or more of dichloromethane, methanol, tetrahydrofuran and N, N-dimethylformamide. The dosage ratio of the compound a to the organic solvent is preferably 1mmol to (10-20) mL.
Specifically, the compound a is dissolved in an organic solvent, the compound Y is added at a certain temperature, and after being uniformly stirred, the mixture is transferred to room temperature for reaction. The room temperature can be 20-35 ℃, and the reaction time is preferably 2-8 h. The compound b is produced through the reaction.
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: adding water to the system for quenching, separating organic phase, extracting water phase with ethyl acetate, combining organic phases, washing with saturated NaCl, anhydrous Na2SO4Drying and spin-drying the solvent to obtain the compound b.
With respect to step c): compound b is reacted with phosphorus tribromide to form compound c.
The mol ratio of the compound b to the phosphorus tribromide is preferably 1: 1-3.
The reaction is preferably carried out in a solvent. The solvent is preferably one or more of diethyl ether, toluene and N, N-dimethylformamide. The dosage ratio of the compound b to the solvent is preferably 1mmol to (1.5-3) mL.
The reaction temperature is preferably 20-120 ℃; the reaction time is preferably 4-12 h. After the reaction, compound c is produced.
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: adding saturated sodium bicarbonate to quench, separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated NaCl, and adding anhydrous Na2SO4Drying and spin-drying the solvent to obtain the compound c.
With respect to step d): compound c is reacted with a nitrogen heterocyclic compound to form compound d.
The nitrogen heterocyclic compound is selected from one or more of the following compounds:
the molar ratio of the compound c to the nitrogen heterocyclic compound is preferably 1 to (1.5-3).
The reaction is carried out under the action of NaH, the introduction of NaH can pull out H atoms on nitrogen heterocyclic rings, N is negatively charged, and C connected with bromine is relatively positively charged, so that the reaction of the N atoms and the N atoms is promoted. The mol ratio of the compound c to NaH is preferably 1 to (2-4). The introduction temperature of the NaH is preferably-40 to-20 ℃.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of anhydrous DMF, anhydrous THF and anhydrous N, N-dimethylacetamide.
Specifically, dissolving the nitrogen heterocyclic compound in a solvent, adding NaH, uniformly mixing, then dropwise adding a solution of a compound c, and controlling the reaction temperature to carry out reaction. Wherein the dosage ratio of the nitrogen heterocyclic compound to the solvent is preferably 1mmol to (1.5-3) mL. The solution of the compound c is a solution of the compound c dissolved in a solvent, and the using amount ratio of the compound c to the solvent is preferably 1mmol to (5-10) mL. Wherein, the solvent for dissolving the nitrogen heterocyclic compound is preferably the same as the solvent for dissolving the compound c; the solvent is of the same kind as the solvent medium described above. The reaction temperature is preferably 20-100 ℃, and the reaction time is preferably 12-48 h. After the reaction, compound d:
wherein R is3The above technical solutions are the same, and are not described herein again. R1Selected from the following structures:
in the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: diluting with water, extracting with diethyl ether, mixing organic phases, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, and gradient eluting with petroleum ether and ethyl acetate as mobile phase and silica gel column to obtain compound d.
With respect to step e): after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I; or compound d is debenzylated, then is reacted with trans-menthyl-2, 8-diene-1-alcohol, and the obtained reactant is reacted with R2I reacting to form the compound of formula I.
The reaction of compound d to remove benzyl groups preferably comprises: and dissolving the compound d in a solvent, adding a Pd/C catalyst, and introducing hydrogen to react to form a debenzylation compound e.
Wherein, the solvent is preferably one or more of methanol, ethyl acetate and ethanol. The preferable dosage ratio of the compound d to the solvent is 1mmol to (4-10) mL. The Pd/C catalyst is a palladium-carbon catalyst, the source of the Pd/C catalyst is not particularly limited, and the Pd/C catalyst is a general commercial product; in the present invention, the Pd/C catalyst is preferably a 10% Pd/C catalyst. In the present invention, the molar ratio of the compound d to the Pd/C catalyst is preferably 1: (0.5-1.5). The amount of the hydrogen gas is preferably such that the system gas pressure is 0.1013 to 0.2026 MPa. The reaction temperature is preferably 20-35 ℃, and the reaction time is preferably 2-8 h. After the reaction, debenzylation product e is generated:
wherein R is1、R3The above technical solutions are the same, and are not described herein again.
In the present invention, after the above-mentioned reaction for removing a benzyl group, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: and filtering the obtained reactant to remove the Pd/C catalyst, spin-drying the solvent, and then performing gradient elution separation by using dichloromethane and methanol as mobile phases through a silica gel column to obtain a compound e.
According to the invention, after compound e has been obtained, it is reacted with trans-menthyl-2, 8-dien-1-ol to form the compound of formula I (corresponding R)2Is H).
The trans-menthyl-2, 8-dien-1-ol has the following structure:
the molar ratio of the compound e to the trans-menthyl-2, 8-diene-1-ol is preferably 1 to (1.5-3).
The reaction is preferably carried out under the action of HCOOH, which is added to promote the formation of carbenium ions of trans-menthyl-2, 8-dien-1-ol which react with the benzene ring. The molar ratio of HCOOH to the compound e is preferably (1.5-3) to 1.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of dichloromethane and THF. The dosage ratio of the compound e to the solvent is preferably 1mmol to (5-20) mL.
The reaction temperature is preferably room temperature, and can be 20-35 ℃; the reaction time is preferably 2-8 h. After reaction, the compound of formula I (corresponding R) is produced2Is H).
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: adding saturated sodium bicarbonate to quench, separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, eluting with petroleum ether and ethyl acetate as mobile phase by silica gel column gradient to obtain compound of formula I (corresponding R)2Is H).
According to the invention, R is obtained2After the compound of the formula I which is H (denoted as compound f), it is reacted with R2I reaction to obtain R2Other compounds of formula I than H.
The R is2In I, R2Is C1-C4 alkyl. The compounds f and R2The molar ratio of I is preferably 1 to (1.2-2).
The reaction is preferably carried out under weakly basic conditions. The alkaline substance providing the weakly alkaline condition is preferably one or more of potassium carbonate, sodium carbonate and sodium hydroxide. The molar ratio of the weakly basic substance to the compound f is preferably (0.1-1) to 1.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of acetone, THF and acetonitrile. The dosage ratio of the compound f to the solvent is preferably 1mmol to (10-15) mL.
The reaction temperature is preferably 20-60 ℃, and the reaction time is preferably 8-16 h. After reaction, the compound (R) of formula I is produced2Not H).
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: diluting with water, extracting with ethyl acetate, mixing organic phases, washing with saturated NaCl, and extracting with anhydrous Na2SO4Drying, eluting with petroleum ether and ethyl acetate as mobile phase by silica gel column gradient to obtain compound of formula I (corresponding R)2Not H).
The preparation method provided by the invention is simple and feasible, has mild conditions, and can efficiently obtain the compound shown in the formula I.
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.
EXAMPLE 1 Synthesis of CIAC001
The synthetic route is as follows:
the synthesis process is as follows:
s1, synthesis of compound 1 a:
3, 5-dihydroxy acetophenone (16mmol) and benzyl bromide (40mmol) were dissolved in acetone (50mL), potassium carbonate (32mmol) was added, and the reaction was refluxed at 65 ℃ overnight. After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, silica gel column chromatography with dichloromethane and methanol as mobile phase and gradient elution separated to obtain product 1a (95.4% yield).
S2, synthesis of compound 1 b:
compound 1a (5mmol) was dissolved in 110mL of a mixed solvent of dichloromethane and methanol (dichloromethane: methanol volume ratio: 10: 1), and sodium borohydride (6mmol) was added at-20 ℃ and stirred for 10 minutes, and then transferred to room temperature (25 ℃) to react for 2 hours. After the reaction is finished, adding water for quenching, separating an organic phase, extracting an aqueous phase by ethyl acetate, combining the organic phase, washing by saturated NaCl, and washing by anhydrous Na2SO4Drying and spin-drying the solvent gave compound 1b (97.9% yield).
S3, synthesis of compound 1 c:
compound 1b (4mmol) was dissolved in 50mL of diethyl ether, phosphorus tribromide (4.8mmol) was added, and the reaction was refluxed at 50 ℃ for 6 hours. Adding saturated sodium bicarbonate to quench after the reaction is finished, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phase, washing with saturated NaCl, and adding anhydrous Na2SO4Drying and spin-drying the solvent gave compound 1c (94.4% yield).
S4, synthesis of compound 1 d:
dissolving 1,2, 3-triazole (5mmol) in anhydrous DMF (50mL), adding NaH at-20 ℃, and stirring for 10min to obtain a reaction solution; compound 1c (2.5mmol) was dissolved in anhydrous DMF (5mL), and the resulting solution was added dropwise to the above reaction mixture, and the mixture was transferred to 120 ℃ for reaction for 24 hours. After the reaction is finished, adding water for dilution, extracting by diethyl ether, combining organic phases, washing by saturated NaCl, and anhydrous Na2SO4Drying, silica gel column chromatography, petroleum ether and ethyl acetate as mobile phase, gradient elution to obtain product 1d (25.2% yield).
S5, synthesis of compound 1 e:
compound 1d (2mmol) was dissolved in 22mL of a mixed solvent (methanol: ethyl acetate volume ratio: 10: 1), Pd/C catalyst (10% w/vPd/C, 200mg) was added, and reaction was carried out for 4h with hydrogen gas. After the reaction, Pd/C was removed by filtration, the solvent was dried by evaporation, and the product 1e was isolated by gradient elution on a silica gel column using dichloromethane and methanol as mobile phases (yield 80.4%).
S6, synthesis of compound 1 f:
dissolving the compound 1e (1mmol) in dichloromethane (5mL), adding trans-menthyl-2, 8-diene-1-ol (2mmol),HCOOH (2mmol), room temperature (25 ℃) for 12 h. After the reaction is finished, adding saturated sodium bicarbonate to quench the reaction, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phase, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, separating with silica gel column and gradient elution with petroleum ether and ethyl acetate as mobile phase to obtain product 1f (purity 97.5%).
Structural characterization of the obtained product 1f is shown in fig. 1-3, fig. 1 is a nuclear magnetic resonance hydrogen spectrum of the product 1f obtained in example 1, fig. 2 is a nuclear magnetic resonance carbon spectrum of the product 1f obtained in example 1, and fig. 3 is a mass spectrum of the product 1f obtained in example 1.
Example 2 Synthesis of CIAC002
The synthetic route is as follows:
the synthesis process is as follows:
s1, synthesis of compound 2 a:
3, 5-dihydroxybenzaldehyde (26mmol) and benzyl bromide (65mmol) were dissolved in acetone (100mL), potassium carbonate (52mmol) was added, and the reaction was refluxed at 60 ℃ overnight. After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, silica gel column chromatography with dichloromethane and methanol as mobile phase and gradient elution to obtain product 2a (yield 90.2%).
S2, synthesis of compound 2 b:
compound 2a (10mmol) was dissolved in 100mL of anhydrous dichloromethane, n-butyl (15mmol) was added at-20 ℃ and reacted at room temperature (25 ℃) for 2 h. After the reaction is finished, adding water for quenching, separating an organic phase, extracting an aqueous phase by ethyl acetate, combining the organic phase, washing by saturated NaCl, and washing by anhydrous Na2SO4Drying and spin-drying the solvent gave compound 2b (92.9% yield).
S3, synthesis of compound 2 c:
compound 2b (8mmol) was dissolved in 50mL of diethyl ether, phosphorus tribromide (9.6mmol) was added, and the reaction was refluxed at 50 ℃ for 6 hours. After the reaction is finished, saturated sodium bicarbonate is addedQuenching, separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated NaCl, and removing anhydrous Na2SO4Drying and spin-drying the solvent gave compound 2c (96.2% yield).
S4, synthesis of compound 2 d:
dissolving imidazole (10mmol) in anhydrous DMF (100mL), adding NaH at-20 ℃, and stirring for 10min to obtain a reaction solution; compound 2c (5mmol) was dissolved in anhydrous DMF (8mL), and the resulting solution was added dropwise to the above reaction mixture, and the mixture was transferred to 120 ℃ for reaction for 24 hours. After the reaction is finished, adding water for dilution, extracting by diethyl ether, combining organic phases, washing by saturated NaCl, and anhydrous Na2SO4Drying, silica gel column chromatography, petroleum ether and ethyl acetate as mobile phase, gradient elution to obtain product 2d (30.4% yield).
S5, synthesis of compound 2 e:
compound 2d (4mmol) was dissolved in 50mL of a mixed solvent (methanol: ethyl acetate volume ratio: 10: 1), Pd/C catalyst (10% w/vPd/C, 400mg) was added, and reaction was carried out for 4h with hydrogen gas. After the reaction, the Pd/C was removed by filtration, the solvent was dried by evaporation, and the product 2e was isolated by gradient elution on a silica gel column using dichloromethane and methanol as mobile phases (yield 76.4%).
S6, synthesis of compound 2 f:
compound 2e (2mmol) was dissolved in dichloromethane (10mL), and trans-menthyl-2, 8-dien-1-ol (4mmol), HCOOH (4mmol) were added and reacted at room temperature (25 ℃ C.) for 12h (product yield 27.8%). After the reaction is finished, adding saturated sodium bicarbonate to quench the reaction, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phase, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, silica gel column chromatography, petroleum ether and ethyl acetate as mobile phase, gradient elution separation to obtain product 2f (purity 95.2%).
EXAMPLE 3 Synthesis of Compound CIAC002
The synthetic route is as follows:
the synthesis process is as follows:
S1-S6: the same as in example 2.
S7, synthesis of compound 2 g:
compound 2f (1mmol) was dissolved in acetone (8mL) and CH was added3I (2.5mmol), potassium carbonate (2mmol) and reflux overnight (94.1% yield of product). After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, silica gel column, petroleum ether and ethyl acetate as mobile phase, gradient elution separation to obtain 2g of product (yield 80.3%, purity 98.1%).
Example 4
Anti-inflammatory and cytotoxic assays
S1, cell count, 5X 10 in DMEM medium (10% serum, 1% double antibody)4Cell density per mL, 200 μ L per well of 96-well plate, and incubation for 24 h.
S2, removing the culture medium, adding 200 mu L of DMEM culture medium without serum and double antibodies, simultaneously adding different doses of the drugs, and incubating for 24 h.
S3, NO concentration test: mu.L of the medium was added with 10. mu.L of 2, 3-diaminonaphthalene solution (concentration: 0.5mg/mL), incubated for 15min, and then 5. mu.L of NaOH solution (concentration: 3M) was added to terminate the reaction. And exciting at 360nm, and detecting the light absorption value at 430 nm. The test results are shown in FIG. 1.
S4, cytotoxicity test: removing residual culture medium, adding 100 μ L paraformaldehyde solution (concentration of 5% w/v), incubating for 5min, removing paraformaldehyde, adding 100 μ L crystal violet (concentration of 0.5% w/v), incubating for 15min, removing crystal violet, washing with distilled water for 3 times, adding 150 μ L anhydrous ethanol, incubating for 20min, and testing absorbance value at 540 nm. The test results are shown in FIG. 4.
The above test was carried out with CBD (cannabidiol) and the compound CIAC001 synthesized in example 1, respectively, as the drugs, and the results are shown in fig. 4. FIG. 4 is a graph showing the effects of CBD derivatives in inhibiting the production of NO by BV-2 cells treated with lipopolysaccharide, wherein A is the anti-inflammatory effect of CBD, C is the anti-inflammatory effect of CIAC001 of the compound in example 1, B is the cytotoxicity effect of CBD, and D is the cytotoxicity effect of CIAC001 of the compound in example 1.
In fig. 4, the A, C graph shows the content of Nitric Oxide (NO), which induces inflammation and thus increases the amount of NO released when Lipopolysaccharide (LPS) is treated on the cells, and in this experiment, the change in NO after the addition of different doses of the drug is measured using the NO content of the non-dosed LPS group as 100%, and the concentration of the drug required when the NO content becomes 50% of the non-dosed LPS group, i.e., IC50, is calculated by fitting, so that a lower value of IC50 indicates a better anti-inflammatory effect of the drug.
In FIG. 4, the B, D graph shows the cytotoxicity of the drug, and this experiment shows that the number of living cells was measured by crystal violet staining, the LPS treatment group without the drug was regarded as 100%, the change in the number of living cells after the addition of the drug at different concentrations was measured, and the concentration of the drug at which the living cells became 50% of the LPS treatment group without the drug, i.e., the Viability, was calculated by fitting, so that the greater the value of Viability, the less the toxicity.
As can be seen from the test results in fig. 4, the IC50 and viatility values of the compound CIAC001 obtained in example 1 are both improved compared with CBD, which demonstrates that it has improved anti-inflammatory effect and reduced toxicity.
Example 5
Anti-inflammatory test
S1, cell count, 5X 10 in DMEM medium (10% serum, 1% double antibody)4Cell density/mL, 2mL per well of 6-well plate, incubate for 24 h.
S2, removing the culture medium, adding 2mL of DMEM culture medium without serum and double antibodies, adding different doses of drugs, and incubating for 6 h.
S3, removing the culture medium, washing with 1mL of PBS buffer solution for 2 times, adding 1mL of Trizol cell lysate, and incubating for 5 min. The lysate was transferred to a 1mL RNA-free centrifuge tube, 200. mu.L chloroform was added, vortexed for 1min, 12000g, and centrifuged at 4 ℃ for 10 min. Adding 400 μ L isopropanol into 400 μ L supernatant, mixing, standing on ice for 10min, then 12000g, centrifuging at 4 deg.C for 7 min. The supernatant was removed, and 1mL of the mixed solution (ethanol: DEPC aqueous solution volume ratio: 3:1) was added thereto, 12000g was added, and the mixture was centrifuged at 4 ℃ for 5 min. Removing supernatant, standing on ice for 3min, adding 25 μ L DEPC water solution, mixing, measuring RNA concentration, and reverse transcribing to cDNA.
And S4, determining the cDNA concentration, configuring the template amount to 600ng/mL, adding DNA synthetase and different primers to carry out qPCR amplification, and determining the content of different genes.
Test effects referring to fig. 5-6, the test experiments of fig. 5 and 6 were performed in the same manner except that the primers were used. Wherein, the effect of CBD derivatives on the inhibition of the generation of inflammatory factor mRNA is shown in FIG. 5, and FIG. 5 is a graph showing the effect of CBD and the compound CIAC003 obtained in example 3 on the inhibition of the generation of inflammatory factor mRNA. FIG. 5 shows the measurement of the mRNA level of inflammatory factors, and 3 selected genes are inflammatory factors positively correlated with the intensity of inflammation; when LPS is added, the inflammatory factors in the Control group are obviously improved, which indicates that inflammation is caused after LPS treatment, when CBD is given, IL-1 beta is inhibited only under the concentration of 10 mu M, and CIAC003 has obvious down-regulation on 3 inflammatory factors under the concentration of 1 mu M, and has dose-dependent benefit under the concentration of 10 mu M, therefore, CIAC003 can better reduce the mRNA expression of the inflammatory factors compared with CBD, and has better anti-inflammatory effect.
The research on the mechanism of inhibiting inflammatory factors by CBD derivatives is shown in figure 6, and figure 6 is a diagram of the research effect of the compound CIAC003 obtained in example 3 on the mechanism of inhibiting inflammatory factors. As can be seen from FIG. 6, after LPS treatment, microglia cells change from resting state M0 to activated state M1, M1 cells release a large amount of proinflammatory factors, which leads to deepening of inflammation, while the body can convert M1 cells to M2 cells, and M2 cells release anti-inflammatory factors, which has an inflammation inhibiting effect, thereby protecting the microglia cells. In the figure, IL-1 beta, IL-6 and iNOS are specific inflammatory factors of M1 state, and are all obviously reduced after CIAC003 is added, which indicates that M1 state cells are reduced. On the other hand, the specific inflammatory factor IL-10 in M2 state is obviously up-regulated after CIAC003 is added, which indicates that the cells in M2 state are increased. Thus, CIAC003 achieves anti-inflammatory effects by promoting the conversion of microglia from the M1 state to the M2 state.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A cannabidiol derivative having the structure shown in formula i:
wherein:
R1selected from the following structures:
R2selected from: h or C1-C4 alkyl;
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
n is 0 to 12.
2. The cannabidiol derivative of claim 1, wherein R is2Selected from: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl;
the halogen is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
3. The cannabidiol derivative according to claim 1, wherein the cannabidiol derivative is selected from one or more of the structures of formula i-1 to formula i-9:
4. a method of preparing a cannabidiol derivative as claimed in any one of claims 1 to 3, comprising the steps of:
a) reacting compound X with benzyl bromide to form compound a;
b) reacting compound a with compound Y to form compound b;
c) reacting compound b with phosphorus tribromide to form compound c;
d) reacting compound c with a nitrogen heterocyclic compound to form compound d;
e) after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I;
or
Removing benzyl from compound d, reacting with trans-menthyl-2, 8-diene-1-ol, reacting with R3I reacting to form a compound of formula I;
wherein:
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
R4selected from: -COCH3or-CHO;
R1selected from the following structures:
the nitrogen heterocyclic compound is selected from one or more of the following compounds:
the compound Y is sodium borohydride or alkane of C1-C12.
5. The preparation method according to claim 4, wherein in the step a), the reaction temperature is 20-60 ℃ and the reaction time is 12-48 h;
the molar ratio of the compound X to the benzyl bromide is 1: 2-6.
6. The method of claim 4, wherein in step b):
the introduction temperature of the compound Y is-78 to-20 ℃,
the reaction temperature is 20-35 ℃, and the reaction time is 2-8 h;
the molar ratio of the compound a to the compound Y is 1: 1-3.
7. The method of claim 4, wherein in step c):
the reaction temperature is 20-120 ℃, and the reaction time is 4-12 h;
the molar ratio of the compound b to the phosphorus tribromide is 1: 1-3.
8. The method according to claim 4, wherein in the step d);
the reaction is carried out under the action of NaH;
the introduction temperature of the NaH is-40 to-20 ℃;
the reaction temperature is 20-100 ℃, and the reaction time is 12-48 h;
the molar ratio of the compound c to the nitrogen heterocyclic compound is 1: 1.5-3;
the molar ratio of the compound c to NaH is 1: 2-4.
9. The method of claim 4, wherein in step e):
the reaction temperature is 20-35 ℃, and the reaction time is 2-6 h.
10. The method of claim 4, wherein in step e):
R2is H, compound d is debenzylated and then reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in formula I;
or
R2Instead of H, compound d is debenzylated, reacted with trans-menthyl-2, 8-dien-1-ol and the resulting reaction mass is reacted with R2I reacting to form a compound of formula I;
the benzyl removal is carried out under the action of a Pd/C catalyst;
the molar ratio of the compound d to the Pd/C catalyst is 1: 0.5-1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110177223.5A CN112898190B (en) | 2021-02-07 | 2021-02-07 | Cannabidiol derivative and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110177223.5A CN112898190B (en) | 2021-02-07 | 2021-02-07 | Cannabidiol derivative and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112898190A true CN112898190A (en) | 2021-06-04 |
| CN112898190B CN112898190B (en) | 2023-10-24 |
Family
ID=76123021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110177223.5A Active CN112898190B (en) | 2021-02-07 | 2021-02-07 | Cannabidiol derivative and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112898190B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021245671A1 (en) * | 2020-06-03 | 2021-12-09 | Epm (Ip), Inc. | Cannabidiolic acid (cbda) derivatives and uses thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030166727A1 (en) * | 2000-06-16 | 2003-09-04 | Raphael Mechoulam | Pharmaceutical compositions comprising cannabidiol derivatives |
| US20150274623A1 (en) * | 2012-10-17 | 2015-10-01 | Northeastern Uiversity | 2-cycloalkyl resorcinol cannabinergic ligands |
| CN106456573A (en) * | 2014-01-13 | 2017-02-22 | 康纳生物技术有限公司 | Novel functionalized 1,3-benzene diols for the treatment of hepatic encephalopathy and their method of use |
| CN108024973A (en) * | 2015-07-16 | 2018-05-11 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | CBD compounds, its composition and the purposes of fluorination |
| WO2021000053A1 (en) * | 2019-07-04 | 2021-01-07 | Canopy Growth Corporation | Cannabinoid derivatives |
-
2021
- 2021-02-07 CN CN202110177223.5A patent/CN112898190B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030166727A1 (en) * | 2000-06-16 | 2003-09-04 | Raphael Mechoulam | Pharmaceutical compositions comprising cannabidiol derivatives |
| US20150274623A1 (en) * | 2012-10-17 | 2015-10-01 | Northeastern Uiversity | 2-cycloalkyl resorcinol cannabinergic ligands |
| CN106456573A (en) * | 2014-01-13 | 2017-02-22 | 康纳生物技术有限公司 | Novel functionalized 1,3-benzene diols for the treatment of hepatic encephalopathy and their method of use |
| CN108024973A (en) * | 2015-07-16 | 2018-05-11 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | CBD compounds, its composition and the purposes of fluorination |
| WO2021000053A1 (en) * | 2019-07-04 | 2021-01-07 | Canopy Growth Corporation | Cannabinoid derivatives |
Non-Patent Citations (3)
| Title |
|---|
| BLASKOVICH, MARK A. T.等: "The antimicrobial potential of cannabidiol", COMMUNICATIONS BIOLOGY, vol. 4, no. 1, pages 7, XP055859252, DOI: 10.1038/s42003-020-01530-y * |
| WILLIAM A. KINNEY等: "Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability", ACS MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 4, pages 424, XP055531564, DOI: 10.1021/acsmedchemlett.6b00009 * |
| 史文强等: "大麻二酚及其类似物研究进展", 药学进展, vol. 44, no. 09, pages 710 - 720 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021245671A1 (en) * | 2020-06-03 | 2021-12-09 | Epm (Ip), Inc. | Cannabidiolic acid (cbda) derivatives and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112898190B (en) | 2023-10-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI84813B (en) | FOERFARANDE FOER FRAMSTAELLNING AV FARMACEUTISKT VERKSAMT KINONDERIVAT. | |
| US20090054376A1 (en) | Benzofuran derivatives with therapeutic activities | |
| Li et al. | Anti-hepatitis B virus lignans from the root of Streblus asper | |
| CA3019890A1 (en) | Bioenzymatic synthesis of tetrahydrocannabivarin (thc-v), cannabinol (cbn), and cannabivarin (cbv) and their use as therapeutic agents | |
| CN103588616B (en) | A kind of Selaginella pulvinata extract and its preparation method and application | |
| CN112898190B (en) | Cannabidiol derivative and preparation method thereof | |
| JP5813832B2 (en) | Aromatic polyacetal and articles containing the same | |
| CN110498784B (en) | Nobiletin derivatives or pharmaceutically acceptable salts thereof, and preparation method and application thereof | |
| Silva et al. | Synthesis of α-and β-lapachone derivatives from hetero diels-alder trapping of alkyl and aryl o-quinone methides | |
| Bercht et al. | Cannabispirone and cannabispirenone, two naturally occurring spiro-compounds | |
| Owellen | Reactions of tetrahydrocarbazolechloroindolenine | |
| Polley et al. | Divergent Total Synthesis of (±)‐Mahanine and Other Carbazole Alkaloids | |
| AU2016212552A1 (en) | Compound containing indoleacetic acid core structure and use thereof | |
| Sharma et al. | Synthesis and anti-inflammatory activity of derivatives of coumarino-lignoid, cleomiscosin A and its methyl ether | |
| Tan et al. | Racemic total synthesis of dactyloidin and demethyldactyloidin through the dl-proline-catalyzed Knoevenagel condensation/[4+ 2] cycloaddition cascade | |
| CN114075201B (en) | Preparation method of sitagliptin impurity | |
| Fraser et al. | Rutaceous constitutents. Part II. Two acridone alkaloids from Atalantia ceylanica (Rutaceae) | |
| Miao et al. | Exquisite Synthesis of a Designed PAR‐1 Antagonist | |
| CA1284640C (en) | Therapeutic compositions based on 3-alkoxyflavone derivatives, and novel 3-alkoxyflavone derivatives | |
| Pitchai et al. | Photo induced synthesis of methyl derivative of cryptosanguinolentine | |
| Wen-Feng et al. | The synthesis, structural study and anticancer activity evaluation of emodin derivatives containing conjugative groups | |
| AU2016100494A4 (en) | Method of isolating phenanthroindolizidine alkaloids from tylophora atrofolliculata with hif-1 inhibitory activity, compositions comprising them and their use | |
| AU2016100495A4 (en) | Method of isolating phenanthroindolizidine alkaloids from tylophora atrofolliculata, compositions comprising them and their medical use | |
| WO2005044821A1 (en) | New camptothecin derivatives and processes of the preparation thereof and the use of the same | |
| Jordaan, A.*, Du Plessis, LM** & Joynt | The structure and synthesis of pavettine, an alkaloid from Pavetta lanceolata Eckl.(Rubiaceae) |
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 | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Wang Xiaohui Inventor after: Jin Sha Inventor after: Lu Yuyuan Inventor after: An Lijia Inventor before: Wang Xiaohui Inventor before: Jin Sha Inventor before: Lu Yuyuan Inventor before: An Lijia |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |