CN104945335A - 紫苏胺类化合物及其制备和应用 - Google Patents
紫苏胺类化合物及其制备和应用 Download PDFInfo
- Publication number
- CN104945335A CN104945335A CN201410119999.1A CN201410119999A CN104945335A CN 104945335 A CN104945335 A CN 104945335A CN 201410119999 A CN201410119999 A CN 201410119999A CN 104945335 A CN104945335 A CN 104945335A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- acid
- pharmaceutical salts
- compound
- phenyl
- 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
- 235000004347 Perilla Nutrition 0.000 title claims abstract description 22
- 241000229722 Perilla <angiosperm> Species 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 amine compound Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 230000001926 lymphatic effect Effects 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Chemical compound CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000012071 phase Substances 0.000 description 10
- 229930007631 (-)-perillyl alcohol Natural products 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 235000005693 perillyl alcohol Nutrition 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003921 oil Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- NDTYTMIUWGWIMO-SNVBAGLBSA-N (-)-perillyl alcohol Chemical compound CC(=C)[C@H]1CCC(CO)=CC1 NDTYTMIUWGWIMO-SNVBAGLBSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-elemene Chemical class CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- JSGZKHJWRITPII-UHFFFAOYSA-N oxoniumylideneazanide Chemical compound O[N] JSGZKHJWRITPII-UHFFFAOYSA-N 0.000 description 2
- RUMOYJJNUMEFDD-UHFFFAOYSA-N perillyl aldehyde Chemical compound CC(=C)C1CCC(C=O)=CC1 RUMOYJJNUMEFDD-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical class CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 1
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108010007508 Farnesyltranstransferase Proteins 0.000 description 1
- 102000007317 Farnesyltranstransferase Human genes 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Natural products CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012627 chemopreventive agent Substances 0.000 description 1
- 229940124443 chemopreventive agent Drugs 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 150000002627 limonene derivatives Chemical class 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000002767 monocyclic monoterpene derivatives Chemical group 0.000 description 1
- 229930003658 monoterpene Natural products 0.000 description 1
- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 150000002977 perillyl alcohol derivatives Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 150000004508 retinoic acid derivatives Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 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 1
- 239000000341 volatile oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/14—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,涉及一系列具有式I结构的紫苏胺类化合物及其制备和应用。所述紫苏胺类化合物包括药学上可接受的盐和溶剂化物,以及含有所述紫苏胺类化合物或其药学上可接受的盐作为活性成分的组合物,可用于治疗癌症。本发明所述的紫苏胺类化合物及其药用盐类具有较好的抗癌活性,其制备方法简单可行,易操作。
Description
技术领域:
本发明涉及一系列新的紫苏胺类化合物,该化合物的盐类和以该化合物或其盐类为活性成分的药物,可用于治疗癌症。本发明还涉及及合成所述化合物的中间体的制备方法。
背景技术:
紫苏醇(perillyl alcohol)为异戊二烯萜类挥发油,广泛存在于紫苏叶、柑桔、樱桃、薄荷等植物中,可以诱导细胞凋亡、抑制肿瘤细胞增殖、诱导肿瘤细胞再分化,是目前已知的少数几个对肿瘤既有化学预防作用又有化学治疗作用的天然产物(胡东,陈燕.食物来源单萜类物质紫苏醇的抗癌作用[J].临床血液杂志,2001,14(3):141-143)。在肿瘤形成初始阶段,紫苏醇不仅能降低动物模型中肿瘤的发生几率,还能减少肿瘤发生种类,对食道癌(Liston B W,Nines R,Carlton P S,et a1.Perillyl alcohol as a chemopreventive agent inN-nitro-somethylvenzylamine-induced rat esophageal tumorigenesis[J].Cancer Research,2003,63(10):2399-2403)、结肠直肠癌(Meadows S M,Mulkerin D,Berlin J,et al.Phase II trial ofperillyl alcohol with metastatic colorectal cancer[J].International Journal of GastrointestinalCancer,2002,32(2-3):125-128)、胰腺癌(Lebedeva I V,Suzz,Vozhilla N,et al.Mechanism ofin vitro pancreatic cancer cell growth inhibition by melanoma differentiation-associatedgene7/interleuk in-24and perillyl alcohol[J].Cancer Research,2008,68(18):7439-7447)和乳腺癌(Yuri T,Danbara N,Tsujita-Kyutoku M,et al.Perillyl alcohol inhibits human breast cancercell growth in vitro and in vivo[J].Breast Cancer Research and Treatment,2004,84(3):251-260,)等肿瘤均有预防和治疗作用,效果显著。在国外已作为抗肿瘤药物进入临床Ⅰ期和临床Ⅱ期研究阶段(Liu G,Oettel K,Ummersen L V,et al.Phase II trial of perilly alcohol(NSC641066)administered daily in patients with metastatic androgen independent prostatecancer[J].Investigational New Drugs,2003,21(3):367-372.Bailey H H,Attia S,Love R R,et al.Phase II trial of daily oral perillyl alcohol(NSC641066)in treatment-refractory metastatic breastcancer[J].Cancer Chemother Pharmacol,2008,62(1):149-157.da Fonseca C O,SchwartsmannG,Fischer J,et al.Preliminary results from a phase I/II study of perillyl alcohol intranasaladministration in adults with recurrent maligant gliomas[J].Surgical Neurology,2008,70(3):259-266.)。
国内外对紫苏醇衍生物的化学修饰仅限于三方面:①将紫苏醇的环外羟基以维A酸酯化,合成维A酸类衍生物,目前未见该类衍生物的药理活性报道(Das B C,Mahalingam S M,Panda L,et al.Design and synthesis of potential new apoptosis agents:hybrid compoundscontaining perillyl alcohol and new constrained retinoids[J].Tetrahedron Letters,2010,51(11):1462–1466)。②将紫苏醇环外羟基和葡萄糖成苷键,合成葡萄糖类衍生物,该类衍生物对小鼠肺癌细胞的抑制活性较紫苏醇略高(Xanthakis E,Magkouta S,Loutrari H,et al.Enzymatic synthesis of perillyl alcohol derivatives and investigation of their antiproliferativeactivity[J].Biocatalysis and Biotransformation,2009,27(3):170-178.)。③在羟基α-碳原子上引入磷酸酯结构或将羟基用磷酸酯结构取代。该类化合物对法尼基转移酶和小鼠胚胎成纤维细胞NIH-3T3未见明显抑制作用(Eummer J T,Gibbs B S,Zahn T J.et al.Novel limonenephosphonate and farnesyl diphosphate analogues:design,synthesis,and evaluation as potentialprotein-farnesyl transferase inhibitors[J].Bioorganic&Medicinal Chemistry,1999,7(2):241-250.)。
紫苏醇水溶性差,口服给药生物利用度低,限制了其临床应用(Liu G,Oettel K,Ummersen L V,,et al.Phase II trial of perilly alcohol(NSC641066)administered daily inpatients with metastatic androgen independent prostate cancer[J].Investigational New Drugs,2003,21(3):367-372.Bailey H H,Attia S,Love R R,et al.Phase II trial of daily oral perillylalcohol(NSC641066)in treatment-refractory metastatic breast cancer[J].Cancer ChemotherPharmacol,2008,62(1):149-157.)。针对以上问题,借鉴本课题组前期对榄香烯、柠檬烯衍生物抗癌构效关系的研究结果,认为增强化合物的极性和水溶性有利于提高抗肿瘤活性(陈娇娇,董金华,景永奎,等.柠檬烯类似物及其制备方法和用途[P].中国专利,200610081622.7,公开号CN101070300.董金华,徐莉英,景永奎,等.一种β-榄香烯含氮衍生物的制备及应用[P].中国专利,200610080037.5,公开号CN1844105.徐莉英,董金华,景永奎,等.β-榄香烯含氮衍生物及其制备方法和用途[P].中国专利,200610081625.0,公开号CN1850779.)。因此,本发明首次明确提出保持紫苏醇的含双键的单环单萜骨架,将羟基用亲水性的含氮基团取代,从而改善水溶性,提高抗肿瘤活性,合成了本发明所述紫苏胺类化合物,并经药理试验研究了其抗肿瘤活性。
发明内容:
本发明以紫苏醇为先导化合物,为提高化合物的极性或亲水性、增强其抗癌活性,将羟基用含氮基团取代,合成了紫苏胺类化合物,并经药理试验证明可抑制多种肿瘤细胞增殖,它们的主要作用为抗肿瘤。
本发明提供紫苏胺类化合物结构如下式I:
其中,R1、R2选自:氢,C1-C12烷基,C1-C12烷氧基,C1-C12烷氧基苯基,含有烯键的C1-C12烷基,含有炔键的C1-C12烷基,含有羟基的C1-C12烷基,含有苯基的C1-C12烷基,C3-C12环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C12烷基、C1-C12烷氧基苯基。
优选地,R1、R2选自:氢,C1-C10烷基,C1-C10烷氧基,C1-C10烷氧基苯基,含有烯键的C1-C10烷基,含有炔键的C1-C10烷基,含有羟基的C1-C10烷基,含有苯基的C1-C10烷基,C3-C10环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C10烷基、C1-C10烷氧基苯基。
更为优选地,R1、R2选自:氢,C1-C10烷基,C1-C4烷氧基,C1-C4烷氧基苯基,含有烯键的C1-C4烷基,含有炔键的C1-C4烷基,含有羟基的C1-C4烷基,含有苯基的C1-C4烷基,C3-C6环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C4烷基、C1-C4烷氧基苯基。
最优选地,R1、R2选自:氢,C1-C10烷基,含有羟基的C1-C4烷基,C3-C6环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C4烷基、C1-C4烷氧基苯基。
本发明优选如下化合物:
化合物1化合物2化合物3化合物4
化合物5化合物6化合物7
本发明提供紫苏胺类化合物及其药用盐类的制备方法,其合成路线如下:
R1,R2如权利要求书所述。
优选:
本发明上述紫苏胺类化合物及其药用盐类的制备过程中所用溶剂为常用的反应溶剂,无特殊要求。
本发明提供了含上述紫苏胺类化合物及其药用盐类,所述的药用盐指常规的酸加成盐,为与与合适的非毒性有机酸或无机酸成的盐。如盐酸,氢溴酸,氢碘酸,硫酸,磷酸,硝酸,乙酸,酒石酸,水杨酸,甲磺酸,丁二酸,柠檬酸,苹果酸,乳酸,富马酸,马来酸等。
本发明提供了一种药物组合物,上述的紫苏胺类化合物及其药用盐类和药学上可被接受的赋形剂组成。发明还提供了紫苏胺类化合物及其药用盐类及其组合物在制备抗癌药物中的用途。
本发明所描述的紫苏胺类化合物,是为改善紫苏醇的水溶性和提高抗癌活性,而在其分子中引入含氮基团所合成的化合物,这些衍生物可能具有更强的生理活性和较大极性,其氨基便于和酸成盐来达到改善水溶性的目的。
本发明的紫苏胺类化合物及其药用盐类具有较好的抗癌活性,其制备方法简单可行,易操作。
具体实施方式:
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
实施例1紫苏醇的合成
将0.1mol紫苏醛溶于100mL无水乙醇中,冰浴下分批加入0.2molNaBH4,加毕后室温反应3h。减压蒸除乙醇,加入30mL水和30mL二氯甲烷,转移至分液漏斗中,分出有机相,水相用二氯甲烷萃取,合并有机相,用水和饱和盐水洗涤,无水硫酸钠干燥。浓缩后得无色透明液体,收率86.8%。
实施例2的合成
将0.06mol实施例1产物和0.12mol三苯基磷溶于50mL二氯甲烷中,冰浴下缓慢滴加12mL四氯化碳和20mL二氯甲烷的混合溶液。加毕室温反应10h。加入200mL环己烷,析出白色固体,抽滤,将滤液浓缩后经柱层析分离得到淡黄色液体,收率70.4%。
实施例3式I化合物的合成通法
将5mmol实施例2产物和7.5mmol碳酸钾溶于10mL丙酮。搅拌下滴加5.5mmol胺类化合物,加热回流反应6-8h。减压蒸除丙酮,加入15mL饱和盐水,转移至分液漏斗中,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥。浓缩后得化合物1-7。
按此合成方法得到:
化合物1:白色油状物。MS(EI)[M+H]+m/z:249.2325.1H NMR(600MHz,CDCl3)δ(ppm):5.59(1H,br s),4.72,4.71(2H,s,s),3.04-2.96(2H,m),2.81-2.73(2H,m),2.38–2.13(8H,m,),1.99–1.93(1H,m),1.85-1.79(1H,m),1.74(3H,s),1.49-1.42(1H,m),1.10(6H,d,J=6.0Hz).
化合物2:黄色油状物。MS(EI)[M+H]+m/z:235.2169.1H NMR(300MHz,CDCl3)δ(ppm):5.59(1H,br s),4.70(2H,s),2.82(2H,s),2.54–2.29(8H,m),2.28(3H,s),2.25–1.79(6H,m),1.73(3H,s),1.54–1.33(1H,m).
化合物3:黄色油状物。MS(EI)[M+H]+m/z:263.2482.1H NMR(600MHz,CDCl3)δ(ppm):5.60(1H,br s),4.77–4.63(2H,m),2.86–2.76(3H,m),2.69-2.42(8H,m),2.15–1.91(5H,m),1.87–1.78(1H,m),1.73(3H,s),1.50–1.38(1H,m),1.10(6H,d,J=6.5Hz).
化合物4:黄色油状物。MS(EI)[M+H]+m/z:220.2060.1H NMR(300MHz,CDCl3)δ(ppm):5.59(1H,br s),4.72(2H,s),2.86-2.76(2H,m),2.38-2,23(5H,m),2.18-1.82(5H,m),1.75(3H,s),1.60–1.41(7H,m).
化合物5:白色固体。熔点223-224℃。MS(EI)[M+H]+m/z:286.2529.1H NMR(600MHz,CDCl3)δ(ppm):5.98(1H,br s),4.71,4.67(2H,s,s),3.49–3.40(2H,m),2.25-2.35(2H,m),2.17–2.05(11H,m),1.96–1.88(1H,m),1.88-1.82(1H,m),1.73-1.65(9H,m),1.51–1.45(1H,m).
化合物6:无色油状物。MS(EI)[M+H]+m/z:240.1957.1H NMR(300MHz,CDCl3)δ(ppm):5.64(1H,br s),4.79–4.64(2H,m),3.63(4H,t,J=5.4Hz),3.03(2H,s),2.67-2.60(4H,m),2.17–1.81(6H,m),1.74(3H,s),1.53–1.39(1H,m).
化合物7:黄色油状物。MS(EI)[M+H]+m/z:234.2216.1H NMR(600MHz,CDCl3)δ(ppm):5.63(1H,br s),4.72,4.70(2H,s,s),3.20(2H,s),2.50–2.45(1H,m),2.15-2.06(3H,m),1.96-1.81(4H,m),1.73(3H,s),1.70–1.43(4H,m),1.28–1.13(6H,m).
实施例4
用MTT法测定了目标化合物对人宫颈癌细胞HeLa,人肝癌细胞HepG2,人结肠癌细胞HCT116,人肺癌细胞A549,人黑色素瘤细胞A375-S2,人纤维肉瘤细胞HT-1080,人原髓细胞白血病细胞HL60七类肿瘤细胞的增殖抑制作用。
1)贴壁细胞选用对数生长期的贴壁肿瘤细胞,用胰酶消化后,用含10%小牛血清的RPMI l640培养基配成5×104/ml的细胞悬液,接种在96孔培养板中,每孔100μl,37℃,5%CO2培养24h。实验组更换新的含不同浓度被测样品(10~100μmol·L-1)的培养液,对照组则更换含等体积溶剂的培养液,每组设3个平行孔,37℃,5%CO2培养48h。弃去上清液,用PBS小心洗2次,每孔加入100μl新鲜配制的含0.5mg/ml MTT的培养基,37℃继续培养4h。小心弃去上清,并加入150μl DMSO,用微型振荡器混匀10min后,用酶标仪在492nm处测定光密度值(OD)。
2)悬浮细胞选用对数生长期的细胞,用含10%小牛血清的RPMI l640培养基配成1×104/ml的细胞悬液,接种在96孔培养板中,每孔50μl,37℃,5%CO2培养24h。实验组加入含不同浓度被测样品(10~100μmol·L-1)的培养液50μl,对照组则加入含等体积溶剂的培养液,每组设3个平行孔,37℃,5%CO2培养48h,每孔加入10μl新鲜配制的含5mg/ml MTT的培养基,37℃继续培养4h。用三联液(SDS10g,10M HCl0.1mL,异丁醇5mL,用蒸馏水稀释至100mL)100μl溶解结晶,37℃孵育12h。用酶标仪在492nm处测定光密度值(OD)。
按以下公式计算药物对肿瘤细胞体外增殖的抑制率(Inhibition Rate,IR%):
IR%=(1-ODsample/ODcontrol)×100%
用ICP1.0.0软件计算药物的半数抑制浓度(IC50)。
结果见下表,与紫苏醇比较,所有目标化合物抑制七种肿瘤细胞株的IC50值均有所降低,因此将紫苏醇结构中的羟基用含氮基团取代可以提高紫苏醇的体外抗肿瘤活性。
表1式Ⅰ化合物和紫苏醇对肿瘤细胞的IC50值
。
Claims (10)
1.一种紫苏胺类化合物及其药用盐,具有式I的结构:
R1、R2选自:氢,C1-C12烷基,C1-C12烷氧基,C1-C12烷氧基苯基,含有烯键的C1-C12烷基,含有炔键的C1-C12烷基,含有羟基的C1-C12烷基,含有苯基的C1-C12烷基,C3-C12环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C12烷基、C1-C12烷氧基苯基。
2.如权利要求1所述的化合物及其药用盐,其特征在于,
R1、R2选自:氢,C1-C10烷基,C1-C10烷氧基,C1-C10烷氧基苯基,含有烯键的C1-C10烷基,含有炔键的C1-C10烷基,含有羟基的C1-C10烷基,含有苯基的C1-C10烷基,C3-C10环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C10烷基、C1-C10烷氧基苯基。
3.如权利要求1所述的化合物及其药用盐,其特征在于,
R1、R2选自:氢,C1-C10烷基,C1-C4烷氧基,C1-C4烷氧基苯基,含有烯键的C1-C4烷基,含有炔键的C1-C4烷基,含有羟基的C1-C4烷基,含有苯基的C1-C4烷基,C3-C6环烷基,或R1、R2和N形成5-10元含氮杂环,或R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C4烷基、C1-C4烷氧基苯基。
4.如权利要求1所述的化合物及其药用盐,其特征在于,
R1、R2选自:氢,C1-C10烷基,含有羟基的C1-C4烷基,C3-C6环烷基,R1、R2和氮形成5-10元含氮杂环,R1、R2和N形成取代或未取代的哌嗪基,所述的取代基为C1-C4烷基、C1-C4烷氧基苯基。
5.如权利要求1所述的化合物及其药用盐,其特征在于,选自
6.如权利要求1所述紫苏胺类化合物及其药用盐,其特征在于,所述的药用盐指常规的酸加成盐,所述的酸为有机酸或无机酸成,选自盐酸,氢溴酸,氢碘酸,硫酸,磷酸,硝酸,乙酸,酒石酸,水杨酸,甲磺酸,丁二酸,柠檬酸,苹果酸,乳酸,富马酸或马来酸。
7.一种药物组合物,其特征在于,包含权利要求1所述的紫苏胺类化合物及其药用盐和药学上可被接受的赋形剂。
8.一种如权利要求1所述的紫苏胺类化合物及其药用盐类的制备方法,其特征在于:所述的化合物的合成路线如下:
R1,R2如权利要求1所述。
9.权利要求1-6任何一项所述紫苏胺类化合物及其药用盐或权利要求7所述的组合物在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特征在于:所述的肿瘤为宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、淋巴癌、慢性髓原白血病、原髓细胞白血病。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410119999.1A CN104945335B (zh) | 2014-03-27 | 2014-03-27 | 紫苏胺类化合物及其制备和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410119999.1A CN104945335B (zh) | 2014-03-27 | 2014-03-27 | 紫苏胺类化合物及其制备和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104945335A true CN104945335A (zh) | 2015-09-30 |
CN104945335B CN104945335B (zh) | 2018-02-16 |
Family
ID=54160466
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410119999.1A Expired - Fee Related CN104945335B (zh) | 2014-03-27 | 2014-03-27 | 紫苏胺类化合物及其制备和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104945335B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111217708A (zh) * | 2020-02-21 | 2020-06-02 | 中国林业科学研究院林产化学工业研究所 | 一种烃基紫苏胺衍生物的制备方法与除草应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1844105A (zh) * | 2006-05-07 | 2006-10-11 | 沈阳药科大学 | 一种β-榄香烯含氮衍生物及制备方法和用途 |
WO2013119304A2 (en) * | 2011-11-21 | 2013-08-15 | Neonc Technologies Inc. | Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof |
-
2014
- 2014-03-27 CN CN201410119999.1A patent/CN104945335B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1844105A (zh) * | 2006-05-07 | 2006-10-11 | 沈阳药科大学 | 一种β-榄香烯含氮衍生物及制备方法和用途 |
WO2013119304A2 (en) * | 2011-11-21 | 2013-08-15 | Neonc Technologies Inc. | Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof |
Non-Patent Citations (7)
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111217708A (zh) * | 2020-02-21 | 2020-06-02 | 中国林业科学研究院林产化学工业研究所 | 一种烃基紫苏胺衍生物的制备方法与除草应用 |
CN111217708B (zh) * | 2020-02-21 | 2022-07-26 | 中国林业科学研究院林产化学工业研究所 | 一种烃基紫苏胺衍生物的制备方法与除草应用 |
Also Published As
Publication number | Publication date |
---|---|
CN104945335B (zh) | 2018-02-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5801873B2 (ja) | 含笑花から抽出したエステル誘導体、その薬物組み合わせもの及び調製方法と用途 | |
US20140235568A1 (en) | Gemcitabine amide derivative and preparation method and use thereof | |
CN103467474B (zh) | 1,6,7,14-位取代的冬凌草甲素衍生物、制备方法及用途 | |
CN102532235A (zh) | 蟾毒配基衍生物及其制备方法、包含该衍生物的组合物、及其用途 | |
WO2016007046A1 (ru) | Замещенные 2-тиоксо-имидазолидин-4-оны и их спироаналоги, противораковый активный компонент, фармацевтическая композиция, лекарственный препарат, способ лечения рака простаты | |
WO2013178021A1 (zh) | 吡咯并[2,1—f][1,2,4]三嗪衍生物及其抗肿瘤用途 | |
CN116917288A (zh) | 一种7,9-二氢嘌呤衍生物及其制药用途 | |
CN114736214B (zh) | 一种倍半萜衍生物、其药物组合物及其制备方法和用途 | |
WO2015096640A1 (zh) | 含噻唑基雷帕霉素类衍生物及其应用 | |
CN101012227A (zh) | 具有抗肿瘤作用的13-正-辛基小檗碱新衍生物 | |
CN114380864A (zh) | 一种双氢青蒿素衍生物、制备方法、药物组合物和其在制备抗肿瘤药物中的应用 | |
CN104945333A (zh) | 紫苏醇类似物及其制备和应用 | |
CN104945335A (zh) | 紫苏胺类化合物及其制备和应用 | |
CN102115460A (zh) | 格尔德霉素衍生物及其制备方法和用途 | |
CN102746212B (zh) | β-榄香烯吲哚衍生物及其制备和应用 | |
CN104945334A (zh) | 紫苏醇衍生物及其制备和应用 | |
CN102952151B (zh) | 3位双β‑咔啉碱类化合物、其制法和其药物组合物与用途 | |
CA3154983C (en) | Lipidoids for nucleic acid transfection and use thereof | |
CN104402833B (zh) | 含有环丁烷取代基的吡嗪类化合物及其组合物及用途 | |
CN102786458B (zh) | 吡咯甲酰胺衍生物、其制备方法和用途 | |
CN114149392B (zh) | 莪术烯含氮衍生物及其制备和应用 | |
CN113024557A (zh) | 一种Peganumine A生物碱结构简化物及其应用 | |
CN106937529A (zh) | 鬼臼毒素衍生物及其应用 | |
CN100484940C (zh) | 一类水溶性喜树碱衍生物及其制备方法和应用 | |
RU2322236C2 (ru) | Лекарственное средство для лечения доброкачественных и злокачественных опухолевых заболеваний, содержащее производное дисоразола |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180216 |