CN115040503B - 螺环二烯酮型木脂素类化合物在制药中的应用 - Google Patents
螺环二烯酮型木脂素类化合物在制药中的应用 Download PDFInfo
- Publication number
- CN115040503B CN115040503B CN202210895719.0A CN202210895719A CN115040503B CN 115040503 B CN115040503 B CN 115040503B CN 202210895719 A CN202210895719 A CN 202210895719A CN 115040503 B CN115040503 B CN 115040503B
- Authority
- CN
- China
- Prior art keywords
- spirodienone
- pharmaceutical composition
- compound
- depression
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229930013686 lignan Natural products 0.000 title claims abstract description 21
- 235000009408 lignans Nutrition 0.000 title claims abstract description 21
- -1 lignan compound Chemical class 0.000 title abstract description 12
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 13
- 230000036506 anxiety Effects 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000006378 damage Effects 0.000 claims abstract description 4
- 229940125782 compound 2 Drugs 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 150000005692 lignans Chemical class 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 239000002249 anxiolytic agent Substances 0.000 claims description 3
- 230000000949 anxiolytic effect Effects 0.000 claims description 3
- 230000001430 anti-depressive effect Effects 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims 2
- 239000011859 microparticle Substances 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000001681 protective effect Effects 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 3
- 208000027418 Wounds and injury Diseases 0.000 abstract description 2
- 210000001943 adrenal medulla Anatomy 0.000 abstract description 2
- 208000014674 injury Diseases 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 5
- 241000218378 Magnolia Species 0.000 description 5
- 241000218394 Magnolia liliiflora Species 0.000 description 5
- 229960003914 desipramine Drugs 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000028389 Nerve injury Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 230000008764 nerve damage Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 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 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 235000017309 Hypericum perforatum Nutrition 0.000 description 2
- 244000141009 Hypericum perforatum Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- JXWKCIXVIBYKKR-UHFFFAOYSA-N ac1l7y7b Chemical compound O1C2=CC(=O)C(OC)=CC2(C2C)CC1CC2C1=CC(OC)=C(OC)C(OC)=C1 JXWKCIXVIBYKKR-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 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
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000005819 Magnolia denudata Species 0.000 description 1
- 235000016094 Magnolia denudata Nutrition 0.000 description 1
- 241000218377 Magnoliaceae Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028748 Nasal obstruction Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IWBJJCOKGLUQIZ-HQKKAZOISA-N hyperforin Chemical compound OC1=C(CC=C(C)C)C(=O)[C@@]2(CC=C(C)C)C[C@H](CC=C(C)C)[C@](CCC=C(C)C)(C)[C@]1(C(=O)C(C)C)C2=O IWBJJCOKGLUQIZ-HQKKAZOISA-N 0.000 description 1
- QOVWXXKVLJOKNW-UHFFFAOYSA-N hyperforin Natural products CC(C)C(=O)C12CC(CC=C(C)C)(CC(CC=C(C)C)C1CCC=C(C)C)C(=C(CC=C(C)C)C2=O)O QOVWXXKVLJOKNW-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000010753 nasal discharge Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- 229960001553 phloroglucinol Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Botany (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了如结构式(1)所示的螺环二烯酮型木脂素类化合物在制备治疗或预防焦虑症和抑郁症的药物中的应用。同时公开了以该类化合物为有效成分的药物组合物,和其制备方法。属于药物技术领域。药理活性试验证明:本发明的化合物1和2对皮质酮所致大鼠肾上腺髓质嗜铬瘤分化细胞(PC12细胞)的损伤具有保护作用,可用于预防和治疗焦虑症或抑郁症。
Description
技术领域:
本发明属于药物技术领域,具体涉及螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症或抑郁症相关药物或保健食品中的应用,同时涉及以其为有效成分的药物组合物,和其制备方法,
背景技术:
当前治疗焦虑和抑郁症的药物主要以化学合成药物为主,但存在副作用大、复发率高等缺点,临床应用具有局限性。因此,开发可长期服用、疗效好且毒性小的药物依然是目前药学研究的热点。
药用植物中分离和发现的活性天然产物一直是创新药物或药物先导化合物发现的重要源泉。从药用植物中也发现众多抗焦虑和抑郁好的活性天然产物,如贯叶连翘(Hypericum perforatum)中发现的间苯三酚类化合物贯叶金丝桃素(Hyperforin)(LifeSciences,1998,63, 499-510)。
大鼠肾上腺髓质嗜铬瘤分化细胞株PC12是一种具有典型神经元特征,并具有高水平肾上腺皮质合成糖皮质激素(glucocorticoids, GCs)受体的细胞系,已被用作模拟高浓度皮质酮刺激时海马神经元损伤的经典模型。与此同时,啮齿动物体内的GCs主要是皮质酮(中草药,2022,53,1093-1099)。抑郁症的重要表现包括过高的皮质酮水平,可诱发神经元和胶质细胞相关的凋亡、自噬和突触可塑性的改变等病理变化。因此可采用皮质酮刺激神经元细胞来模拟焦虑、抑郁的内环境,建立焦虑、抑郁症体外细胞模型(中草药,2022,53,3385-3393;中国药理学与毒理学杂志,2019,33,866)。
紫玉兰(Magnolia liliflora)为木兰科(Magnoliaceae)木兰属 (Magnolia)落叶灌木。紫玉兰与玉兰(Magnolia denudata)同为我国两千多年的传统花卉,在我国大部分城市均有栽培,并已被引种至欧美各国,其树皮、叶和花蕾均可入药,常用作镇痛消炎剂。据《新华本草纲要》记载,紫玉兰具有祛风散寒,通鼻窍的功效,用于治疗鼻塞、鼻渊、风寒头痛、浊涕等症,是民间药材辛夷的重要来源之一 (《新华本草纲要》,上海科学技术出版社,1990,468-469.)。紫玉兰化学成分研究较少,仅见少量木脂素类成分报道(Phytochemistry, 1983,22,763-766;Phytochemistry,1982,21,747–750)并发现部分化合物具有抗炎和抗氧化活性(Industrial Crops and Products,2018,125, 416-424)。
迄今为止,未发现螺环二烯酮型木脂素类化合物1或2的药理活性的报道。
发明内容:
针对现有技术存在的上述不足之处,本发明的目的在于:提供2 个螺环二烯酮型木脂素类化合物,以其为活性成分的药物组合物,其制备方法,以及该类化合物及药物组合物在制备治疗或预防焦虑症和抑郁症的药物及保健食品中的应用。药理活性试验证明本发明的化合物1和2对皮质酮所致大鼠肾上腺髓质嗜铬瘤分化细胞(PC12细胞) 的损伤具有保护作用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
如下结构式所示的螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症和抑郁症的药物中的应用,
螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症和抑郁症的保健食品中的应用。
螺环二烯酮型木脂素类化合物1或2的制备方法,包括以下工艺步骤:取晒干后的紫玉兰叶,粉碎并用95%乙醇冷浸提取三次,合并三次提取液,减压浓缩,得到总浸膏。该浸膏分散于水中用于乙酸乙酯萃取,萃取物经反相中压液相色谱(MCI树脂)进行分离,用甲醇水系统梯度洗脱(30:70、40:60、50:50、60:40、70:30、80:20、90:10 和100:0),经检测合并成13个组份Fr.1~Fr.13。组份4经硅胶柱层析,用石油醚/乙酸乙酯(4:1)洗脱,得到9个亚组分Fr.4.1~Fr.4.9。组分Fr.4.6经高压液相色谱(HPLC)分离(乙腈/水,35:65),得到化合物1。组份6经硅胶柱层析,用石油醚/乙酸乙酯(4:1)洗脱,得到6个亚组分Fr.6.1~Fr.6.6。组分Fr.6.3经硅胶柱层析(石油醚/丙酮,7:3)和凝胶Sephdex LH-20柱层析(氯仿/甲醇,1:1),分离得到化合物2。
螺环二烯酮型木脂素类化合物1和2通过显著改善皮质酮所致 PC12细胞的损伤从而实现其抗焦虑和抗抑郁的作用,从而实现在制备治疗或预防焦虑症和抑郁症药物及保健食品中的应用。
本发明此外还提供了包含螺环二烯酮型木脂素类化合物和至少一种药学上可接受的载体的药物组合物。
上面所述的药学上可接受的载体是指药学领域常规的药物载体,例如,水、葡萄糖、乳糖、阿拉伯胶等和适合在制备固体、半固体、液体或气溶胶形式的制剂中使用的其他载体。组合物可以另外含有稳定剂,增稠剂,和/或着色剂和香料。
本发明的螺环二烯酮型木脂素类化合物及其药学上可接受的载体制备而成的组合物可经口或不经过口给药,给药量因药物不同而各有不同,对成人来说,每天1-100mg较合适。
经口服给药时,首先使化合物与常规的药用辅剂如赋形剂、解剂、黏合剂、润滑剂、抗氧化剂、包衣剂、着色剂、芳香剂、表面活性剂等混合,将其制成颗粒剂、胶囊、片剂等形式给药:非经口给药时可以注射液、输液剂或栓剂等形式给药。制备上述制剂时,可使用常规的制剂技术。
附图说明:
图1为本发明的螺环二烯酮型木脂素类化合物的结构示意图;
图2为本发明的化合物2的单晶X衍射结构示意图;
图3为化合物1和2对皮质酮诱导PC12神经损伤的保护作用,图中,Blank:空白对照组;NC:模型组;DIM:阳性对照组。
具体实施方式:
下面结合附图,用本发明的实施例来进一步说明本发明的实质性内容,但并不以此来限定本发明。根据本发明的实质对本发明进行的改进都属于本发明的范围。
实施例1:
螺环二烯酮型木脂素类化合物1和2的制备及结构鉴定:
制备方法:取晒干后的紫玉兰叶,粉碎并用95%乙醇冷浸提取三次,合并三次提取液,减压浓缩,得到总浸膏。该浸膏分散于水中用于乙酸乙酯萃取,萃取物经反相中压液相色谱(MCI树脂)进行分离,用甲醇水系统梯度洗脱(30:70、40:60、50:50、60:40、70:30、80:20、 90:10和100:0),经检测合并成13个组份Fr.1~Fr.13。组份4经硅胶柱层析,用石油醚/乙酸乙酯(4:1)洗脱,得到9个亚组分Fr.4.1~Fr.4.9。组分Fr.4.6经高压液相色谱(HPLC)分离(乙腈/水,35:65),得到化合物1。组份6经硅胶柱层析,用石油醚/乙酸乙酯(4:1)洗脱,得到6个亚组分Fr.6.1~Fr.6.6。组分Fr.6.3经硅胶柱层析(石油醚/丙酮,7:3)和凝胶Sephdex LH-20柱层析(氯仿/甲醇,1:1),分离得到化合物2。
结构鉴定:本发明所述化合物分子结构式(1)分别对应化合物 1和2:
化合物1(Magnoflorin D):白色无定型粉末;(c 0.01, MeOH);UV(MeOH)λmax(logε)200(5.01);CD(MeOH)λmax(Δε):210 (-14.33),262(+15.37),322(-10.85)nm;IR(KBr)νmax 3410,2928,1732, 1651,1608,1517,1453,1375,1246,1144,869cm–1;1H and 13C NMR spectroscopic data,see Table 2;HREIMS m/z 365.1356[M+Na]+(calc. for C20H22O5Na,365.1359).
化合物2(maglifloenone):白色无定型粉末;C22H26O6;ESI-MS m/z: 409[M+Na]+。1H-NMR(500MHz,CDCl3)δ:6.37(2H,s,H-2,6),2.53 (1H,m,H-7),2.06(1H,m,H-8),0.61(3H,d,J=6.0Hz,H-9),5.92(1H, s,H-3'),5.48(1H,s,H-6'),2.37(1H,m,H-7'a),2.00(1H,d,J=11.4Hz, H-7'b),5.03(1H,t,J=5.8Hz,H-8'),2.31(1H,m,H-9'a),1.73(1H,dd,J =13.7,12.0Hz,H-9'b),3.83(6H,s,3,5-OCH3),3.80(3H,s,4-OCH3), 3.65(3H,s,5'-OCH3);13C-NMR(125MHz,CDCl3)δ:139.1(C-1), 104.6(C-2,6),153.3(C-3,5),136.7(C-4),46.9(C-7),45.3(C-8),14.6 (C-9),50.4(C-1'),180.2(C-2'),101.4(C-3'),183.2(C-4'),153.3(C-5'), 109.0(C-6'),43.6(C-7'),81.9(C-8'),37.8(C-9'),56.2(3,5-OCH3),60.9(4-OCH3),55.3(5'-OCH3)。经与文献报道maglifloenone (Phytochemistry 1982,21,747-750;Natural Product Sciences,2017,23, 119-124.)的1H和13C核磁数据比对,鉴定为同一个化合物。
表1化合物1的氢谱和碳谱数据(CDCl3)
a Measured at a600 MHz,b150 MHz.
实施例2:
化合物1和2对皮质酮诱导PC12神经损伤的保护作用:
(1)实验方法:
PC12细胞接种于含10%FBS及100U/mL双抗(青霉素-链霉素) 的DMEM高糖溶液中,并于温度37℃,5%CO2培养箱中培养至对数生长期,胰酶消化,制成细胞悬液。细胞悬液吸至15mL离心管中, 800rpm,离心5min弃上清液,然后加入新的培养基调整细胞浓度至1×105个/mL。然后取此PC12细胞接种于96孔板中,每孔0.1mL, 并放入细胞培养箱培养23小时。将待测化合物(终浓度20μM)加入到含皮质酮(终浓度150μM)的96孔板中,同时设置空白对照组(培养基)、模型组(培养基及终浓度150μM皮质酮)、阳性对照组[培养基、终浓度150μM皮质酮和终浓度10μM Desipramine(DIM)],24小时后,加入MTS,继续培养2小时,然后用酶标仪于570nm波长下测定吸光度值,并计算细胞存活率。实验重复3次。
(2)实验结果:
实验表明与模型组相比(68.09±0.78%),在20μM浓度下化合物1和2对皮质酮诱导PC12细胞成活率分别为71.5±0.99%和73.0± 1.42%。在相同浓度下,阳性对照药Desipramine(DIM)对皮质酮诱导PC12细胞成活率为90.07±0.45%。该结果提示,化合物1和2 对皮质酮诱导PC12神经损伤的保护作用,具有治疗焦虑症或抑郁症的作用。
实施例3
片剂的制备:
取化合物1和/或2,按其与赋形剂重量比为1:5-1:10的比例加入赋形剂,制粒压片。
实施例4
胶囊剂的制备:
取化合物1和/或2,按其与赋形剂重量比为1:5-1:10的比例加入赋形剂,制成胶囊。
实施例5
口服液制剂的制备:
取化合物1和/或2,以及利用碱金属(锂、钠、钾)或碱土金属(钙、镁)、有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按常规口服液制法制成口服液。
实施例6
颗粒剂或冲剂的制备:
取化合物1和/或2,以及利用碱金属(锂、钠、钾)或碱土金属(钙、镁)、有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按其与赋形剂重量比为5:1的比例加入赋形剂,制成颗粒剂或冲剂。
Claims (6)
1.如下结构式所示的螺环二烯酮型木脂素类化合物1或2在制备治疗或预防焦虑症和抑郁症的药物中的应用,
。
2.药物组合物,其中含有权利要求1中结构式所示的螺环二烯酮型木脂素类化合物1和药学上可接受的载体。
3.根据权利要求2所述的药物组合物,其特征在于,所述的药物组合物为微粒给药系统。
4.根据权利要求2所述的药物组合物,其特征在于,所述的药物组合物剂型为片剂、胶囊、丸剂、口服液、注射剂、缓释制剂、控释制剂。
5.权利要求2所述的药物组合物在制备治疗或预防焦虑症和抑郁症的药物中的应用。
6.根据权利要求1或5所述的应用,其特征在于,所述的螺环二烯酮型木脂素类化合物1和2通过显著改善皮质酮所致PC12细胞的损伤从而实现抗焦虑和抗抑郁的作用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210895719.0A CN115040503B (zh) | 2022-07-26 | 2022-07-26 | 螺环二烯酮型木脂素类化合物在制药中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210895719.0A CN115040503B (zh) | 2022-07-26 | 2022-07-26 | 螺环二烯酮型木脂素类化合物在制药中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115040503A CN115040503A (zh) | 2022-09-13 |
CN115040503B true CN115040503B (zh) | 2023-10-10 |
Family
ID=83167184
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210895719.0A Active CN115040503B (zh) | 2022-07-26 | 2022-07-26 | 螺环二烯酮型木脂素类化合物在制药中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115040503B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009023803A2 (en) * | 2007-08-15 | 2009-02-19 | Abbott Respiratory Llc | Modulated release formulation for the delivery of one or more medicaments |
CN103145724A (zh) * | 2013-03-12 | 2013-06-12 | 西南交通大学 | 一种环烯醚萜类新化合物及其神经保护作用 |
CN103467463A (zh) * | 2013-09-18 | 2013-12-25 | 南开大学 | 一类木脂素类衍生物及其制备方法和用途 |
CN109575091A (zh) * | 2018-12-05 | 2019-04-05 | 昆明医科大学 | 二甲基均苯三酚衍生物及其药物组合物和其应用 |
CN111671780A (zh) * | 2020-05-20 | 2020-09-18 | 沈阳化工大学 | 具有神经细胞保护活性的透骨草木脂素制备方法及其应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5150728B2 (ja) * | 2007-10-19 | 2013-02-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 置換ピペリジノ−ジヒドロチエノピリミジン |
-
2022
- 2022-07-26 CN CN202210895719.0A patent/CN115040503B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009023803A2 (en) * | 2007-08-15 | 2009-02-19 | Abbott Respiratory Llc | Modulated release formulation for the delivery of one or more medicaments |
CN103145724A (zh) * | 2013-03-12 | 2013-06-12 | 西南交通大学 | 一种环烯醚萜类新化合物及其神经保护作用 |
CN103467463A (zh) * | 2013-09-18 | 2013-12-25 | 南开大学 | 一类木脂素类衍生物及其制备方法和用途 |
CN109575091A (zh) * | 2018-12-05 | 2019-04-05 | 昆明医科大学 | 二甲基均苯三酚衍生物及其药物组合物和其应用 |
CN111671780A (zh) * | 2020-05-20 | 2020-09-18 | 沈阳化工大学 | 具有神经细胞保护活性的透骨草木脂素制备方法及其应用 |
Non-Patent Citations (2)
Title |
---|
Spirocyclohexadienone-Type Neolignans with Neuroprotective and Neurite Outgrowth Enhancing Activities from Magnolia liliiflora;Xing-De Wu et al.,;Chem. Biodiversity;第19卷;第1-9页 * |
西南金丝梅的黄酮成分研究;吴庆立;天然产物研究与开发;第10卷(第4期);第15-18页 * |
Also Published As
Publication number | Publication date |
---|---|
CN115040503A (zh) | 2022-09-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5667561B2 (ja) | 4’−デメチルノビレチン又は4’−デメチルタンゲレチンを有効成分として含有する神経突起伸長剤、記憶改善剤、抗アルツハイマー剤、並びに、その製造方法 | |
Liu et al. | An in vivo and in vitro assessment of the anti-inflammatory, antinociceptive, and immunomodulatory activities of Clematis terniflora DC. extract, participation of aurantiamide acetate | |
CN101279964B (zh) | 愈创木烷型倍半萜、其制备方法及其医药用途 | |
WO2010140734A1 (ko) | 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난을 유효성분으로 포함하는 에이엠피케이의 활성화에 의해 매개되는 비만 관련 질환의 예방 또는 치료용 조성물 | |
Tsai et al. | Bioactive constituents of Lindernia crustacea and its anti-EBV effect via Rta expression inhibition in the viral lytic cycle | |
Ma et al. | Cadinane sesquiterpenes from Curcuma phaeocaulis with their inhibitory activities on nitric oxide production in RAW 264.7 cells | |
CN109134486B (zh) | 香豆素并木脂素及其制备方法和用途 | |
CN116637102B (zh) | 黄烷类化合物在制备抗肿瘤的药物中的用途 | |
Wang et al. | Meroterpenoids with a large conjugated system from Ganoderma lucidum and their inhibitory activities against renal fibrosis | |
CN115040503B (zh) | 螺环二烯酮型木脂素类化合物在制药中的应用 | |
Jiao et al. | Diverse lignans with protective effect against hypoxia/oxidative injuries to H9c2 cells from Syringa pinnatifolia Hemsl. | |
CN108659089B (zh) | 一种具有抗氧化作用的甾醇化合物及其在制备药物中的应用 | |
CN113956229B (zh) | 一种紫丁香中的木脂类化合物及其制备方法与应用 | |
Zou et al. | Sweritranslactone D, a hepatoprotective novel secoiridoid dimer with tetracyclic lactone skeleton from heat-transformed swertiamarin | |
CN105566344B (zh) | 一种螺环色原酮及其制备与应用 | |
CN106619611B (zh) | 泽兰内酯作为制备抗肝癌和结肠癌药物中的应用 | |
Yan et al. | 10-Secocycloartane (= 9, 19-cyclo-9, 10-secolanostane) triterpenoid saponins: Huangqiyenins M–X from Astragalus membranaceus (Fisch.) Bge | |
KR100703597B1 (ko) | 타크린 유도에 의한 HepG2 세포의 세포독성에 대한간보호 활성을 지닌 곰피 추출물 또는 그로부터 분리한플로로탄닌류를 함유하는 조성물 | |
CN113214154B (zh) | 三聚苄基异喹啉生物碱、其制法和药物组合物与用途 | |
Bai et al. | Seven undescribed compounds from the flower heads of Helianthus annuus L. | |
CN115703753B (zh) | 一种苯并呋喃型衍生物及其制备方法和应用 | |
CN115521322B (zh) | 一种异戊烯基黄酮化合物及制备方法和应用 | |
CN115177613A (zh) | 含木脂素类化合物futoenone的药物组合物和其应用 | |
CN110204477B (zh) | 一种具有抗氧化作用的二萜生物碱及其在制备药物中的应用 | |
CN113616646B (zh) | 咔啉生物碱在制备抗uvb辐射制剂中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |