CN115181084A - Optimization of synthesis process and pharmacological activity research of daphnetin derivatives - Google Patents
Optimization of synthesis process and pharmacological activity research of daphnetin derivatives Download PDFInfo
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- CN115181084A CN115181084A CN202210935126.2A CN202210935126A CN115181084A CN 115181084 A CN115181084 A CN 115181084A CN 202210935126 A CN202210935126 A CN 202210935126A CN 115181084 A CN115181084 A CN 115181084A
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- daphnetin
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- ATEFPOUAMCWAQS-UHFFFAOYSA-N 7,8-dihydroxycoumarin Chemical class C1=CC(=O)OC2=C(O)C(O)=CC=C21 ATEFPOUAMCWAQS-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 12
- 230000008569 process Effects 0.000 title claims description 5
- 230000000144 pharmacologic effect Effects 0.000 title abstract description 14
- 238000011160 research Methods 0.000 title abstract description 7
- 238000005457 optimization Methods 0.000 title abstract description 4
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- YBGKGTOOPNQOKH-UHFFFAOYSA-N daphnetin Natural products OC1=CC=CC2=C1OC(=O)C=C2O YBGKGTOOPNQOKH-UHFFFAOYSA-N 0.000 claims abstract description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 11
- 238000006266 etherification reaction Methods 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 230000008961 swelling Effects 0.000 claims description 36
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 229960000905 indomethacin Drugs 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 206010061218 Inflammation Diseases 0.000 claims description 13
- 239000000679 carrageenan Substances 0.000 claims description 13
- 229920001525 carrageenan Polymers 0.000 claims description 13
- 235000010418 carrageenan Nutrition 0.000 claims description 13
- 229940113118 carrageenan Drugs 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 230000004054 inflammatory process Effects 0.000 claims description 12
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 239000008096 xylene Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- -1 (+) - α -methyl-6-methoxy-2-naphthylacetyl Chemical group 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 6
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 6
- 229960000991 ketoprofen Drugs 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 claims description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 3
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 3
- 229960002390 flurbiprofen Drugs 0.000 claims description 3
- 229960002009 naproxen Drugs 0.000 claims description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 239000007821 HATU Substances 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 210000003371 toe Anatomy 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- VRPLZTMSEURZKM-UHFFFAOYSA-N 1,1-dibromoethanol Chemical compound CC(O)(Br)Br VRPLZTMSEURZKM-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 206010042674 Swelling Diseases 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 210000002683 foot Anatomy 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 241000222350 Pleurotus Species 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 210000001872 metatarsal bone Anatomy 0.000 description 2
- 235000021590 normal diet Nutrition 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 206010003800 Auricular swelling Diseases 0.000 description 1
- 241000934856 Daphne Species 0.000 description 1
- 241001163443 Daphne giraldii Species 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 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 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- URLKBWYHVLBVBO-UHFFFAOYSA-N p-dimethylbenzene Natural products CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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)
Abstract
The invention belongs to the technical field of medicines. The invention discloses a process optimization and pharmacological activity research of a daphnetin derivative synthesis method, and relates to an 8-OH substituted daphnetin derivative shown in a structural general formula (I). An intermediate II is obtained by etherification reaction of daphnetin and dibromoethanol, an intermediate III is obtained by etherification reaction of the intermediate II and benzyl bromide, an intermediate IV is obtained by nucleophilic substitution reaction of the intermediate III and a group capable of improving the anti-inflammatory activity of the compound, and the intermediate IV removes benzyl in the presence of trifluoroacetic acid to prepare the target compound. Calculated by yieldPharmacological activity experiments prove that the yield of the compound of the original route is improved, the anti-inflammatory pharmacological activity is good, and the preparation method of the daphnetin derivative provided by the invention is simple in step, mild in condition and strong in operability and controllability. The prior art has not disclosed novel methods for the preparation of the derivatives of the invention and the associated pharmacological activities.
Description
Technical Field
The invention belongs to the field of natural medicinal chemistry, and relates to daphnetin derivatives, a preparation method and a process improvement and a pharmacological activity research thereof.
Background
Inflammation is a common clinical disease worldwide, and seriously threatens human health. Having become a major challenge for the public health system, while many scientists have been working on developing new treatments for treating various inflammations, it remains a clinical hotspot and difficulty of global concern. In recent years, a large number of anti-inflammatory drugs have been developed, most of which are natural products or derivatives thereof.
Daphnetin, also known as daphnetin A, is an effective component extracted from daphne giraldii nitsche, mainly exists in daphne plants, and has pharmacological effects of diminishing inflammation and relieving pain. However, daphnetin has the limitations of poor water solubility, low bioavailability, poor stability and the like, so that the application of daphnetin in medicines is limited. The subject group has previously carried out structural modification of daphnetin by using an active ingredient in a natural plant as a lead, but the synthesis yield is low and the research on the pharmacological activity is less.
The invention improves the yield well by carrying out process optimization on the structure modification route. The pharmacological activity of the daphnetin derivative is measured by a xylene-induced mouse auricle swelling model and a carrageenan-induced mouse toe swelling model, so that the daphnetin derivative obtained by modification has a good application prospect in the aspect of anti-inflammation.
Disclosure of Invention
One of the purposes of the invention is to provide a better preparation method of daphnetin derivatives.
Another object of the present invention is to provide pharmacological activity of a series of daphnetin derivatives.
In order to realize the purpose, the invention provides a preparation method of 8-OH substituted daphnetin derivatives shown in a structural general formula (I), and the pharmacological activity research of a mouse auricle swelling model caused by xylene and a mouse toe swelling model caused by carrageenan shows that the daphnetin derivatives have good in-vivo activity when the substituent is indomethacin and ketoprofen.
The 8-OH substituted daphnetin derivative provided by the invention is represented by a structural general formula (I):
in the general structural formula (I), substituent R is selected from substituent group compounds capable of improving anti-inflammatory activity of the compound: indomethacin, flurbiprofen, naproxen, ketoprofen.
Wherein: compound 1: r =1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetyl;
compound 2: r = 2-fluoro-a-methyl (1, 1' -diphenyl) -4-acetyl;
compound 3: r = (+) - α -methyl-6-methoxy-2-naphthylacetyl;
compound 4: r = α -methyl-3-benzoylphenylacetyl;
the preparation method of the 8-OH substituted daphnetin derivative comprises the following steps: etherification reaction and nucleophilic substitution reaction.
The preparation method of the daphnetin 8-OH derivative provided by the invention comprises the following operation steps:
step a, carrying out etherification reaction on daphnetin and dibromoethyl alcohol to obtain an intermediate II shown as the following structural formula;
b, introducing a benzyl protecting group above C-7 phenolic hydroxyl of daphnetin through etherification reaction of the intermediate II and benzyl bromide to obtain an intermediate III shown in the following structural formula;
c, enabling the intermediate III to perform nucleophilic substitution reaction with the connecting group to obtain an intermediate IV shown in the following structural formula;
d, removing benzyl from the intermediate IV in the presence of trifluoroacetic acid to obtain a target compound 1-compound 4;
preferably, the etherification reaction conditions in step a include: potassium iodide (KI) is used as a catalyst, and anhydrous potassium carbonate (K) is used 2 CO 3 ) As a base, the reaction temperature is 80 ℃.
More preferably, step a comprises: firstly, daphnetin (1 eq), K 2 CO 3 (1.25 eq) and KI (0.1 eq) are added into a reaction device, anhydrous DMF is used as a solvent, 2-bromoethanol (3 eq) is slowly added after the anhydrous DMF is magnetically stirred and dissolved, and N is added at the top end of a reflux device 2 Protecting the device, adding a drying device, and carrying out reflux reaction at 85 ℃. After TLC detection reaction is finished, adding a proper amount of diluted hydrochloric acid, stirring and neutralizing until the mixture is acidic, extracting for three times by using ethyl acetate, and collecting an ethyl acetate layer; and washing the ethyl acetate layer with distilled water and saturated salt solution for three times respectively, drying with anhydrous sodium sulfate, performing suction filtration, performing reduced pressure spin-drying on the filtrate, and separating and purifying the residue by silica gel column chromatography to obtain an intermediate II.
Preferably, the etherification reaction conditions in step b include: with anhydrous potassium carbonate (K) 2 CO 3 ) As the alkali, the reaction temperature is 80 ℃.
More preferably, step b comprises: taking the intermediate II (1 eq) in a round bottom flask, taking 15ml of acetonitrile, adding anhydrous potassium carbonate (1.25 eq) and benzyl bromide (1.25 eq) after the acetonitrile is fully dissolved, and carrying out oil bath reflux reaction at 70 ℃. And continuously monitoring the reaction process by adopting a TLC silica gel plate in the reaction process, adding a proper amount of 3mol/L diluted hydrochloric acid into the reaction system to adjust the pH of the reaction system to 5-6, and then purifying by adopting a silica gel column to obtain an intermediate III.
Preferably, the nucleophilic substitution reaction conditions in step c include: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt) are used as condensing agents to react at normal temperature.
More preferably, step c comprises: EDCI (1.5 eq), HOBt (1.5 eq) and substituted carboxylic acid (1 eq) are added into a single-neck round-bottom flask (50 mL), and N, N-Dimethylformamide (DMF) is used for dissolving the compound, the mixture is placed at room temperature for reaction for 1h, then the intermediate III (1 eq) is dissolved in DMF and added into the reaction system, after the TLC plate monitors that the reaction is finished, water is added for quenching and dilution, ethyl acetate is used for extraction for 3 times, ethyl acetate layers are combined for spin-drying the solvent, and then silica gel column purification is adopted to obtain an intermediate IV.
Preferably, step d comprises: trifluoroacetic acid was used as catalyst.
More preferably, step d comprises: and (3) completely dissolving the intermediate IV by taking a proper amount of trifluoroacetic acid, refluxing and debenzylating at 75 ℃ in an oil bath kettle, continuously monitoring the reaction process by using a TLC silica gel plate, directly spin-drying the trifluoroacetic acid by using a rotary evaporator after the reaction is finished, and purifying by using a silica gel column to obtain the target product.
The pharmacological activity research on the target daphnetin derivative is determined based on an inflammation model experiment of mouse auricle swelling caused by xylene and mouse toe swelling caused by carrageenan.
The tested daphnetin derivative substituted at the 8-OH position is tested and screened by a xylene-induced mouse auricle swelling inflammation model, and when the substituent groups are indometacin and ketoprofen, the daphnetin derivative shows more obvious anti-inflammatory activity when the administration concentration is 30 mg/Kg. Through the test and screening of a carrageenan-induced toe swelling inflammation model of mice, when the substituent groups are indomethacin and ketoprofen, the anti-inflammatory activity is more obvious when the administration concentration is 40 mg/Kg.
According to the present invention, other various modifications, substitutions and alterations can be made without departing from the technical spirit of the present invention in accordance with the common technical knowledge and conventional means in the field.
The following examples are provided to further complement the above description, but it should not be construed that the scope of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The invention is better illustrated by the following examples. However, the present invention is not limited to the following examples.
The process flow is as follows:
example 1
Synthesis of Compound 1
(1) Synthesis of intermediate II
Daphnetin (1g, 5.6 mmol), anhydrous potassium carbonate (2.3 g, 16.8mmol) and potassium iodide (138mg, 0.84mmol) were weighed, added to a 50ml two-necked round bottom flask, followed by the addition of the solvent anhydrous DMF (12 ml), the magneton was added, stirred at ambient temperature to dissolve it sufficiently, then 2-bromoethanol (796. Mu.l, 11.2 mmol) was added dropwise slowly, the apparatus was strictly protected with nitrogen, a drying apparatus was added, and the oil was refluxed at 85 ℃ for 72h. After the TLC detection reaction is completed, water is added to quench the reaction, and prepared 3mol/L hydrochloric acid is added to adjust the solution to be acidic (PH = 5). Stirring was carried out until no bubble was generated, 120ml of distilled water was added, and rotary evaporation was carried out at 60 ℃ three times to remove most of DMF contained in the solvent. Extracting the residue with n-butanol for three times, washing the extracted n-butanol with distilled water and saturated saline solution for three times respectively, drying the washed n-butanol with anhydrous sodium sulfate, performing suction filtration, and performing rotary evaporation on the filtrate to obtain a crude product of the intermediate product (I). And (3) filling the mixture into a column by a wet method, purifying the mixture by using petroleum ether and ethyl acetate =2V to 1V as a mobile phase, and purifying the mixture to obtain an intermediate II.
(2) Synthesis of intermediate III
Intermediate II (111mg, 0.5 mmol) was taken in a 20ml round bottom flask, 15ml acetonitrile was taken, after it was sufficiently dissolved, anhydrous potassium carbonate (103.5 mg, 0.75mmol) and benzyl bromide (71.3. Mu.L, 0.6 mmol) were added, and an oil bath was refluxed at 70 ℃. And continuously monitoring the reaction process by adopting a TLC silica gel plate in the reaction process, after the reaction is stopped, adding a proper amount of 3mol/L diluted hydrochloric acid into the reaction system to adjust the pH of the reaction system to 5-6, and then purifying by adopting a silica gel column with EA: PE = 1V: 1V to obtain a pure intermediate III.
(3) Synthesis of intermediate IV
Putting the intermediate III (56.16mg and 0.18mmol) into a 50-ml round-bottom flask, adding 10ml of dichloromethane, adding EDCI (69mg and 0.36mmol) and DMAP (8.8mg and 0.07mmol) after the dichloromethane is fully dissolved, stirring at normal temperature for 10 minutes, adding substituted carboxylic acid indometacin (96.60mg and 0.27mmol), stirring at room temperature for 5 hours, detecting the reaction progress by a TLC plate, and after the reaction is finished, washing by using proper amounts of distilled water and saturated saline water for three times. The dichloromethane organic layer was collected and the solvent dichloromethane was spin dried to give the crude product, which was subsequently purified on a silica gel column using EA: PE = 2V: 3V to give pure intermediate IV.
(4) Synthesis of Compound 1
Taking a proper amount of trifluoroacetic acid to completely dissolve the intermediate IV, refluxing and debenzylating at 75 ℃ in an oil bath pan, continuously monitoring the reaction process by using a TLC silica gel plate, directly drying the trifluoroacetic acid by using a rotary evaporator after the reaction is finished, purifying by using silica gel, taking PE: EA = 3V: 1V as a mobile phase, and obtaining a yellow solid product, wherein the yield is 78.62%, and the melting point is as follows: 68-70 ℃. GF 254 The thin layer of nm silica gel plate was spread out as a dot. 1 H-NMR(500MHz，CDCl 3 )：δ H 7.73(d，J＝9.5，1H)，7.67(d，J＝7.8Hz，2H)，7.60(d，J＝7.8Hz，2H)，7.45(d，J＝8.1Hz，1H)，7.11(d，J＝8.4Hz，1H)，7.10(s，1H)，6.86(d，J＝8.4Hz，6.66(d，J＝8.1Hz，1H)，6.52(d，J＝9.5Hz，1H)，4.45(d，J＝7.3Hz，2H)，4.42(d，J＝7.3Hz，2H)，3.81(s，3H)，3.62(s，2H)，2.42(s，3H)，. 13 C-NMR(150MHz，CDCl 3 )：δ C 171.52，168.39，160.31，156.22，152.59，147.41，144.19，139.39，136.28，133.87，132.47，131.34，130.89，130.48，129.18，123.78，115.13，113.08，112.81，112.49，111.95，111.91，101.18，72.79，64.09，50.78，30.39，13.51.ESI-MS m/z 584.2[M+Na] + (calcd for C 30 H 24 ClNNaO 8 ，584.2).
Example 2
Synthesis of Compound 2
With reference to example 1, pure white solid was obtained in step 3 by using flurbiprofen instead of indomethacin under the same conditions as in example 1. Total yield: 79.86%, GF 254 The thin layer of nm silica gel plate is spread into a point. 1 H-NMR(500MHz，CDCl 3 )：δ H 7.59(d，J＝9.5Hz，1H)，7.54(m，2H)，7.52(d，J＝8.7Hz，1H)，7.51(m，3H)，7.49(d，J＝8.2Hz，1H)，7.49(d，J＝8.2Hz，1H)，7.41(d，J＝8.7Hz，1H)，7.36(s，1H)，6.82(d，J＝9.5Hz，1H)，4.49(m，4H)，3.86(q，，J＝7.2Hz，1H)，1.51(d，，J＝7.2Hz，3H). 13 C-NMR(125MHz，CDCl 3 )：δ C 173.83，160.35，153.51，147.29，144.17，141.24，135.47，132.41，131.09，131.05，129.11，129.07，128.49，127.73，123.68，123.56，123.47，115.37，115.12，113.06，112.68，112.47，72.69，64.08，45.07，18.43.ESI-MS m/z 471.2[M+Na] + (calcd for C 26 H 21 FnaO 6 ，471.2).
Example 3
Synthesis of Compound 3
Referring to example 1, step 3 was carried out under the same conditions as in example 1 except that naproxen was used instead of indomethacin, to obtain a pure white solid product. Total yield: 79.35%, melting point: 58 to 60 ℃. GF 254 The thin layer of nm silica gel plate is spread into a point. 1 H-NMR(500MHz，CDCl 3 )：δ H 7.71(d，J＝9.5，1H)，7.70(d，J＝8.4Hz，1H)，7.69(d，J＝9.3Hz，1H)，7.59(s，1H)，7.40(d，J＝9.3Hz，1H)，7.30(s，1H)，7.19(d，J＝8.5Hz，7.08(d，J＝8.4Hz，1H)，1H)，6.84(d，J＝8.5Hz，1H)，6.35(d，J＝9.5Hz，1H)，4.42(m，4H)，3.81(s，3H)，3.71(d，J＝7.2Hz，1H)，1.59(d，J＝7.2Hz，3H). 13 C-NMR(125MHz，CDCl 3 )：δ C 175.31，160.27，157.77，152.66，147.29，144.18，135.21，133.87，132.62，129.39，129.11，127.49，126.22，126.11，123.68，119.17，112.98，112.71，112.47，105.70，73.01，63.89，55.49，45.59，18.71.ESI-MS m/z 457.2[M+Na] + (calcd for C 25 H 22 NaO 7 ，457.2).
Example 4
Synthesis of Compound 4
Referring to example 1, step 3 Using ketoprofen instead of Indometacin under the same conditions as in example 1, a pale yellow color was obtainedThe solid product is pure product. Total yield: 78.67%, GF 254 The thin layer of nm silica gel plate was spread out as a dot. 1 H-NMR(600MHz，CDCl 3 )：δ H 7.83(d，J＝9.5Hz，1H)，7.68(d，J＝8.3Hz，2H)，7.66(m，2H)，7.57(m，3H)，7.55(d，J＝8.3Hz，2H)，7.16(d，J＝8.5Hz，1H)，6.84(d，J＝8.5Hz，1H)，6.21(d，J＝9.5Hz，1H)，4.45(m，4H)，3.90(q，J＝7.2Hz，1H)，1.57(d，J＝7.2Hz，3H). 13 C-NMR(150MHz，CDCl 3 )：δ C 196.72，174.71，160.28，152.68，147.41，144.32，140.51，138.22，137.53，132.69，132.62，131.64，130.19，129.43，129.32，128.91，128.58，123.83，113.11，112.71，112.62，72.81，64.09，45.48，18.59.ESI-MSm/z481.1[M+Na] + (calcd for C 27 H 22 NaO 7 ，481.1).
Example 5
Pharmacological activity of daphnetin derivative p-xylene induced mouse auricle swelling inflammation model
The experimental principle is as follows: xylene as an inflammation inducer may mimic the true state of acute inflammation in the body. Xylene is used for causing ear edema of mice, belongs to an inflammatory agent in the chemical property range, can induce the release of inflammatory mediators, increase the local capillary permeability, accelerate inflammatory cell infiltration, cause a series of inflammatory reactions such as acute exudative inflammatory edema and the like. Xylene-induced mouse auricle acute swelling model is often used for research and development experiments of innovative drugs, and the anti-inflammatory action of the drugs is explored by simulating the pathological state of acute inflammation of an organism.
The experimental method comprises the following steps: 30 mice were taken and randomly divided into 6 groups of 5 mice each. The groups were compound 1, compound 2, compound 3 and compound 4 administration groups (30 mg/kg), indomethacin positive control group (6 mg/kg) and 0.5% sodium carboxymethylcellulose solution control group, respectively. The respective test drugs were administered to each group by drenching 1 time per day for 5 days with normal diet given during the administration period. After 1 hour of the last administration, 40 μ l of xylene was evenly applied to the anterior and posterior sides of the right auricle of the mouse to cause inflammation for 1 hour. The left ear of the mouse was used as a control, the mouse was sacrificed by removing the neck, both ears were cut along the auricle base line, the ear piece was punched at the same position with a punch having a diameter of 8mm, and the weight was immediately weighed with an analytical balance.
The effect of daphnetin derivatives on xylene-induced auricular swelling in each group of mice and the inhibition rate of each daphnetin derivative were observed. The swelling degree and the swelling inhibition rate of each group were calculated. The difference in the weight of the right ear was taken as the swelling degree, and the swelling rate and the inhibition rate were calculated from the weight of the ear.
The calculation formula is as follows:
swelling degree (mg) = inflamed pleurotus weight-noninflammatory pleurotus weight
Swelling rate (%) = [ (weight of. Proinflammatory ear-weight of. Noninflammatory ear)/weight of. Noninflammatory ear ]. Times.100%
Swelling inhibition (%) = [ (average swelling degree of blank group-average swelling degree of administration group)/average swelling degree of blank group ]. Times 100%
| Compound (I) | Swelling inhibition ratio (%) |
| Indometacin | 56.4 |
| Compound 1 | 64.8 |
| Compound 4 | 59.1 |
Example 6
Pharmacological activity of daphnetin derivative on carrageenan-induced mouse toe swelling inflammation model
The experimental principle is as follows: carrageenan (CRG) is a linear sulfated polysaccharide that causes foot edema, allergic contact dermatitis, and the like. Has wide application prospect in the fields of food, pharmacy, cosmetics and the like. In recent years, the biological properties of carrageenan polysaccharide, such as antivirus, immunoregulation, anticoagulation, antioxidation, anticancer, etc., have been widely studied. Using a model of carrageenan-induced foot swelling in mice, mice were injected with 1% carrageenan along the midline of the foot and toe and developed the same inflammatory response as humans. Comparing the toe volume of the mice before and after swelling, the inhibition effect of the daphnetin derivatives on a carrageenan-induced toe swelling model of the mice is researched, and the daphnetin derivatives can evaluate the anti-inflammatory effect of the compound in vivo.
The experimental method comprises the following steps: 30 mice were taken and randomly divided into 6 groups of 5 mice each. The groups are daphnetin derivative tt-1, tt-2, tt-3 and tt-4 administration groups (40 mg/kg), indometacin positive control group (6 mg/kg) and 0.5% sodium carboxymethylcellulose solution control group. The respective test drugs were administered to each group by drenching 1 time per day for 5 days with normal diet given during the administration period. After 2 hours of the last administration, the thickness of the mouse foot sole is measured by a vernier caliper, and the average value is obtained after repeated measurement for three times, so that the thickness of the mouse foot sole before swelling is calculated. Immediately after completion of the measurement, each mouse was infected with carrageenan at a concentration of 1.0% in a 35. Mu.l subcutaneously in the right hind limb and foot sole, and the injection time of each group was recorded, and the thickness of the foot sole of the mouse was measured with a vernier caliper at 3h according to the above-mentioned method, and the swelling rate and swelling inhibition rate of the foot sole were calculated.
The calculation formula is as follows:
swelling rate = (thickness of postinflammatory metatarsal-thickness of pro-inflammatory metatarsal)/thickness of pro-inflammatory metatarsal × 100%
Swelling inhibition (%) = (average swelling rate in blank group-average swelling rate in administered group)/average swelling rate in blank group × 100%
| Compound (I) | Swelling inhibition ratio (%) |
| Indometacin | 47.6 |
| Compound 1 | 59.6 |
| Compound 4 | 54.0 |
The test result shows that the tested compound 1 and compound 4 have better in-vivo anti-inflammatory activity.
The above embodiments are only used to describe the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, those skilled in the art will recognize that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; however, these modifications or substitutions do not make the essence of the corresponding technical solutions depart from the technical solutions of the embodiments of the present invention, and the scope of the present invention should not be limited to the above specific embodiments.
Claims (8)
1. The daphnetin 8-OH derivative has the following structural general formula:
in the general structural formula (I), the substituent R is selected from substituent group compounds capable of improving the anti-inflammatory activity of the compound: indomethacin, flurbiprofen, naproxen, ketoprofen.
Wherein: compound 1: r =1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetyl;
compound 2: r = 2-fluoro- α -methyl (1, 1' -diphenyl) -4-acetyl;
compound 3: r = (+) - α -methyl-6-methoxy-2-naphthylacetyl;
compound 4: r = α -methyl-3-benzoylphenylacetyl.
2. The process for the preparation of daphnetin 8-OH derivatives according to claim 1, comprising the steps of:
step a, carrying out etherification reaction on daphnetin and dibromoethyl alcohol to obtain an intermediate II shown as the following structural formula;
b, introducing a benzyl protecting group above C-7 phenolic hydroxyl of daphnetin through etherification reaction of the intermediate II and benzyl bromide to obtain an intermediate III shown in the following structural formula;
c, enabling the intermediate III to perform nucleophilic substitution reaction with the connecting group to obtain an intermediate IV shown in the following structural formula;
and d, removing benzyl from the intermediate IV in the presence of trifluoroacetic acid to obtain a target compound 1, a target compound 2, a target compound 3 and a target compound 4.
3. The method of claim 2, wherein step a comprises: firstly adding daphnetin, anhydrous potassium carbonate and potassium iodide into a reaction device, adopting anhydrous DMF as a solvent, slowly adding 2-bromoethanol after dissolving, adopting nitrogen protection, adding a drying device, and carrying out reflux reaction at 85 ℃. And after the TLC detection reaction is finished, carrying out post-treatment purification after the reaction is finished to obtain an intermediate II.
4. The method of claim 2, wherein step b comprises: and (3) putting the intermediate II into a reaction device, dissolving acetonitrile serving as a solvent, adding anhydrous potassium carbonate and benzyl bromide, and carrying out reflux reaction at 70 ℃. After TLC detection reaction is finished, after the reaction is finished, the intermediate III is obtained through post-treatment and purification.
5. The method of claim 2, wherein step c comprises: and (3) putting the intermediate III into a reaction device, dissolving the intermediate III by using dichloromethane as a solvent, adding HATU and DIPEA, stirring for a period of time at normal temperature, adding the substituted acyl chloride compound, and stirring at room temperature. After TLC detection reaction is finished, obtaining a pure intermediate IV through post-treatment.
6. The method of claim 2, wherein step d comprises: and (3) taking a proper amount of trifluoroacetic acid to completely dissolve the intermediate IV, and heating, refluxing and debenzylating. After the TLC detection reaction is finished, a pure target product is obtained through post-treatment.
7. Daphnetin 8-OH derivative of claim 1 tested by an inflammation model of xylene swelling of mouse pinna and carrageenan swelling of mouse toes. It can be seen that compound 1 and compound 4 have superior anti-inflammatory activity to daphnetin and indomethacin.
8. Daphnetin 8-OH derivative of claim 1 for use in a related medical use for anti-inflammatory.
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