CN103739576B - A kind of antivirus andrographolide derivative and its preparation method and application - Google Patents
A kind of antivirus andrographolide derivative and its preparation method and application Download PDFInfo
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- CN103739576B CN103739576B CN201410034947.4A CN201410034947A CN103739576B CN 103739576 B CN103739576 B CN 103739576B CN 201410034947 A CN201410034947 A CN 201410034947A CN 103739576 B CN103739576 B CN 103739576B
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- Prior art keywords
- andrographolide
- ester
- succinic acid
- acid half
- derivative
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 230000002155 anti-virotic effect Effects 0.000 title claims abstract description 7
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims abstract description 44
- 241001597008 Nomeidae Species 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 53
- 239000001384 succinic acid Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 230000000840 anti-viral effect Effects 0.000 abstract description 22
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 6
- 231100000252 nontoxic Toxicity 0.000 abstract description 5
- 230000003000 nontoxic effect Effects 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- 208000015181 infectious disease Diseases 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 240000002853 Nelumbo nucifera Species 0.000 description 5
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 5
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 206010037660 Pyrexia Diseases 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- 230000001754 anti-pyretic effect Effects 0.000 description 4
- 239000002221 antipyretic Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006356 dehydrogenation reaction Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 241000746375 Andrographis Species 0.000 description 3
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 3
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 3
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- -1 andrographolide compound Chemical class 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 206010018691 Granuloma Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 210000004381 amniotic fluid Anatomy 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000012059 conventional drug carrier Substances 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 206010034674 peritonitis Diseases 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000004080 punching Methods 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 239000009413 Chuanxinlian Substances 0.000 description 1
- 206010009866 Cold sweat Diseases 0.000 description 1
- 206010011703 Cyanosis Diseases 0.000 description 1
- 208000019872 Drug Eruptions Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 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 1
- 206010021718 Induced labour Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010024238 Leptospirosis Diseases 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241001113283 Respirovirus Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010047482 Viral upper respiratory tract infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- UKTDQTGMXUHPIF-UHFFFAOYSA-N [Na].S(O)(O)=O Chemical compound [Na].S(O)(O)=O UKTDQTGMXUHPIF-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229930184727 ginkgolide Natural products 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
Abstract
The invention provides a kind of antivirus andrographolide derivative and its preparation method and application, described antivirus andrographolide derivative, its non-toxic acceptable salt pharmaceutically and combinations thereof thing, in terms of infection, antiviral, antiinflammatory and antipyretic-antalgic, it is respectively provided with good application prospect.Described derivant has preferable water solublity and higher oral administration biaavailability.Antivirus andrographolide derivative of the present invention, is raw material by andrographolide, and processing technology is simple, with low cost, can industrialized production.
Description
Technical field
The invention belongs to field of heterocyclic compound, particularly to a kind of Novel antiviral andrographolide derivative and system thereof
Preparation Method and application.
Background technology
Andrographolide system extracts the diterpene ginkgolide obtained in acanthaceous plant Herba Andrographis, is Chinese medicine punching
One of principle active component of lotus, has the function such as heat-clearing and toxic substances removing, removing heat from blood detumescence.
Andrographolide is oral can cause vomiting because of bitter pole.Gastral cavilty can be caused when these product and several formulations are administered orally larger dose
Uncomfortable, loss of appetite.Once the report of drug eruption, upper abdominal pain and anaphylactic shock was caused after having CHUANXINLIAN ZHUSHEYE intramuscular injection.Instead
Should acutely person's symptom visible: uncomfortable in chest, out of breath, pale complexion, cyanotic lips, be in a cold sweat, pulse is thin and delicate, blood pressure drops etc.；Reaction
The lighter normally behaves as stomachache, vomiting, asthma, urticaria, pimple, dizziness, feeling of fullness in the head, sneeze etc..Occur that the time of reaction has i.e.
Time, also there is appearance in 5～20 minutes after injection, after rescuing, typically gradually took a turn for the better in 5～45 minutes, individual other warp
Within 24 hours, begin to recover.Also have and cause the report of acute amniotic fluid blocking person with the exchange induced labor of Herba Andrographis amniotic fluid.
For improving clinical efficacy, after general extraction andrographolide, prepare the injection of various soluble derivative, such as Asia
Sodium bisulfate addition product, sodium sulfonate addition product and succinic acid half-ester monopotassium salt etc..Wherein sodium sulfite addition andrographolide
The national drug standards have been taken in andrographolide succinic acid half-ester monopotassium salt (Potassium DehydroandrograpolidSuccinate Succinate for Injection).The most clinical conventional wearing
Heart lotus lactone succinic acid half-ester monopotassium salt also known as Andrographolide, the numerous studies that more than 30 years are clinical, it was demonstrated that its have the most antipyretic,
Antiinflammatory, promotion adrenal cortex function and sedation, can promote the phagocytic activity of neutrophilic granulocyte macrophage, improves serum
The content of middle lysozyme.Research is thought, andrographolide compound so that inflammation in early days capillary permeability is increased and oozes out,
Edema inhibitory action is notable, and prompting andrographolide compounds is the non-specific anti-inflammatory of a kind of new type.Andrographolide
Wide clinical application in infantile pneumonia, viral upper respiratory tract infection, tracheitis, influenza, leptospirosis and acute carefully
Bacterium property dysentery etc. are wherein the most notable with antipyretic response.
But it is, above-mentioned that oneself knows that medicine dissolubility in water is the most undesirable.Modern pharmacological research shows, andrographolide and
Derivant such as dehydrorographolide, 14-deshydroxy-11,12-two dehydrogenation andrographolide-3,19-disuccinic acid half ester list potassium
Salt, Andrographolide, 14-deshydroxy-11,12-two dehydrogenation andrographolide-3,19-disuccinic acid half ester k-na salt (andrographolide),
Andrographolide sulfonate (Xiyanping), Adduct of andrograp (Lian Bizhi) etc. can suppress blood capillary in early days
Pipe permeability increases and inflammatory exudation and edema, specifically excited Pituitary Adrenalcortical function, promotes ACTH release, increases
Add the biosynthesis of ACTH in antepituitary；There are antiphlogistic antibacterial, inactivated adenovirus, influenza virus, Respirovirus etc. multiple
The effect of virus, is widely used in treatment infantile pneumonia clinically, upper respiratory tract infection (1, Liu Xinjian, Wang Yifei, Li Gui
Raw.Pharmacological research progress (J) of andrographolide and derivant thereof, Chinese crude drug, 2003,26:135-138；2, Dai Guifu, Wang Jun
Peak, He Shuaiwei, etc..Pharmacology activity research progress (J) of andrographolide and derivant thereof, Chinese patent medicine, 2006,28 (7):
1032-1035。)
Andrographolide, dehydrorographolide and 14-deshydroxy-11,12-bis-dehydrogenation andrographolide-3,19-bis-amber
The structure of amber acid half ester is as follows:
Andrographolide dehydrorographolide 14-deshydroxy-11, in 12-bis-dehydrogenation Herba Andrographis
Ester-3,19-disuccinic acid half ester.
Summary of the invention
The invention provides a kind of Novel antiviral andrographolide derivative and its preparation method and application, described is new
Type antivirus andrographolide derivative and combinations thereof thing, in terms of infection, antiviral, antiinflammatory and antipyretic-antalgic, all has
There is good application prospect.
It is an object of the invention to be achieved through the following technical solutions:
A kind of Novel antiviral andrographolide derivative, the formula of described derivant is as follows:
Wherein, can be all or can not be all glycyl, L-alanyl, L-leucyl, L-valyl or L-different for R1, R2, R3
Leucylamino acid residue.
It is another object of the present invention to be achieved through the following technical solutions:
A kind of preparation method of Novel antiviral andrographolide derivative, the formula of described derivant is as follows:
Wherein, can be all or can not be all glycyl, L-alanyl, L-leucyl, L-valyl or L-different for R1, R2, R3
Leucylamino acid residue；
Described preparation method comprises the following steps:
With andrographolide as raw material, it is 520 ~ 620 mm Hg in vacuum, 60 DEG C ~ 200 DEG C, under catalyst action
With succinic anhydrides generation esterification, refluxing 0.5 ~ 10 hour, except vacuum after cooling, the stirring that adds water is dredged to all solidifications and crystallize
Till Saning, sucking filtration, the filter cake normal-temperature vacuum obtained is dried, dried filter cake is added sodium bicarbonate aqueous solution and dissolves, filter
Filtrate, use the hydrochloric acid of 0.1 ~ 12mol/L to adjust the pH to 1 ~ 6, pH of filtrate to be preferably 4, separate out white precipitate, sucking filtration, be dried,
I.e. obtain described Novel antiviral andrographolide derivative.
Further, described catalyst is sodium sulfite or DMAP (DMAP).
Further, also include that the non-toxic of described Novel antiviral andrographolide derivative is pharmaceutically acceptable
Salt.
Further, also include that the non-toxic of described Novel antiviral andrographolide derivative is pharmaceutically acceptable
Salt is as the pharmaceutical composition of active component.
Further, the described Novel antiviral andrographolide derivative drug regimen as active component is also included
Thing, described pharmaceutical composition includes the compound described in claim 1 and pharmaceutically conventional pharmaceutical carrier/or diluent, institute
Stating therapeutically effective amount is 100mg every day, and intravenous drip 3rd ~ 4 is a course for the treatment of.
It is another object of the present invention to be achieved through the following technical solutions:
The application of a kind of described Novel antiviral andrographolide derivative, described derivant can be used for preparing anti-sense
Dye, antiviral, antiinflammatory and ntipyretic analgesic medicine.
Further, the dosage form stating medicine is injection, transfusion, powder pin, drop pill, tablet, dispersible tablet, slow releasing tablet, controlled release
The existing pharmaceutical dosage form of any one of sheet, oral cavity quick disintegrating slice, capsule, soft capsule, granule, Emulsion and targeting preparation.
The present invention having the beneficial effect that compared with prior art
1, Novel antiviral andrographolide derivative of the present invention, has good water solublity and higher being administered orally
Bioavailability, can treat infection, antiviral, antiinflammatory and ntipyretic analgesic medicine；
2, Novel antiviral andrographolide derivative of the present invention, is raw material by andrographolide, processing technology letter
Single, with low cost, can industrialized production.
Detailed description of the invention
Embodiment 1
A kind of Novel antiviral andrographolide derivative, the formula of described derivant is as follows:
Wherein, can be all or can not be all glycyl, L-alanyl, L-leucyl, L-valyl or L-different for R1, R2, R3
Leucylamino acid residue；
Described preparation method comprises the following steps:
With andrographolide as raw material, it is 520 ~ 620 mm Hg in vacuum, 60 DEG C ~ 200 DEG C, under catalyst action
With succinic anhydrides generation esterification, refluxing 0.5 ~ 10 hour, except vacuum after cooling, the stirring that adds water is dredged to all solidifications and crystallize
Till Saning, sucking filtration, the filter cake normal-temperature vacuum obtained is dried, dried filter cake is added sodium bicarbonate aqueous solution and dissolves, filter
Filtrate, use the hydrochloric acid of 0.1 ~ 12mol/L to adjust the pH to 1 ~ 6, pH of filtrate to be preferably 4, separate out white precipitate, sucking filtration, be dried,
I.e. obtain described Novel antiviral andrographolide derivative.
Further, described catalyst is sodium sulfite or DMAP (DMAP).
Further, the present embodiment also includes the non-toxic of described Novel antiviral andrographolide derivative pharmaceutically
Acceptable salt.
Further, the present embodiment also includes the non-toxic of described Novel antiviral andrographolide derivative pharmaceutically
Acceptable salt is as the pharmaceutical composition of active component.
Further, the present embodiment also includes that described Novel antiviral andrographolide derivative is as active component
Pharmaceutical composition, described pharmaceutical composition includes the compound described in claim 1 and pharmaceutically conventional pharmaceutical carrier/or dilute
Releasing agent, described therapeutically effective amount is 100mg every day, and intravenous drip 3rd ~ 4 is a course for the treatment of.
It is another object of the present invention to be achieved through the following technical solutions:
The application of a kind of described Novel antiviral andrographolide derivative, described derivant can be used for preparing anti-sense
Dye, antiviral, antiinflammatory and ntipyretic analgesic medicine.
Further, the dosage form stating medicine is injection, transfusion, powder pin, drop pill, tablet, dispersible tablet, slow releasing tablet, controlled release
The existing pharmaceutical dosage form of any one of sheet, oral cavity quick disintegrating slice, capsule, soft capsule, granule, Emulsion and targeting preparation.
Unit of weight used by the present embodiment is kilogram, it is also possible to for gram；Volume unit is for rising, it is also possible to for cubic meter.
Each raw material described in the present embodiment is on market the conventional products sold.
In the present embodiment, described in each raw material can in the ratio range be given flexible combination, differ at this
One enumerates.
Embodiment 2
The present embodiment is the preferred version on the basis of embodiment 1, and the present embodiment is andrographolide three succinic acid half-ester
Preparation with andrographolide three succinic acid half-ester glycinate.
Described preparation method is: by andrographolide 40g (0.12mol), succinic anhydrides 40g (0. 40mol), sulfurous acid
Sodium 4.0g, is placed in reaction bulb, mixing, sets up reflux and drying tube, begins to warm up, and regulation vacuum is 520 ~ 620 mm
Hg, 100 DEG C, back flow reaction 5 hours, evacuation after cooling.Add 800ml water in reaction bulb, be stirred well to all solidify
Till evacuating with crystallize.Sucking filtration, is dried the filter cake normal-temperature vacuum obtained, and dried filter cake is added sodium bicarbonate aqueous solution molten
Solve, filter to get filtrate, use the hydrochloric acid of 0.1 ~ 12mol/L to adjust the pH to 4 of filtrate, separate out white precipitate, sucking filtration, be dried to obtain and wear
Heart lotus lactone three succinic acid half-ester.
Utilize andrographolide three succinic acid half-ester obtained above, prepare andrographolide three succinic acid half-ester glycine
Ester.
Described preparation method is: takes andrographolide three succinic acid half-ester, adds methylene chloride and make dissolving, adds the sweet of excess
Propylhomoserin, is simultaneously introduced DCC, is heated to reflux 1 ~ 2 hour, and thin layer follows the tracks of reaction, cold rear filtration, vacuum drying, andrographolide three
Succinic acid half-ester glycinate, total recovery is 70 ~ 80%.
Andrographolide three succinic acid half-ester glycinate, pale yellow powder, odorless, bitter in the mouth.Soluble in water, it is slightly soluble in dilute
Ethanol, insoluble in chloroform or ether.Andrographolide three succinic acid half-ester and andrographolide three succinic acid half-ester salt pharmacodynamics
Research shows that its antipyretic response is significantly larger than Andrographolide.
Investigate effective dose and the pharmacological action of described andrographolide three succinic acid half-ester glycinate, for clinical practice
Foundation is provided.Method: Ovum Gallus domesticus album causes rat paw edema, rat granuloma is swollen and mice caused by dimethylbenzene xylene peritonitis model observes punching
The antiinflammatory action of lotus lactone three succinic acid half-ester glycinate；Dry yeast cause rat fever, dinitrophenol,DNP cause rat fever and
Endotoxin causes rabbit fever models and observes the refrigeration function of andrographolide three succinic acid half-ester glycinate；Tube propagation method is seen
Examine the antibacterial action of andrographolide three succinic acid half-ester glycinate.
Result: andrographolide three succinic acid half-ester glycinate dose-effect relationship is obvious: 300mg/kg and 150mg/kg pair
Rat fever caused by dry yeast and dinitrophenol,DNP and the fever in rabbits caused by endotoxin all have good refrigeration function,
75mg/kg is to three kinds of heating functioins the most inconspicuous (seeing table 1, table 2, table 3).400mg/kg and 200mg/kg is to caused by Ovum Gallus domesticus album
Rat paw edema, rat granuloma be swollen and mouse peritoneum inflammation caused by dimethylbenzene all has a good antiinflammatory action, 100mg/kg pair
Three kinds of inflammatory effect the most inconspicuous (seeing table 4, table 5, table 6).
Seeing table 7, the MCI of andrographolide three succinic acid half-ester glycinate escherichia coli and dysentery bacterium is 2mg/kg
It is 1mg/kg conclusion to gold-coloured staphylococci and pneumococcal MCI: andrographolide three succinic acid half-ester glycinate has relatively
Good antipyretic and antiinflammatory action, but its antibacterial action is more weak.
Horse lotus ester tripotassium salt is basically identical with andrographolide three succinic acid half-ester glycinate results of pharmacodynamic test.
Claims (1)
1. a preparation method for antivirus andrographolide derivative, the formula of described derivant is as follows:
Wherein, R1, R2, R3 are all glycyl；
It is characterized in that: preparation process is: by andrographolide 40g, succinic anhydrides 40g, sodium sulfite 4.0g, be placed in reaction bulb
In, mixing, to set up reflux and drying tube, begin to warm up, regulation vacuum is 520 ~ 620 mm Hg, 100 DEG C, and backflow is anti-
Answer 5 hours, evacuation after cooling, add 800ml water in reaction bulb, till being stirred well to all solidify and evacuating with crystallize, take out
Filter, is dried the filter cake normal-temperature vacuum obtained, and dried filter cake adds sodium bicarbonate aqueous solution and dissolves, filter to get filtrate, make
Adjust the pH to 4 of filtrate with the hydrochloric acid of 0.1 ~ 12mol/L, separate out white precipitate, sucking filtration, be dried to obtain andrographolide three succinic acid
Half ester；Utilize andrographolide three succinic acid half-ester obtained above, prepare andrographolide three succinic acid half-ester glycinate；
Take andrographolide three succinic acid half-ester, add methylene chloride and make dissolving, add the glycine of excess, be simultaneously introduced DCC, heat back
Flowing 1 ~ 2 hour, thin layer follows the tracks of reaction, cold rear filtration, vacuum drying, obtains andrographolide three succinic acid half-ester glycinate.
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| CN101376651A (en) * | 2007-08-28 | 2009-03-04 | 北京美倍他药物研究有限公司 | Andrographolide and water-soluble aminoacid ester derivative of dewatered andrographolide |
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| CN101376651A (en) * | 2007-08-28 | 2009-03-04 | 北京美倍他药物研究有限公司 | Andrographolide and water-soluble aminoacid ester derivative of dewatered andrographolide |
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