CN112778264B - Aristolochic acid derivative and application thereof in preparing anti-inflammatory drugs - Google Patents
Aristolochic acid derivative and application thereof in preparing anti-inflammatory drugs Download PDFInfo
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- BBFQZRXNYIEMAW-UHFFFAOYSA-N aristolochic acid I Chemical class C1=C([N+]([O-])=O)C2=C(C(O)=O)C=C3OCOC3=C2C2=C1C(OC)=CC=C2 BBFQZRXNYIEMAW-UHFFFAOYSA-N 0.000 title claims abstract description 144
- 229940124599 anti-inflammatory drug Drugs 0.000 title claims description 6
- -1 methoxy, hydroxy Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 37
- 241000700159 Rattus Species 0.000 abstract description 26
- 239000000679 carrageenan Substances 0.000 abstract description 18
- 229940113118 carrageenan Drugs 0.000 abstract description 18
- 235000010418 carrageenan Nutrition 0.000 abstract description 18
- 229920001525 carrageenan Polymers 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 18
- 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 abstract description 18
- 230000008961 swelling Effects 0.000 abstract description 11
- 238000013508 migration Methods 0.000 abstract description 8
- 230000005012 migration Effects 0.000 abstract description 8
- 238000011161 development Methods 0.000 abstract description 6
- 208000002151 Pleural effusion Diseases 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000000243 solution Substances 0.000 description 54
- 239000007864 aqueous solution Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- BBFQZRXNYIEMAW-UHFFFAOYSA-M Aristolochate I Natural products C1=C([N+]([O-])=O)C2=C(C([O-])=O)C=C3OCOC3=C2C2=C1C(OC)=CC=C2 BBFQZRXNYIEMAW-UHFFFAOYSA-M 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- LGZIKBZSCRORQN-UHFFFAOYSA-N 8-hydroxy-6-nitronaphtho[2,1-g][1,3]benzodioxole-5-carboxylic acid Chemical compound C12=C3C=CC=C(O)C3=CC([N+]([O-])=O)=C2C(C(=O)O)=CC2=C1OCO2 LGZIKBZSCRORQN-UHFFFAOYSA-N 0.000 description 15
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- 229960001138 acetylsalicylic acid Drugs 0.000 description 10
- 210000002683 foot Anatomy 0.000 description 10
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 208000008423 pleurisy Diseases 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000005507 spraying Methods 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 210000000038 chest Anatomy 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 241000758795 Aristolochiaceae Species 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 210000000416 exudates and transudate Anatomy 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000000115 thoracic cavity Anatomy 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000726094 Aristolochia Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910020366 ClO 4 Inorganic materials 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 210000003371 toe Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- GYBINMVKWZEICQ-UHFFFAOYSA-N 8,10-dimethoxy-6-nitronaphtho[2,1-g][1,3]benzodioxole-5-carboxylic acid Chemical compound C1=C2OCOC2=C2C3=CC(OC)=CC(OC)=C3C=C([N+]([O-])=O)C2=C1C(O)=O GYBINMVKWZEICQ-UHFFFAOYSA-N 0.000 description 1
- 241000046617 Aristolochia debilis Species 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 206010063045 Effusion Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000218377 Magnoliaceae Species 0.000 description 1
- 241000218164 Menispermaceae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241000218201 Ranunculaceae Species 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- 206010041277 Sodium retention Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical group OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- KFDKNTQGTAEZGC-UHFFFAOYSA-N phenanthrene-1-carboxylic acid Chemical class C1=CC2=CC=CC=C2C2=C1C(C(=O)O)=CC=C2 KFDKNTQGTAEZGC-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
-
- 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]
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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an aristolochic acid derivative and application thereof in preparing anti-inflammatory medicaments, and experiments prove that the aristolochic acid derivative can obviously inhibit foot swelling of rats caused by carrageenan, and can obviously reduce pleural effusion and leucocyte migration of the rats caused by carrageenan. Therefore, the aristolochic acid derivative has obvious anti-inflammatory effect, can be used for preparing anti-inflammatory medicaments, and has good application and development prospects.
Description
Technical Field
The invention relates to aristolochic acid derivatives and application thereof in preparing anti-inflammatory drugs.
Background
Inflammation is a protective response of the body against external infections or damaging stimuli, and is also a common pathological process for many different types of diseases. Long-term sustained, excessive inflammatory reactions or inflammatory storms can cause serious injury to the body itself and even failure of organs, and therefore pharmaceutical intervention is needed to block the duration and development of inflammation. Currently, there are two main classes of clinically common anti-inflammatory agents: non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs (glucocorticoids). Although both of these anti-inflammatory agents have good clinical anti-inflammatory effects, a large number of adverse reactions and tolerability such as gastric mucosal injury, liver and kidney damage and toxic side effects of heart can be generated after long-term use, and sodium retention in water can be generated. In order to solve the tolerance and adverse reaction of the medicine, finding an anti-inflammatory medicine with novel structure and unique mechanism is always a hot spot in the research and development field of novel anti-inflammatory medicines.
Aristolochic acid (Aristolochic acids) is an aromatic nitro group-containing phenanthrenecarboxylic acid analogue which is widely present in plants of the family Aristolochiaceae, ranunculaceae, magnoliaceae and Menispermaceae, and particularly in higher levels in various parts of plants of the genus Aristolochia of the family Aristolochiaceae. The compounds and in vivo metabolites have serious hepatotoxicity, nephrotoxicity, mutagenic toxicity and carcinogenic toxicity, and the toxicity is closely related to the structure of the m-nitrocarboxylic acid contained in the compounds and in vivo metabolites. The invention takes aristolochic acid compounds as initial raw materials, obtains aristolochic acid derivatives through Sandmeyer reaction, evaluates the anti-inflammatory activity of the aristolochic acid derivatives, discovers that the aristolochic acid derivatives have obvious anti-inflammatory effect, the anti-inflammatory effect is obviously stronger than that of the aristolochic acid compounds which are the initial raw materials for synthesizing the aristolochic acid compounds after the aristolochic acid derivatives are dosed at the same time, and simultaneously, the nitro in the m-nitrocarboxylic acid structure is removed from the molecular structure of the aristolochic acid compounds, so that the hepatotoxicity and the carcinogenicity brought by the nitrocarboxylic acid structure are completely eliminated.
Disclosure of Invention
The invention aims to provide aristolochic acid derivatives and application thereof in preparing anti-inflammatory drugs.
The chemical structure of the aristolochic acid derivative used for preparing the anti-inflammatory medicament is shown as the following formula:
in the formula I, R 1 Is methoxy, hydroxy or hydrogen, R 2 Is chlorine or bromine; when R is 1 Is methoxy, R 2 In the case of chlorine, the first formula is aristolochic acid derivative I; when R is 1 Is methoxy, R 2 In the case of bromine, the first formula is aristolochic acid derivative II; when R is 1 Is hydroxy, R 2 In the case of chlorine, the first formula is aristolochic acid derivative III; when R is 1 Is hydroxy, R 2 Bromine isIn the case of aristolochic acid derivatives IV; when R is 1 Is hydrogen, R 2 In the case of chlorine, the first formula is aristolochic acid derivative V; when R is 1 Is hydrogen, R 2 In the case of bromine, the first formula is aristolochic acid derivative VI.
The aristolochic acid derivative used for preparing the anti-inflammatory medicament in the invention can be aristolochic acid derivative I, II, III, IV, V or VI. It can be separated and purified from traditional Chinese medicine or plant containing aristolochic acid compound to obtain aristolochic acid compound (R 1 Is methoxy, hydroxy or hydrogen, when R 1 In the case of methoxy, the formula II is aristolochic acid I; when R is 1 When hydroxyl, the formula II is aristolochic acid Ia; when R is 1 In the case of hydrogen, the formula II is aristolochic acid II), and then the aristolochic acid II is prepared according to the synthetic route shown; aristolochic acid compounds of formula II (R) 1 Methoxy, hydroxy or hydrogen) and then prepared according to the synthetic route shown.
Synthetic route of aristolochic acid derivatives.
According to the invention, by observing and analyzing the influence of the aristolochic acid derivative on the rat foot swelling caused by carrageenan and the influence of the aristolochic acid derivative on the pleural effusion amount and the leucocyte migration of the rat pleurisy caused by carrageenan, the aristolochic acid derivatives I, II, III, IV, V and VI have obvious anti-inflammatory effects, so that the aristolochic acid derivative can be used for preparing anti-inflammatory medicaments.
In the invention, when the aristolochic acid derivatives I, II, III, IV, V and VI are observed to have obvious anti-inflammatory effect, the anti-inflammatory activity is found to be obviously stronger than that of the aristolochic acid I, ia and II which are the synthetic raw materials of the aristolochic acid derivatives, and the toxicity is obviously reduced; meanwhile, the anti-inflammatory activity of the medicine is found to be obviously superior to that of the positive control medicine aspirin. Therefore, the aristolochic acid derivatives I, II, III, IV, V and VI have remarkable anti-inflammatory effect, can be used for preparing anti-inflammatory medicaments, and have good application and development prospects.
Detailed Description
Example 1:
medicinal materials: the radix Aristolochiae is obtained from Cinnamomum camphora market of Jiangxi province, yunnan Lijiang (lot number F41), and is dry root of Aristolochia (Aristolochia debilis Sieb. Et Zucc.) of Aristolochiaceae, and pulverizing with pulverizer to obtain radix Aristolochiae coarse powder.
Extracting the above radix Aristolochiae with 70% ethanol 100kg, concentrating under reduced pressure until no ethanol smell, extracting with chloroform, and collecting extract according to literature method (Chen Zhongliang, et al, chemical journal 1981,39 (3): 237-242 and Wu Lijun, et al, shenyang pharmaceutical university journal 1982, (16): 19-22), and performing silica gel column chromatography and solvent crystallization to obtain aristolochic acid I (45.8 g), I a (11.3 g) and II (7.1 g).
Dissolving 5.0g aristolochic acid I in 100ml concentrated HCl, cooling to 0-5deg.C, and slowly dripping 20ml NaNO 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 50ml of CuCl hydrochloric acid solution, and after all addition, stirred at 60℃for 2h and left overnight. The pH of the solution is regulated to 3.2 by 30% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative I (2.7 g).
Dissolving 1.0g aristolochic acid Ia in 15ml concentrated HCl, cooling to 0-5deg.C, slowly dripping 5ml NaNO 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 10ml of CuCl hydrochloric acid solution, and after all addition, stirred at 50℃for 3h and left overnight. The pH of the solution is adjusted to 3.5 by 25% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, so that the aristolochic acid derivative III (0.5 g) is obtained.
Dissolving 1.5g aristolochic acid II in 20ml concentrated HCl, cooling to 0-5deg.C, and slowly dripping 5ml NaNO 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 10ml of CuCl hydrochloric acid solution, and after all addition, stirred at 45℃for 4h and left overnight. The pH of the solution is regulated to 3.0 by 30% NaOH, precipitation is separated out, the solution is stood, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative V (0.8 g).
Dissolving 2.0g aristolochic acid I in 50ml concentrated HBr, cooling to 0-5deg.C, and slowly dripping 10ml NaNO 2 Stirring the aqueous solution at 0-5deg.CStirring for 30min, slowly adding diazotization solution into 20ml of CuBr hydrobromic acid solution, stirring for 2h at 55 ℃ after all the solution is added, and standing overnight. The pH of the solution is regulated to 3.5 by 30% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative II (1.3 g).
Dissolving 3.5g aristolochic acid Ia in 70ml concentrated HBr, cooling to 0-5deg.C, slowly dripping 15ml NaNO 2 The aqueous solution was stirred at 0-5℃for 40min, the diazotized solution was slowly added to 20ml of CuBr hydrobromic acid solution, and after all addition, stirred at 70℃for 2.5h and left overnight. The pH of the solution is adjusted to 3.5 by 30% NaOH, precipitate is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative IV (1.3 g).
Dissolving 2.1g aristolochic acid II in 70ml concentrated HBr, cooling to 0-5deg.C, slowly adding 15ml NaNO dropwise 2 The aqueous solution was stirred at 0-5℃for 40min, the diazotized solution was slowly added to 20ml of CuBr hydrobromic acid solution, after all addition, stirred at 50℃for 2.5h and left overnight. The pH of the solution is adjusted to 3.5 by 30% NaOH, precipitate is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative VI (1.5 g).
The physicochemical properties and spectrum data of the aristolochic acid derivatives I to VI prepared above are as follows:
aristolochic acid derivatives I: molecular formula C 18 H 13 ClO 4 Is insoluble in water, soluble in methanol and ethanol, and soluble in sodium hydroxide aqueous solution; spraying 0.5% diphenylamine solution on the thin layer plate, and heating to develop deep blue; ESI-MS (m/z): 329.06[ M+H ]] + 。 13 C NMR(CD 3 OD,100MHz)δppm：170.7、156.3、143.0、141.9、132.0、130.1、128.3、127.8(CH)、125.4、125.3、124.6(CH)、119.2(CH)、117.8(CH)、117.1、105.5(CH)、73.9(CH 2 )、73.1(CH 2 )、55.9(CH 3 )。
Aristolochic acid derivative II: molecular formula C 18 H 13 BrO 4 Is insoluble in water, soluble in methanol and ethanol, and soluble in sodium hydroxide aqueous solution; spraying 0.5% diphenylamine solution on the thin layer plate, and heating to develop deep blue; ESI-MS (m/z): 373.01[ M+H ]] + 。 13 C NMR(CD 3 OD,100MHz)δppm：170.0、156.1、143.8、142.1、131.7、129.5、128.0(CH)、128.0(CH)、127.6、127.0、126.6、119.8(CH)、119.0(CH)、107.5(CH)、106.7、73.9(CH 2 )、73.1(CH 2 )、55.8(CH 3 )。
Aristolochic acid derivative III: molecular formula C 17 H 11 ClO 4 Is insoluble in water, soluble in methanol and ethanol, and soluble in sodium hydroxide aqueous solution; spraying 0.5% diphenylamine solution on the thin layer plate, and heating to black; ESI-MS (m/z): 315.04[ M+H ]] + 。 13 C NMR(CD 3 OD,100MHz)δppm：170.7、157.3、142.2、142.0、134.8、132.1、130.4(CH)、126.7、126.3(CH)、123.7、123.3、119.2(CH)、116.1(CH)、114.4、109.0(CH)、73.9(CH 2 )、73.1(CH 2 )。
Aristolochic acid derivative IV: molecular formula C 17 H 11 BrO 4 Is insoluble in water, soluble in methanol and ethanol, and soluble in sodium hydroxide aqueous solution; spraying 0.5% diphenylamine solution on the thin layer plate, and heating to black; ESI-MS (m/z): 358.99[ M+H ]] + 。 13 C NMR(CD 3 OD,100MHz)δppm：170.0、155.8、143.9、141.3、132.9、131.8、130.7(CH)、128.9、128.5(CH)、124.0、122.1、119.0(CH)、118.1(CH)、111.0(CH)、101.7、73.9(CH 2 )、73.1(CH 2 )。
Aristolochic acid derivative V: molecular formula C 17 H 11 ClO 3 Is insoluble in water, soluble in methanol and ethanol, and soluble in sodium hydroxide aqueous solution; spraying 0.5% diphenylamine solution on the thin layer plate, and heating to develop blue; ESI-MS (m/z): 299.05[ M+H ]] + 。 13 C NMR(CD 3 OD,100MHz)δppm：170.7、142.0、141.0、132.2、131.6、131.2、130.4(CH)、129.6、129.3(CH)、127.8(CH)、127.0(CH)、126.7、125.8(CH)、125.5、119.2(CH)、73.9(CH 2 )、73.1(CH 2 )。
Aristolochic acid derivative VI: molecular formula C 17 H 11 BrO 3 Is insoluble in water, soluble in methanol and ethanol, and soluble in sodium hydroxide aqueous solution; spraying on the thin layer plateHeating 0.5% diphenylamine solution to develop blue; ESI-MS (m/z): 343.00[ M+H ]] + 。 13 C NMR(CD 3 OD,100MHz)δppm：170.0、143.9、140.1、132.4(CH)、131.8、131.4、131.0、130.4(CH)、129.2(CH)、128.5、128.0(CH)、127.7、127.6(CH)、119.0(CH)、118.0、73.9(CH 2 )、73.1(CH 2 )。
Example 2:
dissolving commercially available aristolochic acid I (2.0 g) in 40ml of concentrated HCl, cooling to 0-5deg.C, and slowly dropwise adding 12ml NaNO 2 The aqueous solution was stirred at 0-5℃for 40min, the diazotized solution was slowly added to 20ml of CuCl hydrochloric acid solution, and after all addition, stirred at 45℃for 3h and left overnight. The pH of the solution is regulated to 3.2 by 30% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative I (1.5 g).
Dissolving commercially available aristolochic acid II (1.7 g) in 15ml of concentrated HCl, cooling to 0-5deg.C, and slowly dropwise adding 10ml NaNO 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 10ml of CuCl hydrochloric acid solution, and after all addition, stirred at 60℃for 2h and left overnight. The pH of the solution is regulated to 3.3 by 30% NaOH, precipitation is separated out, the solution is stood, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative V (1.3 g).
Dissolving commercially available aristolochic acid I (5.0 g) in 90ml of concentrated HBr, cooling to 0-5deg.C, and slowly dropwise adding 30ml NaNO 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 50ml of CuBr hydrobromic acid solution, and after all addition, stirred at 45℃for 2.5h and left overnight. The pH of the solution is regulated to 3.0 by 30% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative II (3.8 g).
Dissolving commercially available aristolochic acid Ia (3.0 g) in 60ml of concentrated HBr, cooling to 0-5deg.C, and slowly dropwise adding 17ml NaNO 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 25ml of CuBr hydrobromic acid solution, and after all addition, stirred at 65℃for 2h and left overnight. The pH of the solution is adjusted to 3.1 by 30% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, thus obtaining the aristolochic acid derivative IV (1.0 g).
Will be commercially available horsesBellyacon acid Ia (2.0 g) is dissolved in 20ml concentrated HCl, cooled to 0-5 ℃, and 20ml NaNO is slowly added dropwise 2 The aqueous solution was stirred at 0-5℃for 30min, the diazotized solution was slowly added to 20ml of CuCl hydrochloric acid solution, and after all addition, stirred at 55℃for 2.5h and left overnight. The pH of the solution is adjusted to 3.2 by 30% NaOH, precipitation is separated out, the solution is stood still, suction filtration is carried out, and a filter cake is dried, so that the aristolochic acid derivative III (0.8 g) is obtained.
Dissolving commercially available aristolochic acid II (2.5 g) in 50ml of concentrated HBr, cooling to 0-5deg.C, and slowly dropwise adding 20ml NaNO 2 The aqueous solution was stirred at 0-5℃for 40min, the diazotized solution was slowly added to 20ml of CuBr hydrobromic acid solution, and after all addition, stirred at 60℃for 2h and left overnight. The pH of the solution was adjusted to 3.2 with 30% NaOH, precipitate was separated out, left to stand, suction filtered, and the filter cake was dried to give aristolochic acid derivative VI (1.8 g).
The physicochemical properties and spectrum data of the aristolochic acid derivatives I, II, III, IV, V and VI obtained above were consistent with those of the aristolochic acid derivatives I, II, III, IV, V and VI described in example 1, respectively, through test analysis.
Example 3:
experimental animal and reagent
Experimental animals: SPF SD rats weighing 180-220 g, purchased from experimental animal center of Jiangxi Chinese medical university, and pass number: SCXK (GanP) 2018-0003.
Reagent: aristolochic acid I, ia and II, aristolochic acid derivatives I, II, III, IV, V and VI, aspirin and carrageenan prepared as in example 1 were purchased from Shanghai chemical company and were prepared temporarily to the desired concentration using 0.15% CMC-Na aqueous solution prior to the experiment.
Effect of aristolochic acid derivatives on carrageenan-induced swelling of rat feet
Male SD rats 144 were randomly divided into 12 groups by body weight: normal control group (normal saline), model group (1% carrageenan/normal saline), aspirin (400 mg/kg) positive control group, aristolochic acid I group (80 mg/kg), aristolochic acid Ia group (80 mg/kg), aristolochic acid II group (80 mg/kg), aristolochic acid derivative I group (80 mg/kg), aristolochic acid derivative II group (80 mg/kg), aristolochic acid derivative III group (80 mg/kg), aristolochic acid derivative IV group (80 mg/kg), aristolochic acid derivative V group (80 mg/kg) and aristolochic acid derivative VI group (80 mg/kg), 12 in each group. The mice were orally administered by stomach irrigation, and after 1 hour of administration, the model group and the toe of each experimental group were subcutaneously injected with 0.1mL of 1% carrageenan-physiological saline solution (freshly prepared at the time of clinical use) to cause inflammation, the blank group was injected with 0.1mL of physiological saline into the left lower limb of the model group, and the circumference of the right hind limb after 5 hours before and after the inflammation was measured with a tape, and the swelling degree was calculated.
Swelling = (circumference of pro-inflammatory foot plantar Zhou Chang pro-inflammatory foot plantar)/circumference of pro-inflammatory foot plantar
Statistical analysis
Experimental results are expressed as x±sd, and analysis of variance was performed using SPSS 11.0 software package, and comparisons between groups were performed using t-test.
Results and conclusions
The effect of aristolochic acid derivatives I-VI on carrageenan-induced swelling of rat feet is shown in Table 1.
TABLE 1 Effect of aristolochic acid derivatives on carrageenan-induced rat plantar swelling(n＝12)
Note that: comparison to the normal control group: ** p is less than 0.01; comparison to model set: ## p is less than 0.01; comparison with the corresponding starting material group: ++ p is less than 0.01; in comparison with the group of aspirin, §§ P＜0.01。
as can be seen from table 1: model group rat foot swelling model modeling was successful (< P < 0.01) compared to normal group; compared with the model group, the swelling degree of the toes of the rats in the Aristolochianic acid derivative I, II, III, IV, V and VI groups is obviously reduced ## P < 0.01), thereby indicating that: the aristolochic acid derivative can obviously inhibit the feet of rats caused by carrageenanSwelling, having significant anti-inflammatory effect; and the anti-inflammatory effect of the medicine is obviously better than that of 400mg/kg aspirin @ at 80mg/kg dosage §§ P < 0.01). Meanwhile, compared with the raw material aristolochic acid compound synthesized by aristolochic acid derivatives, the anti-inflammatory effect of the aristolochic acid derivatives I and II synthesized by taking the aristolochic acid I as the raw material is obviously stronger than that of aristolochic acid I # ++ P＜
0.01 A) is provided; similarly, the anti-inflammatory effects of aristolochic acid derivatives III and IV are significantly stronger than that of aristolochic acid Ia # ++ P is less than 0.01), and the anti-inflammatory effect of the aristolochic acid derivatives V and VI is obviously stronger than that of aristolochic acid II # ++ P < 0.01). Because the toxicity of the aristolochic acid compound is closely related to the structure of the m-nitrocarboxylic acid contained in the aristolochic acid compound [3] Whereas the structure of the aristolochic acid derivative does not contain the m-nitrocarboxylic acid structure of the aristolochic acid compound, it is shown that: the aristolochic acid derivatives I-VI have anti-inflammatory activity obviously stronger than that of the aristolochic acid I, ia and II which are synthesized as starting materials, have obviously reduced toxicity, can be used for preparing anti-inflammatory medicaments, and have good application and development prospects.
Example 4
Experimental animal and reagent
Experimental animals: SPF-grade SD rats weighing 180-220 g purchased from Daikovia Biotechnology Co., ltd., eligibility number: SCXK (GanP) 2019-0014.
Reagent: commercially available aristolochic acid I, ia and II (Merck company), aristolochic acid derivatives I, II, III, IV, V and VI prepared as in example 2, aspirin and carrageenan were purchased from Shanghai chemical reagent company and were each prepared temporarily to the desired concentration using 0.15% CMC-Na in water prior to the experiment.
Effect of aristolochic acid derivatives on the amount of pleurisy rat chest exudates and leukocyte migration induced by carrageenan
SD rats 144, male and female halves, were randomly divided into 12 groups: normal control group (normal saline), model group (1% carrageenan/normal saline), aspirin (100 mg/kg) positive control group, aristolochic acid I group (50 mg/kg), aristolochic acid Ia group (50 mg/kg), aristolochic acid II group (50 mg/kg), aristolochic acid derivative I group (50 mg/kg), aristolochic acid derivative II group (50 mg/kg), aristolochic acid derivative III group (50 mg/kg), aristolochic acid derivative IV group (50 mg/kg), aristolochic acid derivative V group (50 mg/kg) and aristolochic acid derivative VI group (50 mg/kg), 12 in each group. The rats were anesthetized shallowly with diethyl ether and fixed on an operating table 1h after 48, 24, 1h gastric lavage administration prior to the experiment, but not after the administration. The right thoracic cavity of the rat was injected with 0.25ml of 1% carrageenan, the rat was sacrificed by breaking its head after 5 hours, the thoracic cavity was opened at the periphery of the diaphragm, the thoracic cavity liquid was sucked out with a syringe or a suction tube, the exudation was recorded, and the cell number was counted.
Statistical analysis
Experimental results are expressed as x±sd, and analysis of variance was performed using SPSS 11.0 software package, and comparisons between groups were performed using t-test.
Results and conclusions
The effect of aristolochic acid derivatives I-VI on the amount of pleurisy rat chest exudates and leukocyte migration caused by carrageenan is shown in Table 2.
TABLE 2 Effect of aristolochic acid derivatives on pleurisy rat chest exudates and leukocyte migration(n＝12)
Note that: comparison to the normal control group: ** p is less than 0.01; comparison to model set: ## p is less than 0.01; comparison with the corresponding starting material group: ++ p is less than 0.01; in comparison with the group of aspirin, §§ P＜0.01。
as can be seen from table 2: model group rat pleurisy model modeling was successful (< P < 0.01) compared to normal group; compared with the model group, the aristolochic acid derivative I, II, III, IV, V and the VI group rat chest effusion amount and the leucocyte migration are obviously reduced ## P < 0.01), thus demonstrating that the aristolochic acid derivatives of the present invention have remarkable effectsIs an anti-inflammatory effect of (a); and the anti-inflammatory effect is obviously better than that of 100mg/kg aspirin at the dosage of 50mg/kg §§ P < 0.01). Meanwhile, compared with the raw material aristolochic acid compound synthesized by the aristolochic acid derivative, the anti-inflammatory effect of the aristolochic acid I and the aristolochic acid II synthesized by taking the aristolochic acid I as the raw material is obviously stronger than that of aristolochic acid I # ++ P < 0.01); similarly, the anti-inflammatory effects of aristolochic acid III and IV are significantly stronger than that of aristolochic acid Ia # ++ P < 0.01), the anti-inflammatory effect of aristolochic acid V and VI is obviously stronger than that of aristolochic acid II # ++ P < 0.01). Since toxicity of aristolochic acid compounds is closely related to the structure of m-nitrocarboxylic acid contained in the aristolochic acid compounds, the structure of aristolochic acid derivatives does not contain the structure of m-nitrocarboxylic acid of aristolochic acid compounds, thereby showing that: the aristolochic acid derivatives I-VI have anti-inflammatory activity obviously stronger than that of the aristolochic acid I, ia and II which are synthesized as starting materials, have obviously reduced toxicity, can be used for preparing anti-inflammatory medicaments, and have good application and development prospects.
The experimental results and analysis of examples 3 and 4 in summary show that: by examining the effect of aristolochic acid derivatives I, II, III, IV, V and VI on the swelling of the rat feet caused by carrageenan and on the amount of pleurisy pleural effusions and leukocyte migration of the rats caused by carrageenan, the results showed that: the aristolochic acid derivatives I, II, III, IV, V and VI can obviously inhibit the foot swelling of rats caused by carrageenan, and can also obviously reduce the pleural effusion amount and leukocyte migration of the rats caused by carrageenan, so that the aristolochic acid derivatives I, II, III, IV, V and VI have obvious anti-inflammatory effect; meanwhile, the anti-inflammatory activity of the aristolochic acid derivatives I-VI is obviously stronger than that of the aristolochic acid I, ia and II which are synthesized by the aristolochic acid derivatives, and the toxicity of the aristolochic acid derivatives is obviously reduced; in addition, the anti-inflammatory activity of the medicine is obviously superior to that of the positive control medicine aspirin. This demonstrates that: the aristolochic acid derivatives I, II, III, IV, V and VI have remarkable anti-inflammatory effect and low toxicity, can be used for preparing anti-inflammatory medicaments, and have good application and development prospects.
Claims (1)
1. An application of aristolochic acid derivatives in preparing anti-inflammatory drugs, which is characterized in that: the molecular structural formula of the aristolochic acid derivative is shown as formula one:
in the formula I, R 1 Is methoxy, hydroxy or hydrogen, R 2 Is chlorine or bromine; when R is 1 Is methoxy, R 2 In the case of chlorine, the first formula is aristolochic acid derivative I; when R is 1 Is methoxy, R 2 In the case of bromine, the first formula is aristolochic acid derivative II; when R is 1 Is hydroxy, R 2 In the case of chlorine, the first formula is aristolochic acid derivative III; when R is 1 Is hydroxy, R 2 In the case of bromine, the formula I is aristolochic acid derivative IV; when R is 1 Is hydrogen, R 2 In the case of chlorine, the first formula is aristolochic acid derivative V; when R is 1 Is hydrogen, R 2 In the case of bromine, the first formula is aristolochic acid derivative VI.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4835178A (en) * | 1985-08-28 | 1989-05-30 | Dr. Madaus & Co. | Methylendioxyphenathrene and stilben derivatives, process for the preparation thereof, pharmaceutical compositions using these, and therapeutic applications |
| CN103989670A (en) * | 2013-02-20 | 2014-08-20 | 孔徐生 | Application of aristolochic acid in preparation of drugs treating rheumatoid arthritis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4835178A (en) * | 1985-08-28 | 1989-05-30 | Dr. Madaus & Co. | Methylendioxyphenathrene and stilben derivatives, process for the preparation thereof, pharmaceutical compositions using these, and therapeutic applications |
| CN103989670A (en) * | 2013-02-20 | 2014-08-20 | 孔徐生 | Application of aristolochic acid in preparation of drugs treating rheumatoid arthritis |
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| Aristolochic acid and its derivatives as inhibitors of snake venom Lamino acid oxidase;Payel Bhattacharjee等;《Toxicon》;第138卷;第4页方案2、摘要、第2页右栏第1段 * |
| Payel Bhattacharjee等.Aristolochic acid and its derivatives as inhibitors of snake venom Lamino acid oxidase.《Toxicon》.2017,第138卷第4页方案2、摘要、第2页右栏第1段. * |
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