CN106109461A - The pharmaceutical composition of bezafibrate and the application in rheumatoid arthritis thereof - Google Patents
The pharmaceutical composition of bezafibrate and the application in rheumatoid arthritis thereof Download PDFInfo
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- CN106109461A CN106109461A CN201610462507.8A CN201610462507A CN106109461A CN 106109461 A CN106109461 A CN 106109461A CN 201610462507 A CN201610462507 A CN 201610462507A CN 106109461 A CN106109461 A CN 106109461A
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- Prior art keywords
- bezafibrate
- compound
- rheumatoid arthritis
- pharmaceutical composition
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- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical group C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960000516 bezafibrate Drugs 0.000 title claims abstract description 36
- 206010039073 rheumatoid arthritis Diseases 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- 238000010828 elution Methods 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 8
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000012259 ether extract Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 238000010829 isocratic elution Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003463 adsorbent Substances 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- RZJRJXONCZWCBN-UHFFFAOYSA-N octadecane Chemical compound CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940038384 octadecane Drugs 0.000 claims 1
- 229910000077 silane Inorganic materials 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 210000002437 synoviocyte Anatomy 0.000 abstract description 8
- 230000010190 G1 phase Effects 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- 229930014626 natural product Natural products 0.000 abstract description 5
- 241000628997 Flos Species 0.000 abstract description 4
- 230000022131 cell cycle Effects 0.000 abstract description 3
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 230000018199 S phase Effects 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000002734 Collagen Type VI Human genes 0.000 description 3
- 108010043741 Collagen Type VI Proteins 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- -1 bezafibrate Compound Chemical class 0.000 description 3
- 230000001427 coherent effect Effects 0.000 description 3
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 229930004725 sesquiterpene Natural products 0.000 description 3
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000000544 articulatio talocruralis Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 102000019267 Hepatic lipases Human genes 0.000 description 1
- 108050006747 Hepatic lipases Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102000043296 Lipoprotein lipases Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- OBOXTJCIIVUZEN-UHFFFAOYSA-N [C].[O] Chemical compound [C].[O] OBOXTJCIIVUZEN-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 210000000454 fifth toe Anatomy 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000457 gamma-lactone group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 235000019626 lipase activity Nutrition 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 210000003684 theca cell Anatomy 0.000 description 1
- 210000001226 toe joint Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses the pharmaceutical composition of bezafibrate and the application in rheumatoid arthritis thereof, containing bezafibrate and a kind of natural product compound (I) of the novel structure of isolated from the dry flower of Flos Caryophylli in the pharmaceutical composition of the bezafibrate that the present invention provides, during compound (I) synergy that bezafibrate and the present invention provide, synovial cell can be made to be stuck in the cell cycle G1 phase, thus suppress synovial cell proliferation, treat rheumatoid arthritis；Therapeutic effect is better than bezafibrate or compound (I) independent role effect.Bezafibrate can develop into the medicine for the treatment of rheumatoid arthritis with compound (I) compositions, compared with prior art has prominent substantive distinguishing features and significantly progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of bezafibrate, be specifically related to the medicine group of bezafibrate
Compound and the application in rheumatoid arthritis thereof.
Background technology
Bezafibrate belongs to fibrate, appears on the market first the seventies in eighties of last century, worldwide have passed through big
Amount clinical practice test, and large scale system clinical trial, be all proved and can reduce triglyceride, increasing high density significantly
Lipoprotein levels, delays the progress of coronary atherosclerosis, reduces the danger that coronary event occurs.Its blood fat reducing
Effect has two kinds of mechanism, and one is that this product can improve lipoprotein lipase and hepatic lipase activity, promotes the decomposition of very low density lipoprotein (VLDL)
Metabolism, makes the level of triglyceride in blood plasma reduce；Next to that the secretion that this product makes very low density lipoprotein (VLDL) reduces.This product reduces
In blood plasma, the effect of triglyceride is eager to excel than the effect reducing cholesterol, also makes high density lipoprotein raise, and this product also may be used in addition
Reduce Fibrinogen.Existing research does not finds that this product has carcinogenic, mutagenic action.
Further investigation to bezafibrate in the recent period shows, bezafibrate has unique effect, is possible not only to improve fat
Metabolism, prior also have improvement to carbohydrate metabolism.Foreign study confirms, long-term taking bezafibrate, to prevention diabetes, improves
Insulin sensitivity has effect, can be used for the disorders of lipid metabolism that diabetics causes, and this point is substantially better than other Bei Te
Quasi drugs.
In rheumatoid arthritis joint injury and reconstructed tissue, synovial cell is target cell, also by number of ways
Becoming participant, the change of its function plays vital effect in the process of disease, and fibroblast-like synoviocyte is sliding
The main component of membrane tissue, take part in articular cartilage damage and periarticular bone destruction, so it is sliding to suppress into fiber-like
Theca cell propagation is one of means for the treatment of rheumatoid arthritis.
Have not yet to see the dependency report of bezafibrate and treatment rheumatoid arthritis.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of bezafibrate, this pharmaceutical composition pricks shellfish containing benzene
The natural product of special and a kind of novel structure, bezafibrate and this natural product can be with Synergistic treatment rheumatoid arthritiss.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of bezafibrate, including bezafibrate, compound as above (I) and the most permissible
The carrier accepted.
The preparation method of compound (I) as above, comprises following operating procedure: (a) is by the dry flower powder of Flos Caryophylli
Broken, with 70～90% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water successively
Saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step (a)
Middle n-butyl alcohol takes thing macroporous resin remove impurity, first with 12 column volumes of 20% ethanol elution, then with 15 posts of 80% ethanol elution
Volume, collects 80% eluent, and concentrating under reduced pressure obtains 80% ethanol elution concentrate；C in () step (b), 80% ethanol elution concentrates
Thing purification on normal-phase silica gel separates, and obtains with the methylene chloride-methanol gradient elution that volume ratio is 80:1,40:1,20:1 and 10:1 successively
To 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 25:1,20:1 and 15:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-phase
Silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 65%, collects 13～17 column volume eluents, washes
De-liquid is concentrated under reduced pressure to give compound (I).
Further, step (a) is extracted with 80% alcohol heat reflux, united extraction liquid.
Further, described macroporous resin is D101 type macroporous adsorbent resin.
The compound (I) as above application in the medicine of preparation treatment rheumatoid arthritis.
The application in the medicine of preparation treatment rheumatoid arthritis of the pharmaceutical composition of bezafibrate as above.
Advantages of the present invention:
Containing bezafibrate and a kind of dry flower from Flos Caryophylli in the pharmaceutical composition of the bezafibrate that the present invention provides
When the natural product of the novel structure of middle isolated, bezafibrate and this natural product independent role, there is treatment rheumatoid
Property arthritis effect；During the two synergy, treatment rheumatoid arthritis effect improves further, can develop into treatment class
The medicine of rheumatic arthritis.The present invention compared with prior art has prominent substantive distinguishing features and significantly progress.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, can be right
Technical scheme is modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: the dry flower (2kg) of Flos Caryophylli is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux,
United extraction liquid, is concentrated into without alcohol taste (3L), successively by petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated
N-butyl alcohol (3L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step
A acetic acid ethyl ester extract D101 type macroporous resin remove impurity in (), first with 12 column volumes of 20% ethanol elution, then uses 80% second
15 column volumes of alcohol eluting, collect 80% eluent, and concentrating under reduced pressure obtains 80% ethanol elution concentrate；In (c) step (b) 80%
Ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 80:1 (10 column volumes), 40:1 (8 column volumes),
The methylene chloride-methanol gradient elution of 20:1 (8 column volumes) and 10:1 (9 column volumes) obtains 4 components；(d) step (c)
Middle component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1 (7 column volumes), 20:1 (8 column volumes) and
The methylene chloride-methanol gradient elution of 15:1 (7 column volumes) obtains 3 components；E in () step (d), component 2 uses octadecyl
The reverse phase silica gel of silane group separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 65%, collects 13～17
Column volume eluent, eluent is concentrated under reduced pressure to give compound (I) (644mg, HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 293.1346, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C16H20O4, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-3 (3.24, m), H-4a
(3.12, dd, J=14.8,13.3Hz), H-4b (2.50, d, J=14.3Hz), H-6 (2.75, qd, J=7.5,2.3Hz), H-7
(2.82, d, J=2.3Hz), H-10a (2.92, d, J=15.7Hz), H-10b (2.38, d, J=15.7Hz), H-12 (5.25,
D, J=5.3Hz), and H-13 (1.18, d, J=7.2Hz), H-14 (0.97, s), H-15 (1.15, s), 12-OMe (3.48, s)；Core
Magnetic resonance carbon modal data δC(ppm, CDCl3, 125MHz): 166.4 (C, 1-C), 128.3 (C, 2-C) 42.1 (CH, 3-C), 41.5
(CH2, 4-C), 212.4 (C, 5-C) 48.7 (CH, 6-C), 47.8 (CH, 7-C), 215.6 (C, 8-C), 48.6 (C, 9-C), 29.5
(CH2, 10-C), 169.7 (C, 11-C), 103.5 (CH, 12-C), 13.2 (CH3, 13-C), 20.4 (CH3, 14-C), 26.8
(CH3, 15-C), 56.7 (CH3, 12-OMe).1756cm in infrared spectrum-1Absorption band and the 236nm absorption band table in UV spectrum
This compound bright contains α, β-unsaturation gamma lactone structure, and passes through13δ in C-NMR spectrumC163.4,124.6 and 174.3
Carbon signal is verified.13C-NMR, DEPT and hsqc spectrum show 16 carbon signals, including four methyl (methoxy
Base), two methylene, four methines (company's oxygen carbon), and six quaternary carbons (two alkene carbon and three carbonyl carbon), with
In conjunction with insatiable hunger sum, upper functional structure shows that this compound is tricyclic structure.1H-NMR spectrum combines hsqc spectrum and shows three methyl
Proton signal δH1.18 (3H, d, J=7.2Hz), 0.97 (3H, s), 1.15 (3H, s), a methoxyl group proton signal δH 3.48
(3H, s), two groups of methene proton signal δH3.12 (2H, dd, J=14.8,13.3Hz) and 2.50 (1H, d, J=14.3Hz),
2.92 (1H, d, J=15.7Hz) and 2.38 (1H, d, J=15.7Hz), three methine proton signal δH3.24 (1H, m),
2.75 (1H, qd, J=7.5,2.3Hz), 2.82 (1H, d, J=2.3Hz), a company oxygen methine proton signal δH 5.25
(1H, d, J=5.3Hz).1H-1There is H-12/H-3/H in H COSY spectrum2-4, H-6/H-7 and H-6/H3-13 coherent signals, with
Time HMBC spectrum in show H2-4 with C-2 and C-5, H-6 and C-1 and C-5, H-7 and C-10, H2-10 with C-1 and C-14, H-12 with
C-2 and C-11, H3-13 with C-5 and C-7, H3-14 with C-8, C-9 and C-10, H3-15 with C-9 and C-10,12-OMe and C-12 phase
OFF signal, can build the connected mode of this compound, and above-mentioned spectral data table by the relevant information in above-mentioned H NMR spectroscopy
This compound bright is tremulane type sesquiterpene.In HMBC spectrum, proton signal δHThe dependency of 3.48 and C-12 shows C-12 position
It is connected with a methoxyl group；H2-4, H-6 and H3-13 and C-5 (δC212.4) dependency shows that C-5 is carbonyl；H3-14 and C-8 (δC215.6) dependency shows that C-8 is ketone carbonyl.In tremulane type sesquiterpene, H-6 Yu H-7 position is generally beta comfiguration, H3-
The 14 usual places of configuration are β positions, H3-15 are configured as α position, H-7 and H embodied in the NOE of this compound tests3-14 coherent signals
Meet the configuration relationship of tremulane type sesquiterpene.In NOESY spectrum, H-3 and H3The coherent signal hint H-3 of-13 is α configuration,
The NOE dependency of H-3 Yu H-12 and both coupling constants show that H-12 is α configuration, then 12-OMe is beta comfiguration.Comprehensive hydrogen
Spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine the following institute of this compound
Showing, spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1. materials and methods
1.1 animal
Selecting male Wistar rat (Tongji Medical College, Huazhong Science and Technology Univ.'s animal experimental center provides), body weight 120g is left
Right.
1.2 reagent and sample
Bezafibrate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Ⅱ
Collagen Type VI (Sigma Co., USA), incomplete Freund's adjuvant (Sigma company), RPMI-1640 (GIBCO company).
1.3 instrument
U.S. nurie CO2Incubator (NU4750 type), Japan's Olympic Pasteur's inverted fluorescence microscope (CKX41 type), U.S.
State's Beckman Coulter flow cytometer (EPICSXL type), Japan's transmission electron microscope (Hitachi's H-7500 type).
1.4 rat model preparations and cell packet
II Collagen Type VI is dissolved in the glacial acetic acid of 0.1mmol/L (the final concentration of II Collagen Type VI by the preparation of CIA rat model
For 2g/L), 4 DEG C are overnight.Then dropped in cold equivalance incomplete Freund's adjuvant fully emulsified.This Emulsion every is big
Mus intradermal injection 0.5ml, point 4, back and tail heel 1 point.Same method booster injection 1 time after 7 days.Refer to according to arthroncus
Every rat articular is marked every day by number marking system, is divided into 0～4 point: 0 point, without red and swollen；1 point, little toe redness and swelling of joints；2
Divide toe joint and pedal swelling；3 points, the sufficient pawl swelling below ankle joint；4 points, including the whole foot pawl swelling within ankle joint.
The exponential accumulation in each joint is scored, is the arthritis index of every rat.
The In vitro culture of synovial cell causes after inflammation the 25th day, and the rat of morbidity is put to death in dislocation, obtains synovial membrane under aseptic condition
Tissue, cuts into about 1mm3Fragment, 0.5mg/ml II Collagenase Type 37 DEG C digestion 6～7h, 1200r/m is centrifuged 8min, adds
Enter RPMI-1640 [be divided into 5 groups: model control group, positive controls, bezafibrate group, compound (I) group, bezafibrate with
Compound (I) compositions group, often organizes all containing 10% hyclone；Positive controls is possibly together with 1.0 × 10-6The first ammonia butterfly of mol/L
Purine, bezafibrate group is possibly together with 2.0 × 10-6The bezafibrate of mol/L, compound (I) group is possibly together with 2.0 × 10-6Mol/L's
Compound (I), bezafibrate and compound (I) compositions group are possibly together with 1.0 × 10-6The bezafibrate of mol/L and 1.0 × 10- 6The compound (I) of mol/L], put 37 DEG C of 5%CO2Cultivating in incubator, had digestive transfer culture, with the 3rd～5 generation cells.
1.5 flow cytomery synovial cell's cycles
Collect cell, blow and beat into single cell suspension with PBS is resuspended, be added slowly in 5ml 75% ethanol of pre-cooling, 4
DEG C fixing overnight；With PBS, its concentration is adjusted to 5 × 106Individual/ml, then takes 400 μ l, adds RAase 20ml, 37 DEG C of water-baths
30min；Add PI 100 μ l, lucifuge dyeing 20min, 300 mesh nylon net filters, flow cytometer.
1.6 statistical method
Experimental data mean ± standard deviation (x ± s) represents, application SPSS18.0 version statistical software carries out single factor test variance
Analyze and t checks, statistically significant for difference with P ＜ 0.05.
2. experimental result
Flow cytometer periodicity analysis results shows, compares with model group, and the positive controls G1 phase increases, and the S phase reduces, poor
Different have statistical significance (P < 0.05)；Bezafibrate and compound (I) compositions group G1 phase substantially increase (P < 0.01), S phase
Significantly reduce (P < 0.01)；Bezafibrate group and compound (I) group G1 phase increase (P < 0.05), and the S phase reduces (P < 0.05).
The table 1 impact on CIA lymphocyte of adjurant arthritis rat cell cycle
| Group | The G1 phase (%) | The S phase (%) |
| Model control group | 64.50±2.26 | 13.82±2.81 |
| Positive controls | 79.24±2.33 | 4.52±0.73 |
| Bezafibrate group | 77.15±3.05 | 4.88±0.74 |
| Compound (I) group | 78.24±2.49 | 4.60±0.78 |
| Bezafibrate and compound (I) compositions group | 84.95±5.02 | 1.34±0.58 |
The above results shows, during compound (I) synergy that bezafibrate and the present invention provide, synovial cell can be made to stop
Stagnant in the cell cycle G1 phase, thus suppress synovial cell proliferation, treat rheumatoid arthritis；Therapeutic effect is better than bezafibrate
Or compound (I) independent role effect.Bezafibrate can develop into treatment rheumatoid arthritis with compound (I) compositions
Medicine.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (7)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a bezafibrate, it is characterised in that: include bezafibrate, chemical combination as claimed in claim 1
Thing (I) and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a) is by fourth
Fragrant dry flower is pulverized, and with 70～90% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses oil successively
Ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extraction
Take thing；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 12 column volumes of 20% ethanol elution, then with 80%
15 column volumes of ethanol elution, collect 80% eluent, and concentrating under reduced pressure obtains 80% ethanol elution concentrate；In (c) step (b)
80% ethanol elution concentrate purification on normal-phase silica gel separates, and is the dichloromethane of 80:1,40:1,20:1 and 10:1 by volume ratio successively
Alkane-methanol elution gradient obtains 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, use volume ratio successively
Methylene chloride-methanol gradient elution for 25:1,20:1 and 15:1 obtains 3 components；E in () step (d), component 2 uses octadecane
The reverse phase silica gel of base silane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 65%, collects 13～17
Individual column volume eluent, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 3 (I), it is characterised in that: step (a) is returned by 80% ethanol heat
Stream extracts, united extraction liquid.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described macroporous resin is D101 type
Macroporous adsorbent resin.
6. the application in the medicine of preparation treatment rheumatoid arthritis of the compound (I) described in claim 1.
7. the pharmaceutical composition of the bezafibrate described in claim 2 answering in the medicine of preparation treatment rheumatoid arthritis
With.
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| CN105884720A (en) * | 2016-04-23 | 2016-08-24 | 陈斌 | Buspirone hydrochloride pharmaceutical composition and medical application thereof |
| CN106117166A (en) * | 2016-06-23 | 2016-11-16 | 崔坤峰 | The pharmaceutical composition of amrinone and the application in hypertension therapeutic thereof |
| WO2017220051A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Benserazide hydrochloride pharmaceutical composition and medical use thereof for lowering blood sugar |
| WO2017220041A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Bezafibrate pharmaceutical composition and application thereof in rheumatoid arthritis |
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| CN114276364B (en) * | 2022-01-06 | 2024-01-26 | 中国科学院新疆理化技术研究所 | Sesquiterpenoids in Artemisia mongolica, and preparation method and application thereof |
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| CN106109461A (en) * | 2016-06-23 | 2016-11-16 | 崔坤峰 | The pharmaceutical composition of bezafibrate and the application in rheumatoid arthritis thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884720A (en) * | 2016-04-23 | 2016-08-24 | 陈斌 | Buspirone hydrochloride pharmaceutical composition and medical application thereof |
| CN106117166A (en) * | 2016-06-23 | 2016-11-16 | 崔坤峰 | The pharmaceutical composition of amrinone and the application in hypertension therapeutic thereof |
| WO2017220051A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Benserazide hydrochloride pharmaceutical composition and medical use thereof for lowering blood sugar |
| WO2017220041A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Bezafibrate pharmaceutical composition and application thereof in rheumatoid arthritis |
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