CN105884720A - Buspirone hydrochloride pharmaceutical composition and medical application thereof - Google Patents
Buspirone hydrochloride pharmaceutical composition and medical application thereof Download PDFInfo
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- CN105884720A CN105884720A CN201610260256.5A CN201610260256A CN105884720A CN 105884720 A CN105884720 A CN 105884720A CN 201610260256 A CN201610260256 A CN 201610260256A CN 105884720 A CN105884720 A CN 105884720A
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- compound
- buspirone hydrochloride
- pharmaceutical composition
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- extract
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- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960001768 buspirone hydrochloride Drugs 0.000 title claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 201000004595 synovitis Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 23
- 238000010828 elution Methods 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000284 extract Substances 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
- 239000007788 liquid Substances 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 7
- 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
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- -1 electuary Substances 0.000 claims description 3
- 239000012259 ether extract Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 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
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002027 dichloromethane extract Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 210000002437 synoviocyte Anatomy 0.000 abstract description 8
- 229930014626 natural product Natural products 0.000 abstract description 5
- 230000022131 cell cycle Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 230000009916 joint effect Effects 0.000 abstract 1
- 230000035755 proliferation Effects 0.000 abstract 1
- 230000001427 coherent effect Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 230000010190 G1 phase Effects 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000018199 S phase Effects 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
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 210000001258 synovial membrane Anatomy 0.000 description 4
- 102000002734 Collagen Type VI Human genes 0.000 description 3
- 108010043741 Collagen Type VI Proteins 0.000 description 3
- 208000009386 Experimental Arthritis Diseases 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 3
- 210000000629 knee joint Anatomy 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000005100 correlation spectroscopy Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- IBMAYSYTZAVZPY-QDMKHBRRSA-N germacrane Chemical group CC(C)[C@H]1CC[C@@H](C)CCC[C@@H](C)CC1 IBMAYSYTZAVZPY-QDMKHBRRSA-N 0.000 description 2
- 238000001052 heteronuclear multiple bond coherence spectrum 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
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000010829 isocratic elution Methods 0.000 description 2
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005160 1H NMR 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
- 208000019901 Anxiety disease 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
- 241000521257 Hydrops Species 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- YMWBTMBPEHUMBA-FAKHFBMMSA-N [(3r,3as,4s,8as)-3-hydroxy-6,8a-dimethyl-8-oxo-3-propan-2-yl-2,3a,4,5-tetrahydro-1h-azulen-4-yl] (e)-2-methylbut-2-enoate Chemical compound C\C=C(/C)C(=O)O[C@H]1CC(C)=CC(=O)[C@@]2(C)CC[C@@](O)(C(C)C)[C@H]12 YMWBTMBPEHUMBA-FAKHFBMMSA-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
- 230000003213 activating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry 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
- 238000000556 factor analysis Methods 0.000 description 1
- 210000000454 fifth toe Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 229930001431 germacrane Natural products 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 230000004660 morphological change 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
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical group 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001226 toe joint Anatomy 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a buspirone hydrochloride pharmaceutical composition and medical application thereof. The buspirone hydrochloride pharmaceutical composition contains buspirone hydrochloride and a natural product compound (I) novel in structure separated from dry rhizomes of Rhizoma Anemarrhenae. When the buspirone hydrochloride and the compound (I) act jointly, synoviocytes can stagnate in a cell cycle G1, so that synoviocyte proliferation is inhibited and synovitis is treated; the treatment effect of the buspirone hydrochloride and the compound (I) in joint action is superior to independent action of the buspirone hydrochloride or the compound (I). The buspirone hydrochloride pharmaceutical composition comprising the buspirone hydrochloride and the compound (I) can be developed as a drug for treating the synovitis. Compared with the prior art, the buspirone hydrochloride pharmaceutical composition has outstanding substantial characteristics and makes remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of buspirone hydrochloride, be specifically related to the medicine of buspirone hydrochloride
Compositions and medical usage thereof.
Background technology
Buspirone hydrochloride sheet is a kind of novel anxiolytic thing, and it is mainly subject to by serotonin (5-HT) 1A in activating brain
Body and change anxiety.
Gonarthromeningitis is a kind of sterile type inflammation, causes due to sprain of knee joint and multiple intraarticular damage.Synovial membrane
Dysfunction joint fluid can be caused cannot normally to generate and absorb, knee joint will produce hydrops.The morphologic change of synovial membrane also can
Invasion and attack knee cartilage, treatment can cause knee joint osseous arthritis not in time, there is the biggest crisis that disables.
Up to now, there is not yet the dependency report of buspirone hydrochloride and pharmaceutical composition thereof and synovitis.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of buspirone hydrochloride, containing hydrochloric acid fourth spiral shell in this pharmaceutical composition
Cyclic ketones and the natural product of a kind of novel structure, buspirone hydrochloride and this natural product can be with Synergistic treatment synovitis.
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 buspirone hydrochloride, including buspirone hydrochloride, compound as claimed in claim 1 (I)
Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses
Solve agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: the dry rhizome of the Rhizoma Anemarrhenae is pulverized by (a), uses
75～85% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturated successively
N-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then with 12 cylinders of 70% ethanol elution
Long-pending, collect 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution is dense
Contracting thing purification on normal-phase silica gel separates, and obtains with the methylene chloride-methanol gradient elution that volume ratio is 85:1,45:1,25:1 and 15:1 successively
To 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1,15:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 1:1；Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects 10～16 column volumes and washes
De-liquid, eluent is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 80% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment synovitis.
The application in the medicine of preparation treatment synovitis of the pharmaceutical composition of above-mentioned buspirone hydrochloride.
Advantages of the present invention:
Containing buspirone hydrochloride and a kind of dry rhizome from the Rhizoma Anemarrhenae in the pharmaceutical composition of the buspirone hydrochloride that the present invention provides
When the natural product of the novel structure of middle isolated, buspirone hydrochloride and this natural product independent role, synovitis is had
Therapeutical effect；During the two synergy, the therapeutic effect of synovitis is improved further, the medicine for the treatment of synovitis can be developed into
Thing.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 scope with this.To the greatest extent
The present invention is explained in detail by pipe with reference to preferred embodiment, it will be understood by those within the art that, can be to the present invention
Technical scheme modify 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 rhizome (2kg) of the Rhizoma Anemarrhenae is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux,
United extraction liquid, is concentrated into without alcohol taste (3L), successively with 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-butanol extraction
Thing；B acetic acid ethyl ester extract D101 type macroporous resin remove impurity in () step (a), first with 8 posts of 25% ethanol elution
Volume, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；
In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 85:1 (10 column volumes),
45:1 (8 column volumes), 25:1 (10 column volumes) and the methylene chloride-methanol gradient elution of 15:1 (8 column volumes)
Obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1 (10 by volume ratio successively
Individual column volume), the methylene chloride-methanol gradient elution of 15:1 (8 column volumes) and 1:1 (6 column volumes) obtain 3 groups
Point；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and is 72% by concentration expressed in percentage by volume
Methanol aqueous solution isocratic elution, collect 10～16 column volume eluents, eluent is concentrated under reduced pressure to give compound (I)
(260mg, HPLC normalization purity is more than 98%).
Structural identification: colourless crystallization, HR-ESIMS shows [M+H]+For m/z 335.2174, molecule can be obtained in conjunction with nuclear-magnetism feature
Formula is C20H30O4, degree of unsaturation is 6.Hydrogen nuclear magnetic resonance modal data δH(ppm, pyridine-d5, 500MHz): H-1 (6.04,
Dd, J=6.7,12.1Hz), H-2 (6.52, dd, J=12.1,9.5Hz), H-3 (7.13, d, J=9.5Hz), H-5a
(3.23, d, J=15.6Hz), H-5b (2.98, dd, J=15.6,9.3Hz), H-6 (5.06, dd, J=9.3,1.4Hz),
H-7 (1.87, m), H-8 (1.53, m), H-9a (2.02, m), H-9b (1.61, m), H-10 (1.96, m),
H-11 (1.77, m), H-12 (0.85, d, J=5.9Hz), H-13 (1.13, d, J=6.8Hz), H-14 (1.20, d,
J=6.8Hz), H-2 ' (2.73, m), H-3 ' (4.25, m), H-4 ' (1.33, d, J=6.1Hz), H-5 ' (1.18, d,
J=7.4Hz)；Carbon-13 nmr spectra data δC(ppm, pyridine-d5, 125MHz): 133.2 (CH, 1-C), 127.4
(CH, 2-C) 135.3 (CH, 3-C), 122.5 (C, 4-C), 28.3 (CH2, 5-C), 77.4 (CH, 6-C),
52.7 (CH, 7-C), 27.7 (CH, 8-C), 35.2 (CH2, 9-C), 42.8 (CH, 10-C), 26.4 (CH,
11-C), 22.1 (CH3, 12-C), 23.8 (CH3, 13-C), 18.4 (CH3, 14-C), 171.2 (C, 15-C),
209.4 (C, 1 '-C), 48.7 (CH, 2 '-C), 70.3 (CH, 3 '-C), 22.0 (CH3, 4 '-C), 13.7 (CH3,
5’-C).1756cm in infrared spectrum-1236nm absorption band during absorption band and UV compose shows that this compound contains α, β-no
Saturated lactone structure, the 3353cm in infrared spectrum-1、1715cm-1With 1624cm-1Absorption band show structure exists hydroxyl,
Ketone group and α, β-unsaturated conjugated system.13C-NMR, DEPT and hsqc spectrum show 20 carbon signals, including five
Methyl, two methylene, ten methines (two company's oxygen carbon and three alkene carbon), and three quaternary carbon (two carbonyl carbon
With an alkene carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is twin nuclei.1H-NMR composes combination
Hsqc spectrum shows five methyl proton signal δH0.85 (3H, d, J=5.9Hz), 1.13 (3H, d, J=6.8Hz), 1.20
(3H, d, J=6.8Hz), 1.33 (3H, d, J=6.1Hz), 1.18 (3H, d, J=7.4Hz), three conjugated alkenes
Proton signal δH6.04 (1H, dd, J=6.7,12.1Hz), 6.52 (1H, dd, J=12.1,9.5Hz) with 7.13 (1H,
D, J=9.5Hz), two company oxygen methine proton signal δH5.06 (1H, dd, J=9.3,1.4Hz) and 4.25 (1H, m).1H-1There is H-1/H-2/H-3, H in H COSY spectrum2-5/H-6/H-7/H-8/H2-9/H-10、H-7/H-11/H3-12、H-11/H3-13
And H-8/H3-14 coherent signals, H-2, H of display in composing in conjunction with HMBC2-9 and H-10 and C-1, H-2, H2-5 and
H-6 Yu C-4 coherent signal can build germacrane sesquiterpene skeleton.1H-1H in H COSY spectrum3-5’/H-2’/H-3’/H3-4’
During coherent signal and HMBC compose, H-2 ' and C-1 ', C-3 ' and C-5 ' and H-3 ' and C-2 ' and C-4 ' coherent signal can build
O-3 '-O-hydroxyl-2 '-espeleton substrate section, HMBC spectrum H-10 and C-1 ' coherent signal shows this fragment and germacrane simultaneously
The position that type sesquiterpene skeleton connects.Additionally HMBC composes H-3, H2-5 and H-6 Yu C-15 coherent signal hint C-6 and C-15
Between exist a lactonic ring structure.In NOESY spectrum, it is assumed that H-8 is beta comfiguration, then H-8 Yu H-10 coherent signal table
Bright H-10 is also beta comfiguration, therefore, O-3 '-O-hydroxyl-2 '-espeleton base should be α configuration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC
Spectrum and NOESY compose, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, three-dimensional structure
Type 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
Select male Wistar rat (Tongji Medical College, Huazhong Science and Technology Univ.'s animal experimental center provides), about body weight 120g.
1.2 reagent and sample
Buspirone hydrochloride 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 Olympic Pasteur's inverted fluorescence microscope (CKX41 type),
U.S.'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 by the preparation of Collagen-induced Arthritis (CIA) rat model
(the final concentration of 2g/L of II Collagen Type VI), 4 DEG C overnight.Then dropped in cold equivalance incomplete Freund's adjuvant the most newborn
Change.By this Emulsion every rat intradermal injection 0.5ml, point 4, back and tail heel 1 point.Same method booster injection after 7 days
1 time.Every day every rat articular is marked according to joint swelling index marking system, be divided into 0～4 point: 0 point, without red and swollen；
1 point, little toe redness and swelling of joints；2 points of toe joints and pedal swelling；3 points, the sufficient pawl swelling below ankle joint；4 points, including ankle
Whole foot pawl swelling within 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 tissue under aseptic condition,
Cut into about 1mm3Fragment, the II Collagenase Type 37 DEG C digestion 6～7h of 0.5mg/ml, 1200r/m is centrifuged 8min, adds 1640
Culture fluid [is divided into 5 groups: model control group, positive controls, buspirone hydrochloride group, compound (I) group, hydrochloric acid fourth
Spirocyclic ketone and compound (I) compositions group, often organize all containing 10% hyclone；Positive controls is possibly together with 1.0 × 10-6mol/L
Methotrexate, buspirone hydrochloride group is possibly together with 2.0 × 10-6The buspirone hydrochloride of mol/L, compound (I) group also contains
Have 2.0 × 10-6The compound (I) of mol/L, buspirone hydrochloride and compound (I) compositions group are possibly together with 1.0 × 10-6mol/L
Buspirone hydrochloride and 1.0 × 10-6The compound (I) of mol/L], it is placed in 37 DEG C of 5%CO2Cultivate in incubator, digestion
Pass on, 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
Fix overnight；With PBS, its concentration is adjusted to 5 × 106Individual/ml, then takes 400 μ l, adds RAase 20ml, 37 DEG C of water-bath 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 carry out one factor analysis of variance 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, difference
There is statistical significance (P < 0.05)；Buspirone hydrochloride and compound (I) compositions group G1 phase substantially increase (P < 0.01),
The S phase significantly reduces (P < 0.01)；Buspirone hydrochloride group and compound (I) group G1 phase increase (P < 0.05), and the S phase subtracts
Few (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 | 65.50±2.26 | 12.82±2.81 |
| Positive controls | 80.24±2.33 | 3.52±0.73 |
| Buspirone hydrochloride group | 78.15±3.05 | 3.88±0.74 |
| Compound (I) group | 79.24±2.49 | 3.60±0.78 |
| Buspirone hydrochloride and compound (I) compositions group | 83.95±5.02 | 1.34±0.58 |
In rheumatoid arthritis (RA) 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 synovial membrane
The main component of tissue, take part in articular cartilage damage and periarticular bone destruction, so it is thin to suppress into fiber-like synovial membrane
Born of the same parents' propagation is one of means for the treatment of RA.
The above results shows, during compound (I) synergy that buspirone hydrochloride and the present invention provide, can make synovial cell
It is stuck in the cell cycle G1 phase, thus suppresses synovial cell proliferation, treat synovitis；Therapeutic effect is better than buspirone hydrochloride
Or compound (I) independent role.Buspirone hydrochloride and compound (I) compositions can be developed into the medicine for the treatment of synovitis.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a buspirone hydrochloride, it is characterised in that: include buspirone hydrochloride, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of buspirone hydrochloride the most according to claim 2, it is characterised in that: pharmaceutically acceptable
Carrier include diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant,
Absorption carrier or lubricant.
The pharmaceutical composition of buspirone hydrochloride the most according to claim 2, it is characterised in that: described dosage form include tablet,
Capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution
Agent, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry rhizome of the Rhizoma Anemarrhenae is pulverized, with 75～85% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses stone successively
Oil ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol
Extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then
With 12 column volumes of 70% ethanol elution, collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；(c) step
Suddenly in (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, and is 85:1,45:1,25:1 and 15:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel,
3 components are obtained successively with the methylene chloride-methanol gradient elution that volume ratio is 20:1,15:1 and 1:1；(e) step (d)
The reverse phase silica gel that middle component 2 is bonded by octadecylsilane separates, and washes with the methanol aqueous solution that concentration expressed in percentage by volume is 72% is isocratic
De-, collect 10～16 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) 80% second
Alcohol circumfluence distillation, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is D101
Type macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in the medicine of preparation treatment synovitis of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described buspirone hydrochloride of claim 2～4 is in the medicine of preparation treatment synovitis
Application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105713065A (en) * | 2016-04-23 | 2016-06-29 | 何淑琼 | Azathioprine pharmaceutical composition and medical application thereof |
| CN105777672A (en) * | 2016-03-16 | 2016-07-20 | 郭根松 | Medical composition of amlodipine besylate and ventricular remodeling effect of medical composition |
| CN106279344A (en) * | 2016-08-14 | 2017-01-04 | 吴芊葭 | A kind of native compound separated from Radix Saposhnikoviae and preparation method thereof, medical applications |
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| CN105753878A (en) * | 2016-03-31 | 2016-07-13 | 河南省洛正制药厂 | Quality control method for synovitis tablets |
| CN105859659A (en) * | 2016-04-27 | 2016-08-17 | 周飞燕 | Medicine composition of buspirone hydrochloride and medical application thereof |
| 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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| CN1909911A (en) * | 2003-10-01 | 2007-02-07 | 浩鼎生技公司 | Treatment of a condition in a mammal with adminisration of aminosugar and uses thereof |
| CN105753878A (en) * | 2016-03-31 | 2016-07-13 | 河南省洛正制药厂 | Quality control method for synovitis tablets |
| CN105859659A (en) * | 2016-04-27 | 2016-08-17 | 周飞燕 | Medicine composition of buspirone hydrochloride and medical application thereof |
| 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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| CN105777672A (en) * | 2016-03-16 | 2016-07-20 | 郭根松 | Medical composition of amlodipine besylate and ventricular remodeling effect of medical composition |
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