CN106309428A - Pharmaceutical composition of nateglinide and application of pharmaceutical composition of nateglinide in biological medicines - Google Patents
Pharmaceutical composition of nateglinide and application of pharmaceutical composition of nateglinide in biological medicines Download PDFInfo
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- CN106309428A CN106309428A CN201610695366.4A CN201610695366A CN106309428A CN 106309428 A CN106309428 A CN 106309428A CN 201610695366 A CN201610695366 A CN 201610695366A CN 106309428 A CN106309428 A CN 106309428A
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- Prior art keywords
- nateglinide
- pharmaceutical composition
- compound
- hyperthyroidism
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- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical group C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 title claims abstract description 43
- 229960000698 nateglinide Drugs 0.000 title claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 206010020850 Hyperthyroidism Diseases 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000010828 elution Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 6
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- -1 electuary Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 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
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000003463 adsorbent Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- 239000003937 drug carrier 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
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 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
- 238000010992 reflux Methods 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
- 239000003292 glue Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 229930014626 natural product Natural products 0.000 abstract description 4
- 210000002966 serum Anatomy 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000036760 body temperature Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 238000011552 rat model Methods 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000003127 radioimmunoassay Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 210000001685 thyroid gland Anatomy 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 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
- 230000009471 action Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- 125000001711 D-phenylalanine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- VGAJNILINWUWOP-UHFFFAOYSA-N Eudesmane Natural products COC(=O)C(=C)C1C(O)C2C(=O)CCC(O)C2(C)CC1OC(=O)C(=C)CO VGAJNILINWUWOP-UHFFFAOYSA-N 0.000 description 1
- 206010020674 Hypermetabolism Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- 241000408529 Libra Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 208000031971 Yin Deficiency Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000009529 body temperature measurement Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 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
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DYEQPYSFRWUNNV-APIJFGDWSA-N eudesmane Chemical compound C1CC[C@@H](C)[C@@H]2C[C@H](C(C)C)CC[C@]21C DYEQPYSFRWUNNV-APIJFGDWSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000457 gamma-lactone group Chemical group 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000009532 heart rate measurement Methods 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical group CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical compound CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000001896 rotating frame Overhauser effect spectroscopy Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229930009674 sesquiterpene lactone Natural products 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 208000005057 thyrotoxicosis Diseases 0.000 description 1
- 210000003462 vein Anatomy 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
- A61K31/33—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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a pharmaceutical composition of nateglinide and application of the pharmaceutical composition of nateglinide in biological medicines. The pharmaceutical composition of the nateglinide provided by the invention contains the nateglinide and a natural product compound (I) with novel structure, and when independently acting, the nateglinide and the compound (I) have treatment effect on hyperthyroidism; and when the nateglinide and the compound (I) act in a combined manner, the treatment effect of the nateglinide and the compound (I) to the hyperthyroidism are further improved, and therefore, the pharmaceutical composition of the nateglinide can be developed into a drug for treating the hyperthyroidism. Compared with the prior art, the pharmaceutical composition of the nateglinide has outstanding substantial characteristics and remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of Nateglinide, be specifically related to the medicine group of Nateglinide
Compound and the application in biological medicine thereof.
Background technology
Nateglinide is D-phenylalanine derivant, belongs to non-sulfonylurea blood sugar lowering, and its mechanism of action is the most logical
Crossing and combine with sulfonylureas receptor on B cell, retardance islet cells ATP sensitive potassium channel is open, causes cell membrane to go to pole
Change, cause calcium channel open, promote insulin secretion；It is a kind of novel blood sugar regulator used during user having meals, can effectively control blood after the meal
Sugar level, have rapid-action, action time is short, causes cardiovascular side effects and the feature such as hypoglycemic incidence is low.
Up to now, there is not yet the dependency report of Nateglinide and pharmaceutical composition thereof and hyperthyroidism.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of Nateglinide, containing Na Gelie in this pharmaceutical composition
How with the natural product of a kind of novel structure, Nateglinide and this natural product can Synergistic treatment hyperthyroidisms.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of pharmaceutical composition of Nateglinide, including Nateglinide, compound (I) and pharmaceutically acceptable carry
Body, is prepared as the dosage form needed；Described compound (I) has a following structural formula:
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, binding agent, wetting agent,
Disintegrating 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: Caulis Sinomenii is pulverized by (a), with 60～70% second
Alcohol circumfluence distillation, united extraction liquid, it is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butyl alcohol extraction
Take, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；N-butyl alcohol extract in (b) step (a)
Use macroporous resin remove impurity, first with 12 column volumes of 10% ethanol elution, then with 15 column volumes of 70% ethanol elution, collect 70%
Eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% ethanol elution concentrate purification on normal-phase silica gel in (c) step (b)
Separate, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 50:1,25:1,15:1 and 5:1 successively；(d)
In step (c), component 4 separates further by purification on normal-phase silica gel, is the methylene chloride-methanol of 10:1,5:1 and 2:1 by volume ratio successively
Gradient elution obtains 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and uses volume
Percentage concentration is the methanol aqueous solution isocratic elution of 70%, collects 7～13 column volume eluents, and eluent is concentrated under reduced pressure to give
Compound (I).
Further, in the preparation method of compound (I), described macroporous resin is AB-8 type macroporous adsorbent resin.
The application in the medicine of preparation treatment hyperthyroidism of the pharmaceutical composition of above-mentioned Nateglinide.
Advantages of the present invention: containing Nateglinide and a kind of structure in the pharmaceutical composition of the Nateglinide that the present invention provides
Novel natural product, when Nateglinide, compound (I) independent role, has therapeutic effect to hyperthyroidism；Those lattice
When how row are with compound (I) synergy, hyperthyroid therapeutic effect improved further, treatment can be developed into
The medicine of hyperthyroidism.
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.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, insults peaking purchased from Shanghai
Learning reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Caulis Sinomenii (2kg) is pulverized by (a), extracts (20L × 3 time) with 65% alcohol heat reflux, united extraction
Liquid, is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol
(4L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract AB-8 type macroporous resin remove impurity, first with 12 column volumes of 10% ethanol elution, then uses 70% ethanol elution
15 column volumes, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, successively with volume ratio be 50:1 (8 column volumes), 25:1 (8 column volumes), 15:1 (8
Column volume) and the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) obtain 4 components；Component 4 in (d) step (c)
Separate further by purification on normal-phase silica gel, successively with volume ratio be 10:1 (8 column volumes), 5:1 (10 column volumes) and 2:1 (5 posts
Volume) methylene chloride-methanol gradient elution obtain 3 components；E in () step (d), component 2 is bonded by octadecylsilane
Reverse phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collects 7～13 column volume eluting
Liquid, eluent is concentrated under reduced pressure to give compound (I) (purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+Na]+For m/z 285.1201, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C15H18O4, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, CD3OD, 500MHz): H-1 α (1.49, m), H-1 β
(1.23, m), H-2 α (2.78, m), H-2 β (2.91, m), H-5 (2.11, m), H-6 α (2.30, m), H-6 β (2.52, m), H-9
(5.24, s), H-13 (1.84, s), H-14 (1.12, s), H-15a (5.46, s), H-15b (5.31, s)；Carbon-13 nmr spectra number
According to δC(ppm, CD3OD, 125MHz): 36.7 (CH2, 1-C), 33.5 (CH2, 2-C), 198.1 (C, 3-C), 145.4 (C, 4-C),
47.1 (CH, 5-C), 26.2 (CH2, 6-C), 142.7 (C, 7-C), 143.0 (C, 8-C), 138.3 (CH, 9-C), 39.1 (C, 10-
C), 120.0 (C, 11-C), 173.1 (C, 12-C), 8.4 (CH3, 13-C), 16.1 (CH3, 14-C), 113.2 (CH2, 15-C).Red
External spectrum shows that this compound contains lactone carbonyl (1736cm-1) structure.1H and13C-NMR shows that this compound contains a α,
β-unsaturation gamma lactone structure [δC142.7 (C-7), 143.0 (C-8), 120.0 (C-11), 173.1 (C-12)], an ethylene
Ylmethyl [δH1.84 (3H, s, H-13)；δC8.4 (C-13)], a methyl proton signal [δH1.12 (3H, s, H-14)；δC16.1 (C-14)], an outer methene proton signal [δ of ringH5.46 (1H, s, H-15a) and 5.31 (1H, s, H-15b)；δC113.2 (C-15) and 145.4 (C-4)] and an olefinic methine proton signal [δH5.24 (1H, s, H-9)；δC143.0
(C-8) and 138.3 (C-9)].Syncaryon magnetic data information and high resolution mass spectrum information can be seen that this compound is typical case
Eudesmane type sesquiterpene lactone compound.Consulting literatures finds, this compound and known compound ent-3-
Hydroxyatractylenolide III has similar structure, by comparing discovery, noval chemical compound with this compound
In many a ketone carbonyl carbon signals and one group of double bond signal.The parsing that the HMBC of this compound is composed is found, H-1/C-
Dependency explanation additional ketone carbonyl in noval chemical compound between 3, H-2/C-3, H-5/C-3 is in C-3 position.With
Time, there is a double bond between coherent signal explanation C-8 and C-9 between H-9/C-8, H-14/C-9.Comprehensive hydrogen is composed, carbon is composed,
HMBC spectrum and ROESY compose, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, three-dimensional
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
The present embodiment uses thyroxin tablet rat molding method to prepare hyperthyroidism rat model, measures the rat heart
Rate, body temperature, body weight and serum T 3, the change of T4 level.Observe the therapeutical effect of medicine disease hyperfunction to thyroid function.
1, materials and methods
1.1 animal
SD rat 60, body weight 200 ± 20g, male and female half and half, Guangxi Medical University's Experimental Animal Center provide.
1.2 reagent and sample
Nateglinide is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.He
Bar azoles (Shanghai Zhongxi Pharmaceutical Co., Ltd.)；Thyroxin tablet (Tianjin Junan biopharmaceutical company) produces.125I-triiodo first shape
Gland original ammonia acid (T3) radioimmunoassay kit,125I-TA (T4) radioimmunoassay kit.
1.3 instrument
Laboratory animal electronic scale (Shanghai Medical Apparatus and Instruments Factory)；Anus thermometre, TN type pellet type twisting balance (Shanghai the second Libra instrument
Device factory)；Electrocardiograph (Japan produces)；5417R low-temperature and high-speed centrifuge (EPPENDORF company of Germany produces).
Prepared by 1.4 rat packets and model
Hyperthyroidism animal model manufacture method: (Lin Lan etc., hyperthyroidism is rather to hyperthyroidism rat thyroid hormone and heart sodium for reference literature
The impact of element, China's TCM basis medical journal, 2005), select thyroxin tablet rat molding method, thyroxin tablet is with distillation
Water dissolution, by 600mg/kg dosage gavage.Animal after modeling show as excitement, bellicose, easily shy, lose weight, drink water and drink
Appetite increase, increased heart rate etc. are modeling success, close with YIN-deficiency type hyperthyroid patient clinical manifestation.
Taking SD rat 60, male and female half and half, before modeling, conventional adaptation raises 3d.Take 10 at random and be only used as normal control
Group, remaining 50 carry out modeling as stated above.It is randomly divided into 5 groups: model control group, positive controls after modelling success
(thiamazole group, 50mg kg-1) and Nateglinide group (80mg kg-1), compound (I) group (80mg kg-1), Nateglinide
With compound (I) compositions group [40mg kg-1Nateglinide+40mg kg-1Compound (I)].After modeling success, according to upper
State dosed administration, once a day, continuous 7 days.Normal group and model control group mouse stomach give purified water.
1.5 heart rate measurement experiments
7d before treatment, after treatment, under rat peace and quiet situation, measures heart rate with electrocardiograph.
1.6 body temperature measurement experiments
7d before treatment, after treatment, measures the rectal temperature of rat when the morning 8.
1.7 body weight determination experiments
7d before treatment, after treatment, measures its body weight after Rat Fast 12h.
1.8 serum T3、T4Determination experiment
1d after the administration of modeling rat last, tail vein blood, separate serum, use radio immunoassay (RIA) to measure,
Concrete operations are carried out according to medicine box description.
1.9 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
2.1 on hyperthyroidism rat model heart rate, the impact of body temperature
Comparing with Normal group, model control group heart rate is substantially accelerated (P ＜ 0.01), body temperature significantly raised (P <
0.01)；Comparing with model control group, Nateglinide and compound (I) compositions group and positive controls heart rate substantially slow down (P
＜ 0.01), body temperature substantially reduces (P ＜ 0.01)；Compare with model control group, Nateglinide group, compound (I) group decreased heart rate
(P ＜ 0.05) hypothermia (P ＜ 0.05).
Result of the test is shown in Table 1.
2.2 on hyperthyroidism rat model serum T 3, the impact of T4 level
Compare with Normal group, model control group serum T 3, T4 value significantly raised (P ＜ 0.01).With model control group
Relatively, Nateglinide substantially reduces (P ＜ 0.01) with compound (I) compositions group and positive controls serum T 3, T4 value；With mould
Type matched group compares, and Nateglinide group, compound (I) group serum T 3, T4 value reduce (P ＜ 0.05).
Result of the test is shown in Table 2.
Table 1 is on hyperthyroidism rat model heart rate, body temperature, the impact of body weight
| Group | Heart rate difference (beat/min) before and after medication | Medication forebody-afterbody temperature approach (DEG C) |
| Normal group | 13.5±2.1 | 0.3±0.06 |
| Model control group | 209.3±19.5 | 1.9±0.21 |
| Positive controls | 84.7±20.5 | 0.7±0.21 |
| Nateglinide group | 103.8±19.9 | 1.1±0.23 |
| Compound (I) group | 101.6±19.1 | 1.1±0.22 |
| Nateglinide and compound (I) compositions group | 83.4±10.2 | 0.7±0.11 |
Table 2 is on hyperthyroidism rat model serum T 3, the impact of T4 level
| Group | T3(ng/ml) | T4(ng/ml) |
| Normal group | 0.98±0.18 | 35.4±6.81 |
| Model control group | 15.83±2.70 | 345.8±25.94 |
| Positive controls | 3.32±1.10 | 39.6±7.91 |
| Nateglinide group | 8.51±1.52 | 109.7±9.63 |
| Compound (I) group | 8.92±1.31 | 108.6±10.22 |
| Nateglinide and compound (I) compositions group | 3.69±1.02 | 45.4±6.93 |
Hyperthyroidism, also known as thyrotoxicosis, is owing to the many reasons in thyroid or outside thyroid causes
In blood, thyroxin excess, acts on tissue and the organ of whole body, cause body nerve, circulate, each system such as digestion emerging
The disease general name that putting forth energy property increases with hypermetabolism is main performance.Hyperthyroidism is the one common endocrine disease of harm human health
Disease, prevalence is about 0.5%～1%, can betide any age, common with young and middle-aged women.Chinese medicine is at treatment thyroid
Hyperfunctioning disease, to improve clinical symptoms aspect curative effect obvious, but Clinical and experimental study has only been in progress in the degree of depth and range,
There is no important breakthrough, and lack the pharmacological research report and high level research carried out with animal model.
The above results shows, when Nateglinide, compound (I) independent role, has treatment effect to hyperthyroidism
Really；When Nateglinide and compound (I) synergy, hyperthyroid therapeutic effect is improved further, Ke Yikai
Send out into the medicine treating hyperthyroidism.
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 (6)
1. the pharmaceutical composition of a Nateglinide, it is characterised in that: include Nateglinide, above-mentioned compound (I) and pharmacy
Upper acceptable carrier, is prepared as the dosage form needed；Described compound (I) has following structural formula,
The pharmaceutical composition of Nateglinide the most according to claim 1, it is characterised in that: pharmaceutically acceptable carrier
Including diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier
Or lubricant.
The pharmaceutical composition of Nateglinide the most according to claim 1, it is characterised in that: described dosage form includes tablet, glue
Wafer, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection,
Suppository, spray, drop or patch.
The pharmaceutical composition of Nateglinide the most according to claim 1, it is characterised in that: the system of above-mentioned compound (I)
Preparation Method, comprises following operating procedure: Caulis Sinomenii is pulverized by (a), with 60～70% alcohol heat reflux extraction, and united extraction liquid,
Be concentrated into without alcohol taste, successively with petroleum 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 n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 10%
12 column volumes of ethanol elution, then with 15 column volumes of 70% ethanol elution, collect 70% eluent, concentrating under reduced pressure obtains 70% second
Alcohol eluting concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 50:1,
The methylene chloride-methanol gradient elution of 25:1,15:1 and 5:1 obtains 4 components；D in () step (c), component 4 uses purification on normal-phase silica gel
Separate further, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 10:1,5:1 and 2:1 successively；(e)
The reverse phase silica gel that in step (d), component 2 is bonded by octadecylsilane separates, water-soluble with the methanol that concentration expressed in percentage by volume is 70%
Liquid isocratic elution, collects 7～13 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I).
The pharmaceutical composition of Nateglinide the most according to claim 4, it is characterised in that: described macroporous resin is AB-8 type
Macroporous adsorbent resin.
6. the pharmaceutical composition of the arbitrary described Nateglinide of Claims 1 to 5 is at preparation treatment hyperthyroidism
Application in medicine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777842A (en) * | 2016-05-28 | 2016-07-20 | 黄芳 | Halcinonide medicine composition and application of same to biological medicine |
| CN106083876A (en) * | 2016-05-31 | 2016-11-09 | 黄芳 | The pharmaceutical composition of cytarabine hydrochloride and the application in biological medicine thereof |
-
2016
- 2016-08-19 CN CN201610695366.4A patent/CN106309428A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777842A (en) * | 2016-05-28 | 2016-07-20 | 黄芳 | Halcinonide medicine composition and application of same to biological medicine |
| CN106083876A (en) * | 2016-05-31 | 2016-11-09 | 黄芳 | The pharmaceutical composition of cytarabine hydrochloride and the application in biological medicine thereof |
Non-Patent Citations (2)
| Title |
|---|
| HUAN YAN ET AL.: "Chlojaponilactones B–E, Four New Lindenane Sesquiterpenoid Lactones", 《HELVETICA CHIMICA ACTA》 * |
| YU ZHAO ET AL.: "Isomeric Eremophilane Lactones from Seneciotsoongianus", 《CHEMISTRY BIODIVERSITY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279198A (en) * | 2016-08-16 | 2017-01-04 | 赵浩浩 | A kind of compound separated from Radix Scrophulariae and preparation method thereof, application |
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