CN105906648A - Ketotifen fumarate pharmaceutical composition and application thereof in biological medicines - Google Patents
Ketotifen fumarate pharmaceutical composition and application thereof in biological medicines Download PDFInfo
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- CN105906648A CN105906648A CN201610335380.3A CN201610335380A CN105906648A CN 105906648 A CN105906648 A CN 105906648A CN 201610335380 A CN201610335380 A CN 201610335380A CN 105906648 A CN105906648 A CN 105906648A
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- 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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- 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)
- A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
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Abstract
The invention discloses a ketotifen fumarate pharmaceutical composition and application thereof in biological medicines. The ketotifen fumarate pharmaceutical composition contains ketotifen fumarate and a novel-structured natural product compound (I). By virtue of the independent action of ketotifen fumarate and the compound (I), the hyperprolactinemia can be treated; and by virtue of the combined action of ketotifen fumarate and the compound (I), the treatment effect to the hyperprolactinemia can be remarkably improved, and the pharmaceutical composition can be developed into a drug for treating the hyperprolactinemia. Compared with the prior art, the ketotifen fumarate pharmaceutical composition has outstanding substantive features and significant progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of ketotifen fumarate, be specifically related to the medicine of ketotifen fumarate
Compositions and the application in biological medicine thereof.
Background technology
Ketotifen fumarate has histamine H1-receptor antagonism and suppression anaphylaxis medium release action, not only anti-allergic effects concurrently
Relatively strong, and duration of efficacy is longer, therefore to preventing various bronchial asthma attacks and the curative effect comparison endogenous of extrinsic asthma
Asthma is more preferably.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of ketotifen fumarate, containing fumaric acid ketone in this pharmaceutical composition
Can be with Synergistic treatment hyperprolactinemia for the natural product of fragrant and a kind of novel structure, ketotifen fumarate and this natural product.
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 ketotifen fumarate, including ketotifen fumarate, 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: Radix Physochlainae is pulverized by (a), with 85～95% 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 extraction in (b) step (a)
Take thing macroporous resin remove impurity, first with 10 column volumes of 8% ethanol elution, then with 12 column volumes of 70% ethanol elution, receive
Collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate is used
Purification on normal-phase silica gel separates, and obtains 4 with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1 and 5:1 successively
Component；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1,5:1 and 2:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtains 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 75%, collects 8～14 column volume eluents, eluting
Liquid is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is AB-8 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 hyperprolactinemia.
The application in the medicine of preparation treatment hyperprolactinemia of the pharmaceutical composition of above-mentioned ketotifen fumarate.
Advantages of the present invention: containing ketotifen fumarate and a kind of knot in the pharmaceutical composition of the ketotifen fumarate that the present invention provides
When the natural product that structure is novel, ketotifen fumarate and this natural product independent role, there is treatment hyperprolactinemia effect；
During the two synergy, treatment hyperprolactinemia effect improves further, can develop into the medicine for the treatment of hyperprolactinemia.
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.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, purchased from Shanghai Ling Feng chemistry
Reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Radix Physochlainae (2kg) is pulverized by (a), extracts (20L × 3 time) with 90% alcohol heat reflux, and merging carries
Take liquid, be concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturation
N-butyl alcohol (4L × 3 time) extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b)
N-butyl alcohol extract AB-8 type macroporous resin remove impurity in step (a), first with 10 column volumes of 8% ethanol elution, then with 70%
12 column volumes of ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；(c) step (b)
In 70% ethanol elution concentrate purification on normal-phase silica gel separate, be 40:1 (8 column volumes), 20:1 (8 posts by volume ratio successively
Volume), the methylene chloride-methanol gradient elution of 10:1 (8 column volumes) and 5:1 (10 column volumes) obtain 4 components；
D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1 (8 column volumes), 5:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (10 column volumes) and 2:1 (5 column volumes) obtains 3 components；(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 75% is isocratic
De-, collect 8～14 column volume eluents, eluent is concentrated under reduced pressure to give compound (I) (purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 263.1209, 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, CD2Cl2, 500MHz): H-1a (2.14, dd,
J=16.0,13.5Hz), and H-1b (2.85, dd, J=16.0,3.7Hz), H-4 (7.26, s), H-5 (2.74, d, J=10.6Hz),
H-8 (3.23, d, J=10.3Hz), H-9 (1.55, m), H-10 (1.77, m), H-12a (5.23, t, J=2.0Hz),
H-12a (5.36, t, J=2.0Hz), H-13a (4.32, dd, J=13.4,2.0Hz), H-13b (4.65, dd, J=13.4,
2.0Hz), and H-14 (1.12, d, J=6.4Hz), H-15 (1.84, s)；Carbon-13 nmr spectra data δC(ppm, CD2Cl2,
125MHz): 42.5 (CH2, 1-C), 199.3 (C, 2-C), 136.5 (C, 3-C), 145.7 (CH, 4-C),
47.5 (CH, 5-C), 73.4 (C, 6-C), 103.7 (C, 7-C), 73.4 (CH, 8-C), 42.4 (CH, 9-C),
40.5 (CH, 10-C), 146.7 (C, 11-C), 112.7 (CH2, 12-C), 69.3 (CH2, 13-C), 15.5 (CH3,
14-C), 16.6 (CH3, 15-C).IR spectrum (1675cm-1) and uv absorption wavelength (238nm) show this chemical combination
Thing contains an alpha, beta-unsaturated ketone carbonyl.Hydrogen spectrum shows that this compound contains an ethylene methyl proton signal [δH1.84 (3H, s,
Me-15)], a bimodal methyl signals [δH1.12 (3H, d, J=6.4Hz, Me-14)], one group of exocyclic double bond signal [δH5.23
(1H, t, J=2.0Hz, H-12a) and 5.36 (1H, t, J=2.0Hz, H-12b)], company's Oxymethylene proton signal
[δH4.32 (1H, dd, J=13.4,2.0Hz, H-13a) and 4.65 (1H, dd, J=13.4,2.0Hz, H-13b)], one
Individual olefinic methine proton signal [δH7.26 (1H, s, H-4)] and a company oxygen methine proton signal [δH3.23 (1H, d,
J=10.3Hz, H-8)].Carbon spectrum 15 carbon signals of display of this compound, wherein have two groups of double key carbon signals, a carbonyl carbon
Signal, a hemiketal carbon signal and three company's oxygen carbon signals.Comprehensive high resolution mass spectrum and nuclear magnetic data show, this compound
It may be a sesquiterpenoids.Consulting literatures understands, and this compound has similar with known compound Lyophyllone A
Structure.Relatively both nuclear magnetic datas understand, compared to known compound, in noval chemical compound the carbon signal of C-6 and C-7 position to
High field displacement, has had more a degree of unsaturation simultaneously in noval chemical compound.So, guess that this compound is possibly together with an extra ring.
Relatively the nuclear magnetic data of noval chemical compound and known compound is it is found that the carbon signal of C-6 and C-7 position is all to high field displacement, knot
Close high-resolution data, can confirm that this compound exists three membered oxygen rings between C-6 and C-7.In NOESY spectrum, H-10
Illustrating that 8-OH is α configuration with the dependency of Me-14, H-5 and H-9 and H-8 Yu Me-14, H-10 Yu Me-14 is β structure
Type.Meanwhile, the dependency explanation lactone ring five membered of Ha-12 Yu H-10 and Ha-13 Yu H-8 is cis condensing with hexatomic ring,
Three membered oxygen rings between C-6 and C-7 be α towards.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document
About correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is determined by ECD test further,
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 dorsal sc injection metoclopramide dihydrochloride for injection to prepare hyperprolactinemia (HPRL) rat model,
Observe medicine and reduce serum prolactin (PRL), rise the anti-high lactotropin of the aspects such as high estradiol (E2), progesterone (P) level
Mass formed by blood stasis effect.
1, materials and methods
1.1 animal
Female unpregnancy Wistar rat 60, SPF level, weight 200～220g, it is purchased from Animal Experimental Study center, Hubei Province.
1.2 reagent and sample
Ketotifen fumarate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Metoclopramide dihydrochloride for injection (paspertin metoclopramide, Xuzhou Lai En pharmaceutcal corporation, Ltd, specification 1mL:10mg)；Methanesulfonic acid bromine is hidden
Booth (Switzerland, 2.5mg/ sheet is dissolved as the aqueous solution of 0.045mg/mL, fully shakes up during use with distilled water after grinding).
E2, P, PRLELISA enzyme linked immunological kit (Shanghai beautiful minister biology company limited).
1.3 instrument
J2714 calorstat (great river, Wuhan electrical instrumentation factory)；RaytoRT-6000 microplate reader, RaytoRT-3100 automatic washing
Trigger (Rayto Life and Analytical Sciences Co., Ltd.).
Prepared by 1.4 rat packets and model
Rat is randomly divided into 6 groups, often group 10, respectively Normal group, model control group, positive controls (methanesulfonic acid
Bromocriptine group, 50mg kg-1) and ketotifen fumarate group (80mg kg-1), compound (I) group (80mg kg-1), rich
Horse acid ketotifen and compound (I) compositions group [40mg kg-1Ketotifen fumarate+40mg kg-1Compound (I)].
Normal group every rat back subcutaneous injection normal saline 1mL, other group rat back subcutaneous injection metoclopramide injections
Liquid 50mg/kg weight, distinguishes periodical injections 1 time, continuous 5d afternoon every morning.Each treated animal, after modeling success, fills
Stomach relative medicine or distilled water, every day 1 time, continuous 20d.Normal group and model control group rat oral gavage give purified water.
1.5PRL level determination is tested
Assay uses enzyme-linked immune analytic method, carries out in strict accordance with experimental implementation flow process in ELISA kit description.
1.6E2, P level determination is tested
Use enzyme-linked immune analytic method, carry out in strict accordance with experimental implementation flow process in ELISA kit description.
1.7 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
2.1 impacts on hyperprolactinemia (HPRL) rat model PRL level
Compare with Normal group, model control group P of Rats RL level significantly raised (P ＜ 0.01)；Compare with model control group,
Ketotifen fumarate significantly reduces (P ＜ 0.01) with compound (I) compositions group and bromocriptine methanesulfonate group PRL level；With
Model control group compares, and ketotifen fumarate group, compound (I) group PRL level reduces (P ＜ 0.05).The results are shown in Table 1.
2.2 impacts on hyperprolactinemia rat model E2, P level
Comparing with Normal group, model control group rat E2, P level substantially reduces (P ＜ 0.01).With model control group ratio
Relatively, ketotifen fumarate significantly improves (P ＜ 0.01) with compound (I) compositions group and bromocriptine methanesulfonate group E2, P level；
Comparing with model control group, ketotifen fumarate group, compound (I) group E2, P level improves (P ＜ 0.05).It is shown in Table 1.
Table 1 is on HPRL P of Rats RL, E2, the impact of P content
Levels of serum PRL concentration increase the function that can upset hypothalamic pituitary gonadal axis, make hypothalamus gonadotropin releasing hormone
(GnRH) synthesize and secretion be obstructed, and reduce the hypophysis sensitivity to GnRH, cause promoting FSH and LH secretion low,
Then ovarian secretion E2, P is not enough, causes follicular dysplasia and inadequate luteal function and causes menoxenia, amenorrhea and infertile etc..
The above results shows, when ketotifen fumarate, compound (I) independent role, has treatment to hyperprolactinemia and makees
With；When ketotifen fumarate and compound (I) synergy, the therapeutic effect of hyperprolactinemia is significantly improved, permissible
Develop into the medicine for the treatment of hyperprolactinemia.
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 ketotifen fumarate, it is characterised in that: include ketotifen fumarate, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of ketotifen fumarate 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 ketotifen fumarate 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)
By Radix Physochlainae pulverize, with 85～95% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, second
Acetoacetic ester 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 column volumes of 8% ethanol elution, then with 70%
12 column volumes of ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；(c) step (b)
In 70% ethanol elution concentrate purification on normal-phase silica gel separate, be the dichloromethane of 40:1,20:1,10:1 and 5:1 by volume ratio successively
Alkane-methanol elution gradient obtains 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, use body successively
The methylene chloride-methanol gradient elution that long-pending ratio is 8:1,5:1 and 2:1 obtains 3 components；E in () step (d), component 2 is used
The reverse phase silica gel of octadecylsilane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collects 8～14
Individual column volume eluent, 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) 90% 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 AB-8
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 hyperprolactinemia of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described ketotifen fumarate of claim 2～4 is at the medicine of preparation treatment hyperprolactinemia
Application in thing.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924339A (en) * | 2016-05-19 | 2016-09-07 | 江苏神龙药业有限公司 | Drug composition of hydrochloric acid pramipexole and application of drug composition in hyperprolactinemia treatment |
-
2016
- 2016-05-15 CN CN201610335380.3A patent/CN105906648A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924339A (en) * | 2016-05-19 | 2016-09-07 | 江苏神龙药业有限公司 | Drug composition of hydrochloric acid pramipexole and application of drug composition in hyperprolactinemia treatment |
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Application publication date: 20160831 |