CN103288670A - Polyhydroxy benzophenone derivative and application thereof - Google Patents

Polyhydroxy benzophenone derivative and application thereof Download PDF

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Publication number
CN103288670A
CN103288670A CN2013101855604A CN201310185560A CN103288670A CN 103288670 A CN103288670 A CN 103288670A CN 2013101855604 A CN2013101855604 A CN 2013101855604A CN 201310185560 A CN201310185560 A CN 201310185560A CN 103288670 A CN103288670 A CN 103288670A
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bbd
asthma
derivative
polyhydroxybenzophenone
application
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CN103288670B (en
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周林福
李飞
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Jiangsu Province Hospital First Affiliated Hospital With Nanjing Medical University
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Jiangsu Province Hospital First Affiliated Hospital With Nanjing Medical University
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Abstract

Polyhydroxy benzophenone derivative and its application, structural formula are as follows:
Figure DDA00003200138700011
The derivative can play loose bronchial smooth muscle, anti-inflammatory and antianaphylactic effect simultaneously, can preferably reach the purpose of Control of asthma symptom.

Description

Polyhydroxybenzophenone derivative and application thereof
Technical field
The present invention relates to pharmaceutical field, polyhydroxybenzophenone derivative and the purposes aspect the treating asthma medicine thereof are provided.This medicine can be brought into play lax bronchial smooth muscle, anti-inflammatory and antianaphylactic effect simultaneously, the control symptoms of asthma.
Background technology
Asthma is a kind of respiratory system common disease and frequently-occurring disease.The whole world have 300,000,000 people, in state-owned 2,000 ten thousand people suffer from asthma.In recent years, pathogenesis of asthma rate and mortality ratio are in rising trend.Wherein, the adult more than 50% and at least 80% child patient bring out by irritated factor, have every year to exceed 180,000 people and die from asthma.
The Hazard Factor of asthma morbidity comprise inherited genetic factors and two aspects of environmental factors.Asthma is relevant with polygenic inheritance, and about 40% asthmatic patient has family history.Often can trace back to the medical history of asthma (pant repeatedly, uncomfortable in chest, cough) or other anaphylactic diseases (allergic rhinitis, atopic dermatitis) such as, relatives of asthmatic patient (the nearly three generations people who has relationship by blood).Most of asthmatic patients belong to allergic constitution, to allergen (acarid, cockroach, pollen, pet skin and soft flocks, mould etc.), some food (milk, egg, fish, shrimp, crab, nut, peanut etc.), medicine (acetylsalicylic acid, the Proprasylyte etc.) allergy of common air-borne transmission, can be associated with allergic rhinitis and (or) allergy such as atopic dermatitis.
β 2Adrenoceptor agonists (β 2Receptor stimulant) by exciting respiratory tract β 2Acceptor, activated adenyl cyclase makes intracellular cyclic monophosphate content increase, Free Ca 2+Reduce, thereby lax bronchial smooth muscle is the choice drug of control asthma in acute attack.β 2Receptor stimulant comprises fugitive and long-acting two types.Fugitive β 2Receptor stimulant has terbutaline, salbutamol and Partusisten, is about 4～6 hours action time.Long-acting beta 2Receptor stimulant has bambuterol, procaterol, Salmeterol and formoterol, and be 10～12 hours action time.In addition, long-acting beta 2Receptor stimulant also has certain anti-airway inflammation, strengthens the effect of mucus-cilium transportation function.
Summary of the invention
The technical problem that solves:
The invention provides a kind of polyhydroxybenzophenone derivative and pharmaceutical use thereof, the most outstanding characteristics of this medicine are to bring into play lax bronchial smooth muscle, anti-inflammatory and antianaphylactic effect simultaneously, promote the control symptoms of asthma.
Technical scheme: the structural formula of polyhydroxybenzophenone derivative provided by the invention is:
Figure BDA00003200138500021
The application of described polyhydroxybenzophenone derivative on preparation treatment bronchial asthma medicine.
A kind of medicine, effective constituent are described polyhydroxybenzophenone derivative.Described pharmaceutical dosage form is tablet, capsule, sprays.
The application of described polyhydroxybenzophenone derivative in treatment bronchial asthma.
Beneficial effect: polyhydroxybenzophenone derivative of the present invention, can bring into play lax bronchial smooth muscle, anti-inflammatory and antianaphylactic effect simultaneously, can reach the purpose of control symptoms of asthma better.
Description of drawings
Fig. 1 is the anti-allergic effects of the acute asthma mouse of BBD, and wherein: Figure 1A soaks into for BBD is dose-dependent inhibition acute asthma airway of mice oxyphie, is best with 4mg/kg; Figure 1B is BBD(4mg/kg) significantly suppress asthma airway of mice inflammation and the high secretion of mucus, HE dyeing and PAS dye * 200; Fig. 1 C is BBD(4mg/kg) under the condition, the total white blood cells of bronchoalveolar lavage fluid and oxyphie differential count; Fig. 1 D is the Th2 cytokine that BBD significantly suppresses asthma mouse bronchial bronchoalveolar lavage fluid; Fig. 1 E is Total IgE in Serum and OVA specific IgE.Mean ± standard deviation, n=8.Compare * P＜0.05, * * P＜0.01 with normal group; Compare #P＜0.01 with asthma group.
Fig. 2 suppresses the rabbit tracheal smooth muscle contraction that methacholine or electric field field stimulation excite for BBD, and wherein Fig. 2 A is the basic methacholine (10 when not adding BBD -6M) convergent force that excites is that 100%, BBD is 10 -6～10 -3The tension force of M concentration gradient is than 10 -8M significantly descends.Fig. 2 B is 100% for the convergent force that the basic electric field field stimulation when not adding BBD excites, and BBD is 10 -7～10 -4The peak contraction tension force of M concentration gradient is than 10 -8M significantly descends.Mean ± standard deviation, n=10.With 10 -8M organizes relatively, * P＜0.05, * * P＜0.01.
Embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are not limited to limit the scope of the invention for explanation the present invention.
Synthesizing of embodiment 1 target compound (BBD)
In being equipped with the 500mL there-necked flask of agitator, input 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 12.64g(65mmol), I-hydroxybenzotriazole (HOBt) 8.78g(65mmol), 2 ', 4 ', 6 ', 4-tetrahydroxy-3-carboxyl-benzophenone 1.74g (60mmol), triethylamine (Et 3N) 6.32g(65mmol) be dissolved in the methylene dichloride of 300mL stirring at normal temperature 30min.Add KWD-2183 2.20g (60mmol), triethylamine (Et 3N) 6.32g(65mmol).Stirred overnight at room temperature.Reaction finishes, and silicagel column is crossed in washing (50mL*3) behind the organic phase anhydrous sodium sulfate drying.Get product B BD.
1HNMR(CDCl 3，D 2O)δ1.44(s，9H)，2.98(s，6H)，3.06(s，6H)，2.83～3.30(m，2H)，5.35(m，1H)，6.04(d，2H)，6.91(t，1H)，7.10(d，2H)，7.11(d，1H)，7.81(dd，1H)，8.31(s，1H)。
Anti-inflammatory and the anti-allergic effects of embodiment 2 target compounds
Acute asthma model: 6～8 64 of BALB/c mouse in age in week (Beijing dimension tonneau China laboratory animal company limited), be divided into normal group, asthma group, BBD group (0.5,1.0,2.0,4.0 and 8.0mg/kg), glucocorticosteroid Dexamethasone group (2.5mg/kg), 8 every group.0th, 14 days abdominal injection antigen 0.2mL[contain ovum protein (OVA, V level, U.S. Sigma company) 100 μ g and aluminium hydroxide 400 μ g] sensitization, played to suck with the 1%OVA solution atomization exciting on the 21st day, every day 1 time, each 1 hour, for three days on end.Normal group replaces OVA sensitization with phosphate buffered saline buffer (PBS) and excites, and negative control group, positive controls are intervened the asthma mouse with PBS and dexamethasone treatment respectively.After last OVA atomizing sucks and excites 24 hours, vetanarcol (70mg/kg) anesthesia, the capable bronchoalveolar lavage of trachea cannula is plucked eyeball and is got the peripheral blood separation of serum, and obtains lung tissue.Detect index: Wright's staining is observed total cellular score and the differential count of bronchoalveolar lavage fluid.Airway inflammation is observed in HE dyeing.The high secretion of air flue mucus is observed in periodic acid snow husband (PAS) dyeing.ELISA observes bronchoalveolar lavage fluid Th2 cytokine (IL-4 and IL-13) level, and Total IgE in Serum and OVA specific IgE (OVA-IgE) level.
The result shows that BBD is dose-dependent inhibition asthma airway of mice oxyphie and raises, and wherein the result for the treatment of of 4mg/kg, 8mg/kgBBD and 2.5mg/kg dexamethasone similar (Figure 1A) determines that the best experimental therapy dosage of BBD is 4mg/kg.BBD(4mg/kg) significantly suppress high total white blood cells and oxyphie ratio (Fig. 1 C) and Th2 cytokine levels (Fig. 1 D), Total IgE in Serum and the OVA-IgE level (Fig. 1 E) of secreting (Figure 1B), bronchoalveolar lavage fluid of asthma airway of mice inflammation and mucus.This proof target compound BBD has anti-inflammatory and anti-allergic effects.
The lax bronchial smooth muscle effect of embodiment 3 target compounds
Tracheae sampling and sample preparations: 10 adult white rabbits (Shanghai Slac Experimental Animal Co., Ltd.) of New Zealand.After every abdominal injection vetanarcol (45mg/kg) anesthesia, operation separates and cuts 2 tracheal ringes (length 5mm), removes epithelium and loose connective tissue.Tracheal ring is dipped in 37 ℃, 5%CO 2, 30mL Krebs organ bath [contain NaCl118mmol/L(M), KCl4.7M, CaCl 22.5M, MgSO 47H 2O1.2M, KH 2PO 41.2M, NaHCO 325.0M, glucose 10.0M].Tracheal ring one end connects force-displacement transducer (U.S. AstroMed company), and the other end is fixed in organ bath with steel disk.0.3g basis passive tension is set.Methacholine excites: tracheal ring is balance 15～30min in organ bath.Increase progressively methacholine (10 gradually -8～10 -3M, U.S. Sigma company), determine basic methacholine concentration (10 -6M).Increase progressively BBD concentration (10 gradually -8～10 -3M), adopt Chart V4.2 software (U.S. PowerLab company) continuous recording tension variation.The electric field field stimulation excites: tracheal ring is connected direct current stimulator (U.S. Grass company), accept electric field field stimulation (EFS, frequency 5Hz, pulse width 5ms, voltage 50V, one-tenth train 5s).Between each the stimulation there is 2min decubation.
The result shows that BBD is concentration dependent and suppresses the tracheal smooth muscle contraction that methacholine excites, 10 -6To 10 -3The tension force of M concentration gradient is than 10 -8M significantly descend (Fig. 2 A).And BBD suppresses the tracheal smooth muscle contraction that the electric field field stimulation excites, 10 -7～10 -4The tension force of M concentration gradient is than 10 -8M significantly descends, and wherein 10 -4The tension force of M concentration is down to 0(Fig. 2 B).This proof target compound BBD has lax bronchial smooth muscle effect.
The preparation of embodiment 4 target compounds (BBD) sprays
Prescription: target compound (BBD) 0.12g, sodium bisulfite 0.50g, trichloro-butyl alcohol 0.10g, distilled water adds to 100ml.
The preparation: take by weighing supplementary material by recipe quantity respectively, add an amount of dissolved in distilled water after, adding distil water is transferred with dilute hydrochloric acid to full dose again
PH value to 5.0, G3 sintered glass funnel are filtered, can in spray container namely.
The preparation of embodiment 5 target compounds (BBD) tablet
Prescription: target compound (BBD) 20mg, use N.F,USP MANNITOL 300mg, erythritol 250mg, aspartame 10mg, spearmint oil 5mg, Magnesium Stearate 6mg.
Preparation: adopt the gradient blending means to carry out target compound (BBD), use N.F,USP MANNITOL, erythritol mixes, be tamanori to contain the 5%PVPK30 aqueous solution, whole grain back particle mixes with aspartame, spearmint oil, Magnesium Stearate again, general tablet producing technology by wet granulation is manufactured experimently forced air drying.Compressing tablet namely.
Above example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.

Claims (5)

1. polyhydroxybenzophenone derivative is characterized in that structural formula is:
Figure FDA00003200138400011
2. the application of the derivative of polyhydroxybenzophenone described in the claim 1 on preparation treatment bronchial asthma medicine.
3. a medicine is characterized in that effective constituent is the described polyhydroxybenzophenone derivative of claim 1.
4. medicine according to claim 3 is characterized in that described pharmaceutical dosage form is tablet, capsule, sprays.
5. the application of the derivative of polyhydroxybenzophenone described in the claim 1 in treatment bronchial asthma.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1638756A (en) * 2002-08-08 2005-07-13 谭文 R-bambuterol, its preparation and therapeutic uses
WO2011074851A2 (en) * 2009-12-14 2011-06-23 ㈜유라팜 Pharmaceutical preparation
CN102448309A (en) * 2009-06-16 2012-05-09 谭文 Use of R-Bambuterol as inhaled medicament and combination therapies for treatment of respiratory disorders
CN102617404A (en) * 2012-04-06 2012-08-01 张长利 Preparation processes of bambuterol hydrochloride and intermediate thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1638756A (en) * 2002-08-08 2005-07-13 谭文 R-bambuterol, its preparation and therapeutic uses
CN102448309A (en) * 2009-06-16 2012-05-09 谭文 Use of R-Bambuterol as inhaled medicament and combination therapies for treatment of respiratory disorders
WO2011074851A2 (en) * 2009-12-14 2011-06-23 ㈜유라팜 Pharmaceutical preparation
CN102617404A (en) * 2012-04-06 2012-08-01 张长利 Preparation processes of bambuterol hydrochloride and intermediate thereof

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