CN103288670B - Polyhydroxy benzophenone derivative and application thereof - Google Patents

Polyhydroxy benzophenone derivative and application thereof Download PDF

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Publication number
CN103288670B
CN103288670B CN201310185560.4A CN201310185560A CN103288670B CN 103288670 B CN103288670 B CN 103288670B CN 201310185560 A CN201310185560 A CN 201310185560A CN 103288670 B CN103288670 B CN 103288670B
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bbd
asthma
derivative
polyhydroxybenzophenone
application
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CN103288670A (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: 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 treating asthma medicine thereof are provided.This medicine can be brought into play lax bronchial smooth muscle, anti-inflammatory and antianaphylactic effect, Control of asthma symptom simultaneously.
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, the M & M of asthma is in rising trend.Wherein, more than 50% adult 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 comprise inherited genetic factors and two aspects of environmental factors.Asthma is relevant with polygenic inheritance, and approximately 40% asthmatic patient has family history.Such as, relatives of asthmatic patient (the nearly three generations people who has relationship by blood) often can trace back to the medical history of asthma (repeatedly pant, uncomfortable in chest, cough) or other anaphylactic diseases (allergic rhinitis, atopic dermatitis).Most of asthmatic patients belong to allergic constitution, to the allergen of common air-borne transmission (acarid, cockroach, pollen, pet skin and soft flocks, mould etc.), some food (milk, egg, fish, shrimp, crab, nut, peanut etc.), medicine (acetylsalicylic acid, Proprasylyte etc.) allergy, can be associated with the allergy such as allergic rhinitis and (or) atopic dermatitis.
β 2adrenoceptor agonists (β 2receptor stimulant) by exciting respiratory tract β 2acceptor, activated adenyl cyclase, makes intracellular Camp Content increase, Free Ca 2+reduce, thereby lax bronchial smooth muscle is the choice drug of Control of asthma 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 solving:
The invention provides a kind of polyhydroxybenzophenone derivative and pharmaceutical use thereof, the most outstanding feature of this medicine is to bring into play lax bronchial smooth muscle, anti-inflammatory and antianaphylactic effect simultaneously, promotes Control of asthma symptom.
Technical scheme: the structural formula of polyhydroxybenzophenone derivative provided by the invention is:
The application of described polyhydroxybenzophenone derivative on preparation treatment bronchial asthma medicine.
A medicine, effective constituent is 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 better the object of Control of asthma symptom.
Accompanying drawing explanation
Fig. 1 is the anti-allergic effects of BBD to acute asthma mouse, wherein: Figure 1A is that BBD is dose-dependent inhibition acute asthma airway of mice eosinophil infiltration, take 4mg/kg as best; Figure 1B is BBD(4mg/kg) significantly suppress airway inflammation in mouse models of asthma and mucus hypersecretion, HE dyeing and PAS dye, and * 200; Fig. 1 C is BBD(4mg/kg) under 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 mouse asthma bronchoalveolar lavage fluid; Fig. 1 E is total IgE in Serum and OVA specific IgE.Mean ± standard deviation, n=8.With normal group comparison, * P<0.05, * * P<0.01; With asthma group comparison, #P<0.01.
Fig. 2 is that BBD suppresses the rabbit tracheal smooth muscle contraction that methacholine or electric field field stimulation excite, and wherein Fig. 2 A is the basic methacholine (10 when not adding BBD -6m) convergent force exciting is that 100%, BBD is 10 -6～10 -3the tension force of M concentration gradient is compared with 10 -8m significantly declines.Fig. 2 B for the convergent force that the basic electric field field stimulation of take while not adding BBD excites be 100%, BBD is 10 -7～10 -4the peak contraction tension force of M concentration gradient is compared with 10 -8m significantly declines.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 the present invention is described.
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) after organic phase anhydrous sodium sulfate drying.Obtain 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: 64 of BALB/c mouse in 6～8 week age (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[are containing ovum protein (OVA, V level, U.S. Sigma company) 100 μ g and aluminium hydroxide 400 μ g] sensitization, within the 21st day, rise with 1%OVA solution atomization and suck and excite, every day 1 time, each 1 hour, for three days on end.Normal group replaces OVA sensitization and excites with phosphate buffered saline buffer (PBS), and negative control group, positive controls are intervened mouse asthma with PBS and dexamethasone in treatment respectively.Last OVA atomization sucks and excites after 24 hours, vetanarcol (70mg/kg) anesthesia, and the capable bronchoalveolar lavage of trachea cannula, plucks eyeball and gets peripheral blood separation of serum, and obtain 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.Hypersecretion 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.
Result demonstration, BBD is dose-dependent inhibition mouse asthma air flue 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 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 airway inflammation in mouse models of asthma and mucus hypersecretion (Figure 1B), bronchoalveolar lavage fluid.This proof target compound BBD has anti-inflammatory and anti-allergic effects.
The lax bronchial smooth muscle effect of embodiment 3 target compounds
Prepared by tracheae sampling and sample: the 10Zhi New Zealand white rabbit (Shanghai Slac Experimental Animal Co., Ltd.) that grows up.After every abdominal injection vetanarcol (45mg/kg) anesthesia, operation is separated and cut 2 tracheal ringes (length 5mm), removes epithelium and loose connective tissue.Tracheal ring is dipped in 37 ℃, 5%CO 2, 30mL Krebs organ bath [containing 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 Bonding pressure movable sensor (U.S. AstroMed company), the other end is fixed on 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 gradually methacholine (10 -8～10 -3m, U.S. Sigma company), determine basic methacholine concentration (10 -6m).Increase progressively gradually BBD concentration (10 -8～10 -3m), adopt Chart V4.2 software (U.S. PowerLab company) continuous recording tension variation.Electric field field stimulation excites: tracheal ring is connected to 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 stimulation, there is 2min decubation.
Result demonstration, 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 compared with 10 -8m significantly decline (Fig. 2 A).And BBD suppresses the tracheal smooth muscle contraction that electric field field stimulation excites, 10 -7～10 -4the tension force of M concentration gradient is compared with 10 -8m significantly declines, 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.
Preparation: take supplementary material by recipe quantity respectively, add after appropriate distilled water dissolving, then adding distil water is to full dose, adjusts with dilute hydrochloric acid
PH value to 5.0, G3 sintered glass funnel filters, filling in spray container and get final product.
The preparation of embodiment 5 target compounds (BBD) tablet
Prescription: target compound (BBD) 20mg, uses N.F,USP MANNITOL 300mg, erythritol 250mg, aspartame 10mg, spearmint oil 5mg, Magnesium Stearate 6mg.
Preparation: adopt gradient blending means to carry out target compound (BBD), with N.F,USP MANNITOL, erythritol mixes, take containing the 5%PVPK30 aqueous solution is tamanori, after whole grain, particle mixes with aspartame, spearmint oil, Magnesium Stearate again, general tablet producing technology by wet granulation is manufactured experimently, forced air drying.Compressing tablet and get final product.
Above example is only explanation technical conceive of the present invention and feature, and its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalent transformations that spirit is done according to the present invention or modification, within all should being encompassed in protection scope of the present invention.

Claims (4)

1. polyhydroxybenzophenone derivative, is characterized in that structural formula is:
2. the application of the derivative of polyhydroxybenzophenone described in claim 1 on preparation treatment bronchial asthma medicine.
3. a medicine, is characterized in that effective constituent is polyhydroxybenzophenone derivative claimed in claim 1.
4. medicine according to claim 3, is characterized in that described pharmaceutical dosage form is tablet, capsule, sprays.
CN201310185560.4A 2013-05-16 2013-05-16 Polyhydroxy benzophenone derivative and application thereof Expired - Fee Related CN103288670B (en)

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Citations (3)

* 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
CN102617404A (en) * 2012-04-06 2012-08-01 张长利 Preparation processes of bambuterol hydrochloride and intermediate thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101152977B1 (en) * 2009-12-14 2012-06-11 근화제약주식회사 Pharmaceutical Formulation Pharmaceutical Formulation

Patent Citations (3)

* 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
CN102617404A (en) * 2012-04-06 2012-08-01 张长利 Preparation processes of bambuterol hydrochloride and intermediate thereof

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