CN104003932A - Compound applicable to prepare medicines for treating asthma - Google Patents
Compound applicable to prepare medicines for treating asthma Download PDFInfo
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- CN104003932A CN104003932A CN201410185723.3A CN201410185723A CN104003932A CN 104003932 A CN104003932 A CN 104003932A CN 201410185723 A CN201410185723 A CN 201410185723A CN 104003932 A CN104003932 A CN 104003932A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a compound of a formula I and crystal thereof, and the compound is applicable to prepare medicines for treating asthma. The formula I is shown in the specification.
Description
Technical field
The present invention relates to a kind of compound for the treatment of asthma and preparation method thereof that can be used as.
Background technology
Bronchial asthma (being called for short: asthma) is a kind of common disease, frequently-occurring disease.At present, global asthmatic patient approximately 300,000,000 people, Chinese patients with asthma approximately 3,000 ten thousand.Asthma is to affect the able-bodied important diseases of people.Treatment not in time, lack of standardization, asthma may be fatal
Bronchial asthma is the complex disease that a many factors causes.Pathogeny is not clear so far, and generally acknowledged mechanism has following three aspects: at present
1, the synthetic regulation and control of type Ⅰ allergy and IgE are disorderly: antigen (allergen) enters after human body for the first time, act on bone-marrow-derived lymphocyte, make it to become plasmocyte and produce IgE, IgE is adsorbed on mastocyte or basophil, its Fc section is combined with the specific receptors of surface of cell membrane, IgE is firmly adsorbed on cytolemma, causes body in sensitization.In the time that corresponding antigens enters sensitization body again, be adsorbed on mastocyte and basophilic leukocyte film and be combined with IgE, cause cytolemma to take off particle, discharge a series of chemical mediators and comprise histamine, slow reacting substance, bradykinin, serotonin and prostaglandin(PG) etc., these biologically active substances can cause the biological effect effects such as telangiectasis, permeability enhancing, smooth muscle spasm and glandular secretion be hyperfunction, cause bronchial asthma.
Much research in recent years shows, increasing of IgE is also relevant with Cellular Immune Disturbances, studies have shown that in a large number the not only change of the amount of having of T cell, also may have functional defect.In addition high IgE also may be relevant with suppressor T cell delay of maturation.
2, airway inflammation changes: by branchofiberoscope and bronchoalveolar lavage technology (BAL), animal model in asthma and asthma patient are carried out to biopsy, prove the inflammatory activity of airway tissue showed different.
3, airway hyperreactivity: airway hyper-reaction is that air flue increases various allobiosiies special or non-specific stimulation.There is airway hyperreactivity in children with bronchial asthma disease.Airway hyper-reaction immediate reaction (type Ⅰ allergy), and sustained reaction.Think at present, continue airway hyper-reaction main relevant with airway inflammation.And the mechanism of airway hyper-reaction is main relevant with inflammatory mediator when inflammation.Research finds that air flue is parallel to the reactivity of histamine, vagusstoff with the coincident with severity degree of condition of roaring along infant.These again with neuroregulation disorder, particularly autonomic nervous dysfunction is relevant.
Known bronchial smooth muscle is subject to sympathetic nerve and parasympathetic nerve duplicate innervation, and is keeping running balance under the adjusting of brain-hypothalamus-hypophysis.Normal people's bronchial smooth muscle tension force depends on the state of excitation of cholinergic receptor, asthma sick child does not have, its parasympathetic nerve tension force increases, alpha-1 adrenergic nervous activity strengthens, Beta-3 adrenergic neural function is low or partly blocked, because these are abnormal, children with bronchial asthma disease airway reactivity hyperfunction, is one of pathophysiological basis of asthma attack.
The main pathology of asthma is changed to bronchial muscular spasm, inflammatory cell infiltration, upper strata basement membrane thickened and air flue myxedema, exuviation cell mixing chip, mucus secretion increases, mucomembranous cilium dysfunction so that cause tunica mucosa bronchiorum plump with segmental bronchus in mucus embolism.The result of above pathological change causes air flue chamber narrow, causes Raw air way resistance to increase, and occurs asthma.
Therefore still need exploitation to carry out the effectively micromolecular compound for the treatment of to asthma.
Summary of the invention
One of object of the present invention is exactly the problem for asthma clinical treatment, develops the purposes of new compound in treatment asthmatic medicament.
I
Another object of the present invention has been to provide a kind of pharmaceutical preparation for the treatment of asthma, and its crystalline form that contains described compound, as activeconstituents, also contains any pharmaceutically acceptable auxiliary agent in addition.When pharmaceutical preparation of the present invention is imposed on to Mammals, during as the mankind, per daily dose is determined by prescriber conventionally, and dosage generally becomes with the severity of age, body weight, sex and the reaction of individual patient and patient's symptom.Conventionally, adult's dosage is 1-500 mg activeconstituents/kg body weight every day, preferably 5-300 mg activeconstituents/kg body weight every day, more preferably 10-200 mg activeconstituents/kg body weight every day.
Brief description of the drawings
Fig. 1 is the X ray diffracting spectrum of formula I compound.
Embodiment
Below by embodiment, the invention will be further described.It should be understood that described in the embodiment of the present invention that preparation method is only used for illustrating the present invention, instead of limitation of the present invention, under design prerequisite of the present invention, preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention.All raw materials of using in embodiment and solvent are all purchased from Sigma Biochemical and Organic Compounds for Research and Diagnostic Clinical Reagents company.
In powder X-ray ray diffraction (XRD), use Cu K α 1 as X x ray tube, at room temperature use powder X-ray ray diffraction device RINT2200/Ultima+ (RIGAKU) or X'Pert Pro MPD (PANalytical) to measure within the scope of the 2 θ diffraction angle of 2 ° to 35 °.For used each diffraction instrument, measuring condition is as follows.
Diffraction instrument: RINT2200/Ultima+ (RIGAKU)
Tube current: 40mA, tube voltage: 40kV, sweep velocity: 4 °/minute
Diffraction instrument: X'Pert Pro MPD (PANalytical)
Tube current: 40 mA, tube voltage: 45kV, sweep velocity: 40.1 °/minute
Although 2 θ values generally illustrate 0.2 ° of about scholar's error, may cause larger error due to measuring condition etc.
Use thermogravimetric/differential thermal analyzer TG/SDTA851e (TG/DTA) (Mettler Toledo) or differential scanning calorimeter DSC821e (DSC), in the dry nitrogen air-flow of 40ml/ minute and under the intensification degree speed of 10 DEG C/min, carry out heat analysis.
Embodiment 1: the preparation of formula I compound
(1) (
esynthesizing of)-4-(2-hydroxy phenyl)-3-butene-2-one
In 100 mL there-necked flasks, add successively Benzaldehyde,2-hydroxy (20.0 mmol), 24 mL acetone, 10 mL water, stirring at room temperature to solid all dissolves, dropwise drip the solution of sodium hydroxide (24 mmol)+20 mL water, reaction solution becomes burgundy clear liquid from faint yellow clear liquid, react completely, rotary evaporation is removed acetone, in raffinate, add 70 mL hot water to red solid all to dissolve, pass into carbonic acid gas 30 about min to reaction solution no longer till variable color, there is faint yellow solid to produce, filter, washing, dry, use acetone/water recrystallization, obtain faint yellow solid, yield: 68.3%, fusing point: 127 ~ 128 ° of C.
(2) (
1E, 4Esynthesizing of)-1-(2-hydroxy phenyl)-5-(4-fluorophenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone
To adding successively in 100 mL there-necked flasks (
e)-4-(2-hydroxy phenyl)-3-butene-2-one (20.0 mmol), 4-fluorobenzaldehyde (20.1mmol), 50 mL dehydrated alcohols, 10 mL water, being stirred to solid all dissolves, dropwise drip the solution of sodium hydroxide (27 mmol)+15 mL water, reaction solution becomes red clear liquid from faint yellow clear liquid, after reaction finishes, rotary evaporation is removed acetone, in raffinate, add 70 mL hot water to red solid all to dissolve, pass into carbonic acid gas 30 about min to reaction solution no longer till variable color, there is faint yellow solid to produce, filter, washing, dry, with dehydrated alcohol/water recrystallization, obtain light yellow crystal, yield: 71%, fusing point: 106 ~ 107 ° of C.
(3) (
1E, 4Esynthesizing of)-1-(2-benzyloxy phenyl)-5-(4-fluorophenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone
In 250 mL there-necked flasks, add successively (
1E, 4E)-1-(2-hydroxy phenyl)-5-(4-fluorophenyl)-1,4-pentadiene-3-ketone (23 mmol), potassiumiodide (0.23 mmol), salt of wormwood (26 mmol), 100 mL acetone, at room temperature stir rear dropping benzyl chlorine (26 mmol), reflux, solution colour is become when faint yellow from redness, react completely, filtered while hot is removed excessive potassiumiodide, salt of wormwood, filtrate revolving desolventized, obtain faint yellow tabular crystal, yield: 83%, fusing point: 83 ~ 84 ° of C.
(4) (
1E, 3Z, 4Esynthesizing of)-1-(2-benzyloxy phenyl)-5-(4-fluorophenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketoxime
In 100 mL single port bottles, add successively (
1E, 4E)-1-(2-benzyloxy phenyl)-5-(4-fluorophenyl)-1, 4-pentadiene-3-ketone (13 mmol), oxammonium hydrochloride (43 mmol), dehydrated alcohol 60 mL, pyridine 30 mL, at room temperature stir, solution becomes yellow clear liquid from suspension, react completely, rotary evaporation is except desolventizing, add 25 mL chloroforms, with 5% dilute hydrochloric acid (volume ratio) acidifying, regulate pH value to be about 6, with 30 mL × 4 washings, dry, filter, precipitation, obtain yellow viscous fluid, add 10 mL ethyl acetate, there is solid to separate out, suction filtration, acetone/water recrystallization, obtain white solid, yield: 66%, fusing point: 123 ~ 124 ° of C.
(5) the fluoro-5-picoline of 2--(
1E, 3Z, 4Esynthesizing of)-1-(2-benzyloxy phenyl)-5-(4-fluorophenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketoxime ether
In 50 mL there-necked flasks, add sodium hydride (2.0 mmol), tetrahydrofuran (THF) 7 mL, at room temperature stir, under ice-water bath condition, drip (
1E, 3Z, 4E)-1-(2-benzyloxy phenyl)-5-(4-fluorophenyl)-1, the solution of 4-pentadiene-3-ketoxime (1.45 mmol)+5 mL tetrahydrofuran (THF)s, remove ice bath, at room temperature stir 2 h, reaction solution becomes redness from yellow, drip the solution of 2-fluoro-5-methyl fluoride pyridine (1.5 mmol)+5 mL tetrahydrofuran (THF)s, under room temperature, react, after reaction finishes, rotary evaporation is except desolventizing, add 25 mL methylene dichloride, regulate pH value to be about 6 with 5% dilute hydrochloric acid (volume ratio), extraction, merge organic phase, anhydrous sodium sulfate drying, filter, precipitation, with silica gel thin-layer chromatography separate [
v(normal hexane):
v(ethyl acetate)=7:1], obtain target compound
.
1H?NMR?(500?MHz,?CDCl
3,?ppm)?δ:?6.01?(m,?1H,?H
1(Py)),?6.02~6.52?(m,?3H,?H
6Py,?Ar(F)CH=C,?H
6Ar(OCH
2)),?7.21~6.71?(m,?14H,?ArH,?ArCH=C),?5.26?(d,
?J=5?Hz,?2H,?H
3,?H
5(ArF))),?5.18?(s,?2H,?Ar(OCH
2)),?4.99?(s,?2H,?N=O-CH
2).
(6) preparation of formula I compound crystal form
Under 40 DEG C of conditions that also stir, in the solution to formula I compound (2. 5g) in ethanol (80ml), dropwise add acetone soln.Further this mixture is stirred 10 minutes at 40 DEG C, to obtain settled solution, and left standstill 6 hours.Filter the formula I compound of collecting precipitation.The crystal of collecting is dissolved in methyl alcohol (40ml), and vapourisation under reduced pressure methyl alcohol.Add aqueous acetone (1 0ml, acetone 9ml+ water 1ml), to obtain settled solution, and left standstill 2 days.Filter the crystal of collecting precipitation, and at 60 DEG C by crystal vacuum-drying 2 hours, thereby obtain the formula I compound of white crystal form.
Embodiment 2: the test of pesticide effectiveness:
Formula I compound is adopted to cavy allergic asthma model determination device anti-asthma activity, and concrete grammar is as follows:
Get body weight 150 ~ 200 g cavys, younger sister's paper guinea pig intraperitoneal injection 1 mL 5% ovum protein normal saline solution, and within the 3rd day and the 5th day after injection, repeat same step sensitization again.To sensitized guinea pig respectively gavage give CMC-Na, positive control drug (SD) and formula I compound, SD dosage is fed 1.25 mg/kg, formula I compound and positive drug with etc. molar dose administration.Above medicine is made into 0.5% CMC-Na suspension.After 1 hour, cavy is placed in to the airtight bell jar of 4 liters, constant voltage sprays into 5% egg white normal saline solution 30 seconds.Then take out observing response progression: 1 grade of expiratory dyspnea only, 2 grades of expiratory dyspnea and cough, 3 grades of violent asthma and even fall.The time that occurs 3 order reactions using animal breathes heavily latent period as drawing, and drawing of each administration group is breathed heavily to latent period and CMC-Na control group carries out statistical procedures, and latent period is longer, shows that anti-asthma activity is stronger.
The impact (n=8) of the tested medicine of table 1 on cavy supersensitivity bronchospasm due to ovum protein
Table 1
| Group | Dosage/(mg/kg) | Asthma is induced latent period |
| CMC-Na | - | 150.125±60.12 |
| SD | 1.25 | 209.875±53.90 |
| Formula I compound | 2.69 | 289.175±31.42 |
| The crystal of formula I compound | 2.67 | 290.375±27.22 |
Can be found out by table 1, formula I compound of the present invention and crystalline form thereof be anti-asthma activity well, and the crystal anti-asthma of formula I compound is active better.
Claims (3)
1. a compound, is characterized in that representing with formula I:
i, according to the compound under claim 1, is characterized in that having the X-ray powder diffraction figure of 2 θ at approximately 5.8,16.5,20.5,25.1 places.
2. the purposes of compound as claimed in claim 1, is characterized in that described compound can be used for the medicine of preparation treatment asthma.
3. a pharmaceutical composition, the compound that it contains claim 1, also contains pharmaceutically acceptable auxiliary agent in addition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185723.3A CN104003932A (en) | 2014-05-05 | 2014-05-05 | Compound applicable to prepare medicines for treating asthma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185723.3A CN104003932A (en) | 2014-05-05 | 2014-05-05 | Compound applicable to prepare medicines for treating asthma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104003932A true CN104003932A (en) | 2014-08-27 |
Family
ID=51364867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410185723.3A Pending CN104003932A (en) | 2014-05-05 | 2014-05-05 | Compound applicable to prepare medicines for treating asthma |
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| Country | Link |
|---|---|
| CN (1) | CN104003932A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108888644A (en) * | 2018-04-08 | 2018-11-27 | 青岛康庆和医药科技有限责任公司 | A kind of Chinese medical extract and application thereof can be used for preparing treatment asthmatic medicament |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1480455A (en) * | 2003-07-18 | 2004-03-10 | 中国药科大学 | 'Sqiqu site' ramification and its preparing method as well as its activity of anti asthma |
| CN101973934A (en) * | 2010-09-06 | 2011-02-16 | 贵州大学 | 1,5-disubstituted aryl-1,4-pentadiene-3-ketoxime ether compound and preparation method thereof and insecticidal activity application |
| CN104143447A (en) * | 2013-08-27 | 2014-11-12 | 成都精容电子有限公司 | Solid electrolytic capacitor |
-
2014
- 2014-05-05 CN CN201410185723.3A patent/CN104003932A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1480455A (en) * | 2003-07-18 | 2004-03-10 | 中国药科大学 | 'Sqiqu site' ramification and its preparing method as well as its activity of anti asthma |
| CN101973934A (en) * | 2010-09-06 | 2011-02-16 | 贵州大学 | 1,5-disubstituted aryl-1,4-pentadiene-3-ketoxime ether compound and preparation method thereof and insecticidal activity application |
| CN104143447A (en) * | 2013-08-27 | 2014-11-12 | 成都精容电子有限公司 | Solid electrolytic capacitor |
Non-Patent Citations (2)
| Title |
|---|
| KAI YUAN ET AL.: "Synthesis and biological evaluation of novel 1-aryl, 5-(phenoxy-substituted) aryl-1,4-pentadien-3-one derivatives", 《MED. CHEM. COMMUN.》 * |
| 薛伟等: "含肟酯类姜黄素衍生物的合成及其抑菌活性研究", 《化学试剂》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108888644A (en) * | 2018-04-08 | 2018-11-27 | 青岛康庆和医药科技有限责任公司 | A kind of Chinese medical extract and application thereof can be used for preparing treatment asthmatic medicament |
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Application publication date: 20140827 |
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