CN106038525A - Composition of artalbic acid derivatives in preparation of anti-rhinitis medicines - Google Patents
Composition of artalbic acid derivatives in preparation of anti-rhinitis medicines Download PDFInfo
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- CN106038525A CN106038525A CN201610474782.1A CN201610474782A CN106038525A CN 106038525 A CN106038525 A CN 106038525A CN 201610474782 A CN201610474782 A CN 201610474782A CN 106038525 A CN106038525 A CN 106038525A
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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
- A61K31/185—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a composition of O-(dichloro-ethylamino)ethyl of artalbic acid and O-(di(2-methylmercapto-ethyl)amido)ethyl derivatives in anti-rhinitis medicines, relates to the field of organic synthesis and medicinal chemistry, and particularly relates to the composition of O-(dichloro-ethylamino)ethyl of artalbic acid and O-(di(2-methylmercapto-ethyl)amido)ethyl derivatives and application of the composition in preparation of anti-rhinitis medicines. The invention discloses the composition of O-(dichloro-ethylamino)ethyl of artalbic acid and O-(di(2-methylmercapto-ethyl)amido)ethyl derivatives and the preparation method thereof. Pharmacological experiments indicate that the composition of O-(dichloro-ethylamino)ethyl of artalbic acid and O-(di(2-methylmercapto-ethyl)amido)ethyl derivatives has an anti-rhinitis effect, and has a value for developing anti-rhinitis medicines.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and its usage.
Background technology
Rhinitis is common clinical and frequently-occurring disease, and the generation of rhinitis is the most relevant with anaphylaxis, belongs to immune inflammation
Category.At present, treatment rhinitis mainly uses the antihistamine drug such as teldane or the antiallergic agent such as tranilast, ketotifen
Thing, these medicines are poor or invalid to chronicity and the recurrent exerbation curative effect of rhinitis.Therefore, definite ingredients, quality controllable and peace
Complete efficient micromolecular compound, in terms of developing treatment of rhinitis medicine, has potential value.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus obtaining
The potential drug of high-efficiency low-toxicity most has important value.
The compound I that the present invention relates to be one within 2011, deliver (Antonella Maggio et al.,
2011.Artalbic acid,a sesquiterpene with an unusual skeleton from Artemisia
Alba (Asteraceae) from Sicily.Tetrahedron Letters, 52 (2011) 4,543 4545) compound, I
Compound I has been carried out structural modification, it is thus achieved that two new derivant i.e. compound III and compound IV, and use chemical combination
Thing III and compound IV is prepared for compositions, and rhinitis activity anti-to said composition is evaluated, and it has anti-rhinitis and lives
Property.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, said composition
The mass percent of middle compound III and compound IV is respectively 95% and 5%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the compositions of the present invention has preferable anti-rhinitis effect.The present invention pharmaceutically can connect
The salt being subject to has same drug effect.
Compositions 10mg/kg oral administration, nose of scratching rat caused by antigen (ovalbumin) and histamine, sneeze are anti-
Answer and nasal cavity vascular permeability raises inhibited, therefore, can be used for the medicine of preparation treatment rhinitis.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by concrete real
Execute any restriction of example, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Artalbic acid
The document that the preparation method of compound Artalbic acid (I) is delivered with reference to Antonella Maggio et al.
(Antonella Maggio et al.,2011.Artalbic acid,a sesquiterpene with an unusual
skeleton from Artemisia alba(Asteraceae)from Sicily.Tetrahedron Letters,52
(2011) 4,543 4545) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Artalbic acid
Compound I (266mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB)
(0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% sodium hydroxide solution of 6mL.Mixture is Celsius 40
Degree stirring 16h.After 16h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.So
Washing organic phase solution 5 times with water and saturated aqueous common salt successively afterwards, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed
Solvent obtains product crude product.Product crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v),
Collect brown concentrate elution band and fling to solvent and i.e. obtain the brown ceramic powder (272mg, 73%) of compound II.
1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),6.06(s,1H),5.76(s,1H),4.99(s,1H),
4.71(s,1H),4.56(s,1H),3.86(s,2H),3.54(s,2H),2.65(s,1H),2.43(s,2H),2.33(s,2H),
2.10(s,1H),1.64(s,3H),1.54(s,1H),1.44(s,2H),0.95(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05
(s),109.43(s),81.86(s),70.27(s),57.68(s),41.26(s),39.07(s),38.86(s),35.69(s),
33.36(s),30.72(s),20.44(s),18.42(s).
HRMS(ESI)m/z[M+H]+calcd for C17H26BrO4:373.1014；found 373.1017.
The synthesis of the O-(bischloroethylamines base) ethyl derivative (III) of embodiment 3 Artalbic acid
1, the synthesis of O-(two hydroxyethylamines) ethyl derivative of Artalbic acid
Compound II (187mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (252mg, 1.5mmol) and diethanolamine (1051mg, 10mmol), mixture is heated to reflux 1h.Reaction
Reactant liquor is poured in 20mL frozen water after end, extract 3 times with equivalent dichloromethane, merge organic facies.Successively with water and saturated
Organic facies after brine It merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects yellow and concentrates elution band
And fling to the faint yellow solid that solvent i.e. obtains O-(two hydroxyethylamines) ethyl derivative of compound Artalbic acid
(146.9mg, 74%).
1H NMR(500MHz,DMSO-d6)δ18.72(s,1H),δ6.11(s,1H),5.80(s,1H),5.14(s,1H),
4.73 (s, 1H), 4.63 (s, 1H), 3.57 (s, 2H), 3.45 (s, 4H), 2.70 (d, J=15.6Hz, 3H), 2.60 (s, 4H),
2.50 (s, 2H), 2.46 (s, 2H), 2.33 (s, 1H), 1.88 (s, 2H), 1.68 (s, 3H), 1.62 (d, J=19.9Hz, 3H),
1.02(s,3H).
13C NMR(125MHz,DMSO-d6)δ202.01(s),176.11(s),149.21(s),148.55(s),117.15
(s),109.60(s),81.93(s),67.25(s),59.28(s),57.88(s),56.83(s),53.74(s),41.36(s),
39.24(s),38.93(s),35.88(s),30.82(s),20.61(s),18.49(s).
HRMS(ESI):m/z[M+H]+calcd for C21H36N1O6:398.2543；found:398.2547.
2, the synthesis of the O-(bischloroethylamines base) ethyl derivative (III) of Artalbic acid
Synthesize O-(two hydroxyethylamines) ethyl derivative of abundant Artalbic acid, by Artalbic acid's
O-(two hydroxyethylamines) ethyl derivative (0.100g, 0.5mmol) is dissolved in 4mL chloroform, be added dropwise over thionyl chloride (0.238g,
2mmol), reactant is heated to reflux 2h.Reactant is cooled to room temperature, the thionyl chloride of dropping Methanol Decomposition excess, reduces pressure dense
Contracting removes solvent.Product, through silica gel column chromatography purification (petroleum ether/acetone 100:0.2, v/v), obtains the faint yellow of compound III
Solid (145.4mg, 67%).
1H NMR(500MHz,DMSO-d6)δ13.05(s,1H),δ6.05(s,1H),5.75(s,1H),4.67(s,2H),
4.58 (d, J=7.5Hz, 1H), 3.68 (s, 4H), 3.50 (s, 2H), 2.86 (s, 2H), 2.74 (s, 2H), 2.62 (d, J=
0.9Hz,3H),2.44(s,2H),2.38(s,2H),2.22(s,1H),1.61(s,3H),1.49(s,1H),1.42(s,2H),
0.95(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.68(s),175.56(s),148.88(s),147.80(s),116.82
(s),109.05(s),81.60(s),66.70(s),57.44(s),55.79(s),53.30(s),41.03(s),39.21(s),
38.80(s),38.49(s),35.44(s),30.38(s),20.17(s),18.05(s).
HRMS(ESI):m/z[M+H]+calcd for C21H34Cl2NO4 +:434.1865；found:434.1861.
The synthesis of O-(two (2-methylmercaptoethyl) amido) ethyl derivative (III) of embodiment 4 Artalbic acid
Prepare abundant compound III, compound III (0.217g, 0.5mmol) is dissolved in 10mL ethanol, under room temperature
Adding sodium methyl mercaptide (0.21g, 3mmol), reactant is heated to reflux 2h.Concentrating under reduced pressure removes solvent, products therefrom silicagel column
Chromatography is purified (petroleum ether/acetone 100:0.3, v/v), obtains yellow solid, i.e. compound IV (0.158g, 69%).
1H NMR(500MHz,Chloroform-d1)δ18.86(s,1H),6.14(s,1H),5.82(s,1H),5.33
(s, 1H), 4.75 (s, 1H), 4.62 (s, 1H), 3.54 (s, 2H), 2.86 (s, 1H), 2.72 (dd, J=18.2,6.8Hz,
11H),2.50(s,2H),2.39(s,2H),2.12(s,6H),1.71(s,3H),1.56(s,2H),1.41(s,1H),1.06
(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.96(s),175.97(s),149.17(s),148.22(s),117.11
(s),109.47(s),81.85(s),67.07(s),57.69(s),53.56(s),52.49(s),41.29(s),39.00(s),
38.79(s),35.63(s),32.15(s),30.74(s),20.43(s),18.43(s),14.87(s).
HRMS(ESI):m/z[M+H]+calcd for C23H40NO4S2 +:434.1865；found:434.1863.
Embodiment 5 present composition causes the impact of rat allergic rhinitis to ovalbumin
Male SD rat, body weight 180～220g, lumbar injection ovalbumin 1mg and gel aluminum hydroxide 10mg, thereafter every
Day injection 1 time, totally 7 times.Beginning from the 14th day, every day instills 1mg/ml ovalbumin normal saline solution at rat both sides nasal cavity
10ul, totally 7 times.Rat sneeze and the number of times of wiping nose in observing at once 30 minutes after last instillation, trial drug is in white of an egg egg
White last instils and is orally administered to for first 1 hour.
The preparation of compositions: the powder that will cross the 95mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 5mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg compositions with the mixing of turbine stirring instrument, makes
Used time i.e. obtains the solution of compositions by the compositions of this 100mg of water dissolution.
From table 1, compositions (10mg/kg) substantially suppresses the sneeze of allergic rhinitis rat caused by ovalbumin and scratches
Grab nose reaction.Compound III and compound IV acts on without this.
Table 1 present composition causes the impact of rat allergic rhinitis to ovalbumin
* p < 0.05, compares with matched group
The impact of the rat rhinitis that histamine is caused by embodiment 6 present composition
Male SD rat, body weight 180～220g, it is orally administered to after trial drug 1 hour, both sides nasal cavity instills 1M histamine
Normal saline solution 10ul, rat sneeze and the number of times of wiping nose in observing 30 minutes.
From table 2, the present composition (10mg/kg) significantly reduces the sneeze number of times of rhinitis rat caused by histamine, right
Nose of scratching reacts in suppression trend.Compound III and compound IV acts on without this.
Table 2 present composition causes the impact of rat rhinitis to histamine
* p < 0.05, compares with matched group
Embodiment 7 present composition causes the impact that rat nasal cavity vascular permeability raises to ovalbumin, histamine
Male SD rat, body weight 180～220g, observe ovalbumin and group with active sensitization rat and normal rat respectively
Nasal cavity vascular permeability that amine causes raises, and the method for sensitization of rat is tested with allergic rhinitis, after initial immunity the 14th day,
Rats by intraperitoneal injection pentobarbital sodium 40mg/kg, from trachea to nasal intubation after anesthesia, intubates this and constant flow pump phase after fixing
Even (0.25ml/min0, with 37 DEG C of normal saline flushing nasal cavities 10 minutes, the 1%Evans indigo plant physiology of rat tail vein injection thereafter
Saline solution 5ml/kg, collected perfusate 10 minutes after 3 minutes.At sensitized rats and normal rat, respectively containing ovum in perfusate
Albumin 1mg/ml and histamine 40ug/ml, the perfusate collected from nasal cavity is centrifuged 10 minutes through 1200 × g, and at 620nm, colorimetric is surveyed
Determine the Evans indigo plant concentration in supernatant, test medicine and antigen or first 1 hour oral administration of histamine perfusion.
From table 3, the nose of allergic rhinitis rat caused by the present composition (10mg/kg) substantially suppression ovalbumin
Chamber vascular permeability.Compound III and compound IV acts on without this.
Table 3 present composition causes the impact that rat nasal cavity vascular permeability raises to ovalbumin
* p < 0.01, compares with matched group
From table 4, present composition 10mg/kg substantially reduces the nasal cavity vascular permeability of rat caused by histamine.Change
Compound III and compound IV acts on without this.
Table 4 present composition causes the impact that rat nasal cavity blood flow permeability raises to histamine
* p < 0.01, compares with matched group
Conclusion: composition oral is administered, nose of scratching rat caused by antigen (ovalbumin) and histamine, sneeze react
And nasal cavity vascular permeability raises and has the effect of significantly inhibiting, therefore, can be used for the medicine of preparation treatment rhinitis.Compound III
Rat caused by antigen (ovalbumin) and histamine scratched nose, sneeze reaction and nasal cavity vascular permeability liter with compound IV
Height does not significantly inhibit effect, therefore, is not useable for the medicine of preparation treatment rhinitis.
The preparation of embodiment 6 composition tablet involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant 18 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixing, encapsulated makes 100.
Claims (10)
1. a compositions, is characterized by that said composition is made up of compound III and compound IV, compound in said composition
The mass percent of III and compound IV is respectively 95% and 5%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the compound IV of compound III
Powder be sufficiently mixed according to mass percent respectively 95% and 5%.
3. a compositions as claimed in claim 1 application in anti-rhinitis medicament thing.
The compositions the most according to claim 3 application in anti-rhinitis medicament thing, is characterized by: described rhinitis is antigen institute
The rhinitis caused.
The compositions the most according to claim 4 application in anti-rhinitis medicament thing, is characterized by: described antigen is white of an egg egg
In vain.
The compositions the most according to claim 5 application in anti-rhinitis medicament thing, is characterized by: described compositions can press down
Scratch caused by ovalbumin processed nose number of times and sneeze reaction.
The compositions the most according to claim 5 application in anti-rhinitis medicament thing, is characterized by: described compositions can press down
The rising of nasal cavity vascular permeability caused by ovalbumin processed.
The compositions the most according to claim 3 application in anti-rhinitis medicament thing, is characterized by: described rhinitis is histamine institute
The rhinitis caused.
The compositions the most according to claim 8 application in anti-rhinitis medicament thing, is characterized by: described compositions can press down
Scratch caused by histamine processed nose number of times and sneeze reaction.
The compositions the most according to claim 8 application in anti-rhinitis medicament thing, is characterized by: described compositions is permissible
The rising of nasal cavity vascular permeability caused by suppression histamine.
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| CN201610474782.1A CN106038525A (en) | 2016-06-24 | 2016-06-24 | Composition of artalbic acid derivatives in preparation of anti-rhinitis medicines |
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| CN201610474782.1A CN106038525A (en) | 2016-06-24 | 2016-06-24 | Composition of artalbic acid derivatives in preparation of anti-rhinitis medicines |
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2016
- 2016-06-24 CN CN201610474782.1A patent/CN106038525A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA MAGGIO等人: ""Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba(Asteraceae) from Sicily"", 《TETRAHEDRON LETTERS》 * |
| JIN-BIN WU等人: ""Biologically Active Constituents of Centipeda minima: Sesquiterpenes of Potential Anti-gllergy Activity"", 《CHEM. PHARM. BULL》 * |
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Application publication date: 20161026 |