CN108239185A - A kind of inclusion compound of quinindium and amine cyclodextrin - Google Patents
A kind of inclusion compound of quinindium and amine cyclodextrin Download PDFInfo
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- CN108239185A CN108239185A CN201810000390.0A CN201810000390A CN108239185A CN 108239185 A CN108239185 A CN 108239185A CN 201810000390 A CN201810000390 A CN 201810000390A CN 108239185 A CN108239185 A CN 108239185A
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- cyclodextrin
- quinindium
- inclusion compound
- amine
- beta
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- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 119
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 150000001875 compounds Chemical class 0.000 title claims abstract description 45
- 150000001412 amines Chemical class 0.000 title claims abstract description 38
- 229960004853 betadex Drugs 0.000 claims abstract description 67
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 65
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 229960001124 trientine Drugs 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 14
- 238000002604 ultrasonography Methods 0.000 claims description 8
- 230000010355 oscillation Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 150000001768 cations Chemical class 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229950005162 benexate Drugs 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012982 microporous membrane Substances 0.000 description 5
- 206010013786 Dry skin Diseases 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 201000004792 malaria Diseases 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 3
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- 150000000779 D-glucopyranoses Chemical class 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- -1 amido modified beta-cyclodextrin Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- AGGKEGLBGGJEBZ-UHFFFAOYSA-N tetramethylenedisulfotetramine Chemical compound C1N(S2(=O)=O)CN3S(=O)(=O)N1CN2C3 AGGKEGLBGGJEBZ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses the inclusion compound of a kind of quinindium and amine cyclodextrin, belongs to pharmaceutical technology field.Amine cyclodextrin is the beta cyclodextrin of amino substitution in the present invention, its inclusion compound with quinindium is prepared using solvent method or ultrasonic method, inclusion compound is formed using amine cyclodextrin and quinindium, other than the clathration of cyclodextrin cavity and quinindium, alkaline environment can be formed in aqueous solution, and ionic interaction is formed with the hydroxyl of quinindium；Amino can form cation in water simultaneously, hydrogen bond action occur with the nitrogen-atoms on quinindium molecule, therefore be more advantageous to the water solubility and stability of enhancing inclusion compound.Inclusion compound stability provided by the present invention is high, good water solubility, is expected to improve the bioavilability of quinindium.Preparation method simplicity, mild condition, easy to operate, suitable commercial Application simultaneously.
Description
Technical field
The present invention relates to a kind of quinindiums and the inclusion compound of amine cyclodextrin, belong to pharmaceutical technology field.
Background technology
Malaria is that most one of disease of infectiousness and life-threatening, the whole world have more than 300,000,000 people and is infected, wherein flat
There is more than 100 ten thousand people death every year.Although malaria is in the world, numerously area has been eliminated extensively, and malaria infection case sum is still
Rising year by year.Cinchona alkaloid quinindium（English name Quinidine, structure is as shown in Formula II）It is that the first kind is applied to malaria
One of drug of disease people, this drug are found almost without side effect.Meanwhile quinindium is also with some other important
Bioactivity, such as heat resistanceheat resistant, anti-arrhythmia.However, due to the poorly water-soluble of quinindium, body is caused to absorb oral medication
It is bad and irregular, significantly limit its application；Therefore, there is an urgent need to a kind of efficient, nontoxic carrier, to increase its clinic
The oral administration biaavailability of application.
Cyclodextrin（Cyclodextrin, abbreviation CD）It is one that amylose generates under cyclodextrin glycosyltransferase effect
The general name of series of annular oligosaccharides, wherein using it is more be the molecule containing 6,7 or 8 glucose sugar units, respectively α-, β-and
Gamma-cyclodextrin；Form cyclodextrin molecular each D- glucopyranoses be chair conformation, each glucose unit with α-Isosorbide-5-Nitrae-
Glucosides key connection cyclization；Since the glycosidic bond of connection glucose unit cannot rotate freely, cyclodextrin forms both ends open, one end
The small and hollow truncated cone shape stereochemical structure in big one end；In its cavity structure, intracavitary portion is due to the shielding action by C-H keys
Foring hydrophobic region, and all hydroxyls are then outside cavity, wherein C-2 and C-3 secondary hydroxyls are distributed in big opening end, and C-6
Primary hydroxyl is distributed in osculum end；Such stereochemical structure causes cyclodextrin to have outer hydrophilic, interior hydrophobic peculiar property；It is three-dimensional
Structure is as follows：
Wherein, n=1,2 or 3, correspond to respectively α-, β-and gamma-cyclodextrin.
After drug molecule forms inclusion compound with cyclodextrin and its derivative, drug water solubility can be enhanced, improve its stability,
Its bad smell can be also covered, reduces its irritation in gastrointestinal tract with adverse reaction and extends release time and the raising of drug
The bioavilability of drug, and with Colon and rectum targeting.Meanwhile it can effectively avoid or reduce using cyclodextrin inclusion technique
The use of solvent, surfactant and lipid.Cyclodextrin inclusion compound biggest advantage is that it can change medicine from molecular level
The property of object and to the pharmacokinetics process of drug almost without interference.There are about 30 kinds of drugs containing cyclodextrin in the world at present
Preparation lists, and the effect of cyclodextrin in these formulations is mainly：It is organic in replacement injection or topical application preparation prescription
Solvent；Improve the oral administration biaavailability of the IIth class and some the IVth class drugs；It reduces GI irritation and increases the saturating of drug
Skin diffusivity etc..By animal and human experimentation, research shows that, cyclodextrin can improve the cross-film of nearly all types of drug
Transhipment.
In three kinds of common cyclodextrin described above, beta-cyclodextrin due to it is cheap and easy to get, be of moderate size and nontoxic etc. excellent
Benign matter and most widely applied, but the water solubility and Binding ability of beta-cyclodextrin are limited, as inclusion main body point
Son is often difficult to the requirement for meeting medicinal application；Therefore, how to carry out appropriate structural modification to beta-cyclodextrin is this field skill
The emphasis of art personnel research and development.
Invention content
The purpose of the present invention is to provide a kind of quinindiums and amine with higher stability, water solubility and bioavilability
The inclusion compound of class cyclodextrin, the inclusion compound contain quinindium and amine cyclodextrin, and the amine cyclodextrin is mono-substituted for 6-
Beta-cyclodextrin, shown in structural formula as I：
Formulas I
Wherein, the arbitrary value in n 0,1,2 and 3, corresponding amine cyclodextrin are followed successively by：Single-（6- amino -6- deoxidations）-β-
Cyclodextrin, list-（6- ethylenediamine -6- deoxidations）Beta-cyclodextrin, list-（6- diethylenetriamine -6- deoxidations）Beta-cyclodextrin and single-
（6- triethylene tetramine -6- deoxidations）Beta-cyclodextrin.
The inclusion compound of quinindium of the present invention and amine cyclodextrin is prepared using solvent inclusion method or ultrasonic method,
The molar ratio of middle quinindium and amine cyclodextrin is 1:2~1:10.
Preparation process using solvent inclusion method is as follows：While stirring to the water dissolved with amine cyclodextrin at 25 ~ 50 DEG C
Quinindium is added in solution, is continued after being protected from light 36 ~ 72 h of stirring, filters off insoluble matter, evaporated under reduced pressure solvent is up to quinindium and amine
The inclusion compound of class cyclodextrin.
It is as follows using the preparation process of ultrasonic method：Amine cyclodextrin at 25 ~ 50 DEG C into sonic oscillation is water-soluble
Quinindium is added in liquid, is then proceeded to after being protected from light 1 ~ 10 h of ultrasound, filters off insoluble matter, evaporated under reduced pressure solvent is up to quinindium and amine
The inclusion compound of class cyclodextrin.
The present invention uses amido modified beta-cyclodextrin, amine cyclodextrin is formed, in addition to cyclodextrin cavity and the packet of quinindium
Outside cooperation, alkaline environment can be formed in aqueous solution, and ionic interaction is formed with the hydroxyl of quinindium；Amino is in water simultaneously
In can form cation, on quinindium molecule nitrogen-atoms occur hydrogen bond action, therefore be more advantageous to enhancing inclusion compound water
Dissolubility and stability.
Amine cyclodextrin of the present invention is C-6 hydroxyls of D- glucopyranoses of beta-cyclodextrin molecule by different ammonia
The derivative of base substitution generation.
The synthetic method of amine cyclodextrin is as follows：First, C-6 hydroxyls of beta-cyclodextrin are carried out with paratoluensulfonyl chloride single
Sulfonylation obtains single 6-OTs- β-CD.Synthesis it is single-（6- amino -6- deoxidations）During beta-cyclodextrin, first by single 6-OTs- β-CD
Tolysulfonyl oxygen groups（-OTs）Use azido group（-N3）Substitution；Azido group is finally reduced to ammonia with triphenylphosphine
Base i.e. obtain target compound list-（6- amino -6- deoxidations）Beta-cyclodextrin；Its synthetic reaction formula is as shown in formula III：
Formula III
And synthesis it is single-（6- ethylenediamine -6- deoxidations）Beta-cyclodextrin, list-（6- diethylenetriamine -6- deoxidations）Beta-cyclodextrin and
Single-（6- triethylene tetramine -6- deoxidations）During beta-cyclodextrin, single 6-OTs- β-CD with aminated compounds are reacted and generate these three
Amine cyclodextrin.Wherein, the aminated compounds is respectively ethylenediamine, diethylenetriamine and triethylene tetramine.Its synthetic reaction
Formula is as shown in formula IV：
Formula III
Wherein, n=0,1 or 2, corresponding aminated compounds are ethylenediamine, diethylenetriamine and triethylene tetramine.
Beneficial effects of the present invention：
（1）The inclusion compound of the amine cyclodextrin of quinindium provided by the present invention, quinindium respectively with it is single-(6- amino -6- takes off
Oxygen)-beta-cyclodextrin, list-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin, list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin
Or solubility difference of the inclusion compound that is formed of list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin in the water of pH=7.5
Improve 8.3,6.5,7.5 and 10.0 times；Wherein with list-(6- triethylene tetramine -6- deoxidations) increasing of-beta-cyclodextrin to quinindium
Molten effect is best.
（2）The preparation method of inclusion compound of the present invention is easy, easy to operate, mild condition, is suitble to industrialized production.
Description of the drawings
Fig. 1 is list-(6- amino -6- deoxidations)-beta-cyclodextrin and quinindium and its solid clathrates1H-NMR compares figure；
Fig. 2 is list-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin and quinindium and its solid clathrates1H-NMR compares figure；
Fig. 3 is list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin and quinindium and its solid clathrates1H-NMR compares
Figure；
Fig. 4 is list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin and quinindium and its solid clathrates1H-NMR compares
Figure.
Fig. 5 is the uv absorption spectra of quinindium（The nm of pH=7.5, λ=330）；
Fig. 6 is concentration-absorbance standard curve figure of quinindium.
Specific embodiment
Further heretofore described method is described below by embodiment, but the scope of the present invention is not by reality
Example limitation is applied, the reagent used in the present embodiment is conventional commercial reagent or the examination prepared according to a conventional method unless otherwise specified
Agent, the method used are conventional method unless otherwise specified.
Embodiment 1
The preparation of quinindium and list-(6- amino -6- deoxidations)-Benexate Hydrochloride
（1）The preparation of single -6-OTs- β-CD
210 g of beta-cyclodextrin that water recrystallized is taken, the three-necked bottle for filling 1300 mL water is added portionwise（3 L）In, room temperature is stirred
It mixes；It weighs 17.2 g sodium hydroxides to be dissolved in 50 mL water, then slowly be added dropwise in the suspension of beta-cyclodextrin
It is gradually clarified to reaction solution, continues to stir 1.5 h；After reaction solution cyclodextrin is completely dissolved change clarification, 26.0 will be contained
G paratoluensulfonyl chlorides are dissolved in 80 mL acetonitriles ultrasounds to clarifying, and solution is slowly added dropwise into reaction solution（It drips off within about 30 minutes）, after
After 2 h of continuous stirring, insoluble matter is filtered off, filtrate is adjusted with the hydrochloric acid of 2 mol/L to pH=7.5, there are a large amount of white precipitates to analyse at this time
Go out.Collected by suction precipitates, and is dissolved in sediment in the distilled water of 450 mL under heating condition, filters insoluble matter, filtrate chamber while hot
Temperature stands 12 h, collects sediment, and heating cools down recrystallization for several times, until thin-layer chromatography shows products pure.
Obtain 17.5 g of final product, yield 8.2%；It is measured by NMR spectrum method, product structure characterizes such as
Under：1H-NMR (500 MHz, DMSO-d 6, ppm)：δ 2.44(s,3H, -CH3), 3.20-3.71 (m, 42H, H-2, -3,
- 4, -5, -6 of β-CD), 4.30-4.45 (m, 6H, 6-OH of β-CD), 4.86 (s, 7H, H-1 of β-CD),
5.66-5.90 (m, 14H, 2-, 3- OH of β-CD), 7.43-7.40 (d, 2H, Ar-H), 7.74-7.77 (d, 2H,
Ar-H)。
（2）Single -6-N3The preparation of-β-CD
By 6.5 g（5.0 mmol）Single 6-OTs- β-CD are dissolved in the DMF of 15 mL dryings, are stirred at room temperature to being completely dissolved, then
Add in Sodium azide（0.4 g, 6.15 mmol）, under nitrogen protections, 10 h are reacted at 75 DEG C, treat to be cooled to room after reaction
Reaction solution is slowly dropped into 300 mL acetone by temperature, and after stirring 30 min, suction filtration takes filter cake, and vacuum drying obtains white powder
5.0 g, yield 85.1%.
（3）The preparation of list-(6- amino -6- deoxidations)-beta-cyclodextrin
It will single -6- N3-β-CD（1.5 g, 1.32 mmol）It is dissolved in 20 mL dryings DMF, adds in triphenylphosphine（1.7g
6.49 mmol）, 2 h are stirred at 25 DEG C；7 mL ammonium hydroxide are slowly added to, the reaction was continued 18 h are filtered to remove insoluble matter, will clarify
Liquid is slowly dropped into 300 mL acetone, and filter cake is filtered to take after stirring 30 min, is dried in vacuo, is obtained 0.95 g of white powder, yield
62.3%。
（4）The preparation of quinindium and list-(6- amino -6- deoxidations)-Benexate Hydrochloride
List-(6- amino -6- deoxidations)-beta-cyclodextrin is added in the reaction bulb of 25 mL（7.9g, 7 mmol）Add in 20 mL's
Distilled water is stirred to dissolving, then adds in quinindium（0.45g, 1 mmol）Ethanol solution, 5 h of ultrasound are protected from light at 25 DEG C,
Be filtered to remove undissolved solid drugs, then with 0.45 μm of filtering with microporous membrane, then filtrate decompression is evaporated can obtain it is white
Color powder, dry 24 h are to get the powdered of quinindium and list-(6- amino -6- deoxidations)-beta-cyclodextrin in vacuum drying chamber
Solid clathrates, inclusion compound1H-NMR is shown in Fig. 1, and A is quinindium in figure（DMSO-d 6）, B be inclusion compound（D2O）, C be list-(6- ammonia
Base -6- deoxidations)-beta-cyclodextrin（D2O）.Since quinindium is not soluble in water, therefore it can not D2O detects NMR signal；And scheme clear in B
The clear related proton signal for showing quinindium illustrates that it forms inclusion compound with list-(6- amino -6- deoxidations)-beta-cyclodextrin.
Embodiment 2
The preparation of quinindium and list-(6- ethylenediamine -6- deoxidations)-Benexate Hydrochloride
（1）Steps of single -6-OTs- β-CD during the preparation method is the same as that of Example 1（1）.
（2）The preparation of list-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin
By 3.0 g（2.3 mmol）6-OTs- β CD are dissolved in the ethylenediamine that 20 mL molecular sieves have been dried, and are stirred at room temperature to complete
It dissolves, reacts 10 h under 80 DEG C of nitrogen protective conditions, after complete reaction, decompression boils off solvent, and a small amount of water is added into reaction bulb
Dissolved solid continues that solvent is evaporated off, and then adds in 2 mL water dissolution products, and be slowly dropped into 400 mL acetone, room
Temperature 30 min of stirring, collected by suction white precipitate, and obtained solid crude product is dried into 24 h in vacuum drying chamber.It will dry
Solid powder be again dissolved in 2 mL distilled water, be filtered to remove a small amount of insoluble matter, filtrate is instilled in 300 mL acetone, is collected white
Color precipitates.Aforesaid operations are repeated to thin-layer chromatography detection free from admixture point to get to pure list-(6- ethylenediamine -6- deoxidations)-β-ring
Dextrin（2.4 g）, yield 87.6%.
（3）The preparation of quinindium and list-(6- ethylenediamine -6- deoxidations)-Benexate Hydrochloride
List-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin is added in 25 mL reaction bulbs（3528 mg, 3 mmol）And add in 20
ML distilled water is stirred to dissolving, then adds in quinindium（456 mg, 1 mmol）Methanol solution, stirring 72 is protected from light at 25 DEG C
H, is filtered to remove undissolved solid, then with 0.45 μm of filtering with microporous membrane, and filtrate is evaporated to obtain white powder, then in vacuum
Pulverulent solids inclusion compounds of 24 h to get quinindium and list-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin is dried in drying box,
Its1H-NMR is shown in Fig. 2, and A is quinindium in figure（DMSO-d 6）, B be inclusion compound（D2O）, C for list-(6- ethylenediamine -6- deoxidations)-β -
Cyclodextrin（D2O）.Since quinindium is not soluble in water, therefore it can not D2O detects NMR signal；And scheme clearly to show Kui Ni in B
The related proton signal of fourth illustrates that it forms inclusion compound with list-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin.
Embodiment 3
The preparation of quinindium and list-(6- diethylenetriamine -6- deoxidations)-Benexate Hydrochloride
（1）Single -6-OTs- β-CD steps that the preparation method is the same as that of Example 1（1）.
（2）The preparation of list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin
By 3.0 g（2.3 mmol）Single 6-OTs- β-CD are dissolved in the diethylenetriamine of 20 mL dryings, are stirred at room temperature to completely molten
Solution under nitrogen protection, 10 h is reacted at 80 DEG C, treat after reaction, reaction solution to be slowly dropped into 400 mL acetone, room temperature
It after stirring 30 min, filters and removes filtrate, collect white precipitate, precipitation is dissolved in a small amount of water, and be further dropped into 300 mL
In acetone, collected by suction white precipitate after 0.5 h is stirred, drying in vacuum drying chamber, obtained solid powder is ground by it
After add in 200 mL ethyl alcohol, 20 min of ultrasound, collect white precipitate.It repeats aforesaid operations to thin-layer chromatography and detects free from admixture
Point is to get pure list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin（2.1 g）, yield 74.4%.
（3）The preparation of quinindium and list-(6- diethylenetriamine -6- deoxidations)-Benexate Hydrochloride
List-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin is added in the reaction bulb of 25 mL（6095 mg, 5 mmol）And
It adds in 20 mL distilled water to stir to dissolving, then adds in quinindium（456 mg, 1 mmol）Ethanol solution, kept away at 25 DEG C
Light 10 h of ultrasound, are filtered to remove undissolved solid, then with 0.45 μm of filtering with microporous membrane, are then evaporated filtrate decompression
White powder can be obtained, in vacuum drying chamber dry 24 h to get quinindium and list-(6- diethylenetriamine -6- deoxidations)-β -
The pulverulent solids inclusion compound of cyclodextrin, inclusion compound1H-NMR is shown in Fig. 3, and A is quinindium in figure（DMSO-d 6）, B be inclusion compound
（D2O）, C be list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin（D2O）.Since quinindium is not soluble in water, therefore it can not D2O
Detect NMR signal；And scheme clearly to show the related proton signal of quinindium in B, illustrate its with list-(6- divinyls three
Amine -6- deoxidations)-beta-cyclodextrin formation inclusion compound.
Embodiment 4
The preparation of quinindium and list-(6- triethylene tetramine -6- deoxidations)-Benexate Hydrochloride
（1）Single 6-OTs- β-CD the step of the preparation method is the same as that of Example 1（1）.（2）Single-(6- triethylene tetramine -6- deoxidations) -
The preparation of beta-cyclodextrin
By 3.0 g（2.3 mmol）Single 6-OTs- β-CD are dissolved in the triethylene tetramine of 20 mL dryings, are stirred at room temperature to completely molten
Solution under nitrogen protection, reacts 12 h in 85 DEG C, treats after reaction, reaction solution to be slowly dropped into 400 mL acetone, room temperature is stirred
It after mixing 30 min, filters and removes filtrate, collect white precipitate, precipitation is dissolved in a small amount of water, and be further dropped into 300 mL third
In ketone, collected by suction white precipitate after 0.5 h is stirred, drying in vacuum drying chamber by it, after obtained solid powder is ground
It adds in 200 mL ethyl alcohol, 20 min of ultrasound, collects white precipitate.It repeats aforesaid operations to thin-layer chromatography and detects free from admixture point,
Up to pure list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin（1.59 g）, yield 54%.
（3）The preparation of quinindium and list-(6- triethylene tetramine -6- deoxidations)-Benexate Hydrochloride
List-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin is added in 25 mL reaction bulbs（6876 mg, 4 mmol）It adds in
20 mL distilled water are stirred to dissolving, then add in quinindium（456 mg, 1 mmol）, 7 h of ultrasound are protected from light at 25 DEG C, are filtered
It removes undissolved solid, then with 0.45 μm of filtering with microporous membrane, filtrate decompression is then evaporated to obtain white powder, then
Dry 24 h are to get the powdered solid of quinindium and list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin in vacuum drying chamber
Body inclusion compound, inclusion compound1H-NMR is shown in Fig. 4 figures that A is quinindium（DMSO-d 6）, B be inclusion compound（D2O）, C be list-(tri- second of 6-
Alkene tetramine -6- deoxidations)-beta-cyclodextrin（D2O）.Since quinindium is not soluble in water, therefore it can not D2O detects NMR signal；And scheme B
In clearly show the related proton signal of quinindium, illustrate its with list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin
Form inclusion compound.
The quinindium that embodiment 1 ~ 4 is prepared is measured with the water-soluble of the inclusion compound of amine cyclodextrin
（1）The measure of quinindium solubility criteria curve
A series of concentration ranges of accurate formulation are 8.5 ~ 13.9 × 10-5 The quinindium aqueous solution of mol/L, uses uv-spectrophotometric
Meter measures the ultraviolet absorption value A at 330 nm of wavelength at its 25 DEG C, then with concentration C（mol/L）For abscissa, with absorbance A
For ordinate fit standard curve A=5157C-0.02712；R2 = 0.996（Quinindium is in the buffer solution of pH=7.5
UV absorption intensity is with concentration at 330 nm（0.085~0.139 mM）Change curve is shown in Fig. 5；Standard curve is shown in Fig. 6）.
（2）The measure of inclusion compound solubility in water
Be separately added into the reaction bulb of 10 mL 0.1 mmol it is mono--(6- amino -6- deoxidations)-beta-cyclodextrin, list-(6- second two
Amine -6- deoxidations)-beta-cyclodextrin, list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin or list-(6- triethylene tetramines -6- takes off
Oxygen)-beta-cyclodextrin.Then 2 mL distilled water are added in stir to dissolving, 0.3 mmol quinindiums is added, is protected from light stirs at room temperature
It mixes 3 days；It is finally the saturated solution for the amine cyclodextrin for obtaining quinindium with 0.45 μm of filtering with microporous membrane.It is surveyed after dilution
Its UV absorption intensity（A values is made to fall 0.3 ~ 0.8）.
List-(6- amino -6- deoxidations)-beta-cyclodextrin, the list-(6- second two of quinindium are measured by ultraviolet specrophotometer
Amine -6- deoxidations)-beta-cyclodextrin, list-(6- diethylenetriamine -6- deoxidations)-beta-cyclodextrin, list-(6- triethylene tetramines -6- takes off
Oxygen)-beta-cyclodextrin and quinindium saturated aqueous solution absorption value A；The extension rate of saturated aqueous solution and corresponding ultraviolet suction
Receipts value is：51/0.359、31/0.472、28/0.612、61/0.360、5/0.446；Quinindium is calculated by standard curve
List-(6- amino -6- deoxidations)-beta-cyclodextrin, list-(6- ethylenediamine -6- deoxidations)-beta-cyclodextrin, list-(6- diethylenetriamines -
6- deoxidations)-beta-cyclodextrin, list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin and quinindium pH=7.5 under 20 oC
Solubility is respectively in water：3.81×10-3mol/L、3.01×10-3 mol/L、3.47×10-3 mol/L、4.58×10- 3Mol/L and 4.59 × 10-4Mol/L is respectively increased：8.3rd, 6.5,7.5 and 10.0 times.
After being included with amine cyclodextrin, the solubility of quinindium in water is improved, and its solubilising is made
With most strong for list-(6- triethylene tetramine -6- deoxidations)-beta-cyclodextrin.
Claims (4)
1. a kind of inclusion compound of quinindium and amine cyclodextrin, it is characterised in that：The amine cyclodextrin is mono-substituted for 6-
Beta-cyclodextrin, shown in structural formula as I：
Formulas I
Wherein, the arbitrary value in n 0,1,2 and 3, corresponding amine cyclodextrin are followed successively by：Single-（6- amino -6- deoxidations）-β-
Cyclodextrin, list-（6- ethylenediamine -6- deoxidations）Beta-cyclodextrin, list-（6- diethylenetriamine -6- deoxidations）Beta-cyclodextrin and single-
（6- triethylene tetramine -6- deoxidations）Beta-cyclodextrin.
2. the inclusion compound of quinindium and amine cyclodextrin according to claim 1, it is characterised in that：Using solvent include method or
Prepared by ultrasonic method, the molar ratio of wherein quinindium and amine cyclodextrin is 1:2~1:10.
3. the inclusion compound of quinindium and amine cyclodextrin according to claim 2, it is characterised in that：Using solvent inclusion method
Preparation process is as follows：Quinindium is added in into the aqueous solution dissolved with amine cyclodextrin while stirring at 25 ~ 50 DEG C, continues to be protected from light
After stirring 36 ~ 72 h, insoluble matter is filtered off, evaporated under reduced pressure solvent is up to quinindium and the inclusion compound of amine cyclodextrin.
4. the inclusion compound of quinindium and amine cyclodextrin according to claim 2, it is characterised in that：Using ultrasonic method
Preparation process is as follows：Quinindium is added in amine cyclodextrin aqueous solution at 25 ~ 50 DEG C into sonic oscillation, then proceedes to keep away
After 1 ~ 10 h of light ultrasound, insoluble matter is filtered off, evaporated under reduced pressure solvent is up to quinindium and the inclusion compound of amine cyclodextrin.
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