CN105330669A - 2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-formic acid polymorphic substance, preparation and application thereof - Google Patents
2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-formic acid polymorphic substance, preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a 2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-formic acid or a polymorphic substance of its solvate, in addition, the invention also discloses a preparation method and an application of 2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-formic acid or the polymorphic substance of its solvate as a biological activity component. The disclosed 2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-formic acid or the polymorphic substance of its solvate provides a bulk drug substance form which is better than an amorphous state, and provides a better selection for preparing the medicinal preparations for treating oral ulcer, insulin resistance, diabetes, fatty liver, nonalcoholic steatohepatitis and atherosclerosis.
Description
Technical field
The present invention relates to the also polymorphic form of [2,3-b] Nicotinicum Acidum, its preparation method and the application of 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene.
Background technology
2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum (amlexanox) is at first used as anti-allergic medication, have and suppress fat hydrogen synthase, histamine release and leukotriene is suppressed to generate, and the smooth muscle shrinks function that antagonism leukotriene causes, also have the effect accelerating aphtha healing, be treat one of effective, the most the most frequently used medicine of stomatocace simultaneously.As a kind of anti-inflammatory Claritin, 5% pastes goes on the market, by BlockDrug company production and selling in U.S.'s approval in December, 1996 as stomatocace medicine.Subsequently, gone on the market a series of other drug dosage form, includes but not limited to oral film, sprays, mouth paster, oral cavity adhesion tablet etc.Recently, US12/0208836 reports the another one novelty teabag of amlexanox, and namely preparation treatment obesity and relative disease, include but not limited to insulin resistant, diabetes, fatty liver, non-alcoholic hepatitis and atherosclerosis.
As everyone knows, the crystal type form of compound, compared with amorphous article, has better stability, can extend the quality guaranteed period of bulk drug, and is more conducive to the preparation of preparation.Therefore, bulk drug is prepared into crystal type form, as polymorphic form, the normally optimal selection of bulk drug physical form.But not yet there is at present the polymorphic form of 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum (i.e. compound shown in formula (I)) to report.
Summary of the invention
An object of the present invention is to provide the polymorphic form of 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum or its solvate.
An object of the present invention is to provide the preparation method and application of 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene also polymorphic form of [2,3-b] Nicotinicum Acidum or its solvate.
The polymorphic form of 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene disclosed by the invention also [2,3-b] Nicotinicum Acidum or its solvate can be prepared by following several method:
1,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in single solvent add thermosol clear after, leave standstill and be cooled to below room temperature or room temperature and separate out solid.
2,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in mixed solvent add thermosol clear after, leave standstill and be cooled to below room temperature or room temperature and separate out solid.
3,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in single solvent add thermosol clear after, be cooled to below room temperature or room temperature under stirring and separate out solid.
4,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in single solvent add thermosol clear after, be cooled to below room temperature or room temperature, under stirring, in system, drip poor solvent, separate out solid.
5,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in mixed solvent add thermosol clear after, be cooled to below room temperature or room temperature under stirring, separate out solid.
6,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in mixed solvent add thermosol clear after, be cooled to below room temperature or room temperature under stirring, drip poor solvent simultaneously, separate out solid.
7,2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum join in single solvent or mixed solvent and reflux, clearly molten, backflow or stir, is cooled to below room temperature or room temperature, separates out solid.
Single solvent described in the present invention refers to: water, alcohol, ester, ketone, ether, acid amides, sulfone, alkane, haloalkane, pyridines, nitrile, aromatic hydrocarbon, one in cyclic ethers class or sulfoxide type solvents, specifically, described single solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, ethylene glycol, propylene glycol, acetone, butanone, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl formate, ethyl acetate, propyl formate, isopropyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl formate, DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), water, pyridine, acetonitrile, benzene, toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, ethylene glycol bisthioglycolate propyl ether, ethylene glycol ether, normal hexane, chloroform, methylene dichloride, 1,2-ethylene dichloride, triethylamine, Trimethylamine 99, pyridine, N-methylmorpholine, N-crassitude, acetonitrile, water, one in sherwood oil and tetracol phenixin, but be not limited to above-mentioned solvent.
Mixed solvent described in the present invention is water, alcohol, ester, ketone, ether, acid amides, sulfone, alkane, haloalkane, pyridines, nitrile, aromatic hydrocarbon, two or more mixing solutions in cyclic ethers class or sulfoxide type solvents, specifically, includes but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, ethylene glycol, propylene glycol, acetone, butanone, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl formate, ethyl acetate, propyl formate, isopropyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl formate, DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), water, pyridine, acetonitrile, benzene, toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, ethylene glycol bisthioglycolate propyl ether, ethylene glycol ether, normal hexane, chloroform, methylene dichloride, 1,2-ethylene dichloride, tetracol phenixin, triethylamine, Trimethylamine 99, pyridine, N-methylmorpholine, N-crassitude, acetonitrile, two or more mixing solutions in water and sherwood oil, when mixed solvent is above-mentioned two kinds of solvents, the ratio of two kinds of solvents is 100: 1-1: 100.
Poor solvent described in the present invention is water, alcohol, ester, ketone, ether, acid amides, sulfone, alkane, haloalkane, pyridines, nitrile, aromatic hydrocarbon, one or more mixing solutions in cyclic ethers class or sulfoxide type solvents, include but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, ethylene glycol, propylene glycol, acetone, butanone, ether, isopropyl ether, tetrahydrofuran (THF), 1, 4-dioxane, ethyl formate, ethyl acetate, propyl formate, isopropyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl formate, water, pyridine, acetonitrile, benzene, toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, ethylene glycol bisthioglycolate propyl ether, ethylene glycol ether, normal hexane, chloroform, methylene dichloride, tetracol phenixin, 1, 2-ethylene dichloride, triethylamine, Trimethylamine 99, pyridine, N-methylmorpholine, N-crassitude, acetonitrile, one or more mixing solutions in water and sherwood oil, when mixed solvent is above-mentioned two kinds of solvents, the ratio of two kinds of solvents is 100: 1-1: 100.
The invention discloses three kinds of polymorphic forms of 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum or its solvate, i.e. polymorphic form I ~ III.
The measuring condition of the X-ray powder diffraction pattern in the present invention:
Sample size: about 100mg,
Target: Cu,
Filter disc: monochromatic,
Voltage/current: 40kV/100mA,
Slit: SS/DS1 °, RS0.3mm,
Sweep velocity: 8 °/point
Scope: 3-50.
In the X-ray powder diffraction pattern of 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene disclosed by the invention also polymorphic form of [2,3-b] Nicotinicum Acidum or its solvate, the peak of peak intensity more than 15 is shown in the following table:
The polymorphic form of 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum or its solvate
Peak in its X-ray powder diffraction pattern has following characteristics:
| Angle of diffraction (2 θ, °) | Intensity (I/I 0) | Angle of diffraction (2 θ, °) | Intensity (I/I 0) |
| 8.840 | 18 | 14.940 | 100 |
| 25.520 | 16 |
2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene provided by the invention also [2,3-b] polymorphic form of Nicotinicum Acidum or its solvate can be single a kind of polymorphic form when using, and also can be the mixture of two or more polymorphic form.
2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene disclosed by the invention also [2,3-b] polymorphic form of Nicotinicum Acidum or its solvate can be prepared into treatment stomatocace, obesity and relative disease, include, but are not limited to stomatocace, insulin resistant, diabetes, fatty liver, non-alcoholic hepatitis and atherosclerotic medicine.
The invention still further relates to the pharmaceutical preparation containing 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene also polymorphic form of [2,3-b] Nicotinicum Acidum or its solvate.Preparation in the present invention refers to 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum or its solvate polymorphic form separately or with the pharmaceutically acceptable pharmaceutical necessities of necessity, be prepared into suitable pharmaceutical dosage form, make it to be suitable for by include but not limited to oral, suck, intravenous injection, abdominal injection, skin note, intramuscular injection, collunarium, eye drip, suction, administration in anus, the administering mode application such as vagina administration or Epidermal administration.Wherein said suitable pharmaceutical dosage form includes but not limited to the formulation such as transfusion, common liquid drugs injection, powder pin, freeze-dried powder, oral liquid, syrup, tablet, pill, capsule, granule, gel, soft capsule, suppository, aerosol or emulsifiable paste.2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2, 3-b] polymorphic form of Nicotinicum Acidum or its solvate accounts for the 0.1-100% of weight of formulation, 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2 containing 0.01mg-500mg in unit using dosage, 3-b] polymorphic form of Nicotinicum Acidum or its solvate, proper unit using dosage is 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene containing 0.1mg-100mg also [2, 3-b] polymorphic form of Nicotinicum Acidum or its solvate.Unit using dosage refers to and can be applied to patient and the unit of easy handling and packaging, i.e. single dosage.
The present invention relates to containing 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] pharmaceutical preparation of polymorphic form of Nicotinicum Acidum or its solvate, it comprises the acceptable tensio-active agent of physiology, carrier, thinner, vehicle, smoothing agent, suspensoid, filmogen and coating aids or its combination, and compound disclosed by the invention.The accepted carrier or the thinner that are used for the treatment of purposes are known at pharmaceutical field, and such as in Remington ' sPharmaceuticalSciences (Lei Mingdun pharmacopedics), 18thEd., MackPublishingCo., Easton, PA (1990)) in have description, herein its full content is incorporated herein by reference.
Sanitas, stablizer, dyestuff, sweeting agent, perfume compound, spices etc. can be provided in the pharmaceutical preparation containing 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene also polymorphic form of [2,3-b] Nicotinicum Acidum or its solvate that the present invention relates to.Such as, the ester as the Sodium Benzoate of sanitas, xitix and P-hydroxybenzoic acid can be added.In addition, antioxidant and suspensoid can be used.
In different embodiments, alcohol, ester, sulfated fatty alcohol etc. can be used as tensio-active agent; Sucrose, glucose, lactose, starch, crystalline cellulose, N.F,USP MANNITOL, light anhydrous silicic acid salt, magnesium aluminate, aluminic acid methyl siliconic acid magnesium, synthetic aluminium silicate, calcium carbonate, Calcium hydrogen carbonate, secondary calcium phosphate, calcium carboxymethylcellulose etc. can be used as vehicle; Magnesium Stearate, talcum, sclerosis wet goods can be used as smoothing agent; Oleum Cocois, sweet oil, sesame oil, peanut oil, soybean can be used as suspensoid or lubricant; As the derivative of the carbohydrates such as such as Mierocrystalline cellulose or sugar cellacefate or can be used as suspensoid as the methyl acetate-ethylmethacrylate copolymer of poly derivative; And the softening agent of such as phthalate etc. can be used as suspensoid.
The present invention relates to containing 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2; 3-b] pharmaceutical preparation of polymorphic form of Nicotinicum Acidum or its solvate can produce by known method; such as, by mixing, dissolving, granulation, manufacture lozenge, grinding, emulsification, the packing of routine, to retain or the working method such as compressing tablet is produced.
Therefore according to the present invention, the pharmaceutical composition used can use one or more physiology acceptable carriers comprising vehicle and auxiliary to prepare in conventional manner, this vehicle and auxiliary be conducive to active compound to be treated as pharmacy can preparation.Suitable preparation depends on selected route of administration.Can as be applicable in this area and use any known technology, carrier and vehicle understanding.
Injection can be prepared into following conventionally form: as solution or suspension, be applicable to the solid dosage making solution or suspension before the injection, or as emulsion.Suitable vehicle is, such as water, salt solution, glucose, N.F,USP MANNITOL, lactose, Yelkin TTS, albumin, Sodium Glutamate, cysteine hydrochloride etc.In addition, if needed, injection medicine composition can containing subsidiary nontoxic on a small quantity, such as wetting agent, pH buffer reagent etc.The buffer reagent that physiology is applicable to includes but not limited to Hank solution, Ringer solution or normal saline buffer solution.If needed, influx and translocation preparation (such as liposome) can be used.
For transmucosal administration, the permeate agent being suitable for permeability barrier can be used in described preparation.
The pharmaceutical preparation of administered parenterally, such as, by injecting or continuous infusion, comprises with the aqueous solution of the active compound of water-soluble form existence.In addition, the suspensoid of active compound can be prepared as suitable oily injection suspension.Suitable lipophilic solvent or carrier comprise the fatty oil of such as sesame oil etc., or other organic oil of such as soya-bean oil, grapefruit oil or almond oil etc., or the such as Acrawax such as ethyl oleate or triglyceride level, or liposome.Aqueous injection suspensions can comprise the material increasing this suspension viscosity, such as sodium cellulose glycolate, sorbyl alcohol or dextran.Optionally, this suspension can also comprise suitable stablizer or strengthen this compound dissolution to prepare the reagent of high concentrate formulation.Injection formulations can exist with unit dosage with additional sanitas, such as, be in ampoule or multi-dose container.Described composition can adopt the formulation that such as suspensoid, solution or emulsion are such in oiliness or aqueous carrier, and said composition can comprise the reagent such as such as suspensoid, stablizer and/or dispersion agent.Or before use in order to redissolve with carriers such as suitable such as sterile pyrogen-free waters, described activeconstituents can be powder type.
For oral administration, by combining described active compound and medicine acceptable carrier well known in the art, can easily compound described in prescription.In order to make patient's orally ingestible to be treated, such carrier can make the compounds of this invention be configured to tablet, pill, lozenge, capsule, liquid, gel, syrup, paste, suspension etc.Can be obtained by following method and be used for oral pharmaceutical preparation: active compound is mixed with solid excipient; any grinding gained mixture and by processing granular mixture; if needed, carry out processing to obtain tablet or lozenge core after adding suitable auxiliary.Suitable vehicle particularly such as sugar etc. weighting agent, comprise lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation, such as W-Gum, wheat starch, rice starch, yam starch, gelatin, tragakanta, methylcellulose gum, Vltra tears, Xylo-Mucine and/or Povidone (PVP).If need to add disintegrating agent, such as crosslinked polyvinylpyrrolidone, agar or Lalgine or the alginates of such as sodium alginate.Suitable bag quilt is carried out to lozenge core.For this purpose, can use concentrated sugar soln, this sugar soln optionally comprises gum arabic, talcum, polyvinylpyrrolidone, carbopol gel (carbopolgel), polyoxyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvent or solvent mixture.In order to identify or characterize the various combination of active compound doses, dyestuff or pigment can be added in tablet or dragee coatings.For this purpose, can use concentrated sugar soln, this sugar soln optionally comprises gum arabic, talcum, polyvinylpyrrolidone, carbopol gel, polyoxyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvent or solvent mixture.In order to identify or characterize the various combination of active compound doses, dyestuff or pigment can be added in tablet or dragee coatings.
Can be used in oral pharmaceutical preparation and comprise the sucking fit capsule that gelatin makes, and the capsule that is soft, sealing that the gelatin of such as glycerine or sorbyl alcohol and softening agent are made.Sucking fit capsule can comprise the activeconstituents mixed with the lubricant of the tackiness agent of the weighting agent of such as lactose, such as starch and/or such as talcum or Magnesium Stearate and optional stablizer.In soft capsule, activeconstituents solubilized or be suspended in suitable liquid, such as fatty oil, Liquid Paraffin or aqueous polyoxyethylene glycol.In addition, stablizer can be added.The preparation of all oral administrations should reach the dosage being suitable for this administration.
For orally administering, described composition can be formulated into the form of tablet or lozenge according to a conventional method.
For inhalation, for compound of the present invention by using suitable propelling agent, such as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas, carry easily with the form of spraying from supercharging bag or atomizer.When pressurised aerosol, by providing the valve of conveying and metering amount to determine dose unit.The powdered mixture that the capsule of the such as gelatin used in sucker or insufflator and cartridge case can be inclusion compound and the such as suitable powder base such as lactose or starch by prescription.
The invention also discloses pharmacy field known for comprising the multi-medicament composition carried in intraocular, nose and in ear.The permeate agent being suitable for these purposes is normally known in the field.Pharmaceutical composition for intraocular conveying comprises the aqueous eye drop of the active compound of water-soluble form, such as eye drops or with gelling gum form or form of hydrogels; Ophthalmic ointment; Ophthalmic suspension, such as particulate, be suspended in and comprise little polymer beads, fat-soluble preparation and microballoon in liquid carrier medium; And ocular inserts.In order to stability and comfortableness, these suitable pharmaceutical preparations the most often and be preferably configured to aseptic, isotonic with pharmaceutical preparation that is buffering.Pharmaceutical composition for carrying in nose also can comprise drops and sprays, is usually prepared into and simulates nasal discharge in many aspects to guarantee to maintain normal ciliary action.As is well understood in the art, suitable preparation the most often and be preferably isotonic, slightly cushion so that pH is maintained 5.5 to 6.5, and it the most often and the drug stabilizing agent preferably including anti-microbial preservative and be suitable for.Pharmaceutical preparation for carrying in ear is included in suspensoid and the ointment of topical application.Common solvent for this kind of aural preparations comprises G & W.
Compound also can be formulated into the rectal compositions of such as suppository or enema,retention, such as, comprise the suppository base of conventional such as theobroma oil or other glyceride.
Except aforesaid preparation, compound can also be configured to depot formulation.This prolonged action preparation is by implanting (such as subcutaneous or intramuscular) or carrying out administration by intramuscularly.Thus, suitable polymkeric substance or hydrophobic material (such as can accept the emulsion in oil) or ion exchange resin such as can be used to carry out compound described in prescription, or be the sl. sol. derivatives such as such as slightly soluble salt by its prescription.
For hydrophobic compound, suitable pharmaceutical carrier can for comprise phenylcarbinol, non-polar surfactant, can the cosolvent system of the organic polymer miscible with water and aqueous phase.Common cosolvent system used is VPD altogether solution system, and it is the phenylcarbinol of 3%w/v, the Liquid Macrogol of non-polar surfactant's polysorbate (POLYSORBATE) 80TM and 65%w/v of 8%w/v supplied the solution of volume by dehydrated alcohol.Certainly, can the ratio of co-solvent system be changed considerably and not destroy its solubleness and toxic characteristic.In addition, cosolvent component can be changed: other hypotoxic non-polar surfactant such as can be used to replace polysorbate 80 TM; The segment size of polyoxyethylene glycol can be changed; Other biocompatible polymer of such as polyvinylpyrrolidone etc. can replace polyoxyethylene glycol; And other sugar or polysaccharide can replace glucose.
Or, other delivery system of hydrophobic pharmaceutical compounds can be adopted.The delivery medium of dewatering medicament or the well known examples of carrier are liposome and emulsion.Such as, although usually with higher toxicity for cost, also some organic solvent will can be adopted, methyl-sulphoxide.In addition, use slow-released system to carry compound, such as, comprise the semipermeable matrices of the solid hydrophobic polymers of medicine.Those skilled in the art are known and establish many slow-release materials.According to its chemical property, slow releasing capsule can discharge described compound within several weeks to 100 day.
Use the reagent that technology known to a person of ordinary skill in the art gives for administration in cell.Such as, this kind of reagent can encapsulated enter liposome.When forming liposome, all molecules existed in aqueous are all incorporated into aqueous interior.The inclusion of described liposome not only not by the impact of external micro-environment, and merges mutually due to liposome and cytolemma, and this inclusion is effectively delivered to tenuigenin.Bag quilt can be carried out by using-system specific antibody to liposome.Liposome will be targeted the organ of expectation and the Organic selection be supposed to absorbs.Or, directly can give little hydrophobicity organic molecule in cell.
The present invention relates to containing 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] pharmaceutical preparation of polymorphic form of Nicotinicum Acidum or its solvate can be prepared into treatment stomatocace, obesity and relative disease, include, but are not limited to stomatocace, insulin resistant, diabetes, fatty liver, non-alcoholic hepatitis and atherosclerotic medicine.
Accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction pattern of 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene also polymorphic form III of [2,3-b] Nicotinicum Acidum or its solvate;
Specific embodiment
Method a: under backflow, by 500mg2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum is dissolved in 30ml acetic acid, slowly room temperature is down to after stirring 30min, and in stirred at ambient temperature 3h, filter the solid of separating out, the dry 3h of ambient temperature in vacuum, obtains light yellow solid 199mg.The X-ray powder diffraction pattern of this crystal formation is shown in Fig. 1.
As can be seen from Figure 1, the peak of peak intensity more than 15 in the X-ray powder diffraction pattern of above-mentioned 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene also polymorphic form of [2,3-b] Nicotinicum Acidum or its solvate has following characteristics respectively:
| Angle of diffraction (2 θ, °) | Intensity (I/I 0) | Angle of diffraction (2 θ, °) | Intensity (I/I 0) |
| 8.840 | 18 | 14.940 | 100 |
| 25.520 | 16 |
Claims (8)
- The polymorphic form of 1.2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum or its solvate.
- 2. 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene in claim 1 also [2,3-b] polymorphic form of Nicotinicum Acidum or its solvate, the X-ray powder diffraction pattern that it is characterized by described 2-amino-7-sec.-propyl-5-oxo-5H-[1] the chromene also polymorphic form of [2,3-b] Nicotinicum Acidum or its solvate has following peak:
- 3. 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2 in any one of claim 1-2,3-b] polymorphic form of Nicotinicum Acidum or its solvate, it is characterized by unit using dosage when described polymorphic form is applied as active constituents of medicine is 0.1mg-100mg.
- 4. 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene according to any one of claim 1-2 also [2,3-b] preparation method of polymorphic form of Nicotinicum Acidum or its solvate, it is characterized by: 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene also [2,3-b] Nicotinicum Acidum adds single solvent or mixed solvent, add thermosol to lower the temperature clearly afterwards, be cooled to below room temperature or room temperature, under stirring, in system, drip poor solvent, separate out solid.
- 5. 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene according to any one of claim 1-2 also [2,3-b] Nicotinicum Acidum or its solvate treats the application of stomatocace, obesity and relative disease in preparation.
- 6., according to the application described in claim 5, it is characterized by described stomatocace, obesity and relative disease is: stomatocace, insulin resistant, diabetes, fatty liver, non-alcoholic hepatitis and atherosclerosis.
- 7. containing 2-amino-7-sec.-propyl-5-oxo-5H-[1] chromene in any one of at least one claim 1-2 also [2,3-b] preparation of polymorphic form of Nicotinicum Acidum or its solvate, it is characterized by that described preparation is tablet, capsule, common flour injection, lyophilized injectable powder, pharmaceutical solutions, aerosol, spray, paste, patch, eye drops, ear drop or implant etc. use via injection, oral, suctions, Transdermal absorption, eye drip, droplet ear, rectum or a vagina administration mode.
- 8. treat stomatocace, insulin resistant, diabetes, fatty liver, non-alcoholic hepatitis and atherosclerotic application according to the preparation described in claim 7 in preparation.
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| CN112704684A (en) * | 2021-01-13 | 2021-04-27 | 南京医科大学 | Medical application of substance for knocking down or inhibiting STING active substance |
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Application publication date: 20160217 |