CN101597272B - Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof - Google Patents
Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof Download PDFInfo
- Publication number
- CN101597272B CN101597272B CN2009101431121A CN200910143112A CN101597272B CN 101597272 B CN101597272 B CN 101597272B CN 2009101431121 A CN2009101431121 A CN 2009101431121A CN 200910143112 A CN200910143112 A CN 200910143112A CN 101597272 B CN101597272 B CN 101597272B
- Authority
- CN
- China
- Prior art keywords
- ailamode
- potassium
- preparation
- hydrate
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a sodium salt compound of Iguratimod and a hydrate or solvate thereof. The slat of the Iguratimod is far advantageous over the Iguratimod in water solubility, powder flowability and power stability. The compounds can be used in the preparation of medicaments for treating diseases such as rheumatoid arthritis, chronic infectious arthritis, osteoarthritis and ankylosing spondylitis and relieving pains caused by muscle or soft tissue damages and arthralgia. The invention also provides a preparation method of the sodium salt compound and the hydrate or solvate thereof, the use (medicinal compositions and medicinal composition preparation and use) of the compounds in medicaments, and the like.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, relate to Ailamode derivative compound, and preparation method thereof with its application in medicine.
Background technology
Ailamode (Iguratimod; T-614); Chemical name is N-[3-(formamido-)-4-oxygen-6-phenoxy-4H-1-chromene-7-yl]-NSC-249992; English name: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide, molecular structural formula is following:
Molecular formula C
17H
14N
2O
6S, molecular weight 374.4.
Ailamode is the NSAIDs that a kind of new selectivity suppresses cyclooxygenase-2, has antipyretic-antalgic, arthritis, immunoregulation effect, and treatment rheumatic arthritis, rheumatoid arthritis, osteo-arthritis and ankylosing spondylitis are had excellent curative effect; The pain that also can alleviate the damage of muscle, soft tissue and cause and arthralgia etc., it can not only selectivity suppress cyclooxygenase-2, and can regulate the T-cell; The factor capable of inhibiting cell (comprises il-1; 6,8) generation and suppress lymphocytic hyperplasia has the autoimmunization regulating effect; Determined curative effect; Spinoff is little, and onset is rapid, and the patient that other medicines are failed to respond to any medical treatment is effective.
The special permission communique of TOHKEMY 2001-240540 discloses compound structure, method for making and the purposes of Ailamode; One Chinese patent application publication number CN1931159A discloses a kind of micronized Ailamode and preparation method thereof, to expect through making the Ailamode micronize improve its oral prepns dissulution and bioavailability; One Chinese patent application publication number CN1944420A discloses a kind of crystal habit and compsn thereof of Ailamode; One Chinese patent application publication number CN101095671A discloses a kind of Iguratimod oral double-layer sustained-release preparation; One Chinese patent application publication number CN1531925A discloses the technology and the solid preparation thereof of a kind of preparation colatemo (Ailamode) solid preparation; One Chinese patent application publication number CN1462748A provides a kind of preparation method of Ailamode; One Chinese patent application publication number CN1451373A provides and has related to Ailamode tablet and preparation method thereof.
Ailamode is as new and effective NSAIDs; When medication preparation, also there is deficiency: the one, Ailamode is insoluble in water; When oral administration, because medicine difficult insoluble in water causes containing in the common preparation compsns of Ailamode; Its active ingredient is difficult for moistening and indiffusion in water; The oral dosage form for preparing with conventional pharmaceutical adjunct and dispersion coefficient is easy in gastrointestinal fluid that crystallization or deposition are separated out and can not stripping, has greatly influenced the stripping of medicine and absorbs, and has unfavorable factor; The 2nd, the light weight of Ailamode compound, the easy electrostatic interaction that produces; Cause Ailamode compound (bulk drug) can be gathered into flocculence, lack fragility, be difficult to pulverize; Mobile very poor; In formulation preparation, be difficult to mix, the formulation preparation of Ailamode and the raising of quality are brought very big difficulty, also be unfavorable for the big needs of producing of industry with pharmaceutical excipient; The 3rd, Degradation can take place in the less stable of Ailamode, and this brings hidden danger can for the storage and the quality and safety of medicine preparation.
In order to produce pharmaceutical prepn, usually advantageously adopt the pharmaceutical active compounds of the specific salts form contain acidic group or base, they for example have better solvability, better stripping and absorption behavior, better stability or better properties curve usually.Use specific salts, also can be favourable to the preparation of active compound or pharmaceutical prepn, perhaps to meet medicine regulatory authority require favourable.
Therefore, under the prerequisite of the pharmacological properties that does not change the Ailamode compound, improve Ailamode water-soluble, flowability, to be easy to comminuted, stability etc. be crucial and significant.
Summary of the invention
The contriver finds that through experiment the protium tool ionization tendency on the sulfuryl amine group of Ailamode is easy to and the alkaline matter salify, and this gives the water-soluble possibility of bringing that improves the Ailamode compound.Yet; When considering to improve water-soluble; Also to consider the pharmacological action that can not change and destroy Ailamode; And to consider that also institute's salt-forming compound should have satisfactory stability property, is applied to pharmaceutical prepn with the derivative salt that is convenient to Ailamode as active constituents of medicine to the human body safety non-toxic.
Based on above consideration and requirement, the inventor obtains the verivate of Ailamode through experiment and screening, and promptly the potassium salt compound of Ailamode has been obtained satisfied effect.
The invention provides potassium salt compound, its hydrate and the solvolyte of Ailamode, and preparation method thereof with they application in medicine.
The invention provides compound, its hydrate and the solvolyte of a kind of formula (I):
But; Also should be appreciated that Ailamode potassium of the present invention, for its various solids or dissolved salt; Under which kind of situation, the molecular structural formula of above-mentioned expression can not be understood that all it has shown the actual arrangement relatively of potassium metal ion and organic anion.The potassium metal ion also can be arranged in another position of the atom of relative negatively charged ion, for example it can be with sulphonamide on the direct coordinate of nitrogen-atoms.Therefore, the present invention provides the Ailamode potassium salt compound shown in the formula (II)
Formula (I) and formula (II) are on all four on chemical structural formula is represented.
Ailamode potassium of the present invention is a kind of solid chemical compound, in the preparation process, for keeping peculiar structural form, may contain a certain amount of water molecules or solvent molecule, and therefore, the present invention also comprises the hydrate or the solvolyte of above-mentioned Ailamode potassium.
For example; The semihydrate of Ailamode potassium, monohydrate, sesqui hydrate, duohydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, pentahydrate, five sesquialter hydrates, hexahydrate, six sesquialter hydrates, heptahydrate, seven sesquialter hydrates, eight hydrates, octuple semihydrate, nonahydrate, nine sesquialter hydrates, decahydrate, or the like;
Again for example; The ethoxy of Ailamode potassium, methylate, acetone solvate, acetonitrile solvate; Said solvolyte comprises that per molecule Ailamode potassium contains the solvent molecule of half point, a part, 1.5 molecules, 2 molecules, 2.5 molecules, 3 molecules, 3.5 molecules, 4 molecules, 4.5 molecules, 5 molecules, 5.5 molecules, 6 molecules, 6.5 molecules, 7 molecules, 7.5 molecules, 8 molecules, 8.5 molecules, 9 molecules, 9.5 molecules or 10 molecules, or the like.
Should explain; The hydrate or the solvolyte of above-mentioned many Ailamode potassium of enumerating; Be Ailamode potassium of the present invention contingent situation in crystallization or purge process, any hydrate or solvolyte in them only are the existence forms of Ailamode potassium of the present invention; Normally may command or the removal of crystal water that is contained or recrystallisation solvent; For example through adding thermal burn or calcining crystal water or recrystallisation solvent are removed, therefore, the hydrate of above-mentioned many Ailamode potassium of enumerating or solvolyte still belong to the content of technical scheme content of the present invention and scope of patent protection.
Ailamode potassium of the present invention is further reacted by Ailamode and makes; Preparing method for Ailamode; Domestic and foreign literature has been reported multiple compound method route; Can take with 4-chloro-3 mononitro-benzene methyl ethers is starting raw material, makes Ailamode through 7 steps reactions such as nucleophilic substitution, reduction, methylsulfonylization, lid Te Man-Koch reaction, acidylate, hydrolysis, cyclisation, and synthetic route is following:
The present invention provides a kind of method for preparing above-mentioned Ailamode potassium, its hydrate or its solvolyte; Comprise Ailamode and alkaline potassium compound are reacted in the solvent that is fit to; And further remove reaction solvent, Ailamode potassium deposition is separated out, and further throw out is carried out drying.
In above-mentioned preparation, " alkaline potassium compound " is Pottasium Hydroxide (KOH), alkyl potassium alcoholate (KOR), and particular methanol potassium is or/and one of potassium ethylate, potassium hydride KH (KH), alkylamine potassium (KNR), and wherein R is C
1-C
4Alkyl; The solvent that is fit to that adopts is the mixture of water, ethanol, methyl alcohol, acetone, N, N,N-DIMETHYLACETAMIDE, THF, methylene dichloride, ethylene dichloride, acetonitrile, n-propyl alcohol, Virahol 、 diox, terepthaloyl moietie, N-Methyl pyrrolidone, methyl-sulphoxide or their any two or more solvents; In order to react fully fully; The pH value of reaction solution system should be alkalescence, and the preferred solvent that adopts is the mixture of water, ethanol, methyl alcohol, acetone, Virahol, N, N,N-DIMETHYLACETAMIDE or their any two or more solvents.
In addition; The amount of the mixture of independent solvent or two kinds, multiple solvent can select to make initial compounds; Being Ailamode and alkaline potassium compound, is dissolved, but this amount also can be selected to make one or both initial compounds only be partly dissolved and have suspension-s.Be included in solution or the suspension-s of first kind of initial compounds and be included in the solution of second kind of initial compounds or the ratio of all kinds of SOLVENTS in the suspension-s can change.The preparation of the solvent mixture that reacts therein for Ailamode and alkaline potassium compound, it is preferred wherein containing water or alcohol.
Because Ailamode and alkaline potassium compound are equimolar amount (or etc. mole ionic charge amount) reactions; Under normal conditions; The aspect is considered in order to make Ailamode fully react, improve yield and to reduce cost etc.; Feeding intake when reaction, should make the mole number of alkaline potassium compound be equal to or greater than the mole number of Ailamode.
The reaction in being fit to solvent of Ailamode and alkaline potassium compound can be carried out in wide temperature range, preferably carries out to about 100 ℃ temperature at about-10 ℃.When operation under common normal atmosphere, particularly preferably in to the temperature of the boiling point of solvent for use or solvent mixture, carrying out from about-10 ℃.Particularly preferably in from making an appointment with-10 ℃ to about 90 ℃ temperature, to carry out, more, especially to about 75 ℃ temperature, carry out from about 5 ℃ particularly preferably in from about 0 ℃ to about 85 ℃.When preparation sylvite of the present invention; Usually useful is to establish many successive temperature or TR; For example make Ailamode form solution through being heated to higher temperature at the beginning, add alkaline potassium compound then, further reduce temperature afterwards so that sylvite separates.The formation of salt (react, separate out or precipitate) can be carried out under the pressure of wide region equally; For example it can under atmospheric pressure carry out; Also can under lower pressure, carry out, for example remove through distillation simultaneously in a vacuum and desolvate, perhaps under higher pressure, carry out; If for example plan to be heated to the above temperature of solvent boiling point, preferably under about 1 normal atmosphere to about 5 barometric points, carrying out.
The preparation of Ailamode potassium of the present invention can be carried out in conventional equipment.During scale operation, preferably batchwise operation carries out in conventional whisk, for example in glass or enamelled vessel or stainless steel vessel.Can add Ailamode at the beginning and add alkaline potassium compound then, perhaps can add alkaline potassium compound at the beginning and add Ailamode then, perhaps two kinds of initial compounds also can be metered in the reaction vessel simultaneously.The adding of material can be a or be divided into many parts and carries out, and perhaps can add by continuous measurement, and what mixture was favourable before Ailamode potassium separated stirs some times under the condition of confirming, like several minutes, and several hours, tens hours etc.
Preferably through utilizing filtration or spinning gained solid Ailamode potassium to carry out, Ailamode potassium can separate from solvent or the solvent mixture that Ailamode and alkaline potassium compound react therein in aftertreatment.But; The condition of carrying out according to reaction; In order to obtain high yield and high purity, also can advantageously before separating Ailamode potassium, at first mixture be cooled to low relatively temperature, for example cool to room temperature, about below 0 ℃ or 0 ℃; And/or under atmospheric pressure or in a vacuum remove partly solvent and/or add one or more other solvents, the for example insoluble relatively therein alcohol of Ailamode potassium or ether or ketone through distillation.Isolating Ailamode potassium can wash as usual and is dry, if desired, also can be further purified through recrystallization.
Concrete, in preparation Ailamode potassium, its hydrate or its solvolyte, the alkali of alkali metal cation is provided; That is: alkaline potassium compound; Be Pottasium Hydroxide, potassium ethylate or potassium methylate, suitable reaction solvent is the mixture of water, ethanol, methyl alcohol, acetone, Virahol or they any two or three, in order to react fully fully; The pH value of reaction solution system should be alkalescence; Suitable is pH >=8.5 of reaction solution system, like pH=8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5 or 14, or the like;
In above-mentioned preparation; Ailamode and alkaline potassium compound (for example Pottasium Hydroxide, potassium ethylate or potassium methylate) are with equimolar quantitative response; In order to make Ailamode and alkaline potassium compound sufficient reacting, complete, the molar weight that feeds intake of alkaline potassium compound should be equal to or greater than the molar weight of Ailamode; Further the solvent in the reaction system is removed; For example through Rotary Evaporators steam to remove, cryoprecipitation after-filtration, lyophilize, the anti-solvent of adding (like acetone or ether) filter post precipitation or the combination of this several method; Remove the solvent in the reaction system, obtain solids, and the solids that obtains is carried out purifying (like recrystallization or/and washing); Dry gained solids promptly gets Ailamode potassium of the present invention; In when reaction, preferred Ailamode is dissolved in alkaline potassium compound and is clear and bright solution in the reaction solvent, can react fully like this, complete and easy handling.
Optionally, can in the reaction solution system, add gac in the above-mentioned preparation process, again activated carbon filtration removed after the processing of decolouring.
Perhaps, necessary, the contriver finds in actual fabrication; When Ailamode and alkaline potassium compound are dissolved in the reaction solvent, usually can chromogenesis and coupling reaction takes place, this possibly be that reaction system has not clear deposits yields; The Ailamode potassium that can cause generating is brown or khaki solid, changes in order to eliminate colour developing, when Ailamode and alkaline potassium compound are dissolved in the reaction solvent; Should add gac and decolour, be white in color or off-white color with the sylvite of the Ailamode that guarantee to generate, common; The add-on of gac is 0.1～2.5% (W/V), room temperature or heated and stirred 10～60 minutes, and the filtering and removing gac promptly gets clear and bright reaction solution; Further the solvent in the reaction system is removed, for example through Rotary Evaporators steam to remove, cryoprecipitation after-filtration, lyophilize, the anti-solvent of adding (like acetone or ether) filter post precipitation or the combination of this several method, removes the solvent in the reaction system; Obtain solids; And the solids that obtains carried out purifying (like recrystallization or/and washing), dry gained solids promptly gets Ailamode potassium of the present invention.Certainly; In the above-mentioned decolorization; Following scope 0.15～2% (W/V), 0.2～1.5% (W/V), 0.25～1% (W/V), 0.3～0.5% (W/V), 0.1～1% (W/V), 0.15～2% (W/V) or 0.2～2.5% (W/V) of the add-on of gac for choosing wantonly, or the like; Room temperature or heated and stirred 10～50 minutes, 15～55 minutes, 20～50 minutes, 25～45 minutes, 30～40 minutes, 35～45 minutes, 20～40 minutes or 30～50 minutes, or the like.
In the above-mentioned preparation, the exsiccant method comprises heating, drying, decompression or vacuum-drying, lyophilize or their combination.
Be to be understood that; Lyophilize is a kind of sophisticated, conventional drying means, and lyophilize mainly contains two steps, i.e. refrigerating process and drying process; Be that solute is dissolved in water or other solvent that is fit to; Make its cryocoagulation at low temperatures, again with its by solidify attitude directly distillation remove and desolvate and obtain dry body, have be prone to control, material damage is few, do not destroy the structure of matter, do not produce advantage such as impurity.In refrigerating process, speed of cooling can be controlled, and speed of cooling is fast; Can suppress solute and form the crystalline process; Vice versa, and therefore, common dried solute can be in non-crystalline state; Refrigerative speed in the control refrigerating process also might produce xln or microcrystal or their mixture.
The technical scheme of Ailamode potassium produced according to the present invention, its hydrate or solvolyte, preferably Ailamode and Pottasium Hydroxide, potassium methylate, potassium ethylate, potassium hydride KH reaction.
Ailamode potassium of the present invention, its hydrate or its solvolyte are a kind of solid chemical compounds, and its solid form can be crystal (monocrystalline type, polymorphic), noncrystal form, also can be crystal and non-crystal mixture or amorphous body, or the like; It should also be understood that; The crystal and the noncrystal form of Ailamode potassium, its hydrate or its solvolyte can transform each other; For example can non-crystal Ailamode potassium or its hydrate be dissolved in the alcoholic acid aqueous solution; Its crystallization is separated out and obtain the compound of the crystal habit of Ailamode potassium or its hydrate; For example with Ailamode potassium or its hydrate quick freezing soluble in water of crystal habit, carry out Ailamode potassium or its hydrate that lyophilize can obtain noncrystal form again.Also be to be understood that; The hydrate of Ailamode potassium and Ailamode potassium also can transform each other; For example the decompression of the hydrate of Ailamode potassium being heated to 120 ℃ makes crystal water discrete and not with the Ailamode potassium of crystal water; Again for example will be not soluble in water with the Ailamode potassium of crystal water, carry out crystallization or recrystallization processing with the solvent that contains water, can obtain the hydrate of Ailamode potassium.But no matter be crystal, noncrystal or crystal and non-crystal mixture, all have the molecular structural formula of Ailamode potassium of the present invention, its hydrate or its solvolyte.
Concrete, the present invention also provides the preparation method of Ailamode potassium, its hydrate or its solvolyte:
Ailamode and described alkaline potassium compound are joined in the solvent, to the reflux temperature condition of solvent, make Ailamode and alkaline potassium compound dissolving, add the gac of 0.1～2.5% (W/V) at 25 ℃; Room temperature or heated and stirred 10～60 minutes; The filtering and removing gac is in room temperature or be lower than and make institute's salify crystallization, suction filtration under the room temperature condition; With draining after acetone, ether, ethanol or the washed with isopropyl alcohol, be drying to obtain Ailamode potassium of the present invention, its hydrate or its solvolyte;
In above-mentioned preparation; Said alkaline potassium compound is selected from Pottasium Hydroxide, potassium methylate, potassium ethylate or potassium hydride KH; Said solvent is selected from one or more in water, ethanol, methyl alcohol, acetone, Virahol, methylene dichloride, ethylene dichloride, the acetonitrile; Optionally can be through reducing Tc or/and steam except that the formation of partial solvent with accelerate crystallisation; Calculate at the reacting weight that feeds intake; Ailamode and alkaline potassium compound with etc. mole or near equimolar amount proportioning, for example Ailamode and alkaline potassium compound are 1 in the mole number ratio range: the reacting weight that feeds intake of (1～1.2), the charging capacity proportioning of the alkaline potassium compound of promptly per 1 mole Ailamode and 1～1.2 mole; Preferred Ailamode and alkaline potassium compound are 1 in the mole number ratio range: (1～1.1) or 1: the reacting weight that feeds intake of (1～1.05), preferred Ailamode and alkaline potassium compound are 1: 1 the reacting weight that feeds intake in the mole number ratio range.
Concrete, Ailamode and Pottasium Hydroxide are added in an amount of purified water, under 10～90 ℃, make the dissolving of Ailamode and Pottasium Hydroxide; The gac that adds 0.1～2.5% (W/V); Room temperature or heated and stirred 10～60 minutes, the filtering and removing gac optionally reduces temperature or/and steaming removes partial purification water and makes abundant crystallization; Suction filtration; With draining after ethanol, acetone, ether or the washed with isopropyl alcohol, be drying to obtain Ailamode potassium of the present invention or its hydrate, said purified water comprises zero(ppm) water, deionized water, water for injection etc.
Concrete; Ailamode and Pottasium Hydroxide are added in an amount of purified water, Ailamode and Pottasium Hydroxide are dissolved fully, add the gac of 0.1～2.5% (W/V); Room temperature or heated and stirred 10～60 minutes; The filtering and removing gac with reaction solution cooling and lyophilize, promptly gets sylvite or its hydrate of Ailamode of the present invention.
Concrete; Ailamode and alkaline potassium compound are joined in an amount of water, methyl alcohol, ethanol, acetone, Virahol, acetonitrile, N, N,N-DIMETHYLACETAMIDE, THF, methylene dichloride or their any two kinds mixed solvents; To the reflux temperature condition of solvent, make Ailamode and alkaline potassium compound dissolving in 10 ℃, add the gac of 0.1～2.5% (W/V), room temperature or heated and stirred 10～60 minutes; The filtering and removing gac; Optionally reduce temperature and make abundant crystallization or/and steaming removes the partial reaction solvent, suction filtration is with draining after ethanol, acetone, ether or the washed with isopropyl alcohol; Be drying to obtain sylvite, its hydrate or its solvolyte of Ailamode of the present invention, said alkaline potassium compound is selected from Pottasium Hydroxide, potassium methylate, potassium ethylate or potassium hydride KH.
Concrete, Ailamode and alkaline potassium compound are joined in proper amount of acetone and water or acetone and the ethanol mixed solvent, in 10 ℃ to the solvent refluxing temperature; Make the dissolving of Ailamode and alkaline potassium compound; The gac that adds 0.1～2.5% (W/V), room temperature or heated and stirred 10～60 minutes, filtering and removing gac; Optionally reduce temperature and make abundant crystallization or/and steaming removes the partial reaction solvent; Suction filtration with draining after acetone, ether, Virahol or the washing with alcohol, is drying to obtain sylvite, its hydrate or its solvolyte of Ailamode of the present invention.Acetone and water or acetone and alcoholic acid volume ratio are optional; Also can with acetone Ailamode be dissolved respectively; Water or ethanol dissolve alkaline potassium compound, two kinds of solution are mixed, to reach the purpose of in acetone and water or acetone and ethanol mixed solvent, reacting again.
Special; The contriver finds; Ailamode and alkaline potassium compound react in the mixture of water, ethanol, methyl alcohol, acetone, Virahol, acetonitrile, N, N,N-DIMETHYLACETAMIDE or their any two or more solvents, be easy to react and operate, and the Ailamode potassium that obtains are easy to drying, solvent residual amount is few, the pressed powder homogeneity is good; Therefore, the invention provides the Ailamode verivate shown in the following formula, its hydrate or its thinner thing:
It is characterized in that it is reacted in the solvent that is fit to by Ailamode and alkaline potassium compound, optionally, add the amounts of activated carbon of 0.1～2.5% (W/V); Room temperature or heated and stirred 10～60 minutes, the filtering and removing gac is further removed reaction solvent; And carry out drying and prepare, wherein:
Alkaline potassium compound is selected from Pottasium Hydroxide, potassium ethylate, potassium methylate, potassium hydride KH or alkylamine potassium;
The solvent that is adopted is the mixture of water, ethanol, methyl alcohol, acetone, Virahol, acetonitrile, N, N,N-DIMETHYLACETAMIDE or their any two or more solvents.
Ailamode potassium provided by the invention, its hydrate or its thinner thing; When they are used to treat as active ingredient; The general patient's said derivative of simple Ailamode that directly do not give; Usually all be that therefore, the present invention also provides corresponding pharmaceutical compositions and preparation method with the form appearance of the pharmaceutical composition that contains pharmaceutically acceptable carrier.
Can pass through administration Ailamode potassium of the present invention, its hydrate or its thinner thing of any appropriate, but common administered through oral, Transdermal absorption or injection administration.In order to carry out this type application, generally use Ailamode potassium of the present invention, its hydrate or its thinner thing with the pharmaceutical compositions that contains pharmaceutically acceptable carrier, but, the definite form of said composition depends on form of medication naturally.
Further; The present invention also provides a kind of pharmaceutical composition that contains above-mentioned Ailamode potassium, its hydrate or its thinner thing; And contain one or more pharmaceutically acceptable carriers; The content of Ailamode potassium wherein of the present invention, its hydrate or its thinner thing is 1～100mg, for example 1mg, 2mg, 3mg, 5mg, 8mg, 10mg, 12mg, 15mg, 18mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 70mg, 80mg, 90mg, 100mg.
Further; Ailamode potassium of the present invention, its hydrate or its thinner thing do not use to the patient with simple chemical usually; But be processed into compsn (preparation) form that the patient is easy to accept, be the application of active ingredient (bulk drug) in pharmaceutical composition (preparation) so the present invention also provides Ailamode potassium, its hydrate or its thinner thing.With Ailamode potassium of the present invention, its hydrate or its thinner thing is active ingredient (bulk drug); And contain one or more pharmaceutically acceptable pharmaceutical carriers; Be mixed with form through any suitable administration; Can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics; Comprise oral prepns, cutaneous permeable agent, injection formulations, non-oral liquid preparation, or the like, oral prepns is like oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent or the like; Cutaneous permeable agent is like the emulsifiable paste of Transdermal absorption, gel, emulsion, emulsion agent, patch etc.; Injection is like powder ampoule agent for injection and injection liquid, or the like; And for example eye drop, nasal drops, [or the like.Also can be the formulation such as quick-release, slowly-releasing, controlled release of above various formulations, for example oral dispersible tablet, slow releasing tablet, chewable tablet, slow releasing capsule, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets, effervescent granule, or the like.Especially; By means known in the art preparations, be preferred for preparing the tablet (comprising dispersible tablet, slow releasing tablet, chewable tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets) that uses on the pharmaceutics, capsule (comprise that stomach dissolves, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc.; The ointment of Transdermal absorption, gelifying agent, emulsion agent, emulsion agent, patch etc. are to satisfy the various needs in the clinical use.
Be to be understood that; For oral or injection; According to method well known in the art; Pharmaceutical carrier is matrix or the auxiliary material that keeps pharmaceutical dosage form, selects or make up use for use according to different medicaments usually, optionally comprises vehicle or thinner; For example Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, Expex, Prist, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, Ucar 35, glycerine, Schardinger dextrins and verivate thereof, or the like; Also can comprise tackiness agent, for example polyvidone (Vinylpyrrolidone polymer), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, X 5363, XG 550, or the like; Also comprise lubricant, for example Magnesium Stearate, Triple Pressed Stearic Acid, talcum powder, stearyl fumarate, Sodium Lauryl Sulphate BP/USP, or the like; Also can comprise disintegrating agent, for example sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, crosslinked carboxymethyl fecula sodium, pregelatinized Starch, or the like; Also comprise tensio-active agent, for example sodium lauryl sulphate, Tween-80, or the like; Also can comprise pH value regulator or buffer reagent, for example phosphate buffered saline buffer, Hydrocerol A, Trisodium Citrate, acetate buffer, Hydrogen chloride, yellow soda ash, Pottasium Hydroxide, or the like; Also can comprise sanitas, for example Sodium Benzoate, POTASSIUM SORBATE GRANULAR WHITE, methyl paraben, propylben, or the like; Also can comprise stablizer and oxidation inhibitor, for example Calcium Disodium Edetate, S-WAT, vitamins C, or the like; Also can comprise the taste regulator, for example maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, strawberry flavour, or the like; Also can comprise other conventional, appropriate additive in addition.It is also understood that when formulation is tablet or capsule, can be the film dressing.The material that is used for the film dressing comprises suitable seed dressing agent, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, or the like; Also can comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, or the like; Also comprise suitable solubilizing agent, like Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, like titanium oxide, various red stone, pink pigment, or the like.
For the gelifying agent of Transdermal absorption, contain Ailamode potassium of the present invention, its hydrate or its thinner thing and gel matrix as activeconstituents.Wherein gel matrix is selected from one or more mixtures with any mixed in carbomer, chitosan, sucralfate, Vinylpyrrolidone polymer, Ucar 35, ethanol, glycerine, polyoxyethylene glycol, Z 150PH, methylcellulose gum, TKK 021, Natvosol, hydroxypropylcellulose, hypromellose, Xylo-Mucine, Prist, gelatin, the sodium-alginate.Gelifying agent can further contain transdermal enhancer (as: one or more in laurocapram, Ucar 35, ethanol, Therapeutic Mineral Ice, spearmint oil, eucalyptus oil, borneol, Virahol, urea, the oleic acid are with the mixture of any mixed), wetting Agent for Printing Inks (one or more are with the mixture of any mixed in water, glycerine, Ucar 35, polyoxyethylene glycol, sorbyl alcohol, the maltose alcohol), pH regulator agent (like trolamine, diethylolamine, tromethane, quadrol, diethylamine, laurylamine, ammonia soln, sodium hydrogencarbonate, sodium hydroxide or Pottasium Hydroxide, hydrochloric acid, phosphoric acid salt, Citric Acid and salt thereof), solubilizing agent (, sodium lauryl sulphate serial, Polyoxyethylene hydrogenates the Oleum Ricini, peregal, methyl-sulphoxide), sanitas and oxidation inhibitor like tween series, sapn (as in ethanol, parachlorometacresol, Thiomersalate, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, phenylformic acid, Sodium Benzoate, trichloro-butyl alcohol, benzalkonium chloride, Morpan BB, Tegosept M, ethyl p-hydroxybenzoate, propylben, sulphite, NAC, vitamins C, vitamin E, the di-tert-butyl hydroxy toluene one or more with the mixture of any mixed), stablizer (like disodium EDTA, YD 30 two calcium disodiums or oxalic acid triamine pentaacetic acid), or the like.
Ointment for Transdermal absorption; Ointment base comprises greasing base and water-soluble base, and wherein greasing base is preferably one or more mixtures with any mixed in Triple Pressed Stearic Acid, glyceryl monostearate, POLYOXYL 40 STEARATE, paraffin, whiteruss, Vaseline (comprising white vaseline, Yellow Vaselin), yolk, hexadecanol, stearyl alcohol (being called VLTN 6 again), sapn series (like Arlacel-60, Arlacel-40, Arlacel-85, Arlacel-20 etc.), beeswax, the Vegetable oil lipoprotein (like Viscotrol C, VT 18, Semen Maydis oil, sunflower seeds wet goods); Wherein water-soluble base is preferably one or more mixtures with any mixed in glycerine, Ucar 35, sorbyl alcohol, polyoxyethylene glycol series (Liquid Macrogol, PEG 400, cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, polyoxyethylene glycol 8000 etc.), tween series (like tween-80, Tween-60, Tween-40 etc.), sodium lauryl sulphate, urea, peregal (like paregal O, peregal A etc.), ethanol, the methyl-sulphoxide.In the ointment; Can also contain an amount of sanitas and oxidation inhibitor, sanitas and oxidation inhibitor be in ethanol, parachlorometacresol, Thiomersalate, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, phenylformic acid, Sodium Benzoate, trichloro-butyl alcohol, benzalkonium chloride, Morpan BB, Tegosept M, ethyl p-hydroxybenzoate, propylben, sulphite, NAC, vitamins C, vitamin E, the di-tert-butyl hydroxy toluene one or more with the mixture of any mixed; In the ointment; Can also contain an amount of transdermal enhancer, transdermal enhancer is selected from one or more mixtures with any mixed in laurocapram (Azone), Ucar 35, ethanol, Therapeutic Mineral Ice, eucalyptus oil, spearmint oil, borneol, Virahol, urea, the oleic acid; In the ointment, optionally can also contain wetting Agent for Printing Inks, thickening material etc.
Should be appreciated that above-mentioned " optionally comprising " is meant promptly can optionally select to use, and also can not use.
Aforesaid pharmaceutical composition; Contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with form, can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics through any suitable administration; Ailamode potassium of the present invention, its hydrate or its thinner thing are active substances wherein; Can also comprise the material that other has pharmaceutical active in the pharmaceutical composition, form a kind of pharmaceutical composition of compound, come combination therapy.
Aforesaid preparation of drug combination method; This method comprises processes acceptable any pharmaceutical dosage form on the pharmaceutics with Ailamode potassium, its hydrate or its thinner thing and pharmaceutically acceptable pharmaceutical carrier thorough mixing, and preferred pharmaceutical dosage form is tablet (comprising dispersible tablet, slow releasing tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets etc.), capsule (comprise that stomach dissolves, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid); The ointment of Transdermal absorption, gelifying agent, emulsion agent, emulsion agent, patch etc.
Under the usual condition; Ailamode potassium of the present invention, its hydrate or its thinner thing and pharmaceutically acceptable pharmaceutical carrier exist with pulverulence; Its thorough mixing there is crucial effect for the steady quality of medicine preparation; Assemble in order to prevent that active ingredient from forming; During solid preparation, can not active ingredient and pharmaceutical carrier be processed the even good preparation of content in preparation through simple blending means, for example the dispersing and mixing through stepped mixing or long period makes Ailamode potassium, its hydrate or its thinner thing and pharmaceutical carrier thorough mixing even.Perhaps pharmaceutical carriers such as Ailamode potassium, its hydrate or its thinner thing and Vinylpyrrolidone polymer, polyoxyethylene glycol, Prist are processed solid dispersion, to reach well-mixed purpose through solid dispersions technique.
Description of drawings:
Relevant accompanying drawing provided by the invention is following:
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of Ailamode potassium salt compound
1H NMR (300MHz, DMSO-d
6);
Fig. 2 is the carbon-13 nmr spectra figure of Ailamode potassium salt compound
13C NMR (300MHz, DMSO-d
6);
Fig. 3 is the infrared absorpting light spectra IR (cm of Ailamode potassium salt compound
-1, the KBr compressing tablet).
The advantage or the characteristics of Ailamode potassium of the present invention, its hydrate or its thinner thing:
1. Ailamode potassium of the present invention, its hydrate or its thinner thing; The basic salt ylidene ligands of being selected for use---potassium ion is safe, and human body is not had extra spinoff, and Ailamode potassium stable in properties of the present invention; Be difficult for decomposing, be easy to preserve and use as bulk drug.
2. the sylvite of Ailamode of the present invention, its hydrate or its thinner thing do not change the medicine effect of Ailamode, water-soluble good promoter action are arranged but form sylvite to what improve Ailamode.Through the rough determination comparison, Ailamode, Ailamode potassium water dissolution characteristic (normal temperature and pressure) are relatively like following table 1:
Table 1
Can find out that by table 1 the water-soluble Ailamode that is far longer than of Ailamode potassium of the present invention shows that it is outstanding water-soluble.
3. the water-soluble of the excellence of Ailamode potassium of the present invention has good promoter action for its stripping in preparation, and be especially for oral prepns, significant.
Be to be understood that oral medicament need pass through GI absorption could get into blood of human body reaching antiviral effect, the quality of oral absorption directly affects the result of treatment of medicine.According to the notion of pharmaceutics, bioavailability (Bioavailability) refers to that medicine is absorbed to get into and sanguimotorly utilizes degree and utilize speed.Compare Ailamode, Ailamode potassium of the present invention has excellent water-soluble, gets into aspect sanguimotor degree and the speed absorbing for the oral drug preparation that with it is active ingredient, has important promoter action and meaning.Medicament gets into the absorption process behind the stomach and intestine; Divide two stages, i.e. disintegration dispersion and gastrointestinal wall absorb two stages, at first need in gastric juice or intestinal juice, disintegration scatter; And then contact and be attached to gastrointestinal wall and absorb and get into blood; This two stages all can influence the performance with drug effect that absorbs of medicine, and Ailamode is prepared as water-soluble good sylvite derivative form, and the medicine dissolution rate is significantly accelerated; Improved its disintegration dispersive degree and rate of dispersion in gastric juice or intestinal juice greatly; Then medicament active composition is more abundant with contacting of gastrointestinal wall, is attached to that gastrointestinal wall absorbs and to get into the active ingredient of blood also more abundant, and this raising for the bioavailability of efficacy component Ailamode potassium is significant; Also have, the rapid absorption of Ailamode potassium for quick acting, reaches in the medicine of anti-inflammatory analgesic and acts on.
With following experiment the advantage of Ailamode potassium of the present invention stripping in preparation is described, experiment as follows.
Experimental technique: the selection of preparation model; Lactose and pregelatinized Starch are the most frequently used pharmaceutical excipients in the oral prepns; Therefore be pharmaceutical excipient with starch (50%) and pregelatinized Starch (49%); Magnesium Stearate is lubricant (1%), and the Ailamode, Ailamode potassium that with content are 25mg respectively are as active ingredient.
Specimen preparation: is wet granulation, whole grain, the drying that wetting agent is equal to water, compressing tablet obtains the tablet of Ailamode, Ailamode potassium respectively, is that research model is tested the wherein stripping situation of active substance with these two kinds of tablets.
Dissulution content assaying method: get specimen; According to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), be dissolution medium with phosphate buffered saline buffer (pH7.5), rotating speed is that PM 50 changes; Operation in accordance with the law; In the time of 25 minutes, get solution 10ml and filter, get subsequent filtrate as need testing solution; It is an amount of approximately that other gets the Ailamode reference substance, and accurate the title decides, and is diluted to 10 μ g/ml solution with phosphate buffered saline buffer (pH7.5), as reference substance solution.Measure with the HPLC method, detect wavelength 250～263nm.Limit is 85% of a labelled amount, should be up to specification.
The dissulution of sample (accumulation) is measured the result and RSD (RSD) sees the following form.
Table 2 dissulution (accumulation) result (n=10)
Above table 2 is measured the result and is shown that the dissulution of Ailamode potassium in the time of 25 minutes is good, and very is superior to the dissulution of Ailamode model sample significantly.Demonstrate potassium good performance aspect the preparation stripping of Ailamode of the present invention.
4. performances such as powder accumulation density, powder flowbility relatively
Conventional; The flowability of bulk drug powder is extremely important for the preparation process (like preparation procedures such as granulation, can, compressing tablets) of oral solid formulation, and the flowability of bulk drug powder directly has influence on the uniformity coefficient of effective constituent in pharmaceutical prepn or the compsn and the homogeneity of quality.Tap density is big, the bulk drug powder of good fluidity, is very favorable for the preparation of oral solid formulation.
Ailamode potassium compound of the present invention is difficult for producing static, and the good fluidity of powder is compared with Ailamode, has tangible advantage at aspect of performances such as powder accumulation density, powder flowbilitys.It is thus clear that, be made as Ailamode potassium compound of the present invention to Ailamode, can well solve Ailamode compound light weight, be prone to produce electrostatic interaction and assemble shortcoming such as agglomerating, mobile difference, bring great convenience for the preparation of pharmaceutical prepn.
Through relatively finding; Disclosed micronized Ailamode of one Chinese patent application publication number CN1931159A and preparation method thereof, it is through preparing fine powder material with adding the method that elutriation goes out after the solvent method dissolving, but powder accumulation density is very little; Still light weight, powder are light attitude; Flowability is still relatively poor, and this preparing method's cost also can bring dissolvent residual also than higher.
And the tap density of Ailamode potassium powder of the present invention is bigger, and through measuring, when granularity was 80 orders, the powder accumulation density of Ailamode potassium was more than 6.5 times of Ailamode powder accumulation density, and powder is grains of sand attitude, and is mobile fabulous.
5. be easy to smashing comparison
Disclosed micronized Ailamode of one Chinese patent application publication number CN1931159A and preparation method thereof; It is through preparing fine powder material with adding the method that elutriation goes out after the solvent method dissolving; It is through preparing fine powder material with adding the method that elutriation goes out after the solvent method dissolving, and is still undesirable, though the Ailamode powder diameter that this method obtains can be below 50 microns; But this preparing method's cost is high, and can bring dissolvent residual.
In the medication preparation, the most conventional, most economical breaking method is mechanical solid breaking method.Adopt KH-100 type medicine kibbler respectively Ailamode and Ailamode potassium of the present invention to be carried out the routine pulverizing under the same terms; The powder that obtains is carried out 50 orders, 80 orders, 100 orders, 200 orders to sieve; The sieve percentage of powder amount of calculating obtains following data:
The percent passing of table 3 Ailamode and Ailamode potassium powder
Can find out by last table 3; Routine is under the same conditions pulverized; Ailamode potassium powder in 50 orders, 80 orders, 100 orders, 200 purpose percent passings all much larger than the Ailamode powder; Therefore Ailamode potassium powder fragility big, be easy to pulverize, can be easy, economical obtain micronized powder, demonstrate Ailamode potassium in the superiority that is easy to aspect comminuted.
6. reversible reduction test
Get a certain amount of Ailamode potassium compound of the present invention respectively and be dissolved in an amount of zero(ppm) water, regulate making pH value of solution≤4 with the hydrochloric acid of 0.1mol/L, have white precipitate and generate, the solid collected by filtration thing is dried behind the distilled water wash, and through check, solids is an Ailamode.This shows that Ailamode potassium of the present invention has changed the physicochemical property of Ailamode, do not change and destroy the pharmacological action of Ailamode.
7. stability test
Get a certain amount of Ailamode potassium of the present invention respectively, by " TP of relevant stability is observed Ailamode potassium of the present invention and had satisfactory stability property in 2005 editions two ones of the Chinese pharmacopoeia, meets medicinal requirements.
The inventor research Ailamode stable the time; Find through destructive test; The less stable of Ailamode, Ailamode are especially unstable in character under acidic conditions, and relative substance content can increase largely; Can produce more degraded product, but next relatively stable at alkaline condition.Ailamode potassium is the alkaline matter that generates through chemical reaction, and from the related substance analysis that heat stability test produced, the contriver finds that pleasantly surprisedly the thermostability of Ailamode potassium significantly improves than Ailamode, tests as follows:
Adopt the HPLC method to measure the related substance of Ailamode or its potassium.Method: adopt W.S C18 post, 3.9mm * 15cm (5 μ m); With methyl alcohol-0.1% phosphoric acid (42: 58) as moving phase; Flow velocity 1.0ml/min; Detect wavelength 250～263nm.Sample size 10 μ l.Theoretical plate number is calculated by Ailamode should be not less than 4000.
Get Ailamode potassium and Ailamode respectively and put in the weighing bottle, spread out＜the 5mm thin layer, place 45 ℃ of thermostat containers to place 10 days, detect, and with result and comparison in 0 day, the result sees table 4 respectively at sampling in 5,10 days.
Table 4 high temperature test result
Mensuration result shows that Ailamode potassium and Ailamode high temperature were placed 10 days for 45 ℃, and each is investigated in the item, and water absorbability does not have considerable change; Content descends to some extent, and the content decline degree of Ailamode is greater than Ailamode potassium; Total impurities content increases to some extent in the related substance, and the total impurities content of Ailamode is far longer than the total impurities content of Ailamode potassium, and the total impurities content of Ailamode is that the total impurities content of Ailamode potassium is more than 2 times.Can find out that the stability of Ailamode potassium significantly improves than Ailamode.
8. Ailamode potassium of the present invention is to the therapeutic action test of rat arthritis model
Rheumatoid arthritis is to be the autoimmune disorder of pathological manifestations with synovial hyperplasia property inflammation.The synovium of joint fibroblast-like cells is the important component in the rheumatoid arthritis synovial membrane, has the characteristic of abnormality proliferation, can secrete multiple inflammatory factor and growth factor, promotes the rheumatoid arthritis synovitis to take place and development.The propagation that suppresses synovial tissue can become a kind of effective way of controlling the rheumatoid arthritis state of an illness.
Model trial: adopt collagen-induced property sacroiliitis (collagen-induced arthritis; CIA) set up rat arthritis model; Promptly give the rat feeding Ailamode potassium of the present invention in the model process inducing to set up, and set up blank control group, control group is observed, the cycle is two months.Test-results shows; The animal groups of feeding Ailamode potassium of the present invention detects in foot swelling, joint deformity outward appearance; And foot pathology synovium of joint hyperplasia, inflammatory cell invade pathologic section context of detection such as profit, compares with control group, and pathology is slight; All have significant difference (p＜0.05), demonstrate Ailamode potassium of the present invention and have good effect aspect treatment bone and joint diseases, the inflammation of bone.
9. atlas analysis: the potassium of Ailamode of the present invention and Ailamode carried out hydrogen nuclear magnetic resonance spectrogram (solvent DMSO-d
6) analyze, the hydrogen spectrum of finding Ailamode has the absorption peak of 1H in about 10.1 positions, through analyze in the Ailamode structure-NHSO
2Near the absorption peak of protium in the-group, and the hydrogen spectrogram of Ailamode potassium of the present invention does not have absorption peak this position, can confirm as when forming Ailamode sylvite of the present invention replaced by positively charged ion potassium due to, meet the structure of Ailamode sylvite of the present invention fully.
Further, based on the above-mentioned advantage or the characteristics of Ailamode potassium of the present invention, Ailamode sylvite of the present invention or ammonium salt and compsn thereof, application in the following areas:
(1) application in the medicine of preparation treatment rheumatic arthritis, rheumatoid arthritis, osteo-arthritis and ankylosing spondylitis;
(2) application in the medicine of diseases such as the pain that causes, alleviation arthralgia preparing the damage of alleviating muscle and soft tissue.
Also can be applicable to following pain or symptom: dysmenorrhoea, toothache, wound pain, neurodynia (like sciatica, trigeminal neuralgia), postoperative pain, cancer pain; Acute sprain or soft tissue contusion; Fracture pain, sprain pain; Cold, fever with and the whole body pain that causes; Scapulohumeral periarthritis, bursitis, tendinitis and tenosynovitis.
Embodiment
In implementation process of the present invention, the various embodiments that those of ordinary skills produce on the basis that does not depart from the scope of the present invention with spirit with modify conspicuous and be to carry out easily.Come Ailamode potassium of the present invention, its hydrate or its solvolyte through following embodiment, and preparation method thereof specify with its should be used as further in medicine, but do not represent the embodiment limitation of the present invention.
Method one. get Ailamode 1g (about 2.67mmol) and add the 400ml absolute ethyl alcohol, after the reflux dissolving, add the solution that 150mg Pottasium Hydroxide (about 2.67mmol) forms again in the 10ml absolute ethyl alcohol; 80 ℃ mix, react, and looking needs to add the 280mg gac, stir insulation decolouring and filtering gac; To filtrate to revolve do to remove and desolvate, obtain solids, remove cleaning solvent with cold ethanol or ether repetitive scrubbing or rinsing with Rotary Evaporators; Drying promptly gets Ailamode potassium.Molecular formula C
17H
13N
2O
6SK, results of elemental analyses:
% theoretical value C:49.50H:3.18N:6.79
% measured value C:49.56H:3.22N:6.81.
Method two. get Ailamode 1g (about 2.67mmol) and add the stirring of 80ml zero(ppm) water; Furnishing suspension-s state; In addition be added to the drips of solution of 151mg Pottasium Hydroxide (about 2.7mmol) in 4ml zero(ppm) water in the suspension-s of above-mentioned Ailamode and stir, all add the potassium hydroxide solution continued and stir and Ailamode is dissolved fully be clear and bright solution, add the 100mg gac and stir and decolour; Remove by filter gac, filtrating can be handled through following method and obtained Ailamode potassium:
(1) will filtrate and revolve the dried water solvent of removing with Rotary Evaporators, and obtain pressed powder, with acetone rinsing 1～2 time, drying promptly gets Ailamode potassium, its hydrate.
(2) filtrating is put carry out lyophilize in the lyophilizer and handle, drying obtains Ailamode potassium, and wherein freeze-drying process is following:
| Operation | Temperature rise rate | Time (h) | Temperature (℃) | |
| 1 | Pre-freeze | 5 | Be refrigerated to-40 ℃ by |
|
| 2 | Insulation | 1 | -35℃ | |
| 3 | Vacuumize | 1 | -35℃ | |
| 4 | Heat up | 6 ℃/hour | 5 | Be warming up to-5 ℃ |
| 5 | Heat up | 1.5 | -5 ℃ are warming up to 0 ℃ | |
| 6 | Heat up | 1.5 | 0 ℃ is warming up to 10 |
|
| 7 | Heat up | 2 | 10 ℃ are warming up to 26 |
|
| 8 | Insulation | 4 | 26℃ |
(3) will filtrate and revolve dried 60% the water solvent of removing with Rotary Evaporators, and stir after adding acetone, and put refrigerator overnight, and take out rate, behind the washing with acetone, drying obtains Ailamode potassium, its hydrate.
Method three. after getting the dissolving of Ailamode 1g (about 2.67mmol) adding 150ml acetone reflux, drip the solution that 15lmg Pottasium Hydroxide (about 2.7mmol) forms in the 5ml absolute ethyl alcohol, after adding fully; Insulated and stirred is mixed, reaction; Reduce to room temperature, suction filtration, filter cake is washed 2～4 times with acetone; Drying promptly gets Ailamode potassium.
The above-mentioned Ailamode potassium that makes is consistent with theoretical value through ultimate analysis.
1HNMR(DMSO-d
6)δ：9.65(1H，s)，9.05(1H，s)，8.30(1H，s)，7.30(2H，t)，7.23(2H，d)，7.01(1H，t)，6.87(2H，d)，2.59(3H，s)。
13CNMR(DMSO-d
6)δ：39.70，103.47，110.32，113.09，117.32，121.98，122.70，129.59，143.69，146.69，151.52，154.50，158.28，160.41，169.44。
IR (cm
-1, the KBr compressing tablet): 3503,3463,3347,3246,2929,2853,2762,2666,2597,2401; 2307,2176,2122,2023,1679,1597,1547,1464,1369,1289,1227; 1164,1108,1001,960,916,855,759,691,635,587,538.
Method one. get Ailamode 1g (about 2.67mmol) and add the 200ml acetonitrile, after the reflux dissolving, add 151mg Pottasium Hydroxide (about 2.7mmol) again at the solution that in the 10ml absolute ethyl alcohol, forms; 70 ℃ mix, react, and looking needs to add proper amount of active carbon, stir insulation decolouring and filtering gac; To filtrate to revolve do to remove and desolvate, obtain solids, remove cleaning solvent with cold ethanol or ether repetitive scrubbing or rinsing with Rotary Evaporators; Drying promptly gets Ailamode potassium.
Method two. get Ailamode 1g (about 2.67mmol) and add the 300ml absolute ethyl alcohol, after the reflux dissolving, add the solution that 227mg potassium ethylate (about 2.7mmol) forms again in 17ml ethanol; Stirring at normal temperature is mixed, reaction, adds the amounts of activated carbon of 0.15% (W/V), 55～90 ℃ of heated and stirred 20 minutes; The filtering and removing gac, will filtrate with Rotary Evaporators revolve dried remove 2/3rds solvents after, cooling is left standstill; Filter; Obtain solids with acetone or cold alcohol flushing 2 times, drying promptly gets Ailamode potassium.
Embodiment 3. Ailamode potassium and preparations thereof
After getting the dissolving of Ailamode 1g (about 2.67mmol) adding 160ml acetone reflux, drip the solution that 150mg Pottasium Hydroxide (about 2.67mmol) forms in 2ml zero(ppm) water, after adding fully; Insulated and stirred is mixed, reaction; Reduce to room temperature, suction filtration, filter cake is washed 2～4 times with acetone; Drying promptly gets Ailamode potassium, its hydrate.
Embodiment 4. Ailamode potassium and preparations thereof
Get Ailamode 1g (about 2.67mmol) add the heating of 20ml N make separate fully after, drip the solution that 150mg Pottasium Hydroxide (about 2.67mmol) forms in the 10ml absolute ethyl alcohol, fully after the adding; Insulated and stirred is mixed, reaction; Reduce to room temperature, suction filtration, filter cake is washed 2～4 times with acetone; Drying promptly gets Ailamode potassium.
Embodiment 5. as the main ingredient composition, adopts suitable pharmaceutical adjunct prescription and technology with Ailamode potassium or its hydrate, processes oral tablet, capsule, granule; The gelifying agent of external application, emulsion agent, patch; The injection liquid that injection is used, powder ampoule agent for injection etc., the active ingredient that the per unit preparation contains (being converted into the Ailamode meter) is 5～50mg, is preferably 5mg, 10mg, 12.5mg, 20mg, 25mg, 30mg, 50mg.
Embodiment 6. contains the tablet or the capsule of Ailamode potassium
The preparation method: (1) is pulverized former, auxiliary material and is crossed 80～100 sieves respectively, and with pregelatinized Starch, N.F,USP MANNITOL and Microcrystalline Cellulose mixing, adds Ailamode potassium, and the equivalent stepped mixing is even, and is subsequent use.
(2) sodium lauryl sulphate is dissolved in an amount of zero(ppm) water, gets the mixed powder wet method system softwood of (1) preparation, 30 mesh sieves granulations, 55 ℃ of dryings 2 hours.
(3) get above-mentioned particle, add the Sodium Croscarmellose and the Magnesium Stearate of recipe quantity, the whole grain of 20 mesh sieves.Be pressed into 1000, control pressure 3.5～4kg promptly gets tablet; Perhaps granule filling is gone in 1000 Capsuleses (stomach dissolve or enteric solubility), promptly get capsule or enteric coated capsule, every or every capsules (per unit preparation) contain Ailamode potassium and are respectively 25mg, 22mg, 15mg, 20mg.
Preparing method two (dry granulation): the pregelatinized Starch in the above-mentioned prescription, N.F,USP MANNITOL, Microcrystalline Cellulose are pulverized; Cross 100 mesh sieves, 85 ℃ through drying under reduced pressure more than 12 hours to constant weight, be cooled to room temperature at drying conditions (in the moisture eliminator); Take by weighing recipe quantity Ailamode potassium and sodium lauryl sulphate and above-mentioned dry auxiliary material; Mix back dry granulation (using the dry granulation machine), add sodium starch glycolate and Magnesium Stearate again, be compressed to 1000 after mixing; Promptly get tablet, supply to orally use.Or above-mentioned particle powder is filled in 1000 Capsuleses (stomach dissolve or enteric solubility), promptly getting capsule or enteric coated capsule, every or every capsules (per unit preparation) contain Ailamode potassium and are respectively 25mg, 22mg, 15mg, 20mg.
The tablet of embodiment 6. Ailamode potassium or capsule and preparation thereof
Prescription is formed: Ailamode 20g, N.F,USP MANNITOL 70g, pregelatinized Starch 50g, low-substituted hydroxypropyl cellulose 25g, Pottasium Hydroxide 3g, polyvidone 5g, Magnesium Stearate 2g.
The preparation method: (1) mixes Ailamode and N.F,USP MANNITOL, and behind 40% aqueous ethanolic solution dissolved hydrogen potassium oxide 3g, to Ailamode and N.F,USP MANNITOL mixed powder wet method system softwood, 30 mesh sieves are granulated with the aqueous ethanolic solution of this Pottasium Hydroxide, and oven dry is subsequent use.Can make the Ailamode reaction generate Ailamode potassium in this preparation process.
(2) above-mentioned particle and pregelatinized Starch, low-substituted hydroxypropyl cellulose, polyvidone and Magnesium Stearate are mixed, whole grain is pressed into 1000; Perhaps particle powder is filled in 1000 Capsuleses (stomach dissolves or enteric solubility), promptly gets tablet or capsule.
Prescription: Ailamode potassium 0.2g, methylcellulose gum 1.7g, ethyl p-hydroxybenzoate 0.03g, Ucar 35 4g adds purified water to 100g.
Preparation: get methylcellulose gum and evenly be spread on 50ml purified water surface, make its natural swelling after, stir, other gets that Ailamode potassium grinds and molten loosing in wherein in Ucar 35; Add methocel solution, stir, add the solution of ethyl p-hydroxybenzoate in suitable quantity of water again, stir; Add water to 100g, stir, get the agent of Ailamode potassium gel; Be packed as 5 bottles, every bottled gelifying agent 20g, promptly getting every bottle (per unit preparation), to contain Ailamode potassium be 40mg.Confession skin is smeared, the Transdermal absorption external application.
Prescription: Ailamode potassium 2g, polyoxyethylene glycol-400 15m, absolute ethyl alcohol 10ml, card crosses nurse (940) 1g, trolamine 4.5g, laurocapram 2g, glycerine 5ml, zero(ppm) water adds to 100g.
Preparation: take by weighing the recipe quantity carbomer, add an amount of zero(ppm) water, place, make its complete swelling after, add glycerine, trolamine, laurocapram successively and stir, subsequent use.Other gets Ailamode potassium 2g, adds ethanol, PEG 400 etc. and an amount of zero(ppm) water, and is evenly mixed.This liquid is slowly added card cross in the gel matrix of nurse, the limit edged stirs, and the final vacuum that the stirs degassing is distributed into every pipe 20g again, seals to get final product, and supplies skin to smear the Transdermal absorption external application.
Embodiment 9. injection Ailamode potassium powder injection and preparations thereof
Ailamode potassium 12g
N.F,USP MANNITOL 100g
The pH regulator agent is an amount of
Water for injection adds to 1300ml
Ailamode potassium, the N.F,USP MANNITOL of getting recipe quantity add the dissolving of 1000ml water for injection, and adding pH regulator agent adjusting pH is 8.5～9, add the injection water to 1300ml; With the filtering with microporous membrane degerming, under hundred grades of conditions, carry out in sterile filling to 1000 cillin bottle, add plug after the inspection loading amount; Box out, the glass bottle is sent into to carry out freeze-drying in the disinfectant freeze drying box dry: pre-freeze 5 hours, temperature drop to-35 ℃; Distilled 8 hours for the first time, temperature rises to-5 ℃; Distilled 7 hours for the second time, temperature rises to 25 ℃, takes out behind vacuum gland or the inflated with nitrogen gland, and jewelling lid labeling gets product, and every bottle of freeze-dried powder contains Ailamode potassium 12mg.
Claims (2)
1. the Ailamode verivate shown in the following formula:
2. method for preparing the described Ailamode verivate of claim 1, it comprises reacts Ailamode and alkaline potassium compound in the solvent that is fit to, and further remove reaction solvent, and carry out drying, wherein:
Alkaline potassium compound is selected from Pottasium Hydroxide, potassium ethylate, potassium methylate or potassium hydride KH;
The reaction solvent that is adopted is the mixture of water, ethanol, methyl alcohol, acetone, Virahol, acetonitrile, N, N,N-DIMETHYLACETAMIDE or their any two or more solvents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101431121A CN101597272B (en) | 2008-06-05 | 2009-05-15 | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810108980 | 2008-06-05 | ||
| CN200810108980.1 | 2008-06-05 | ||
| CN2009101431121A CN101597272B (en) | 2008-06-05 | 2009-05-15 | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101597272A CN101597272A (en) | 2009-12-09 |
| CN101597272B true CN101597272B (en) | 2012-07-04 |
Family
ID=41418893
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009101431117A Pending CN101597271A (en) | 2008-06-05 | 2009-05-15 | The derivative of Ailamode, its preparation method and medicinal application |
| CN2009101431121A Expired - Fee Related CN101597272B (en) | 2008-06-05 | 2009-05-15 | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009101431117A Pending CN101597271A (en) | 2008-06-05 | 2009-05-15 | The derivative of Ailamode, its preparation method and medicinal application |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN101597271A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807515A (en) * | 2012-09-04 | 2012-12-05 | 江苏昊华精细化工有限公司 | Method for synthesizing 3-methylsulfonylamido-4-phenoxy-6-(N-formyl)amidoacetylphenol |
| CN107021891A (en) * | 2017-04-24 | 2017-08-08 | 常州佳德医药科技有限公司 | A kind of preparation method of Ailamode intermediate |
| CN107582537A (en) * | 2017-09-26 | 2018-01-16 | 江苏正大清江制药有限公司 | A kind of pharmaceutical composition of Ailamode |
| CN113968836A (en) * | 2020-07-25 | 2022-01-25 | 华创合成制药股份有限公司 | Benzopyran derivative and application thereof in treatment of rheumatoid arthritis |
| CN113968838B (en) * | 2020-07-25 | 2024-04-02 | 华创合成制药股份有限公司 | Thiobenzopyran compound and application thereof in treatment of rheumatoid arthritis |
| CN115703772A (en) * | 2021-08-09 | 2023-02-17 | 天地恒一制药股份有限公司 | Iguratimod eutectic crystal, and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1462748A (en) * | 2003-06-18 | 2003-12-24 | 江苏扬子江药业集团有限公司 | Preparation of 3-(formamide)-7-(methylsulfonyl amine)-6-(phenoxy)-4H-1-(benzopyran)-4-ketone |
| US20050070543A1 (en) * | 2003-07-11 | 2005-03-31 | Pharmacia Corporation | Compositions of a chromene or phenyl acetic acid cyclooxygenase-2 selective inhibitor and an ACE inhibitor for the treatment of central nervous system damage |
-
2009
- 2009-05-15 CN CNA2009101431117A patent/CN101597271A/en active Pending
- 2009-05-15 CN CN2009101431121A patent/CN101597272B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1462748A (en) * | 2003-06-18 | 2003-12-24 | 江苏扬子江药业集团有限公司 | Preparation of 3-(formamide)-7-(methylsulfonyl amine)-6-(phenoxy)-4H-1-(benzopyran)-4-ketone |
| US20050070543A1 (en) * | 2003-07-11 | 2005-03-31 | Pharmacia Corporation | Compositions of a chromene or phenyl acetic acid cyclooxygenase-2 selective inhibitor and an ACE inhibitor for the treatment of central nervous system damage |
Non-Patent Citations (1)
| Title |
|---|
| JP特开2003-171375A 2003.06.20 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101597272A (en) | 2009-12-09 |
| CN101597271A (en) | 2009-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104892604B (en) | A kind of synthetic method of CDK4 inhibitor | |
| CN101597272B (en) | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof | |
| JP2010527996A (en) | Tenofovir disoproxil-hemifumarate co-crystal | |
| CN101633662A (en) | Prasugrel pharmaceutical acid addition salt as well as preparation method and pharmaceutical application thereof | |
| CN103113405B (en) | Benfotiamine polymorphs body, preparation method and application thereof | |
| CN110054624A (en) | Berberine hydrochloride and caffeic acid eutectic object and preparation method and its composition and purposes | |
| EP3279201A1 (en) | Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor | |
| CN104628796A (en) | Gastrodin medicine, and composition and use thereof | |
| US20220002306A1 (en) | Crystal form of upadacitinib and preparation method and use thereof | |
| CN105801568B (en) | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition | |
| CN101747305A (en) | Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof | |
| EP3135666A1 (en) | (s)-oxiracetam crystal form iii, preparation method therefor, and application thereof | |
| CN102276447A (en) | Naproxen hydrate crystal, preparation method thereof and medicinal composition containing naproxen hydrate crystal and sumatriptan | |
| CN105820130A (en) | Triazole propionate URAT1 inhibitor, preparation method thereof and purpose of triazole propionate URAT1 inhibitor for treating hyperuricemia and gout | |
| CN101665449B (en) | Water-soluble prodrug of tamibarotene, and preparation method and applications thereof | |
| CN104045615A (en) | (1S)-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D-glucose of crystal form A, and preparation method and application thereof | |
| CN108640910A (en) | Aprepitant L-PROLINE solvate-composition and eutectic | |
| CN101993417A (en) | Stable novel crystal form of dimemorfan phosphate | |
| KR20210042041A (en) | Phenolamine Form B crystal, production method and composition and use thereof | |
| CN106032377A (en) | Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout | |
| CN101693713B (en) | New crystal system of entecavir, preparation process and medicament application thereof | |
| CN101514189B (en) | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof | |
| CN104693192A (en) | Crystal form A of compound as well as preparation method and application thereof | |
| CN101906101B (en) | Rotundine crystal B-type solid matter and preparation method as well as applications | |
| CN102093234A (en) | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: Hualin Road, Jinan District of Fuzhou city in Fujian province 350001 No. 330 Building No. second room 1505 Jinghua collar Applicant after: Yang Xihong Address before: 721006 two sets of Zhao Jia Zhuang, Shigu Town, Weibin District, Shaanxi, Baoji Applicant before: Yang Xihong |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120704 Termination date: 20150515 |
|
| EXPY | Termination of patent right or utility model |