CN101597272A - The potassium salt compound of Ailamode, its preparation method and medicinal application - Google Patents
The potassium salt compound of Ailamode, its preparation method and medicinal application Download PDFInfo
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Abstract
The present invention relates to Ailamode potassium salt compound, its hydrate or its solvate.Behind the Ailamode salify, its water-soluble Ailamode that is far superior to, and also its powder flowbility and stability also have excellent improvement than Ailamode.This compounds can be used to prepare the damage for the treatment of rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, alleviation muscle or soft tissue and the medicine of diseases such as the pain that causes and alleviation arthralgia.Further, the present invention also provides the preparation method of Ailamode potassium salt compound, its hydrate or its solvate, and their application (pharmaceutical composition, preparation of pharmaceutical compositions, purposes) in medicine etc.
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 group-4H-1-chromene-7-yl]-amsacrine, English name: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide, molecular structural formula is as follows:
Ailamode is the NSAID (non-steroidal anti-inflammatory drug) that a kind of new selectivity suppresses cyclooxygenase-2, has antipyretic-antalgic, arthritis, immunoregulation effect, to treatment rheumatic arthritis, rheumatoid arthritis, osteoarthritis and ankylosing spondylitis have excellent curative effect, also can alleviate muscle, the damage of soft tissue and the pain that causes 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, side effect 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; Chinese patent application publication number CN1931159A discloses a kind of micronized Ailamode and preparation method thereof, to expect by making the Ailamode micronize improve its oral preparations dissolution rate and bioavailability; Chinese patent application publication number CN1944420A discloses a kind of crystal habit and composition thereof of Ailamode; Chinese patent application publication number CN101095671A discloses a kind of Iguratimod oral double-layer sustained-release preparation; Chinese patent application publication number CN1531925A discloses the technology and the solid preparation thereof of a kind of preparation colatemo (Ailamode) solid preparation; Chinese patent application publication number CN1462748A provides a kind of preparation method of Ailamode; Chinese patent application publication number CN1451373A provides and has related to Ailamode tablet and preparation method thereof.
Ailamode is as new and effective NSAID (non-steroidal anti-inflammatory drug), when medication preparation, also there is deficiency: the one, Ailamode is insoluble in water, when oral administration, because medicine difficult insoluble in water, cause containing in the common preparation compositions of Ailamode, its active ingredient is difficult for moistening and indiffusion in water, be easy in gastrointestinal fluid that crystallization or precipitation are separated out and can not stripping with the oral dosage form of the pharmaceutical adjunct of routine and dispersion system preparation, greatly influence the stripping of medicine and absorbed, had unfavorable factor; The 2nd, the light weight of Ailamode compound, easily produce electrostatic interaction, 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 preparation, 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 preparation, 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 will be to the human body safety non-toxic, to consider that also institute's salt-forming compound should have satisfactory stability, is applied to pharmaceutical preparation with the derivative salt that is convenient to Ailamode as active constituents of medicine.
Based on above consideration and requirement, the inventor by experiment and screening obtains the derivative of Ailamode, and promptly the potassium salt compound of Ailamode has been obtained satisfied effect.
The invention provides potassium salt compound, its hydrate and the solvate of Ailamode, and preparation method thereof with they application in medicine.
The invention provides compound, its hydrate and the solvate 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 relative arrangement 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 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 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 solvate of above-mentioned Ailamode potassium.
For example, the semihydrate of Ailamode potassium, monohydrate, sesqui hydrate, dihydrate, 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 ethylate of Ailamode potassium, methylate, acetone solvate, acetonitrile solvate, described solvate 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 illustrate; the hydrate or the solvate of above-mentioned many Ailamode potassium of enumerating; it is Ailamode potassium of the present invention contingent situation in crystallization or purge process; any hydrate or solvate in them; it only is the existence form of Ailamode potassium of the present invention; normally may command or the removal of crystal water that is contained or recrystallisation solvent; for example crystal water or recrystallisation solvent are removed by adding thermal burn or calcining; therefore, the hydrate of above-mentioned many Ailamode potassium of enumerating or solvate 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; preparation method for Ailamode; domestic and foreign literature has been reported multiple synthetic method route; can take with 4-chloro-3 mononitro-benzene methyl ethers is starting raw material; make Ailamode through 7 steps reactions such as nucleophilic substitution, reduction, methylsulfonylization, lid Te Man-Koch reaction, acidylate, hydrolysis, cyclisation, synthetic route is as follows:
The invention provides a kind of method for preparing above-mentioned Ailamode potassium, its hydrate or its solvate, comprise Ailamode and alkaline potassium compound are reacted in the solvent that is fit to, and further remove reaction solvent, Ailamode potassium precipitation is separated out, and further throw out is carried out drying.
In above-mentioned preparation, " alkaline potassium compound " is potassium 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, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, acetonitrile, n-propyl alcohol, Virahol, diox, ethylene glycol, 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, dimethyl formamide, 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.Be included in the solution of first kind of initial compounds or the suspension and be included in the solution of second kind of initial compounds or the ratio of all kinds of SOLVENTS in the suspension 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 under common normal atmosphere, operating, 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 temperature range, for example make Ailamode form solution by 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 by 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 from about 1 normal atmosphere to about 5 barometric points, carry 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 determining, as several minutes, and several hours, tens hours etc.
Preferably by utilizing filtration or centrifugation 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, cool to room temperature, about below 0 ℃ or 0 ℃ for example, and/or under atmospheric pressure or in a vacuum remove partly solvent and/or add one or more other solvents, for example insoluble relatively therein alcohol of Ailamode potassium or ether or ketone by distillation.Isolating Ailamode potassium can wash as usual and is dry, if desired, also can be further purified by recrystallization.
Concrete, in preparation Ailamode potassium, its hydrate or its solvate, the alkali of alkali metal cation is provided, that is: alkaline potassium compound, be potassium hydroxide, potassium ethylate or potassium methylate, the reaction solvent that is fit to 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, as 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 potassium 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 by Rotary Evaporators steam to remove, cryoprecipitation after-filtration, lyophilize, the anti-solvent of adding (as 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 carried out purifying (as 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 be 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 color reaction takes place; this may be that reaction system has not clear deposits yields; the Ailamode potassium that can cause generating is brown or khaki solid; change in order to eliminate colour developing; when Ailamode and alkaline potassium compound are dissolved in the reaction solvent; should add gac decolours; sylvite with the Ailamode that guarantee to generate is white in color or off-white color; common; the add-on of gac is 0.1～2.5% (W/V); room temperature or heated and stirred 10～60 minutes; the filtering and removing gac promptly gets clear and bright reaction solution; further the solvent in the reaction system is removed; for example steam and remove by Rotary Evaporators; the cryoprecipitation after-filtration; lyophilize; adding anti-solvent (as acetone or ether) filters post precipitation or the combination of this several method; remove the solvent in the reaction system; obtain solids; and the solids that obtains carried out purifying (as 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, lyophilize mainly contains two steps, be 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 easily 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, 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 solvate, preferably Ailamode and potassium hydroxide, potassium methylate, potassium ethylate, potassium hydride KH reaction.
Ailamode potassium of the present invention, its hydrate or its solvate 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 solvate can transform mutually, for example non-crystal Ailamode potassium or its hydrate can 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 mutually, 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 solvate.
Concrete, the present invention also provides the preparation method of Ailamode potassium, its hydrate or its solvate:
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 at 25 ℃, the gac that adds 0.1～2.5% (W/V), room temperature or heated and stirred 10～60 minutes, the filtering and removing gac, in room temperature or be lower than and make institute's salify crystallization under the room temperature condition, suction filtration, 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 solvate;
In above-mentioned preparation, described alkaline potassium compound is selected from potassium hydroxide, potassium methylate, potassium ethylate or potassium hydride KH, described solvent is selected from water, ethanol, methyl alcohol, acetone, Virahol, methylene dichloride, ethylene dichloride, in the acetonitrile one or more, optionally can be by 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), it is the charging capacity proportioning of the alkaline potassium compound of 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 potassium hydroxide are added in an amount of purified water, under 10～90 ℃, make the dissolving of Ailamode and potassium 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 reduce temperature and make abundant crystallization or/and steaming removes partial purification water, 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, described purified water comprises distilled water, deionized water, water for injection etc.
Concrete, Ailamode and potassium hydroxide are added in an amount of purified water, Ailamode and potassium hydroxide are dissolved fully, the gac that adds 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 an amount of water, methyl alcohol, ethanol, acetone, Virahol, acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), in 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 ℃, 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 reduce temperature and make abundant crystallization or/and steaming removes the partial reaction solvent, suction filtration, use ethanol, acetone, drain after ether or the washed with isopropyl alcohol, be drying to obtain the sylvite of Ailamode of the present invention, its hydrate or its solvate, described alkaline potassium compound is selected from potassium 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, the 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, be drying to obtain sylvite, its hydrate or its solvate 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 reacting in acetone and water or acetone and ethanol mixed solvent again.
Especially, the contriver finds, Ailamode and alkaline potassium compound react in the mixture of water, ethanol, methyl alcohol, acetone, Virahol, acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE or their any two or more solvents, be easy to react and operate, and the Ailamode potassium that obtains is easy to drying, solvent residual amount is few, the pressed powder homogeneity is good, therefore, the invention provides the Ailamode derivative 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 potassium 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, dimethyl formamide, 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 for the treatment of as active ingredient, the general patient's said derivative of simple Ailamode that directly do not give, usually all be form appearance with the pharmaceutical composition that contains pharmaceutically acceptable carrier, therefore, the present invention also provides corresponding pharmaceutical compositions and preparation method.
Administration Ailamode potassium of the present invention, its hydrate or its thinner thing that can be by any appropriate, but usually by oral, Transdermal absorption or injection administration.Use in order to carry out this class, 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 composition (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 preparations, cutaneous permeable agent, injection formulations, non-oral liquid preparation, or the like, oral preparations is as oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent or the like; Cutaneous permeable agent is as the emulsifiable paste of Transdermal absorption, gel, emulsion, emulsion agent, patch etc.; Injection is as 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 is molten, 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, usually select for use or be used in combination according to different medicaments, optionally comprise vehicle or thinner, for example Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, poloxamer, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin and derivative thereof, or the like; Also can comprise tackiness agent, for example polyvidone (polyvinylpyrrolidone), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, xanthan gum, or the like; Also comprise lubricant, for example Magnesium Stearate, 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, croscarmellose sodium, 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 conditioning agent or buffer reagent, for example phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, yellow soda ash, potassium hydroxide, or the like; Also can comprise sanitas, for example Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, propylparaben, 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 conditioning agent, for example maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, strawberry flavour, or the like; Also can comprise additive other routine, appropriate 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 Drug coating, 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, as Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, as titanium dioxide, various ferric oxide, 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, polyvinylpyrrolidone, propylene glycol, ethanol, glycerine, polyoxyethylene glycol, polyvinyl alcohol, methylcellulose gum, ethyl cellulose, Natvosol, hydroxypropylcellulose, hypromellose, Xylo-Mucine, poloxamer, gelatin, the sodium alginate.Gelifying agent can further contain transdermal enhancer (as: laurocapram, propylene glycol, ethanol, menthol, spearmint oil, eucalyptus oil, borneol, Virahol, urea, in the oleic acid one or more are with the mixture of any mixed), wetting Agent for Printing Inks (water, glycerine, propylene glycol, polyoxyethylene glycol, sorbyl alcohol, one or more are with the mixture of any mixed in the maltose alcohol), the pH regulator agent is (as trolamine, diethanolamine, tromethane, quadrol, diethylamine, lauryl amine, ammonia soln, sodium bicarbonate, sodium hydroxide or potassium hydroxide, hydrochloric acid, phosphoric acid salt, Citric Acid and salt thereof), solubilizing agent is (as tween series, sapn series, sodium lauryl sulphate, polyoxyethylene hydrogenated castor oil, peregal, methyl-sulphoxide), sanitas and oxidation inhibitor are (as ethanol, parachlorometacresol, Thiomersalate, Sorbic Acid, potassium sorbate, phenylformic acid, Sodium Benzoate, trichloro-butyl alcohol, benzalkonium chloride, Morpan BB, Tegosept M, ethyl p-hydroxybenzoate, propylben, sulphite, aminothiopropionic acid, vitamins C, vitamin-E, one or more are with the mixture of any mixed in the di-tert-butyl hydroxy toluene), stablizer is (as disodium EDTA, ethylenediamine tetraacetic acid (EDTA) 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 stearic acid, glyceryl monostearate, polyoxyl 40 stearate, paraffin, whiteruss, Vaseline (comprises white vaseline, Yellow Vaselin), lanolin, hexadecanol, stearyl alcohol (being called stearyl alcohol again), sapn series is (as Arlacel-60, Arlacel-40, Arlacel-85, Arlacel-20 etc.), beeswax, Vegetable oil lipoprotein is (as Viscotrol C, soybean oil, Semen Maydis oil, the sunflower seeds wet goods) one or more in are with the mixture of any mixed; Wherein water-soluble base is preferably glycerine, propylene glycol, sorbyl alcohol, polyoxyethylene glycol series (Liquid Macrogol, poly(oxyethylene glycol) 400, cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, polyoxyethylene glycol 8000 etc.), tween series is (as tween-80, Tween-60, Tween-40 etc.), sodium lauryl sulphate, urea, peregal is (as paregal O, peregal A etc.), ethanol, in the methyl-sulphoxide one or more are with the mixture of any mixed.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, phenylformic acid, Sodium Benzoate, trichloro-butyl alcohol, benzalkonium chloride, Morpan BB, Tegosept M, ethyl p-hydroxybenzoate, propylben, sulphite, aminothiopropionic acid, 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), propylene glycol, ethanol, menthol, 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 through any suitable administration, can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics, 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 makes 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 is molten, 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, when the preparation solid preparation, can not active ingredient and pharmaceutical carrier be made evenly good preparation of content by simple blending means, for example the dispersing and mixing by stepped mixing or long period makes Ailamode potassium, its hydrate or its thinner thing and pharmaceutical carrier thorough mixing are even.Perhaps pharmaceutical carriers such as Ailamode potassium, its hydrate or its thinner thing and polyvinylpyrrolidone, polyoxyethylene glycol, poloxamer are made solid dispersion, to reach well-mixed purpose by solid dispersions technique.
Description of drawings:
Relevant accompanying drawing provided by the invention is as follows:
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).
Advantage or the characteristics of Ailamode potassium of the present invention, its hydrate or its agent compound:
1. Ailamode potassium of the present invention, its hydrate or its agent compound, selected basic salt ylidene ligands---potassium ion is safe, and human body is not had extra side effect, 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 agent compound do not change the medicine effect of Ailamode, water-soluble good facilitation are arranged but form sylvite to what improve Ailamode. Through the Preliminary Determination comparison, Ailamode, the water-soluble solution characteristic of Ailamode potassium (normal temperature and pressure) are compared as follows table 1:
Table 1
As can be seen from 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 facilitation for its stripping in preparation, and be especially for oral formulations, significant.
Be to be understood that oral medicament need to just can enter blood of human body reaching antiviral effect through GI absorption, the quality of oral absorption directly affects the result for the treatment of of medicine. According to the concept of pharmacy, bioavilability (Bioavailability) refers to that medicine is absorbed to enter and sanguimotorly utilizes degree and utilize speed. Compare Ailamode, Ailamode potassium of the present invention has excellent water-soluble, enters aspect sanguimotor degree and the speed in absorption for the oral drug preparation take it as active ingredient, has important facilitation and meaning. Medicament enters the absorption process behind the stomach and intestine, divide two stages, it is two stages of disintegration dispersion and Gastrointestinal Wall Absorption, at first need in gastric juice or intestinal juice, disintegration scatter, and then contact and be attached to gastrointestinal wall and absorb and enter blood, this two stages all can affect the performance with drug effect of absorbing of medicine, Ailamode is prepared as water-soluble good sylvite derivative form, drug-eluting speed is significantly accelerated, degree and the rate of dispersion of its disintegration dispersion in gastric juice or intestinal juice have greatly been improved, then medicament active composition is more abundant with contacting of gastrointestinal wall, be attached to Gastrointestinal Wall Absorption and to enter the active ingredient of blood also more abundant, this raising for the bioavilability of efficacy component Ailamode potassium is significant; Also have, the quick 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, tests as follows.
Experimental technique: the selection of preparation model, lactose and pregelatinized starch are the most frequently used pharmaceutic adjuvants in the oral formulations, therefore take starch (50%) and pregelatinized starch (49%) as pharmaceutical excipient, dolomol is lubricant (1%), and the Ailamode take content as 25mg, Ailamode potassium are as active ingredient respectively.
Sample preparation: the wet granulation that is equal to take water as wetting agent, whole grain, drying, compressing tablet obtains respectively the tablet of Ailamode, Ailamode potassium, tests the wherein stripping situation of active material take these two kinds of tablets as research model.
Dissolution rate 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), take phosphate buffer (pH7.5) as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, in the time of 25 minutes, get solution 10ml and filter, get subsequent filtrate as need testing solution; It is an amount of, accurately weighed approximately that other gets the Ailamode reference substance, is diluted to 10 μ g/ml solution, in contrast product solution with phosphate buffer (pH7.5). Measure with the HPLC method, detect wavelength 250～263nm. Limit is 85% of labelled amount, should be up to specification.
The dissolution rate of sample (accumulation) measurement result and relative standard deviation (RSD) see the following form.
Table 2 dissolution rate (accumulation) result (n=10)
Above table 2 measurement result shows that the dissolution rate of Ailamode potassium in the time of 25 minutes is good, and is better than very significantly the dissolution rate of Ailamode model sample. Demonstrate potassium good performance aspect the preparation stripping of Ailamode of the present invention.
4. the Performance Ratios such as powder accumulation density, powder flowbility
Conventional, the flowability of bulk drug powder is extremely important for the preparation process (such as 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 of active ingredient in pharmaceutical preparation or the composition and the homogeneity of quality. Bulk density is large, 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 obvious advantage at aspect of performances such as powder accumulation density, powder flowbilitys. As seen, Ailamode is made as Ailamode potassium compound of the present invention, can well solves Ailamode compound light weight, easily produce electrostatic interaction and assemble the shortcomings such as agglomerating, poor fluidity, bring great convenience for the preparation of pharmaceutical preparation.
By relatively finding, disclosed micronized Ailamode of Chinese patent application publication number CN1931159A and preparation method thereof, it is by 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 preparation method's cost is also higher, also can bring dissolvent residual.
And the bulk density of Ailamode potassium powder of the present invention is larger, and after measured, when granularity was 80 order, 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 Chinese patent application publication number CN1931159A and preparation method thereof, it is by preparing fine powder material with adding the method that elutriation goes out after the solvent method dissolving, it is by preparing fine powder material with adding the method that elutriation goes out after the solvent method dissolving, still undesirable, although the Ailamode powder diameter that the method obtains can be below 50 microns, but this preparation method's cost is high, and can bring dissolvent residual.
In the medicine preparation, the most conventional, the most most economical breaking method is mechanical solid breaking method. Adopt KH-100 type medicine pulverizer respectively the routine that Ailamode and Ailamode potassium of the present invention carry out under the same terms to be pulverized, 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 be found out by upper 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 large, 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 respectively a certain amount of Ailamode potassium compound of the present invention and be dissolved in an amount of distilled 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, distilled water washing post-drying, through check, solids is 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 respectively a certain amount of Ailamode potassium of the present invention, by " test method of relevant stability is observed Ailamode potassium of the present invention and had good stability in 2005 editions two ones of the Chinese pharmacopoeia, meets medicinal requirements.
The inventor research Ailamode stable the time, find by destructive testing, the less stable of Ailamode, Ailamode is especially unstable in character under acid condition, relative substance content can increase largely, can produce more catabolite, but next relatively stable at alkali condition. Ailamode potassium is the alkaline matter that generates by chemical reaction, and from the related substance analysis that heat stabilization test produces, the inventor finds that pleasantly surprisedly the heat endurance 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 mobile phase; Flow velocity 1.0ml/min; Detect wavelength 250～263nm. Sample size 10 μ l. Theoretical cam curve is calculated by Ailamode should be not less than 4000.
Get respectively Ailamode potassium and Ailamode and put in the measuring cup, spread out into＜the 5mm thin layer, place 45 ℃ of insulating boxs to place 10 days, detect respectively at sampling in 5,10 days, and with result and comparison in 0 day, the results are shown in Table 4.
Table 4 hot test result
Measurement result shows, 45 ℃ of placements of Ailamode potassium and Ailamode high temperature 10 days, and each is investigated in the item, and hygroscopicity is without significant change; Content descends to some extent, and the content decrease 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 the autoimmune disease take the synovial hyperplasia inflammation as pathological manifestations. 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 the inflammation factor and growth factor, promotes the rheumatoid arthritis synovitis to occur 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 test: adopt Collagen-induced Arthritis (collagen-induced arthritis, CIA) set up rat arthritis model, namely give the rat feeding Ailamode potassium of the present invention in the model process inducing to set up, and the foundation blank is organized, control group is observed, and the cycle is two months. Result of the test shows, the animal groups of feeding Ailamode potassium of the present invention detects in foot swelling, dysarthrasis outward appearance, and foot pathology synovium of joint hyperplasia, inflammatory cell are invaded the pathologic section context of detection such as profit, compare with control group; 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-d6) analyze, the hydrogen spectrum of finding Ailamode has the absworption peak of 1H in about 10.1 positions, be by analysis in the Ailamode structure-NHSO2The absworption peak of protium in the-group, and the hydrogen spectrogram of Ailamode potassium of the present invention near this position without absworption peak, due to being replaced by cation potassium in the time of can being defined as forming Ailamode sylvite of the present invention, meet the structure of Ailamode sylvite of the present invention fully.
Further, based on above-mentioned advantage or the characteristics of Ailamode potassium of the present invention, Ailamode sylvite of the present invention or ammonium salt and composition thereof, application in the following areas:
(1) application in the medicine of preparation treatment rheumatic arthritis, rheumatoid arthritis, osteoarthritis and ankylosing spondylitis;
(2) application in the medicine of the 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, neuralgia (such as sciatica, trigeminal neuralgia), postoperative pain, cancer pain; Acute sprain or soft tissue bruise; Fracture pain, sprain pain; Cold, fever with and the whole body pain that causes; Scapulohumeral periarthritis, bursal synovitis, myotenositis and tenosynovitis.
Embodiment
In implementation process of the present invention, various embodiments that those of ordinary skills produce on the basis that does not depart from the scope of the present invention with spirit and modify conspicuous and be to carry out easily.Come Ailamode potassium of the present invention, its hydrate or its solvate by the following examples, 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 dehydrated alcohol, after the reflux dissolving, add the solution that 150mg potassium hydroxide (about 2.67mmol) forms in the 10ml dehydrated alcohol again, 80 ℃ mix, react, and looking needs to add the 280mg gac, stir insulation decolouring and filtering gac, filtrate is spin-dried for except that desolvating with Rotary Evaporators, obtains solids, remove cleaning solvent with cold ethanol or ether repetitive scrubbing or rinsing, drying promptly gets Ailamode potassium.Molecular formula C
17H
13N
2O
6SK, results of elemental analyses:
% theoretical value C:49.50 H:3.18 N:6.79
% measured value C:49.56 H:3.22 N:6.81.
Method two. get Ailamode 1g (about 2.67mmol) and add the stirring of 80ml distilled water, furnishing suspension state, in addition the drips of solution of 151mg potassium hydroxide (about 2.7mmol) in 4ml distilled water is added in the suspension of above-mentioned Ailamode and stirring, all add to continue to stir behind the potassium hydroxide solutions and Ailamode is dissolved fully be clear and bright solution, add the 100mg gac and stir decolouring, remove by filter gac, filtrate can be handled through following method and be obtained Ailamode potassium:
(1) filtrate is spin-dried for Rotary Evaporators removes water solvent, obtain pressed powder, with acetone rinsing 1～2 time, drying promptly gets Ailamode potassium, its hydrate.
(2) filtrate is put carry out lyophilize in the lyophilizer and handle, drying obtains Ailamode potassium, and wherein freeze-drying process is as follows:
| 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) filtrate is spin-dried for Rotary Evaporators removes 60% water solvent, stir after adding acetone, put refrigerator overnight, pumping 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 151mg potassium hydroxide (about 2.7mmol) forms in the 5ml dehydrated 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 potassium hydroxide (about 2.7mmol) again at the solution that forms in the 10ml dehydrated alcohol, 70 ℃ mix, react, and looking needs to add proper amount of active carbon, stir insulation decolouring and filtering gac, filtrate is spin-dried for except that desolvating with Rotary Evaporators, obtains solids, remove cleaning solvent with cold ethanol or ether repetitive scrubbing or rinsing, drying promptly gets Ailamode potassium.
Method two. get Ailamode 1g (about 2.67mmol) and add the 300ml dehydrated 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, the amounts of activated carbon that adds 0.15% (W/V), 55～90 ℃ of heated and stirred 20 minutes, the filtering and removing gac, with filtrate with Rotary Evaporators be spin-dried for remove 2/3rds solvents after, cooling is left standstill, and filters, and obtains 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 potassium hydroxide (about 2.67mmol) forms in 2ml distilled 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 dimethyl formamide make separate fully after, drip the solution that 150mg potassium hydroxide (about 2.67mmol) forms in the 10ml dehydrated 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.
Embodiment 5. as the main ingredient composition, adopts suitable pharmaceutical adjunct prescription and technology with Ailamode potassium or its hydrate, makes 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.
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 standby.
(2) sodium lauryl sulphate is dissolved in an amount of distilled 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 croscarmellose sodium 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 (the molten or enteric solubility of stomach), promptly get capsule or enteric coated capsule, every or every capsules (per unit preparation) contain Ailamode potassium and are respectively 25mg, 22mg, 15mg, 20mg.
Preparation 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, for orally using.Or above-mentioned particle powder is filled in 1000 Capsuleses (the molten or enteric solubility of stomach), 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, potassium 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 potassium hydroxide, and oven dry is standby.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 (the molten or enteric solubility of stomach), promptly gets tablet or capsule.
Embodiment 7. agent of Ailamode potassium gel and preparations thereof
Prescription: Ailamode potassium 0.2g, methylcellulose gum 1.7g, ethyl p-hydroxybenzoate 0.03g, propylene glycol 4g adds purified water to 100g.
The preparation: get methylcellulose gum and evenly be spread on 50ml purified water surface, make its natural swelling after, stir, other gets, and Ailamode potassium grinds in propylene glycol and molten loosing in wherein, adds methocel solution, stirs evenly, add the solution of ethyl p-hydroxybenzoate in suitable quantity of water again, stir, add water to 100g, stir evenly, 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.Smear the Transdermal absorption external application for skin.
Prescription: Ailamode potassium 2g, polyoxyethylene glycol-400 15m, dehydrated alcohol 10ml, card crosses nurse (940) 1g, trolamine 4.5g, laurocapram 2g, glycerine 5ml, distilled water adds to 100g.
Preparation: take by weighing the recipe quantity carbomer, add an amount of distilled water, place, make its complete swelling after, add glycerine, trolamine, laurocapram successively and stir, standby.Other gets Ailamode potassium 2g, adds ethanol, poly(oxyethylene glycol) 400 etc. and an amount of distilled 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 smears the Transdermal absorption external application for skin.
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, adding pH regulator agent adjusting pH is 8.5～9, add the injection water to 1300ml,, under hundred grades of conditions, carry out in sterile filling to 1000 cillin bottle with the filtering with microporous membrane degerming, add plug after checking 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 (10)
1. the Ailamode derivative shown in the following formula, its hydrate or its thinner thing:
2. method for preparing the described Ailamode derivative of claim 1, its hydrate or its thinner thing, 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 potassium hydroxide, potassium ethylate, potassium methylate, potassium hydride KH;
The reaction solvent that is adopted is the mixture of water, ethanol, methyl alcohol, acetone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, acetonitrile, n-propyl alcohol, Virahol, diox, ethylene glycol, N-Methyl pyrrolidone, methyl-sulphoxide or their any two or more solvents, and the preferred solvent that adopts is the mixture of water, ethanol, methyl alcohol, acetone, Virahol, acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE or their any two or more solvents.
3. method for preparing the described Ailamode sylvite of claim 1, its hydrate or its thinner thing, it comprises:
Make Ailamode and potassium hydroxide, potassium ethylate or potassium methylate hybrid reaction in reaction solvent, wherein reaction solvent is selected from the mixture of water, ethanol, methyl alcohol, acetone, Virahol or they any two or three, and the pH of reaction solution system 〉=8.5 (as pH=8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5 or 14).
4. according to the preparation method of claim 2 or 3 described Ailamode sylvite, its hydrate or its thinner thing, wherein the reacting weight that feeds intake of Ailamode and alkaline potassium compound is 1 with the mole number ratio range: (1～1.2), and Ailamode and alkaline potassium compound are dissolved in the reaction solvent.
5. according to the preparation method of claim 2 or 3 described Ailamode sylvite, its hydrate or its thinner thing, wherein by Rotary Evaporators steam to remove, cryoprecipitation after-filtration, lyophilize or add anti-solvent and make the filtering method of post precipitation remove solvent in the reaction system, obtain solids, and the solids that obtains carried out purifying, drying promptly gets the Ailamode sylvite that ends, its hydrate or its thinner thing.
6. method for preparing the described Ailamode sylvite of claim 1, its hydrate or its thinner thing, it comprises:
Ailamode and alkaline potassium compound are joined in the solvent, to the reflux temperature condition of solvent, make Ailamode and alkaline potassium compound dissolving at 25 ℃, the gac that adds 0.1～2.5% (W/V), room temperature or heated and stirred 10～60 minutes, the filtering and removing gac, in room temperature or be lower than and make institute's salify crystallization under the room temperature condition, suction filtration, use acetone, ether, drain after ethanol or the washed with isopropyl alcohol, dry, promptly get Ailamode potassium of the present invention, its hydrate or its solvate, wherein said alkaline potassium compound is selected from potassium hydroxide, potassium methylate, potassium ethylate or potassium hydride KH, described solvent is selected from water, ethanol, methyl alcohol, acetone, Virahol, methylene dichloride, ethylene dichloride, in the acetonitrile one or more; Perhaps
Ailamode and potassium hydroxide are added in an amount of purified water, under 10～90 ℃, make the dissolving of Ailamode and potassium 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 reduce temperature and make abundant crystallization or/and steaming removes partial purification water, 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, described purified water comprises distilled water, deionized water, water for injection etc.; Perhaps
Ailamode and potassium hydroxide are added in an amount of purified water, Ailamode and potassium hydroxide are dissolved fully, the gac that adds 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 get sylvite or its hydrate of Ailamode of the present invention; Perhaps
Ailamode and alkaline potassium compound are joined an amount of water, methyl alcohol, ethanol, acetone, Virahol, acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), in 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 ℃, 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 reduce temperature and make abundant crystallization or/and steaming removes the partial reaction solvent, suction filtration, use ethanol, acetone, drain after ether or the washed with isopropyl alcohol, be drying to obtain the sylvite of Ailamode of the present invention, its hydrate or its solvate, described alkaline potassium compound is selected from potassium hydroxide, potassium methylate, potassium ethylate or potassium hydride KH; Perhaps
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, the 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, be drying to obtain sylvite, its hydrate or its solvate of Ailamode of the present invention.
7. a pharmaceutical composition contains the described Ailamode sylvite of claim 1, its hydrate or its thinner thing and pharmaceutically acceptable pharmaceutical carrier, and wherein the content of Ailamode sylvite, its hydrate or its thinner thing is 1～100mg.
8. the described pharmaceutical composition of claim 7, its pharmaceutical dosage form comprises: oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent; The ointment of Transdermal absorption, gelifying agent, emulsion agent, emulsion agent, patch; Powder ampoule agent for injection and injection liquid.
9. method for preparing claim 7 or 8 described pharmaceutical compositions, this method comprises Ailamode sylvite, its hydrate or its thinner thing and pharmaceutically acceptable pharmaceutical carrier thorough mixing, make acceptable any pharmaceutical dosage form on the pharmaceutics, preferred pharmaceutical dosage form is oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent; The ointment of Transdermal absorption, gelifying agent, emulsion agent, emulsion agent, patch; Powder ampoule agent for injection and injection liquid.
10. the Ailamode derivative 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, further remove reaction solvent, and carry out drying and prepare, wherein:
Alkaline potassium compound is selected from potassium 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, dimethyl formamide, N,N-DIMETHYLACETAMIDE or their any two or more solvents.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN113968838A (en) * | 2020-07-25 | 2022-01-25 | 华创合成制药股份有限公司 | Thiobenzopyran compound and application thereof in treatment of rheumatoid arthritis |
| 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 |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| 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 |
| WO2005016249A2 (en) * | 2003-07-11 | 2005-02-24 | 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 |
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| 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 |
| CN113968838A (en) * | 2020-07-25 | 2022-01-25 | 华创合成制药股份有限公司 | Thiobenzopyran compound and application thereof in treatment of rheumatoid arthritis |
| 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 |
| WO2022022373A1 (en) * | 2020-07-25 | 2022-02-03 | 华创合成制药股份有限公司 | Benzopyran derivative and use thereof in preparation of drug for treating rheumatoid arthritis |
| WO2022022372A1 (en) * | 2020-07-25 | 2022-02-03 | 华创合成制药股份有限公司 | Thiobenzopyran compound and application thereof in preparation of drug for treating rheumatoid arthritis |
| AU2021317306B2 (en) * | 2020-07-25 | 2024-01-18 | HC Synthetic Pharmaceutical Co., Ltd. | Thiobenzopyrans and their use in preparation of drugs for treatment of rheumatoid arthritis |
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| 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 |
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| CN101597271A (en) | 2009-12-09 |
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