CN1903869A - Tibifudine derivative salt and its preparation method and pharmaceutical application - Google Patents
Tibifudine derivative salt and its preparation method and pharmaceutical application Download PDFInfo
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Abstract
The present invention relates to metal salt derivative of tibifdine, in particular, it relates to sodium salt and potassium salt derivative of tibifdine and its hydrate. Besides, said invention also provides a method for preparing metal salt derivative of tibifdine and its hydrate, and also provides preparation composition containing metal salt derivative of tibifdine or its hydrate, its preparation method and medicine application.
Description
Technical field the invention belongs to medical technical field, the derivative salt that relates to Telbivudine with and preparation method thereof with it in pharmaceutically application.
The background technology Telbivudine is a specific specificity, nucleoside analog optionally, is also referred to as LdT, the special Telbivudine of English name, and its chemical name is 1-(2 '-deoxidation-β-L-arbinofuranose base)-thymus pyrimidine, molecular structural formula is as follows:
Molecular formula C
10H
14N
2O
5Telbivudine has very strong restraining effect to hepatitis B (HBV) virus, according to the external model that infects based on HBV, and the tentative infected animal model of hepatitis B infection, demonstrate efficient, safe therapeutic action.
International publication WO00/09531 (its in China Patent No. 99809553.2, publication number CN1320128) discloses Telbivudine at the purposes of treatment hepatitis B virus infection and pharmaceutical composition etc.
Telbivudine water-soluble relatively poor is unfavorable for the preparation of pharmaceutical preparation and the application of medicine.
Summary of the invention the purpose of this invention is to provide the metal-salt derivative of a kind of highly water-soluble, stable Telbivudine, especially the sodium salt of Telbivudine and sylvite derivative compound, with and hydrate, further, the present invention also provides a kind of metal-salt derivative of Telbivudine or method of its hydrate of preparing, and the preparation compositions and the preparation of compositions method thereof of metal-salt derivative or its hydrate of Telbivudine also is provided.
The contriver is by a large amount of experiments and analyze discovery, on the uridylic ring of Telbivudine
The protium of functional group has very faint ionization tendency and manifests extremely weak acidity, and in solvent medium especially in the solvent medium (as the aqueous solution, the alcoholic solution of alkalescence) of alkalescence, and the space steric effect of molecule makes on the uridylic ring
Exist the change of enol-type structure with 4 ketone groups, this gives the synthetic possibility of bringing of the metal-salt derivative of Telbivudine of the present invention, that is: Telbivudine can be prepared into alkali metal salt.The invention provides the metal salt compound of Telbivudine, its pharmaceutically acceptable solvate or its hydrate with following structural formula:
Telbivudine potassium:
The metal salt compound of Telbivudine of the present invention is a kind of solid chemical compound, in preparation process,, can contain a certain amount of water molecules for keeping peculiar structural form, therefore the present invention also provides the hydrate of Telbivudine metal salt compound, and its molecular structural formula is as follows:
Should be noted that, solid chemical compound has crystal water and is subjected to crystallization method usually, crystalline environment is (as temperature, solvent, vapour pressure), condition effect such as crystal seed guiding crystallization and pre-treatment, therefore, the present invention has stipulated that the span of a is 0.5～5, usually a value is 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5, be referred to as the semihydrate of Telbivudine metal-salt (sodium salt or sylvite) respectively, monohydrate, the sesqui hydrate, dihydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, pentahydrate.
By molecular structural formula as can be seen, Telbivudine metal-salt provided by the invention (sodium salt or sylvite), as the metal-salt derivative of Telbivudine, its molecular structure is compared with Telbivudine, is introducing metal ion (Na
+Or K
+) after, carbon-nitrogen bond becomes two keys by singly-bound, and the carbonyl of the two keys of carbon-oxygen also becomes carbon-oxygen singly-bound, finally forms Telbivudine metal-salt of the present invention (sodium salt or sylvite).As can be seen, this because Na
+Or K
+Participation and the enol isomery of the Telbivudine that takes place and salifiable process is not common acid-base neutralisation reaction, but reconfiguring on the molecular linkage bit architecture taken place, therefore, the metal-salt of formed Telbivudine of the present invention (sodium salt or sylvite) is a species specific metal-salt (sodium salt or the sylvite) compound of Telbivudine, and this is the constructional feature of Telbivudine metal-salt of the present invention (sodium salt or sylvite).
But, also be to be understood that, the sodium salt of Telbivudine of the present invention, sylvite or its hydrate, 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 metal ion and organic anion.Metal ion also can be arranged in another position of the atom of relative negatively charged ion, for example it can be with uridylic on-the nitrogen-atoms coordinate of CO-N-group, or the oxygen element coordinate that links to each other with 2 carbon of uridylic, the embodiment of resonance motion between the element that these coordinate positions also are the intramolecule structures for example can be to represent with the structural formula of following formula V or VI:
The invention provides a kind of method for preparing sodium salt, sylvite or its hydrate of above-mentioned Telbivudine, comprise Telbivudine and the suitable alkali that desired alkali metal cation can be provided are reacted in the solvent that is fit to, and in reaction solution, add acetone or Virahol as anti-solvent, desired salt is precipitated in solution separate out, and further throw out is carried out drying.
In above-mentioned preparation, it is sodium hydroxide, sodium methylate, sodium ethylate and potassium hydroxide, potassium methylate, potassium ethylate that the suitable alkali of desired alkali metal cation can be provided, the solvent that is fit to that adopts is the mixture of water, methyl alcohol, ethanol or they any two or three, in order to react fully fully, the pH value of reaction solution system should be alkalescence, and suitable is pH 〉=9 of reaction solution system.
Because Telbivudine and sodium hydroxide, sodium alkoxide or potassium hydroxide, potassium alcoholate are the equimolar amount reactions, and it is valuable raw material that Telbivudine is compared, under normal conditions, the aspect is considered in order to make Telbivudine fully react, improve yield and to reduce cost etc., feeding intake when reaction, should make the mole number of sodium hydroxide, sodium alkoxide or potassium hydroxide, potassium alcoholate equal or be slightly larger than the mole number of Telbivudine.
The contriver finds from a large amount of experimental implementation, as long as dissolve in the solution of the suitable alkali of Telbivudine and equimolar alkali metal cation, promptly can be fully in the aqueous solution of sodium hydroxide or potassium hydroxide, or in the alcoholic solution of sodium alkoxide or potassium alcoholate, and the pH value of solution is not less than 9, all can make Telbivudine and sodium hydroxide or potassium hydroxide or sodium alkoxide or potassium alcoholate fully, fully react usually.Usually, usually can adopt concentration is the alcoholic solution (comprising the mixing solutions of methyl alcohol, ethanol or their both any ratios etc.) or the aqueous solution of sodium hydroxide/potassium hydroxide of 0.01～2mol/L, the sodium hydroxide of preferred 1mol/L/or aqueous solutions of potassium, perhaps the alcoholic solution of the sodium alkoxide/potassium alcoholate of suitable concentration (comprising the mixing solutions of methyl alcohol, ethanol or their both any ratios etc.) reacts with Telbivudine, the alcoholic solution (comprising the mixing solutions of methyl alcohol, ethanol or their both any ratios etc.) of preferred sodium hydroxide/potassium hydroxide; In addition, optionally can heat, can also add that activated carbon decolours to reaction soln, refining degerming, filtration treatment reaction soln, can also be when producing precipitation to the reaction solution processing of lowering the temperature.
Obtain after the sedimentary thick thing,, can carry out drying to above-mentioned reacted throw out and obtain metal-salt or its hydrate of Telbivudine of the present invention with two kinds of following methods,
Method one. with throw out with acetone or washed with isopropyl alcohol after, it is dissolved in the water makes the aqueous solution, carry out freeze-drying with freeze-drying, obtain white or off-white color pressed powder, promptly obtain Telbivudine metal-salt of the present invention or its hydrate.
Method two. with throw out with acetone or washed with isopropyl alcohol after, to constant weight, obtain white or off-white color pressed powder in 35 ℃～120 ℃ drying under reduced pressure, promptly obtain Telbivudine metal-salt of the present invention or its hydrate.
The technical scheme of Telbivudine metal-salt produced according to the present invention or its hydrate is characterized in that Telbivudine and sodium hydroxide, sodium methylate, sodium ethylate or potassium hydroxide, potassium methylate, potassium ethylate reaction.
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, speed of cooling in the control refrigerating process also might produce xln or microcrystal or their mixture.
Telbivudine metal-salt of the present invention or its hydrate are a kind of solid chemical compounds, and its solid form can be crystal, noncrystal form, also can be crystal and non-crystal mixture; It should also be understood that, the crystal of Telbivudine metal-salt or its hydrate and noncrystal form can transform mutually, for example can be with in non-crystal Telbivudine metal-salt or its hydrate alcoholic acid aqueous solution, its crystallization is separated out and obtain the compound of the crystal habit of Telbivudine metal-salt or its hydrate, again for example with Telbivudine metal-salt or its hydrate quick freezing soluble in water of crystal habit, carry out lyophilize and can obtain Telbivudine metal-salt or its hydrate of noncrystal form, but no matter be crystal, noncrystal or crystal and non-crystal mixture all have the molecular structural formula of Telbivudine metal-salt of the present invention or its hydrate.
Certainly, Telbivudine metal salt hydrates or solvate have been the invention still further relates to, also be to be understood that, the hydrate of Telbivudine metal-salt and Telbivudine metal-salt also can transform mutually, for example the decompression of the hydrate of Telbivudine metal-salt being heated to 120 ℃ makes crystal water discrete and not with the Telbivudine metal-salt of crystal water, again for example will be not soluble in water with the Telbivudine metal-salt of crystal water, carry out crystallization or recrystallization processing with the solvent that contains water, can obtain the hydrate of Telbivudine metal-salt.
Telbivudine metal-salt of the present invention and hydrate thereof, the application that is used for preparing the hepatitis b virus infected medicine of treatment.
Telbivudine metal-salt or its hydrate are used for the treatment of hepatitis b virus infected as active ingredient, the general simple Telbivudine metal-salt of patient or the chemical substance of its hydrate of directly not giving, usually all be form appearance with the pharmaceutical composition that contains pharmaceutical carrier, therefore, the present invention also provides corresponding pharmaceutical compositions and preparation method.
A kind ofly be used for the treatment of hepatitis b virus infected pharmaceutical composition, contain Telbivudine metal-salt of the present invention or its hydrate and pharmaceutically acceptable carrier, wherein in unit formulation, the content of the hydrate of Telbivudine metal-salt or Telbivudine metal-salt is 1mg～1000mg, the content of preferred Telbivudine metal-salt or its hydrate is 5mg～200mg, more preferably the content of Telbivudine metal-salt or its hydrate is 10mg～100mg, for example 15mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 150mg, 200mg, or the like.Above-described composition, " unit formulation " is meant the medicament of every one preparation compositions or individual packaging, for example each tablet, each seed lac wafer, each bag granule, each bottleneck are obeyed solution, each bottle injection liquid, each bottle powder ampoule agent for injection, or the like.
Telbivudine metal-salt provided by the present invention and hydrate thereof are compared Telbivudine, has good water dissolution performance, it is a kind of ideal raw material medicine, with Telbivudine metal-salt of the present invention or its hydrate is active ingredient, 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, injection formulations, non-oral liquid preparation, or the like, as oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent or the like; And for example injection comprises powder ampoule agent for injection and injection liquid, or the like, the emulsion of non-for another example oral eye drop, nasal drops, [, Transdermal absorption, 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, slow releasing capsule, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets, born of the same parents rise particle, or the like.Especially, by the means known in the art preparation, be preferred for preparing the tablet (comprising dispersible tablet, slow releasing 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., to satisfy the various needs in the clinical use, be used for the treatment of resistance of hepatitis B (HBV-DNA) virus.
Be to be understood that, 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, generally comprise vehicle or thinner, for example Microcrystalline Cellulose, lactose, starch, dextrin, calcium phosphate, sucrose, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin and derivative thereof, or the like; Also can comprise viscous substance, for example polyvidone, 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 Xylo-Mucine, polyvinylpolypyrrolidone, pregelatinized Starch, W-Gum, 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, sodium 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 the agent type 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.
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, Telbivudine metal-salt or its hydrate are active substances wherein, has the effect that suppresses hepatitis B replication, can also comprise the material that other has pharmaceutical active in the pharmaceutical composition, form a kind of pharmaceutical composition of compound, come the hepatitis b virus infected of combination therapy stubbornness and other accompanying infection.The material that is used for the pharmaceutical active of suitable other of this purpose comprises one or more antiviral agents, for example didanosine, lamivudine, zidovudine, Abacavir, Entecavir, Clevudine, Adefovir, adefovir ester, Famciclovir, ganciclovir, emtricitabine, ribavirin, tynofovir, or the like; Can also comprise one or more immunomodulators, for example interferon-' alpha ', interferon-beta, interferon-, Zadaxin, or the like.
Aforesaid preparation of drug combination method, this method comprises makes acceptable any pharmaceutical dosage form on the pharmaceutics with Telbivudine metal-salt or its hydrate 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) etc.Under the usual condition, Telbivudine metal-salt or its hydrate and pharmaceutically acceptable pharmaceutical carrier exist with pulverulence, its thorough mixing there is crucial effect for the steady quality of medicine preparation, because it is less as the Telbivudine metal-salt or the content of its hydrate in medicament of active ingredient, assemble in order to prevent that active ingredient from forming, can not active ingredient and pharmaceutical carrier be made evenly good preparation of content by simple blending means, and should just may make Telbivudine metal-salt or its hydrate and pharmaceutical carrier thorough mixing by stepped mixing; Perhaps especially, Telbivudine metal-salt or its hydrate be dissolved in the water form solution (having very excellent water miscible advantage) based on Telbivudine metal-salt or its hydrate, use this solution with the pharmaceutical carrier thorough mixing is even in the mode of spraying or liquid stream then, and help in operation subsequently (as granulations, drying, stirring, mechanical workout etc.) make the abundant mixing of active ingredient with make lose drop to minimum.
Though described concrete associated viscera of the present invention, also should be included within the scope of the invention to conspicuous some modification of experienced technical staff in the art or the situation that is equal to.
Telbivudine metal-salt of the present invention or its hydrate, the application that is used for preparing the hepatitis b virus infected medicine of treatment.
Telbivudine sodium salt of the present invention and sylvite have beat all, good water-soluble, through measuring, the water solubility of Telbivudine sodium salt and sylvite is all greater than 350mg/ml at normal temperatures and pressures, be far longer than the water solubility of Telbivudine, this has great importance in the preparation of pharmaceutical preparation and the application of medicine and the aspects such as performance of drug effect for Telbivudine sodium salt and sylvite.This good solubleness has improved its bioavailability, and the medicine dissolution rate is significantly accelerated, and makes that human body is easier to absorb.In addition, Telbivudine sodium salt and sylvite are a kind of compounds of meta-alkalescence, when orally using, can also effectively cushion the influence of hydrochloric acid in gastric juice to pharmaceutical preparation.
Telbivudine sodium salt and sylvite are the compound of highly water-soluble, and is more favourable for the preparation of various medicaments especially injection, liquid preparation, need not to add various solubilizing agent, improved the quality quality and the security of pharmaceutical preparation; In addition, Telbivudine is prepared as water-soluble good sodium salt and sylvite, efficacy component Telbivudine metal-salt continues in gastrointestinal fluid, stably discharges, to reach the good slow releasing effect and the lasting performance of drug action when also helping being prepared as slow release formulation (as oral slow releasing tablet, slow releasing capsule); Also have, Telbivudine is prepared as water-soluble good sodium salt and sylvite, important meaning is also arranged for absorbing of efficacy component.
Be to be understood that, Telbivudine and derivative salt thereof are as the hepatitis B virus inhibitor, need long-term prescription, the medication cycle or the course of treatment are generally all in half a year even more than 1 year, therefore, be prepared as medicament for oral use, easy to use, help patient's prolonged application and compliance, and oral medicament need just can enter blood of human body to reach antiviral effect through GI absorption, 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 enter and sanguimotorly utilizes degree and utilize speed.Telbivudine metal-salt of the present invention or its hydrate have very good water-soluble, enter aspect sanguimotor degree and the speed in absorption for the oral drug preparation that with it is active ingredient, have important promoter action and meaning.Medicament enters the absorption process behind the stomach and intestine, divide two stages, be that 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 enter blood, this two stages all can influence the performance with drug effect of absorbing of medicine, Telbivudine is prepared as the Telbivudine sodium salt and the sylvite of highly water-soluble, 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, be attached to that gastrointestinal wall absorbs and to enter the active ingredient of blood also more abundant, this becomes the raising of bioavailability of Telbivudine sodium salt and sylvite significant for drug effect; Also have, Telbivudine is the hepatitis B virus inhibitor of " concentration dependent ", be that antiviral curative effect and Plasma Concentration are closely related, under certain intake, Plasma Concentration is bigger, antiviral effect better, because water miscible very big spoke degree improves, Telbivudine sodium salt and the sylvite absorption rate in stomach and intestine is fast, soak time is more concentrated, Plasma Concentration and blood peak concentration (being the maximum value of blood Chinese traditional medicine concentration) after helping improving greatly it and absorbing, this is significant for the hepatitis B virus resisting curative effect that improves Telbivudine sodium salt and sylvite.
The application in the hepatitis b virus infected medicine of preparation treatment of Telbivudine sodium/sylvite of the present invention and hydrate thereof.
Telbivudine sodium salt of the present invention or/chemistry and the physical properties and the pharmacological property of sylvite and hydrate thereof.
(1) water-soluble degree＞350mg/ml, the aqueous solution is alkalescence,
(2) stability of the aqueous solution: 55 ℃ were heated 7 days, loses all less than 6.5%,
(3) stability of solid state: get the Telbivudine sodium salt or/the sylvite sample places 60 ℃ of baking ovens, measures its content at the the 0th, the 5th, the 10th day with HPLC respectively, loss is all less than 4.1%,
(4) sucting wet stability: respectively with the Telbivudine sodium salt or/sylvite places 40 ℃ of constant temperature, saturated KNO
3In the moisture eliminator that solution and NaCl solution exist, in the 0th, 10,20 day sampling and testing, all samples content was all greater than 99.07%, and degradation product impurity does not surpass 1%,
(5) biological activity of external hepatitis B virus resisting: the 2.2.15 cell strain that application can replication in vitro be expressed the HBV transfection, from external angle, to Telbivudine sodium salt of the present invention or/the anti-HBV activity of sylvite tests, 2.2.15 cell strain the has been transfection full genome of HBV, can secrete the female oncocyte of HBV-DNA particulate people liver system, adopting the change that detects secretor type HBV-DNA titre in the cell culture fluid supernatant liquor is the important indicator that reflection HBV-DNA duplicates.Experiment showed, Telbivudine sodium salt of the present invention or/sylvite has very strong restraining effect to the 2.2.15 cell strain of HBV transfection secretion HBV-DNA.
Description of drawings relevant accompanying drawing provided by the invention is as follows:
Fig. 1 is the carbon-13 nmr spectra figure of Telbivudine sodium
13C NMR (150MHz, DMSO-d
6);
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of Telbivudine sodium
1H NMR (600MHz, DMSO-d
6);
Fig. 3 is the carbon-13 nmr spectra figure of Telbivudine potassium
13C NMR (150MHz, DMSO-d
6);
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of Telbivudine potassium
1H NMR (600MHz, DMSO-d
6);
Fig. 5 is the infrared absorption spectra (KBr compressing tablet) of Telbivudine sodium;
Further, for the ease of comparing, the present invention also provides the relevant collection of illustrative plates of Telbivudine,
Fig. 6 is the carbon-13 nmr spectra figure of Telbivudine
13C NMR (150MHz, DMSO-d
6);
Fig. 7 is the hydrogen nuclear magnetic resonance spectrogram of Telbivudine
1H NMR (600MHz, DMSO-d
6);
Fig. 8 is the infrared absorption spectra (KBr compressing tablet) of Telbivudine.
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 the metal-salt of Telbivudine of the present invention done further specifying by the following examples, but do not represent the embodiment limitation of the present invention.
Embodiment one. Telbivudine sodium and preparation thereof
Get Telbivudine 0.91g (3.5mmol), add methyl alcohol 40ml and make its dissolving, filter, filtrate is stand-by, in filtrate, add the methanol solution 7.5ml that contains 0.15 gram sodium hydroxide (3.8mmol), stir, make solution even, optionally can be to the reaction solution heat treated, decompression revolves partly that methyl alcohol makes it to be colloidal, adds the mixed solution of 12ml acetone or Virahol or acetone and any ratio of Virahol then, suction filtration after the placement crystallization, filter cake in 45 ℃ of vacuum-dryings 5 hours, promptly gets target product with the mixed solution washing of proper amount of acetone or Virahol or acetone and any ratio of Virahol 2～3 times.
1HNMR(600MHz.DMSO-d
6)：δ7.25(1H，S)，6.25(1H，t)，5.49(1H，s)，5.30(1H，s)，4.19(1H，m)，3.66(1H，)，3.52(2H，m)，1.99-1.90(2H，m)，1.69(3H，s)ppm。
13CNMR(150MHz.DMSO-d
6)：δ174.3，158.4，134.0，109.1，86.4，83.9，70.6，61.7，39.6，13.9ppm。
In above-mentioned preparation, also available ethanol replaces methyl alcohol, makes Telbivudine sodium of the present invention.
Embodiment two. Telbivudine sodium and preparation thereof
Get Telbivudine 1.09g (4.2mmol) under the room temperature, adding concentration is the aqueous sodium hydroxide solution 4.4ml of 1mol/l, stirs, and obtains a clear and bright solution.As needs, can adopt that activated carbon decolour, smart filter is handled to this clear and bright solution.
The acetone that adds 15ml to above-mentioned clear and bright solution, stirred 1 hour, make it to be the thickness attitude after revolving most solvent with the rotation concentrating instrument, make it to produce stiff soup compound and stirring with the 2min time to wherein dripping acetone or different alcohol again, suction filtration, filter cake is with 3 * 10ml Virahol or washing with acetone, under 30～35 ℃ high vacuum dry 22 hours, promptly gets the Telbivudine sodium hydrate.
If necessary, the filter cake after the washing can also be dissolved in sodium salt and the hydrate thereof that carries out lyophilize in the 5ml distilled water and obtain Telbivudine.
Its hydrogen spectrum of its infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment three. Telbivudine potassium and preparation thereof
Get Telbivudine 0.99g (3.8mmol), add methyl alcohol 45ml and make its dissolving, in solution, add the methanol solution 2.2ml that contains 0.23 gram potassium hydroxide (4.1mmol), stir, make solution even, optionally can be to the reaction solution heat treated, filter, filtrate decompression is revolved partly methyl alcohol, the mixed solution that adds 8ml acetone or Virahol or acetone and any ratio of Virahol is then placed suction filtration after the crystallization, and filter cake is with the mixed solution washing of proper amount of acetone or Virahol or acetone and any ratio of Virahol 2～3 times, in 45 ℃ of vacuum-dryings 5 hours, promptly get Telbivudine potassium.
1HNMR(600MHz.DMSO-d
6)：δ7.19(1H，S)，6.22(1H，t)，5.47(1H，s)，5.27(1H，s)，4.22(1H，m)，3.66(1H，)，3.52(2H，d)，1.99-1.88(2H，m)，1.66(3H，s)ppm。
13CNMR(150MHz.DMSO-d
6)：δ173.9，158.1，133.6，109.2，86.4，83.9，70.5，61.7，39.6，14.1ppm。
In above-mentioned preparation, also available ethanol replaces methyl alcohol, makes Telbivudine potassium of the present invention.
Embodiment four. Telbivudine potassium and preparation thereof
Get Telbivudine 1.20g (4.6mmol), add the potassium hydroxide aqueous solution 5ml of 1mol/l, stir and make its dissolving clear and bright,, can adopt that activated carbon decolour, smart filter processing this clear and bright solution as needs.
Above-mentioned clear and bright solution is joined in the acetone (or Virahol) of 15ml, stirred 0.5 hour, reaction solution concentrated to make it to be behind the thick shape make it to produce stiff soup compound and stirring to wherein dripping acetone or different alcohol with the 2min time, suction filtration, filter cake is with 3 * 10ml Virahol or washing with acetone, drying is 20 hours under 30～35 ℃ high vacuum, promptly gets Telbivudine potassium.
Its hydrogen spectrum of nuclear magnetic resonance spectroscopy and carbon spectrum and infrared absorption thereof are consistent with accompanying drawing.
Embodiment five. Telbivudine sodium and preparation thereof
Get Telbivudine 0.5mmol, add methyl alcohol 9ml and make its dissolving, in solution, add the methanol solution 17ml of the sodium methylate that contains 0.51mmol, stir, make solution even, most methyl alcohol is revolved in decompression, the mixed solution that adds 3ml acetone or Virahol or acetone and any ratio of Virahol is then placed suction filtration after the crystallization, and filter cake is with the mixed solution washing of proper amount of acetone or Virahol or acetone and any ratio of Virahol 2～3 times, in 45 ℃ of vacuum-dryings 5 hours, promptly get target product.
In above-mentioned preparation, also available ethanol replaces methyl alcohol, makes Telbivudine sodium of the present invention.
Embodiment six. Telbivudine potassium and preparation thereof
Get Telbivudine 0.57mmol, add methyl alcohol 6.5ml and make its dissolving, in solution, add the methanol solution 20ml that contains the 0.57mmol potassium ethylate, stir, make solution even, optionally can carry out the essence filter to reaction solution handles, filtrate decompression is revolved most solvent, the mixed solution that adds 6ml acetone or Virahol or acetone and any ratio of Virahol then, suction filtration after the placement crystallization, filter cake in 40 ℃ of vacuum-dryings 3 hours, promptly gets Telbivudine potassium with the mixed solution washing of proper amount of acetone or Virahol or acetone and any ratio of Virahol 2～3 times.
In above-mentioned preparation, also available ethanol replaces methyl alcohol, makes Telbivudine potassium of the present invention.
Embodiment seven. Telbivudine sodium tablet and preparation
Get Telbivudine sodium 50g and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Telbivudine sodium 50g
Starch 65g
Lactose 22g
Polyvidone (K
30) 2.5g
Magnesium Stearate 1.5g
Water is an amount of
By above prescription, carry out wet granulation, make Telbivudine sodium and said medicine carrier thorough mixing even, dry whole grain back and make 1000 with tabletting machine, every contains active ingredient Telbivudine sodium is the 50mg/ sheet.
In addition, also can adopt conventional packaging technique that the tablet of above-mentioned preparation is carried out Cotton seeds, can obtain the dressing diaphragm, for example can adopt the dressing solution that contains HPMC, titanium dioxide, polyoxyethylene glycol, Tween-80, iron oxide yellow, red iron oxide, citric acid diethyl ester and water to carry out Cotton seeds, obtain Telbivudine sodium dressing diaphragm.
Embodiment seven. the agent of Telbivudine natrium capsule
Get Telbivudine sodium 100g and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Telbivudine sodium 100g
Lactose 80g
Methylcellulose gum 5g
Xylo-Mucine 4g
Magnesium Stearate 1.5g
Water is an amount of
By above prescription, carrying out wet granulation makes Telbivudine sodium and above-mentioned pharmaceutical carrier thorough mixing except that Magnesium Stearate even, drying whole grain back and Magnesium Stearate mixing packs in 1000 Capsuleses, contain active ingredient Telbivudine sodium 100mg/ grain in every capsules, for orally using, be used for the hepatitis B virus resisting treatment.
Embodiment eight. Telbivudine potassium tablets and preparation
Get Telbivudine potassium 60g and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Telbivudine potassium 60g
N.F,USP MANNITOL 50g
Cross-linked carboxymethyl cellulose 25g
Starch 20g
Stearic acid 1.2g
Water is an amount of
By above prescription, carry out wet granulation and make Telbivudine potassium and said medicine carrier thorough mixing even, dry whole grain back and make 1000 with tabletting machine, every contains active ingredient Telbivudine potassium is the 60mg/ sheet, supplies to orally use, and is used for hepatitis B virus resisting and treats.
Embodiment nine. Telbivudine potassium enteric coated capsule
Similarly, get Telbivudine potassium 50g, add an amount of carrier auxiliary material of people (as Microcrystalline Cellulose, lactose, polyvinylpyrrolidone, Deng), wet grain is granulated and is made Telbivudine potassium and said medicine carrier thorough mixing even, adds after whole in 1000 the enteric solubility Capsuleses of packing into behind the Magnesium Stearate mixing, and promptly getting every, to contain active ingredient Telbivudine potassium be the enteric coated capsule of 50mg, for orally using, be used for the hepatitis B virus resisting treatment.
Embodiment ten. Telbivudine potassium hydrate powder ampoule agent for injection
Get Telbivudine potassium 100g, N.F,USP MANNITOL 150g, add injection water dissolving and be diluted to 1780 milliliters, regulate pH with phosphate buffer and add injection water to 2000 milliliter after 9, smart filter, divide in can to the 1000 bottle cillin bottle, carry out lyophilize by lyophilized injectable powder preparation technology, can be prepared into 1000 bottles of injection Telbivudine potassium hydrate lyophilized injectable powders, every bottle contains Telbivudine potassium 100mg, use for injection, be used for the hepatitis B virus resisting treatment.
Embodiment 11. the Telbivudine sodium injection
Get Telbivudine sodium 35g, add the dissolving of injection water and be diluted to 1300 milliliters, add stirring and evenly mixing behind the propylene glycol 90ml again, regulate pH with phosphate buffer again and add injection water to 2000 milliliter after 9 ± 0.5, smart filter divides in can to the 1000 bottle ampoule sealing by fusing bottleneck, can be prepared into 1000 bottles of Telbivudine sodium injections, every bottle contains Telbivudine sodium 35mg.Use for injection, be used for the hepatitis B virus resisting treatment.
Embodiment 12. Telbivudine potassium oral liquid
Get Telbivudine potassium 0.5g, maltose alcohol 6g, methyl p-hydroxybenzoate 0.2g, flavoring orange essence is an amount of, transfers pH to 7.5～8.5 with citric acid buffer agent after above component is dissolved in water, and making overall solution volume is 100 milliliters, divide and be filled in 10 vials, encapsulation promptly gets every bottle of oral liquid that contains Telbivudine potassium 50mg for 10ml, can be used for the treatment of children's hepatitis B virus resisting.
Embodiment 13. Telbivudine sodium particle
Get Telbivudine sodium 2g, other gets Xylitol 30g, starch 13g, potassium benzoate 0.3g.With suitable quantity of water that Telbivudine sodium dissolving back adding strawberry flavour is an amount of, wet granulation, abundant mixing, oven dry, whole grain are packaged into 10 bags, promptly make every bag of granule that contains Telbivudine sodium 200mg, are used for the treatment of hepatitis B virus resisting.
Prescription: Telbivudine sodium 55g
Lactose 45g
Sodium starch glycolate 25g
Microcrystalline Cellulose 70g
Water is an amount of
Magnesium Stearate 2g
Preparation method: earlier above-mentioned material separated pulverizing is crossed 100 mesh sieves.Lactose, sodium starch glycolate, Microcrystalline Cellulose thorough mixing is even, be sprayed to above-mentioned mixed pressed powder with the Telbivudine sodium water solution, make Telbivudine sodium and said medicine carrier thorough mixing even, make softwood, oven dry after 40 mesh sieves are granulated, the whole grain of 40 mesh sieves, add the Magnesium Stearate mixing, the control tablet weight is pressed into 1000, promptly gets every dispersible tablet that contains Telbivudine sodium 55mg.This tablet can disperse in water in speed fast (in three minutes) disintegration, reaches the effect of quick-release onset, is used for the treatment of hepatitis B virus resisting.
Embodiment 15. Telbivudine potassium sheet (slow release formulation)
Prescription: Telbivudine potassium 100g
Vltra tears (K
4M) 155g
Lactose 28g
Magnesium Stearate 1.8g
The 8% polyvidone aqueous solution is an amount of
Preparation method: with Telbivudine potassium, Vltra tears (K
4M), lactose makes Telbivudine potassium and said medicine carrier thorough mixing even with 8% polyvidone aqueous solution wet granulation, behind oven dry, the whole grain, add the Magnesium Stearate mixing, the control tablet weight, be pressed into 1000, promptly getting content is the Telbivudine potassium sustained release tablets of 61mg, is used for the treatment of hepatitis B virus resisting.
Vltra tears is a hydrophilic polymer, as framework material, meets the expansion of water or Digestive system and forms the gel barrier in said preparation, and the diffusion of control Telbivudine potassium is to play the effect of slowly-releasing.
Embodiment 16. the composite tablet of Telbivudine potassium and lamivudine
Select suitable pharmaceutical carrier and auxiliary material for use, press method for preparing tablet thereof, be prepared into the composite tablet that each sheet medicine contains two kinds of active ingredients of Telbivudine potassium 55mg and lamivudine 100mg.
Embodiment 17. the composite tablet of Telbivudine sodium and didanosine
Select suitable pharmaceutical carrier and auxiliary material for use, press method for preparing tablet thereof, be prepared into the composite tablet that each sheet medicine contains two kinds of active ingredients of Telbivudine sodium 100mg and didanosine 200mg.
Embodiment 18. the composite tablet of Telbivudine sodium and adefovir ester
Select suitable pharmaceutical carrier and auxiliary material for use, press method for preparing tablet thereof, be prepared into the composite tablet that each sheet medicine contains two kinds of active ingredients of Telbivudine sodium 100mg and adefovir ester 10mg.
Embodiment 19. any prepared Telbivudine sodium/sylvite and hydrate thereof the application in the hepatitis b virus infected medicine of preparation treatment among the embodiment one to embodiment five.
Claims (13)
1. the derivative of Telbivudine shown in the formula (I), its pharmaceutically acceptable solvate or its hydrate:
(I), X is an alkali metal cation in the formula,
X＝Na，K，1/2Mg，1/2Ca。
2. the sodium salt compound of the described Telbivudine of claim 1 has following molecular structural formula
3. the potassium salt compound of the described Telbivudine of claim 1 has following molecular structural formula
4. the hydrate of the metal-salt of a Telbivudine, its molecular structural formula is as follows:
, wherein, X is Na ion and K ion, and a is the number of the contained crystal water of per molecule Telbivudine metal-salt, and the span of a is 0.5～5.
5. according to the hydrate of the metal-salt of the described Telbivudine of claim 4, comprise semihydrate, monohydrate, sesqui hydrate, dihydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, the pentahydrate of Telbivudine metal-salt.
6.. method for preparing the metal-salt and the hydrate thereof of the described Telbivudine of claim 1 to 5, this method comprises reacts Telbivudine and the suitable alkali that desired alkali metal cation can be provided in the solvent that is fit to, and in reaction solution, add acetone or Virahol, desired salt is precipitated in solution separate out, and further throw out is carried out drying.
7. the described preparation method of claim 6, it is sodium hydroxide, sodium methylate, sodium ethylate and potassium hydroxide, potassium methylate, potassium ethylate that the suitable alkali of desired alkali metal cation can be provided, and the solvent that is fit to that adopts is the mixture of water, methyl alcohol, ethanol or they any two or three.
8. the described preparation method of claim 6, can adopt following two kinds of methods that throw out is carried out drying further:
Method one. with throw out with acetone or washed with isopropyl alcohol after, it is dissolved in the water makes the aqueous solution, carry out freeze-drying with freeze-drying, obtain white or off-white color pressed powder, promptly obtain Telbivudine metal-salt or its hydrate.
Method two. with throw out with acetone or washed with isopropyl alcohol after, to constant weight, obtain white or off-white color pressed powder in 35 ℃～120 ℃ drying under reduced pressure, promptly get and promptly obtain Telbivudine metal-salt or its hydrate.
9. the described preparation method of claim 6 is characterized in that Telbivudine and sodium hydroxide, sodium methylate, sodium ethylate or potassium hydroxide, potassium methylate, potassium ethylate reaction.
10. a pharmaceutical composition contains described any one the Telbivudine metal-salt of claim 1 to 5 or its hydrate and pharmaceutically acceptable carrier.
11. pharmaceutical composition according to claim 10, wherein in unit formulation, the content of the hydrate of Telbivudine metal-salt or Telbivudine metal-salt is 1mg～1000mg, the content of preferred Telbivudine metal-salt or its hydrate is 5mg～200mg, and more preferably the content of Telbivudine metal-salt or its hydrate is 10mg～100mg.
12. be used to prepare claim 10 or 11 described arbitrary method for compositions, this method comprises makes acceptable any pharmaceutical dosage form on the pharmaceutics with Telbivudine metal-salt or its hydrate and pharmaceutically acceptable carrier thorough mixing, and preferred pharmaceutical dosage form is tablet, capsule, granule, oral solution, injection.
13. sharp 1 to 5 described any one Telbivudine metal-salt or its hydrate of requiring preparing the application for the treatment of in the hepatitis b virus infected medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200610101214 CN1903869A (en) | 2006-07-02 | 2006-07-02 | Tibifudine derivative salt and its preparation method and pharmaceutical application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362787B (en) * | 2008-10-09 | 2012-05-23 | 浙江沙星医药化工有限公司 | Method for preparing telbivudine |
| CN104650168A (en) * | 2013-11-23 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Telbivudine monohydrate compound |
| CN107655982A (en) * | 2016-07-23 | 2018-02-02 | 复旦大学附属华山医院 | A kind of method of Sebivo content in detection blood plasma |
-
2006
- 2006-07-02 CN CN 200610101214 patent/CN1903869A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362787B (en) * | 2008-10-09 | 2012-05-23 | 浙江沙星医药化工有限公司 | Method for preparing telbivudine |
| CN104650168A (en) * | 2013-11-23 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Telbivudine monohydrate compound |
| CN107655982A (en) * | 2016-07-23 | 2018-02-02 | 复旦大学附属华山医院 | A kind of method of Sebivo content in detection blood plasma |
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