CN101182331A - Adefovir dipivoxil ester colalin derivatives as well as preparation method and uses thereof - Google Patents
Adefovir dipivoxil ester colalin derivatives as well as preparation method and uses thereof Download PDFInfo
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Abstract
The present invention discloses an adefovir dipivoxil cholic acid class derivative and also relates to a preparation method and applications thereof at the medical aspect. The adefovir dipivoxil cholic acid class derivative is a hepatic targeting precursor drug of adefovir; compared with the adefovir dipivoxil, the adefovir dipivoxil cholic acid class derivative can improve the concentration of the adefovir in liver after being taken orally, and the adefovir dipivoxil cholic acid class derivative can be used as a preferential drug for the treatment of resisting virus and especially resisting hepatitis virus.
Description
Technical field:
The present invention relates to medical technical field, exactly it is adefovir dipivoxil ester colalin derivatives and its production and use.
Background technology:
Two (new pentane acyloxy methoxyl group) phosphatidyl methoxies of adefovir ester (Adefovir dipivoxil) chemical name: 9-[2-[] ethyl] VITAMIN B4, the CA accession number is [142340-99-6], molecular formula: C
20H
32N
5O
8P, its structural formula is suc as formula 1:
Adefovir ester is the prodrug of Adefovir, is the purine analog derivative, can be oral, and oral posthydrolysis is an Adefovir, does not need phosphorylation that antivirus action is promptly arranged.This product can suppress the activity of HBV DNA polymerase, and can penetrate among the DNA of hepatitis B virus, suppresses duplicating of virus, to lamivudine and the drug-fast HBV virus strain of Famciclovir, very strong restraining effect is all arranged, the clinical treatment that is used for hepatitis.
The compound patent that Adefovir is applied for the earliest is Czechoslovakia patent CS 263951, and priority date is 1985.04.25, and equal patent has EP 206459, and US 4808716.Other patent comprises US 4724233, WO 9904774, WO 0035460 etc.Adefovir phosphate-based electronegative, oral back absorbs not good in intestines, therefore bioavailability is very low, U.S. Gilead Sciences company has developed adefovir ester for this reason, it can be rapidly by esterase hydrolyzed after oral, discharge the free Adefovir and enter in portal system and the body circulation, and have high bioavailability, final Adefovir excretes through kidney.In September, 2002, adefovir ester is used for the treatment of the adult and significantly increases with serum transaminase with virus replication is active first in U.S.'s listing, or liver histological is the chronic viral hepatitis B infection of reactivity pathology.Because adefovir ester has certain renal toxicity, therefore limited the use of its optimum dose, it can not be treated with the maximum dosage of hepatitis B virus resisting.Have kidney Chinese traditional medicine amount behind the research article report adefovir ester rat oral gavage be liver ten surplus times (Meng Zhiyun, Dou Guifang, Sun Wen kind, Zhu Xiaoxia, Zhang Liang, Tang Zhongming.Adefovir two pyrrole furan esters are in the intravital pharmacokinetics of macaque and in the intravital tissue distribution of rat " Chinese J Pharmacol Toxicol " in December, 2003, and 17 (6): 447～450), long-term prescription notes Toxicity of Kidney.
The Gilead Sciences company of development adefovir ester has applied for this medicine in China relevant patent: patent publication No. CN1251592A (nucleotide analog compound), four kinds of crystal formation states of adefovir ester are provided, and provide the adefovir dipivoxil crystal salt of part to comprise as inorganic acid salt and organic acid salts such as methylsulfonic acid, ethyl sulfonic acid such as hemisulfic acid, Hydrogen bromides.Patent publication No. CN 1569861A (medicinal acid addition salt of adefovir ester and the application on medicine thereof) provides door winter oxygen acid adefovir ester salt, taurine adefovir ester salt, gluconic acid adefovir ester salt, fructose adefovir ester salt.Patent publication No. CN1603331A (two (pivaloyloxymethoxy) phosphatidyl methoxies of 9-{2-[] ethyl } the VITAMIN B4 glucuronate and preparation method thereof), glucuronic acid adefovir ester salt is provided.Patent publication No. CN 1528766A (oxalic adefovir dipivoxil and crystal formation thereof and Preparation method and use) provides oxalic adefovir dipivoxil salt.Above-mentioned several pieces of patents all do not relate to adefovir dipivoxil ester colalin derivatives, do not relate to the characteristics that adefovir dipivoxil ester colalin derivatives has the liver target yet.
Summary of the invention:
The invention provides adefovir dipivoxil ester colalin derivatives and its production and use.
Adefovir dipivoxil ester colalin derivatives, comprise adefovir ester cholic acid coupling compound and adefovir ester cholic acid class salt and their crystalline form, polycrystal form, amorphous form, solvate, steric isomer and tautomer, solvate of the present invention comprises the moisture form of adefovir dipivoxil ester colalin derivatives, as hydrated crystal.The adefovir ester cholic acid coupling compound is the compound of adefovir ester with amido linkage and cholic acid or chlolic acid derivatives coupling gained, and its structural formula feature is seen formula 2; Adefovir ester cholic acid class salt is the salt of adefovir ester and cholic acid or chlolic acid derivatives reaction gained, and its structural formula feature is seen formula 3.
Formula 2:
Wherein C represents cholic acid, remaining structure or the group of chlolic acid derivatives and adefovir ester generation acid amides reaction back.
Formula 3:
Wherein steroid cholic acid represents cholic acid, chlolic acid derivatives, and a, b are 1.
Adefovir dipivoxil ester colalin derivatives of the present invention can be crystalline form, amorphous form or polycrystal form, preferred crystal form; Adefovir dipivoxil ester colalin derivatives can be for solvate, non-solvent compound, contain crystal water, do not contain crystal water, preferably contains crystal water or does not contain crystal water.The steric isomer of adefovir dipivoxil ester colalin derivatives and tautomer are also within the protection domain of this patent.
Adefovir ester cholic acid coupling compound of the present invention, the mol ratio of adefovir ester and cholic acid or chlolic acid derivatives is 1: 1 in its structure.
Adefovir ester cholic acid class salt of the present invention, the mol ratio of adefovir ester and cholic acid or chlolic acid derivatives is 1: 1 in its structure.
Adefovir ester raw material of the present invention can use for crystal, polycrystal, amorphous solid, oily matter and above-mentioned two or more raw material forms mix.
Cholic acid class of the present invention comprises cholic acid and chlolic acid derivatives.The chemical formula of cholic acid of the present invention is 3a, 7a, and 12a-trihydroxy-cholestane-24-acid is also referred to as cholic acid, ursodeoxycholic acid, colalin, cholalic acid etc. simultaneously.Chlolic acid derivatives; all contain the acid of steroidal structure to comprise Deoxycholic Acid, dehydrocholic acid, Chenodiol, ursodesoxycholic acid, Hyodeoxycholic Acid, lithocholic acid, glycocholic acid, taurocholate, glycochenodeoxycholate, ox sulphur gallodesoxycholic acid, sweet ammonia Deoxycholic Acid, taurodeoxycholic acid, sweet ammonia Hyodeoxycholic Acid, ox sulphur Hyodeoxycholic Acid, sweet ammonia ursodesoxycholic acid, ursodeoxycholic acid, sweet ammonia lithocholic acid, taurolithocholic acid etc., and steroidal structure of the present invention as shown in Equation 4.
Formula 4:
Cholic acid and derivative thereof with the steroidal structure as the common parent nucleus, can from human or animal's bile, extract or synthetic, belong to the steroidal acids that contains carboxyl or other acid group, comprise suc as formula 5, cholic acid or the chlolic acid derivatives structure shown in formula 6, formula 7 or the formula 8:
Formula 5:
R wherein
1, R
2, R
3And R
4Be respectively hydrogen atom or hydroxyl; And X is-OH ,-NH-(CH
2)
nSO
3H ,-NH-(CH
2)
n-CO
2H, (wherein n is the integer of 1-10) or each seed amino acid and above-mentioned cholic acid or reacted remaining structure of chlolic acid derivatives generation acid amides or group.
Formula 6:
Wherein the definition in the X cotype 5 is identical.
Formula 7:
Wherein the definition in the X cotype 5 is identical.
Formula 8:
Wherein the definition in the X cotype 5 is identical.
Cholic acid is the cholesterol metabolic end product, is biliary main component, is playing an important role aspect the absorption of digestion fat and liposoluble vitamin.The hepatic secretion cholic acid drains into enteric cavity to bile from gall-bladder, is heavily absorbed at terminal ileum thereupon; Again also be secreted in the bile once more by the liver cell picked-up at liver.This efficiently the mechanism of depositary's cholic acid total amount be known as enterohepatic circulation.Small intestine and liver are re-absorbed efficient, add the heavy body of cholic acid transporter in this system, make this system for the development of useful for drug delivery very big prospect be arranged.The cholic acid transporter comprises sodium ion-taurocholate transhipment polypeptide on the people's small intestine cells sodium dependency cholic acid transporter that is positioned at human small intestine's cell and liver cell film surface; they can combine with cholic acid and a series of derivative thereof specifically; thereby its absorption is entered cell interior; therefore be that targeting vector can improve the concentration of medicine in liver with cholic acid or chlolic acid derivatives, the toxic reaction at other positions of health is minimized.As endogenic natural aglucon, cholic acid or chlolic acid derivatives have good bio-compatibility, thereby are suitable for the carrier as hepatic targeting drug.Adefovir dipivoxil ester colalin derivatives is the liver target prodrug of Adefovir, compares with adefovir ester and can improve the concentration of Adefovir in liver after oral, better suppress hepatitis B virus duplicate.
Adefovir ester cholic acid coupling compound of the present invention can be prepared by following method:
(1) acidic-groups such as carboxyl in employing mixed anhydride method activation cholic acid or the chlolic acid derivatives, adefovir ester contacted or heat with certain mol proportion with activatory cholic acid or chlolic acid derivatives prepare, in the preparation process, the mol ratio of activatory cholic acid or chlolic acid derivatives and adefovir ester is 0.01: 1～100: 1, be preferably 0.5: 1～2: 1, the reagent of activation cholic acid or chlolic acid derivatives comprises chloro-formic esters such as Vinyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate.
(2) or adopt acid groups such as carboxyl in active ester method activation cholic acid or the chlolic acid derivatives, adefovir ester contacted or heat with certain mol proportion with activatory cholic acid or chlolic acid derivatives prepare, in the preparation process, the mol ratio of activatory cholic acid or chlolic acid derivatives and adefovir ester is 0.01: 1～100: 1, be preferably 0.5: 1～2: 1, activatory cholic acid or chlolic acid derivatives comprise the methyl esters of cholic acid or chlolic acid derivatives, ethyl ester, the p-nitrophenyl phenolic ester, pentafluorophenyl esters, pentachlorophenyl ester, the N-hydroxy-succinamide ester, N-hydroxyphthalimide ester, 1-hydroxy benzo triazole ester etc.; Reaction can add dicyclohexylcarbodiimide, DIC is an additive, so not only can reduce side reaction, can also improve productive rate.
(3) or adopt the condensing agent method to make adefovir ester and cholic acid or chlolic acid derivatives, condensing agent contact or heat with certain mol proportion and prepare, in the preparation process, the mol ratio of cholic acid or chlolic acid derivatives and adefovir ester is 0.01: 1～100: 1, is preferably 0.5: 1～2: 1; It is condensing agent that dicyclohexylcarbodiimide or DIC are adopted in reaction, can add N-hydroxy-succinamide ester, N-hydroxyphthalimide ester, 1-hydroxy benzo triazole ester etc. as additive, so not only side reaction can be reduced, productive rate can also be improved.
According to above-mentioned preparation method, the solvent that is used to dissolve adefovir ester, activatory cholic acid or chlolic acid derivatives, cholic acid or chlolic acid derivatives, condensing agent there is no particular restriction, as long as suitable solubleness is arranged.The examples of solvents that is fit to comprises methyl alcohol, dehydrated alcohol, contains ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, dimethyl sulfoxide (DMSO), the N of certain water gaging, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methyl acetate, ethyl acetate, Iso Butyl Acetate, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), toluene, tetrahydrofuran (THF), 1,4-dioxane, glycol dimethyl ether, methylene dichloride, ethylene dichloride, trichloromethane, tetrachloromethane, ether etc.These solvents may use separately or two or more solvents are united use, particular methanol, dehydrated alcohol, the ethanol that contains certain water gaging, N, dinethylformamide, N,N-dimethylacetamide.
According to above-mentioned preparation method, the solvent that is used for refining adefovir ester cholic acid coupling compound there is no particular restriction, as long as they can suitably dissolve the adefovir ester cholic acid coupling compound.The example of the solvent that is fit to comprises methyl alcohol, dehydrated alcohol, contains ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, dimethyl sulfoxide (DMSO), the N of certain water gaging, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methyl acetate, ethyl acetate, Iso Butyl Acetate, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), toluene, tetrahydrofuran (THF), 1,4-dioxane, glycol dimethyl ether, methylene dichloride, ethylene dichloride, trichloromethane, tetrachloromethane, ether etc.These solvents may use separately or two or more solvents are united use.Preferred ethanol or the acetic acid ethyl ester of adopting.Solvent for use can be removed by conventional method, as decompression or vacuum-drying, volatilization, spraying drying, lyophilize, cold filtration or its combination, with the adefovir ester cholic acid coupling compound of preparation solid crystals form, amorphous form and polycrystal form.Preferred decompression or vacuum-drying, volatilization and the cold filtration of adopting is to prepare the adefovir ester cholic acid coupling compound of crystalline form, and decompression or vacuum-drying temperature are 0～80 ℃, and preferred temperature is 20～60 ℃.Simultaneously, preferably adopt spraying drying and lyophilize to prepare the adefovir ester cholic acid coupling compound of amorphous form.Also adefovir ester cholic acid coupling compound crude product can be dissolved in the poor solvent of impurity such as adefovir ester, cholic acid, catalyzer, by product, precipitation is removed impurity, obtains purified adefovir ester cholic acid coupling compound.
Be the solid-state conjugates of preparation in the presence of solvent, its recrystallization method comprises: at first, the adefovir ester cholic acid coupling compound is dissolved in a kind of solvent or the mixed solvent.Thereafter, with the solution that obtains at a certain temperature (60～60 ℃) leave standstill, make and separate out precipitation, preferred dwell temperature is-20～30 ℃; Or suitable precipitation solvent mixed with this solution to be settled out the adefovir ester cholic acid coupling compound, temperature is-60～60 ℃ during precipitation, preferred precipitation temperature is-20～30 ℃; Filtering precipitate, with suitable cleaning solvent washing and dry, temperature is-20～60 ℃ during washing, preferred wash temperature is-10～30 ℃; Obtain final adefovir ester cholic acid coupling compound.
Precipitation solvent or cleaning solvent in present method there is no particular restriction, as long as adefovir ester cholic acid coupling compound solubleness therein is less.The example of the solvent that is fit to comprises water, organic solvent such as cold methanol, methylene dichloride, ethylene dichloride, trichloromethane, tetrachloromethane, ether, sherwood oil etc.These solvents may use separately or two or more solvents are united use.
Be the solid-state adefovir ester cholic acid coupling compound of preparation in the presence of solvent, also the adefovir ester cholic acid coupling compound crude product of preparation can be carried out separation and purification with suitable chromatographic column, obtain purified adefovir ester cholic acid coupling compound.
As above Zhi Bei adefovir ester cholic acid coupling compound can be the form of anhydride or the form of hydrate.If the adefovir ester cholic acid coupling compound that obtains is the form of solvate, can dryly removes intermolecular solvent or remove by solvent exchange.
For improving the purpose of adefovir ester cholic acid coupling compound productive rate, can improve the concentration of adefovir ester cholic acid coupling compound in the solution by heating.Perhaps, the adefovir ester cholic acid coupling compound is dissolved in the The suitable solvent, can removes partial solvent by vacuum-drying or volatilization then.Equally, can add crystal seed to promote the precipitation of adefovir ester cholic acid coupling compound.
Adefovir ester cholic acid class salt of the present invention can be by following method preparation.Adefovir ester cholic acid class salt can prepare by simply adefovir ester being contacted or heats with certain mol proportion with the cholic acid or derivatives thereof, and at this moment, adefovir ester preferably is present in the solution phase.More preferably, adefovir ester and cholic acid or derivatives thereof all be present in solution mutually in.Particularly, can prepare adefovir ester cholic acid class salt by the following method: adefovir ester is dissolved in the appropriate solvent, then the cholic acid or derivatives thereof is dissolved in this solvent; Perhaps the cholic acid or derivatives thereof is dissolved in the appropriate solvent separately, and then the solution that obtains is mixed with the solution of prior lysed adefovir ester, temperature of reaction is carried out under-20～80 ℃, and preferred temperature of reaction is 0～60 ℃.
In the preparation process of adefovir ester cholic acid class salt, the mol ratio of cholic acid or chlolic acid derivatives and adefovir ester is 0.01: 1～100: 1, is preferably 0.5: 1～2: 1.
The solvent that is fit to that is used to prepare adefovir ester cholic acid class salt there is no particular restriction, as long as they can dissolve adefovir ester.This solvent can also be used to dissolving or suspendible cholic acid or derivatives thereof.The example of the solvent that is fit to comprises methyl alcohol, dehydrated alcohol, contains ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, dimethyl sulfoxide (DMSO), the N of certain water gaging, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methyl acetate, ethyl acetate, Iso Butyl Acetate, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), toluene, tetrahydrofuran (THF), 1,4-dioxane, glycol dimethyl ether, methylene dichloride, ethylene dichloride, trichloromethane, tetrachloromethane, ether etc.These solvents may use separately or two or more solvents are united use.Preferred dehydrated alcohol or 95% ethanol of adopting.Solvent for use can be removed by conventional method, as decompression or vacuum-drying, volatilization, spraying drying, lyophilize, cold filtration with and combination, with the adefovir ester cholic acid class salt of preparation solid crystals form, amorphous form and polycrystal form.Preferred decompression or vacuum-drying, volatilization and the cold filtration of adopting is to prepare the adefovir ester cholic acid class salt of crystalline form, and decompression or vacuum-drying temperature are 0～100 ℃, and preferred temperature is 20～60 ℃.Simultaneously, preferably adopt spraying drying and lyophilize to prepare the adefovir ester cholic acid class salt of amorphous form.Also adefovir ester cholic acid class salt crude product can be dissolved in the poor solvent of adefovir ester or cholic acid, precipitation is removed unreacted raw material, obtains purified adefovir ester cholic acid class salt.
For the solid-state salt of preparation in the presence of solvent, at first, adefovir ester and cholic acid or derivatives thereof are dissolved in a kind of solvent or the mixed solvent.Thereafter, with the solution that obtains at a certain temperature (60～60 ℃) leave standstill, make and separate out precipitation, preferred dwell temperature is-20～30 ℃; Or suitable precipitation solvent mixed with this solution to be settled out adefovir ester cholic acid class salt, temperature is-60～60 ℃ during precipitation, preferred precipitation temperature is-20～30 ℃; Filtering precipitate, with suitable cleaning solvent washing and dry, temperature is-20～80 ℃ during washing, preferred wash temperature is-10～40 ℃; Obtain final adefovir ester cholic acid class salt.
Suitable precipitation solvent or cleaning solvent there is no particular restriction, as long as adefovir ester cholic acid class salt solubleness therein is less.The example of the solvent that is fit to comprises water, organic solvent such as methylene dichloride, ethylene dichloride, trichloromethane, tetrachloromethane, ether, sherwood oil etc.These solvents may use separately or two or more solvents are united use.
For the solid-state salt of preparation in the presence of solvent, also adefovir ester and cholic acid or derivatives thereof can be dissolved in a kind of solvent or the mixed solvent, carry out separation and purification with suitable chromatographic column, obtain final adefovir ester cholic acid class salt.The adefovir ester cholic acid class salt crude product of preparation can also be carried out separation and purification with suitable chromatographic column, obtain purified adefovir ester cholic acid class salt.
As above Zhi Bei adefovir ester cholic acid class salt can be the form of anhydride or the form of hydrate.If the adefovir ester cholic acid class salt that obtains is the form of solvate, can dryly removes intermolecular solvent or remove by solvent exchange.For improving the purpose of adefovir ester cholic acid class salt productive rate, can be by the concentration of adefovir ester and cholic acid or derivatives thereof in the heating raising solution.Perhaps, adefovir ester and cholic acid or derivatives thereof are dissolved in the The suitable solvent, can remove partial solvent by vacuum-drying or volatilization then.Equally, can add crystal seed to promote the precipitation of adefovir ester cholic acid class salt.
Adefovir dipivoxil ester colalin derivatives according to the present invention can be used as activeconstituents and particularly uses in the viral hepatitis in the treatment virus disease.The present invention also provides the medicinal compositions that contains adefovir dipivoxil ester colalin derivatives, contains adefovir dipivoxil ester colalin derivatives in the said composition as activeconstituents, and acceptable auxiliary material pharmaceutically.Adefovir dipivoxil ester colalin derivatives of the present invention can be used in combination with other activeconstituents.
When the present invention is applied to when clinical, it can be mixed with to comprise tablet, capsule, granule, pill, the liquid oral formulation that orally uses; The injection liquid of injection, powder ampoule agent for injection, liposome, emulsion, nanoparticle, mixture; The emulsion of external application, ointment; Through the oral cavity or the oral tablet of my humble abode administration.
Advantage of the present invention is: adefovir ester and cholic acid or chlolic acid derivatives are prepared into conjugates or salt, can obtain oral Adefovir prodrug with liver targeting, thereby the concentration of adefovir ester parent drug Adefovir in the raising liver strengthens result of treatment.
Embodiment
With reference to following examples formation of the present invention and operation are made explanation more specifically.But these embodiment should not be considered to limitation of the scope of the invention.
The structural formula of embodiment 1 adefovir ester cholic acid coupling compound
Formula 9:
R wherein
1, R
2, R
3And R
4Be respectively hydrogen atom or hydroxyl.
The structural formula of embodiment 2 adefovir ester cholic acid class salt
Formula 10:
Wherein X be-OH ,-NH-(CH
2)
nSO
3H, ,-NH-(CH
2)
n-CO
2H (wherein n is the integer of 1-3).
The structural formula of embodiment 3 adefovir ester cholic acid class salt
Formula 11:
R wherein
1, R
2, R
3And R
4Be respectively hydrogen atom or hydroxyl; Wherein X be-OH ,-NH-(CH
2)
nSO
3H, ,-NH-(CH
2)
n-CO
2H (wherein n is the integer of 1-3).
The preparation of embodiment 4 adefovir ester cholic acid conjugates
The 5.0g cholic acid is put into 20mL methyl alcohol, with HCl, H
3PO
4Or H
2SO
4Make catalyzer backflow 2h, 0 ℃ left standstill 12 hours, separated out precipitation, filtered, and with the washing precipitation of 5mL cold methanol, drying obtains the 4.56g Methyl cholate; 4.23g Methyl cholate and 5.01g buttery adefovir ester are dissolved in the 5mL dehydrated alcohol fully, backflow 0.1h,-20 ℃ left standstill 12 hours, be settled out white solid, filter, residue then with 40 ℃ of vacuum-dryings of residue, obtains 6.32g white powder adefovir ester cholic acid conjugates solid with the washing of 5mL ether.
The preparation of embodiment 5 adefovir ester Hyodeoxycholic Acid conjugates
Hyodeoxycholic Acid 3.93g and triethylamine 1.4mL are dissolved in the 30mL dimethyl formamide, be cooled to-20 ℃, slowly add isobutyl chlorocarbonate 1.4mL again, react after 5 minutes, add the adefovir ester of 5.01g lenticular and the solution that triethylamine 1.4mL is dissolved in the 20mL dimethyl formamide, after 30 minutes, room temperature was placed 2 hours at-20 ℃ of stirring reactions.Reactant is filtered to remove triethylamine muriate wherein, filtrate evaporated under reduced pressure is concentrated obtain crude compound 1 again.Product added among the chloroform 20mL dissolves, filter discard not tolerant, filtrate with 1% hydrochloric acid soln washed twice after, the chloroform layer reduction vaporization is obtained crude compound 2.Crude compound 2 usefulness ethanol one re-crystallizing in ethyl acetate obtains 3.38g white powder adefovir ester Hyodeoxycholic Acid conjugates solid for twice.
The preparation of embodiment 6 adefovir ester Deoxycholic Acid conjugates
5.01g buttery adefovir ester and 3.93g Deoxycholic Acid are dissolved in the 8mL ethanol fully, add dicyclohexylcarbodiimide (DCC) 2.06g again, after the normal-temperature reaction 5 minutes, reactant is filtered to remove dicyclohexylurea (DCU) wherein, and-20 ℃ left standstill 12 hours, and were settled out white solid, filter, residue then with 40 ℃ of vacuum-dryings of residue, obtains 5.72g white powder adefovir ester Hyodeoxycholic Acid salt solid with the washing of 5mL ether.
The preparation of embodiment 7 adefovir ester cholates
5.01g buttery adefovir ester and 4.09g cholic acid are dissolved in the 5mL dehydrated alcohol fully, and 40 ℃ of removal of solvent under reduced pressure then with 40 ℃ of vacuum-dryings of residue, obtain 8.90g white powder adefovir ester cholate solid.
The preparation of embodiment 8 adefovir ester Hyodeoxycholic Acid salt
5.01g Adefovir crystalline esters and 3.93g Hyodeoxycholic Acid are dissolved in the 5mL dehydrated alcohol fully,-20 ℃ left standstill 12 hours, be settled out white solid, filter, residue washs with the 5mL ether, with 40 ℃ of vacuum-dryings of residue, obtain 6.16g white powder adefovir ester Hyodeoxycholic Acid salt solid then.
The preparation of embodiment 9 adefovir ester ursodeoxycholic hydrochlorates
5.01g Adefovir dipivoxil amorphous condensates and 3.93g ursodesoxycholic acid are dissolved in the 5mL trimethyl carbinol fully, and lyophilize obtains 8.73g white powder adefovir ester ursodeoxycholic hydrochlorate solid.
The preparation of embodiment 10 adefovir ester deoxycholates
5.01g buttery adefovir ester and 7.86g Deoxycholic Acid are dissolved in the 10mL dehydrated alcohol fully, spraying drying, use 10mL trichloromethane stirring and dissolving then, filter and remove insolubles, trichloromethane is removed in decompression, with the vacuum-drying of residue room temperature, obtain 7.32g white powder adefovir ester deoxycholate solid then.
The preparation of embodiment 11 adefovir ester CDCs
10.02g buttery adefovir ester and 3.93g Deoxycholic Acid are dissolved in the 10mL dehydrated alcohol fully, carry out separation and purification, obtain 7.19g white powder adefovir ester CDC solid with silicagel column.
The preparation of embodiment 12 adefovir ester dehydrocholates
5.01g buttery adefovir ester and 4.02g dehydrocholic acid are dissolved in the 5mL dehydrated alcohol fully, 60 ℃ of removal of solvent under reduced pressure, then with 60 ℃ of vacuum-dryings of residue, obtain 8.86g adefovir ester dehydrocholate crude product, carry out separation and purification with silicagel column, obtain 7.53g white powder adefovir ester dehydrocholate solid.
The preparation of embodiment 13 adefovir ester taurocholate
5.01g buttery adefovir ester and 5.22g taurocholate are dissolved in the 5mL dehydrated alcohol fully; add the 50mL ether; be settled out white solid; filter; residue washs with the 5mL ether; with 30 ℃ of vacuum-dryings of residue, obtain 8.56g white powder adefovir ester taurocholate solid then.
The preparation of embodiment 14 adefovir ester lithocholates
5.01g buttery adefovir ester and 3.77g lithocholic acid are dissolved in the 5mL dehydrated alcohol fully, add the 50mL sherwood oil, be settled out white solid, filter, residue 5mL petroleum ether, with 20 ℃ of vacuum-dryings of residue, obtain 7.67g white powder adefovir ester lithocholate solid then.
The preparation of embodiment 15 adefovir ester GC
5.01g buttery adefovir ester and 4.66g glycocholic acid are dissolved in the 5mL dehydrated alcohol fully, add an amount of adefovir ester GC crystal seed,-40 ℃ left standstill 12 hours, be settled out white solid, filter, residue 5mL petroleum ether then with 50 ℃ of vacuum-dryings of residue, obtains 7.43g white powder adefovir ester GC solid.
Get adefovir ester Hyodeoxycholic Acid conjugates 17.48g; even with 200g lactose, 50g Microcrystalline Cellulose, 5g sodium starch glycolate thorough mixing in nodulizer; with the wetting softwood of making of ethanol; the drying of granulating back adds the 2.8g Magnesium Stearate; mixing; be pressed into 1000, promptly get adefovir ester Hyodeoxycholic Acid conjugates sheet, every contains 17.48mg adefovir ester Hyodeoxycholic Acid conjugates (being equivalent to the about 10mg/ sheet of adefovir ester).
Embodiment 17 adefovir ester Deoxycholic Acid conjugates preparation of drug combination
Get adefovir ester Deoxycholic Acid conjugates 17.48g; even with 200g lactose, 50g Microcrystalline Cellulose, 5g sodium starch glycolate thorough mixing in nodulizer; with the wetting softwood of making of ethanol; the drying of granulating back adds the 2.8g Magnesium Stearate; mixing is pressed into 1000, and is enteric coated; promptly get adefovir ester Deoxycholic Acid conjugates enteric coated tablet, every contains 17.48mg adefovir ester Deoxycholic Acid conjugates (being equivalent to the about 10mg/ sheet of adefovir ester).
Embodiment 18 adefovir ester Hyodeoxycholic Acid salt preparation of drug combination
Get adefovir ester Hyodeoxycholic Acid salt 17.84g; even with 200g lactose, 50g Microcrystalline Cellulose, 5g sodium starch glycolate thorough mixing in nodulizer; with the wetting softwood of making of ethanol; the drying of granulating back adds the 2.8g Magnesium Stearate; mixing; be pressed into 1000, promptly get adefovir ester Hyodeoxycholic Acid salt sheet, every contains 17.84mg adefovir ester Hyodeoxycholic Acid salt (being equivalent to the about 10mg/ sheet of adefovir ester).
Embodiment 19 adefovir ester deoxycholate preparation of drug combination
Get adefovir ester deoxycholate 17.84g; even with 200g lactose, 50g Microcrystalline Cellulose, 5g sodium starch glycolate thorough mixing in nodulizer; with the wetting softwood of making of ethanol; the drying of granulating back adds the 2.8g Magnesium Stearate; mixing is pressed into 1000, and is enteric coated; promptly get adefovir ester deoxycholate enteric coated tablet, every contains 17.84mg adefovir ester deoxycholate (being equivalent to the about 10mg/ sheet of adefovir ester).
The research that embodiment 20 adefovir esters, adefovir ester Hyodeoxycholic Acid conjugates, adefovir ester Hyodeoxycholic Acid salt Mouse Liver, nephridial tissue distribute
Experimental animal: Kunming mouse, body weight 18～22g, male and female half and half are provided by China Medicine University's animal center.Conformity certification number is: SCXK (Soviet Union) 2006-2007.
Trial drug: adefovir ester (the honest day fine pharmaceutcal corporation, Ltd in Jiangsu Province provides); Adefovir ester Hyodeoxycholic Acid conjugates, adefovir ester Hyodeoxycholic Acid salt (medicament teaching and research room of China Medicine University provides).
Test method: select 63 Kunming mouses for use, be divided into 3 groups at random, fasting 12h, press the 45mgkg-1 adefovir ester, 78.6mgkg-1 adefovir ester Hyodeoxycholic Acid conjugates (78.6mg adefovir ester Hyodeoxycholic Acid conjugates is equivalent to the 45mg adefovir ester), 80mgkg-1 adefovir ester Hyodeoxycholic Acid salt (80mg adefovir ester Hyodeoxycholic Acid salt is equivalent to the 45mg adefovir ester) is gastric infusion respectively, after administration 0.5,1,2,4,8,12,24h is the bloodletting treated animal that kills alive respectively, get liver and kidney, tissue washes down with physiological saline, claim weight in wet base with analytical balance, with distilled water by making homogenate at 1: 3, add 10% trichoroacetic acid(TCA) 1mL, vortex, high speed centrifugation 3min gets supernatant liquor, uses the concentration of adefovir ester parent drug Adefovir in the high performance liquid phase methods analyst tissue of reliability conclusive evidence.
Test-results:
The adefovir ester group:
Liver: C
Max: 4.5 μ g/g, T
Max: 2.1h, AUC
0 → 24(56.5 μ g/g) h
Kidney: Cmax:30.6 μ g/g, Tmax:3.0h, AUC
0 → 24(402.0 μ g/g) h
Adefovir ester Hyodeoxycholic Acid conjugates group:
Liver: C
Max: 8.8 μ g/g, T
Max: 5.2h, AUC
0 → 24(154.9 μ g/g) h
Kidney: Cmax:25.6 μ g/g, Tmax:4.8h, AUC
0 → 24(369.3 μ g/g) h
Adefovir ester Hyodeoxycholic Acid salt group:
Liver: C
Max: 8.3 μ g/g, T
Max: 5.0h, AUC
0 → 24(129.6 μ g/g) h
Kidney: Cmax:24.4 μ g/g, Tmax:4.9h, AUC
0 → 24(363.6 μ g/g) h
The result sees accompanying drawing for details:
Fig. 1 is: the result of study that Adefovir distributes in adefovir ester, adefovir ester Hyodeoxycholic Acid conjugates, the adefovir ester Hyodeoxycholic Acid salt murine liver tissue
Fig. 2 is: the result of study that Adefovir distributes in adefovir ester, adefovir ester Hyodeoxycholic Acid conjugates, the adefovir ester Hyodeoxycholic Acid salt mouse nephridial tissue
Conclusion (of pressure testing): under identical dosage, by the adefovirdipivoxil C in liver, the nephridial tissuemax、T
max、AUC
0→24Comparison, Ah De Fuwei ester hyodesoxycholic acid conjugates, the administration of Aldoforwe ester hyodesoxycholic acid salt mouse stomach have obvious liver target feature.
Although disclose the preferred embodiment of the invention for illustrational purpose, it will be understood by those skilled in the art that Under the prerequisite that does not break away from the present invention such as the disclosed scope and spirit of claims, can to the present invention make different modifications, Add and replacement.
Claims (10)
1. adefovir dipivoxil ester colalin derivatives comprises adefovir ester cholic acid coupling compound and adefovir ester cholic acid class salt and their crystalline form, polycrystal form, amorphous form, solvate, steric isomer and tautomer; The adefovir ester cholic acid coupling compound is the compound of adefovir ester with amido linkage and cholic acid or chlolic acid derivatives coupling gained, and its structural formula feature is seen formula 1; Adefovir ester cholic acid class salt is the salt of adefovir ester and cholic acid or chlolic acid derivatives reaction gained, and its structural formula feature is seen formula 2.
Formula 1:
Wherein C represents cholic acid, remaining structure or the group of chlolic acid derivatives and adefovir ester generation acid amides reaction back.
Formula 2:
Wherein steroid cholic acid represents cholic acid, chlolic acid derivatives, and a, b are 1.
2. adefovir dipivoxil ester colalin derivatives as claimed in claim 1, the crystalline form of preferred adefovir ester cholic acid coupling compound.
3. adefovir dipivoxil ester colalin derivatives as claimed in claim 1, the crystalline form of preferred adefovir ester cholic acid class salt.
4. adefovir dipivoxil ester colalin derivatives as claimed in claim 1; wherein said cholic acid class; be cholic acid and chlolic acid derivatives; comprise cholic acid; Deoxycholic Acid; dehydrocholic acid; Chenodiol; ursodesoxycholic acid; Hyodeoxycholic Acid; lithocholic acid; glycocholic acid; taurocholate; glycochenodeoxycholate; ox sulphur gallodesoxycholic acid; sweet ammonia Deoxycholic Acid; taurodeoxycholic acid; sweet ammonia Hyodeoxycholic Acid; ox sulphur Hyodeoxycholic Acid; sweet ammonia ursodesoxycholic acid; ursodeoxycholic acid; sweet ammonia lithocholic acid; all contain the acid of steroidal structure taurolithocholic acids etc., and steroidal structure of the present invention as shown in Equation 3.
Formula 3:
5. the preparation method of adefovir ester cholic acid coupling compound as claimed in claim 1 is characterized in that comprising following key step:
Employing mixed anhydride method or active ester method activate the acid groups such as carboxyl in cholic acid or the chlolic acid derivatives, adefovir ester are contacted or heats with certain mol proportion with activatory cholic acid or chlolic acid derivatives prepare; Perhaps adopt the condensing agent method to make adefovir ester and cholic acid or chlolic acid derivatives, condensing agent contact or heat with certain mol proportion and prepare.
6. the preparation method of adefovir ester cholic acid class salt as claimed in claim 1 is characterized in that comprising following key step:
Adefovir ester contacted or heat with certain mol proportion with cholic acid or chlolic acid derivatives prepare.
7. adefovir dipivoxil ester colalin derivatives as claimed in claim 1, it is as the purposes of antiviral.
8. adefovir dipivoxil ester colalin derivatives as claimed in claim 1, it is as the purposes of anti-hepatitis virus medicament.
9. a pharmaceutical composition contains the described adefovir dipivoxil ester colalin derivatives of claim 1 as activeconstituents.
10. composition according to claim 9 is characterized in that comprising the tablet, capsule, granule, pill, the liquid oral formulation that orally use; The injection liquid of injection, powder ampoule agent for injection, liposome, emulsion, nanoparticle, mixture; The emulsion of external application, ointment; Through the oral cavity or the oral tablet of my humble abode administration.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101307076A (en) * | 2008-05-30 | 2008-11-19 | 秦引林 | Prodrug with liver-targeted anti-HBV effect |
| CN104610415A (en) * | 2014-11-13 | 2015-05-13 | 昆明贵金属研究所 | Liver-targeting platinum anticancer drug and synthetic method thereof |
| WO2016045642A1 (en) * | 2014-09-28 | 2016-03-31 | National Institute Of Biological Sciences, Beijing | Polymeric bile acid derivatives inhibit hepatitis b and d virus and ntcp transport |
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2007
- 2007-11-30 CN CNA2007101908343A patent/CN101182331A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101307076A (en) * | 2008-05-30 | 2008-11-19 | 秦引林 | Prodrug with liver-targeted anti-HBV effect |
| WO2016045642A1 (en) * | 2014-09-28 | 2016-03-31 | National Institute Of Biological Sciences, Beijing | Polymeric bile acid derivatives inhibit hepatitis b and d virus and ntcp transport |
| CN106794188A (en) * | 2014-09-28 | 2017-05-31 | 华辉安健（北京）生物科技有限公司 | Polymerization bile acid derivative suppresses hepatitis type B virus and Hepatitis D virus and NTCP transports |
| JP2017530194A (en) * | 2014-09-28 | 2017-10-12 | フアフイ ヘルス リミテッドＨｕａｈｕｉ Ｈｅａｌｔｈ Ｌｔｄ． | Inhibition of hepatitis B and D viruses and NTCP transport by polymerized bile acid derivatives |
| JP2019077710A (en) * | 2014-09-28 | 2019-05-23 | フアフイ ヘルス リミテッドＨｕａｈｕｉ Ｈｅａｌｔｈ Ｌｔｄ． | Polymeric bile acid derivatives that inhibit hepatitis b and d viruses and ntcp transport |
| CN106794188B (en) * | 2014-09-28 | 2022-12-02 | 华辉安健（北京）生物科技有限公司 | Polymeric bile acid derivatives inhibit hepatitis B and delta virus and NTCP trafficking |
| US11701369B2 (en) | 2014-09-28 | 2023-07-18 | Huahui Health Ltd. | Polymeric bile acid derivatives inhibit Hepatitis B and D virus and NTCP transport |
| CN104610415A (en) * | 2014-11-13 | 2015-05-13 | 昆明贵金属研究所 | Liver-targeting platinum anticancer drug and synthetic method thereof |
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