CN106432338A - Posaconazole derivative, synthesis and application in prolonged action preparation thereof - Google Patents
Posaconazole derivative, synthesis and application in prolonged action preparation thereof Download PDFInfo
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- CN106432338A CN106432338A CN201510480312.1A CN201510480312A CN106432338A CN 106432338 A CN106432338 A CN 106432338A CN 201510480312 A CN201510480312 A CN 201510480312A CN 106432338 A CN106432338 A CN 106432338A
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Abstract
The invention relates to a posaconazole derivative, synthesis and an application in a prolonged action thereof. The invention relates to a formula of a compound and salt, N-oxide, quaternary ammonium and stereoisomer of the compound, wherein R1-R8 are defined according to what is claimed. The invention also relates to a preparation formula of an intermediate body and a method of the compound. The invention further relates to a formula of an application of the compound as a drug, especially the application in preventing or treating fungal infection. The detailed formulas are in the specification.
Description
Technical field
The present invention relates to organic chemistry, particularly prodrug and pharmaceutical preparation.
Background technology
Posaconazole (Posaconazolc), molecular formula：C37H42F2N8O4.Posaconazole is the derivant of Itraconazole, in the second filial generation antifungal drug in triazole class of listing in 2006.Has a broad antifungal spectrum, for Candida, Histoplasma capsulatum, fills in many pityrosporion ovales, bipolar bacterium zygomycete, Fusarium spp., yeast.There is powerful inhibitory activity including the non-white beads bacterial strain of resistance to fluconazol, Cryptococcus histolyticus and aspergillosiss；Especially to the relatively rarer but fungal disease of life-threatening（Zygomycosises, fusaridiosises and coccidioidomycosiss etc.）Also effective.This product be applied to multiple amphotericin is not resistant to or intractable adult invasive infections with fungi treatment；To high-risk patient prophylactic, for the patient of more than 13 years old, immunologic hypofunction, particularly suffer from graft versus host disease（Graft versus host disease, GVHD）Hematopoietic stem cell transplantation person, leukaemic and leukopenic patient for a long time due to chemotherapy.This product, than control drug fluconazol and Itraconazole, can more effectively be prevented aggressive aspergillin infection and can reduce the related case fatality rate of invasive infections with fungi.
The dosage form of external listing has oral administration mixed suspension, injection, slow releasing tablet at present, and wherein injection employs Sulfobutyl ether β _ cyclodextrin to improve the water solublity of posaconazole, also increases the incidence rate of side reaction simultaneously.Cyclodextrin is a kind of new adjuvant occurring in recent years, and because this adjuvant has preferable solubilization to multiple insoluble drugs, thus the domestic use to this adjuvant has the trend of quick increase.But up to the present we understand to its safety not deeply.This adjuvant of document report has certain hemolytic, nephrotoxicity and carcinogenecity, and there is likely to be more serious toxic and side effects still not known to us, thus it is using more preferably prudent.
The serious effectively treatment limiting fungal infection of daily maintenance metering of posaconazole.This administration schedule leads to the higher workload of clinical staff, and importantly, the patient compliance of difference, therefore increased the probability giving suboptimal dose, ultimately result in appearance refractory fungal strain.When the compliance of patient is problem, the dosage form of long-acting dosage is one and possible solution, wherein single-dose leads to sustained release drugs in in the period of extending.This dosage form simplifies the dosage regimen that patient's needs are observed, the probability of the non-compliance occurring when therefore reducing using more accurate dosage regimen.One of these dosage forms are reservoirs
(depot) preparation, it can be with various administrations, including intramuscular injection.Prepare depot dosage injection, slowly absorbed the drug from medicine-feeding part with providing, generally can keep treatment level a few days or several weeks in entire patient every time.
Depot dosage injection has cost.The volume of injection is bigger, injection more pain；It is therefore desirable to as far as possible by the volume minimization of injection.
It is an object of the present invention to provide posaconazole derivant and preparation, its interior this medicine of delivery during duration under the concentration effective for treatment mammal (including people).These posaconazole forms and preparation must be safe, that is, have the side effect of minimum and have suitable pharmacokinetics distribution.
It is an object of the present invention to provide posaconazole derivant and preparation, it can improve one or more following pharmacokinetic parameters with respect to currently available preparation：Longer half-life, increase volume of distribution, extend drug release, the acting duration of lasting plasma concentration or longer.
It is an object of the present invention to provide for posaconazole derivant and the preparation of Clopidogrel when compared with currently available dosage form.
It is an object of the present invention to provide the chemically stable derivant of posaconazole.It is a further object to provide the chemically stable preparation of posaconazole.It is a still further object of the present invention to provide the soluble derivative of posaconazole.
It is an object of the invention to the agent number of the posaconazole that will give minimizes.It is an object of the present invention to provide allowing posaconazole derivant or the preparation of bolus injection.Another object of the present invention is the reservoir providing posaconazole in patients.
It is an object of the present invention to provide avoiding the posaconazole injectable formulation of the proper volume of pain administration.
It is an object of the present invention to provide posaconazole derivant and the preparation of refractory fungal strain appearance can be reduced.
It is an object of the present invention to provide posaconazole derivant and the preparation of intracellular posaconazole concentration can be increased.
Content of the invention
Inventor has surprisingly observed that some posaconazole derivants with the dissolubility distribution attracting people's attention present valuable high-dissolvability in some lipophilic solvents.Particularly, some posaconazole derivants of the present invention are highly suitable for lipid formulation and injectable depot formulations.These preparations even all present effective plasma concentration upon administration in 2 months.In addition, the present invention reaches this finally required increase drug load in the way of to patient and all convenient administration of clinical staff and extends delivery.
The present invention relates to a kind of formula (I) compound and its salt, N- oxide, quaternary amine and stereoisomer：
（）
Wherein：
R1It is hydrogen or C1-6Alkyl；
R2It is gonane base or selected from following group
Symbology C2-6Alkylidene；
R3、R4And R5It is independently each C6-18Alkyl or gonane base；
R6、R7And R7It is independently each C1-6Alkyl.
The invention still further relates to the method for preparation formula (I) compound, its salt and stereochemistry heterogeneous forms, and it is related to intermediate used in these preparation methoies.
The invention still further relates to being used as formula (I) compound of medicine itself, its salt, N- oxide, quaternary amine and stereochemistry heterogeneous forms.The invention still further relates to Pharmaceutical composition, it comprises this paper specific formula (I) compound of pharmaceutically acceptable carrier and effective dose.
The invention further relates to above-mentioned compound, compositionss and pharmaceutical compositions are used for prevention more than 13 years old and patient's aggressive aspergillosiss and monilial infection；Treatment pars oralis pharyngises candidiasiss, including Itraconazole and/or the oidiomycotic medicine of the intractable pars oralis pharyngises of fluconazol.Or express in other words, the present invention relates to for prevention more than 13 years old and patient's aggressive aspergillosiss and monilial infection；Treatment pars oralis pharyngises candidiasiss, including Itraconazole and/or the oidiomycotic compound of the intractable pars oralis pharyngises of fluconazol, compositionss and Pharmaceutical composition.Similarly, the present invention relates to a kind of be used for prevention more than 13 years old and patient's aggressive aspergillosiss and monilial infection；Treatment pars oralis pharyngises candidiasiss, including Itraconazole and/or the oidiomycotic method of the intractable pars oralis pharyngises of fluconazol, by giving to need compound as herein described, compositionss and the Pharmaceutical composition of its patient effective amounts.
The invention still further relates to a kind of improve posaconazole lipotropy or extend posaconazole release or the method for pharmacological activity, the method includes for posaconazole being converted into formula (I) compound or its pharmaceutically acceptable salt.
The invention further relates to formula (VI) chemical group is as the purposes introducing group
(VI)
Wherein R1And R2Each press defined above；With wave (Represent) represent combination with the oxygen atom of medicine.
The present invention relates to a kind of formula (I) compound and its salt, N- oxide, quaternary amine and stereoisomer：
（）
Wherein：
R1It is hydrogen or C1-6Alkyl；
R2It is gonane base or selected from following group
Symbology C2-6Alkylidene；
R3、R4And R5It is independently each C6-18Alkyl or gonane base；
R6、R7And R8It is independently each C1-6Alkyl.
Unless otherwise indicated, as institute's used time above and below, using following definition.
" C as group or moieties used herein1-4Alkyl " is defined as the straight or branched saturated hydrocarbons group with 1-4 carbon atom, such as methyl, ethyl, 1- propyl group, 2- propyl group, 1- butyl, 2- butyl, 2- methyl isophthalic acid-propyl group.
“C1-6Alkyl " includes C1-4Alkyl group and its have 5 or 6 carbon atoms higher level homologue, such as 1- amyl group, 2- amyl group, 3- amyl group, 1- hexyl, 2- hexyl, 2-methyl-1-butene base, 2- methyl-1-pentene base, 2- ethyl -1- butyl, 3- methyl -2- amyl group etc..C1-6It is concerned with C in alkyl1-4Alkyl.
" C as group or moieties6-18Alkyl " is defined as with 6-18
The straight or branched saturated hydrocarbons group of individual carbon atom, such as heptane base, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, myristyl, pentadecyl, cetyl, heptadecyl, octadecyl, 4,8- dimethyl hexadecyl base, 4- ethyl -11- methyl pentadecyl, 5- butyl dodecyl etc..
C3-7Cycloalkyl is the full name of cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.
Term " C2-6Alkylidene " definition and corresponding " C2-6Alkyl " is identical, but is bivalence rather than monovalence.So, bivalence C2-6Alkyl is defined as the straight or branched saturation divalent hydrocarbyl mission with 2-6 carbon atom, such as 1,2- second diyl or ethylene, 1,3- glyceryl or trimethylene, 1,2- glyceryl or propylene, 1,4- fourth diyl or tetramethylene, 1,3- fourth diyl or 1,3- butylidene, 1,2- fourth diyl or 1,2- butylidene, 1,5- penta diyl or pentamethylene, 1,6- dihexyl or 1,6- hexylidene etc., also includes alkylidene group, such as ethylidene, propylidene etc..
Term " gonane base " refers to both steroid and sterol groups, it is combined with the oxygen of formula (I) compound or carbon atom, this it may be the case that, combined by the specific carbon atom with hydroxyl in 4- ring gonane structure, described hydroxyl does not appear in formula (I) compound end.
Term " steroid " refers to polycyclic compound, and it has common parent nucleus, and it is 17- carbon atom ring system condensing, reducing, the cyclopentanoperhy drophenanthrene of formula (VII).
（）
In one embodiment, steroid group has two methyl and the aliphatic lateral chain being connected with parent nucleus.In one embodiment, steroid group is formula (VIII) group, and wherein wave represents the key being connected in formula (I) compound.
（）
Term " sterol " refers to carry the steroid of hydroxyl on C-3 and skeleton is mostly cholestane.Other carbon atom may be present in side chain.
Particularly, term " gonane base " includes the group form of following compound：Ah manys' sterol；Cholecalciferols, such as hydroxycholecalciferol (calcifediol, dihydroxycholecalciferol, 24,25- double hydroxycholecalciferol, Calcitriol)；Cholesterol, such as cholesterol itself, 19- Iodocholesterol, azacosterol, Dihydrocholesterol, cholesteryl ester, aphyllidine (desmosterol), hydroxycholesterol oxycholesterol, ketocholestrol；Dihydrotachysterol；Vitamin D2, such as 25- HEC；Fusidic Acid；Lanosterol；Plant sterol is such as casted off a skin steroidal, ergosterol (whitanolide (liquor-saturated eggplant lactone)), sitosterol, stigmasterol；Cycloartenol；Zoosterol；And its derivant.As a term used herein example, the group form of cholesterol is referred to herein as cholesteryl.The group form of Dihydrocholesterol is referred to herein as cholesteric alkyl.
Provide the sterols of concern and the chemical constitution of steroid, as follows
Ah manys' sterol
Azacosterol
Calcifediol
Calcitriol
Campesterol
Cholecalciferol
Dihydrocholesterol
Cholesterol
Cycloartenol
Desmosterol
Dihydrotachysterol
Dihydroxycholecalciferol
24,25- double hydroxyvitamin D3
Vitamin D2
Ergosterol
Fusidic Acid
Hydroxycholecalciferol
Hydroxycholesterol oxycholesterol
25-hydroxy-vitamin D2
19- Iodocholesterol
Ketone cholesterol
Pilus Caprae seu Oviss steroid
Sitosterol
Stigmasterol
It should be noted that the radical position on any molecular moiety used in definition can be that this is partly gone up Anywhere, as long as it is chemically stably.When any variable occurs more than once in any part, respective definition is independent.In the definition of variable, group used includes all possible isomer, unless otherwise stated.For example, amyl group includes 1- amyl group, 2- amyl group and 3- amyl group.
Whenever hereinafter using term " formula (I) compound " or " the compounds of this invention " or similar terms, it means that including formula (I) compound, its salt and its stereochemical isomeric form.
Formula (I) compound can have several chiral centres, particularly works as R2Or R3When being gonane base, and existed with stereochemistry heterogeneous forms." stereochemistry heterogeneous forms " used herein be defined as that formula (I) compound can have, formed by identical atom is closed by the bond of same sequence, but there is all possible compound of different non-interchangeable three dimensional structures.In the case of wherein using (R) or (S) to name the absolute configuration of chiral atom in substituent group, what this name was considered is the substituent group of whole compound and non-orphaned.
Except as otherwise referring to or illustrating outer, the chemical name of compound includes the mixture of the be possible to stereochemistry heterogeneous forms that described compound is likely to be of.Described mixture can contain all diastereomers of basic molecular structure and the enantiomer of described compound.The no matter pure form of all stereochemistry heterogeneous forms of the compounds of this invention or mixture each other are intended to cover within the scope of the present invention.
The compound being mentioned above is defined as with the pure stereoisomeric forms in any ratio of intermediate being substantially free of other enantiomer of the identical basic molecular structure of described compound or intermediate or the isomer of diastereomer form.Especially, term " stereoisomerism is pure " is related to that (i.e. a kind of isomer is minimum is 80% with stereoisomerism excessive at least 80%, and the possible isomer of other is up to 20%) to the at most stereoisomerism excessively a kind of compound of 100% (i.e. isomer is 100% and without other isomers) or intermediate, more particularly, it is related to compound or the intermediate with excessive 90% at most 100% of stereoisomerism, even more particularly there is stereoisomerism excessive 94% at most 100%, and most particularly there is compound or the intermediate of excessive 97% at most 100% of stereoisomerism.Term " enantiomer-pure " and " diastereomer is pure " should understand in a similar manner, but it is then enantiomeric excess and the diastereomeric excess being respectively provided with discussed mixture.
The pure stereoisomeric forms in any ratio of the compounds of this invention and intermediate can be obtained by applying program known in the art.For example, can be by separated from one another by enantiomer with optically active acid or their diastereoisomeric salt of alkali selective crystallization.The example is tartaric acid, dibenzoyl tartaric acid, ditoluoyltartaric and camphorsulfonic acid.Or, can be by the chromatographic technique enantiomer separation using chiral stationary phase.Described pure stereochemistry heterogeneous forms also can pure stereochemistry heterogeneous forms of correspondence derived from suitable raw material, condition is that this reaction stereospecificity occurs.Preferably, if requiring special stereoisomer, described compound will be synthesized by stereospecificity preparation method.These methods are by advantageously using the raw material of enantiomer-pure.
The diastereomer racemate of formula (I) compound discretely can be obtained by conventional method.The suitable physical separation method that can favorably use is such as selective crystallization and chromatography, such as column chromatography.
The present invention is also intended to all isotopes including the atom occurring on the compounds of this invention.Isotope includes the atom that those have same atoms ordinal number but have different quality number.By general example and be not limited by this, the isotope of hydrogen includes tritium and deuterium.The isotope of carbon includes C-13 and C-14.
For therapeutic use, the salt of formula (I) compound is that wherein gegenion is those salt pharmaceutically acceptable, and this salt is referred to alternatively as pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry addition salts.But the salt of acceptable bronsted lowry acids and bases bronsted lowry is it is also seen that there is purposes in non-pharmaceutical, for example, it is used for preparation or the pharmaceutically acceptable compound of purification.All salt, no matter whether pharmaceutically acceptable, it is included within the scope of the present invention.
Above-mentioned pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry addition salts are intended to comprise the non-toxic bronsted lowry acids and bases bronsted lowry addition salt form of the therapeutic activity that formula (I) compound can be formed.Pharmaceutically acceptable acid-addition salts can be obtained with the acid treatment of suitable anionic form conveniently by by described alkali form.Suitable anion comprises，Such as acetate、Benzenesulfonic acid root、Benzoate anion、Bicarbonate radical、Bitartrate、Bromide、Ca-EDTA、Camphorsulfonic acid root、Carbonate、Chloride、Citrate、Dihydrochloride、Edetic acid root、Ethionic acid root、Propionic ester lauryl sulphate acid root、Ethyl sulfonic acid root、Fumaric acid radical、Glucoheptose acid group、Glucose acid group、Glutamate、To hydroxyl acetylamino phenylarsonic acid root、Hexyl resorcin root、Hai Baming、Hydrobromic acid root、Salt acid group、Hydroxynaphthoic acid root、Iodide、Hydroxyethylsulfonic acid. root、Lactate、Lactose acid group、Malate、Maleate、Almond acid group、Methanesulfonate、MB、Methyl nitrate、Methylsulfate、Glactaric acid root、LOMAR PWA EINECS 246-676-2 root、Nitrate anion、Flutter acid group (embonate)、Pantothenate、Phosphate radical/hydrogen phosphate、Polygalacturonic acid group、Salicylate、Stearate radical、Alkali formula acetate、Amber acid radical、Sulfate radical、Tannic acid root、Tartrate anion、8- dramamine root、Triethiodide compound etc..Conversely, described salt form can be by being converted into free alkali form with suitable alkali process.
Formula containing acid proton (I) compound also can be converted into its non-toxic metal or amine addition salt form by the suitable organic and inorganic alkali process with cationic form.Suitable basic salt comprises with organic cation salt as the formation such as benzathine benzylpenicillin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine；And with metal cation as the formation such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc salt.Conversely, described salt form can be by being converted into free form with suitable acid treatment.
" N- oxide " form of the compounds of this invention is intended to those compounds including in wherein triazole ring or several nitrogen-atoms oxidized (such as one-or two-oxide).Can there is (mixture of such as 1-N- oxide, 2-N- oxide and 4-N- oxide triazole) with single position isomer or each position isomer mixture form in described nitrogen monoxide.
Term " quaternary amine " used above is defined as, by the basic nitrogen of formula (I) compound with the quaternizing agent being suitable for (for example, optionally substituted alkyl halide, aryl halide or arylalkyl halide, such as Methyl iodide or benzyl iodide) between reaction, the quaternary ammonium salt that formula (I) compound can be formed.Also can be using other reactants of the leaving group having carried, such as trifluoromethanesulfonic acid Arrcostab, alkyl mesylate and alkyl tosylate.Quaternary amine carries a positively charged nitrogen.Pharmaceutically acceptable gegenion includes chloride ion, bromide ion, iodide ion, trifluoroacetic acid root and acetate.The gegenion selecting can be introduced using ion exchange resin.The quaternary amine of formula (I) compound can be by obtaining quaternary ammonium list or disalt acquisition by nitrogen heterocyclic ring bromoethyl acetate alkylation.
Some formula (I) compounds can also tautomeric form exist.Although not in above structural formula clear illustration, these forms are intended to be included within the scope of the invention.
One embodiment of this invention is related to formula (I) compound, wherein applies one or more following conditions：
a)R1It is hydrogen or C1-6
Alkyl；
b)R2It is gonane base or selected from following group：
c)R3、R4And R5It is independently each C6-18
Alkyl or gonane base；
d)R6、R7And R8It is independently each C1-6
Alkyl.
One embodiment of this invention is related to formula (I) compound, wherein applies one or more following conditions：
a)R1It is C1-6Alkyl；
b)R2Be gonane base or
R in this group3It is gonane base.
One embodiment of this invention is related to formula (I) compound and its any subgroup (subgroup), and wherein said gonane base is cholesteric alkyl.
One embodiment of this invention is related to formula (I) compound and its any subgroup, wherein R1It is ethyl.
One embodiment of this invention is related to the salt of formula (I) compound and its any subgroup, wherein R1It is hydrogen, described salt is a sodium salt.
One embodiment of this invention is related to any one in following compounds：
4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base] -2- (trimethylammonio)-ethyl phosphonic acid ester
2- (caprinoyl epoxide) ethyl -4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base] sodium phosphate
4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base] -2-（Nonane epoxide）Ethyl phosphonic acid ester sodium
2,3- is double（Caprinoyl epoxide）Propyl group -4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base]-sodium phosphate
4- [4- [4- [4- [[(3R, 5R) -5- (2, 4- difluorophenyl) -5- (1, 2, 4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1, 2, 4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base]-ethyl (3R, 8R, 9S, 10R, 13S, 14S, 17R) -10, 13, 17- trimethyl -17- ((R) -6- methyl heptane -2- base) -2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- 14-1H- cyclopenta [a] phenanthrene-3- base phosphate ester
2-((4-[4-[4-[4-[[(3R,5R)-5-(2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S,3S) amyl- 3- base -2- base]-epoxide) (ethyoxyl) phosphinylidyne epoxide) ethyl (3S，8R，9S，10R，13S，14S，17R)-10，13，17- trimethyl -17- ((R) -6- methyl heptane -2- base) -2，3，4，7，8，9，10，11，12，13，14，15，16，17- ten tetrahydrochysene -1H- cyclopenta [a] phenanthrene -3- base succinate
The present invention also provides the method that one kind prepares formula as defined above (I) compound or its pharmaceutically acceptable salt, it comprises to be converted into pharmaceutically acceptable salt by posaconazole phosphorylation and as desired or necessary by the compound obtaining, or vice versa as the same.
Described phosphorylation can be carried out by different way.A kind of Phosphorylation (a1) can be reacted by making posaconazole and the phosphoramidite of formula (II) in suitable reaction medium, thus obtain the phosphite ester of formula (III), then make described formula (III) further
Phosphite ester to complete with oxidant reaction,
（）
（）
Wherein
R1And R2Each it is defined as above；
R9And R10It is independently each, optionally by C3-7Cycloalkyl or the C of phenyl replacement1-6
Alkyl, optionally substituted phenyl or C3-7Cycloalkyl；Or R9And R10
Coupled nitrogen-atoms form optionally substituted 5- or 6- unit saturated heterocyclic together, and wherein said substituent group is selected from C1-4
Alkyl and phenyl.
Preferably R9And R10
It is independently each C1-6Alkyl, phenyl, or coupled nitrogen-atoms form morpholine ring together.This reaction can be in the solvent (such as dichloromethane or oxolane) of reaction without adverse affects, weak acid (as tetrazolium, 5- methyl isophthalic acid H- tetrazolium, 1,2, in the presence of 4- (dimethylamino) pyridine of 4-1H- triazole, pyridine hydrobromide salt or imidazole hydrochloride compound and optional catalysis, carry out under room temperature or higher temperature.Then make the phosphite ester of formula (III) and oxidant (the such as peracid, such as 3- chloroperoxybenzoic acid or H obtaining2O2, preferably 30% aqueous hydrogen peroxide solution) and reaction, obtain the phosphate ester of final formula (I).This reaction less than room temperature, such as can be carried out at 0-20 DEG C in the solvent of reaction without adverse affects, such as dichloromethane or oxolane.
A kind of alternative Phosphorylation (a2) by suitable anhydrous response medium, such as in acetone, dichloromethane and potassium carbonate, can make the chlorinated phosphate of posaconazole and formula (IV) react to complete.This reaction can be carried out at room temperature.
(IV)
Another kind of Phosphorylation (a3) can make posaconazole and PCl in the presence of a base3
Reaction thus obtains the midbody compound of formula (V),
R-O-PCl2And then make formula (V) compound and formula R (V)1- OH compound and formula R2-OH
Compound reaction is realized, and wherein R1 and R2 is each defined as above；And R is
Posaconazole and PCl3Reaction can carry out at such as 0 DEG C in the solvent of reaction without adverse affects, such as dichloromethane or oxolane, in -20 to+20 DEG C of temperature ranges.Suitable alkali includes pyridine and N- Methylimidazole..
Formula (V) compound and formula R1-OH
Compound and with formula R2- OH compound (wherein R1And R2Be defined as above) obtain formula as defined above (I) compound consecutive reaction can at a temperature of room temperature it is not necessary to separate formula V compound under carry out.These consecutive reactions can be completed with any given order, for example, be firstly introduced into formula R2- OH compound, is then re-introduced into formula R1- OH compound.
It is that formula (I) end-product is hydrolyzed back posaconazole minimization, final material, whencesoever form, such as filter cake, available washing with acetone is to displace the water hydrolyzing required for this phosphate ester.
According to method known to those skilled in the art, the compound obtaining optionally can be converted into pharmaceutically acceptable salt, or vice versa as the same.
Further, according to functional group known in the art conversion reaction, formula (I) compound can be transformed into each other.For example, nitro amino can be reduced to by amino N-alkylation, halogen atom another kind of halogen can be converted to.
The pure stereochemistry heterogeneous forms of formula (I) compound can be obtained by applying methods known in the art.Diastereomer can be separated by physical method (such as selective crystallization) and chromatographic technique such as counter-current distribution, liquid chromatography etc..
Formula (I) compound can be obtained with the racemic mixture form of enantiomer, and it can be separated from one another according to method for splitting known in the art.Can by have racemic formula (I) compound alkaline or acid enough pass through respectively with suitable chiral acid, chiral alkali reaction, be converted into the salt form of corresponding diastereomer.Then, the salt form of described diastereomer is for example passed through selectivity or fractional crystallization separates, then pass through alkali or acid thus discharges described enantiomer.The method of one alternative enantiomeric form of separation formula (I) compound includes liquid chromatography, especially with the liquid chromatography of chiral stationary phase.Described pure stereochemistry heterogeneous forms also can corresponding pure stereochemistry heterogeneous forms derived from suitable raw material, premise is that described reaction stereospecificity is carried out.Preferably, if requiring special stereoisomer, described compound can be synthesized by stereospecificity preparation method.These methods can easily utilize the raw material of enantiomer-pure.
The invention still further relates to midbody compound, it can be used for preparing formula (I) compound；Its salt, N- oxide, quaternary amine and stereoisomer.Thus, the present invention relates to the phosphoramidite of formula (II) and its salt, N- oxide, quaternary amine and its stereoisomer,
（）
Wherein R1、R2、R9
And R10Each as defined herein.
The invention still further relates to the phosphite ester of formula (III) as defined above and its salt, N- oxide, quaternary amine and stereoisomer,
（）
Wherein R1And R2Each as defined herein.
The invention still further relates to the chlorinated phosphate of formula (IV) as defined above and its salt, N- oxide, quaternary amine and stereoisomer,
(IV)
Wherein R1And R2Each as defined herein.
In further one side, the present invention relates to formula (VI) chemical group is as the purposes introducing group
（）
Wherein R1And R2Each press the definition of any one in embodiment presented herein；With wave (Represent) represent combination with the oxygen atom of medicine.
This is introduced into group in the further prodrug of the other medicinal compounds of design (need not with posaconazole about) is valuable.
Term " introducing group " refers to the chemical group combining by the key that can rupture under specific use condition and the medicine functional group of medicine (general and), i.e. part.Medicine and the key introducing between group can be by enzyme or the fractures of non-enzymatic pathway.Under conditions of use, for example, after giving patient, medicine and the key introducing between group can rupture and discharge parent drug.The fracture introducing group spontaneous can carry out (for example passing through hydrolysis), or be catalyzed by another reagent or induce, for example, pass through enzyme, by light, by acid or by changing or being exposed to physics or ambient parameter, the such as change of temperature, pH etc..These reagent can be endogenic for the condition of described use, such as the acid condition of enzyme or gastric present in the body circulation of the patient giving this prodrug, or this reagent can exogenous provide.
The invention still further relates to Pharmaceutical composition, it comprises pharmaceutically acceptable carrier and the compound defined herein of effective dose as active component or its pharmaceutically acceptable salt.
The Pharmaceutical composition of the present invention is parenteral, do not pass through administered orally, for example intravenouss, intramuscular, in subcutaneous, intraperitoneal, intraarticular, intralesional (intralesionally), ventricle, through intraspinal injection, intraosseous infusion or percutaneously administration.The Pharmaceutical composition of the present invention also can be in position, wound site, airtight joint space or body cavity in the brain of human or animal through in cavernous sinus, in myocardium inside and outside film or tumor (intraturnorally)
Give.
Therefore, the compounds of this invention can be made the small-volume injection (SVP) for bolus injection or reservoir devices injection or the bulk capacity injection (LVP) for venoclysises.Or, by using skin patch, the compounds of this invention can be made and supply percutaneous drug administration preparation.
Described parenteral administration can adopt suspension, solution or the emulsion form of such as oiliness or aqueous medium, and can comprise formula agent, such as pH adjusting agent, chelating agent, isotonic agent, suspending agent, stabilizer or dispersant.Usually, those typically used as excipient of intravenous injection can be used in the preparation of the present invention, as long as said preparation presents suitable viscosity, the injection capacity reducing and acceptable pH scope.
The method with the various Pharmaceutical compositions of a certain amount of active component for the preparation is known for those skilled in the art, or according to the disclosure it will be clear that understanding.
Unit dosage forms can be prepared by mixing the compounds of this invention or its pharmaceutically acceptable salt and sterile media.Different with concentration according to medium used, described compound can be suspended or dissolved in medium.In preparing solution, compound dissolution can be used for injection filtration sterilization, then in the suitable phial of filling people or ampoule and seal.Advantageously, the adjuvant of such as local anesthetic, preservative and buffer agent is dissolved in medium.For enhanced stability, described compositionss can be filled and freeze after medicine bottle and moisture is removed in vacuum.Pharmaceutical composition and then be rendered as powder type, for later use suitable medium dissolving, such as using front using aseptic aqueous solution.Suspension is prepared in a substantially similar manner, but this compound is suspended in medium rather than is dissolved in medium, and sterilizes and can not be accomplished by filtration.Surfactant or wetting agent is may include to promote being uniformly distributed of described compound in compositionss.
Injection preparation can be rendered as unit dosage forms for example in ampoule or in multi-dose container.
For percutaneous (such as local) administration purpose, prepare dilute aseptic, aqueouss or part aqueous solution (normally about 0.1%-5% concentration), other aspects are similar to above-mentioned parenteral solution.
The therapeutically effective amount of the compounds of this invention required for prevention or the described medical symptom for the treatment of can apply the common preclinical and clinical method of medical domain promptly determine by those of ordinary skill in the art.The dosage of described compound to be given or its pharmaceutically acceptable salt depends on individual state, and according to custom, described dosage can be made to be adapted to the symptom of described individual state for reaching optimum efficiency.Therefore, it is of course depend upon the frequency being administered and treatment or prevents effect of compound used and acting duration in each case, but additionally depends on the property of disease or disease and the sex of seriousness and institute's treatment target, age, the response of body weight, the medicine simultaneously taken and individuality and be acute or preventative depending on described treatment.The percentage ratio of medicine present in preparation is also a factor.Dosage can be adjusted according to weight function and paediatric applications.
The compounds of this invention has purposes, and reason is that they have pharmacological activity in animal (including people).Particularly, described compound can be used for treating or prevents fungal infection, including yeast infection.For example, they can be used for treating the local fungal infection being caused in human body by Candida, Trichophyton, Microsporon or Epidermophyton species and other organism or by the microbial mucosal infections of Candida albicans (such as thrush and vaginals candidiasis).They can be additionally used in treating by such as Candida (as Candida albicans), Cryptococcus histolyticus, Aspergillus flavus, Aspergillus fumigatus, coccidioides immitises, secondary coccidioides immitises
(Paracoccidiode), the systemic fungal infection that histoplasma capsulatum or blastomyceses species cause.
In addition, except the following disease needing posaconazole treatment, fungemia, fungus in respiratory tract disease, digestive tract mycosises, urethra mycosises, fungal meningitiss, cryptococcal meningitiss, tinea unguium, cryptococcosises, ball mycosiss
Etc. (coccidiomycosis), outside, the compounds of this invention can be used for treating Fangal peritonitis in the mycosises medicament of deep position.
The compounds of this invention also acts as oidiomycotic prevention medicament in immuno-compromised patients, patient, Organ Transplantation Patients, AIDS patient or old or paediatric population that for example those suffer from hematologic cancer.
Therefore, the compounds of this invention, its pharmaceutically acceptable salt or its any subgroup can be used as medicine.The described purposes as medicine or Therapeutic Method comprise for the experimenter infecting or easily are given to be effective against and fungal infection by experimenter's whole body of fungal infection (inclusion yeast), the particularly described medicine of the amount of the relevant symptom of candida infection.
The invention still further relates to the compounds of this invention, its pharmaceutically acceptable salt or its any subgroup are used for the purposes of the medicine of preparation prevention or treatment fungal infection.In other words, the invention still further relates to being used for preventing or treat formula (I) the compounds of this invention, its pharmaceutically acceptable salt or its any subgroup of fungal infection.
The invention still further relates to one kind improves the lipophilic method of posaconazole, the method includes for described posaconazole being converted into formula (I) compound, its pharmaceutically acceptable salt or its any subgroup.
In addition, the invention still further relates to a kind of extend the method that posaconazole discharges, the method includes for posaconazole being converted into formula (I) compound, its pharmaceutically acceptable salt or its any subgroup.
The following example is intended to the exemplary illustration present invention, and does not limit it in this.
Embodiment 1：4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base] -2- (trimethylammonio)-ethyl phosphonic acid ester
Flow process 1
As shown in above flow process 1, at room temperature, in anhydrous methylene chloride, in the presence of N, N- diisopropylethylamine, choline chloride and phosphorylation agent cyanoethyl N, N- diisopropyl chloro phosphoramidite reacts, then with posaconazole coupling, subsequently aoxidized with 30% aqueous hydrogen peroxide solution, crude product posaconazole derivant is obtained with one-step method.At room temperature, in methyl alcohol, using ammonium hydroxide, cyanoethyl protecting group is ruptured.By the di-phosphate ester obtaining pass through in methyl alcohol with sodium hydrate aqueous solution (0.1M)
Reaction, is further converted to corresponding ammonium phosphate amphion salt.
Embodiment 2：Preparation
2- (caprinoyl epoxide) ethyl -4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base] sodium phosphate
Flow process 2
As shown in above flow process 2, at room temperature, in anhydrous methylene chloride, the reaction between 1- decanoyl chloride and ethylene glycol in the presence of triethylamine obtains hydroxy ester.At room temperature, in anhydrous methylene chloride, in N, in the presence of N- diisopropylethylamine, with phosphorylation agent cyanoethyl N, the reaction of N- diisopropyl chloro phosphoramidite, then with posaconazole coupling, subsequently aoxidized with 30% aqueous hydrogen peroxide solution, posaconazole derivant is obtained with one-step method.At room temperature, in methyl alcohol, using ammonium hydroxide, cyanoethyl protecting group is ruptured.The di-phosphate ester obtaining is passed through to carry out saponification further with sodium hydrate aqueous solution (0.1M) in methyl alcohol, then in dichloromethane, in the presence of DMAP, is acylated with positive pelargonyl chloride and triethylamine, obtains three second ammonium phosphate.Using cation exchange, obtain corresponding sodium salt.
Embodiment 3:Preparation 4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base] -2-（Nonane epoxide）Ethyl phosphonic acid ester sodium
Flow process 3
As shown in above flow process 3, in refluxing toluene, in the presence of p-methyl benzenesulfonic acid, the hydroxy ether that the reaction between 1 nonyl alcohol and ethylene glycol obtains.At room temperature, in anhydrous methylene chloride, in N, in the presence of N- diisopropylethylamine, the hydroxy ether obtaining and phosphorylation agent cyanoethyl N, N- diisopropyl chloro phosphoramidite reacts, then with posaconazole coupling, subsequently aoxidized with 30% aqueous hydrogen peroxide solution, posaconazole derivant is obtained with one-step method.At room temperature, in methyl alcohol, using ammonium hydroxide, cyanoethyl protecting group is ruptured, by the di-phosphate ester obtaining pass through in methyl alcohol with sodium hydrate aqueous solution
(0.1M) react and be converted into sodium salt.
Embodiment 4:Preparation 2,3- is double（Caprinoyl epoxide）Propyl group -4- [4- [4- [4- [[(3R, 5R) -5- (2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base]-sodium phosphate
Flow process 4
As shown in above flow process 4, at room temperature, in anhydrous methylene chloride, in the presence of pyridine, 2- phenyl -1, the ester that the reaction between 3- dioxane -5- alcohol and 1- decanoyl chloride obtains.Then, the hydrogen under the palladium dydroxide and atmospheric pressure that are carried using carbon, compound is hydrogenated, is quantitatively obtained glycol.Then the glycol obtaining and 1- decanoyl chloride carry out monoacylated obtaining primary alconol.At room temperature, in anhydrous methylene chloride, in N, in the presence of N- diisopropylethylamine, with phosphorylation agent cyanoethyl N, the reaction of N- diisopropyl chloro phosphoramidite, then with posaconazole coupling, subsequently aoxidized with 30% aqueous hydrogen peroxide solution, posaconazole derivant is obtained with one-step method.At room temperature, in methyl alcohol, using ammonium hydroxide, cyanoethyl protecting group is ruptured.The di-phosphate ester obtaining is passed through in methyl alcohol by sodium hydrate aqueous solution
(0.1M) react further, then in dichloromethane, in the presence of DMAP, be acylated by positive pelargonyl chloride and triethylamine, obtain three second ammonium phosphate.Using cation exchange, obtain corresponding sodium salt.
Embodiment 5:Preparation 4- [4- [4- [4- [[(3R, 5R) -5- (2, 4- difluorophenyl) -5- (1, 2, 4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1, 2, 4- triazole -3- ketone -2- [(2S, 3S) amyl- 3- base -2- base]-ethyl (3R, 8R, 9S, 10R, 13S, 14S, 17R) -10, 13, 17- trimethyl -17- ((R) -6- methyl heptane -2- base) -2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- 14-1H- cyclopenta [a] phenanthrene-3- base phosphate ester
Flow process 5
As shown in above flow process 5, at room temperature, in anhydrous tetrahydro furan, in the presence of N, N- diisopropylethylamine, the phosphorylation agent ethyl n of cholesterol and brand-new, N- diisopropyl chloro phosphoramidite reacts, then with posaconazole coupling, subsequently aoxidized with 30% aqueous hydrogen peroxide solution, required posaconazole derivant is obtained with one-step method.
Embodiment 6:Preparation
2-((4-[4-[4-[4-[[(3R,5R)-5-(2,4- difluorophenyl) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -1,2,4- triazole -3- ketone -2- [(2S,3S) amyl- 3- base -2- base]-epoxide) (ethyoxyl) phosphinylidyne epoxide) ethyl (3S，8R，9S，10R，13S，14S，17R)-10，13，17- trimethyl -17- ((R) -6- methyl heptane -2- base) -2，3，4，7，8，9，10，11，12，13，14，15，16，17- ten tetrahydrochysene -1H- cyclopenta [a] phenanthrene -3- base succinate
Flow process 6
As shown in above flow process 6, in backflow dichloromethane, in the presence of DMAP, so that cholesterol is reacted with succinic anhydrides and obtain carboxylic acid, it is converted into its acyl chlorides with thionyl chloride in toluene, and at room temperature, in dichloromethane, in the presence of triethylamine, further with glycol reaction, obtain derivant.At room temperature, in anhydrous tetrahydro furan, in N, in the presence of N- diisopropylethylamine, with the phosphorylation agent ethyl n of brand-new, N- diisopropyl chloro phosphoramidite reacts, then with posaconazole coupling, subsequently aoxidized with 30% aqueous hydrogen peroxide solution, required posaconazole derivant is obtained with one-step method.
Embodiment 7:Testing data
Diffusivity aspergillosis in guinea pig and candidiasis
All using without specific pathogen in all experiments（SPF）Guinea pig（Body weight is 400-500g）.In the left neck vein of animal conduit being inserted venous perfusion process to be subjected, vein is combined, and connect the conductive pipe on micro control charge pump.By animal via the lateral vein of penis or via the conduit implanted, with Aspergillus fumigatus（4,000CFU/g body weight）Or with candida albicans（4,000CFU/g body weight）Infection.In latter 1 hour of infection, carry out intravenous therapy（5mg/kg/ days）.To every group of experimental animal（Every group of laboratory animal number is shown in " N " hurdle）, it is recorded in the mean survival time in each natural law（MST）, and percentage survival（%surv）.To each group during test the animal of death and in test survival but the animal that was killed later, research its deep tissues of counting（Liver,spleen,kidney, lung are in brain）In, Aspergillus fumigatus and candida albicans quantity.Measure the CFU/g of remnants in culture positive hepatic, and be shown in table 3（After intravenouss are processed）, represented with average log10CFU/g." %neg " in table 1 is shown in the deep tissues percentage rate after process in culture-feminine gender.Therefore, in " MST ", " %surv " and " %neg " each hurdle of more effective test compound, there is high value, and in " CFU/g " hurdle, there is low value.
By data, posaconazole derivant has the ability of stronger anti-fungal infection.
Table 1 pharmacology pharmacodynamic result
Claims (17)
1. formula（
）Compound and its salt, N- oxide, quaternary ammonium salt and stereoisomer:
（）
Wherein：
R1It is hydrogen or C1-6Alkyl
R2It is gonane base or selected from following group
Symbology C2-6Alkylidene；
R3、R4And R5It is independently each C6-18Alkyl or gonane base；
R6、R7And R7It is independently each C1-6Alkyl.
2. the compound of claim 1, wherein R2It is gonane base or selected from following group：
.
3. the compound of claim 1, wherein
R2It is gonane base or group
；R in this group3It is gonane base.
4. the compound of any one of claim 1-3, wherein said gonane base is cholesteric alkyl.
5. the compound of any one of claim 1-4, wherein R1It is ethyl.
6. the salt of the compound of any one of claim 1-4, wherein R1It is hydrogen and described salt is a sodium salt.
7. a kind of Pharmaceutical composition, it comprises the compound of any one of pharmaceutically acceptable carrier and claim 1-6 of effective dose as active component or its pharmaceutically acceptable salt.
8. the Pharmaceutical composition of claim 7, wherein this Pharmaceutical composition intravenous, intramuscular, in subcutaneous, intraperitoneal, intraarticular, intralesional, ventricle, through intraspinal injection, intraosseous infusion or percutaneously administration.
9. the compound of any one of claim 1-6 or its pharmaceutically acceptable salt, it is used as medicine.
10. the compound of any one of claim 1-6 or its pharmaceutically acceptable salt are used for preventing or treat the purposes of the medicine of fungal infection.
The compound of any one of 11. claim 1-6 or its pharmaceutically acceptable salt, it is used for preventing or treats in fungal infection.
A kind of 12. preventions or the method for the treatment of fungal infection, it includes compound or its pharmaceutically acceptable salt giving to need any one of this kind of claim 1-6 of patient effective amounts prevented or treat.
A kind of 13. formulas preparing any one of claim 1-6（I）Compound or its pharmaceutically acceptable salt obtain method, and it comprises：
A1) in suitable reaction medium, posaconazole and formula are made（II）Obtain phosphoramidite reaction, thus obtain formula（III）Phosphite ester, then make described formula further（III）Obtain phosphite ester and oxidant reaction；Or
（）
（）
A2) in suitable anhydrous response medium, posaconazole and formula are made（IV）Chlorinated phosphate reaction；Or
(IV)
A3) in the presence of a base, posaconazole and PCl are made3Reaction thus obtains formula（V）Midbody compound, R-O-PCl2, and make formula (V)（V）Compound and R1- OH compound and formula R2- OH compound reacts;
B) optionally the compound of generation is converted into pharmaceutically acceptable salt or vice versa；Wherein:
R1And R2Each press defined in demand for independence；
R9And R10It is independently each optionally by C3-7Cycloalkyl or the C of phenyl replacement1-6Alkyl, optionally substituted phenyl or C3-7Cycloalkyl；Or R9And R10Coupled nitrogen-atoms form optionally substituted 5- or 6- unit saturated heterocyclic together, and wherein said substituent group is selected from C1-4Alkyl or phenyl；With
R is.
14. chlorinated phosphates pressing the phosphoramidite of formula (II), the phosphite ester of formula (III) or formula (IV) defined in claim 13.
15. formulas (VI) chemical group is as the purposes introducing group
(VI)
Wherein R1 and R2 each presses defined in claim 1；With wave (Represent) represent combination with the oxygen atom of medicine.
A kind of 16. lipophilic methods improving posaconazole, it comprises for described posaconazole to be converted into the compound of any one of claim 1-6 or it will learn upper acceptable salt.
A kind of 17. methods of the release extending posaconazole, it comprises for described posaconazole to be converted into the compound of any one of claim 1-6 or it will learn upper acceptable salt.
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| CN107033186A (en) * | 2016-02-04 | 2017-08-11 | 武汉朗来科技发展有限公司 | Posaconazole derivative, its pharmaceutical composition and purposes |
| CN110156763A (en) * | 2018-02-12 | 2019-08-23 | 北京普祺医药科技有限公司 | A kind of posaconazole derivative, pharmaceutical composition with and application thereof |
| CN110938093A (en) * | 2018-09-21 | 2020-03-31 | 陕西合成药业股份有限公司 | Posaconazole phosphate monocholine salt and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107033186A (en) * | 2016-02-04 | 2017-08-11 | 武汉朗来科技发展有限公司 | Posaconazole derivative, its pharmaceutical composition and purposes |
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| CN110938093A (en) * | 2018-09-21 | 2020-03-31 | 陕西合成药业股份有限公司 | Posaconazole phosphate monocholine salt and preparation method and application thereof |
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| JP7026264B2 (en) | 2018-09-21 | 2022-02-25 | 華創合成制薬股▲ふん▼有限公司 | Posaconazole phosphate monocholine salt, its preparation method and use |
| CN110938093B (en) * | 2018-09-21 | 2022-08-19 | 华创合成制药股份有限公司 | Posaconazole phosphate monocholine salt and preparation method and application thereof |
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