CN109956974A - Liver delivers adefovir precursor medicament nucleosides cyclic phosphate compound and application - Google Patents

Liver delivers adefovir precursor medicament nucleosides cyclic phosphate compound and application Download PDF

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Publication number
CN109956974A
CN109956974A CN201711408931.5A CN201711408931A CN109956974A CN 109956974 A CN109956974 A CN 109956974A CN 201711408931 A CN201711408931 A CN 201711408931A CN 109956974 A CN109956974 A CN 109956974A
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compound
substituted
unsubstituted
formulas
pharmaceutically acceptable
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席志坚
徐华强
陆春平
孙锋
伍中山
虞华
童志强
曹中莹
蒋旸
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Hangzhou State Biotechnology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides antivirus medicine nucleosides cyclic phosphate compound and application based on liver-specific delivery technology (liver delivering) (Liver Specific Delivery (LSD)), specifically, the present invention provides compound of formula I and its isomers, officinal salt, hydrate, solvate and corresponding pharmaceutical compositions.Combine individually or with other antiviral drugs the application in antiviral, the especially application in treatment anti-hepatitis B virus (HBV) the present invention also provides the compounds of this invention.

Description

Liver delivers adefovir precursor medicament nucleosides cyclic phosphate compound and application
Technical field
The present invention relates to be based on liver-specific delivery technology (liver delivering) (Liver Specific Delivery (LSD)) antivirus medicine, the preparation and application of nucleosides cyclic phosphate compound or its optical isomer, hydrate, Solvate, officinal salt and pharmaceutical composition.
Background technique
The serious prestige of the virus such as hepatitis type B virus (HBV), Hepatitis D virus (HDV), human immunodeficiency virus (HIV) Coerce human health.By taking hepatitis type B virus as an example, virus B hepatitis (hepatitis B) is that one kind is drawn by hepatitis type B virus It rises, based on liver inflammatory lesion, and the disease of multiple organ injury can be caused.According to the World Health Organization (WTO) investigation result There is the 2.4 hundred million people person that is chronic hepatitis-B infection in it has been shown that, the estimation whole world, is estimated to be 780,000 people every year and dies of hepatitis B infection, Wherein 650,000 people die of cirrhosis caused by chronic hepatitis B and liver cancer, and it is complete that 130,000 people, which die of acute hepatitis B infection, One major issue of ball health.
The drug of anti-hepatitis B virus, main one kind are nucleotide drugs, such as: Aldoforwe ester, tenofovir Ester (TDF), tenofovir Chinese mugwort draw phenol amine (TAF), Entecavir, Lamivudine, Sebivo etc., and the mechanism of action is in cell Interior activation can inhibit the DNA or rna polymerase activity of virus at triphosphoric acid metabolin, prevent the synthesis of DNA or RNA, reach suppression The purpose of virus replication processed.
Some ucleotides compounds, such as: adefovirdipivoxil, tenofovir etc. are in high elecrtonegativity under physiology PH.Institute With oral administration, cross-film ability is poor, and bioavilability is low；Meanwhile increasing the toxic side effect of gastrointestinal tract and kidney.However, carrying out Esterification transformation, forms ester prodrug, for example, Aldoforwe ester, tenofovir disoproxil etc., can be improved bioavilability and tissue point Cloth.But ester hydrolase is widely distributed in vivo, and before causing drug also not arrive at liver cell, majority is just hydrolyzed to electronegative life Object active constituent (adefovirdipivoxil, tenofovir etc.), which is not easily accessed liver cell, and by the proximal end of active transport to kidney Tubule, it is easy to cause renal toxicity.
Annular phosphate (4- aryl -2- oxo-1,3,2-dioxaphosphorinane hexamethylene) front body structure has good liver Specific delivery performance, mechanism is very clear, and 4- aryl the position of substitution is by the Cytochrome P450 isoenzymes family in liver cell In CYP3A specific catalytic, generate hydroxyl, then open loop generates negatively charged phosphoric acid intermediate, which not easily passs through Cell membrane and be present in intracellular, under phosphodiesterase-catalyzed, by hydrolysis, beta-elimination reaction generates Nucleotide monophosphates Object is closed, continues under nucleotide kinase enzyme effect, generates biologically active nucleotide triphosphoric acid compound, meanwhile, metabolism is secondary It is anti-that with anti-oxidant and free radical the glutathione of rich content in liver cell 1,4- addition can occur for product aryl vinyl ketone It answers and is removed, not yet find that the addition product has the report of side effect.
However, still lacking the HIV suppression chemical combination that activity is high, liver-specific delivery is strong and toxic side effect is low at present Object, therefore, there is an urgent need in the art to develop that active high, liver-specific delivery is strong and less toxic side effect and other advantages New virus inhibiting compound.
Summary of the invention
The present invention has synthesized the annular phosphate of antiviral nucleotide drug, then further to its aromatic ring substituents Transformation, obtain a kind of prodrug with more liver delivering effect, keep its curative effect higher, the smaller advantage of toxic side effect.
The first aspect of the present invention, provide it is a kind of such as following formula I compound represented or its optical isomer, pharmaceutically Acceptable salt, hydrate or solvate:
Wherein:
Each R1Be independently chosen from halogen, nitro, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, replace or not Substituted C3-C8 naphthenic base, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino radical, replace or Unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester group, substituted or unsubstituted C2-C6 alkanoyl, replace or not Substituted C2-C6 alkyl amide；Wherein, the substitution, which refers to, has one or more substituent groups selected from the group below: halogen, C1- C3 alkyl, C1-C3 halogenated alkyl, nitro, hydroxyl, amino, cyano；
R2、R3It is each independently halogen (F, Cl, Br or I)；
M is 0,1,2 or 3.
In another preferred example, in Formulas I, in addition to the chirality indicated, other each chiral centres are R type or S type.
In another preferred example, R2For Cl, and R3For F；Or R2For Cl, and R3For Br.
In another preferred example, the optical isomer includes tautomer, cis-trans-isomer, conformer, Mesomeric compound and optical isomer with mapping or diastereomeric relationship.
In another preferred example, the compound is selected from the group:
In another preferred example, the salt of the Formulas I compound represented is Formulas I compound represented and inorganic acid or organic The salt that acid is formed by officinal salt or the Formulas I compound represented is that Formulas I compound represented is reacted with alkali and is formed by Officinal salt.The Formulas I compound represented or its salt is amorphous substance or crystal.
The second aspect of the present invention, provides a kind of pharmaceutical composition, and the pharmaceutical composition includes therapeutically effective amount The compound as described in first aspect present invention or its optical isomer, pharmaceutically acceptable salt, hydrate or solvent Compound；With pharmaceutically acceptable adjuvant, diluent or carrier.
The third aspect of the present invention provides compound or its optical isomer, medicine as described in the first aspect of the invention The purposes of acceptable salt, hydrate or solvate on, is used to prepare treatment and/or prevention and hepatitis type B virus (HBV) pharmaceutical composition of relevant acute or chronic disease is infected.
The fourth aspect of the present invention provides a kind of preparation method of compound of formula I as described in the first aspect of the invention, The method includes the steps:
(i) in atent solvent, Formulas I a compound and Formulas I b compound is subjected to condensation reaction, obtain compound of formula I.
In formula, each group is as defined above described in text.
In another preferred example, in the step (i), the reagent is selected from the group: dicyclohexylcarbodiimide (DCC), pyridine, triethylamine, N, N- diisopropylethylamine or combinations thereof；Preferably DCC and pyridine.
In another preferred example, in the step (i), the atent solvent is selected from the group: N, N- dimethyl formyl Amine, pyridine, methylene chloride, tetrahydrofuran or combinations thereof；Preferably N,N-dimethylformamide, pyridine or its mixed solvent.
In another preferred example, the reaction temperature of the step (i) is 30-120 DEG C, preferably 50-100 DEG C, (excellent It is selected in 90 ± 5 DEG C or so).
In another preferred example, the reaction time of the step (i) be 0.5-72 hours, preferably 0.5-24 hours, It is more preferably 8-16 hours.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific embodiment
The present inventor's in-depth study by long-term is found for the first time by the screening study to a large amount of compounds: a kind of Compound of formula I (wherein 2 and 5 of phenyl ring part are different halogens) with specific structure, has unexpectedly non- The antiviral activity of Chang Youyi, the liver significantly improved delivering property and significantly reduced toxic side effect.Based on above-mentioned discovery, invention People completes the present invention.
Term
PMEA:9- [2- (phosphonylmethoxy base) ethyl] adenine.
As used herein, term " C1-C6 alkyl " refers to the linear or branched alkyl group with 1~6 carbon atom, such as first Base, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, or similar group.
As used herein, term " C2-C6 alkanoyl " finger-type such as " linear or branched alkyl group-with 1~6 carbon atom The substituent group of carbonyl " structure, such as acetyl group, propiono, bytyry, or similar group.
As used herein, term " C1-C6 alkylamino radical " finger-type such as " linear or branched alkyl group-with 1~6 carbon atom The substituent group of amido " structure, such as methylamino, dimethylamino, ethylamino-, Propylamino, diethylin, or similar group.
Term " halogen " refers to F, Cl, Br and I.
In the present invention, term " containing ", "comprising" or " comprising " indicate that various composition can be applied to of the invention mix together It closes in object or composition.Therefore, term " mainly by ... form " and " consist of " were included in term " containing ".
In the present invention, term " pharmaceutically acceptable " ingredient refers to suitable for people and/or animal and without excessive bad pair It reacts (such as toxicity, stimulation and allergy), that is, has the substance of reasonable benefit/risk ratio.
In the present invention, amount or table that term " effective quantity " refers to therapeutic agent treatment, alleviates or prevent target disease or situation Reveal the detectable amount for treating or preventing effect.The figure of the object is depended on for the accurate effective quantity of certain an object and is good for The combination of therapeutic agent and/or therapeutic agent that health situation, the property and degree of illness and selection are given.Therefore, it preassigns Accurate effective quantity is useless.However, the effective quantity can be determined with routine experiment for the situation that Mr. Yu gives, Clinician can judge.
Herein, except place is illustrated, term " substitution " refers to that one or more hydrogen atoms on group are selected from down The substituent group of group replaces: halogen, C1-C3 alkyl, C1-C3 halogenated alkyl, nitro, hydroxyl, amino, cyano.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, Such as the compound of single chiral or the mixture (i.e. racemic modification) of various different chipal compounds.All chemical combination of the invention Among object, each asymmetric carbon atom can be optionally the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and Formulas I chemical combination Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of object.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Some compounds in the present invention may use water or the crystallization of various organic solvents or recrystallization, in this case, It is likely to form various solvates.Solvate of the invention includes solvate such as hydrate of stoichiometry etc., also includes The compound comprising variable water formed when being prepared with lyophylization.
It will be understood that after the compound of the present invention preparation, there may be various thermodynamically stable isomers, such as tautomerisms Body, conformer, mesomeric compound and optical isomer with mapping or diastereomeric relationship etc., it is above-mentioned to change form After having read disclosure of the invention, it would have been obvious for a person skilled in the art.
Compound of formula I and its preparation
Antiviral nucleotide drug can be allowed to concentrate in liver cell releasing by liver delivery mechanism to provide one kind Efficient, the less toxic liver delivering pro-drug put, inventor are prepared for compound of formula I:
Wherein:
Each R1Be independently chosen from halogen, nitro, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, replace or not Substituted C3-C8 naphthenic base, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino radical, replace or Unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester group, substituted or unsubstituted C2-C6 alkanoyl, replace or not Substituted C2-C6 alkyl amide；Wherein, the substitution, which refers to, has one or more substituent groups selected from the group below: halogen, C1- C3 alkyl, C1-C3 halogenated alkyl, nitro, hydroxyl, amino, cyano；
M is 0,1,2 or 3；
R2、R3It is each independently halogen (F, Cl, Br or I)；
And in Formulas I, in addition to the chirality indicated, other each chiral centres are R type or S type.
The compound can be raceme, or be optical isomer, and the two all has certain antiviral activity.It is excellent The compound of formula I of choosing has structure selected from the group below:
In another preferred example, the P2 and 4 in phosphate ring structure aromatic groups are cis- each other, and P2 is R Configuration, C4 be S type, i.e., following compound:
In another preferred example, R2For Cl, and R3For F；Or R2For Cl, and R3For Br.
In another preferred example, the optical isomer includes tautomer, cis-trans-isomer, conformer, Mesomeric compound and optical isomer with mapping or diastereomeric relationship.
In another preferred example, the compound is following compound:
Compound of Formula I the preparation method is as follows:
The present invention also provides the method for preparing compound of formula I.A kind of preferred method is Chem. 1973,10,35.
Compound Ia and Ib be dissolved in suitable solvent (such as DMF, pyridine or its mixed solvent, especially DMF: pyridine (5: 1) it in), is added condensing agent (such as DCC), carries out condensation reaction under suitable conditions and (such as react 0.5- under 30- reflux temperature 72 hours), form compound of Formula I.
Wherein, each reactant can be bought by commercially available approach, can also use commercially available raw material, normal by this field It is prepared by the method for rule.
Pharmaceutical composition and method of administration
Due to the compounds of this invention have the excellent inhibitory activity to hepatitis type B virus, the compounds of this invention and Its various crystal form, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and be containing the compounds of this invention The pharmaceutical composition of main active can be used for treating, prevent and alleviate by hepatitis type B virus caused by disease.Root According to the prior art, the compounds of this invention can be used for treating following disease: disease caused by the infection such as HBV, HCV, HIV and HCMV Disease.
Pharmaceutical composition of the invention include safe and effective amount within the scope of the compounds of this invention or its be pharmacologically subjected to Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound is enough obviously Improve the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contain 0.1-1000mg the compounds of this invention/ Agent more preferably contains 0.5~500mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or jello Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines In object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on Tie up plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as )、 Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes (but being not limited to): oral, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.Particularly preferred application Mode is oral.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, tender taste agent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant. Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 0.2~1000mg, preferably 0.5~100mg.Certainly, specific dosage is also contemplated that administration route, patient health situation Etc. factors, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include:
(1) liver delivering property is high, and compound can only be in the CYP3A in the cytochrome P 450 isozymes family in liver cell Specific catalytic generates bioactive molecule, the high negative electrical charge of bioactive molecule band, it is not easy to be discharged outside liver, so concentration is more in liver Height reaches liver delivering effect.
(2) activity is high, because of liver delivering property, there are in liver, antiviral activity also can be mentioned greatly more drugs It is high.
(3) toxic side effect is low: the same dose of prodrugs, seldom in the amount of the Viability molecule of extrahepatic metabolism, thus to kidney, The toxicity of the main organs such as brain substantially reduces.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
{ [- 2- oxo-1,3,2-dioxaphosphorinane ring is by (4S) -4- (the chloro- 2- fluorophenyl of 5-) by 2- by embodiment 1 (2R) -9- Alkane -2- base] methoxy ethyl adenine preparation PA1019
9- [2- (phosphonylmethoxy base) ethyl]-adenine (5.5g, 20mmol) is dissolved in N,N-dimethylformamide In (100mL) and pyridine (20mL), it is separately added into dicyclohexylcarbodiimide (4.1g, 20mmol) and (S) -3- (chloro- 2- fluorine of 5- Phenyl) -1,3-PD (39mg, 0.208mmol), reaction mixture is heated to 95 degree or so, reacts 16h, end of reaction will Reaction solution vacuum rotary steam removes organic solvent, and crude product is dissolved in ethyl acetate, and with saturated common salt water washing, anhydrous sodium sulfate is dry Dry, evaporating solvent under reduced pressure, silica gel column chromatography (methylene chloride: methanol=20:1 to 10:1) obtains white solid 3.8g, yield: 42%, Rf=0.3 (methylene chloride: methanol=10:1),1H NMR(400MHz,CDCl3) δ 8.36 (d, J=4.6Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.62-7.37 (m, 1H), 7.35-7.30 (m, 1H), 7.04 (td, J=9.4,3.0Hz, 1H), 5.82 (dd, J=42.3,10.8Hz, 1H), 5.61 (s, 2H), 4.79-4.19 (m, 4H), 4.15-3.87 (m, 4H), 2.33–1.95(m,2H)ppm.Chiral resolution, obtain (2R)-9- 2- [(2R, 4S)-4- (the chloro- 2- fluorophenyl of 5-) oxo-1-2-, 3,2- dioxaphosphepin thiacyclohexane -2- bases] methoxy ethyl } adenine, PA1019-cis,1H NMR(400MHz,CDCl3) δ, 8.09 (d, J=9.6Hz, 2H), 7.60-7.41 (m, 2H), 7.38-7.26 (m, 1H), 7.18 (s, 2H), 5.81 (d, J= 9.5Hz, 1H), 4.53 (ddd, J=11.1,7.3,3.8Hz, 1H), 4.36 (t, J=5.1Hz, 2H), 4.26-4.11 (m, 1H),4.08–3.83(m,4H),2.13–1.89 (m,2H)ppm。
{ [- 2- oxo-1,3,2-dioxaphosphorinane ring is by (4S) -4- (the chloro- 5- fluorophenyl of 3-) by 2- by embodiment 2 (2R) -9- Alkane -2- base] methoxy-propyl adenine preparation PA1020
Prepared using method similar to Example 1, by 9- [2- (phosphonylmethoxy base) ethyl]-adenine (54mg, 0.198mmol), dicyclohexylcarbodiimide (113mg, 0.594mmol) and (S) -3- (the chloro- 5- fluorophenyl of 3-) -1,3- the third two Alcohol (40mg, 0.198mmol) end of reaction, obtains 35mg white solid, yield: 40%, Rf=0.4 (methylene chloride: methanol =10:1),1H NMR(400MHz,CDCl3) δ 8.36 (d, J=4.1Hz, 1H), 7.91 (d, J=1.8Hz, 1H), 7.16- 7.01 (m, 2H), 6.93 (dd, J=11.9,10.0Hz, 1H), 5.68 (s, 2H), 5.60-5.07 (m, 1H), 4.76-4.18 (m,4H),4.17–3.74(m,5H),2.31– 1.93(m,2H)ppm。
{ [- 2- oxo-1,3,2-dioxaphosphorinane ring is by (4S) -4- (the chloro- 2- fluorophenyl of 3-) by 2- by embodiment 3 (2R) -9- Alkane -2- base] methoxy ethyl adenine preparation PA1022
Prepared using method similar to Example 1, by 9- [2- (phosphonylmethoxy base) ethyl]-adenine (54mg, 0.198mmol), dicyclohexylcarbodiimide (113mg, 0.594mmol) and (S) -3- (the chloro- 2- fluorophenyl of 3-) -1,3- the third two Alcohol (39mg, 0.208mmol) end of reaction, obtains 48mg white solid, yield: 55%, Rf=0.4 (methylene chloride: methanol =10:1),1H NMR(400MHz,CDCl3) δ 8.34 (d, J=3.7Hz, 1H), 7.93 (d, J=20.2Hz, 1H), 7.62- 7.31 (m, 2H), 7.21-7.02 (m, 1H), 6.01 (d, J=39.7Hz, 2H), 5.81 (d, J=48.9Hz, 1H), 4.73- 4.22(m,4H),4.15–3.71(m,4H), 2.33–2.00(m,2H)ppm。
Embodiment 4 (2R) -9- { 2- [(4S) -4- (3,5- dichlorophenyl) -2- oxo-1,3,2-dioxaphosphorinane thiacyclohexane - 2- base] methoxy ethyl adenine preparation PA1023
It is prepared using method similar to Example 1, by (R) -9- [2- (phosphonylmethoxy base) ethyl]-adenine (54mg, 0.198mmol), dicyclohexylcarbodiimide (113mg, 0.594mmol) and (S) -3- (3,5- dichlorophenyl) -1,3- Propylene glycol (46mg, 0.208mmol) end of reaction, obtains 36mg white solid, yield: 40%, Rf=0.4 (methylene chloride: Methanol=10:1),1H NMR(400MHz,CDCl3) δ 8.33 (d, J=3.8Hz, 1H), 7.89 (d, J=3.4Hz, 1H), 7.33 (dt, J=16.8,1.8Hz, 1H), 7.18 (dd, J=3.9,1.7 Hz, 2H), 5.85 (d, J=18.8Hz, 2H), 5.65- 4.92 (m, 1H), 4.73-4.16 (m, 4H), 4.14-3.79 (m, 4H), 2.14 (dd, J=17.8,12.7Hz, 2H).
{ [- 2- oxo-1,3,2-dioxaphosphorinane ring is by (4S) -4- (the chloro- 4- fluorophenyl of 3-) by 2- by embodiment 5 (2R) -9- Alkane -2- base] methoxy ethyl adenine preparation PA1024
Prepared using method similar to Example 1, by 9- [2- (phosphonylmethoxy base) ethyl]-adenine (54mg, 0.198mmol), dicyclohexylcarbodiimide (113mg, 0.594mmol) and (S) -3- (the chloro- 4- fluorophenyl of 3-) -1,3- the third two Alcohol (40mg, 0.198mmol) end of reaction, obtains 60mg white solid, yield: 68%, Rf=0.4 (methylene chloride: methanol= 10:1),1H NMR(400MHz,CDCl3) δ 8.32 (d, J=3.1Hz, 1H), 7.96 (d, J=10.6Hz, 1H), 7.41-7.33 (m, 1H), 7.20-7.04 (m, 2H), 6.35 (d, J=73.6Hz, 2H), 5.38 (dd, J=166.1,11.0Hz, 1H), 4.74–4.27(m,4H),4.09–3.93 (m,4H),2.29–1.74(m,2H)ppm。
Reference examples 6 (2R) -9- { 2- [(2R, 4S) -4- (3- chlorphenyl) -2- oxo-1,3,2-dioxaphosphorinane thiacyclohexane - 2- base] methoxy ethyl adenine preparation PA1021
Prepared using method similar to Example 1, by 9- [2- (phosphonylmethoxy base) ethyl]-adenine (6.05g, 22mol), dicyclohexylcarbodiimide (13.6g, 66mol) and (S) -3- (the chloro- 5- fluorophenyl of 3-) -1,3- propylene glycol (4.1g, 22mmol) end of reaction obtains 6.0g white solid, yield: 64%, Rf=0.4 (methylene chloride: methanol=10:1),1H NMR(400MHz,CDCl3) δ 8.35 (d, J=4.0Hz, 1H), 7.93 (s, 1H), 7.38-7.29 (m, 3H), 7.15 (dd, J= 32.8,5.2Hz, 1H), 6.93-6.93 (m, 1H), 5.92 (d, J=15.0Hz, 2H), 5.40 (dd, J=161.6,10.6Hz, 1H),4.74–4.21(m,4H),4.12–3.83 (m,4H),2.32–1.67(m,2H)ppm。
Reference examples 7 (2R) -9- { 2- [(2R, 4S) -4- (3- chlorphenyl) -2- oxo-1,3,2-dioxaphosphorinane thiacyclohexane - 2- base] methoxy ethyl adenine preparation (preparation of Pradefovir)
Using article: J, Am, Chem, Soc, 2004,126,5154-5163, disclosed technology contents are prepared.1H NMR(400MHz,CDCl3): δ: 8.352 (s, 1H), 7.907 (s, 1H), 7.285-7.354 (m, 3H), 7.106 (d, J= 6.8Hz, 1H), 5.802 (s, 2H), 5.591 (d, J=10.8Hz, 1H), 4.624-4.681 (m, 1H), 4.443-4.468 (m, 2H),4.235-4.321(m,1H),3.899-4.031(m,4H),1.980-2.109(m, 2H)ppm。
Preparation-obtained compound is as shown in following table in each embodiment of table 1
The evaluation of the external people's hepatomicrosome of embodiment 8 metabolism
Measuring method:
1) reagent source
People's hepatomicrosome (HLM, Human Liver Microsomes) is purchased from IVT (In Vitro Technologies), Lot number SSP X008070.
Compound PA1019, PA1020, PA1021, PA1022, PA1023, PA1024 are tested, methanol (traditional Chinese medicines examination is dissolved in Agent), the storage liquid that concentration is 25mM is made.
2) reaction process
Enzymatic reaction is in 100mM KH2PO4It is carried out in buffer solution (pH 7.4), test compound concentration is 25uM, people Hepatomicrosome concentration is 2mg/ml, and NADPH concentration is 2mM.Reaction is started by the NADPH being eventually adding, in isothermal vibration water-bath In pot after reaction 5min, the methanol of 1.5 times of volumes is added immediately to terminate reaction.
3) sample treatment and analysis method
Sample pre-treatments:
With Eppendorf desk centrifuge with maximum (top) speed 13,600rpm centrifugation 20 minutes.Supernatant is taken, nitrogen evaporator is used It re-dissolves after drying to mobile phase A (aqueous solution of 0.1% formic acid v/v).
The rate of 2 Vitro hepatic microsomal metabolism compound of table release monophosphate product PMEA
Annotation: S configuration is cis-: such as without special statement, referring to that C4 is S configuration, P2 and its 4 virtue in phosphate ring structure Perfume base group is cis- each other
Interpretation of result: in vitro, compound PA1019, PA1020, PA1021, PA1022, PA1023, PA1024 quilt People's hepatomicrosome is activated into monophosphate metabolite PMEA, and there are significant differences for the conversion rate of different compounds.Unexpectedly , for being all several compounds of racemate form, the rate that PA1019 is converted to PMEA is higher than reference examples PA1021, And significantly larger than PA1022 and PA1024.Wherein, the conversion rate of PA1019 is 4.1 times (tables 3) of PA1022 respectively.
The experiment of 9 compound Tissue distribution of embodiment
9.1 methods:
Zoopery
Male SD rat, 180~300g of weight, Shanghai western Poole-Bi Kai experimental animal Co., Ltd provide.Buck Adapt to environment 3 days or more, it tests evening before that day fasting 12 hours, can't help water.Prepare PA1019-cis's and Pradefovir Solution (Cremophor EL: ethyl alcohol: physiological saline=10:10:80, V/V/V).Checked before administration the weight of animals whether with Requirement of experiment is consistent, and chooses 12 rats and is grouped, and the medical fluid of 0.036mmol/kg is given in every group of 2 rats, stomach-filling.Respectively In 0.5h, 1h, 3h, 6h, 12h and for 24 hours, sample is acquired after rat is euthanized with carbon dioxide gas.
9.2. data are analyzed
Concentration of the metabolite of each compound in liver corresponds to the time and is made into column distribution map.The tissue of PMEA is dense Area (AUC under degree-time graph0-t), use pair in the non-compartment model of WinNonLin6.2.1 (Pharsight, CA) Number-linear trapezoid method is fitted calculating.
9.3 experimental result
Compound PA1019-cis and Pradefovir can activate Viability product PMEA, but PA1019- in liver The liver blood ratio of cis ratio Pradefovir is higher, has more tissue specificity.
To sum up, compound of formula I of the invention (especially PA1019 and PA1019-cis) has higher activity and liver The characteristics of specific delivery, when treatment it is required dosage it is lower, thus there is higher safety and lower toxic side effect.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.
Using adefovirdipivoxil as active constituent, the aromatic ring that m-chloro replaces, Pradefovir, in CYP3A enzyme effect are finally found Under, it is metabolized to the generating rate highest of adefovirdipivoxil, close to (US200707214668B2) more than 5 times of 3,5- dichloro aryl.

Claims (7)

1. a kind of such as following formula I compound represented or its optical isomer, pharmaceutically acceptable salt, hydrate or solvation Object:
Wherein:
Each R1Be each independently selected from the following group: halogen, nitro, hydroxyl, amino, cyano, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkanamine It is base ,-COOH, substituted or unsubstituted C2-C6 alkyl carboxyl, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C2-C6 alkanoyl, substituted or unsubstituted C2-C6 alkyl amide；Wherein, the substitution refers to is selected from down with one or more The substituent group of group: halogen, C1-C3 alkyl, C1-C3 halogenated alkyl, nitro, hydroxyl, amino, cyano；
R2And R3It is each independently halogen (F, Cl, Br or I)；
M is 0,1,2 or 3.
2. compound as described in claim 1 or its optical isomer, pharmaceutically acceptable salt, hydrate or solvation Object, which is characterized in that R2For Cl, and R3For F；Or R2For Cl, and R3For Br.
3. compound as claimed in claim 1 or 2 or its optical isomer, pharmaceutically acceptable salt, hydrate or solvent Compound, which is characterized in that the compound is selected from the group:
4. compound a method according to any one of claims 1-3 or its optical isomer, pharmaceutically acceptable salt, hydrate or Solvate, which is characterized in that the salt of the Formulas I compound represented is Formulas I compound represented and inorganic acid or organic acid The salt for being formed by officinal salt or the Formulas I compound represented is that Formulas I compound represented reacts that be formed by can with alkali Pharmaceutical salts.The Formulas I compound represented or its salt is amorphous substance or crystal.
5. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition includes therapeutically effective amount such as claim 1-4 Compound described in any one or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate；Pharmaceutically Acceptable adjuvant, diluent or carrier.
6. compound or its optical isomer, pharmaceutically acceptable salt, hydrate or solvation as described in claim 1-4 The purposes of object, which is characterized in that be used to prepare treatment and/or prevention it is relevant acute to hepatitis type B virus (HBV) infection or The pharmaceutical composition of chronic disease.
7. the preparation method of compound of formula I as described in claim 1, which is characterized in that comprising steps of
(i) in atent solvent, Formulas I a compound and Formulas I b compound is subjected to condensation reaction, obtain compound of formula I.
In formula, the definition of each group is as described in the appended claim 1.
CN201711408931.5A 2017-12-22 2017-12-22 Liver delivers adefovir precursor medicament nucleosides cyclic phosphate compound and application Pending CN109956974A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030225277A1 (en) * 2002-05-13 2003-12-04 Kopcho Joseph J. Process for preparation of cyclic prodrugs of PMEA and PMPA
CN101475594A (en) * 2009-02-06 2009-07-08 廖国超 Liver targeted antivirus precursor medicament annular phosphoester and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030225277A1 (en) * 2002-05-13 2003-12-04 Kopcho Joseph J. Process for preparation of cyclic prodrugs of PMEA and PMPA
CN101475594A (en) * 2009-02-06 2009-07-08 廖国超 Liver targeted antivirus precursor medicament annular phosphoester and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REDDY, K. RAJA ET AL.: "Pradefovir: A Prodrug That Targets Adefovir to the Liver for the Treatment of Hepatitis B", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

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