WO2007101371A1

WO2007101371A1 - Preparation and use of purine bis-amino acid esters

Info

Publication number: WO2007101371A1
Application number: PCT/CN2006/000663
Authority: WO
Inventors: Yushe Yang; Xiaozhong Fu; Zhan Li; Ruyun Ji
Original assignee: Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences; Nanjing Changao Pharmaceutical Science & Technology Co., Ltd.
Priority date: 2006-03-06
Filing date: 2006-04-13
Publication date: 2007-09-13
Also published as: CN101033238A; CN101033238B

Abstract

The invention provides purine bis-amino acid esters represented by formula (I), and pharmaceutically-acceptable inorganic or organic salts thereof, wherein R1 is an amino group; R2 is an amino-protected or free L-amino acid; n is 0 or 1; X is O or S. The invention also provides the preparation of such compounds and the use of such compounds as active substance in preparation of a medicament for the treatment of viral diseases. (I)

Description

Preparation method and use of terpenoid compound

FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry and antiviral infection therapeutics, and in particular to terpenoids and their use in the preparation of antiviral drugs. BACKGROUND ART Hepatitis B is a disease caused by hepatitis B virus (HBV) that is seriously harmful to human health. According to statistics, there are about 350 million chronic HBV carriers in the world, and about 1 million people die each year from diseases caused by HBV. About 120 million people in China are carriers of hepatitis B virus, 28 million hepatitis B patients, and one-third of hepatitis B patients will evolve into chronic hepatitis, cirrhosis or primary liver cancer (HCC). The main drugs for the treatment of chronic hepatitis B include interferons, nucleoside antiviral drugs and immunomodulators. Nucleoside antiviral drugs are inhibitors of viral DNA polymerases or reverse transcriptases that stop the synthesis of viral DNA strands and thereby inhibit viral replication. Among nucleoside anti-HBV drugs, acyclic nucleoside phosphonates have an important role as analogs of nucleoside 5'-monophosphates, which can bypass rate limiting during nucleoside analog activation. The primary phosphorylation reaction, therefore, also has an inhibitory effect on DNA viruses that do not encode viral thymidine kinase (TK), with a broader spectrum of antiviral activity (Erik De Clercq Nature Rev. 2002, 1, 13). In addition, since the structure of the compound is different from that of the L-nucleoside drug, no cross-resistance is generated between the clinically applied L-nucleoside anti-HBV drug such as lamivudine. (Doo E Gastroenterology 2001, 120:1000; Das, KJ Virol 2001, 75:4771) ₀ Because of these characteristics, acyclic nucleoside phosphonates represent a class of highly promising antiviral drugs. Adefovir diputelohydroquinone (bis(POM)PMEA, abbreviated as ADV) is a double of 9-[2-(phosphonodecyloxy)ethyl]adenine adefovir (PMEA, Adefovir) The pivaloyloxymethyl ester prodrug, approved by the FDA in September 2003, is the second nucleoside small molecule anti-HBV drug marketed after lamivudine. ADV has strong antiviral activity against hepatitis B virus (HBV), duck hepatitis B virus (DHBV), and variant hepatitis B virus (YMDD) resistant to lamivudine in vitro and in vivo (Yen MF. Expert Opin Pharmacother. 2004, 5 (11): 2361-7 )» Clinical studies have shown that this drug can significantly improve the liver histology of patients, reduce serum HBV-DNA and transaminase levels, increase the conversion of e antigen (HBeAg), and regardless of the state of HBeAg, Genotype, ethnic differences, or the presence or absence of a variant virus resistant to lamivudine did not affect ADV's anti-HBV activity (Anneke K Raney. Expert Opin. Investig Drugs 2003, 12(8): 1281- 1295). However, ADV applications also have the following major defects: (1) Chemical instability, which is highly sensitive to serum enzyme-mediated hydrolysis and does not effectively increase drug concentration at the site of action (Pieter Annaert, Pharmaceutical Research. 1997, 14(4) : 492-496 ); (2) The transport of one molecule of nucleic acid requires the release of two equivalents of potentially toxic formaldehyde and pivalic acid (Jae-Taeg Hwang. Drugs of the Future 2004, 29(2); 163-177). The new generation of adefovir prodrugs are designed to increase the metabolic stability of the drug, prolong the duration of action, increase the bioavailability of the drug, and reduce the toxicity of the drug. Human peptide transporters are an integrated cytoplasmic membrane protein that mediates the absorption of di- and tripeptides in humans and belongs to the family of proton-dependent oligopeptide transporters. At present, two human peptide transporters (PepTl, PepT2) with transport activity are cloned and functionally confirmed. PepTl is called intestinal peptide transporter, which is mainly present on the comb membrane of intestinal epithelial cells, and mediates the reverse concentration. The gradient of the substrate-proton co-transport process, the natural L-amino acid is its suitable transport substrate (Isabbel Rubio-Aliaga TRENDS in Pharmacological Sciences, 2002, 23(9): 434-440). Due to the clarification of this mechanism, Recently, amino acid ester modification methods have been used for antiviral nucleoside derivatives to improve bioavailability and enhance drug efficacy, such as acyclovir and ganciclovir proline ester prodrugs L. -Valaciclovir and L-Valganciclovir increased the bioavailability of the original drug from 6% to 20% to 63% and 61%, respectively (Birger Brodin. Pharmacology & Toxicology. 2002, 90: 285-29; Raymund R Razonable, Expert Rev. Anti-infect. Ther. 2004, 2 (1): 27-42 ). The penicillin double L-valine and isoleucine ester derivatives developed by MEDIVIR AB can significantly improve the bioavailability of the original drug and make the drug resistant to varicella virus, scorpion virus and EB-virus. Role (Per Engelhardt, US 0020188125); The L-valine ester derivative BRL 44385 of 9-(3-hydroxypropyl-1-oxo)guanine developed by Smithline Beecham can improve the bioavailability of the original drug. The drug has a potent inhibitory effect on DNA viruses (parotid virus 1/2, varicella virus, cytomegalovirus, hepatitis B virus, etc.) (Harnden, Michael, WO9509855). The above results show the advantages of amino acid ester modification methods in improving the pharmacokinetics of nucleoside antiviral drugs. SUMMARY OF THE INVENTION One object of the present invention is to provide novel terpenoids having antiviral activity, particularly anti-hepatitis B (HBV) and AIDS (HIV) virus activity, and pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a process for the preparation of the above novel anthraquinone compound having antiviral activity, particularly against hepatitis B and HIV virus activity, and a pharmaceutically acceptable salt thereof. A further object of the present invention is to provide the use of such compounds and their salts as active substances in the manufacture of a medicament for the treatment of infectious diseases caused by viral infectious diseases, in particular HBV and HIV viruses. The present invention provides an anthraquinone diaryl acid ester of the formula (I) and a pharmacologically acceptable inorganic or organic salt thereof:

(I) In the formula (I), Ri is an amino group;

R ₂ is an amino-protected or free L-form amino acid; n is 0 or 1; X is 0 or S. The present invention also provides two processes for preparing a bismuth compound bisamino acid ester having the structure of the above formula (I) and a salt thereof. Method 1: Perform Process I as follows:

Illustrative: a. 2-bromoethanol, hydrazine, hydrazine-dimethylaminopyridine, dicyclohexylcarbodiimide, 0~25 ° C, 6-24 hours; b. isobutyl chloroformate, N-曱Benzoline, hydrogen sulfide, -20~-10°C, 1~4 hours; c.1,2-dibromoethane, sodium hydride, -20~0°C, 1~5 hours; chloroanthryl chloride Sulfonate, tetra-n-butylammonium hydrogen sulfate, 0~25°C, 6~12 hours; d. Ν,Ν'-dicyclohexyl-4-morphine-oxime (DCMC), 1,8-two Azabicyclo[5,4,0]undec-7-ene (DBU) is a base, 25-90 ° C, 4-48 hours; e. Hydrogen chloride saturation / 1,4-dioxane or acetyl chloride /methanol, -10 25 0.5-6 hours. Method one includes the following steps:

(1) Preparation of N-tert-butoxy-reactive (BOC) L-amino acid ester N-tert-butoxycarbonyl L-amino acid and 2-bromoethanol in an aprotic solvent in the presence of dicyclohexylcarbodiimide (DCC) and indole, indole-diaminopyridine (DMAP), in 0 ~ Reacting at 25 ° C for 6-24 hours to obtain N-tert-butoxycarbonyl L-amino acid bromoethyl ester; or

N-tert-butoxycarbonyl L-amino acid is reacted in isobutyl chloroformate, N-methylmorpholine, hydrogen sulfide gas at a low temperature of -20 - -10 ° C for 1-4 hours to obtain N-tert-butoxycarbonyl group. L-aminothiocarboxylic acid, and then react with 1,2-dibromoacetamidine in an aprotic solvent in the presence of a strong base at a low temperature of -20 ~ 0 ° C for 1-5 hours to obtain N-un Butyloxycarbonyl L-aminothiocarboxylic acid-2-bromoethyl ester; bromochloromethane is reacted with chlorosulfonic acid to give chlorodecyl chlorosulfonate, chlorodecyl chlorosulfonate and N-tert-butoxycarbonyl L -Amino acid is reacted in an inert solvent-water two-phase system in the presence of a phase transfer catalyst, tetra-n-butylammonium hydrogen sulfate, at 0 to 25 ° C for 6 to 12 hours to obtain N-tert-butoxycarbonyl L-amino acid. Chlorodecyl ester.

(2) various N-tert-butoxycarbonyl L-amino acids or L-aminothiocarboxylates and 9-[2-(phosphonomethoxy)ethyl]adenine in a polar aprotic solvent, Ν,Ν'-Dicyclohexyl-4-morpholinyl-indole (DCMC) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as a base, at 25 ~ 90. C reaction 4-48 hours, the product is obtained.

(3) The product prepared in the above step 2 is in a polar or non-polar solvent in the presence of hydrogen chloride-saturated 1,4-dioxane or acetyl chloride/nonanol at -10 to 25 ° C. The reaction was carried out for 0.5 6 hours to obtain the product compound.

(4) A corresponding pharmaceutically acceptable salt is prepared as needed. For example, the guanidine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and formed into a sulfate, a phosphate, a lemon with three equivalents of a mineral acid such as sulfuric acid, phosphoric acid and an organic acid such as citric acid or maleic acid. The citrate and maleate are prepared in a pharmaceutically acceptable manner according to methods known in the art. (Method 2: Flow II is carried out according to Scheme II below)

a. Oxalyl chloride, hydrazine, Ν'-diethyl hydrazide (DEF), 0~50 ° C, 0.5 ~ 4.5 hours; b. N, N-dimethylaminopyridine (DMAP), dicyclohexylcarba Amine (DCC), 0~25°C, 6~24 hours; c. Pyridine, triethylamine, 0~25°C, 1 - 10 hours; d. Saturated hydrogen chloride/1,4-dioxane or Acetyl chloride / sterol, -10 ~ 25 ° C, 0.5 ~ 6 hours. Method two includes the following steps: (1) 9-[ ² _ (phosphonomethoxy)ethyl] adenine in an inert solvent in the presence of a halogenating agent oxalyl chloride and a catalyst, hydrazine, Ν'-diethyl hydrazide, 0 to 50 °C, the reaction is carried out for 0.5 to 4.5 hours to obtain a dichlorophosphonate of 9-[2-(phosphonomethoxy)ethyl]adenine.

(2) N-tert-butoxycarbonyl L-amino acid and ethylene glycol in an aprotic solvent, in the presence of dicyclohexylcarbodiimide and indole, indole-diamidopyridine, at 0-25 ° C From 6 to 24 hours, N-tert-butoxycarbonyl L-amino acid-hydroxyethyl ester was obtained.

(3) a dichlorophosphonate of 9-[2-(phosphonomethoxy)ethyl]adenine and N-tert-butoxycarbonyl L-amino acid-hydroxyethyl ester in an inert solvent in pyridine In the presence of triethylamine, the reaction is carried out at 0 to 25 ° C for 1 to 10 hours to obtain a product compound.

(4) The product compound obtained in the above step (3) is in a polar or non-polar solvent in the presence of hydrogen chloride-saturated 1, 4-dioxane or acetyl chloride/nonanol at -10 to 25°. C, the reaction is carried out for 0.5 to 6 hours to obtain a product compound.

(5) A corresponding pharmaceutically acceptable salt is prepared as needed. For example, the guanidine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and formed into a sulfate, a phosphate, and a triple equivalent of a mineral acid such as sulfuric acid, phosphoric acid, and an organic acid such as citric acid or maleic acid. Citrate and maleate salts and the like are prepared as pharmaceutically acceptable salts by methods known in the art. The present invention further provides the use of the adefovir bisphosphonate compound of the formula (I) and a salt thereof for the preparation of a medicament for treating an infectious disease caused by a viral infectious disease, particularly a hepatitis B virus. The pharmacologically acceptable salt of the compound of the present invention specifically includes a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, and tannic acid, acetic acid, propionic acid, oxalic acid, and propylene. Acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, An acid addition salt of an acidic acid such as citric acid, picric acid, methanesulfonic acid or ethanesulfonic acid with an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with a base such as sodium, potassium, calcium or aluminum. a salt of an inorganic base, an ammonium salt, a methylamine salt, an ethylamine salt, an ethanolamine salt or the like, or a salt formed with a basic amino acid such as lysine, arginine or ornithine. Representative examples of the compound of the formula (I) of the present invention are as follows:

(1) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxy-aminoamino-3-mercaptoyloxy)ethyl]phosphonomethoxy Alkyl adenine;

(2) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-Butoxycarbonylamino-acetoxy)ethyl]phosphonyloxyl]ethyl} gland嘌呤

(3) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxy-amino-3-mercaptobutyrylthio)ethyl]phosphonomethoxy Ethyl}adenine;

(4) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-Butoxycarbonylamino-3-phenylpropionylthio)ethyl]phosphonohydrazide] Ethyl}adenine;

(5) (2S, 2' S) -9-{2-[0,0'-bis[(1-tert-butoxycarbonyl-2-pyrrolidinylsulfonylthio)ethyl]phosphonomethoxy] Ethyl}adenine;

(6) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-4-methylpentanoylthio)ethyl]phosphonomethoxy] Ethyl}adenine;

(7) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxymethylamino-3-mercaptovalerylthio)ethyl]phosphonohydrazideoxy Ethyl}adenine;

(8) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxy-aminoamino-3-indolylbutanoyloxy)-indenyl]phosphonoyl Alkyl]ethyl}adenine;

(9) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxy-amino-amino-4-mercaptoyloxy)methylene]phosphonoyl Alkyl]ethyl}adenine;

(10) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxyamino)-3-mercaptoyloxy)methylene]phosphonohydrazide Alkyl]ethyl}adenine; (11) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-mercaptoyloxy)ethyl]phosphonocarbonyloxy]ethyl} Adenine. trihydrochloride;

(12) (2S, 2' S) -9- {2-[0,0'-bis[(2-aminoacetoxy)ethyl]phosphonohydrazide]ethyl} adenine. Trihydrochloride Salt

(13) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-indolylbutanoylthio)ethyl]phosphonyloxyl]ethyl} gland三.Trihydrochloride;

(14) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-phenylpropionylthio)ethyl]phosphonyloxyl]ethyl}gland三.Trihydrochloride;

(15) (2S, 2' S) -9-{2-[0,0'-bis[(2-pyrrolidinyl)sulfonyl)ethyl]phosphonyloxy]ethyl} adenine. Acid salt

(16) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-4-methylpentanoylthio)ethyl]phosphonyloxyl]ethyl} gland三.Trihydrochloride;

(17) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-methylpentanoylthio)ethyl]phosphonyloxyl]ethyl} gland三.Trihydrochloride;

(18) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-indolylbutanoyloxy)methylene]phosphonomethoxy]ethyl } adenine. trihydrochloride;

(19) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-4-methylpentanoyloxy)indolyl]phosphonomethoxy]ethyl } adenine. trihydrochloride;

(20) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-mercaptoyloxy)methylene]phosphonooxyl]ethyl } adenine. trihydrochloride;

(21) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxy-amino-3-mercaptobutyryloxy)ethyl]phosphonoyloxyl Alkyl adenine;

(22) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-Butoxycarbonylamino-3-phenyl)propionyloxy]ethyl]phosphonomethoxymethoxy Adenine (23) (2S, 2' S) -9-{2-[0,0'-bis[(1-tert-butoxycarbonyl-2-pyrrolidinyloxy)ethyl]phosphonohydrazideoxy Ethyl}adenine;

(24) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxymethylaminopropionyloxy)ethyl]phosphonohydrazide]ethyl} Adenine

(25) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-Butoxycarbonylamino-4-methylpentanoyloxy)ethyl]phosphonyloxyloxy Ethyl}adenine;

(26) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-methylbutyryloxy)ethyl]phosphonomethoxy]ethyl} Adenine. trihydrochloride;

(27) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-phenylpropanoyloxy)ethyl]phosphonomethoxy]ethyl} Adenine, trihydrochloride;

(28) (2S, 2' S) -9-{2-[0,0'-bis[(2-pyrrolidinyloxy)ethyl]phosphonyloxy]ethyl} adenine. Trihydrochloride

(29) (2S, 2' S) -9-{2-[0,0'-bis[(2-aminopropanoyloxy)ethyl]phosphonohydrazide]ethyl} adenine. Acid salt

(30) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-4-methylpentanoyloxy)ethyl]phosphonomethoxy]ethyl} Adenine. Trihydrochloride. The structure of the above compounds is shown in Table -1

Table-1 Compound number and structure

Number η X Ri R ₂

1 1 ο -NH ₂ BOC-L-Ile 1 o -NH ₂ BOC-Gly

1 s - 3⁄4 BOC-L-Val

1 s - H ₂ BOC-L-Phe

1 s - H ₂ BOC-L-Pro

1 s - H ₂ BOC-L-Leu

1 s -NH ₂ BOC-L-Ile

0 0 -NH ₂ BOC-L-Val

0 0 - H ₂ BOC-L-Leu

0 o - Li ₂ BOC-L-Ile

1 o -NH ₂ L-Ile

1 0 -NH ₂ Gly

1 s - H ₂ L-Val

1 s -NH ₂ L-Phe

1 s -NH ₂ L-Pro

1 s - Li ₂ L-Leu

1 s - H ₂ L-Ile

0 o - H ₂ L-Val

0 0 - H ₂ L-Leu

0 0 -NH ₂ L-Ile

1 0 Mom BOC-L-Val

1 o -MI ₂ BOC-L-Phe

1 0 - H ₂ BOC-L-Pro

1 0 -NH ₂ BOC-L-Ala

1 0 -NH ₂ BOC-L-Leu

1 0 - Li ₂ L-Val 27 1 0 - Li ₂ L-Phe

28 1 0 - H ₂ L-Pro

29 1 0 -NH ₂ L-Ala

30 1 o -NH ₂ L-Leu The steroid bi-amino acid esters and pharmacologically acceptable salts thereof claimed in the present invention have a function of treating infectious diseases caused by viral infectious diseases, particularly HBV and HIV viruses. The bismuth compound diamino acid ester and the pharmacologically acceptable salt thereof claimed in the present invention have activity similar to or stronger than those of the nucleoside small molecule anti-HBV drug of the prior art for treating viral infectious diseases. Therefore, these compounds are useful for the preparation of novel drugs for the treatment of viral infectious diseases, particularly infectious diseases caused by HBV and HIV viruses. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further illustrated by the following examples, but these examples are in no way intended to limit the invention. In all the examples, the melting point was measured by a MEL-TEMP melting point apparatus, the thermometer was not corrected; 1H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed by δ (ppm); the silica gel for separation was not described as 200-300 mesh. . The compounds of the invention can be prepared by two methods. The compound of the invention is prepared according to method one:

1. Starting from 1,3-dioxolane, the intermediate 9-[2-(phosphonomethoxy) was synthesized by a known method (Nucleoside & Nucleotide 1996, 15, 1771) in several steps. ) Ethyl] anthracene derivatives. 2. N-tert-butoxycarbonyl (BOC) L-amino acid and 2-bromoethanol in a non-polar solvent such as toluene, dichlorodecane, chloroform or tetrahydrofuran, in hydrazine, hydrazine-dimethylaminopyridine, bicyclo The reaction is carried out at 0 to 25 ° C for 6 to 24 hours in the presence of hexylcarbodiimide. The optimum condition is to react with dichlorosilane as a solvent at 10 to 25 ° C for 12-24 hours to obtain N-tert-butoxycarbonyl ( BOC) L-amino acid-bromoethyl ester.

3, N-tert-butoxycarbonyl L-amino acid and isobutyl chloroformate (IBCF) and hydrogen sulfide 'gas in toluene, dichlorodecane, chloroform, tetrahydrofuran low temperature -30 ~ 10 ° C reaction 1 ~ 10 hours To give N-tert-butoxycarbonyl L-aminothiocarboxylic acid. The optimum conditions are tetrahydrofuran as a solvent, and the reaction is carried out at -20 to 10 for 2 to 4 hours. The obtained product and 1,2-dibromoethane are in an aprotic solvent such as toluene, dichlorodecane, chloroform or tetrahydrofuran in the presence of sodium hydride, sodium t-butoxide, lithium t-butoxide, sodium ethoxide or the like. The reaction is carried out at -40 to 10 ° C for 0.5 to 10 hours. The optimum reaction conditions are as follows: tetrahydrofuran is used as a solvent in the presence of sodium hydride at -20 to 0 ° C for 2 to 5 hours. N-tert-Butoxycarbonyl L-aminothiocarboxylic acid-2-bromoethyl ester was obtained.

4, N-tert-butoxycarbonyl (BOC) L-amino acid and bromochloromethane and chlorosulfonate should be obtained as chloropurinyl chlorosulfonate in an inert solvent-water two-phase system (dichloromethane-water, chloroform) - in water, carbon disulfide-water, carbon tetrachloride-water, etc., in the presence of phase transfer catalyst, tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, react at -20~25 °C 0.5~ After 24 hours, a chloromethyl ester of N-tert-butoxycarbonyl L-amino acid was obtained. The optimum reaction conditions are dichloromethane-water as the reaction system, and tetra-n-butylammonium hydrogen sulfate as the phase transfer catalyst, and the reaction is carried out at 0 to 15 ° C for 6 to 12 hours.

5. N-tert-Butoxycarbonyl L-amino acid-bromoethyl ester, N-tert-butoxycarbonyl L-aminothiocarboxylic acid-2-bromoethyl ester, N-tert-butoxycarbonyl L-amino acid The base ester and 9-[2-(phosphonomethoxy)ethyl]adenine in a polar aprotic solvent such as N,N-dimercaptoamide, dimethyl sulfoxide or pyridine, in Ν,Ν' -dicyclohexyl-4-morpholinyl-indole or 1,8-diazabicyclo[5,4,0] In the presence of undecane-7-ene, the reaction is carried out at 25-90 ° C for 4 ~ 48 hours to obtain compounds 1 ~ 10; the optimal reaction conditions are N, N-dimercaptocarboxamide as solvent, in hydrazine, hydrazine '-Dicyclohexyl-4-morpholinyl-indole is reacted with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) at 40-80 ° C, 6 ~ 24 hours.

6. Compounds 1 to 10 are present in a polar solvent such as ethyl acetate, isopropyl acetate or 1,4-dioxane in the presence of hydrogen chloride saturated 1,4-dioxane or acetyl chloride/nonanol. The reaction is carried out at -20 - 25 ° C for 0.5-12 hours to obtain compounds 11-20. The optimum reaction conditions are as follows: 1,4-dioxane is used as a reaction solvent, and the reaction is carried out at 0 to 10 ° C for 3 to 6 hours in the presence of a hydrogen chloride-saturated 1,4-dioxane.

7. Prepare the corresponding salt as needed. The hydrazine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and forms a sulfate, a phosphate, a citrate with three equivalents of a mineral acid such as sulfuric acid, phosphoric acid and an organic acid such as citric acid, maleic acid or the like. And maleate or the like is prepared into a pharmaceutically acceptable salt by a conventional method. The compound of the invention is prepared according to method two:

1, 9-[2-(phosphonodecyloxy)ethyl]adenine is used as a raw material, according to the known method (Mark D. Erion. et al J. Am. Chem. Soc. 2004, 126, 5154-5163) Preparation of dichloro 9-[2-

(phosphonooxyalkyl)ethyl]adenine.

2. N-tert-butoxycarbonyl L-amino acid and ethylene glycol in a non-polar solvent such as toluene, dichlorodecane, chloroform or tetrahydrofuran, in 1^,:^-diaminopyridine, dicyclohexylcarbal The reaction is carried out at 0-25 °C for 6-24 hours in the presence of imine. The optimum conditions are to react with dichloromethane as solvent at 10-25 °C for 12-24 hours to obtain N-tert-butoxycarbonyl L-amino acid-hydroxyl. Ethyl ester. '

3, 9-[2-(phosphonomethoxy)ethyl]adenine dichlorodecanoate and N-tert-butoxycarbonyl L-amino acid-hydroxyethyl ester in toluene, dichloromethane, chloroform, Non-polar such as tetrahydrofuran In the solvent, in the presence of pyridine and triethylamine, the reaction is carried out at 0 to 25 ° C for 1 to 10 hours. The optimum reaction conditions are dichloromethane, solvent, at 0-10 ° C, and the reaction is carried out for 2 to 6 hours. Compound 21 ~ 25.

4. Compounds 21 to 25 are saturated with 1, 4 - dioxane or B in a nonpolar solvent such as 1, 4-dioxane, ethyl acetate, isopropyl acetate or dichlorodecane. In the presence of acid chloride/sterol, the reaction is carried out at -10 to 100 ° C for 0.5-6 hours. The optimum reaction conditions are as follows: 1, 4-dioxane as solvent in hydrogen chloride saturation under 1, 4-dioxane conditions , reacting at 0~10 °C for 2 ~ 4 hours to obtain compounds 26 ~ 30.

5. Prepare the corresponding salt as needed. The hydrazine compound trihydrochloride is freed with sodium hydrogencarbonate, sodium carbonate or the like and forms a sulfate, a phosphate, a citrate with three equivalents of a mineral acid such as sulfuric acid, phosphoric acid and an organic acid such as citric acid, maleic acid or the like. And maleate or the like is prepared into a pharmaceutically acceptable salt by a conventional method. Example 1: (2S, 2' S) -9-ί2- "0,0'-bis"(2-tert-butoxycarbonylamino-3-mercaptoloyloxy)ethyl 1phosphonyloxyloxy Preparation of 1 ethyl}adenine (Compound 1)

1.1 ( 1S) - Preparation of tert-butyl oxime (2-bromoethoxy)carbonyl 2-methylbutylaminodecanoate (V)

Ν-tert-Butoxycarbonyl-L-isoleucine (5.00 g, 0.02 mol), 2-bromoethanol (2.98 g, 0.024 mol) was dissolved in 200 ml of dry dichloromethane and cooled to 10 ° with a water-water bath. C, hydrazine, hydrazine-dimethylaminopyridine (2.92 g, 0.023 mol) was added in portions. After the addition, the system was stirred for 15 minutes. Then slowly add dicyclohexyl diimide (4.53g, 0.022mol) A solution of 30 ml of dichloromethane. After the addition, the reaction temperature was naturally raised to room temperature for 12 hours. The insoluble matter in the system was filtered, and the solvent was distilled off. 100 ml of ethyl acetate was added to the obtained residue, and the solid in the system was sufficiently precipitated by standing at a low temperature (-10 ° C) for 6 hours. After filtration, the filtrate was washed with 100 x 2 ml of water, washed with 200 ml of brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product, 8.65 g. Obtained as a colorless oil of tert-butyl 1-[(2-bromoethoxy)carbonyl]-2-methylbutylamino Phthalate ester (a) 4.86 g, yield 68.39%.

¹ H NMR (CDC1 ₃ ): 4.99 (d, J = 8.15 Hz, 1H), 4.48-4.37 (m, 2H), 4.28 (m, 1H), 3.52-3.47 (m, 2H), 1.87 (m, 1H) , 1.42(s, 9H), 1.22-1.17(m, 2H), 0.94-0.87(m,6H); EI-MS(m/e): 323, M+

1.2: ( 2S, 2' S ) -9-ί2-ΓΟ,0'-biguanide (2-tert-butoxycarbonylamino-3-methylpentanoyloxy)ethyl 1phosphonylmethoxylethyl } Preparation of adenine compound 1)

tert-Butyl 1-[(2-bromoethoxy)carbonyl]-2-methylbutylaminodecanoate (a) (0.63 g, 1.8 mmol), 9-[2- (phosphine) Acylmethoxy)ethyl]adenine (0.10 g, 0.36mnol) and hydrazine, Ν'-dicyclohexyl-4-morpholinyl-indole (0.21 g, 0.72 mmol) suspended in 10 ml of dry mash, Ν-two The mercaptocarboxamide was reacted at room temperature for 24 hours, and then reacted at 80 ° C for 4 hours. The reaction solvent was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml) was added to the residue, and the mixture was allowed to stand at -5 to 0 ° C for 6 hours, and the insoluble materials were filtered off, and the filtrate was washed with 1% citric acid, water and saturated brine, and anhydrous sodium sulfate. The mixture was dried, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjj Yield: 15.17%. ¹ H NMR (CDC1 ₃ ): 6 = 8.32 (s, lH), 7.96 (s, lH), 5.87 (brs, 2H), 5.21-5.40 (m, 2H), 4.39 (t, J = 5.32 Hz, 2H) ₅ 4.10-4.37(m,10H), 3.93(m,2H), 3.81(d, J=8.41Hz, 2H), 1.84(m,2H), 1.42(s, 18H), 1.05-1.26(m,4H ), 0.85-0.91(m, 12H). EI-MS(m/e): 787, M+ Example 2: ( 2S, 2' S ) -9-ί2-ΓΟ, 0'-双Γ (2-Uncle Preparation of butoxycarbonylamino-acetoxy)ethyl 1phosphonylmethoxy 1ethyl} adenine compound 2)

2.1: Preparation of tert-butyl-1-(2-bromoethoxy)carbonyl 1 methylcarbamate (a)

Br

N-tert-butoxycarbonyl-glycine (3.70 g, 0.021 mol), 2-bromoethanol (3.47 g, 0.028 mol) was dissolved in 200 ml of dry dichloromethane, and cooled to 10 ° C in a water-water bath. This was added hydrazine, hydrazine-dimethylaminopyridine (3.10 g, 0.025 mol). After the addition, the system was stirred for 15 minutes. Then, a solution of dicyclohexylcarbodiimide (4.53 g, 0.022 mol) in 30 ml of dichloromethane was slowly added dropwise. The subsequent procedure was similar to the synthesis of compound 1.1 to give colorless oil (a) 3.21 g, yield 54.39%.

2.2: ( 2S, 2' S ) -9-ί2-ΓΟ, 0'-bis((2-tert-butoxycarbonylamino-acetoxy)ethyl 1phosphonomethoxylethyl) adenine (compound) 2) Preparation

At room temperature, (a) (0.99 g, 3.55 mmol), 9-[2-(phosphonomethoxy)ethyl]adenine (0.16 g, 0.59mnol) and hydrazine, Ν'-dicyclohexyl- 4-morpholinyl-indole (0.33 g, 1.13 mmol) was suspended in 10 ml of dry hydrazine, hydrazine-dihydrazinamide, reacted at room temperature for 24 hours, and then reacted at 80 ° C for 4 hours. The reaction solvent was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml) was added to the residue, and the mixture was allowed to stand at -5 to 0 ° C for 6 hours, and the insoluble material was filtered off, and the filtrate was washed with 1% citric acid, 7 and saturated brine, anhydrous sodium sulfate. The mixture was dried, filtered, and the filtrate was evaporated,jjjjjjjj Yield: 13.15%.

¹ H NMR (CDC1 ₃ ): 8 = 8.26 (s, lH), 8.11 (s, lH), 5.44 (brs, 2H), 4.38-4.45 (m, 2H), 4.23-4.3 l(m,8H), 3.93 -4.01 (m, 6H), 3.84 (d, J = 8.52 Hz, 2H), 1.43 (s, 18H). EI-MS (m/e): 675, M+. Example 3: ( 2S , 2' S Preparation of -9-ί2-ΓΟ,0'-bis((2-tert-butoxycarbonylamino-3-methylbutanoylthio)ethyl 1phosphonylmethoxy 1ethyl 1 adenine (Compound 3)

3.1 : Preparation of (SV 2-tert-butoxycarbonylamino-3-methylmonothiobutyric acid (V)

The Ν-tert-butoxycarbonyl-L-proline (2.50 g, 0.0115 mol) was dissolved in 25 ml of dry tetrahydrofuran, cooled to -15 ° C with a water-salt bath, and N-methylmorpholine (11.54 g, 0.0575 mol) and isobutyl chlorodecanoate (1.74 g, 0.0126 mol), and the system was stirred for ³⁰ minutes. In the reaction system, the temperature is kept below -15 °C, and the hydrogen peroxide gas is introduced into the system. The aeration time lasts for 1.5-2 hours. After the hydrogen sulfide gas in the system is absorbed to saturation, the reaction is kept for 2 hours to complete the reaction. . Add 40ml of anhydrous ether, adjust the pH of the system to 3 with 0.1M hydrochloric acid, and take The organic layer was washed with 2×20 ml of water, 2×20 ml of brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Acid (a) 2.22g, yield 82.85%.

¹ H NMR (CDCl ₃ ): 5.06 (m, 1H), 4.24 (m, lH), 2.27 (m, 1H), l, 43 (s, 9H), 0.93-0.89 (m ₅ 6H).

3.2: Preparation of (IS)-tert-butyl-I-[(2-bromoethylthio)carbonyl]-2-methylpropylcarbamate (V)

Sodium hydride (0.17 g, 4.29 mmol) was added to 10 ml of tetrahydrofuran, stirred and cooled to -15 ° C in an ice-salt bath. (S)-2-tert-butoxycarbonylamino-3-indolyl monosulfide was slowly added dropwise. A solution of (a) (1.00 g, 4.29 mmol) in 2 ml of tetrahydrofuran was added dropwise, the reaction was kept for 1.5 hours, and the reaction was carried out for 2 hours at room temperature, and 1,2-dibromo-alkane (1.60 g, 8.58 mol) was slowly added dropwise. The solution of 5 ml of tetrahydrofuran was added dropwise, and the system was reacted at room temperature for 12 hours. The system was filtered, and the filtrate was washed with 2×20 ml of water, 2×20 ml of brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) Light yellow oil (S) 2-tert-butoxycarbonylamino-3-methylmonothiobutanoic acid-2-bromoethyl ester (b) 0.59 g, yield 40.52%.

¹ H NMR (CDCl ₃ ): 4.95 (d, J = 8.95 Hz, 1H), 4.26 (m, lH), 3.42 (t, J = 7.34 Hz ₅ 2H), 3.29 (t J = 6.6 Hz, 2H) 2.25(m, 1H), 1.46(s,18H), 0.99(d ₅ J=6.78Hz, 3H), 0.86(d, J=6.96Hz, 3H).

3,3: ( 2S, 2' S ) -942-ΓΟ,0'-bis((2-tert-butoxy-amino-3-mercaptobutanoylthio)ethylphosphonium methoxyl 1ethyl Preparation of adenine (compound 3)

(S)-2-tert-Butoxycarbonylamino-3-mercaptomonothiobutanoic acid-2-bromoethyl ester (b) (0.44 g, 1.3 mmol) and 9-[2-(phosphonomethoxy) Ethyl] adenine (0.08 g, 0.26 mmol) and hydrazine, Ν'-dicyclohexyl-4-morpholinyl-hydrazine (0.15 g, 0.26 mmol) suspended in 10 ml of dry hydrazine, Ν-dimercaptopurine In the amide, the reaction was carried out at room temperature for 24 hours, and then at 80 ° C for 5 hours. The reaction solvent was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml, ethyl acetate) was added to the residue, and the mixture was allowed to stand at -5 to 0 ° C, and the insoluble materials were filtered off. The filtrate was washed with 10×2 ml of 1% citric acid, 7 J and saturated brine, dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. EtOAc m. Yield: 13.09%.

¹ H NMR (CDC1 ₃ ): 5 = 8.27 (s, lH), 8.05 (s, lH), 6.18 (brs, 2H), 5.21-5.39 (m, 2H), 3.97-4.4 l (m, 8H), 3.91 (t, J=4.89Hz, 2H), 3.79(d, J=8.41Hz, 2H), 3.04-3.21(m, 4H), 2.24(m,2H) ₃ 1.42(S,18H), 0.96(d, J = 6.84 Hz, 6H), 0.83 (d, J = 6.65 Hz, 6H). ESI-MS (m/e): 792.2, (M+H)+. Example 4: ( 2S, 2' S ) 9-{2-"0,0'-bis"(2-tert-Butoxycarbonylamino-3-phenylpropionylsulfide)ethyl 1phosphonylmethyl 1 ethyl} adenine (Preparation of Compound 4)

N-tert-butoxy-L-phenylalanine was used as a starting material, and was prepared in a similar manner to that of Example 3 to obtain a white amber compound ( 2S, 2' S ) -9-{2-[0 , 0'-bis[(2-tert-butoxycarbonylamino-3-phenylpropionylthio)ethyl]phosphonohydrazide]ethyl} adenine 61 mg. Yield: 12.67 %. ¹ H NMR (CDC1 ₃ ): 8 = 8.31 (s, lH) ₅ 8.01 (s, lH), 7.11-7.26 (m, 10H), 6.12 (brs, 2H), 5.44-5.37 (m, 2H), 4.09- 4.45 (m, 8H), 3.81-3.90 (m, 4H), 3.14-3.31 (m, 4H), 2.88-3.13 (m, 4H), 1.42 (S, 18H). Example 5: ( 2S, 2' S ) -9-ί2- "0,0'-bis[(1-tert-butoxy-oxy-2-pyrrolidinylsulfonylthio)ethyl 1phosphonylmethyl group Preparation of 1 ethyl}adenine (Compound 5)

Ν-tert-Butoxycarbonyl-L-proline was used as a starting material, which was prepared in a similar manner to that of Example 3 to give a pale brown oily compound (2S, 2's) -9-{2-[0,0 '-Bis[(1-tert-butoxycarbonyl-2-pyrrolidinylsulfonyl)ethyl]phosphonohydrazide]ethyl}adenine 55 mg, Yield: 18.61%.

¹ H NMR (CDC1 ₃ ): 8 = 8.35 (s ₅ lH), 8.07 (s, lH), 5.84 (brs, 2H), 4.47 (m, 2H), 4.36-4.24 (m ₅ 6H), 3.83-3.96 ( m, 4H), 3.38-3.57 (m, 4H), 3.14-3.26 (m, 4H), 1.42 (S, 18H), 2.13-2.24 (m, 4H), 1.91-2.02 (m, 4H), 1.43 ( d, J=l 6.67Hz,

18H). Example 6: ( 2S, 2' S ) -9-ί2-ΓΟ, 0'-bis "(2-tert-butoxyamino-4-mercapto-valerylthio)ethyl 1phosphonomethoxy 1 Preparation of ethyl}adenine (compound 6)

Ν-tert-Butoxycarbonyl-L-proline was used as a starting material to prepare a white foamy compound (2S, 2' S ) -9-{2-[0,0'. - bis[(2-tert-butoxycarbonylamino_4-mercaptoylthio)ethyl]phosphonohydrazide]ethyl}adenine 67 mg, Yield: 31.38%.

¹ H NMR (CDC1 ₃ ): S = 8.31 (s, lH), 7.97 (s, lH), 5.97 (brs, 2H), 5.24-5.41 (m, 2H), 4.51-4.28 (m, 8H), 3.91- 4.02 (m, 4H), 3.23-3.41 (m ₅ 4H), 1.72-1.80 (m, 4H), 1.07 (brs, 12H). Example 7: ( 2S, 2' S ) -942-"0,0'-biguanide (2-tert-butoxymethylamino-3-methylpentanoylthio)ethyl 1phosphonyloxyl 1 Adenine (Preparation of Compound 7)

Ν-tert-butoxy-l-isoleucine was used as a starting material, and was prepared in a similar manner to that of Example 3 to give a white foamy compound (2S, 2's) -9-{2-[0 , 0'-bis[(2-tert-butoxycarbonylamino-3-mercapto-valerylthio)ethyl]phosphonomethoxy]ethyl} adenine, 81 mg, Yield: 35.23%.

¹ H NMR (CDC1 ₃ ): S = 8.36 (s, lH), 8.04 (s, lH), 5.87 (brs, 2H) ₅ 5.18-5.34 (m, 2H), 4.32-4.42 (m, 4H), 4.08- 4.11 (m, 4H), 3.92 (m, 2H), 3.81 (d, J = 8.66Hz 2H), 3.02-3.18(m, 4H), 1.92-1.99 (m, 2H), 1.42(s, 18H), 1.11-1.17 (m, 4H), 0.79-0.98 (m, 12H). Example 8: ( 2S, 2 ^/ S ) -942-"0,0'-bis"(2-tert-butoxycarbonylamino-3-methylbutanoyloxy)methylene 1phosphonyloxyl 1 Preparation of ethyl} adenine (compound 8)

8.1 : Chlorochlorosulfonate (a)

Chlorosulfonic acid (100 ml, 1.5 mol), bromochlorosilane ( ⁵⁰ ml, ^0.75 mol) was placed in a reaction flask, and the reaction system was slowly heated to reflux for 3 hours. After the reaction was completed, the system was cooled to room temperature, and then poured slowly into 500 g of crushed ice. After the water was melted, it was extracted with dichloromethane (400×2 ml, ), and the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under normal pressure, and the residue was evaporated under reduced pressure to collect 45-50 ° C / 9-10 mmHg fractions. The product was obtained in 30.25 g, yield: 24.4%.

¹ H NMR (CDC1 ₃ ): 5.96 (s, 2H) 8.2: ( IS )-tert-Butyl-l-((chloromethyl)carbonyl 1-2-methylpropyl carbamate

Preparation of (b)

N-tert-Butoxycarbonyl-L-proline (3.00 g, 0.0138 mol), sodium hydrogencarbonate (4.59 g, 0.0546 mol) and tetra-n-butylammonium hydrogen sulfate (0.47 g, 0.00138 mol) to 50 ml of water In a system with 50 ml of dichloromethane, the water salt bath was cooled to 0 ° C, and a solution of chloropurinyl chlorosulfonate (a) (2.78 g, 0.0167 mol) in 14 ml of dichloromethane was slowly added dropwise with vigorous stirring. After the dropwise addition, the system naturally rose to room temperature and reacted for 12 hours. The organic layer was separated, washed with 2×10 ml of brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) g. Yield: 80.77 %.

¹ H NMR (CDC1 ₃ ): 5.83 (d, J = 5.86 Hz, lH) ₅ 5.58 (d, J = 5.37 Hz, lH), 4.97 (d J = 8.3 Hz, IH), 4.23-4.21 (m, lH) , 2.15 (m, IH), 1.41 (s, 9H), 0.96 (d, J = 6.83 Hz, 3H), 0.89 (d, J = 6.84 Hz, 3H).

8.3: ( 2S, 2' S ) -942-ΓΟ,0'-bis((2-tert-butoxycarbonylamino-3-methylbutanoyloxy) fluorenyl 1phosphonomethoxy 1 ethyl} Preparation of adenine (Compound 8) 9-[2-(phosphonomethoxy)ethyl]adenine (0.10 g, 0.36 mmol), tert-butyl 1-[(chloroindolyl)carbonyl]-2 - mercaptopropyl carbamate (b) (0.48 g, 1.8 mmol), hydrazine, Ν'-dicyclohexyl-4-hydranyl-indole (0.21 g, 0.72 mmol) suspended in 10 ml of dry N- In methyl-2-pyrrolidone, react at room temperature for 24 hours and then react at 80 ° C for 5 hours. Pour the system into 5 ml of 1% citric acid and 5 ml of ethyl acetate, extract, separate the organic phase, and continue to use 2 x 5 ml of acetic acid in the aqueous phase. Ethyl ester extraction, ester layer combination, continue to wash with 2x5ml 1% citric acid, water and saturated brine The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by column chromatography (eluent: chloroform:methanol: 25:1) Yield: 20.8 %.

¹ H NMR (CDC1 ₃ ): S = 8.28 (s, lH), 7.97 (s, lH), 6.18 (brs, 2H), 5.66-5.72 (m, 4H), 5.21-5.36 (m, 2H), 4.41 ( m, 2H), 4.27-4.3 l(m,2H), 3.91(m,2H), 3.85(d, J=5.09Hz, 2H), 2.13-2.18(m,2H) ₅ 1.42(s, 18H), 0.96 (d, J = 6.32 Hz,

6H), 0.84 (d, J = 6.78 Hz ₅ 6H). Example 9: ( 2S, 2' S ) -9-{2-"0,0'-bis"(2-tert-butoxyamino-4-methylpentanoyloxy)methylene 1phosphonoyl Methoxy 1 Adenine (Preparation of Compound 9)

N-tert-butoxycarbonyl-L-leucine was used as a starting material, and was obtained in a similar manner to that of Example 8 to give a white foamy compound (2S, 2's) -9-{2-[0,0 '-Bis[(2-tert-butoxycarbonylamino-4-indolylpentanoyloxy)methylene]phosphonohydrazide]ethyl}adenine 26 mg, yield: 9.56%.

¹ H NMR (CDC1 ₃ ): 8 = 8.34 (s, lH), 8.06 (s, lH), 6.21 (brs, 2H), 5.76-5.91 (m, 4H), 5.18-5.29 (m, 2H), 4.52- 4.36(m, 4H), 3.94(m,2H), 3.91(d, J=5.97Hz, 2H), 1.71-1.93(m,6H), 1.42(s, 18H), 0.9 l(t, J=5.5 Hz, 12H). Example 10: ( 2S, 2' S ) -9-ί2- "0,0'-bis"(2-tert-butyl carbonylamino-3-methylpentanoyloxy)methylene 1phosphonomethoxy Base 1 ethyl} adenine (preparation of compound 10

Ν-tert-butoxy-l-isoleucine was used as a starting material, and was prepared in a similar manner to that of Example 8 to give a white foamy compound (2S, 2's) - 9-{2-[0, 0'-bis[(2-tert-butoxycarbonylamino-3-mercaptoloyloxy)methylene]phosphonomethoxy]ethyl}adenine 85 mg, yield: 15.56%.

¹ H NMR (CDC1 ₃ ): S = 8.28 (s, lH), 7.96 (s, lH), 6.09 (brs, 2H), 5.59-5.72 (m, 4H), 5.08-5.21 (m, 2H), 4.38 ( m, 2H), 4.23-4.3 l(m, 2H), 3.89(m, 2H), 3.82 (d, J = 7.33 Hz, 2H), 1.84 (m, 2H), 1.41 (s, 18H), 1.07-1.16 (m, 4H), 0.81 - 0.95 (m, 12H).

Example 11: ( 2S, 2' S ) -9-ί2-oxime, 0'-biguanide (2-amino-3-methylpentanoyloxy)ethyl 1-phosphonomethoxy-1-ethyl} gland Preparation of trihydrochloride compound 11)

The compound prepared in Example 1 (0.21 g, 0.267 mmol) was dissolved in 1 ml of dry 1,4-dioxane, and the system was cooled to 0 ° C with a salt bath under nitrogen, and slowly added dropwise with stirring at 15%. A solution of hydrogen chloride in 1, 4-dioxane (1 ml, 4 mmol) was incubated for 1 hour, and then reacted at room temperature for 3 hours until the product was fully converted. After standing for 30 minutes, the supernatant in the system was aspirated, and the solid was washed with 5×2 ml of ethyl acetate, and the mixture was allowed to stand for 5 times. The solvent was discarded, and the residue was sufficiently dried to give a white foamy solid, 0.176 g, yield: 95.24% .

¹ H NMR (CD ₃ OD): 8 = 8.43 (s, lH), 8.39 (s, lH), 4.55 (t, J = 5.08 Hz, 2H), 4.38 - 4.53 (m ₅ 4H) 4.21 - 4.36 (m, 4H) , 4.06-4. ll(m,2H), 3.98-4.02(m, 4H), 1.98-2.01(m,2H), 1.34-1.57(m, 4H), 0.96-1.03(m, 12H). ESI-MS: 588.2 (M+H)+ „ Example 12: (2S, 2' S) -9-ί2- "0,0'-bis"(2-aminoacetoxy)ethyl 1phosphonohydrazide Preparation of gas-based 1 ethyl) adenine. Trihydrochloride (Compound 12) The compound prepared in Example 2 was used as a starting material to give a white powder (yield: 22 mg). 87.76%. 'H MRCCDsOD): 8=8.54(brs,4H), 8.49(s,lH), 8.42(s,lH), 4.44(m, 2H), 4.3 l(m, 4H) 4.16(m,4H), 3.97 (d, J = 7.82 Hz, 2H), 3.92 (m, 2H), 3.85 (s, 4H). EI-MS (m/e): 475 M+. Example 13: ( 2S, 2' S ) -9-ί2- "0,0'-bis"(2-amino-3-methylbutanoylthio)ethyl 1phosphonylmethoxy 1ethyl} gland Preparation of trihydrochloride (Compound 13)

Acetyl chloride (0.077 ml, 1.06 mmol) and decyl alcohol (0.058 ml, 1.36 mmol) were placed in 1.6 ml of dry ethyl acetate, and the system was cooled to -5 to 0 ° C in a water salt bath for 30 minutes. The compound (30 mg, 0.0379 mmol) of the compound prepared in Example 3 was dissolved in ethyl acetate. After the dropwise addition, the reaction was allowed to stand for 2 hours, and then naturally raised to room temperature for 6 hours until the product was sufficiently converted. After standing for 30 minutes, the supernatant in the system was discarded, and the solid was washed with 5 x 2 ml of ethyl acetate, and allowed to stand for 5 times. The solvent was discarded, and the residue was sufficiently dried to give a white semi-solid 13 mg, yield: 58.03%.

¹ H NMR (CD ₃ OD): 5 = 8.43 (s, lH) ₃ 8.39 (s, lH), , 4.58 (t, J = 4.69 Hz, 2H), 4.14-4.22 (m, 6H), 3.98-4.02 ( m,4H) , 3.3 l(t, J=6.26Hz, 4H), 2.26-2.4 l(m, 2H), 1.12(d,J=6.85,6H), 1.04(d, J=7.04Hz, 6H) ESI-MS: 592.1 (M+H)+. Example 14: ( 2S, 2' S ) -9-ί2- "0,0'-biguanide (2-amino-3-phenylpropionylsulfide)ethyl 1phosphonylmethoxy 1ethyl} gland Preparation of trihydrochloride (Compound 14) The compound prepared in Example 4 was used as a starting material to give a white powdery product (yield: 84.46%). ¹ H NMR (CD ₃ OD): 5-8.38 (s, lH), 8.35 (s, lH), 7.28-7.38 (m, l OH), 4.56 (m, 4H), 4.05 - 4.18 (m, 4H), 3.96 (t, J = 4.59 Hz), 3.91 (d, J = 8.25 Hz, 2H), 3.24 (m, 4H), 3.13-3.19 (m, 4H). Example 15: ( 2S , 2' S ) -9-ί2-ΓΟ, 0'-bis((2-pyrrolidinoylsulfonyl)ethyl 1phosphonyloxyl 1ethyl} adenine. Trihydrochloride Preparation of the salt (Compound 15) Using the compound obtained in Example 5 as a starting material, m.p.

¹ H NMR (CD ₃ OD): S = 8.44 (s, lH), 8.40 (s, lH), 4.68 (m, 2H), 4.56 (m, 2H), 4.17-4.19 (m, 4H), 3.97-4.01 (m, 4H), 3.39 (t, J = 6.96 Hz, 4H), 3.33 (m, 4H), 2.50-2.56 (m, 2H), 2.07-2.16 (m, 6H). ESI-MS: 588.1 (M +H)+ ₀ Example 16: ( 2S, S ) -9-ί2- "0,0'- biguanide (2-amino-4-methylpentanoylthio)ethyl 1phosphonylmethoxy 1 B Preparation of adenine. Trihydrochloride (Compound 16) The compound prepared in Example 6 was used as a starting material, which was obtained in a similar manner to that of Example 13 to give a colorless gel-like semisolid 7 mg. 46.34%.

¹ H NMR (CD ₃ OD): 8 = 8.42 (s, lH), 8.37 (s, lH), 4.55 (m, 2H), 4.18-4.26 (m, 6H), 4.0 l (m, 4H), 3.3 l (m, 4H), 1.72-1.81 (m, 4H), 1.02 (m, 12H). ESI-MS: 620.2 (M+H)+. Example 17: ( 2S, 2' S ) -9-ί2- "0,0'-bis"(2-amino-3-methylpentanoylthio)ethyl 1phosphonylmethoxy 1ethyl} gland The trihydrochloride salt (Compound 17 was prepared by the procedure of Example 13 using the compound obtained in Example 7 to give a white fluffy solid, 14 mg, yield: 50.26%. ¹ H NMR (CD ₃ OD): 5 = 8.41 (s, lH), 8.36 (s, lH), 4.56 (t, J = 5.12 Hz, 2H), 4.18 - 4.25 (m, 6H), 3.91-4.01 (m , 4H), 3.24 (m, 4H), 2.07 (m, 2H), 1.24-1.61 (m, 4H), 0.97-1.08 (m, 12H) ESI-MS: 620.2 (M+H)+. Example 18: ( 2S, 2' S ) -9-ί2- "0,0'-bis"(2-amino-3-mercaptobutyryloxy)methylene 1phosphonyloxy oxime ethyl Preparation of adenine. Trihydrochloride (Compound 18) The compound prepared in Example 8 was obtained from the compound obtained in Example 8 to give a white foamy solid (yield, yield: 57.45%).

'HNMRCCDsOD):

8.37(S,1H), 5.65-5.91(m,4H), 4.57 (t,J=4.89Hz, 2H), 4.11(m,2H), 4.08(d, J=8.22Hz, 2H), 4.02(t , J = 4.89 Hz, 2H), 2.14-2.21 (m ₅ 2H), 1.02-1.16 (m, 12H). ESI-MS: 532.1 (M+H)+. Example 19: ( 2S, 2' S ) -9-ί2-oxime, 0'-biguanide (2-amino-4-mercaptoyloxy)methylene 1phosphonomethoxy 1 ethyl} Preparation of adenine. Trihydrochloride [Compound 19) Using the compound prepared in Example 9 as a starting material,yield to give a white foamy solid (yield: 90.74%).

¹ H NMR (CD ₃ OD): 5 = 8.42 (s, lH) ₅ 8.38 (s, lH), 5.85-5, 73 (m, 4H), 4.56 (t, J = 5.13 Hz, 2H), 4.18 (m) , 2H), 4.09 (d, J = 8.43 Hz, 2H), 4.02 (t, J = 4.76 Hz, 2H), 1.71-1.86 (m ₅ 6H), 1.01 (m, 12H). Example 20: ( 2S, 2' S ) -9-ί2-ΓΟ, 0'-bis((2-amino-3-methylpentanoyloxy)methylene 1phosphonomethoxy 1 ethyl} Preparation of adenine. Trihydrochloride (Compound 20) Using the compound prepared in Example 10 as a starting material, m.p. ^I H NMR (CD ₃ OD): 5 = 8.41 (s, lH), 8.36 (s, lH), 5.73-5.89 (m, 4H), 4.56 (t, J = 5.13 Hz, 2H), 4.18 (m, 2H) ), 4.08 (d, J = 8.07 Hz, 2H), 4.0 l (t, J = 5.14 Hz, 2H), 2.05 (m, 2H), 1.32-1.61 (m, 4H), 0.97-1.06 (m, 12H) ). Example 21: ( 2S, 2' S ) -942-"0,0'-bis"(2-tert-butoxyamino-3-methylbutyryloxy)ethyl 1phosphonomethoxy 1 Preparation of ethyl i-adenine (Compound 21)

21.1 : Preparation of ( 1S ) -tert-butyl-1-anthracene (2-hydroxyethoxy)carbonyl 1-2-methylpropyl carbamate)

N-tert-butoxycarbonyl L-proline (0.22 g, 1 mmol), ethylene glycol (0.06 g, 1 mmol), placed in 15 ml of dry dichloromethane, cooled to 10 ° C in an ice-water bath, fractionated Add hydrazine, hydrazine-diguanamine pyridine (0.122 g, lmmol), stir the system for 15 minutes, slowly add dropwise a solution of dicyclohexylcarbodiimide (0.22 g, 1.1 mmol) in 10 ml of dichloromethane, add After completion, the reaction temperature was naturally raised to room temperature for 24 hours. The insoluble material in the system was filtered, and the solvent was evaporated. The residue was dissolved in ethyl acetate (10 ml), and stood at low temperature (-10 ° C), and filtered, and the filtrate was 2×5 ml of 1 M aqueous potassium hydrogen carbonate, water and 5%. The mixture was washed with sodium carbonate, dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated. 1-[(2-Hydroxyethoxy)carbonyl]-2-mercaptopropylcarbamate (a) 0.167 g, Yield: 76.95%.

'H MRCCDCls): 5.15 (d ₅ J=8.43 Hz ₅ IH), 4.20-4.27 (m, 3H), 3.77 (t, J=4.59 Hz, 2H), 3.24 (brs, IH) 1.81 (m, IH) , 1.41 (s, 9H), 1.21-1.13 (m, 2H), 0.85-0.91 (m ₅ 6H). 21.2: Preparation of dichloro 9-fluorene 2-(phosphonomethoxy)ethyl 1 adenine (b) Oxalyl chloride (0.54 ml, 6.28 mmol) was slowly added dropwise to the mixture containing 9-[2-(phosphonooxyl) Base ethyl) adenine (0.50 g, 1.8 mmol), N,N-diethyl decylamide (0.20 ml, 1.9 mmol) in 14 ml of dichloromethane, refluxed for 3 hrs. Quenching, to TLC detection of diclonal conversion is complete. The system was cooled to room temperature, and concentrated under reduced pressure. EtOAc m. The resultant was dissolved in 2 ml of dry dichloromethane, cooled to 0 ° C in an ice salt bath, and 0.3 ml of pyridine was slowly added thereto, and kept at a low temperature (served below 0 ° C).

21.3: ( 2S, 2' S ) -9-{2-"0,0'-biguanide (2-tert-butoxyamino-3-methylbutyryloxy)ethyl 1-phosphonomethoxy Preparation of 1-ethyladenine (Compound 21) tert-Butyl 1-[(2-hydroxyethoxy)-based]-2-mercaptopropylaminodecanoate (a) (0.94 g, 3.6 mmol) Triethylamine (1.50 ml, 10.78 mmol) was dissolved in 6 ml of dry dichloromethane, and the system was cooled to 0 ° C with an ice salt bath, and dichloro 9-[2-(phosphonodecyloxy) was slowly added dropwise. Ethyl adenine (b) in dichlorosilane solution, after completion, the reaction was kept for 1 hour, and then slowly raised to room temperature for 4 hours. The solution was washed with 3×1 ml of water, 2×mlll% of citric acid and saturated saline, respectively. The magnesium ruthenate was dried, filtered, and the filtrate was concentrated. The residue was purified eluted eluted eluted eluted eluted elution

¹ H NMR (CDC1 ₃ ): 8.36 (s, lH), 8.09 (s, lH), 6.21 (brs, 2H), 5.25-5.41 (m, 2H), 4.45 (t, J = 6.25 Hz, 2H), 4.11 -4.36(m,10H), 3.97(t,J=5.51Hz ₅ 2H), 3.82(d, J=9.35Hz, 2H), 2.02-2.18(m,2H), 1.42(s,18H), 0.96( d ₅ J=6.41 Hz,

6H), 0.82 (d ₅ J = 6.59 Hz, 6H). EI-MS (m/e): 759, M+. Example 22: ( 2S, 2' S ) -942-"0,0'-bis"(2-tert-butoxyamino-3-phenyl)propionyloxy 1ethyl 1phosphonylmethyl group Preparation of ethyl adenine (compound 22)

°%vzz :古^ '

^^WWW ^) J^-.OOJ-3)-6- (sz 's^) u ^ ^ξΐ

'(ΗΐΛπ)£ς·ε-ςε·ε

'(He 3⁄4 98'ε-6//ε K

°%ΐΐ7·π :古^

' ⁰¹

ΙΖ

' ^^^ , solution -1 丄-

Z'99S : SH-IS3 '(H8t' ^s )8£"I '(Η )Π·ε_86 \ΉΖ 3⁄408"8=£ ^£ Ρ)ΐ8·£ 5

°%L6-£l :

Good'嗲

C99000/9001N3/X3d llfTOl/IOOi O N-tert-butoxyl L-leucine was used as a starting material to give a pale yellow foamy solid (yield: 8.47%).

¹ H NMR (CDC1 ₃ ): 8.36 (s, lH), 8.04 (s, lH), 6.24 (brs, 2H), 5.25-5.40 (m, 2H), 4.24-4.42 (m, 12H), 3.94 (m, 2H), 3.85 (d, J=8.47Hz, 2H), 1.44-1.59 (m, 6H), 1.42(s,18H), 0.9 l(t, J=6.59Hz, 12H). EI-MS(m/ e): 787, M+. Example 26: ( 2S, S ) -9-{2-"0,0'-biguanide (2-amino-3-methylbutanoyloxy)ethyl 1phosphonomethoxylethyl) gland Preparation of Trihydrochloride (Compound 26) Using the compound prepared in Example 21 as a starting material, a procedure similar to that of Example 11 was afforded to afford white white solid (yield: 13.

¹ H NMR (CD ₃ OD): 8.41 (s, lH), 8.36 (s, lH), 4.54 (t, J = 4.76 Hz, 2H), 4.40-4.47 (m, 4H), 4.3 l (m, 4H) , 3.98-4.02 (m, 6H), 2.30-2.33 (m, 2H), 1.04-1.16 (m, 12H). EI-MS (m/e): 559, M+. Example 27: ( 2S, S ) -942-"0,0'-bis"(2-amino-3-phenylpropanoyloxy)ethyl 1phosphonyloxyl 1ethyl} adenine. Preparation of the hydrochloride salt (Compound 27) The title compound was obtained from the compound obtained in Example 22, and was obtained in the same manner as in Example 11 to give a white semi-solid 0.106 g, yield: 91.51%.

¹ H NMR (CD ₃ OD): 5 = 8.37 (s, lH) ₅ 8.35 (s, lH), 7.25-7.36 (m, 10H), 4.5 l (t, J = 5.09 Hz, 2H), 4.27-4.3 l (m, 6H), 4.22-4.26 (m, 4H), 3.98-4.0 l (m, 4H), 3.16-3.28 (m, 4H), ESI-MS: 656.3 (M+H) + Example 28: ( 2S, 2' S ) -942-"0,0'-bis[(2-pyrrolidinyloxy)ethyl 1-phosphonomethoxy-1-ethyl}adenine. Trihydrochloride (Compound 28 Preparation The compound prepared in Example 23 was used as a starting material, and was obtained in a procedure similar to the method of Example 11 to give a white semi-solid, 0.106 g, yield: 91.51%.

¹ H NMR (CD ₃ OD): 5 = 8.43 (s ₅ lH), 8.39 (s, lH), 4.49-4.55 (m, 4H), 4.52 (m, 2H), 4.11 (m, 4H), 3.99- 4 , 01 (m, 4H), 3.37-3.43 (m, 4H), 2.41-2.45 (m, 2H), 2.06-2.19 (m, 6H). ESI-MS: 556.2 (M+H)+. Example 29: ( 2S, 2' S ) -9-ί2- "0,0'-bis"(2-aminopropanoyloxy)ethyl 1 phosphonomethoxymethoxyethyl} adenine. Preparation of the acid salt (Compound 29) Using the compound prepared in Example 24 as a starting material, a procedure similar to that of Example 11 afforded a white solid semi-solid 26 mg, yield: 77.65%.

¹ H NMR (CD ₃ OD): 5 = 8.42 (s, lH), 8.38 (s, lH), 4.55 (t, J = 5.08 Hz, 2H), 4.43 (t, J = 4.41 Hz, 2H), 4.29- 4.32 (m, 4H), 4.18 (q, J = 7.14 Hz, 2H), 4.01 (m, 4H), 1.56 (d, J = 7.28 Hz, 6H). EI-MS (m/e): 503, M+. Example 30: ( 2S, 2' S ) -9-ί2-ΓΟ, 0'-bis((2-amino-4-methylpentanoyloxy)ethyl 1phosphonylmethoxy 1ethyl adenine Preparation of Trihydrochloride (Compound 30) Using the compound prepared in Example 25 as a starting material, a procedure similar to that of Example 11 afforded a pale yellow semi-solid 46 mg, yield: 81.45%.

¹ H NMR (CD ₃ OD): S = 8.44 (s, lH), 8.41 (s, lH), 4.57 (m, 2H), 4.31 (m, 4H), 4.11 (m, 4H), 4.08-4.1 l ( m, 4H), 4.02 (d, J = 7.42 Hz ₃ 2H), 1.71-1.85 (m, 6H), 0.98 (t, J = 5.76 Hz, 12H), EI-MS (m/e): 587, M+ . Example 31: Determination of in vitro antiviral activity

1, try ^ r method: (1) Cytotoxicity assay The inhibitory effect of the drug on the growth of HepG 2215 was tested by 3-(4, 5-dimethylthiazol-2-yl)-2 ₅ 5-diphenyl tetrazolium bromide assay (MTT). A bottle of HepG 2215 cells was taken and digested with trypsin to prepare a single cell suspension. After counting, the cell concentration was adjusted to 2 x 104 cells/ml, and added to a 96-well culture plate. Place in a cell culture incubator and incubate overnight at 37 ° C, 5% CO 2 . After the supernatant was aspirated, DMEM medium (5% fetal bovine serum) containing different concentrations of the drug was added. After 9 days of action, 10 μM of hydrazine was added to each well and incubation was continued for 4 hours. The supernatant was carefully aspirated, 150 l of DMSO was added to each well, and after shaking gently, the OD value at 570 nm was measured with a microplate reader.

(2) Inhibition test for hepatitis B virus-DNA (HBV-DNA) a) Cellular drug treatment A bottle of HepG 2215 cells was prepared by trypsinization to prepare a single cell suspension, and the cell concentration was adjusted to 2x104 cells/ml. Add to a 24-well cell culture plate (1 ml/well). 37. C, 5% C02 culture overnight. The 24-well cell culture plate was taken out, and the supernatant was aspirated, followed by the addition of five 5-fold dilutions of the drug, and the positive control drug. The culture was continued, and the medium containing the drug was changed every 3 days, and the supernatant of each well was collected on a ninth day into a centrifuge tube - frozen at 20 ° C for use. b) Fluorescence quantitative PCR reaction serum samples (lOOul) were placed in the lysate (1 mmol/L Tris-Hcl, pH 8.0, 10 mmol/L Nacl, O.lmmol/L EDTA, 0.5% SDS, 0.8 mg/ml proteinase K) 37 Incubate at °C for 5 h, then extract twice with phenol chloroform and chloroform, and then precipitate with ethanol. Dissolved in 50 μl of water for PCR amplification.

2 ul of viral DNA was placed in a 48 μl reaction mixture, including 5 mmol/L MgCl2, 0.2 mmol/L 2.5 U Gold Taq polymerase per dNTP, 0.2 U UNG enzyme and Each was 0.4 mmol/L and the probe was 0.15 mmol/L. After 5 min at 37 ° C, the cells were denatured at 95 ° C for 3 min and 30 s, 94 ° C for 20 s, and 60 ° C for 40 s (fluorescence signal detection) for 41 cycles, and finally stored at 4 ° C. The Taqman probe sequence used was detected: 5TAM-CCAGCAGCGCCTCCTCCTGC-3 'TAMARA; Primer sequence: Forward primer: 5'-CCC TCAGGCTCAGGGCATA-3 ', Reverse primer: 5'- CTTCCTGACTGCCGATTGGT-3.

2. Test cell line:

HepG 2215 cells, cited in the Molecular Virus Laboratory of Fudan University. The cell line is obtained by transfecting the receptor cell HepG2 with two head-to-tail HBV DNA whole gene recombinant plasmids, which can stably secrete HBsAg, HBeAg and intact Dane particles in vitro, and can also produce a large number of replication intermediates ( RI). The cells were cultured in DMEM containing 10% fetal bovine serum.

3. The positive control group was adefovir Dipivoxil.

4. Each compound inhibits EC ₅ by HBV-DNA in HepG2.2.15 cells. The cytotoxic CC _5Q and the SI value of the action selection index are shown in Table-2. Table-2 Inhibitory effect of test compound on HBV-DNA in HepG2.2.15 cells Compound No. ^a EC ₅₀ (Mm) ^b CC ₅₀ (MM) ^C SI

1 5.87 269 45.93

5 0.25 818 3176.47

6 6.63 3583 540.57

7 11.59 2303 198.96

11 0.095 6636 69523.81

13 0.752 28712 38167.17

14 0.208 10984 52727.27 15 0.096 795 8203.12

16 0.946 18939 20000.00

17 0.211 3409 16129.03

18 0.304 3378 11094.52

19 0.0655 6318 96416.18

20 0.34 8560 25111.11

21 270 454 1.68

22 93.18 217 2.33

23 5.87 19393 3303.23

26 1.31 2587 1963.21

27 0.31 2590 8142.85

28 13.33 6242 468.18

29 12.57 1840 146.38

30 1.00 1128 1128 Adefovir 0.517 540 1044.48 a. EC ₅ . : Half effective concentration b. CC ₅ . : half cytotoxic concentration c. SI: interaction selectivity index (CC _5G /EC ₅₀ )

From Table 2, it is understood that the compounds claimed in the present invention have similar or better anti-HBV activity and action selectivity index to the positive control adefovir dipivalate, indicating that they have a better therapeutic index.

Claims

Rights request

A class of bismuth compound bisphenols represented by the following formula (I): and pharmaceutically acceptable salts thereof:

among them,

Amino group;

An amino-protected or free L-form amino acid;

n is 0 or 1;

X is 0 or 8.

The quinone diamino acid ester according to claim 1 or a pharmacologically acceptable salt thereof, wherein the quinone diamino acid ester is selected from the group consisting of the following compounds:

(1) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxymethylamino-3-methylpentanoyloxy)ethyl]phosphonohydrazide Alkyl adenine;

(2) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-acetoxy)ethyl]phosphonomethoxy]ethyl} gland嘌呤

(3) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxy-oxoamino-3-indolylbutanoylthio)ethyl]phosphonohydrazideoxy Ethyl}adenine;

(4) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-3-phenylpropionylthio)ethyl]phosphonomethoxy] Ethyl}adenine;

(5) (2S, 2' S ) -9-{2-[0,0'-bis[(1-tert-butoxy-based 2-pyrrolidinoylsulfonyl)ethyl]phosphonyloxyloxy Ethyl}adenine;

(6) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-4-mercaptovalerylthio)ethyl]phosphonocarbonyloxy] Ethyl}adenine;

(7) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-3-mercapto-valerylthio)ethyl]phosphonomethoxy Ethyl}adenine;

(8) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxymethylamino-3-indolylbutanoyloxy)phosphonium]phosphonohydrazide Alkyl]ethyl}adenine;

(9) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-Butoxycarbonylamino-4-methylpentanoyloxy) fluorenyl]phosphonohydrazide Alkyl adenine;

(10) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-3-mercaptoyloxy)methylene]phosphonoyl Alkyl]ethyl}adenine;

(11) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-mercaptoyloxy)ethyl]phosphonocarbonyloxy]ethyl} Adenine. trihydrochloride;

(12) (2S, 2' S) -9-{2-[0,0'-bis[(2-aminoacetoxy)ethyl]phosphonomethoxy]ethyl} adenine. Trihydrochloride Salt

(13) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-indolylbutanoylthio)ethyl]phosphonyloxy]ethyl} adenine .

(15) (2S, 2' S) -9-{2-[0,0'-bis[(2-pyrrolidinylthio)ethyl]phosphonomethoxy]ethyl} adenine. Acid salt

(16) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-4-mercaptoylthio)ethyl]phosphonooxyloxy]ethyl} gland三.Trihydrochloride;

(17) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-methylpentanoylethyl)phosphonyloxy]ethyl} adenine. Trihydrochloride

(19) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-4-mercaptoyloxy)methylene]phosphonomethoxy]ethyl } adenine. trihydrochloride;

(20) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-methylpentanoyloxy)indolyl]phosphonomethoxy]ethyl } adenine. trihydrochloride;

(21) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxyamino)-3-mercaptobutyryloxy)ethyl]phosphonomethoxy Alkyl adenine;

(22) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-Butoxycarbonylamino-3-phenyl)propanoyloxy]ethyl]phosphonomethoxymethoxy Adenine

(23) (2S, 2' S ) -9-{2-[0,0'-bis[(1-tert-butoxycarbonyl-2-pyrrolidinoyloxy)ethyl]phosphonohydrazide Alkyl adenine;

(24) (2S, 2'S)-9-{2-[0,0'-bis[(2-tert-butoxymethylaminopropionyloxy)ethyl]phosphonomethoxy]ethyl} Adenine

(25) (2S, 2' S) -9-{2-[0,0'-bis[(2-tert-butoxycarbonylamino-4-mercaptoyloxy)ethyl]phosphonomethoxy Alkyl adenine;

(26) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-methylbutyryloxy)ethyl]phosphonyloxyl]ethyl} Adenine. trihydrochloride;

(27) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-3-phenylpropanoyloxy)ethyl]phosphonocarbonyloxy]ethyl} Adenine. trihydrochloride;

(29) (2S, 2' S) -9-{2-[0,0'-bis[(2-aminopropanoyloxy)ethyl]phosphonomethoxy]ethyl} adenine. Acid salt

(30) (2S, 2' S) -9-{2-[0,0'-bis[(2-amino-4-mercaptoyloxy)ethyl]phosphonocarbonyloxy]ethyl} Adenine. Trihydrochloride.

The bismuth compound diamino acid ester according to Claim 1 or a pharmacologically acceptable salt thereof, wherein the pharmaceutically acceptable salt is: the quinone diamino acid ester and hydrochloric acid, hydrobromic acid, a mineral acid salt formed by hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid; with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, An acid salt formed from picric acid, methanesulfonic acid or ethanesulfonic acid; an acid addition salt formed with an acidic amino acid of aspartic acid or glutamic acid; or a salt formed with an inorganic base of sodium, potassium, calcium or aluminum Ammonium salt, guanamine salt, ethylamine salt, ethanolamine salt; or a salt formed with a basic amino acid of lysine, arginine or ornithine. 4. A method of preparing the bis-amino acid ester of the steroid of claim 1 comprising the steps of:

(1) N-tert-butoxycarbonyl amino acid and 2-bromoethanol are reacted in an aprotic solvent in the presence of dicyclohexylcarbodiimide and hydrazine, hydrazine-dimethylaminopyridinium to give hydrazine-tert-butoxycarbonyl L-amino acid bromoethyl ester; or

The Ν-tert-butoxycarbonyl L-amino acid is reacted with isobutyl chlorodecanoate, hydrazine-hydrazinomorpholine and hydrogen sulfide gas to obtain hydrazine-tert-butoxycarbonyl L-aminothiocarboxylic acid, and then 2-Dibromoethane is reacted in an aprotic solvent in the presence of a strong base to obtain Ν-tert-butoxycarbonyl L-aminothiocarboxylic acid-2-bromoethyl ester;

Chlorochloro chlorosulfonate and Ν-tert-butoxycarbonyl L-amino acid are reacted in a two-phase system in the presence of a phase transfer catalyst, tetra-n-butylammonium hydrogen sulfate, to obtain a ruthenium-tert-butoxycarbonyl L-amino acid. Methyl ester

(2) various Ν-tert-butoxycarbonyl L-amino acids or L-amino thiocarboxylates and 9-[2-(phosphonomethoxy)ethyl]adenine in a polar aprotic solvent, The product is obtained by reacting hydrazine, Ν'-dicyclohexyl-4-morpholinyl-hydrazine or 1,8-diazabicyclo[5,4,0]undec-7-ene as a base;

(3) The product obtained in the above step (2) is reacted in a polar or non-polar solvent in the presence of hydrogen chloride-saturated 1,4-dioxane or acetyl chloride/methanol to give a product;

(4) The product obtained in the step (3) is prepared into a corresponding pharmaceutically acceptable salt according to a usual method as needed.

5. A method of preparing a compound of claim 1 comprising the steps of: (1) ⁹ _[ ² _ (phosphonodecyloxy) ethyl] adenine is reacted in an inert solvent in the presence of a halogenating agent oxalyl chloride and a catalyst hydrazine, Ν'-diethylformamide to give 9-[ a dichlorophosphonate of 2-(phosphonomethoxy)ethyl]adenine;

(2) Ν-tert-butoxylate L-amino acid and ethylene glycol are reacted in an aprotic solvent in the presence of dicyclohexylcarbodiimide and hydrazine, hydrazine-diaminoamidopyridine to give hydrazine-tert-butyl Oxycarbonyl N-amino acid-hydroxyethyl ester;

(3) 9-[2-(phosphonomethoxy)ethyl]adenine dichlorophosphonate with Ν-tert-butoxycarbonyl L-amino acid-hydroxyethyl ester in an inert solvent in pyridine The reaction is carried out in the presence of triethylamine to obtain a product;

(4) The product obtained in the step (3) is reacted in a polar or non-polar solvent in the presence of hydrogen chloride-rich 1,4-dioxane or acetyl chloride/nonanol to obtain the corresponding compound;

(5) The product obtained in the above step is prepared into a corresponding pharmaceutically acceptable salt according to a usual method as needed.

6. A pharmaceutical composition comprising at least one steroid bi-amino acid ester of claims 1 to 3 as an active ingredient, and a pharmaceutically acceptable salt thereof, said compound being capable of binding at least one pharmaceutically acceptable Excipient or carrier.

7. Use of a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment of a viral infectious disease.

8. Use according to claim 7, characterized in that the viral infectious disease is an infectious disease caused by hepatitis B virus and HIV.