CN1197869C - Aminoglycoside compound having antiviral activity - Google Patents

Abstract

A chemosynthetic method is used for obtaining compounds in a formula (I) and acid salt, wherein R1 and R2 represent (C (=NH)NH2) or COR 3, R3 represents one or a plurality of base groups of guanidino alkyl, amino alkyl, aminoguanidine base alkyl, etc., and base groups represented by R1 and R2 can be different as well as the same. The acid salt is formed by the compounds which can be accepted by pharmacology. Acids comprise the inorganic acids of hydrochloric acids, sulphuric acids, hydrogen bromide, phosphoric acids, carboxylic acids, etc. and the organic acids of formic acids, acetic acids, citric acids, lactic acids, fumaric acids, tartaric acids, gluconic acids, etc. The compounds have the favorable effect of inhibiting HIV viruses.

Description

Aminoglycoside compound with antiviral activity and preparation method thereof

The present invention relates to a series of new aminoglycoside compounds and their pharmaceutically acceptable acid salts; the present invention also relates to the preparation method and production method of this series of new compounds; Medicinal use.

The series of new compounds belong to water-soluble aminoglycoside compounds and are derivatives of α, α-trehalose.

RNA viruses are closely related to many human diseases, such as AIDS and dengue fever caused by human immunodeficiency virus (HIV) infection. All over the world, due to the rapid mutation of HIV virus and the lack of effective therapeutic drugs, AIDS is spreading rapidly. The development of effective drugs for the treatment of HIV infection has become the most challenging problem in the world.

Most of the anti-HIV drugs currently used in clinical and research are enzyme inhibitors that target proteins such as reverse transcriptase (RT), protease (PR) and integrase (IN). drug resistance. However, the special complex space and sequence structure of RNA make it have the characteristics of high sequence conservation and conformational variability. Drugs targeting RNA can overcome the defect that enzyme preparations are prone to drug resistance, and thus become a more promising method for designing antiviral drugs. Favorable new target.

Trehalose is a double pond widely distributed in nature. It can be used as a structural component and provide energy in organisms. Moreover, it is an anti-stress metabolite of many organisms and has protection for cells and biological macromolecules. effect. Recent studies have revealed that a key link in the life cycle of HIV is the regulation of TAR-RNA replication by Tat protein, and the blockage of this process will lead to the blockage of HIV virus replication. Many studies have shown that aminoglycoside compounds such as Gentamicin, Kanamycin, Neomycin, etc. can produce stronger binding ability and certain recognition ability (Litovchick, A, et al, Biochemistry 2000, 39, 2838; FEBS Letters., 1999, 445, 73), in which some compounds can inhibit the specific combination of Tat protein and TAR-RNA and show certain anti-HIV virus activity, which is a class of extremely developed Promising anti-HIV prodrugs.

To this end, we designed and synthesized a series of aminoglycoside compounds with trehalose as the parent based on the characteristics of the interaction between Tat protein and TAR-RNA and the molecular recognition of the interaction between small molecule compounds and RNA, and studied their effects on Tat The effect of the protein on the regulation of TAR-RNA and the inhibition of HIV virus replication were evaluated, and the results showed that the generalization has obvious anti-HIV replication effect in vitro.

The present invention relates in particular to compounds of formula (I) and to the pharmaceutically acceptable acid salts formed by these compounds.

Formula (I)

in:

Among them: R ₁ and R ₂ represent (C(=NH)NH ₂ ) or COR ₃ , R ₃ represents one or several groups of guanidinohydrocarbyl, aminohydrocarbyl and aminoguanidinohydrocarbyl, etc., R ₁ and R ₂ The represented groups may be the same or different.

This patent includes the above-represented compounds and the pharmaceutically acceptable acid salts formed by these compounds.

- "hydrocarbyl" is defined as straight-chain or branched, saturated or unsaturated; cyclic or acyclic; aromatic or non-aromatic; heterocyclic or non-heterocyclic;

- "Guanidinohydrocarbyl" is defined as a hydrocarbyl group containing guanidino at the end or middle carbon, and the number of guanidino can be 1-3, where the meaning of hydrocarbyl is as defined above;

——"Aminohydrocarbyl" is defined as the terminal or middle carbon of the hydrocarbon group with amino groups attached, the number of amino groups attached can be 1-3, and the hydrogens attached to the amino groups can be arbitrarily replaced by one or two straight-chain or branched Chain (C ₁ -C ₆ )hydrocarbyl. Here the meaning of hydrocarbyl is as defined above;

——"Aminoguanidinyl hydrocarbon group" is defined as the terminal or middle carbon of the hydrocarbon group with both amino and guanidino groups attached. The amino and guanidino groups are not connected to the same carbon at the same time. 3. The hydrogen attached to the amino group can be optionally replaced by one or two straight-chain or branched (C ₁ -C ₆ ) hydrocarbon groups. Here the meaning of hydrocarbyl is as defined above;

The salts of pharmaceutically acceptable acids refer to the salts of inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, carbonic acid and organic acids such as formic acid, acetic acid, citric acid, lactic acid, fumaric acid, tartaric acid and gluconic acid. Water or salts without water of crystallization;

As an optimization, the substituent group involved in the present invention is changed to R ₁ =R ₂ =COR ₃ , R ₃ represents a hydrocarbon group with a guanidine group at the end of the group, the number of guanidine groups can be 1-3, and the hydrocarbon group Can be C ₁ -C ₆ straight or branched chain alkyl and alkenyl, C ₁ -C ₆ straight or branched alkoxy, C ₁ -C ₆ straight or branched aminoalkyl, containing Phenyl and substituted phenyl substituents and C ₁ -C ₆ straight or branched chain alkyl and alkenyl groups containing heterocyclic and substituted heterocyclic substituents.

As an optimization, the substituent groups involved in the present invention are changed as follows: R ₁ =H, R ₂ =COR ₃ , R ₃ represents a hydrocarbon group with a guanidino group at the end of the group, and the number of guanidine groups can be 1-3 The hydrocarbon group can be C ₁ -C ₆ straight chain or branched chain alkyl and alkenyl, C ₁ -C ₆ straight chain or branched chain alkoxy, C ₁ -C ₆ straight chain or branched chain aminoalkane C ₁ -C ₆ straight or branched chain alkyl and alkenyl groups containing phenyl and substituted phenyl substituents and heterocyclic and substituted heterocyclic substituents.

As an optimization, the substituent group involved in the present invention changes as R ₁ =R ₂ =COR ₃ , R ₃ represents a hydrocarbon group with an amino group attached to the terminal or middle carbon, and the number of amino groups attached can be 1-3 , the hydrogen on the connected amino group can be arbitrarily substituted by one or two C ₁ -C ₆ straight chain or branched chain hydrocarbon groups, or not substituted, and the hydrocarbon group connected to the amino group can be a C ₁ -C ₆ straight chain Or branched chain alkyl and alkenyl, C ₁ -C ₆ linear or branched alkoxy, C ₁ -C ₆ containing phenyl and substituted phenyl substituents and heterocyclic and substituted heterocyclic substituents Straight chain or branched alkyl and alkenyl, phenyl and substituted phenyl, heterocyclic and substituted heterocyclic, etc.

As an optimization, the substituent groups involved in the present invention are changed to R ₁ =H, R ₂ =COR ₃ , R ₃ represents a hydrocarbon group with amino groups attached to the terminal or middle carbon, and the number of amino groups attached can be 1- 5, the hydrogen on the connected amino group can be arbitrarily substituted by one or two C ₁ -C ₆ straight chain or branched chain hydrocarbon groups, or not substituted, the hydrocarbon group connected to the amino group can be C ₁ -C ₆ Straight chain or branched chain alkyl and alkenyl, C ₁ -C ₆ straight chain or branched alkoxy, C ₁ -C containing phenyl and substituted phenyl substituents and heterocyclic and substituted heterocyclic substituents ₆ straight chain or branched alkyl and alkenyl, phenyl and substituted phenyl, heterocyclic and substituted heterocyclic, etc.

According to the invention, preferred compounds for formula (I) are:

is R ₁ =H; R ₂ =COR ₃

R ₂ =-CH ₂ NH ₂ ; -CH ₂ CH ₂ CH ₂ NH ₂ ; -CH ₂ N(C=NH)NH ₂ ; -CH ₂ CH ₂ CH ₂ N(C=NH)NH ₂ ; CH(NH _{2 ) CH2CH2CH2N} (C ₌ NH) _NH2

is R ₁ =R ₂ =COR ₃

R ₃ =-CH ₂ NH ₂ ; -CH ₂ CH ₂ CH ₂ NH ₂ ; -CH ₂ N(C=NH)NH ₂ ; -CH ₂ CH ₂ CH ₂ N(C=NH)NH ₂ ; CH(NH ₂ ) _{CH2CH2CH2N (} C=NH) _{NH2 ;}

is R ₁ =H;

R ₂ =-C(=NH)NH2

is R ₁ =R ₂ ;

R ₁ =-C(=NH)NH2

These compounds and the pharmaceutically acceptable acid salts formed by these compounds.

The preferred compounds and their addition salts with pharmaceutically acceptable acids form part of the complete content of the present invention.

According to the present invention, for the preparation method of the compound of formula (I), it is characterized in that using α, α-trehalose as raw material:

α,α-Trehalose

This preparation includes the following processes:

Trehalose was used as raw material to prepare bromotrehalose in anhydrous DMF solvent in the presence of Ph ₃ P and NBS as bromination agent.

Bromotrehalose can be reacted with acetic anhydride in the presence of anhydrous pyridine to prepare acetylated bromotrehalose.

Acetylated trehalose bromide is reacted with sodium azide in anhydrous DMF solution to obtain acetylated trehalose azide.

Acetylated azide trehalose is deacetylated in anhydrous methanol solvent under the action of a catalytic amount of sodium methoxide to obtain azide trehalose.

Azide trehalose, and use 10% Pd/C catalyst to carry out catalytic hydrogenation to obtain amino trehalose.

Amino trehalose can be reacted with S-methylisothiourea in aqueous solution under alkaline conditions to obtain guanidinotrehalose.

Amino trehalose in DMF solution, DCC condensation with Cbz-protected amino acid can obtain Cbz-protected amino acid-conjugated trehalose.

The Cbz-protected amino acid-conjugated trehalose was deprotected by catalytic hydrogenation with 10% Pd/C catalyst to obtain amino acid-conjugated trehalose.

Amino acid-conjugated trehalose reacts with S-methylisothiourea in aqueous solution under alkaline conditions to obtain guanidino acid-conjugated trehalose

The present invention also relates to a pharmaceutical composition, comprising at least one compound of formula (I) or a pharmaceutically acceptable acid salt formed by these compounds as an active ingredient, alone or in combination with one or more pharmaceutically acceptable, inert non-toxic excipients or carriers.

Among the pharmaceutical compositions according to the invention, particular mention may be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transdermal, nasal, rectal, translingual, especially tablets Or dragees, capsules, lozenges, suppositories, skin gels, injectable preparations, etc.

The compound of the present invention has obvious antiviral activity. A pharmaceutical combination containing at least one compound of formula (I) or a pharmaceutically acceptable acid salt formed by these compounds as an active ingredient compound can therefore be used for the treatment of viruses, etc., especially for the treatment of HIV virus.

Part of the compounds have been screened for the activity of inhibiting HIV-1 virus replication in vitro, and the results show that the compounds have certain activity of inhibiting HIV-1 virus replication.

The following examples are used to further illustrate the present invention but not to limit the present invention.

The starting materials and/or reagents used are known products or products prepared according to known procedures.

The structures of the compounds described in the examples and synthetic procedures were determined according to conventional spectroscopic techniques (infrared, UV, NMR, MS).

Example 1 Preparation of bromotrehalose

Dissolve 3 g of trehalose in 30 ml of anhydrous DMF, cool in an ice bath, add 5.7 g of NBS, stir until completely dissolved, add 8.5 g of Ph ₃ P in batches, stir at room temperature for 2 hours, heat up in an oil bath, and react at 50°C After 48 hours, 20 ml of methanol was added to terminate the reaction, DMF was evaporated under reduced pressure, the product was dissolved in water, and impurities were removed by extraction with chloroform, and the water layer was evaporated under reduced pressure to obtain a viscous liquid. The product is a mixture of monobromine and dibromine, which is ready for use.

Example 2 Preparation of acetylated trehalose bromide

Add the monobromine and dibromine substitution mixture obtained in Example 1 to a pre-mixed solution of 50 milliliters of anhydrous pyridine and 25 milliliters of acetic anhydride, stir and react at room temperature for 48 hours, pour into ice water, suction filter, fully wash with water, and dry , to obtain 6.8 grams of product, which is a mixture of monobromo and dibromotrehalose, separated by column chromatography to obtain a single monobromo and dibromotrehalose product.

Example 3 Preparation of monoacetylated trehalose azide

Dissolve 2.5 g of monobromotrehalose in 40 ml of anhydrous DMF, stir to dissolve, add 0.7 g of sodium azide, heat and stir, react at 90-100°C for 24 hours, filter to remove insoluble matter, and distill the filtrate to remove DMF under reduced pressure , dissolved in water, extracted with dichloromethane, the dichloromethane layer was dried overnight with anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain 2.2 g of a light yellow solid, which was monoacetylated trehalose azide, which was set aside.

Example 4 Preparation of Monoazide Trehalose

The monoacetylated azide trehalose obtained in Example 3 was dissolved in 65 ml of anhydrous methanol, a catalytic amount of sodium metal was added, the reaction was stirred at room temperature for 18 hours, 2 g of cation exchange resin was added to neutralize the reaction solution until pH = 6, and the resin was removed by filtration , and the solvent was distilled off under reduced pressure to obtain 1.12 g of white solid, which was trehalose monoazide.

The preparation of embodiment 5 monoamino trehalose

The monoazide trehalose obtained in Example 4 was dissolved in 10 ml of methanol, 10% Pd/C catalyst was added, hydrogen gas was introduced, hydrogenolysis was carried out at 4 atmospheres for 24 hours, the catalyst was removed by filtration, and the solution was evaporated to remove the solvent under reduced pressure to obtain 1.05 g of self-colored solid is monoamino trehalose.

Embodiment 6 monoguanidino trehalose

Add 100 mg of monoaminotrehalose obtained in Example 5 to an aqueous solution of 500 mg of S-methylisothiourea sulfate neutralized with ammonia water, stir to dissolve, heat, react at 80-90°C for 24 hours, and evaporate under reduced pressure The solvent and the residue were purified by reverse-phase silica gel column chromatography to obtain a white solid, 62 mg of monoguanidinotrehalose.

Example 7 Preparation of Cbz-protected aminoacetic acid monoconjugated trehalose

Dissolve 150 mg of monoaminotrehalose obtained in Example 5 in 5 ml of DMF, add 500 mg of Cbz-protected aminoacetic acid, stir to dissolve, add 500 mg of DCC in an ice bath, stir for 24 hours, remove insoluble matter by filtration, and evaporate the filtrate under reduced pressure The solvent and the residue were separated by reverse-phase silica gel column chromatography to obtain 160 mg of Cbz-protected aminoacetic acid-conjugated trehalose as a white solid.

Example 8 Preparation of mono-conjugated trehalose with aminoacetic acid

The Cbz-protected aminoacetic acid mono-conjugated trehalose obtained in Example 7 was dissolved in 5 ml of methanol, 10% Pd/C catalyst was added, hydrogen gas was introduced, hydrogenolysis was carried out at 4 atmospheres for 24 hours, the catalyst was removed by filtration, and the solution was evaporated under reduced pressure. After removing the solvent, 80 mg of white solid was obtained, which was glycine monoconjugated trehalose.

Example 9 Preparation of guanidinoacetic acid monoconjugated trehalose

Add 100 mg of aminoacetic acid monoconjugated trehalose obtained in Example 8 into 500 mg of S-methylisothiouronium sulfate aqueous solution neutralized with ammonia water, stir to dissolve, heat, and react at 80-90°C for 24 hours. The solvent was evaporated under pressure, and the residue was purified by reversed-phase silica gel column chromatography to obtain 75 mg of white solid, which was guanidinoacetic acid mono-conjugated trehalose.

Example 10 Preparation of arginine monoconjugated trehalose

Dissolve 150 mg of monoaminotrehalose obtained in Example 5 in 5 ml of DMF, add 500 mg of N ^α -nitro-N-benzyloxycarbonyl-arginine, stir to dissolve, add 500 mg of DCC in an ice bath, and stir for 24 hours. The insoluble matter was removed by filtration, the solvent was distilled off from the filtrate under reduced pressure, and the residue was separated by reverse-phase silica gel column chromatography to obtain 110 mg of N ^α -nitro-N-benzyloxycarbonyl-arginine monoconjugated trehalose as a white solid.

N ^α -nitro-N-benzyloxycarbonyl-arginine monoconjugated trehalose was dissolved in 5 ml of methanol, added with 10% Pd/C catalyst, fed with hydrogen, hydrogenolyzed at 4 atmospheres for 24 hours, filtered The catalyst was removed, and the solution was evaporated to remove the solvent under reduced pressure to obtain a white solid, which was 80 mg of arginine monoconjugated trehalose.

Example 11 Preparation of N ^α -nitro-N-benzyloxycarbonyl-arginine

Step A: N ^α -nitro-arginine preparation

Slowly add 100 g of L-arginine hydrochloride into 200 ml of concentrated sulfuric acid at room temperature, stir at room temperature to dissolve, and pump out HCl gas under reduced pressure until the reaction solution stops bubbling to obtain a clear solution. Slowly add 50 g of powdered ammonium nitrate under stirring, and after 15 minutes, depressurize to remove air bubbles, and pour the reactant into crushed ice while stirring to obtain an aqueous solution. The precipitate was washed several times with water, ethanol and ether, and dried. The product was recrystallized in water to obtain 98 g of the product, yield: 86.5%, melting point: 255°C (dec.).

Step B: Preparation of N ^α -nitro-N-benzyloxycarbonyl-arginine

5.8 grams of N ^α -nitro-arginine was dissolved in 26.4ml of 1N NaOH aqueous solution, in an ice-salt bath, 7 grams of benzyloxycarbonyl chloride and 26.4ml of 1N NaOH aqueous solution were added dropwise below 0°C, after the addition was completed, reacted for 1 hour, and used Adjust the pH to 2-3 with HCl to obtain an oily product, place it in the refrigerator to crystallize, filter, and recrystallize the product with methanol-water mixed solvent, yield: 52%, melting point: 127-128°C.

Example 13 Preparation of Trehalose Disubstituted Derivatives

Trehalose disubstituted derivatives can be prepared from the dibromotrehalose prepared in Example 2 in a similar manner to the monosubstituted derivatives.

Pharmacological studies of compounds of the present invention.

Example 12: In vitro experiment of inhibiting HIV-1 replication.

MT ₄ cells in good growth state were made into a cell suspension with a concentration of 40×10 ⁵ cells/ml, and 100 microliters per well were added to a 96-well plate. The drug to be tested was sterilized by filtration, serially diluted with RPMI1640 culture medium (1.0 μM, 0.5 μM, 0.25 μM, 0.125 μM, 0.0625 μM, 0.03125 μM), and 50 μL per well was added to a 96-well plate. Add 50 μL of HIV-1 with a titer of 100 TCID ₅₀ and 1000 TCID ₅₀ (tissue cultured infection dose) respectively, and make 4 duplicate wells for each combination of drug concentration and virus titer. Positive control (AZT+ _MT4 cells+HIV-1), negative control (water+ _MT4 cells+HIV-1), drug toxicity control (drug+ _MT4 cells) and blank control ( _MT4 cells+HIV-1 ). Cultured for 7 days at 37°C, 5% CO ₂ . The growth of the cells was regularly observed every day, 50 μL of fresh medium was added to each well on the third day of culture, and cytopathic changes (CPE) were observed on the sixth day.

All experiments were carried out in a biosafety level 3 (BSL-3) laboratory in accordance with the operating procedures and repeated twice. Calculate inhibition rate and IC ₅₀ .

Claims (12)

1. the formed salt of the compound of formula (I) and these compounds in pharmaceutically acceptable acid

Formula (I)

R ₁, R ₂Represent COR ₃, R ₃Represent a kind of of guanidine radicals alkyl, hydrocarbyl amino and amino guanidine radicals alkyl, R ₁, R ₂The group of representative can be the same or different

---" alkyl " is defined as C ₁-C ₆The alkane or the alkene of straight or branched

---" guanidine radicals alkyl " is defined as on the end of hydrocarbyl group or the middle carbon and contains guanidine radicals, and the quantity of guanidine radicals can be 1-3, and the implication of alkyl such as front define here

---" hydrocarbyl amino " is defined as on the end of hydrocarbyl group or the middle carbon and is connected with amino, and being connected with amino quantity can be 1-3, and the hydrogen that is connected on the amino can be arbitrarily by one or two straight or branched (C ₁-C ₆) alkyl; Here the implication of alkyl such as front define

---" amino guanidine radicals alkyl " is defined as on the end of hydrocarbyl group or the middle carbon and is connected with amino and guanidine radicals simultaneously, amino and guanidine radicals is not connected on the same carbon simultaneously, quantity amino and guanidine radicals can be respectively 1-3, and the hydrogen that is connected on the amino can be arbitrarily by one or two straight or branched (C ₁-C ₆) alkyl; Here the implication of alkyl such as front define.

The formed salt in pharmaceutically acceptable acid of compound of 2 formulas according to claim 1 (I) is meant that hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, carbonic acid mineral acid and formic acid, acetate, citric acid, lactic acid, fumaric acid, tartrate and gluconic acid organic acid form contains crystal water or does not contain the salt of crystal water.

3 formulas according to claim 1 or 2 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds is characterized in that R ₁=R ₂=COR ₃, R ₃Represent the end of group to contain the hydrocarbyl group of guanidine radicals, the quantity of guanidine radicals can be 1-3, and alkyl can be C ₁-C ₆Straight or branched alkyl and thiazolinyl.

4 formulas according to claim 1 or 2 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds is characterized in that R ₁=R ₂=COR ₃, R ₃Represent to be connected with amino hydrocarbyl group on end or the middle carbon, being connected with amino quantity can be 1-3, and the hydrogen that is connected on the amino can be arbitrarily by one or two C ₁-C ₆The alkyl of straight or branched replace, can not replace yet, connecting amino hydrocarbyl group can be C ₁-C ₆Straight or branched alkyl and thiazolinyl.

5 formulas according to claim 1 or 2 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds, they are R ₁=R ₂=COR ₃

R ₃＝-CH ₂NH ₂；-CH ₂CH ₂CH ₂NH ₂；-CH ₂N(C＝NH)NH ₂；-CH ₂CH ₂CH ₂N(C＝NH)NH ₂；CH(NH ₂)CH ₂CH ₂CH ₂N(C＝NH)NH ₂。

6 formulas according to claim 1 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds is characterized in that R ₁=H, R ₂=COR ₃, R ₃Represent the end of group to contain the hydrocarbyl group of guanidine radicals, the quantity of guanidine radicals can be 1-3, and alkyl can be C ₁-C ₆Straight or branched alkyl and thiazolinyl.

7 formulas according to claim 1 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds is characterized in that R ₁=H, R ₂=COR ₃, R ₃Represent to be connected with amino hydrocarbyl group on end or the middle carbon, being connected with amino quantity can be 1-5, and the hydrogen that is connected on the amino can be arbitrarily by one or two C ₁-C ₆The alkyl of straight or branched replace, can not replace yet, connecting amino hydrocarbyl group can be C ₁-C ₆Straight or branched alkyl and thiazolinyl.

8 formulas according to claim 1 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds, it is R ₁=H; R ₂=COR ₃R ₃=-CH ₂NH ₂-CH ₂CH ₂CH ₂NH ₂-CH ₂N (C=NH) NH ₂-CH ₂CH ₂CH ₂N (C=NH) NH ₂CH (NH ₂) CH ₂CH ₂CH ₂N (C=NH) NH ₂

9 formulas according to claim 1 (I) compound and the formed salt in pharmaceutically acceptable acid of these compounds, they are R ₁=H; R ₂=-C (=NH) NH ₂

The preparation method of 10 formulas (I) compound is characterized in that using α, and α-trehalose is as raw material (as figure below):

α, α-trehalose structure

Such compound comprises following process:

With the trehalose is raw material, in the dry DMF solvent, at Ph ₃P exists down, is bromizating agent prepared in reaction bromo trehalose with NBS

The bromo trehalose prepares acetylize bromo trehalose with acetic anhydride again under anhydrous pyridine participates in

Acetylize bromo trehalose obtains acetylize nitrine trehalose through reacting in anhydrous DMF solution with sodiumazide

Acetylize nitrine trehalose in the anhydrous methanol solvent, the deacetylated azide trehalose that obtains under the sodium methylate effect of catalytic amount

The azide trehalose carries out catalytic hydrogenation with the 10%Pd/C catalyzer, obtains amino trehalose

Amino trehalose under the alkaline condition, can get the guanidine radicals trehalose with the reaction of S-methyl-isothiourea in the aqueous solution

Amino trehalose carries out with the amino acid of Cbz protection that DCC contracts and the amino acid that can obtain the Cbz protection is puted together trehalose in DMF solution

The amino acid of Cbz protection is puted together trehalose and is carried out the catalytic hydrogenation deprotection with the 10%Pd/C catalyzer and obtain amino acid and put together trehalose

Amino acid is puted together trehalose in the aqueous solution, under the alkaline condition, can obtain guanidino-acid with the reaction of S-methyl-isothiourea and put together trehalose.

11 pharmaceutical compositions, comprise at least a according to claim 1 to 9 each formula (I) compound or these compounds formed at pharmaceutically acceptable hydrochlorate as activeconstituents,, inert pharmaceutically acceptable, nontoxic vehicle or carrier in conjunction with one or more.

12 compositions according to claim 11 is characterized in that it being the composition that is used for antiviral therapy.