The preferred acceptable organic acid of medicine comprises cholic acid, Chenodiol, ursodesoxycholic acid, Deoxycholic Acid, tartrate, toxilic acid, fumaric acid, particularly fumaric acid.

Preferred counter ion are fumarate ions.

Formula III compound is salt.

Suitable pharmaceutically acceptable solvate is hydrate.

In addition, the present invention also provides the preparation method of formula III and/or pharmaceutically acceptable solvate.This method comprises formula I compound:

With counter ion II defined above^--source reaction, after this if necessary, then prepares its pharmaceutically acceptable solvate.

Suitable counter ion II^--source is pharmaceutically acceptable organic acid.

Preferred source of counter ions is fumaric acid.

Formula I compound and counter ion II^--reaction between source is normally carried out under conventional salt-forming condition, for example, in solvent, be generally C1---C4 alkanol solvent as ethanol, can provide under the arbitrary temp that generates required suitable speed, conventionally in the temperature raising for example at the temperature of solvent refluxing, be conveniently molar weight approximately to wait but preferably by slightly excessive counter ion II^--in the situation in source by formula I compound and counter ion II^--source is mixed then crystallization and is gone out required product (III).

The pharmaceutically acceptable solvate of formula III compound can be prepared by conventional chemical process.

Prepared by the method that formula I compound is described in can the patent documentation that be CN101575318B according to Chinese invention patent notification number.

Suitable source of counter ions is knownly through commercial sources, can easily obtain, fumaric acid for example, or can prepare required source of counter ions according to known method.

The stability of the compounds of this invention can be measured with conventional quantitative analysis method; For example the stability of solid chemical compound can be measured with the stability test of accelerating, for example dsc (DSC), thermo-gravimetric analysis (TGA) and the test of the thermoisopleth in intensification.This test comprises room temperature storage test.(in wherein during known under temperature and humidity control condition storage test compound).The quantitative analysis of test compound is before storage period, in storage period or after storage period.Stability with respect to suitable reference standard determination test compound.

As mentioned above, compound of the present invention is compared with corresponding free alkali, and it has significantly high solvability in water.The ordinary method of measuring like this stability of the compounds of this invention in the aqueous solution be included in known temperature condition and known during in mensuration in the aqueous solution of test compound, be settled out the degree of parent free alkali, we find that formula III compound demonstrates good aqueous stability.II wherein particularly^--the formula III compound of the fumaric acid radical representing is stable especially in the aqueous solution.II wherein that more surprised is^--the formula III compound of the fumaric acid radical representing is abnormal stablizing in the aqueous solution.

Described test compound quantitative analysis test can ordinary method, conventionally uses chromatography, and for example high pressure lipuid chromatography (HPLC) is carried out.

As mentioned above, compound of the present invention has practical therapeutic activity.

Therefore, the invention provides formula III compound and/or the pharmaceutically acceptable solvate as therapeutic active substance.

Like this, the invention provides as treatment and/or suppress hepatitis b virus infected formula III compound and/or pharmaceutically acceptable solvate.

Formula III compound and/or pharmaceutically acceptable solvate can himself form be used, and the form that preferably also can contain the pharmaceutical composition of pharmaceutically acceptable carrier is used.

Therefore, the present invention also provides a kind of pharmaceutical composition that contains formula III compound and/or pharmaceutically acceptable solvate and pharmaceutically acceptable carrier.

Term used herein " pharmaceutically acceptable " comprises compound, composition and the component to people and animal doctor's use, and for example, term " pharmaceutically acceptable salt " comprises the upper acceptable salt of animal doctor.

Suitable pharmaceutical composition is the composition of unit dosage, for example oral liquid, tablet, capsule, injection liquid, sprays.

Optimum pharmaceutical composition is oral liquid, sprays.

According to the convention on conventional medicine, carrier can comprise thinner, weighting agent, disintegrating agent, wetting agent, lubricant, tinting material, seasonings or other conventional additives.

Optimum composition is to be configured to unit dosage.

Conventionally, activeconstituents can aforementioned pharmaceutical compositions form be used.

The present invention also provides a kind of contain formula III compound and/or the application of pharmaceutically acceptable solvate on the medicine of production for treating and/or inhibition hepatitis B virus.

Provide embodiments of the invention below for further illustrating and describe in more detail the present invention.

Embodiment 1

4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylic acid, ethyl ester fumarate

By compound 4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylic acid, ethyl ester 5.12 grams (0.01mol) and fumaric acid 1.17 grams (0.01mol) are dissolved in 125 milliliters of the ethanol of boiling.This hot solution is through diatomite filtration, then Slow cooling under mild stirring, standing a few hours in the temperature environment of 0-5 ℃, separate out 4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester fumarate crystal, leach 4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylic acid, ethyl ester fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 6.28 grams of products.

Embodiment 2

By compound 4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl) 1.17 grams of 5.12 grams of-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylic acid, ethyl ester fumarates and fumaric acid are stirred to solid and all dissolve in 125 milliliters of ethanol refluxing.Add gac, this hot solution, through diatomite filtration, is cooled to room temperature in stirring.Standing a few hours in the temperature environment of 0-5 ℃, separate out 4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester fumarate crystal, leach 4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 6.27 grams of products.

The present invention can summarize with other the specific form without prejudice to spirit of the present invention or principal character.Therefore,, no matter from which point, above-mentioned embodiment of the present invention all can only think explanation of the present invention can not limit the present invention.

Claims

1.4-(the chloro-4-fluorophenyl of 2-)-6-(morpholine-1-ylmethyl)-2-(2,4,6-trifluorophenyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylic acid, ethyl ester (I) fumaric acid (II) salt (III);

｛（Ⅰ）H｝+Ⅱ^ˉ

（Ⅲ）

2. the compound of claim 1 is treated hepatitis B and/or slows down the application in hepatitis B virus infective medicament in preparation.