CN102827206A - Pradefovir crystal - Google Patents
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- CN102827206A CN102827206A CN2012103443337A CN201210344333A CN102827206A CN 102827206 A CN102827206 A CN 102827206A CN 2012103443337 A CN2012103443337 A CN 2012103443337A CN 201210344333 A CN201210344333 A CN 201210344333A CN 102827206 A CN102827206 A CN 102827206A
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Abstract
The invention discloses a crystal of (+)-cis-9-(2-(4-((S)-(3-chlorphenyl)-2-oxygen-1, 3, 2-dioxo phosphorus heterocyclic hexa-ring-2-methylene)-1-ethyl) adenine mesylate (Pradefovir), a drug of the crystal, a preparation method of the crystal and the like.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field; Particularly; The present invention relates to (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } crystal and the medicine and the preparation method of VITAMIN B4 mesylate (Pradefovir).
Background technology
(+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } structure of VITAMIN B4 mesylate (Pradefovir) is suc as formula shown in (I):
This compound is the preceding drug compound of the Adefovir in 200510098771.X number disclosed preceding drug compound of Chinese patent, can be used for treatment or prevention of liver disease or metabolic disease, comprises hepatitis B etc.Yet prior art does not have open or enlightenment will be studied the crystallography of this compound.
And this compound carries out crystallization, and crystal distributes very complicated, and many crystallizations go out polycrystalline, are not easy to obtain monocrystalline.Yet; Through the long-term and arduous research of the inventor; In solvents and mixed solvent many as the existing astronomical figure, found that finally the acetonitrile of low levels or methanol in water can carry out effective crystallization to this compound, obtained monocrystalline; The curative effect that has not only kept original compound, and can bring such as the excellent properties that improves stability etc.
Summary of the invention
The object of the present invention is to provide new (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2-dioxy phospha six ring-2-methylene radical]-1-ethyl } crystal of VITAMIN B4 mesylate (Pradefovir).In addition, the present invention also provides this crystalline medicine and preparation method etc.
Particularly; In first aspect; The invention provides (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } crystal of VITAMIN B4 mesylate; It is characterized in that it has the X-ray powder diffraction shown in Fig. 1 or 2 basically.(+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } the VITAMIN B4 mesylate also claims Pradefovir, has suc as formula the structure shown in (I).
In this article, the crystal with X-ray powder diffraction as shown in Figure 1 basically is also referred to as the I N-type waferN, and the peak parameter of its X-ray powder diffraction is as shown in table 1 basically; Crystal with X-ray powder diffraction as shown in Figure 2 basically is also referred to as the I N-type waferN, and the peak parameter of its X-ray powder diffraction is as shown in table 2 basically.
It is various to be used for the crystalline solvent species in the prior art, and the mixed solvent of the solvent composition of different sorts and ratio can't be counted especially, and the crystallization practice is also stayed in experience basically, generally can't dope the crystal formation that crystallization goes out according to crystallization condition.And the inventor passes through the research long-term and arduous to Pradefovir, and has relied on some fortune, has found to be used for the mixed solvent prescription of crystallization Pradefovir finally.So; The crystal of preferred first aspect present invention be (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3,2 – dioxy phosphas, six ring-2-methylene radical]-the 1-ethyl } VITAMIN B4 mesylate crystalline in the acetonitrile of low levels or methanol in water.Wherein, the I N-type waferN is a crystalline in the aqueous solution of the acetonitrile of low levels; The II N-type waferN is a crystalline in the methanol in water of low levels.More preferably wherein, low levels is 1-10% (V/V), and more preferably 2-8% (V/V) is more preferably 3-7% (V/V), most preferably is 4-5.5% (V/V), like 4% (V/V) or 5.5% (V/V).
In addition, the inventor finds that the ratio of Pradefovir and mixed solvent also can influence the crystalline quality that crystallization goes out to a certain extent.So, further preferred in the crystal of first aspect present invention, and (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3; 2 – dioxy phosphas, six ring-2-methylene radical]-the 1-ethyl } mass volume ratio of VITAMIN B4 mesylate and the aqueous solution is 0.5-2:40-80 (g/ml), is preferably 0.8-1.6:50-70 (g/ml), is more preferably 1-1.4:55-65 (g/ml); Most preferably be 1.1-1.3:60 (g/ml), like 1.2:60 (g/ml).
In second aspect; The invention provides the crystalline method of preparation first aspect present invention; It is characterized in that, with (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3; 2 – dioxy phosphas, six ring-2-methylene radical]-the 1-ethyl } the VITAMIN B4 mesylate is dissolved in the water of low acetonitrile or methanol content, carries out crystallization.
Preferably in the method for second aspect present invention, low levels is 1-10% (V/V), and more preferably 2-8% (V/V) is more preferably 3-7% (V/V), most preferably is 4-5.5% (V/V), like 4% (V/V) or 5.5% (V/V).
Also preferred in the method for second aspect present invention; (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2-dioxy phospha six ring-2-methylene radical]-1-ethyl } mass volume ratio of VITAMIN B4 mesylate and the aqueous solution is 0.5-2:40-80 (g/ml); Be preferably 0.8-1.6:50-70 (g/ml); Be more preferably 1-1.4:55-65 (g/ml), most preferably be 1.1-1.3:60 (g/ml), like 1.2:60 (g/ml).
In the third aspect; The invention provides and be used to treat or the medicine of prevention of liver disease or metabolic disease; It comprises the crystal and the acceptable accessories of first aspect present invention, and preferably its crystal and acceptable accessories by first aspect present invention is formed.In this article, acceptable accessories refers to nontoxic weighting agent, stablizer, thinner, adjuvant or other pharmaceutical adjuncts.For example, thinner, vehicle are like water, saline water, Microcrystalline Cellulose etc.; Weighting agent is like starch, sucrose etc.; Tackiness agent is like starch, derivatived cellulose, alginate, gelatin and/or Vinylpyrrolidone polymer; Wetting agent is like glycerine; Disintegrating agent is like agar, lime carbonate and/or sodium hydrogencarbonate; Absorption enhancer is like quaternary ammonium compound; Tensio-active agent is like cetyl alcohol; Absorption carrier is like kaolin and/or soap clay; Lubricant is like talcum powder, calcium stearate/magnesium, polyoxyethylene glycol etc.In addition, pharmaceutical composition of the present invention can also further contain other auxiliary material, like flavouring agent, sweeting agent etc.The medicine of third aspect present invention can further include other and is used to treat or the activeconstituents of prevention of liver disease or metabolic disease.
Known technology according to this area; Can pharmaceutical composition be processed various formulations according to the needs of therapeutic purpose, route of administration, preferred said composition is a unit dosage form, like freeze-dried, tablet, capsule, pulvis, emulsion agent, aqueous injection or sprays; More preferably this pharmaceutical composition be injection type (as; Lyophilized injectable powder) or oral dosage form, be more preferably oral dosage form (as, tablet or capsule).Medicine can be used through conventional route, and is particularly in the intestines, for example oral, for example with tablet or Capsule form, uses; Or non-enteron aisle uses, and for example with injectable solutions or suspensoid form, uses; Or nose uses.
In fourth aspect, the crystal that the invention provides first aspect present invention is used for treating or the application of the medicine of prevention of liver disease or metabolic disease in preparation.Medicine of the present invention is used with effective dose, and wherein effective dose is normally in the crystalline amount of first aspect present invention.Effective dose can be unit dosage form (as, a slice, a pin, a ball or potion) medicine in content, also can be the patient's of required treatment/prevention unitary dose (like, per weight dosage).Drug manufacturer can be at an easy rate mean body weight through the patient colony of required treatment/prevention with the content in the medicine of the patient's of required treatment/prevention the per weight dosage unit of being converted into dosage form; For example; The mean body weight of adult patient can be 60kg; Therefore multiply by adult's per weight dosage through mean body weight, the content of the medicine of the unit dosage form that can obtain being used for being grown up.
In this article, the patient can be a Mammals, like people, rabbit, dog or mouse, preferably people.Dose,equivalent conversion relation according to known laboratory animal of those of ordinary skills and people (usually can be referring to the instruction of medicine administrative organs such as FDA, SFDA; Also can referring to " Huang Jihan etc. in the pharmacological testing between animal and the dose,equivalent between the animals and human beings body convert. Chinese clinical pharmacology and therapeutics; 2004,9 (9): 1069-1072 ") can derive people's per weight dosage from the dosage of laboratory animal.For example, for laboratory animal mouse commonly used, according to above-mentioned document, its conversion relation with the adult is about 12:1; For experimental animal rat commonly used, according to above-mentioned document, its conversion relation with the adult is about 6:1.In this article, effective dose (in the content in the medicine) can be preferably 1mg-50mg of 0.1-500mg, is more preferably 2mg-10mg.
The application of preferred fourth aspect present invention is the application that is used for treating or preventing the medicine of hepatitis B in preparation.The application of also preferred fourth aspect present invention is to be used for reducing the application in the medicine of patient hepatitis B virus level in preparation.
Aspect the 5th; The invention provides the crystalline method that detects first aspect present invention; It is characterized in that, doubtful crystal is carried out the X-ray powder diffraction detect, resulting X-ray powder diffraction and the X-ray powder diffraction shown in Fig. 1 or 2 are compared.Those skilled in the art can utilize X-ray powder diffraction test set to obtain the crystalline diffracting spectrum, and many equipment are commercial.Testing conditions also can be well-known to those skilled in the art; Like voltage: 46kv; Electric current: 40mA; Copper k α radiation, λ:
etc.Position of spectral line (number of degrees at Bragg ' s 2 θ angles are represented usually), height of spectral line, relative abundance and/or spacing according to collection of illustrative plates leave d parameters such as (expressions with
usually), and whether those skilled in the art can compare out doubtful crystal is exactly the crystal of first aspect present invention.
Beneficial effect of the present invention is, has obtained the excellent crystal of character of Pradefovir, and it has good temperature and appropriateness stability, and purity is high, does not contain solvent and moisture, is more convenient for the flexibility of preparation technical process, also is convenient to standing storage.
For the ease of understanding, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, its in full content all include this paper in and carry out reference, just look like their in full in this article entire teachings gone over.
Below will describe in detail the present invention through concrete embodiment and accompanying drawing.What need particularly point out is that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this specification sheets, many variations of the present invention, change have been obviously all concerning one of ordinary skill in the art.
Description of drawings
Fig. 1: I type (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } the X-ray powder diffraction of VITAMIN B4 mesylate
Fig. 2: II type (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2-dioxy phospha six ring-2-methylene radical]-1-ethyl } the X-ray powder diffraction of VITAMIN B4 mesylate
Embodiment
(+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } preparation and the evaluation of I type crystal formation of VITAMIN B4 mesylate
One, compound synthetic
Basically with reference to preparing method's preparation (+)-suitable-9-{2-of Chinese patent 200510098771.X number [4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2-dioxy phospha six ring-2-methylene radical]-1-ethyl } the VITAMIN B4 mesylate.
Concrete steps are following:
Step 1:
| Regent | MW. | Charging capacity | mmol | Mol ratio | Remarks |
| Compound 5 | 186 | 0.85g | 4.58 | 1 | |
| Adefovir | 273 | 1.25g | 4.58 | 1 | |
| Oxalyl chloride | 1.4mL | ||||
| N, the N-NMF | 101 | 0.5g | 4.95 | 1.08 | |
| Pyridine | 0.75mL | 9.16 | 2 | ||
| Triethylamine | 3.7mL | 29.06 | 6.3 | ||
| Ethanol | 15mL | ||||
| Acetate | 1.65mL | ||||
| Methylene dichloride | 75mL | ||||
| The Pradefovir mesylate | 423 | 1.2g | 63% |
(1.25g, 4.58mmol) and N, (0.5g 4.95mmol), slowly drips oxalyl chloride (1.4ml) to the N-NMF in the 35ml methylene dichloride, to add Adefovir.The concentrating under reduced pressure solvent obtains bullion, be dissolved in the 25ml methylene dichloride, 0 ° of C of temperature control, slowly add pyridine (0.75mL, 9.16mmol).Be cooled to-78 ° of C then, another part is contained compound 5, and (0.85g, 4.58mmol) (3.7mL, methylene dichloride 29.06mmol) (15mL) solution splashes into when-78 ° of C, while temperature control < 60 ° of C with triethylamine.Reaction is risen again to 0 ° of C after finishing.After the organic phase washing, solvent is removed in the organic phase decompression, the dissolving crude product that obtains adds acetate (1.65ml) and refluxed 2 hours in 15ml ethanol.Be cooled to 25-30 ° of C, splash into methylsulphonic acid 4ml, Kong Wen ≦ 25 ℃, suction filtration obtains compound 6 (1.2g, yield: white powder 63%).
Compound 6
1H NMR (400MHz, MeOD): δ 8.25-8.15 (2H, m), 7.38-7.29 (3H, m), 7.18-7.11 (1H, m), 4.60-4.57 (2H, m), 4.55-4.50 (1H, m), 4.28-4.20 (2H, m), 4.16-4.00 (4H, m), 2.03-1.97 (2H, m).
Two, the crystallization of I N-type waferN and evaluation
The above-mentioned powder 1.2g adding 60ml that obtains is contained in the acetonitrile of 4% (V/V) water, stir when being heated to 65 ℃, to dissolving fully, be cooled to 28 ℃ then, finding has crystal to separate out, suction filtration, and the reservation crystal is then directly in 55 ℃ of oven for drying.The crystal powder of getting acquisition detects with PHI-5400 type x-ray photoelectron analyser (can available from U.S. PE company); Test parameter is: voltage: 46kv; Electric current: 40mA; Copper k α radiation; λ:
detected result shows with this method to obtain steady I type monocrystalline shown in Fig. 1 and table 1.
The peak tabulation of table 1I N-type waferN
| PeakNo. | 2θ | FWHM | d-value | Intensity | I/I0 |
| 1 | 10.480 | 0.235 | 8.4342 | 680 | 7 |
| 2 | 11.200 | 0.329 | 7.8936 | 961 | 10 |
| 3 | 12.220 | 0.259 | 7.2369 | 1880 | 20 |
| 4 | 13.220 | 0.282 | 6.6917 | 3163 | 33 |
| 5 | 16.760 | 0.306 | 5.2854 | 9516 | 100 |
| 6 | 17.820 | 0.353 | 4.9733 | 7926 | 83 |
| 7 | 18.560 | 0.212 | 7.7767 | 696 | 7 |
| 8 | 19.000 | 0.329 | 4.6670 | 973 | 10 |
| 9 | 19.860 | 0.353 | 4.4668 | 1714 | 18 |
| 10 | 20.680 | 0.282 | 4.2915 | 2878 | 30 |
| 11 | 21.580 | 0.400 | 4.1145 | 946 | 10 |
| 12 | 22.340 | 0.447 | 3.9762 | 7091 | 75 |
| 13 | 23.600 | 0.306 | 3.7667 | 1028 | 11 |
| 14 | 24.440 | 0.329 | 3.6391 | 2350 | 25 |
| 15 | 25.120 | 0.282 | 3.5421 | 1014 | 11 |
| 16 | 25.780 | 0.259 | 3.4529 | 1631 | 17 |
| 17 | 26.560 | 0.329 | 3.3533 | 8298 | 87 |
| 18 | 27.660 | 0.282 | 3.2224 | 2503 | 26 |
| 19 | 28.100 | 0.188 | 3.1729 | 1997 | 21 |
| 20 | 28.580 | 0.353 | 3.1207 | 8785 | 92 |
| 21 | 29.520 | 0.329 | 3.0234 | 615 | 6 |
| 22 | 30.440 | 0.376 | 2.9341 | 998 | 10 |
| 23 | 31.060 | 0.212 | 2.8769 | 535 | 6 |
| 24 | 31.500 | 0.541 | 2.8378 | 704 | 7 |
| 25 | 32.980 | 0.259 | 2.7137 | 529 | 6 |
| 26 | 34.000 | 0.471 | 2.6346 | 1067 | 11 |
| 27 | 37.600 | 0.400 | 2.3902 | 675 | 7 |
| 28 | 38.540 | 0.282 | 2.3340 | 585 | 6 |
| 29 | 41.760 | 0.282 | 2.1612 | 724 | 8 |
| 30 | 55.860 | 0.306 | 1.6440 | 524 | 6 |
Embodiment 2
(+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phosphas, six ring-2-methylene radical]-1-ethyl } preparation and the evaluation of II crystal formation of VITAMIN B4 mesylate
The powder 1.2g that obtains in the above-mentioned instance 1 " synthesizing of compound " is added 60ml contain in the methyl alcohol of 55% (V/V) water, stir when being heated to 55 ℃, to dissolving fully; Be cooled to 25 ℃ then, finding has crystal to separate out, suction filtration; Keep crystal, then directly in 55 ℃ of oven for drying.The crystal powder of getting acquisition detects with PHI-5400 type x-ray photoelectron analyser (can available from U.S. PE company); Test parameter is: voltage: 46kv; Electric current: 40mA; Copper k α radiation; λ:
detected result shows with this method to obtain steady I I type monocrystalline shown in Fig. 2 and table 2.
The peak tabulation of table 2II N-type waferN
| PeakNo. | 2θ | FWHM | d-value | Intensity | I/ |
| 1 | 10.600 | 0.259 | 8.3390 | 202 | 13 |
| 2 | 11.240 | 0.282 | 7.8656 | 281 | 19 |
| 3 | 12.340 | 0.400 | 7.1668 | 403 | 27 |
| 4 | 13.340 | 0.282 | 6.6317 | 463 | 31 |
| 5 | 15.220 | **** | 5.8165 | 96 | 6 |
| 6 | 16.840 | 0.282 | 5.2605 | 1455 | 96 |
| 7 | 17.900 | 0.376 | 4.9513 | 1509 | 100 |
| 8 | 19.120 | **** | 4.6380 | 138 | 9 |
| 9 | 19.960 | 0.306 | 4.447 | 194 | 13 |
| 10 | 20.740 | 0.329 | 4.2792 | 398 | 26 |
| 11 | 21.660 | **** | 4.0995 | 129 | 9 |
| 12 | 22.400 | 0.353 | 3.9657 | 993 | 66 |
| 13 | 23.660 | **** | 3.7573 | 100 | 7 |
| 14 | 24.520 | 0.353 | 3.6274 | 289 | 19 |
| 15 | 25.180 | **** | 3.5338 | 149 | 10 |
| 16 | 25.860 | 0.353 | 3.4424 | 209 | 14 |
| 17 | 26.620 | 0.329 | 3.3459 | 1014 | 67 |
| 18 | 27.380 | 0.188 | 3.2547 | 211 | 14 |
| 19 | 27.720 | 0.282 | 3.2155 | 324 | 21 |
| 20 | 28.160 | 0.188 | 3.1663 | 274 | 18 |
| 21 | 28.620 | 0.329 | 3.1164 | 966 | 64 |
| 22 | 29.700 | **** | 3.0055 | 103 | 7 |
| 23 | 34.040 | 0.235 | 2.6316 | 165 | 11 |
Embodiment 3
The stability of the compound of crystal of the present invention and prior art relatively
Present embodiment has been described crystal of the present invention (the II N-type waferN of the I N-type waferN of embodiment 1 preparation and embodiment 2 preparations; Be numbered sample 1 and sample 2 respectively) and according to the stable contrast experiment of this compound of prior art (one Chinese patent application 200510098771.X is numbered sample 3) preparation.
Under 65 ℃, carry out the high-temperature stable property testing, the result is as shown in the table, and this shows that crystal of the present invention has high-temperature stability more than prior art.
Under 40 ℃, carry out through the stability test in June, the result is as shown in the table, and this shows crystal of the present invention than prior art, and is under prolonged preservation, more stable.
Embodiment 4
The comparison of the anti-HBV effect of the compound of crystal of the present invention and prior art
Present embodiment has been described the clinical trial of the anti-hepatitis B virus (HBV) of crystal of the present invention (the I N-type waferN of embodiment 1 preparation).Particularly, make a definite diagnosis the adult patients that infects HBV for 47 and accept test, its average HBV dna level is 10
7.9/ mL treats, and oral 5mg every day crystal of the present invention continued for 48 weeks, and average HBV dna level reduces to 10
-4.09/ mL does not have obvious resistance and produces; Simultaneously, the control group of taking adefovir ester than the same period has Toxicity of Kidney still less.
Embodiment 4
Comprise crystalline pharmaceutical composition of the present invention
According to the prescription of table 3, get crystal of the present invention (the I N-type waferN of embodiment 1 preparation and the II N-type waferN of embodiment 2 preparations are numbered sample 1 and sample 2 respectively) respectively and according to prior art (one Chinese patent application 200510098771.X; Be numbered sample 3) preparation this compound; Evenly mixed with Microcrystalline Cellulose and starch, to granulate with the wetting back of ethanol, dry back adds Magnesium Stearate; Compressing tablet promptly makes tablet.
Table 3 tablet formulation
The tablet of processing carries out the dissulution test, and the result is as shown in the table, shows sample 1 and 2 than sample 3, and better stripping so more helps absorbing.
Claims (10)
1. (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3; 2 – dioxy phosphas, six ring-2-methylene radical]-the 1-ethyl } crystal of VITAMIN B4 mesylate (Pradefovir), it is characterized in that it has the X-ray powder diffraction shown in Fig. 1 or 2 basically.
2. the described crystal of claim 1 is characterized in that, its be (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3,2 – dioxy phosphas, six ring-2-methylene radical]-the 1-ethyl } VITAMIN B4 mesylate crystalline in the acetonitrile of low levels or methanol in water, preferably wherein low levels is 1-10% (V/V); 2-8% (V/V) more preferably; Be more preferably 3-7% (V/V), most preferably be 4-5.5% (V/V), like 4% (V/V) or 5.5% (V/V).
3. the described crystal of claim 2 is characterized in that, and wherein (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3; 2 – dioxy phosphas, six ring-2-methylene radical]-the 1-ethyl } mass volume ratio of VITAMIN B4 mesylate and the aqueous solution is 0.5-2:40-80 (g/ml), is preferably 0.8-1.6:50-70 (g/ml), is more preferably 1-1.4:55-65 (g/ml); Most preferably be 1.1-1.3:60 (g/ml), like 1.2:60 (g/ml).
4. the arbitrary described crystalline method of preparation claim 1-3 is characterized in that, with (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3; 2-dioxy phospha six ring-2-methylene radical]-the 1-ethyl } the VITAMIN B4 mesylate is dissolved in the water of low acetonitrile or methanol content, carries out crystallization, and preferably wherein low levels is 1-10% (V/V); 2-8% (V/V) more preferably; Be more preferably 3-7% (V/V), most preferably be 4-5.5% (V/V), like 4% (V/V) or 5.5% (V/V); Also preferably wherein (+)-suitable-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1; 3; 2-dioxy phospha six ring-2-methylene radical]-the 1-ethyl } mass volume ratio of VITAMIN B4 mesylate and the aqueous solution is 0.5-2:40-80 (g/ml), is preferably 0.8-1.6:50-70 (g/ml), is more preferably 1-1.4:55-65 (g/ml); Most preferably be 1.1-1.3:60 (g/ml), like 1.2:60 (g/ml).
5. be used to treat or the medicine of prevention of liver disease or metabolic disease, it comprises arbitrary described crystal and the acceptable accessories of claim 1-3.
6. the described medicine of claim 5, it is an oral dosage form, is preferably tablet.
7. the arbitrary described crystal of claim 1-3 is used for treating or the application of the medicine of prevention of liver disease or metabolic disease in preparation.
8. the application of claim 7, it is the application that is used for treating or preventing the medicine of hepatitis B in preparation.
9. the application of claim 7, it is to be used for reducing the application in the medicine of patient hepatitis B virus level in preparation.
10. test right requires the arbitrary described crystalline method of 1-3, it is characterized in that, doubtful crystal is carried out the X-ray powder diffraction detect, and resulting X-ray powder diffraction and the X-ray powder diffraction shown in Fig. 1 or 2 are compared.
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| CN201210344333.7A CN102827206B (en) | 2012-09-17 | 2012-09-17 | Pradefovir crystal |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396453A (en) * | 2013-08-12 | 2013-11-20 | 西安新通药物研究有限公司 | Pharmaceutical use of Pradefovir |
| CN112010905A (en) * | 2020-05-07 | 2020-12-01 | 西安新通药物研究有限公司 | Paradifovir mesylate crystal form and application thereof |
| CN112028940A (en) * | 2020-05-07 | 2020-12-04 | 西安新通药物研究有限公司 | Tenofovir phosphate crystal form and preparation and application thereof |
| CN113264964A (en) * | 2020-05-11 | 2021-08-17 | 西安新通药物研究股份有限公司 | Cytarabine prodrug MB07133 crystal form D and application thereof |
| WO2021223398A1 (en) * | 2020-05-07 | 2021-11-11 | 西安新通药物研究股份有限公司 | Crystal form for treating liver disease and use thereof |
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| CN113264964A (en) * | 2020-05-11 | 2021-08-17 | 西安新通药物研究股份有限公司 | Cytarabine prodrug MB07133 crystal form D and application thereof |
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| CN102827206B (en) | 2015-06-17 |
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