CN102827206B - Pradefovir crystal - Google Patents
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- CN102827206B CN102827206B CN201210344333.7A CN201210344333A CN102827206B CN 102827206 B CN102827206 B CN 102827206B CN 201210344333 A CN201210344333 A CN 201210344333A CN 102827206 B CN102827206 B CN 102827206B
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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 medicinal chemistry art, specifically, the present invention relates to (+)-cis-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) and medicine thereof and preparation method.
Background technology
(+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phospha six ring-2-methylene radical]-1-ethyl } VITAMIN B4 mesylate (Pradefovir) structure as shown in the formula (I):
This compound is the prodrug compound of the Adefovir in prodrug compound disclosed in No. 200510098771.Xth, Chinese patent, may be used for treatment or prevention of liver disease or metabolic disease, comprises hepatitis B etc.But prior art is open or enlighten and will study the crystallography of this compound.
And this compound carries out crystallization, crystal distribution is very complicated, and many crystallizations go out polycrystalline, is not easy to obtain monocrystalline.But, through the research that the present inventor is long-term and arduous, in solvents many as existing astronomical figure and mixed solvent, final find low levels acetonitrile or the aqueous solution of methyl alcohol can carry out effective crystallization to this compound, obtain monocrystalline, not only remain the curative effect of original compound, and the excellent properties such as improving stability etc. can be brought.
The solvent species that can be used for crystallization in prior art is various, and the mixed solvent of the solvent composition of different sorts and ratio cannot count especially, and crystallization practice is also stayed substantially in experience, generally cannot dope according to crystallization condition the crystal formation that crystallization goes out.And the present inventor is by the research long-term and arduous to Pradefovir, and rely on some fortune, finally find the mixed solvent formula that can be used for crystallization Pradefovir.So, the crystal of preferred first aspect present invention is (+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phospha six ring-2-methylene radical]-1-ethyl } crystallization in the acetonitrile of low levels or the aqueous solution of methyl alcohol of VITAMIN B4 mesylate.Wherein, I N-type waferN is crystallization in the aqueous solution of the acetonitrile of low levels; II N-type waferN is crystallization in the aqueous solution of the methyl alcohol of low levels.More preferably wherein, low levels is 1-10%(V/V), be more preferably 2-8%(V/V), be more preferably 3-7%(V/V), most preferably be 4-5.5%(V/V), as 4%(V/V) or 5.5%(V/V).
In addition, the present inventor finds, the ratio of Pradefovir and mixed solvent also can affect the quality of the crystal that crystallization goes out to a certain extent.So, in the crystal of first aspect present invention further preferably, (+)-cis-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), as 1.2:60(g/ml).
In second aspect, the invention provides the method for the crystal of preparation first aspect present invention, it is characterized in that, by (+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phospha six ring-2-methylene radical]-1-ethyl } 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), be more preferably 2-8%(V/V), be more preferably 3-7%(V/V), most preferably be 4-5.5%(V/V), as 4%(V/V) or 5.5%(V/V).
Also preferred in the method for second aspect present invention, (+)-cis-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), as 1.2:60(g/ml).
In the third aspect, the invention provides and be used for the treatment of or the medicine of prevention of liver disease or metabolic disease, it comprises the crystal of first aspect present invention and pharmaceutically acceptable auxiliary material, and preferably it is made up of the crystal of first aspect present invention and pharmaceutically acceptable auxiliary material.In this article, pharmaceutically acceptable auxiliary material refers to nontoxic weighting agent, stablizer, thinner, adjuvant or other pharmaceutical adjuncts.Such as, thinner, vehicle, as water, physiological saline, Microcrystalline Cellulose etc.; Weighting agent, as starch, sucrose etc.; Tackiness agent, as starch, derivatived cellulose, alginate, gelatin and/or polyvinylpyrrolidone; Wetting agent, as glycerine; Disintegrating agent, as agar, calcium carbonate and/or sodium bicarbonate; Absorption enhancer, as quaternary ammonium compound; Tensio-active agent, as cetyl alcohol; Absorption carrier, as kaolin and/or soap clay; Lubricant, as talcum powder, calcium stearate/magnesium, polyoxyethylene glycol etc.In addition, pharmaceutical composition of the present invention can also contain other auxiliary material, further as flavouring agent, sweeting agent etc.The medicine of third aspect present invention can further include other and is used for the treatment of or the activeconstituents of prevention of liver disease or metabolic disease.
According to the known technology of this area, can according to therapeutic purpose, route of administration need pharmaceutical composition is made various formulation, preferred said composition is unit dosage form, as 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 (e.g., tablet or capsule).Medicine can be used by conventional route, particularly in intestines, such as oral, such as in the form of a tablet or capsule, uses; Or parenteral administration, such as, with injectable solutions or suspended form, use; Or nose uses.
In fourth aspect, the invention provides the application of crystal in the medicine for the preparation for the treatment of or prevention of liver disease or metabolic disease of first aspect present invention.Medicine of the present invention is used with effective dose, and wherein effective dose is normally with the gauge of the crystal of first aspect present invention.Effective dose can be the content in the medicine of unit dosage forms (e.g., a slice, a pin, a ball or potion), also can be the unitary dose (e.g., per weight dosage) of the patient of required treatment/prevention.The per weight dose lonvestion of the patient of required treatment/prevention is become the content in the medicine of unit dosage forms by the mean body weight that drug manufacturer can pass easily through the PATIENT POPULATION of required treatment/prevention, such as, the mean body weight of adult patient can be 60kg, therefore being multiplied by the per weight dosage of adult by mean body weight, the content in the medicine of the unit dosage forms for being grown up can being obtained.
In this article, patient can be Mammals, as people, rabbit, dog or mouse, and preferably people.Dose,equivalent conversion relation according to laboratory animal known to ordinary skill in the art and people (usually can see the instruction of the medicine administrative organs such as FDA, SFDA, also can see " Huang Jihan etc. dose,equivalent in pharmacological testing between animal and between animals and human beings body converts. Chinese Clinical pharmacology and therapeutics; 2004,9 (9): 1069-1072 ") the per weight dosage of people can be derived from the dosage of laboratory animal.Such as, for conventional laboratory animal mouse, according to above-mentioned document, it is about 12:1 with the conversion relation of adult; For conventional experimental animal rat, according to above-mentioned document, it is about 6:1 with the conversion relation of adult.In this article, effective dose (content meter with in medicine) can be that 0.1-500mg is preferably 1mg-50mg, is more preferably 2mg-10mg.
The application of preferred fourth aspect present invention is the application in the medicine for the preparation for the treatment of or prevention hepatitis B.Also preferably the application of fourth aspect present invention is for the preparation of the application reduced in the medicine of hepatitis B virus level in patient.
In the 5th, the invention provides the method for the crystal detecting first aspect present invention, it is characterized in that, the detection of X-ray powder diffraction is carried out to doubtful crystal, obtained X-ray powder diffraction and X-ray powder diffraction are as shown in the figures 1 and 2 compared.Those skilled in the art can utilize X-ray powder diffraction test set to obtain the diffracting spectrum of crystal, and much equipment is commercial.Testing conditions also can be well-known to those skilled in the art, as voltage: 46kv, and electric current: 40mA, copper k α radiation, λ:
deng.According to the position of spectral line (number of degrees at usual Bragg ' s 2 θ angle represent) of collection of illustrative plates, height of spectral line, relative abundance and/or spacing from d (usually with
represent) etc. parameter, those skilled in the art comparison can go out the crystal whether doubtful crystal is exactly first aspect present invention.
Beneficial effect of the present invention is, obtains the crystal of the excellent of Pradefovir, and it has good temperature and appropriate stability, and purity is high, not containing solvent and moisture, is more convenient for the adaptability of preparation technical process, is also convenient to standing storage.
For the ease of understanding, the present invention refer to open source literature, and these documents are to more clearly describe the present invention, and its entire contents is all included in and carried out reference herein, just look like their in full in this article entire teachings gone over.
Below will be described in detail the present invention by specific embodiment and accompanying drawing.It is important to note that these descriptions are only exemplary descriptions, do not form limitation of the scope of the invention.According to the discussion of this specification sheets, many changes of the present invention, to change concerning one of ordinary skill in the art be all obviously.
Summary of the invention
The object of the present invention is to provide new (+)-cis-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, present invention also offers the medicine and preparation method etc. of this crystal.
Specifically, in first aspect, the invention provides (+)-cis-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, it is characterized in that, it has X-ray powder diffraction as shown in the figures 1 and 2 substantially.(+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phospha six ring-2-methylene radical]-1-ethyl } VITAMIN B4 mesylate also claims Pradefovir, has structure as shown in the formula (I).
In this article, have the crystal of X-ray powder diffraction as shown in Figure 1 substantially also referred to as I N-type waferN, the peak parameter of its X-ray powder diffraction is substantially as shown in table 1; Have the crystal of X-ray powder diffraction as shown in Figure 2 substantially also referred to as I N-type waferN, the peak parameter of its X-ray powder diffraction is substantially as shown in table 2.
Accompanying drawing explanation
Fig. 1: I type (+)-cis-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
Fig. 2: II type (+)-cis-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
Embodiment 1
(+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phospha six ring-2-methylene radical]-1-ethyl } Preparation and identification of I type crystal formation of VITAMIN B4 mesylate
One, the synthesis of compound
The basic preparation of the preparation method with reference to No. 200510098771.Xth, Chinese patent (+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2-dioxy phospha six ring-2-methylene radical]-1-ethyl } VITAMIN B4 mesylate.
Concrete steps are as follows:
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, N-METHYLFORMAMIDE | 101 | 0.5g | 4.95 | 1.08 | |
| Pyridine | 0.75mL | 9.16 | 2 | ||
| Triethylamine | 3.7mL | 29.06 | 6.3 | ||
| Ethanol | 15mL | ||||
| Acetic acid | 1.65mL | ||||
| Methylene dichloride | 75mL | ||||
| Pradefovir mesylate | 423 | 1.2g | 63% |
In 35ml methylene dichloride, add Adefovir (1.25g, 4.58mmol) and N, N-METHYLFORMAMIDE (0.5g, 4.95mmol), slowly drip oxalyl chloride (1.4ml).Concentrating under reduced pressure solvent obtains crude product, is dissolved in 25ml methylene dichloride, and temperature control 0 ° of C, slowly adds pyridine (0.75mL, 9.16mmol).Then-78 ° of C are cooled to, another part is contained compound 5 (0.85g, 4.58mmol) instill when-78 ° of C with methylene dichloride (15mL) solution of triethylamine (3.7mL, 29.06mmol), simultaneously temperature control <-60 ° of C.Rise again to 0 ° of C after reaction terminates.After organic phase washing, solvent is removed in organic phase decompression, and the dissolving crude product obtained, in 15ml ethanol, adds acetic acid (1.65ml) and refluxes 2 hours.Be cooled to 25-30 ° of C, instillation methylsulphonic acid 4ml, Kong Wen≤25 DEG C, suction filtration obtains compound 6 (1.2g, yield: 63%) white powder.
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).
The crystallization of two, I N-type waferN and qualification
The above-mentioned powder 1.2g that obtains is added 60ml containing 4%(V/V) in the acetonitrile of water, stirring while being heated to 65 DEG C, to dissolving completely, being then cooled to 28 DEG C, find that there is crystal and separate out, suction filtration, retain crystal, then direct in 55 DEG C of oven for drying.The crystal powder PHI-5400 type x-ray photoelectron analyser (can purchased from American PE company) getting acquisition detects, and test parameter is: voltage: 46kv, electric current: 40mA, copper k α radiation, λ:
detected result as shown in figure 1 and table 1, shows can obtain stable I type monocrystalline by the method.
The peak list 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
(+)-cis-9-{2-[4-[(S)-(3-chloro-phenyl-)-2-oxygen-1,3,2 – dioxy phospha six ring-2-methylene radical]-1-ethyl } Preparation and identification of II crystal formation of VITAMIN B4 mesylate
The powder 1.2g obtained in above-mentioned example 1 " synthesis of compound " is added 60ml containing 55%(V/V) in the methyl alcohol of water, stir while being heated to 55 DEG C, to dissolving completely, then be cooled to 25 DEG C, find that there is crystal and separate out, suction filtration, retain crystal, then direct in 55 DEG C of oven for drying.The crystal powder PHI-5400 type x-ray photoelectron analyser (can purchased from American PE company) getting acquisition detects, and test parameter is: voltage: 46kv, electric current: 40mA, copper k α radiation, λ:
detected result, as shown in Fig. 2 and table 2, shows can obtain stable II type monocrystalline by the method.
The peak list of table 2II N-type waferN
| PeakNo. | 2θ | FWHM | d-value | Intensity | I/I 0 |
| 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 compares
Present embodiment describes crystal of the present invention (I N-type waferN prepared by embodiment 1 and II N-type waferN prepared by embodiment 2, be numbered sample 1 and sample 2 respectively) and the stability contrast experiment of this compound for preparing according to prior art (Chinese patent application 200510098771.X is numbered sample 3).
At 65 DEG C, carry out high-temperature stability test, result is as shown in the table, and this shows that crystal of the present invention has high-temperature stability more than prior art.
Carry out through stability test in June at 40 DEG C, result is as shown in the table, and this shows that crystal of the present invention is than prior art, under long-term preservation, more stable.
Embodiment 4
The comparison of the compound Anti-HBV activity effect of crystal of the present invention and prior art
Present embodiment describes the clinical trial of the anti-hepatitis B virus (HBV) of crystal of the present invention (I N-type waferN prepared by embodiment 1).Specifically, make a definite diagnosis the adult patients acceptance test infecting HBV for 47, its average HBV DNA level is 10
7.9/ mL, treats, oral 5mg every day crystal of the present invention, and continue 48 weeks, average HBV DNA level reduces to 10
-4.09/ mL, produces without obvious resistance; Meanwhile, less Toxicity of Kidney is had than the control group taking adefovir ester of the same period.
Embodiment 4
Comprise the pharmaceutical composition of crystal of the present invention
According to the formula of table 3, get crystal of the present invention (I N-type waferN prepared by embodiment 1 and II N-type waferN prepared by embodiment 2 respectively, be numbered sample 1 and sample 2 respectively) and according to prior art (Chinese patent application 200510098771.X, be numbered sample 3) this compound of preparing, be mixed evenly with Microcrystalline Cellulose and starch, granulate with after ethanol wet, after drying, add Magnesium Stearate, compressing tablet, i.e. obtained tablet.
Table 3 tablet formulation
The tablet made carries out Dissolution Rate Testing, and result is as shown in the table, shows that sample 1 and 2 is than sample 3, can better stripping, is so more conducive to absorbing.
Claims (19)
1. structure is such as formula the crystal of the compound shown in (I), it is characterized in that, it has X-ray powder diffraction as shown in Figure 1 substantially, or it has X-ray powder diffraction as shown in Figure 2 substantially,
2. crystal according to claim 1, is characterized in that, it has X-ray powder diffraction as shown in Figure 1, or it has X-ray powder diffraction as shown in Figure 2.
3. the method for the crystal of preparation described in claim 1 or 2, it is characterized in that, be dissolved in the water of low acetonitrile or methanol content by structure such as formula the compound shown in (I), carry out crystallization, wherein low acetonitrile or methanol content are 1-10%V/V,
4. method according to claim 3, is characterized in that, wherein low acetonitrile or methanol content are 2-8%V/V.
5. method according to claim 4, is characterized in that, wherein low acetonitrile or methanol content are 3-7%V/V.
6. method according to claim 5, is characterized in that, wherein low acetonitrile or methanol content are 4-5.5%V/V.
7. method according to claim 6, is characterized in that, wherein low acetonitrile or methanol content are 4%V/V or 5.5%V/V.
8. method according to claim 3, is characterized in that, wherein structure is 0.5-2:40-80g/ml such as formula the mass volume ratio of the compound shown in (I) and the aqueous solution.
9. method according to claim 8, is characterized in that, wherein structure is 0.8-1.6:50-70g/ml such as formula the mass volume ratio of the compound shown in (I) and the aqueous solution.
10. method according to claim 9, is characterized in that, wherein structure is 1-1.4:55-65g/ml such as formula the mass volume ratio of the compound shown in (I) and the aqueous solution.
11. methods according to claim 10, is characterized in that, wherein structure is 1.1-1.3:60g/ml such as formula the mass volume ratio of the compound shown in (I) and the aqueous solution.
12. methods according to claim 11, is characterized in that, wherein structure is 1.2:60g/ml such as formula the mass volume ratio of the compound shown in (I) and the aqueous solution.
13. are used for the treatment of or the medicine of prevention of liver disease or metabolic disease, and it comprises arbitrary described crystal of claim 1-2 and pharmaceutically acceptable auxiliary material.
14. medicines according to claim 13, it is oral dosage form.
15. medicines according to claim 14, it is tablet.
The application of arbitrary described crystal in the medicine for the preparation for the treatment of or prevention of liver disease or metabolic disease of 16. claim 1-2.
The application of 17. claims 16, it is the application in the medicine for the preparation for the treatment of or prevention hepatitis B.
The application of 18. claims 16, it is for the preparation of the application reduced in the medicine of hepatitis B virus level in patient.
19. test rights require the method for arbitrary described crystal of 1-2, it is characterized in that, carry out the detection of X-ray powder diffraction to doubtful crystal, obtained X-ray powder diffraction and X-ray powder diffraction are as shown in the figures 1 and 2 compared.
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| CN103396453B (en) * | 2013-08-12 | 2014-07-16 | 西安新通药物研究有限公司 | Pharmaceutical use of Pradefovir |
| 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 |
| CN113583048B (en) * | 2020-05-07 | 2023-09-01 | 西安新通药物研究股份有限公司 | Tenofovir Wei Linsuan ester c crystal form and preparation and application thereof |
| CN113651853A (en) * | 2020-05-07 | 2021-11-16 | 西安新通药物研究股份有限公司 | Paradofovir mesylate C crystal form 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 |
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| CN1964967A (en) * | 2004-06-08 | 2007-05-16 | 症变治疗公司 | Lewis acid mediated synthesis of cyclic esters |
| TWI324931B (en) * | 2003-05-12 | 2010-05-21 | Metabasis Therapeutics Inc | Process for preparation of cyclic prodrugs of pmea and pmpa |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI324931B (en) * | 2003-05-12 | 2010-05-21 | Metabasis Therapeutics Inc | Process for preparation of cyclic prodrugs of pmea and pmpa |
| CN1964967A (en) * | 2004-06-08 | 2007-05-16 | 症变治疗公司 | Lewis acid mediated synthesis of cyclic esters |
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