CN103923124A - Crystalline-state anti-hepatitis B virus drug - Google Patents
Crystalline-state anti-hepatitis B virus drug Download PDFInfo
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Abstract
The invention aims to provide a crystalline-state acyclic nucleotide analogue represented by the formula I and a crystalline-state non-toxic pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the crystalline-state acyclic nucleotide analogue represented by the formula I and the crystalline-state non-toxic pharmaceutically acceptable salt thereof as active components, and a use of the crystalline-state acyclic nucleotide analogue represented by the formula I and the crystalline-state non-toxic pharmaceutically acceptable salt thereof in preparation of drugs for treating viral hepatitis B.
Description
Technical field
The present invention relates to the acyclic nucleotide acid-like substance of the crystal form shown in formula I and the non-toxicity pharmacy acceptable salt of crystal form thereof, and the purposes of the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in formula I and crystal form thereof in preparation hepatitis B medicine:
Salt or organic acid salt that the non-toxicity pharmacy acceptable salt of described crystal form is mineral acid; The crystalline characteristics of these crystal form acyclic nucleotide acid-like substances and non-toxicity pharmacy acceptable salt thereof can be analyzed collection of illustrative plates by X powder diffraction and determine.
Background technology
The invention provides the acyclic nucleotide acid-like substance of the crystal form shown in formula I and the non-toxicity pharmacy acceptable salt of crystal form thereof:
The solid of the crystal form of medicine or the salt of crystal form have easy purifying, easily large-scale is synthetic, has good flowing property.
Summary of the invention
Investigator's discovery of the present invention, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in formula I and crystal form thereof has advantages of easy purifying and preparation.
Investigator of the present invention also finds, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in formula I and crystal form thereof has better physical stability.
Investigator of the present invention is surprised to find that, after the non-toxicity pharmacy acceptable salt rat oral gavage administration of the acyclic nucleotide acid-like substance of the crystal form shown in formula I and crystal form thereof, the individual difference of pharmacokinetic parameter is less.
Investigator of the present invention is also surprised to find that, after the non-toxicity pharmacy acceptable salt rat oral gavage administration of the acyclic nucleotide acid-like substance of the crystal form shown in formula I and crystal form thereof, the dependency of maximum plasma concentration Cmax and lower area of blood concentration-time curve AUC and dosage is better.
Therefore, one aspect of the present invention provides the acyclic nucleotide acid-like substance of the crystal form shown in formula I and the non-toxicity pharmacy acceptable salt of crystal form thereof:
The crystalline characteristics of these crystal form acyclic nucleotide acid-like substances and non-toxicity pharmacy acceptable salt thereof can be analyzed collection of illustrative plates by X powder diffraction and determine.
The salt that the present invention also provides the acyclic nucleotide acid-like substance shown in I and organic acid to form.
The salt that the present invention also provides the acyclic nucleotide acid-like substance shown in I and mineral acid to form.
The present invention also provides hydrate or the solvate of the acyclic nucleotide acid-like substance shown in the formula I with crystal character and non-toxicity pharmacy acceptable salt thereof.
The present invention also provides the acyclic nucleotide acid-like substance of the crystal form shown in formula I, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 11.00 ± 0.10,13.42 ± 0.10,14.44 ± 0.10,18.58 ± 0.10,18.67 ± 0.10,22.16 ± 0.10,23.12 ± 0.10,25.56 ± 0.10,27.71 ± 0.10.
The present invention also provides the salt C25H27N5O6PHCl of the crystal character of the acyclic nucleotide acid-like substance shown in formula I and hydrochloric acid formation, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 8.72 ± 0.10,9.89 ± 0.10,11.19 ± 0.10,14.41,18.10 ± 0.10,20.15 ± 0.10,21.74 ± 0.10,22.25 ± 0.10,22.34 ± 0.10,26.58 ± 0.10,30.13 ± 0.10.
The salt C25H27N5O6PH that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and phosphoric acid to form
3pO
4, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 10.13 ± 0.10,11.09 ± 0.10,11.20 ± 0.10,14.09 ± 0.10,14.76,17.72 ± 0.10,19.63 ± 0.10,21.27 ± 0.10,22.80 ± 0.10,24.60 ± 0.10.
The salt C25H27N5O6PCH that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and methylsulfonic acid to form
3sO
3h, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 10.20 ± 0.10,12.50 ± 0.10,12.70 ± 0.10,17.70 ± 0.10,19.29 ± 0.10,21.83 ± 0.10,24.16 ± 0.10,27.19 ± 0.10.
The salt C25H27N5O6PC that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and Citric Acid to form
6h
8o
7, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 11.22 ± 0.10,12.51 ± 0.10,14.34 ± 0.10,15.51 ± 0.10,17.31 ± 0.10,17.71 ± 0.10,20.00 ± 0.10,20.59 ± 0.10,22.59 ± 0.10,28.30 ± 0.10.
The salt C25H27N5O6PC that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and fumaric acid to form
4h
4o
4, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 4.94 ± 0.10,12.03 ± 0.10,18.11 ± 0.10,22.06,24.78 ± 0.10,5.21 ± 0.10,30.38 ± 0.10.
The salt C25H27N5O6PC that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and L-TARTARIC ACID to form
4h
6o
6, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 9.09 ± 0.10,10.10 ± 0.10,13.60 ± 0.10,14.06 ± 0.10,14.69 ± 0.10,16.15 ± 0.10,17.44 ± 0.10,20.87 ± 0.10,22.76 ± 0.10,24.43 ± 0.10,31.50 ± 0.10.
The salt C25H27N5O6PC that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and L MALIC ACID to form
4h
6o
5, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 4.78 ± 0.10,10.56 ± 0.10,11.28 ± 0.10,13.11 ± 0.10,13.50 ± 0.10,16.98 ± 0.10,19.34 ± 0.10,22.57 ± 0.10,24.33 ± 0.10,29.27 ± 0.10.
The salt C25H27N5O6PC that the present invention also provides the acyclic nucleotide acid-like substance shown in formula I and D-malic acid to form
4h
6o
5it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 4.84 ± 0.10,13.08 ± 0.10,13.65 ± 0.10,16.96 ± 0.10,18.31 ± 0.10,19.61 ± 0.10,24.59 ± 0.10,29.63 ± 0.10.
The present invention provides a kind of pharmaceutical composition on the other hand, and the acyclic nucleotide acid-like substance shown in its contained I and non-toxicity pharmacy acceptable salt thereof are as pharmaceutical excipient conventional in activeconstituents and pharmacy field.
The present invention also provides a kind of pharmaceutical composition, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in the formula I that wherein, comprises 1mg to 500mg in per unit dosage and crystal form thereof is as pharmaceutical excipient conventional in activeconstituents and pharmacy field.
The present invention also provides a kind of pharmaceutical composition, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in the formula I that wherein, comprises 10mg to 100mg in per unit dosage and crystal form thereof is as pharmaceutical excipient conventional in activeconstituents and pharmacy field.
The present invention also provides the non-toxicity pharmacy acceptable salt of the crystal form acyclic nucleotide acid-like substance shown in formula I and crystal form thereof in the purposes of preparing in hepatitis B medicine.
According to pharmaceutical composition of the present invention, it can be for example following formulation: tablet is such as but not limited to fast-release tablet, slowly sheet, controlled release tablet, film coated tablet, coated tablet, buccal tablet, Sublingual tablet, biological adhesive tablet etc.; Capsule is such as but not limited to hard capsule, soft capsule etc.; Injection is such as but not limited to water type injection aseptic or bacteriostatic agent, oleo-injection, lyophilize powder injection, injectable microsphere etc.; The sprays that sprays is used etc. with, the local skin spraying of, nasal spray such as but not limited to mouth spray; Aerosol sucks with aerosol, local skin aerosol etc. such as but not limited to lung; Nasal drop is such as but not limited to solution, a nasal gel etc. for collunarium; Powder inhalation is such as but not limited to powder inhalation for oral cavity, powder inhalation for nasal cavity, powder inhalation etc. for local skin.The preparation technology of these preparations is that art technology people can prepare according to its existing knowledge or with reference to being correlated with textbook or reference book.
Embodiment
Further illustrate the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
Reference example 1[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] preparation of phosphonic acids two (2-oxyethyl group) phenyl ester (R-1)
144g (0.50mol) [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids, 276g (2.00mmol) Pyrocatechol monoethyl ether and 390g1-N-methyl-2-2-pyrrolidone N-are heated to 85 DEG C, then add 63g triethylamine, add 309g (1.50mmol) DCC, in 100 DEG C of heated and stirred 16 hours.Cooling, elimination solid; Filtrate decompression is concentrated, with the separation of silica gel (200-300 order) post, use methylene dichloride: methyl alcohol (20: 1) mixed solvent wash-out, collect required component, evaporated under reduced pressure.By residue re-crystallizing in ethyl acetate, obtain I35g, fusing point 110-112 DEG C.Ultimate analysis C
25h
27n
5o
6p calculated value: C 56.92%, H 5.73%, N 13.28%, P 5.87%.Measured value: C 56.72%, H 5.71%, N 13.18%, P 5.88%.
Reference example 2[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] preparation of phosphonic acids two (2-oxyethyl group) phenyl ester hydrochloride (R-2)
13gR-1 is dissolved in to 50ml acetone, drips the diethyl ether solution of hydrogenchloride, to pH be 2-3, backflow 10min, cooling, separates out solid naturally, is dried, and obtains R-213.3g, fusing point 178-186 DEG C.Ultimate analysis C
25h
27n
5o
6pHCl calculated value: C 53.24%, H 5.54%, Cl 6.29%, N 12.42%, P 5.49%; Measured value (%): C 53.31%, H 5.58%, Cl 6.19%, N 12.41%, P 5.40%.
Embodiment 1[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester (I
1) preparation
By 5g ethyl acetate/ethanol for R-1 (V/V=10: 1～100: 1) heating for dissolving, leave standstill and naturally cool to room temperature, have crystallization slowly to separate out, be then placed in 0-4 DEG C of refrigerator overnight.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
1target compound 3.9g, fusing point 112-113 DEG C.Ultimate analysis C
25h
27n
5o
6p calculated value: C 56.92%, H 5.73%, N 13.28%, O 18.20%, P 5.87%.Measured value: C 56.62%, H 5.71%, N 13.18%, P 5.88%.
Embodiment 2[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester hydrochloride (I
2) preparation
1.3g (2.53mmol) R-1 is dissolved in to 5ml acetone (water content < 0.2%), drip the diethyl ether solution of hydrogenchloride, control rate of addition, within approximately 5 minutes, finish, to pH be 2-3, the volume of ether and acetone is controlled at (1: 5～1: 30), backflow 10min, naturally cooling, separates out solid.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
21.33g, fusing point 184-186 DEG C.Ultimate analysis C
25h
27n
5o
6pHCl calculated value: C 53.24%, H 5.54%, Cl 6.29%, N 12.42%, O 17.02%, P 5.49%; Measured value (%): C 53.31%, H 5.58%, Cl 6.19%, N 12.41%, P 5.40%.
Embodiment 3[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester phosphoric acid salt (I
3) preparation
1.3g (2.53mmol) R-1 is dissolved in to 5ml acetone (water content 2%～4%), drips the phosphoric acid of 0.3ml85%, be back to clarification, cooling, separates out white solid naturally.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
31.4g, fusing point 158-1160 DEG C.Ultimate analysis C
25h
27n
5o
6pH
3pO
4calculated value: C 48.00%, H 5.32%, N 11.20%, O 25.58%, P 9.90%; Measured value: C 48.12%, H 5.36%, N 11.21%, P 9.80%.
Embodiment 4[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester mesylate (I
4) preparation
1.3g (2.53mmol) R-1 is dissolved in to 5ml acetone (water content 2%～5%), adds 0.4ml methylsulfonic acid, leave standstill and naturally cool to room temperature, have crystallization slowly to separate out, be then placed in 0-4 DEG C of refrigerator overnight.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
41.43g, fusing point 140-142 DEG C.
1H-NMR?(D
2O)δ(ppm)：8.04(d，1H)，7.91(d，1H)，7.13(m，1H)，6.84-7.05(m，5H)，6.73(m，1H)，6.47(m，1H)，4.34-4.37(m，2H)，4.12-4.15(m，2H)，3.86-3.97(m，5H)，2.65(s，3H)，1.29(t，3H)，1.19-1.21(m，6H)。Ultimate analysis C
25h
27n
5o
6pCH
3sO
3h calculated value: C 50.08%, H 5.50%, N 11.23%, O 23.09%, P 4.97%, S 5.14%; Measured value: C 50.18%, H5.45%, N 11.20%, P 4.91%, S 5.18%.
Embodiment 5[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester citrate (I
5) preparation
1.3g (2.53mmol) R-1 is dissolved in to 10ml acetone (water content < 0.2%), adds 0.53g (2.53mmol) Citric Acid, continue backflow 30min, cooling, separates out white solid naturally.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
51.47g, fusing point 150-152 DEG C.Ultimate analysis C25H27N5O6PC
6h
8o
7calculated value (%): C 51.74%, H 5.32%, N9.73%, O 28.90%, P 4.30%; Measured value (%): C 51.63%, H 5.31%, N 9.77%, P 4.35%.
Embodiment 6[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester fumarate (I
6) preparation
2.6g (5.06mmol) R-1 is dissolved in to 16ml acetone, add 0.6g (5.16mmol) fumaric acid and appropriate water (ratio of controlling acetone and water is 16: 1～100: 1), be back to clarification, naturally cooling cooling, separates out white solid, suction filtration, the cold washing with alcohol of 10ml for filter cake, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
62.83g, fusing point 154-157 DEG C.Ultimate analysis C
25h
27n
5o
6pC
4h
4o
4calculated value (%): C54.12%, H 5.32%, N 10.88%, O 24.86%, P 4.81%; Measured value (%): C 54.21%, H 5.34%, N 10.78%, P 4.85%.
Embodiment 7[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester L-TARTARIC ACID salt (I
7) preparation
1.3g (2.53mmol) R-1 is dissolved in to 10ml acetone, adds 0.38g (2.53mmol) L-TARTARIC ACID, heating melts; After cooling, separate out oily matter, drip appropriate water (ratio of controlling acetone and water is 90: 1～100: 1), stir clarification, be heated to 40 DEG C of left and right, stir, separate out white solid.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
71.27g, fusing point 60-66 DEG C.Ultimate analysis C
25h
27n
5o
6pC
4h
6o
6calculated value (%): C 51.40%, H 5.36%, N 10.34%, O 28.33%, P 4.57%; Measured value (%): C51.37%, H 5.37%, N 10.44%, P4.54%.
Embodiment 8[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester L MALIC ACID salt (I
8) preparation
1.3g (2.53mmol) R-1 is dissolved in to 10ml acetone (water content < 0.2%), adds 0.33g (2.53mmol) L MALIC ACID, continue backflow 30min, cooling, separate out solid.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
81.19g, fusing point 98-101 DEG C.Ultimate analysis C
25h
27n
5o
6pC
4h
6o
5calculated value: C 52.61%, H5.48%, N 10.59%, O 26.60%, P 4.68%; Measured value (%): C 52.49%, H 5.39%, N10.62%, P 4.78%.
Embodiment 9[[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester D-malic acid salt (I
9) preparation
1.3g (2.53mmol) R-1 is dissolved in to 10ml acetone (water content < 0.2%), adds 0.33g (2.53mmol) D-malic acid, continue backflow 30min, cooling, separate out solid.Filter, wash with cold recrystallisation solvent, natural drying at room temperature 6 hours, then 60 DEG C of vacuum-drying 8 hours, obtains I
91.06g, fusing point 114-116 DEG C.Ultimate analysis C
25h
27n
5o
6pC
4h
6o
5calculated value: C 52.61%, H 5.48%, N 10.59%, O 26.60%, P 4.68%; Measured value (%): C 52.52%, H 5.41%, N10.63%, P 4.74%.
The sign of embodiment 10 crystal types
Adopt powder x-ray diffraction method and dsc (DSC) to characterize the crystal type of target compound of the present invention.
Powder x-ray diffraction test condition and method: instrument model: DMAX-2500; Experimental technique: be 200-300 order by testing sample porphyrize, scanning angle scope 3.0-60.0 degree, sweep velocity is counting 0.15 degree/second.
Dsc test condition and method: instrument model: TGA-7; Experimental technique: it is 10.00 DEG C/min that heat-up rate is set, heats up, and observes and note down 20.00 DEG C of dq/dt in-300.00 DEG C of temperature ranges changing.
Test result:
Fig. 1 [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester (I
1) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 2 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester hydrochloride (I
2) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 3 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester phosphoric acid salt (I
3) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 4 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester mesylate (I
4) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 5 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester citrate (I
5) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 6 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester fumarate (I
6) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 7 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester L-TARTARIC ACID salt (I
7) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 8 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester L MALIC ACID salt (I
8) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
Fig. 9 is [[(R)-2-(6-amino-purine-9-yl)-1-methyl-oxyethyl group-] methyl] phosphonic acids two (2-oxyethyl group) phenyl ester D-malic acid salt (I
9) powder X-ray diffracting spectrum; X-coordinate is 2 θ angles, the intensity that ordinate zou is absorption peak.
The evaluation of anti-HBV effect in embodiment 11 bodies
By the sheldrake random packet of vertical transmission infection, the DHBV DNA detection positive, 10 every group.Gavage gives the testing compound of water and various dose respectively, once a day, and totally 30 days.Respectively before administration, venous blood collection the 14th day time after the 7th day, the 14th day, the 28th day and drug withdrawal after administration, adopt outer standard TaqMan real-time fluorescence PCR method to measure serum DHBV DNA content.The results are shown in Table 11-1.
Table 11-1 interior resisting virus activity rating result
The Pharmacokinetic Evaluation of embodiment 12 Oral Administration in Rats administrations
12-1 experiment condition
Through conditions such as more different mobile phase composition ratios, flow velocity and pH, determine the concentration of measuring bioactive molecule PMPA with following chromatographic condition.
Analytical column: Discovery ODS, 250 × 4.6mm I.D., 5 μ m particle diameters, Supelco company of the U.S.
Pre-column: C
18guard column, Phenomenex company of 4.0 × 3.0mm I.D. U.S.
Column temperature: 24 DEG C; Moving phase: methanol-water-formic acid (20: 80: 0.5, v/v/v)
Flow velocity: 0.5mL/min; Sample size: 20 μ L
Interior mark: PMEA (the 4 μ g/mL aqueous solution)
Measure the concentration of PMPA by following mass spectrum condition: ion source is electro-spray ionization (TurboIonspray) source; Positive ion mode detects; Injection electric is 4000V; Source temperature is 350 DEG C; Atomization gas (NEB) is 8; Roller shutter gas (CUR) is 11; Collision gas (CAD) is 5; Scan mode is multiple-reaction monitoring (MRM), is respectively m/z274 → m/z162 (PMPA, collision voltage CE is 40V) and m/z288 → m/z176 (interior mark PMEA, CE is 35V) for the ionic reaction of quantitative analysis; Be 200msec sweep time.
12-2 experimental result
(1) rat intravenous injection gives the pharmacokinetics test of PMPA
5 of male SD rats, intravenous injection gives PMPA normal saline solution, and every mouse dosage is 1.08mg/kg, respectively at before administration and administration after 5min, 15min, 30min, 45min, 1.0h, 2.0h, 3.0h, 6.0h, 8.0h, 12.0h is in eyeground vein clump blood sampling 0.5mL, centrifugal 10min (3500r.p.m.), isolates blood plasma, to be measured in-20 DEG C of freezing preservations.Measure the plasma drug level of its different time.
(2) rat oral gavage gives the pharmacokinetics test of target compound
Male SD rat, fasting 16h, random packet, 5/group, gavage gives the target compound of tween 80 suspendible respectively, and dosage is 10mg/kg, before administration and administration after 0.25,0.5,0.75,1.0,1.5,2.0,3.0,6.0,12.0,24.0 hours, in rat eyeground vein clump blood sampling 0.5mL, the centrifugal 10min of 3500r.p.m., isolates blood plasma, to be measured in-20 DEG C of freezing preservations.Measure to obtain the plasma drug level of its different time.
(3) pharmacokinetic parameter calculates
By Plasma Concentration-time data input computer, adopt non-chamber modelling to calculate pharmacokinetic parameter.T
maxand C
maxadopt measured value, calculate AUC by trapezoidal method
0-tvalue and AUC
0-∞value, with semilog graphing method, calculates T by the concentration point of eliminating phase end
1/2, and obtain main pharmacokinetic parameter.
The major impetus mathematic(al) parameter of table 12-1 PMPA rat vein administration
The major impetus mathematic(al) parameter of table 12-2 R-1 rat oral gavage administration
Table 12-3I
1the major impetus mathematic(al) parameter of rat oral gavage administration
Table 12-4I
2the major impetus mathematic(al) parameter of rat oral gavage administration
Table 12-5I
4the major impetus mathematic(al) parameter of rat oral gavage administration
Table 12-6I
6the major impetus mathematic(al) parameter of rat oral gavage administration
The Cmax of embodiment 13 Oral Administration in Rats administrations and the dependency evaluation of AUC and dosage
Male SD rat, fasting 16h, random packet, 3/group, gavage gives the target compound of tween 80 suspendible respectively, and dosage is respectively 1mg/kg, 5mg/kg, 10mg/kg and 50mg/kg, before administration and administration after 0.25,0.5,0.75,1.0,1.5,2.0,3.0,6.0,12.0,24.0 hours, in rat eyeground vein clump blood sampling 0.5mL, the centrifugal 10min of 3500r.p.m., isolates blood plasma, to be measured in-20 DEG C of freezing preservations.Measure to obtain the plasma drug level of its different time.
After adopting SPSS11.5 software to target compound administration, main pharmacokinetic parameter AUC and Cmax analyze, the correlation analysis of AUC and Cmax by dosage and each animal, obtain the relation conefficient of linear regression equation, again relation conefficient is carried out to t inspection, in the dosage range that investigation is verified, the body of medicine exposes the dependency with dosage.
The Cmax of table 13-1 Oral Administration in Rats administration and the relation conefficient of AUC and dosage
The tablet composition of embodiment 14 20mg/ sheets
Selection lactose is thinner, low-substituted hydroxypropyl cellulose is disintegrating agent, Microcrystalline Cellulose is as the thinner that has certain disintegration concurrently, the polyvinylpyrrolidone aqueous solution is as tackiness agent, butyl hydroxy anisol and Citric Acid are oxidation inhibitor, starch is weighting agent, and Magnesium Stearate is as lubricant, by 20mg/ sheet I
4unitary dose carry out prescription screening, in Table 14-1.
Preparation technology: by activeconstituents I
4and the auxiliary material such as Microcrystalline Cellulose, lactose crosses respectively 100 mesh sieves, for subsequent use; By the I of recipe quantity
4and the auxiliary material such as Microcrystalline Cellulose, lactose, by volume the progressively increase principle of method of equivalent is fully mixed; Above-mentioned miscellany is added 3% the polyvinylpyrrolidone aqueous solution appropriate, limit edged is mixed, makes softwood, granulates twice through 20 mesh sieves, and wet granular is put 40 ± 5 DEG C, and moisture≤3% is controlled in forced air drying; In dry particle, add the Magnesium Stearate of recipe quantity, cross 20 mesh sieves, whole grain; Select the circular punch die that diameter is 8mm, debugging tablet weight adjuster, heavily meets the requirements the sheet of Simvastatin element sheet, and theoretical value is 200 ± 15mg.Regulating pressure-regulator to make slice, thin piece hardness is 60～80 newton (6～8kg) again, compressing tablet.
Table 14-1 prescription screening table (100 consumptions) (unit: gram)
Experimental result through prescription screenings such as dissolution rate, homogeneity and circulation ratios shows, No. 1 prescription indices all meets design requirements.According to 3 batch samples of No. 1 formula preparation, carry out accelerated stability test, the results are shown in Table 14-2.
Table 14-2 acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%) stability test result
The capsule composition of embodiment 1580mg/ grain
Select lactose as thinner, polyvinylpolypyrrolidone (PVP XL) as disintegrating agent, polyvidone (K30) as tackiness agent, Magnesium Stearate as lubricant, by 80mg/ grain I
4unitary dose carry out prescription screening, in Table 15-1.
Preparation technology: by I
4and auxiliary material lactose, polyvinylpolypyrrolidone, Magnesium Stearate cross respectively 80 mesh sieves, for subsequent use; By the I of recipe quantity
4, lactose, polyvinylpolypyrrolidone, by volume the progressively increase principle of method of equivalent is fully mixed, crosses 60 mesh sieve 3 times; Get the polyvidone that model is K30 (K30) appropriate, the stirring and dissolving that adds water, is mixed with the solution that concentration is 5% (W/V), for subsequent use; Above-mentioned miscellany is added to appropriate tackiness agent (35～45ml), and limit edged is mixed, makes softwood, granulates twice through 40 mesh sieves, and wet granular is put 60 ± 5 DEG C of oven dry; Regulate loading amount; In dry particle, add the Magnesium Stearate of recipe quantity, cross 40 mesh sieves mixed 2 times, whole grain; Filling.
Table 15-1 prescription screening table (100 consumptions) (unit: gram)
The prescription screening evaluation test results such as mobility of particle, homogeneity and technique circulation ratio show, No. 2 prescription indices all meets design requirements.According to 3 batch samples of No. 2 formula preparations, carry out accelerated stability test, the results are shown in Table 15-2.
Table 15-2 acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%) stability test result
Claims (16)
1. the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in formula I and crystal form thereof:
2. the salt of the pharmaceutically acceptable mineral acid of non-toxicity of the crystal form of acyclic nucleotide acid-like substance claimed in claim 1.
3. the pharmaceutically acceptable organic acid salt of the non-toxicity of the crystal form of acyclic nucleotide acid-like substance claimed in claim 1.
4. the acyclic nucleotide acid-like substance of the crystal form shown in formula I claimed in claim 1, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 7.64 ± 0.10,9.88 ± 0.10,10.81 ± 0.10,14.22 ± 0.10,14.92 ± 0.10,15.81 ± 0.10,16.54 ± 0.10,17.77 ± 0.10,19.14 ± 0.10,19.95 ± 0.10,22.11 ± 0.10,22.95 ± 0.10,25.42 ± 0.10.
5. the salt C of the crystal form that the acyclic nucleotide acid-like substance shown in formula I claimed in claim 1 and hydrochloric acid form
25h
27n
5o
6pHCl, is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 8.72 ± 0.10,9.89 ± 0.10,11.19 ± 0.10,14.41 ± 0.10,18.10 ± 0.10,20.15 ± 0.10,21.74 ± 0.10,22.25 ± 0.10,22.34 ± 0.10,26.58 ± 0.10,30.13 ± 0.10.
6. the salt C of the crystal form that the acyclic nucleotide acid-like substance shown in formula I claimed in claim 1 and phosphoric acid form
25h
27n
5o
6pH
3pO
4, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 10.13 ± 0.10,11.09 ± 0.10,11.20 ± 0.10,14.09 ± 0.10,14.76,17.72 ± 0.10,19.63 ± 0.10,21.27 ± 0.10,22.80 ± 0.10,24.60 ± 0.10.
7. the salt C of the crystal form that the acyclic nucleotide acid-like substance shown in formula I claimed in claim 1 and methylsulfonic acid form
25h
27n
5o
6pCH
3sO
3h, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 10.20 ± 0.10,12.50 ± 0.10,12.70 ± 0.10,17.70 ± 0.10,19.29 ± 0.10,21.83 ± 0.10,24.16 ± 0.10,27.19 ± 0.10.
8. the salt C of the crystal form that the acyclic nucleotide acid-like substance shown in formula I claimed in claim 1 and Citric Acid form
25h
27n
5o
6pC
6h
8o
7, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 11.22 ± 0.10,12.51 ± 0.10,14.34 ± 0.10,15.51 ± 0.10,17.31 ± 0.10,17.71 ± 0.10,20.00 ± 0.10,20.59 ± 0.10,22.59 ± 0.10,28.30 ± 0.10.
9. the salt C of the crystal form that the acyclic nucleotide acid-like substance shown in formula I claimed in claim 1 and fumaric acid form
25h
27n
5o
6pC
4h
4o
4, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 4.94 ± 0.10,12.03 ± 0.10,18.11 ± 0.10,22.06,24.78 ± 0.10,5.21 ± 0.10,30.38 ± 0.10.
10. the salt C of the crystal form that the acyclic nucleotide acid-like substance shown in formula I claimed in claim 1 and L-TARTARIC ACID form
25h
27n
5o
6pC
4h
6o
6, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 9.09 ± 0.10,10.10 ± 0.10,13.60 ± 0.10,14.06 ± 0.10,14.69 ± 0.10,16.15 ± 0.10,17.44 ± 0.10,20.87 ± 0.10,22.76 ± 0.10,24.43 ± 0.10,31.50 ± 0.10.
The salt C of the crystal form that the acyclic nucleotide acid-like substance shown in 11. formula I claimed in claim 1 and L MALIC ACID form
25h
27n
5o
6pC
4h
6o
5, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, there are at least three and be selected from the absorption peak that is about following position: 4.78 ± 0.10,10.56 ± 0.10,11.28 ± 0.10,13.11 ± 0.10,13.50 ± 0.10,16.98 ± 0.10,19.34 ± 0.10,22.57 ± 0.10,24.33 ± 0.10,29.27 ± 0.10.
The salt C of the crystal form that the acyclic nucleotide acid-like substance shown in 12. formula I claimed in claim 1 and D-malic acid form
25h
27n
5o
6pC
4h
6o
5it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates representing with 2 θ angles, has at least three and is selected from the absorption peak that is about following position: 4.84 ± 0.10,13.08 ± 0.10,13.65 ± 0.10,16.96 ± 0.10,18.31 ± 0.10,19.61 ± 0.10,24.59 ± 0.10,29.63 ± 0.10.
13. 1 kinds of pharmaceutical compositions, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in its contained I and crystal form thereof is as pharmaceutical excipient conventional in activeconstituents and pharmacy field.
Composition described in 14. claims 13, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in the formula I that wherein, comprises 1mg to 500mg in per unit dosage and crystal form thereof is as pharmaceutical excipient conventional in activeconstituents and pharmacy field.
Composition described in 15. claims 13, the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form shown in the formula I that wherein, comprises 10mg to 100mg in per unit dosage and crystal form thereof is as pharmaceutical excipient conventional in activeconstituents and pharmacy field.
The purposes of the non-toxicity pharmacy acceptable salt of the acyclic nucleotide acid-like substance of the crystal form described in 16. claim 1-12 and crystal form thereof in preparation hepatitis B medicine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310013609.8A CN103923124A (en) | 2013-01-15 | 2013-01-15 | Crystalline-state anti-hepatitis B virus drug |
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997024361A1 (en) * | 1995-12-29 | 1997-07-10 | Gilead Sciences, Inc. | Nucleotide analogs |
| CN103845345A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Hepatitis treatment medicament |
-
2013
- 2013-01-15 CN CN201310013609.8A patent/CN103923124A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997024361A1 (en) * | 1995-12-29 | 1997-07-10 | Gilead Sciences, Inc. | Nucleotide analogs |
| CN103845345A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Hepatitis treatment medicament |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
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