CN116492363A - Novel nucleoside phosphoramidate compound composition and process for producing the same - Google Patents
Novel nucleoside phosphoramidate compound composition and process for producing the same Download PDFInfo
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- CN116492363A CN116492363A CN202310544149.5A CN202310544149A CN116492363A CN 116492363 A CN116492363 A CN 116492363A CN 202310544149 A CN202310544149 A CN 202310544149A CN 116492363 A CN116492363 A CN 116492363A
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- A61P31/14—Antivirals for RNA viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the field of pharmaceutical preparations, and relates to an oral preparation which comprises (a) a compound shown as a formula (1) or pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof; and (b) an adsorbent. The invention also relates to a preparation method of the oral preparation and application of the oral preparation in medicaments for preventing and/or treating hepatitis C. The oral preparation of the invention can be completely dissolved out, has good absorption in vivo, less impurities and good stability.
Description
The present application is a divisional application of chinese patent application CN201711326836.0 with the application date of 2017, 12 and 12, and the name of the present application is "new composition of nucleoside phosphoramidate compound and preparation method thereof".
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an oral preparation of isopropyl (2S) -2- ((([ 1,1' -biphenyl ] -4-yloxy) (((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidine-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionate, and a preparation method and application thereof.
Background
Hepatitis C Virus (HCV) infection is a worldwide epidemic of over 2 million people with chronic infections worldwide, 15% of egypt, 4.8% of pakistan, 3.2% of china, and the first three in the world. The clinical manifestations of hepatitis C virus infection are various, mild to inflammation, severe to liver cirrhosis and liver cancer. Chronic hepatitis c may also be complicated with some extrahepatic manifestations including rheumatoid arthritis, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphomas and delayed skin porphyria, etc., possibly due to abnormal immune responses in the body. And various complications such as ascites and abdominal cavity infection, upper gastrointestinal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, liver failure and the like can appear in the decompensation period of the liver cirrhosis of the third liver.
HCV belongs to the family flaviviridae, genus hepacivirus, which has a similar genetic structure to the other two genera in the flaviviridae, namely pestiviruses and flaviviruses. Currently, the standard method of treating HCV infection is interferon and ribavirin combination therapy. However, only 50% of the treated subjects respond to this method and interferon has significant side effects such as influenza-like symptoms, weight loss and fatigue weakness, whereas interferon and ribavirin combined therapy produces considerable side effects including hemolysis, anemia, fatigue and the like.
In addition, drugs that have been developed for the treatment of HCV infection include protease inhibitors, thiazolidine derivatives, thiazolidines and benzanilides, phenanthrenequinones, helicase inhibitors, nucleoside polymerase inhibitors and gliotoxins, antisense phosphorothioate oligonucleotides, inhibitors of IRES-dependent translation, ribozymes, nucleoside analogues, and the like. Currently, nucleoside phosphates are an important development in the art for the treatment of flaviviridae, especially HCV, infections.
CN104031104a discloses a novel nucleoside phosphoramidate compound represented by the formula (1) having a chemical name of (2S) -2- (([ 1,1' -biphenyl ] -4-yloxy) (((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionic acid isopropyl ester (hereinafter referred to as "compound of formula (1"),
CN104031104a reports that isopropyl (2S) -2- ((([ 1,1' -biphenyl ] -4-yloxy) (((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidine-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionate has excellent antiviral activity, has small toxicity to cells, and can be used for treating flaviviridae virus, especially hepatitis c virus infection.
No suitable formulation comprising the compound or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof has been reported so far. Isopropyl (2S) -2- ((([ 1,1' -biphenyl ] -4-yloxy) (((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionate) is a prodrug that exerts its antiviral effect by being converted to an active metabolite in the liver, and thus an oral administration form may be a more suitable administration form. However, as is well known in the art, many problems are faced in studying the formulation of such formulations, such as long-term stability of the formulation, control of related substances, absorption of the drug, bioavailability, and the like. These problems are determined by a number of factors, such as the absorption of the drug, including dissolution or release of the drug from the formulation, dissolution of the drug under physiological conditions, and permeability in the gastrointestinal tract, among others.
In the course of preliminary prescription studies, the inventors of the present invention found that the solubility and permeability of the compound of formula (1) are to be improved, and that the compound is easily agglomerated in water, thus providing a great challenge for formulation prescription studies of the compound.
It is therefore desirable to provide an oral preparation of isopropyl (2S) -2- ((([ 1,1' -biphenyl ] -4-yloxy) (((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionate which has a completely soluble, well-absorbed in vivo, less impurities, low hygroscopicity and good stability.
Disclosure of Invention
An object of the present invention is to provide an oral preparation comprising a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof, which is completely dissolved and has good stability.
Another object of the present invention is to provide a method for preparing the oral preparation of the present invention.
It is a further object of the present invention to provide the use of the oral formulation of the present invention for the manufacture of a medicament for the prevention and/or treatment of flaviviridae, in particular HCV, infections.
The above object is achieved by the following technical means.
The present invention provides an oral formulation comprising (a) a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof; and (b) an adsorbent.
The invention provides a compound of formula 1a, which is a stereoisomer of a compound of formula 1, and has the chemical name of (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy ] phosphoryl ] amino ] propionic acid isopropyl ester, which is suitable for treating patients infected with hepatitis C virus,
the inventors of the present invention determined the inhibitory activity of the compound of formula 1a on HCV 1b and 1a replicons using the methods of experimental examples 1 and 2 in CN105985355a, and as a result, showed that the compound of formula 1a has significantly better inhibitory activity on HCV virus than the compound of formula 1.
In some embodiments, the oral formulation of the present invention comprises (a) a compound of formula (1 a) or a pharmaceutically acceptable salt, solvate, hydrate or crystal thereof; and (b) an adsorbent.
In the oral formulation of the present invention, using any morphology of the compound of formula (1 a) or a combination of amorphous and adsorbent, the resulting formulation has very good stability, and although the amorphous has metastable properties, limiting its commercial application, the inventors of the present invention unexpectedly found that the formulation properties remained very stable after accelerated 6 months and long-term 6 months testing, with no significant change in various indices. Meanwhile, the prepared oral preparation of the present invention is also very stable using the crystalline form of the compound of formula (1 a).
Thus, in some specific embodiments, the oral formulation according to the present invention, wherein the compound of formula (1 a) is in crystalline form or amorphous form.
Preferably, the oral formulation of the invention is in solid form. In some embodiments, oral formulations of the present invention include tablets, capsules, pills, granules, powders, pellets, lozenges, cachets, and the like. In a specific embodiment, the oral formulation of the present invention is a tablet, capsule, granule. In some embodiments, the oral formulations of the present invention further comprise a disintegrant, a lubricant, and/or a filler.
In some embodiments, the disintegrant is selected from one or more of corn starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxypropyl cellulose, pregelatinized starch. More preferably, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and low substituted hydroxypropyl cellulose.
In some embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, polyethylene glycol.
In some embodiments, the filler is selected from mannitol, starches, sugars, celluloses, and inorganic salts.
In some embodiments, the oral formulation according to the present invention, wherein the compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof comprises about 15% -85% (w/w) of the formulation tablet weight, the adsorbent comprises about 15% -85% (w/w) of the formulation tablet weight, the disintegrant comprises about 0% -20.0% (w/w) of the formulation tablet weight, the lubricant comprises about 0% -15.0% (w/w) of the formulation tablet weight, and the filler comprises about 0% -30% (w/w) of the formulation tablet weight, based on the amount of the compound of formula (1).
In some embodiments, the oral formulation according to the present invention, wherein the compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof comprises about 20% -50% (w/w) of the formulation tablet weight, the adsorbent comprises about 30% to about 60% (w/w) of the formulation tablet weight, the disintegrant comprises about 5% to 15.0% (w/w) of the formulation tablet weight, the lubricant comprises about 0.2% to 10.0% (w/w) of the formulation tablet weight, and the filler comprises about 10% to 20% (w/w) of the formulation tablet weight, based on the amount of the compound of formula (1).
In other embodiments, the oral formulation according to the present invention, wherein the compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof comprises from about 30% to about 50% (w/w) of the formulation tablet weight, the adsorbent comprises from about 30% to about 50% (w/w) of the formulation tablet weight, the disintegrant comprises from about 5% to 15.0% (w/w) of the formulation tablet weight, the lubricant comprises from about 0.5% to 5.0% (w/w) of the formulation tablet weight, and the filler comprises from about 10% to 20% (w/w) of the formulation tablet weight, based on the amount of the compound of formula (1).
The adsorbent of the invention can be an auxiliary material with porous surface and adsorption effect. For example, in some embodiments, the adsorbent is selected from the group consisting of crospovidone, microcrystalline cellulose, lactose, cyclodextrin, low-substituted hydroxypropyl cellulose, silica.
In one embodiment, crospovidone is used as the adsorbent, preferably, crospovidone having a particle size of 10-30 μm is used as the adsorbent.
In another embodiment, cyclodextrin is used as the adsorbent.
In another embodiment, low substituted hydroxypropylcellulose is used as the adsorbent. The low-substituted hydroxypropyl cellulose can be used for internal addition in wet granulation in tablet production, and can also be added externally or internally and externally at the same time, so that the effect is better.
In other embodiments, inorganic acid salts or inorganic salts are used as adsorbents. Inorganic acid salts include sodium phosphate, calcium phosphate, potassium sulfate, sodium dihydrogen phosphate, and disodium hydrogen phosphate; the inorganic salt comprises sodium chloride, calcium chloride, and potassium chloride.
In addition, diatomite, surface porous cellulose, and pharmaceutical excipients such as salts thereof, starch, saccharides and the like can also be used as the adsorbent of the present invention.
The invention provides a preparation method of the oral preparation, which comprises the step of combining all components in the oral preparation. The inventors of the present invention found that the compound of formula (1) can be dissolved in a readily soluble solvent in the formulation of the present invention, and then the formulation can be prepared so as to be more completely dissolved.
In some embodiments, according to the preparation method of the preparation of the present invention, the compound of formula (1) is dissolved in a solvent which is easily soluble, and then mixed with an adsorbent, and then granulated, tableted, and coated to prepare an oral preparation. In other embodiments, according to the process for preparing the formulation of the present invention, the compound of formula (1) and the adsorbent are dissolved in a readily soluble solvent, and then granulated, tableted, and coated to prepare an oral formulation.
In some embodiments, the oral formulation of the invention is prepared by a process comprising:
a) Uniformly mixing the adsorbent in the device;
b) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof in a solvent with stirring; and
c) Adding the mixture of step b) to the adsorbent of step a), drying, and then preparing granules.
In some specific embodiments, the oral formulation of the invention is prepared by a process comprising:
a) Uniformly mixing the adsorbent in the device;
b) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof in a solvent with stirring;
c) Adding the mixture obtained in the step b) into the adsorbent obtained in the step a), and drying the adsorbent in a fluidized bed to obtain particles;
e) Optionally mixing the dried granules with a disintegrant, a lubricant and a filler;
f) Tabletting the mixed particles; and
g) And (5) coating.
In some specific embodiments, the method of preparing an oral formulation according to the present invention above, wherein the solvent in step b) is an alcoholic solvent, preferably the alcoholic solvent is selected from one or more of methanol, ethanol and isopropanol. In a more preferred embodiment, the compound of formula (1) is dissolved in ethanol.
In some specific embodiments, the oral formulation of the invention is prepared by a process comprising:
a) Uniformly mixing the adsorbent with the prescription amount in a wet granulator;
b) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof in an alcoholic solvent with stirring;
c) Adding the mixture of step b) to the adsorbent of step a) to produce wet granules;
d) Drying the wet particles by using a fluidized bed;
e) Optionally mixing the dried granules with a disintegrant, a lubricant and a filler;
f) Tabletting the mixed particles; and
g) And (5) coating.
In some embodiments, the oral formulation of the invention is prepared by a process comprising:
a) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof and an adsorbent in a solvent to form a mixed solution; and
b) The mixed solution is dried and then granulated.
In some specific embodiments, the oral formulation of the invention is prepared by a process comprising:
a) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof and an adsorbent in a solvent to form a uniformly dispersed mixed solution;
b) Drying the mixed solution by adopting a spray drying device to prepare mixed powder;
c) Mixing the mixed powder with a disintegrating agent and a lubricant; and
d) Tabletting.
In other embodiments, the oral formulation of the invention is prepared by a process comprising:
a) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof and an adsorbent in a solvent to form a uniformly dispersed mixed solution;
b) Drying the mixed solution by adopting a fluidized bed drying device to prepare mixed powder;
c) Mixing the mixed powder with a disintegrating agent and a lubricant; and
d) Tabletting.
In one embodiment of the present invention, the present inventors add the compound of formula (1 a) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof and silica into ethanol, stir and disperse uniformly, then dry the mixed solution to prepare mixed powder by using a spray drying device, then mix with a disintegrant and a lubricant, and directly compress the mixture into tablets.
In some embodiments, the solvent of the present invention is preferably selected from the group consisting of alcoholic solvents and diethylene glycol monoethyl ether.
In one embodiment, the oral preparation according to the invention uses crospovidone and microcrystalline cellulose with particle sizes of 3-100 μm as adsorbents, plus croscarmellose sodium or sodium carboxymethyl starch as disintegrants. Preferably, croscarmellose sodium is used as the disintegrant.
The inventors of the present invention found that when crospovidone is used as an adsorbent in the oral preparation of the present invention, the dissolution endpoint varies when the particle size of the crospovidone varies. Preferably, the present invention uses crospovidone having a particle size of 10-30 μm. Preferably, the coating material comprises hypromellose, lactose, or glyceryl triacetate. The formulation according to the invention preferably has a coating of 2 to 4% (w/w) of the total weight of the formulation.
In the present invention, the effect of pH on the dissolution profile of the formulation was also studied. The results show that the preparation of the invention shows good dissolution and stability in a relatively wide pH range. In the dissolution medium of buffer solution with the same pH value, such as pH1.2, pH3.0, pH4.5 or pH6.8, the dissolution curves among batches of the preparation are consistent, the difference among batches is small, and the process is stable.
The invention provides the use of the oral formulation of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of flaviviridae, in particular HCV, infection.
When the oral formulation of the present invention is administered, the compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof is converted into an active form in vivo to exert an antiviral effect. In one embodiment, the present invention provides a method of treating, preventing or managing HCV comprising orally administering to a patient a formulation of the present invention, a compound of formula (1), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof, in an amount that is equivalent in molar amount to a therapeutically effective amount of the compound of formula (1).
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be selected from the group consisting of: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, tartaric acid, amino acids, methanesulfonic acid or the like.
The term "solvate" refers to a form of the compound of the invention that forms a complex, either solid or liquid, by coordination to a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
The term "crystalline" refers to various solid forms, including crystalline forms, amorphous forms, formed from the compounds described herein. The term "plain tablet" means that the formulation according to the invention is an uncoated tablet.
The oral preparation has good stability, can be stored for a long time, has complete dissolution, good in vivo absorption, less impurities, low hygroscopicity, simplified storage and transportation conditions and the like.
Drawings
Fig. 1: configuration confirmation diagram of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2 r,3r,4r,5 r) -5- (2, 4-dioxo 3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy ] phosphoryl ] amino ] propionate.
Fig. 2: a dissolution profile of the formulation obtained from example 9, wherein ph1.2 represents the dissolution profile of the formulation obtained from example 9 in a ph1.2 buffer of 0.05% sodium dodecyl sulfate; pH3.0 represents the dissolution profile of the formulation from example 9 in pH3.0 buffer; pH4.5 shows the dissolution profile of the formulation from example 9 in pH4.5 buffer; the pH6.8 shows the dissolution profile of the formulation obtained in example 9 in a buffer at pH 6.8.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. The materials used in the examples below, except as specified, were all commercially available, with the film coating premix being the gastric-soluble coating premix powder opadry (295K 620013) available from Carlekang.
Example 1: preparation of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy ] phosphoryl ] amino ] propionate
Step 1 Synthesis of isopropyl (S) -2- [ [ (1, 1' -biphenyl-4-yloxy) (pentafluorophenoxy) phosphoryl ] amino ] propionate
Phosphorus oxychloride (1.53 kg,10 mol) and methylene dichloride (10L) are added into a 50L glass reaction kettle under the protection of nitrogen, stirred and cooled to below-30 ℃. A solution of triethylamine (1.01 kg,10 mol) in dichloromethane (5L) was added dropwise, keeping the internal temperature below-30 ℃. After the completion of the dropwise addition, a solution of 4-hydroxybiphenyl (1.7 kg,10 mol) in tetrahydrofuran (3.4L) was slowly added dropwise, followed by Bi Jiaoban min. The internal temperature was controlled below-30℃and L-alanine isopropyl ester hydrochloride (1.68 kg,10 mol) was added, a solution of triethylamine (2.02 kg,20 mol) in methylene chloride (8.0L) was added dropwise and stirred for 30min. Heating to about 0 ℃, dropwise adding a solution of pentafluorophenol (1.84 kg,10 mol), triethylamine (1.01 kg,10 mol) in dichloromethane (7.0L), heating the reaction exotherm during the dropwise adding process, heating the inner temperature to room temperature after the dropwise adding, filtering after the reaction is completed, washing a filter cake with dichloromethane 2.5Lx4, combining the filtrates, washing the filtrate with 25L of purified water, separating the liquid, concentrating an organic phase under reduced pressure, adding heptane 5 Lx2 with solvent, centrifuging, vacuum drying, and weighing to obtain the title compound in the form of an off-white solid.
Step 2 Synthesis of isopropyl (S) -2- [ [ (S) - (1, 1' -biphenyl-4-yloxy) (pentafluorophenoxy) phosphoryl ] amino ] propionate
In a 30L reactor, isopropyl (S) -2- [ [ (1, 1' -biphenyl-4-yloxy) (pentafluorophenoxy) phosphoryl ] amino ] propionate (3.70 kg,7.0 mol), methyl tert-butyl ether (2.40 kg), n-heptane (9.0 kg), triethylamine (77 g,0.7 mol), pentafluorophenol (43 g,0.21 mol) were added under nitrogen, and heated to 40℃with vigorous mechanical stirring. After completion of the reaction, the mixture was centrifuged and dried in vacuo to give the title compound.
Step 3 Synthesis of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy ] phosphoryl ] amino ] propanoate
1- [ (2R, 3R,4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl ] pyrimidine-2, 4- (1H, 3H) -dione finished product (1.30 kg,5.0 mol) and tetrahydrofuran (15.6L) are added into a 50L glass reaction kettle, stirred, nitrogen protected and cooled to below-10 ℃. Tert-butylmagnesium chloride solution (8.0L, 8.0 mol) was added dropwise, and the reaction was continued at 0-5℃for 1 hour. Adding isopropyl (S) -2- [ [ (S) - (1, 1' -biphenyl-4-oxy) (pentafluorophenoxy) phosphoryl ] amino ] propionate (2.12 kg,4.0 mol), reacting at 5-10 ℃ after the dripping, sampling after 10-11 h, monitoring by HPLC, cooling to below 0 ℃ after the reaction is complete, adding 2N hydrochloric acid (4.0L, 8.0 mol) into the reaction solution, and quenching the reaction. The quenching process is controlled at 0-10 ℃. After the completion of the dropwise addition, stirring for 10min. Concentrating under reduced pressure, evaporating to obtain solid-liquid residue, adding ethyl acetate (40.0L), and purified water (20.0L), and separating. Adding 5% sodium carbonate aqueous solution (10.0L) into the organic phase for washing, then washing with water, filtering, spin-drying, adding dichloromethane 7.0L again, concentrating to obtain oily foam, adding isopropyl acetate (15.0L) into the oily foam, dissolving, cooling, and precipitating a large amount of white precipitate. Cooling, filtering and drying the filter cake. Dissolving with isopropyl acetate, heating and stirring. Adding active carbon, stirring for 30min, filtering while hot, cooling, filtering, and drying the filter cake to obtain white solid.
ESI-MS m/z:604.2[M+H] - 。
1 HNMR(300MHz,DMSO-d 6 )δ:11.48(s,1H),7.67(d,2H),7.64-7.62(m,2H),7.59(d,1H),7.47(t,2H),7.37(t,1H),7.33(d,2H),6.04(d,1H),6.02(d,1H),5.83(d,1H),5.57(d,1H),4.89-4.84(m,1H),4.42-4.39(m,1H),4.29-4.24(m,1H),4.05-4.02(m,1H),3.88-3.82(m,2H),1.29-1.24(m,6H),1.16-1.15(m,6H)。
Example 2: configuration confirmation of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy ] phosphoryl ] amino ] propionate
15mg of the compound of formula 1a prepared in example 1 are weighed into a 3mL vial and 5mL of a volume ratio of 2:1 in a mixed solvent system of dichloromethane/n-heptane, shaking the obtained clear solution, covering a small bottle with a sealing film, puncturing a hole on the small bottle, and standing at room temperature for 6 days to obtain crystals.
And (3) carrying out X-ray single crystal diffraction data collection on the single crystal sample obtained by the method, and analyzing the single crystal structure of the single crystal sample. Table 1 lists single crystal structure data and structure refinement parameters for n-heptane solvates of the compound of formula 1 a. Single crystal structural analysis determines the absolute configuration of the chiral centers in the compound of formula 1a, i.e., P1 (S), C20 (R), C21 (R), C22 (R) C24 (R), C13 (S) as shown in fig. 2. The asymmetric structural unit comprises two molecules of the compound of the formula 1a and two molecules of n-heptane.
Table 1: single crystal structure data sheet for compound of formula 1a
EXAMPLE 3 solid oral forms of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methoxy ] phosphoryl ] amino ] propionate formulation
TABLE 2 prescriptions
| Compounds of formula (1 a) | 25.64 |
| Crosslinked povidone | 38.46 |
| Microcrystalline cellulose | 15.38 |
| Lactose and lactose | 12.82 |
| Croscarmellose sodium | 7.69 |
| Totals to | 100.00 |
Units: weight% (w/w).
The preparation method comprises the following steps:
a. uniformly mixing a prescription amount of a compound shown in a formula (1 a) and crospovidone and microcrystalline cellulose in a wet granulator, and adding a proper amount of the mixture
Preparing wet granules from ethanol of (a);
b. drying the wet granules;
c. uniformly mixing the dried particles with lactose and croscarmellose sodium;
d. and filling the mixed particles into capsules.
The formulation of this example disintegrated rapidly and dispersed uniformly in an in vitro dissolution test.
Examples 4-6 solid oral forms of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-yloxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methoxy ] phosphoryl ] amino ] propionate formulation
The present example examined the dissolution in vitro of formulations prepared with adsorbents of different proportions, to determine whether or not they could be dispersed as an indicator of the dissolution in vitro.
TABLE 3 prescriptions
Units: weight% (w/w)
The preparation method comprises the following steps:
a) Uniformly mixing a compound of the formula (1 a) with silicon dioxide, microcrystalline cellulose, lactose, croscarmellose sodium and magnesium stearate;
b) Tabletting.
The experimental results show that: the formulations of examples 4 to 6 all disintegrated rapidly and dispersed homogeneously in an in vitro dissolution test. EXAMPLE 7 solid oral forms of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-yloxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methoxy ] phosphoryl ] amino ] propionate formulation
In this example, the in vitro dissolution of a preparation prepared by spray drying was mainly examined, and the time to complete dissolution was used as an index.
TABLE 4 prescriptions
| Compounds of formula (1 a) | 33.33 |
| Silica dioxide | 33.33 |
| Microcrystalline cellulose | 4.47 |
| Lactose and lactose | 17.87 |
| Croscarmellose sodium | 10.00 |
| Magnesium stearate | 1.00 |
| Totals to | 100.00 |
Units: weight% (w/w)
The preparation method comprises the following steps:
a) Adding a proper amount of ethanol into a compound of formula (1 a) and silicon dioxide in a prescription amount, stirring to uniformly disperse the mixed solution, and drying the mixed solution by using a spray drying device to obtain mixed powder of the compound of formula (1 a) and the silicon dioxide;
b) Uniformly mixing mixed powder of a compound of the formula (1 a) and silicon dioxide with microcrystalline cellulose, lactose, croscarmellose sodium and magnesium stearate;
c) Tabletting.
Experimental results show that the preparation prepared by adopting a spray drying method can be completely dissolved in 10 minutes in an in vitro dissolution experiment.
EXAMPLE 8 solid oral forms of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methoxy ] phosphoryl ] amino ] propionate formulation
In this example, whether the adsorbent was completely eluted was mainly examined as to whether the adsorbent was an inorganic acid salt.
TABLE 5 prescription
| Compounds of formula (1 a) | 33.33 |
| Sodium phosphate | 33.33 |
| Microcrystalline cellulose | 11.67 |
| Lactose and lactose | 10.67 |
| Croscarmellose sodium | 10.00 |
| Magnesium stearate | 1.00 |
| Totals to | 100.00 |
Units: weight% (w/w)
The preparation method comprises the following steps:
a) Uniformly mixing a compound of formula (1 a) with sodium phosphate, microcrystalline cellulose, lactose, croscarmellose sodium and magnesium stearate according to a prescription amount;
b) Tabletting.
The results show that the preparation prepared in the embodiment can be rapidly disintegrated and completely dissolved in an in vitro dissolution experiment.
EXAMPLE 9 solid oral forms of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methoxy ] phosphoryl ] amino ] propionate formulation
TABLE 6 prescription
Units: weight% (w/w)
The preparation method comprises the following steps:
a) Uniformly mixing adsorbent crosslinked povidone and microcrystalline cellulose;
b) Stirring and dissolving the compound of the formula (1 a) in a proper amount of ethanol, and slowly adding the mixture into an adsorbent to prepare wet particles;
c) Drying the wet particles in the step b) by adopting a fluidized bed, controlling the air inlet temperature to be about 60+/-5 ℃ and controlling the material temperature to be about 50 ℃;
d) Uniformly mixing the particles dried in the step c) with croscarmellose sodium, lactose and magnesium stearate;
e) Pressing the mixed powder in a tablet press;
f) And (3) placing the plain tablets in a coating machine, and spraying a film coating premix for coating.
Comparative example 1 solid oral form of isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methoxy ] phosphoryl ] amino ] propionate formulation
The present example examined the dissolution properties of the formulations prepared with conventional adjuvants in an in vitro dissolution experiment.
TABLE 7 prescriptions
| Compounds of formula (1 a) | 85.00 |
| Croscarmellose sodium | 14.00 |
| Magnesium stearate | 1.00 |
| Totals to | 100.00 |
Units: weight% (w/w).
The preparation method comprises the following steps:
a) Uniformly mixing a compound of formula (1 a) with croscarmellose sodium and magnesium stearate in a prescription amount;
b) Tabletting.
Experimental results show that the preparation prepared in the embodiment is agglomerated at the bottom of a dissolution cup after disintegration in an in-vitro dissolution experiment, and the medicine cannot be released.
Experimental example 1 dissolution Properties of the preparation of the invention
The preparation prepared in example 9 was measured for dissolution by the dissolution method (second method of the fourth edition of the general rule 0931, 2015 of the Chinese pharmacopoeia) and 1000ml of a buffer solution of pH1.2, a buffer solution of pH3.0, a buffer solution of pH4.5 and a buffer solution of pH6.8 containing 0.05% sodium dodecyl sulfate was used as a dissolution medium at a rotation speed of 50 rpm. Sampling and detection are carried out at 5, 10, 15, 20, 30, 45 and 60 minutes respectively. The detection is carried out according to high performance liquid chromatography (the general rule 0512 of the fourth edition of 2015 of Chinese pharmacopoeia). Adopting octadecylsilane chemically bonded silica gel column, and column temperature: 30 ℃, detector: UV/DAD detector, detection wavelength 254nm, mobile phase: water-methanol (35:65), flow rate: 1.0ml/min. The dissolution curve was plotted from the data obtained from the experiment, as shown in fig. 2.
Experiments show that the preparation of the invention can be completely dissolved in the various dissolution media, and meets the regulations.
Experimental example 2 stability of the formulation of the present invention
The preparation prepared according to example 9 was left for 6 months at a temperature of 40.+ -. 2 ℃ under acceleration of 75%.+ -. 5% relative humidity and a temperature of 25.+ -. 2 ℃ under long-term conditions of 60%.+ -. 10% relative humidity, and the dissolution rate was measured according to the dissolution rate measurement method (second method of the fourth edition of the Chinese pharmacopoeia, 2015 edition, general rule 0931) using 1000ml of a buffer solution of pH1.2 containing 0.05% sodium dodecyl sulfate as a dissolution medium at a rotation rate of 50 rpm. The determination of the related substances and the content is carried out according to a high performance liquid chromatography (the general rule 0512 of the fourth edition of 2015 of Chinese pharmacopoeia) by adopting an octadecylsilane chemically bonded silica column with the column temperature: 30 ℃, detector: UV/DAD detector, detection wavelength 254nm, mobile phase: water-methanol (35:65). The experimental results are shown in Table 8.
TABLE 8 stability data for formulations of the invention
| Sample storage time and storage conditions | Content of | Dissolution rate | Total impurities |
| Day 0 | 101.7％ | 96.8％ | 0.13％ |
| Accelerated test for 1 month (40 ℃ C.+ -. 2 ℃ C., RH 75%.+ -. 5%) | 101.9％ | 99.1％ | 0.14％ |
| Accelerated test for 2 months (40 ℃ C.+ -2 ℃ C., RH75% + -5%) | 100.5％ | 100.8％ | 0.11％ |
| Accelerated test for 3 months (40 ℃ C.+ -2 ℃ C., RH75% + -5%) | 100.7％ | 100.8％ | 0.11％ |
| Accelerated test for 6 months (40 ℃ C.+ -2 ℃ C., RH75% + -5%) | 101.0％ | 97.3％ | 0.14％ |
| Long-term test for 3 months (25 ℃ + -2 ℃ C., RH60% + -10%) | 100.5％ | 98.1％ | 0.13％ |
| Long-term test for 6 months (25 ℃ + -2 ℃ C., RH60% + -10%) | 100.6％ | 97.3％ | 0.18％ |
From the above experimental results, it can be seen that the isopropyl (S) -2- [ [ [ (S) - (1, 1' -biphenyl-4-oxy) ] - [ ((2 r,3r,4r,5 r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy ] phosphoryl ] amino ] propionate preparation of the present invention can be sufficiently eluted in four eluting mediums, i.e., a ph1.2 buffer solution, a ph3.0 buffer solution, a ph4.5 buffer solution, and a ph6.8 buffer solution containing 0.05% sodium dodecyl sulfate, and has stable preparation properties, few impurities, and various indexes are not significantly changed after acceleration for 6 months and long term for 6 months, which meets the regulations.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes may be made thereto without departing from the spirit and scope of the invention, the scope of the invention being limited not by the foregoing detailed description but by the appended claims.
Claims (13)
1. An oral formulation comprising (a) a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof,
and
(b) An adsorbent.
2. The formulation according to claim 1, wherein the compound of formula (1) is a compound of formula (1 a),
3. the formulation according to claim 2, wherein the compound of formula (1 a) is in crystalline form or amorphous form.
4. A formulation according to any one of claims 1 to 3, wherein the adsorbent is selected from one or more of crospovidone, microcrystalline cellulose, cyclodextrin, diatomaceous earth, inorganic salts, inorganic acid salts, surface porous cellulose and salts thereof, starch, sugars and silica.
5. The formulation according to any one of claims 1-4, wherein the formulation is in solid form, preferably the formulation is a tablet or capsule.
6. The formulation according to any one of claims 1-5, further comprising a disintegrant, a lubricant and/or a filler.
7. The formulation according to any one of claims 1-6, wherein the compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof, based on the amount of the compound of formula (1), comprises 15% -85% (w/w) of the tablet weight of the formulation, the adsorbent comprises 15% -85% (w/w) of the tablet weight of the formulation, the disintegrant comprises 0% -20.0% (w/w) of the tablet weight of the formulation, the lubricant comprises 0% -15.0% (w/w) of the tablet weight of the formulation, and the filler comprises 0% -30% (w/w) of the tablet weight of the formulation.
8. A process for preparing a formulation according to any one of claims 1 to 7, comprising the step of combining the components of the formulation according to any one of claims 1 to 7.
9. A process according to claim 8, comprising granulating a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof and an adsorbent.
10. The method according to claim 9, wherein said granulating comprises the steps of:
a) Uniformly mixing the adsorbent in the device;
b) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof in a solvent with stirring; and
c) Adding the mixture of step b) to the adsorbent of step a), drying, and then preparing granules.
11. The method according to claim 9, wherein said granulating comprises the steps of:
a) Dissolving a compound of formula (1) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or crystal thereof and an adsorbent in a solvent to form a mixed solution; and
b) The mixed solution is dried and then granulated.
12. The method according to claim 10 or 11, wherein the solvent is an alcoholic solvent, preferably the alcoholic solvent is selected from one or more of methanol, ethanol and isopropanol.
13. Use of a formulation according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment and/or prophylaxis of flaviviridae virus, in particular hepatitis c virus infection.
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