TW213922B - - Google Patents

Description

213922 A6 B6 Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (1) The present invention relates to a 5-propa-1-alkynyl-χ used in the treatment or prevention of hepatitis B virus infection — (5 — 〇-Trimethylacetaldehyde-D-furan arabinosyl) uracil and its pharmaceutically acceptable salt. Hepatitis B virus (HBV) is a major viral pathogen worldwide. It is most common in Asia, and Africa under the Sahara is also quite common. In terms of etiology, this virus can cause major liver cancer, and it is estimated that 80% of liver cancer is caused by other people. In the United States, 10,000 people are hospitalized each year for HBV disease, and an average of 250 people die from an emergency. It is estimated that there are between 50,000 and 10,000 infectious carriers in the United States. 25% of the original will become chronic hepatitis, and usually evolve into cirrhosis. It is estimated that 5,000 people die from HBV-related cirrhosis each year in the United States, and about 1,000 people die from HBV-related liver cancer. Even though there are widespread HBV vaccines, there is still a need for effective anti-HBV compounds. Because there are about 22,000 million carriers of permanent infections in the world who cannot benefit from vaccine inoculation, and there is still a very high risk of getting HBV-induced liver disease. These carriers have become susceptible to continued disease, especially for regional or high-risk groups such as IV drug abusers and homosexuals. Therefore, there is a great need for effective antiviral agents that can simultaneously control chronic infections and slow the progression of liver cancer. Clinical symptoms of HBV infection include headache, fever, malaise, nausea, vomiting, anorexia, and abdominal pain. The replication of the virus is usually controlled by the immune response, and the recovery period of the human remains for several weeks or months, but the infection may be delayed into the above-mentioned permanent chronic liver disease. " Viral Infections of Humans " (sec-ond edition, Ed ·, Evans »AS · (1982) Plenum Publi — (please read the precautions first and then SfW this page) 丨 Installation_ Order · Line · This paper size is applicable China Sleepy Family Standard (CNS) A4 specification (210 X 297 mm) -3-213922 A6 B6 V. Description of the invention (2) shing Corporation, New York) Chapter 1 2 describes in more detail the pathogens of viral hepatitis infection . European Patent Bulletin 2 2 3 8 4A 1 shows a nucleoside for the treatment or prevention of retroviruses, including H IV, or infections caused by hepatitis B virus. It is now found that we have reviewed the European Patent Announcement 0 3 7 5 1 64-5 -propane 1 monoalkynyl 1 1 (5-0-trimethylacetyl acetyl 1/9 1 D-furan arabinose) urine Pyrimidines have the advantageous properties of treating or preventing retroviral or similar retroviral infections, especially hepatitis B infections, when used in specific liver viruses. The European patent application 91305147. 0 which we have jointly examined shows a parental compound for the treatment of hepatitis, especially hepatitis B virus infection 1 1 (/ 3-D-arabinofuranosyl)-5_propion-1 alkyne Uracil and its esters. One of the features of the present invention is the use of 5-propan-1-one-base 1-1-1 (5-O-trimethylacetamide / 3-D-arabinofuranosyl) uracil, which is a compound of the following formula (I)

(Please read note f of the page first and then write this page). Binding · Order. Thread-

• Q Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy i

(Enol or ketone form) or its physiologically acceptable form, to produce drugs for the treatment or prevention of hepatitis B infection. The present invention also proposes a mammal suffering from hepatitis B virus infection (this paper scale is applicable to China Sleepless Family Standard (CNS) A4 specifications (210 X 297 mm). 2139 ^ 2 A6 B6 Employee Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs印 f 五. Description of the invention (3) Especially for humans) The treatment or prevention method, which includes giving the mammal an effective amount of 5-propane-1 monoalkynyl-1 (5-0 trimethylacetamide / 3-D-arabinofuranosyl) uracil or its physiologically acceptable substrate. Another feature of the invention is a pharmaceutical formulation for anti-hepatitis B, which includes 5-propion-1 monoalkynyl-1- (5-0-trimethylacetyl ketone D-arabinofuranosyl) uracil Or a physiologically acceptable carrier, and a pharmaceutically acceptable carrier. Another feature of the invention is 5-propion-1 monoalkynyl-1-one (5-0-trimethylacetonitrile / 3-D-arabinofuranosyl) uracil, or its physiologically acceptable compound in treatment Or use to prevent hepatitis B virus infection. Hepatitis B that can be treated according to the present invention is discussed below. Using the compound of the invention, an advantageous therapeutic effect for the treatment or prevention of hepatitis B infection can be obtained. For example, this compound can be easily absorbed from the stomach and intestines, so it can be taken orally to a high plasma concentration of the parent nucleoside. Physiologically acceptable salts of the invention include alkali salts, such as those derived from appropriate breakers, such as alkali metals (eg sodium), alkaline earth metals (eg magnesium), and ammonium and N X t (where X is an alkyl group). Physiologically acceptable diaphragms include pharmacologically acceptable diaphragms. Invented compound 5-propan-1-ynyl-1-one (5-0-trimethylacetaldehyde-D-arabinofuranosyl) uracil or its physiologically acceptable compound can be used to treat any clinical symptoms To be administered to mammals, including humans (v patients); appropriate routes include oral, rectal, nasal, topical (including meridian and sublingual), vaginal and non-intestinal (including subcutaneous, intramuscular, intradermal, vertebral) Tube and epidural)). Know the best way to follow (please read the precautions on the $ page first and then fill out this page). 丨 Packing · Ordering · Thread. This paper scale is applicable to China National Standard (CNS) A 4 specifications (210 X 297 mm)- 5-213922 A6 B6 The Central Bureau of Economic Affairs of the Ministry of Economic Affairs, the Ministry of Economic Affairs and the People's Republic of China and the Ministry of Economic Affairs and the People's Republic of China. 5. The description of the invention (4). The amount of the inventive compound required for the treatment of hepatitis virus infection depends on many factors, including the severity of the condition to be treated and the characteristics of the patient, and is ultimately determined by the referring physician. However, in each case, the appropriate dosage is usually 1 to 100 ms per kilogram of body weight per day, preferably 5 to 30 mg per kilogram per day; the optimal amount is about 15 mg per kilogram per day. The effective dose can be given in 2, 3, 4 or more sub-doses at appropriate intervals throughout the day. This sub-dose is administered in unit dosage form, for example, containing 10 to 2000 mg, preferably 2 to 500 mg, and preferably 100 to 400 mg of the invention compound per single dose. Alternatively, if the patient needs it, it can be given by continuous injection. The compound of the invention can be used alone or in combination with other therapeutic agents, for example, other antiviral agents such as 9- (2-hydroxy-ethylethylmethyl) guanine (acyclovir), which is used to treat hepatitis virus infection , Especially HSV, especially including those of HSV (1) category, with-degassing 3-S nitrothymidine (diodine (zidovudine)) or 2 z, 3 'one or two deoxynucleosides, such as 2 > , — Dideoxycytosine, 2 one, 3 < _ dideoxyinosine, 2 >,-dideoxyadenosine or 2 one, 3 /-dideoxyguanosine, which is used to treat retrovirus infections , Especially human immunodeficiency virus (HI V) infections, interferons, especially 2-interferon and soluble proteins such as CD <, or any other agent that has a beneficial effect when combined with the inventive compound composition, such as analgesics or fever Agents are used in combination to treat or prevent viral infections. (Please read the precautions on the back first and then this page) Binding · Ordering · Thread · The paper size is applicable to China National Standard (CNS) A 4 specifications (210 X 297 mm) -6-Central Bureau of Standards, Ministry of Economic Affairs Employee Consumer Cooperative Yinli 2U922 A6 _B6 V. Description of the invention (S) The medicine used in the present invention preferably includes at least one compound of the invention (> active ingredient and one or more pharmaceutically acceptable carriers and optional other treatments) The pharmaceutical formulation form of the agent. The carrier is compatible with other formulation components and does not prejudice the person taking the medication. It is necessary for an acceptable formulation of the invention to include a formulation made by any method known in the art. The formulation of a single-dose form of any one of the above-mentioned continuous administration. This method includes the step of combining the active component with a carrier as one or more auxiliary components. Generally, the active component is first combined with a liquid carrier or a ground solid carrier Or a combination of the two, and then, if necessary, shape them to obtain a formula. The formula suitable for oral administration can be a separate unit containing a predetermined amount of active ingredients such as capsules, cachets, or lozenges; powder or granules ; In aqueous liquids Solutions or suspensions in non-aqueous liquids; edible foam or foaming milk; or water-in-oil emulsions and water-in-oil emulsions. The active ingredient can be in the form of nine, slurry or can be contained in lipid particles. Compressed or molded with one or more auxiliary components. Compressed ingots are compressed free-flowing active components such as powders or granules in a suitable machine, optionally mixed with a binder (eg povidone, gelatin, hydroxypropyl methyl) Based cellulose), lubricants, inert diluents, disintegrants (such as sodium starch glycolate, cross-linked Pov done, cross-linked sodium carboxymethyl cellulose), surface active or dispersing agents, prepared. Molded ingots are made by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The lozenges are coated and marked at will, and can be used, for example, to suit the desired release curve difference Proportion of hydroxypropyl methylcellulose is formulated to slowly or controlly release the active ingredient, or formulated into a formula that is soluble or bubbling when added to liquid. (Please read the notes on < ^ face first (^^ this page again) 丨 Install · Order.; Line · This paper ruler Applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1. 7-2139 ^ 2 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economy, Industry and Consumer Cooperatives 5. Instructions for invention (6) Fill in the appropriate charging machine Into loose or compressed powder, one or more additives are optionally added to make capsules. Examples of suitable additives include binders such as povidone; gelatin, lubricants, inert diluents and disintegrants, like tablets. Capsules can also be formulated Into H-containing granules or individual subunits, the active ingredient is released slowly or under control. This can be extruded and pelletized by adding an extrusion aid (such as microcrystalline cellulose) and a diluent such as lactose to the drug It can be coated with a semi-permeable membrane (such as ethyl cellulose, Eudragit WE30D) to produce a entangled release. Edible foam or cream theoretically includes; 50-70% edible oils, especially vegetable oils, including corn oil, peanut oil, sunflower oil, olive oil, and soybean oil; 2-10%-or more surfactants, especially lecithin , Polyhydric alcohols, polyhydric polymer esters include glycerin fatty acid esters, polyglycerin fatty acid esters (such as decaglycerol tetraoleate), or sorbitol fatty acid esters (such as sorbitol monostearate); 1- 4% suitable for ingestion of propellants, especially compressed gas propellants, especially nitrogen, vaporized nitrogen or nitrous oxide, or gaseous hydrocarbons, especially propane, butane or isobutane; 0.5-30% one Or a variety of viscosity modifiers with a particle size of 10-50 microns, especially powder or colloidal silica; and optionally 0.5-10% —or a variety of suitable and non-toxic colorants, flavoring agents, or sweeteners. The preferred concentration of the active ingredient in this formula is 10-46%, preferably 30%. The above foam or cream can be prepared in a conventional manner, for example, by mixing edible oil, surfactant and any other soluble components, adding a viscosity modifier and grinding the mixture to form a uniform dispersion and suspension. The active ingredient is incorporated into the milled mixture until it is evenly distributed. Finally, after mixing the mixture into an appropriate dispersing container, please (please read the precautions on the back and then this page)-丨 installed. The size of this paper is the general Chinese National Standard (CNS) A4 specification (210 X 297 mm > 2139 ^ 2 A6 B6 Printed by the IK Industrial Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of invention (7) A specific amount of propellant is incorporated into the mixture. If it is an infection of the eye or other external tissues, such as mouth and skin Ru, the preferred formulation is containing, for example, 0.075 to 20% w / w, preferably 0.2 to 15% w / w, most preferably 0.5 to 10% w / w of the active ingredient local Oil buds or creams .... When formulated into an ointment, they can be used together with the active ingredients as a paraffin or water-miscible oil base. Or, the active ingredients are formulated with an oil-in-water cream base or an oil-in-water base. If necessary, the aqueous phase of the cream base may include, for example, at least 40-45% w / w polyols, ie, alcohols with two or more hydroxyl groups, such as propylene glycol, butane-1,3 —Diol, mannitol, sorbitol, glycerin, polyethylene glycol and mixtures thereof. The topical formulation may include promoting active ingredients in the skin or its Compounds that are absorbed or penetrated in other application areas. Such transdermal penetration enhancers include dimethylsulfoxide and its homogenates. The oil phase of the emulsion formulations of the present invention only includes emulsifiers (or emulg-ent), but it is desirable It includes at least one emulsifier and fat or oil or a mixture of both fat and oil. Preferably, it contains both a hydrophilic emulsifier and a lipophilic emulsifier as a stabilizer. It also includes oil and fat. Emulsifier and stabilizer (Or no stabilizer) constitutes the emulsified wax, and the wax and oil and / or fat constitute the emulsified oil base that forms the oil phase of the cream formulation. Emulsifiers and emulsified stabilizers suitable for the formulation of the present invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate. The oil or fat suitable for formulation is selected based on the desired cosmetic properties, because the active compound is formulated in pharmaceutical emulsions Most of the oil used in the dissolution (please first pay attention to the «$ side and then fill out this page)-丨 installation · order · line-this paper standard applies to China ’s 0 standard (CNS) A 4 specifications (210 X 297 Mm) 2 139 ^ 2 A6 B6 Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. The description of invention (8) is extremely low. The cream is preferably non-greasy, non-staining and washable, and should have an appropriate viscosity to Avoid leakage from tubes or other containers. Available with straight or branched bonds, single or dibasic alkyl esters such as diisoadipate, isostearate stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, Decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a branched ester of Crodamol CAP, the last three of which are preferred esters. Use individually or in combination according to the desired properties. Alternatively, high melting point lipids such as paraffin wax and / or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. 5% w / w。 The preferred concentration of the component in the formulation is 0.5 to 20%, preferably 0.5 to 10%, especially about 1.5% w / w. Formulations suitable for topical administration in the oral cavity include sunflower-shaped tablets containing active ingredients in adjusted materials, usually sucrose and gum arabic or tragacanth; tablets containing sugar in inert materials such as gelatin And glycerin, or the active ingredient in sucrose and gum arabic; mouthwash, which includes the active ingredient in a suitable liquid carrier. Recipes for rectal administration can be suppositories with suitable qualities such as cocoa butter or higher fatty alcohols (e.g., Pharmacopoeia) or triglycerides and saturated fatty acids (e.g. Witepsol). The carrier is a solid formulation suitable for nasal administration including a coarse portion with a particle size of 20 to 500 microns. The method of administration is to rapidly inhale the grate channel from a powder container near # 子. The carrier is a suitable liquid formulation, such as #spray or nasal drops, including water or oil solution of the active ingredient. (Please read the precautions on the back before writing this page) This paper scale is applicable to the National Standard (CNS) A 4 specifications (210 X 297 mm) -10-139 ^ 2 A6 B6 Economic Central Standard Bureau Printed by the Industry and Consumer Cooperatives 5. Description of the invention (9) The formula suitable for vaginal administration can be the formula of Ziguan, tampon, cream, gel, paste, foam or spray, except for the active ingredients. It also contains vectors known in the technical community. Formulations suitable for parenteral administration include aqueous and non-aqueous non-barley injections, which may contain anti-gas agents, group granules, bacteriostatic agents, and solutions that make the formulation isotonic with the patient's blood; and may include suspensions and Aqueous and non-aqueous sterile suspension of thickener. The formulations can be single-dose or multi-dose containers, such as sealed ampoules and vials, which can be stored under lyophilized strips, and only need to add a sterile liquid carrier, such as water for injection, before use. Instant injections and suspensions can be prepared from the aforementioned sterile powders, granules and lozenges. The preferred single-dose formulation contains the above-mentioned daily dose or sub-dose, or an appropriate proportion of the active ingredient. It is known that in addition to the above components, the formulation of the present invention may include other agents conventionally used in the studied formulation, for example, those suitable for oral administration may include flavoring agents. Inventive compounds can be prepared by any known method of similar compounds (for example, UK Patent Specification 1 601 020, EP Bulletin 6 1283 and 27 0 65, or 1 〇151113 from .11. And 8 & 1: 1: 1 ,? . ". J. Org. Chern. (1983) 4 8. 1854-1862), and the method described below. The compound of the present invention can be shown as follows: A. The compound of formula (I) [ie, 1- (々-D-arabinofuranosyl) -5 ---------------------------------- ------ install ------ order ----- 【Line (please read the note first and then write the page) This paper size is applicable to China National Standard (CNS) A4 specifications ( 210 X 297 Gongmeng) ~ 11-2139 22 · Λ6 B6 V. Description of the invention (10) Bingyi 1 Yiji Jiuria] 〇

C = CCH,

(Π) (Please read the precautions on the back before filling this page) 5 * ‘3’3

Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and reacts with a compound that provides trimethylacetyl at the 5th position of the sugar part; or B. Compound (III) of formula (Π) where B is purinyl or pyrimidinyl (Except 5-propion-1 alkynyl uracil), react with 5-propan-1 alkynyl uracil; then, or at the same time, arbitrarily convert, if the compound formed is a compound of formula (I) into its base ; Or, if the compound formed is 塩, convert it into a different 塩 or compound of formula (I). Afterwards, the active compound can be combined with a carrier to formulate a pharmaceutical formulation against HBV. In terms of method Α, the compound of formula (I) can be prepared from the compound of formula (I). This paper is also suitable for the Chinese and Western Yujia Standard (CNS) A 4 specifications (210 X 297 mm) -12-Α6 Β6 Central Ministry of Economic Affairs Standard Μι Ά Industrial and Consumer Cooperatives printed five, the description of the invention (11), the preparation method is described in EP notice 272065, for example, using a suitable cooling agent such as trimethyl acetyl halide (such as chlorinated compounds) or trimethyl acetic anhydride , Preferably in the presence of a base such as pyridine or triethylamine (which also serves as the reaction solvent), 0 ° _70t :, preferably 0 °-30 * C temperature acetylation. The ratio of the acetylating agent to the compound of formula (I) is preferably about 1.2: lw / w. Furthermore, the compound of formula (I) can also be prepared from the compound of formula (I) using appropriate trimethylacetate (e.g. methyl ester) in the presence of pyridine or triethylamine which is also a reaction solvent. In addition, the esterification reaction can be carried out in, for example, a solvent such as pyridine or dimethylformamide, a coupling agent such as N, N-dicyclohexylsulfonated diimide, and a catalytic base such as 4-dimethyl The aminoaminopyridine was carried out using the aforementioned acetylating agent. Next, the reaction product ester is isolated in a conventional manner. To method B, the B group is preferably a purine or pyrimidinyl group, which can be used, for example, an enzyme such as a phosphorylase in the presence of a phosphate base at a temperature of p Η 5.0-9.0 and 15 °-90 ° C. Good 40 °-60t: Give the esterified sugar to 5-propan-1-alkynyluracil. The invention can also be prepared in a conventional manner, for example, a compound of formula (Ε) reacts with an appropriate base to form a corresponding base, and then acetylates. Moreover, the corresponding sodium salt can be formed by reacting the esterified compound with a base such as sodium hydride. The other derivatives of the invention can also be prepared according to conventional methods. The following examples illustrate the invention and should not limit the invention. Example 1

5—Propyl-1—Quicki-1— (5—0—Trimethyl ethyl alcohol-D-D-D This paper scale is in accordance with China ’s National Standard (CNS) A4 specifications (210 X 297 mm) (please first (Please fill in this page for the notes on the 4MC) -13-:, 3 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Labor and Consumers Cooperatives V. Description of Invention (12) Eyebrow arabic g) Urine favors 1 1 (/ 3 — 1-arabinofuranosyl) —5-propan-1-block uracil (0.28 g, 1 mmol, synthesized by the method described in EP Bulletin 272065) in anhydrous pyridine (the stirring solution in 5 min at 0 t: Under anhydrous nitrogen, a solution of trimethyl acetyl chloride (0.15 m, 0.14 g, 1.2 mmol) in anhydrous dichloromethane (5mi2) was added dropwise over 10 minutes. The mixture was stirred at 0¾ for 90 minutes , And then stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the remaining pyridine was co-evaporated with part of ethanol (3x25mi) to produce oil. Chromatography was performed on a silica gel column and eluted with 8% methanol / dichloromethane to produce The pure product was triturated with ether to produce a white solid identified as the target compound. Mpt: 204-210 ^ 0 Analytical measurement: C 55.74, Η 6.011, 7.65% experiment: C 55.95, Η 6.006, Ν 7.525% ^ (dffDMS0) 11.55 (lH, 6s, NH), 7.58 (lH, s, H-6), 4.4-4.13- (2H, m, H- 5 '). 4.08-3.89 (3H, m, H-2,, H-3', H-4 *), 1.97 (3H, s, C = (CH3), 1.19ppm (9H, s, tBu). Fen Shi Example 2 (please read the precautions on 3 sides before filling in this page) 丨 installation. Order-i line- This paper size is applicable to China National Standard (CNS) A 4 specifications (210 X 297 mm) -14-2139 ^ 2 A6 B6 Fifth, the description of the invention (13) 5-propion one 1-a certain one one (5-trimethyl ethyl brewing a call one D-Ying Zui Holabose sugar) urinary uridine sodium surprise A suspension of sodium hydride in anhydrous tetrahydrofuran (4m) (0. 05 g 8 0 96 w / v suspension in oil, 1.66 mmol, (washed with anhydrous tetrahydrofuran several times) was added to 5-propylene 1-1-alkynyl-1 1- (5-trimethylacetaldehyde-1 / 3-D-arabinofuranosyl) uracil (◦. 0 6 g, 1.6 4 mmol) in a stirring solution in anhydrous tetrahydrofuran , To be sure that there is no moisture. After 1 hour, the solvent is evaporated to produce 0.1 g of the required sodium salt. The following example illustrates the pharmaceutical formulation of the invention, in which the active component A is the compound of formula (I) Thing. (Please read the precautions on page i and then this page) The Central Sample Bureau of the Ministry of Economic Affairs β Industry Consumer Cooperative Printed Tubes Example A Eye shovel water active component 0.5 g sodium chloride, analytical grade 0.9 g Th i omer sa1 0.001 g of pure water is added to 100 id 1 P Η is adjusted to 7.5 峬 渝 例 B: Blooming formula The following formulas A, B and C are granulated by components and povidone solution, then added magnesium stearate and pressed to obtain . This paper scale is applicable to the Chinese National Standard (CNS) A 4 specifications (210 X 297 mm) 15-15 2139 ^^ A6 B6 printed by the Ministry of Economic Affairs Central Standards Bureau employee consumer cooperative 5 clothing, invention description (14) Formulation A ( a) Active ingredient (b) Lactose B. P. (c) Pov i done B · P (d) Sodium starch glycolate (e) Magnesium stearate

Formulation B (a) Active ingredient (b) Lactose (c) Avicel PH 101 (d) Povidone BP (e) Sodium starch glycolate (f) Magnesium stearate formulation C mr / sat m κ / record 250 250 210 26 15 9 20 12 5 3 500 300 m κ / recording m κ / recording 250 250 150-60 26 15 9 20 12 5 3 500 300 m β / recording (please read the precautions on the back before filling in this page) --install . Order. U The size of this paper is in accordance with Chinese National Standard (CNS) A4 specifications (210 X 297 mm)-16 16 2139 ^ 2 5. Description of the invention (15) Active ingredient 100 Lactose 200 Starch 50 Povidone 5 Stearic acid Magnesium 4 359 The following formulas D and E are prepared by direct compression of the mixed components. The lactose used in formula E is the direct compression type. Formula D m κ / Nylon active component 250 Pregelatinized starch NF15 150 400 (please read the back Please pay attention to this page and then write this page.) The Ministry of Economic Affairs Central Standards Bureau R Industrial Consumer Cooperatives printed the formula E IP / tablet active ingredient 250 lactose 150 Av i ce1 100. The paper size is in accordance with China National Standard (CNS) A4 specifications ( 210 X 297 mm) -17-2139 ?, 2 A6 B6 V. Description of the invention (16) 500 Formula F (捽Formula) This formula is obtained by wet granulation of the following components and Povidone solution, then adding magnesium stearate and pressing. / Ingot (a) Active component (b) Hydroxypropyl methylcellulose (Methocel K4M Premium ) (c) Lactose BP (d) Povidone BPC (e) Magnesium stearate 500 112 53 28 __7 700 The drug is released after about 6-8 hours and completely after 12 hours -------- ---------------- Installed ------ ordered ------ line (please read the precautions on the back before 9 ^ this page) Central Bureau of Standards, Ministry of Economic Affairs β: Printed by the Industrial and Commercial Cooperative Society Example C: Gel formula Formula A The gel formula is obtained by blending the uncompressed components of the formula D in Example B above and filling it into a two-piece hard gelatin capsule. Formula B (Below) The paper is prepared in a similar manner. The paper scale is applicable to the Chinese Standard (CNS) A 4 specifications (210 X 297 mm) -18-2139? .2 A6 B6 V. Description of the invention (17 (a ) Active ingredient (b) Lactose BP · (c) Sodium starch glycolate (d) Magnesium stearate mg / shot capsule 250 143 25 2 420 (Please read the precautions on the back before writing this page) i Pack-

Formulation C mg / fl. It is printed by the R and Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. (A) Active component 250 (b) Macrogol 4000 BP 350 600 Capsule is to melt Macrogol 4 0 0 0 BP and disperse the active component. It is obtained from the melt and filled into a two-piece hard gelatin capsule.

Fang D in g / duty ϋ Active component 250 This paper scale is applicable to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) -19-2139? .2 A6 B6 V. Description of the invention (18) Lecithin 100 Peanut oil 100 450 capsules are made by dispersing the active ingredients in lecithin and peanut oil and filling the dispersion into soft, elastic gelatin capsules. Formulation E (漽 释 腿 ϋ) The following controlled-release formulation is obtained by extruding the components (a), (b) and (c) using an extruder, followed by spheroidizing and drying the extrudate. The dry granules are then coated with a controlled release film (d) and filled into a two-piece, hard gelatin capsule. mg / halo (a) Active component 250 (b) Microcrystalline cellulose 125 (c) Lactose BP 125 (d) Ethyl cellulose 13 513 (please note the parent before writing this page) Ministry of Economic Affairs Printing and injection of BR by the Central Bureau of Standards and Staff Consumer Cooperatives. Case D: Active component 0.200 This paper scale is applicable to China National Standard (CNS) A 4 specifications (210 X 297 mm) -20-A6 B6 2139 * ^ 2- 5. Description of the invention (19) Sterile, pyrogen-free phosphate buffer (pH 7.0) is added to 10 ml. The active ingredient is dissolved in most of the basic acid buffer (3 5-40t!), Then make up the volume and pass Sterile filter is filtered into a sterile l〇m and amber color glass bottle (type 1) and sealed with a sterile stopper and jacket. Example F:: fl / l meat pancreatic active group 0.20 g phenyl alcohol_ 0.10 g

Glycofurol 75 1.45 g water for injection is appropriately added to 3.00 ml (please note $ item before f page) 丨 Pack. Order · The active ingredient is soluble in glycofurol. Then add benzyl alcohol and dissolve, add water to 3m J ?. The mixture is filtered through a sterile microporous filter and sealed in a 3m sterile glass bottle (Class 1). Fenshi Example F: Floating active component of syrup county sorbitol solution glycerin dispersible cellulose sodium benzoate This paper scale is applicable to China National Standard (CNS) A 4 specifications (210 X 297 public line _ Ministry of Economic Affairs Central Standard Printed by the Bureau of Male Workers and Consumers Cooperatives 0.2500 g 1.5000 g 2.0000 g 0.0750 g 0.0050 g -21-2139 ^ 2 Α6 Β6 Central Bureau of Standards of the Ministry of Economic Affairs 8 Industrial and Consumer Cooperation Du Printed 5. Description of invention (20) Seasoning, Peach 17.42. 3169 0.0125ml pure water is appropriate to 5.000ml sodium benzoate dissolved in part of pure water and added sorbitol solution. Add active component and disperse it. Disperse thickener (dispersible cellulose) in glycerin. Mix The two dispersions were adjusted to the required volume with pure water. Example Η: Suppository mg / agent active component (63 am) 250 stearin, used in BP (Witepsol H15-Dynamit Nobel) 1770 2020 The active component is a powder, at least 90% of the particles are 63 wm in diameter or smaller. One-fifth of the Witeps〇l Η 15 is melted in a steam cooker up to 45 ° C. The active component is sieved through 2 0 0 wm sieve and mix with silverson equipped with cutting head Add to the molten base layer until a uniform dispersion is obtained. The mixture is maintained at 4 5 * C, and the remaining Witepsol Η 15 is added to the suspension and stirred until uniformly mixed. The suspension is passed through a 2 5 0 wm stainless pin sieve and, in continuous With stirring, cool to 40¾. At 38Ϊ: to 40t: (Please read the precautions on the back before writing this page) i Pack-Book.

U This paper scale is applicable to the Chinese national standard (CNS> A4 specifications (210 X 297 mm> -22-2139 ^ ** · A6 B6 5. At the temperature of the invention description (21)》 2. 0 2 g mixture wave Cool it to room temperature with a suitable plastic medicine. ° Make the suppository test Example H: Qiangongtuo active ingredient 63wm Anhydrous glucose potato powder magnesium stearate 250 380 363 _7 1000 Write this page]-Pack directly to mix the above components and directly compress the resulting mixture to obtain a pessary. Fen Shi Example I: Partially Threaded Line Printed Cream Active Compound 5.00g Glycerol 2.00 g Eucalyptus Stearyl Alcohol 6.75g Sodium Lauryl Sulfate 0.75g White Soft Paraffin 12.50g Liquid Paraffin 5. OOg This paper is again applicable to the National Standard (CNS) A 4 specifications (210 X 297 public law) -23-Α6 Β6 V. Description of the invention (22) Gas cresol 0.10s (please read the precautions first and then the winter page) Pure water is added to 100 · 00β The active compound is dissolved in the mixture of pure water and glycerin and heated to 7 0 υ . The remaining components are heated together at 7 Ot. Blend the two and emulsify .Cool and filter into the container. Because 5-propa-1-alkynyl-1-1- (5--0-trimethylacetic acid-1 / 3-D-arabinofuranosyl) uridine in the body-converted into parent Compound 1 (/ S-D-arabinyl furanosyl)-5_propane-1-alkynyl uracil, so antiviral tests were carried out on the parent compounds, although the bioavailability test is in the invention compound (and its base) (HangG disease, human HBV production cell line HepG2, 2. 2.15, described in Sells et al., PNAS 84: 1005, 1987 and J. Virol. 62: 2836, 1988), apparently chronic HBV The waitability of infected hepatocytes. It is proved to be infectious by its pathogenicity in chimpanzees. This cell strip is used outside the skull to identify compounds with anti-H BV activity. The Ministry of Economic Affairs Central Standards Bureau Staff Consumer Cooperative printed 5 clothes The layer culture was treated with 1_100ϋΜ active compound 1-(cold D-arabinofuranosyl) _5 -propion-1 monoynyluracil for 10 days. The supernatant containing extracellular virus particle DNA (Dane particles) was at the 10th Remove on day and treat with proteinase K (lmg / miH and sodium dodecyl sulfate (1%) Incubate at 50¾ for 1 hour. DNA is extracted with equal volume of phenol, followed by gaseous extraction, and precipitated with ammonium acetate and propanol. This paper is also applicable to China National Standard (CNS) Grade 4 (210 X 297 public goods) -24-A6 B6 V. Description of the invention (23) DN A precipitate was dissolved and collected in nitro using Schleicher and Schuell (S & S, 10 Optical Ave ·, Keene »NH 03431, Publication # 700 * 1987) Cellulose, and treated as Southern, J. Mol. Biol. 98: 503, 1975. The cells were collected, and the cells were lysed with guanidine isothiocyanate to obtain intracellular DNA. Intracellular DNA operates in the same way as extracellular DNA. After being killed by ammonium acetate and propanol, the intracellular DNA precipitate was dissolved, endonuclease restriction enzyme, H-ind Iff, cut, applied to an agarose gel, and then treated as described in Southern to determine The amount of copy-type intermediate type. The antiviral effect of the drug is determined by measuring the reduction in the amount of Dane particles (extracellular DNA) squeezed into the culture medium and the reduction in similar intracellular replication intermediates (intracellular replication type). (Please read the precautions on the $ page first and then f this page) i Pack · Order-if the paper size printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is in accordance with the Chinese National Standard (CNS) Grade 4 (210 X 297); *) -25-2139 ^. ^ A6 B6 V. Description of the invention (24) Table 1 ΙΟΟ / iMl — (> 3-D_Yanan arabinosyl) —5—propa-1-alkynyl very uracil pair B Percent (increase) inhibition of Hepatitis D DNA hh Experiment number Intracellular replication-type DNA released by extracellular medium Experiment 1 95.1% 87.9% Experiment 2 92.4% 92.2% Experiment 3 87.6¾ 79.1¾ Experiment 4 86.5¾ 75.5 % (Please read the precautions on the back and then fill out this page) The paper printed by the R and Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs is printed in accordance with the Chinese National Standard (CNS) Grade 4 (210 X 297 mm) -26-2139 ^ 3 A6 B6 V. Description of the invention (25) Table 2 (reduced) oil and glucose ratio of hepatitis B virus DNA in extracellular medium_Zhexibi_ 1_ (It is a D-arabinofuranosyl group) Experiment 5 Experiment 6 One 5-propanone 1 concentration of alkynyl uran (please read the precautions on the back before filling in the clothing page) ΙΟΟμΜ 94-4 98.5 (88 ) (95.3) 33μΜ 87.4 89.1 ΙΙμΜ Ν. I. 71.5 37μΜ 55.3 Ν. I. Binding N. I. = unmeasured inhibition rate The parentheses are the% reduction of intracellular type B virus DNA replication type. Q. The Ministry of Economic Affairs, Central Standards Bureau, S Industry and Consumer Cooperatives printed a copy of the appropriate standard home country) 1 (21 * Gong 97 27 2139 ^ 2 A6 B6 V. Invention description (26) Table 3 Hepatitis B specific B Inhibition of endogenous replication (RF) DNA. Fen Luo 7 (Please read the precautions on the back before filling in this page) 1 1 (/ S_D — B furan ala 1μΜ 1 Ομ Μ ΙΟΟμΜ primary glycosyl) 5 -Concentration of propion-1-alkynyl uracil 35 $ 33% 42% The measurement of oral bioavailability by the Ministry of Economic Affairs, Central Bureau of Standardization, Beigong Consumer Cooperatives, and the dose of 5 Om g / kg administered to Long Evans Rat Example 1 compound and parental compound. Urine was collected 24, 48 hours after administration, ultrafiltration, and analyzed by reverse phase high-pressure liquid chromatography. The oral bioavailability of the compound of Example 1 and parental compound was collected 4 1 in the urine at 8 o'clock (/ 3-arabinyl furanosyl)-5-propane 1-alkynyl uracil, which is the percentage of the parent compound. The urine recovery rate of the compound (% Dose) 'Example 1 64.89 Parent compound 9.70 This paper scale is applicable to China Standard (CNS) A 4 specifications (210 X 297 public dreams) ~ 28 " 2139 ^^ A6 B6 V. Description of the invention (27) The cell toxicity of shame is evaluated by cell growth inhibition. On the 96-well culture dish The lower-layer fusion culture of growing Vero cells is exposed to different dilutions of the drug, and daily ingestion with tetrazolinm day (MTT) determines the cell viability on the replication culture. The concentration required to inhibit 50% cell viability at 96 hours is called It is CC I D5 .. CCIDso (w Μ) for 96hr in the example (please read the notes before reading this page) 1 4 7 7 The paper standard printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is printed in accordance with Chinese national standards ( CNS) A 4 specifications (210 X 297 mm) -29-

Claims (1)

6. Attachment 1 (a) of the patent application park: No. 81 1 09500 Special Correction Application Chinese application patent scope amendment Amendment 1 of the Republic of China in 1982 6 years-a kind of anti-hepatitis B pharmaceutical composition, which contains 5- Propyl-1, one-block one- (5—0—trimethyl ethyl alcohol /?-D-B furan arabinosyl) uracil or its physiologically acceptable salt as active ingredient, and pharmaceutically acceptable The carrier. 2. The pharmaceutical composition according to item 1 of the patent application scope is a dosage form suitable for oral administration. 3 _ If the pharmaceutical composition according to item 1 of the patent application is in the form of tablets or capsules. 4. The pharmaceutical composition according to item 1 of the patent application scope is a dosage form suitable for parenteral administration. 5. A pharmaceutical composition according to any one of items 1 to 4 of the patent application scope, whose unit dosage form contains 10 to 100 mg of active ingredient. --------------- ^ -------- installed ------ tr --- < 4 (Please read the precautions on the back before filling this page ) The paper printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs is again applicable to the Chinese National Standard (CNS) A 4 specifications (210 X 297 mm)