KR20100087241A - Adefovir dipivoxil orotic acid salt and process for the preparation - Google Patents

Abstract

The present invention relates to a novel salt of Adefovir dipivoxil and a method for preparing the same, and in particular, by reacting adefovir dipivoxyl with orrotic acid in water without using an organic solvent, represented by Chemical Formula 1 Provided are methods for synthesizing novel adefovir dipoxyl ororates.

[Formula 1]

Description

Adefovir dipivoxil orotic acid salt and process for the preparation}

The present invention relates to compounds in the form of new salts and to compositions thereof, in particular 9- [2- [bis (pivaloyloxy) -methoxy] phosphinyl] methoxy] ethyl [adenine orotate ( Hereinafter referred to as adefovir dipoxyl orotate.), And a pharmaceutical composition comprising the salt. The invention also relates to a process for the preparation of new salt compounds of said adefovir difficile.

Acute and chronic liver infections caused by Hepatitis B virus (HBV) have been selected as a major public health crisis affecting nearly 2 billion people in the United States, including 1.7 million (WHO report). It is estimated that there are 350 million chronic carriers of HBV in the world. According to the Centers for Disease Control, nearly 3 to 7 million people die each year from complications associated with infections such as liver cirrhosis and hepatocellular carcinoma. A significant number of liver transplant recipients continue to need effective anti-HBV therapy.

HBV is recognized as an important etiology for causing liver cancer in many people. HBV infection also results in blunt hepatitis, a fatal disease that destroys the liver. Chronic hepatitis infection causes chronic persistent infections, fatigue, cirrhosis, liver cancer and death. The epidemiology of HBV infection is similar to that of human immunodeficiency virus (HIV). Many HIV carriers are coinfected with HBV. However, HBV shows 100 times higher infectivity than HIV. Currently three anti-HBV drugs have been approved for clinical use, but there is a significant medical need due to the rapid development of resistance and dosing-limiting toxicity associated with therapy. Drugs approved for clinical use include alpha interferon, genetically engineered proteins, and nucleoside analogs such as lamivudine, and entacapvir. Another approved anti-HBV drug is Adefovir dipivoxil, which is considered a mononucleotide phosphonate analog.

Adefovir dipivoxil is an antiviral drug and a nucleotide reverse transcriptase inhibitor. Adefovir difficile is a representative drug that has antiviral activity in human against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). . Chem., 1994, 37, 1857-1864 and J. Infect. Dis., 1997, 176 (2), 406. Such adefovir difficile has been developed in various forms in amorphous and anhydrous crystalline form, crystalline hydrate form, solvate form, and salt form in accordance with the needs of pharmaceutical formulations and materials stability, industrial productivity and the like. In particular, Korean Patent No. 0618663 introduces various crystalline forms and acid addition salts. In particular, inorganic acid salts such as hemisulfate, hydrogen bromide, hydrogen chloride, nitric acid and mesylate, ethane sulfonate, β-naphthalenesulfonate, α-naphthalenesulfonate, (S) -camphorsulfonic acid, succinic acid, fumaric acid, maleic acid, Organic acid salts such as ascorbic acid and nicotinic acid are introduced. However, in order to prepare these salts, since adefovir difficile is poorly soluble in water, a method for preparing adefovir difficile salts by dissolving adefovir difficile in an organic solvent and reacting with inorganic or organic acids is introduced.

However, this manufacturing method has a disadvantage in that residual organic solvent problems caused by using an organic solvent may occur. In addition, some organic acids have low solubility in the organic solvents used, and an excessive amount of organic solvents have to be used to dissolve them. The production of these salts may take several months, which is a problem in terms of commercial production and economics. There is.

These various forms of adefovir difficile acid addition salts are known to differ in their physicochemical and pharmaceutical properties. Therefore, in selecting these crystal forms, it is necessary to determine the form of the salt in consideration of various factors such as stability, clinical use, manufacturing cost, industrial productivity, and the like. Disclosed are a new salt capable of mass production of phosphorus and a method of preparing the same.

Therefore, the present inventors have conducted research to synthesize acid addition salts that satisfy various factors as described above and are useful for the pharmacological treatment of adefovir difficile. Orrotic acid known as vitamin B ₁₃ Was used to synthesize adefovir difficile ororate.

Orotenic acid, a vitamin B ₁₃ , is a growth promoter found in milk, and its function and source are relatively unknown. However, vitamin B ₁₃ is known to be abundant in milk and vegetables, and it is a vitamin necessary for the synthesis of nucleic acids. It is known as a vitamin that helps the cell regeneration process and liver function. It is commonly known that it is used universally in.

Further, the pka value of orotic acid is known to be about 2.4 in the literature. Therefore, since the pka value of adefovir difficile is known to be about 3.75, it can be predicted that orotic acid and adefovir difficile can form acid addition salts.

Therefore, it is expected that orotic acid having such an advantage forms adefovir difficile acid and acid addition salts to increase the effect of adefovir difficile drug, and has excellent physicochemical stability and commercial productivity, and residual organic solvent by using water as a reaction solvent. There is no problem at all, and a method for mass production in a simple process has been developed to complete the present invention.

In order to achieve the above object, the present invention relates to a method for preparing adefovir difficyl ororate and its salt represented by the formula (1) without using an organic solvent as adefovir difficile and orotic acid as shown in Scheme 1 below It is a method for preparing adefovir difficile ororate in aqueous solution.

Scheme 1

Adefovir difficile used in Scheme 1 is described in US Pat. No. 5,663,159 and J. Med. Chem., 1994, 37, 1857 can be readily prepared by the method described, orotic acid is a commercially available organic acid.

However, although pka values of adefovir difficile and orotic acid are in the range where salts can be made, orotic acid is poorly soluble in both organic solvents and water, and adefovir difficile is poorly soluble in water. Salts were not readily prepared by simply mixing and dissolving known acids and bases in a solvent or aqueous solution and then precipitating the salts. However, it was found that each of the basic adefovir difficile and the acidic orotic acid can be converted into an aqueous solution by neutralization with a strong acid such as hydrochloric acid and a strong base such as sodium hydroxide in the aqueous solution. Is dissolved in an aqueous acid solution (preferably an aqueous hydrochloric acid solution), and the acidic substrate, orotic acid, is dissolved in an alkaline aqueous solution (preferably an aqueous sodium hydroxide solution), and then the two solutions are mixed to form adefovir dipoxyl ororate. This is generated at a high speed. At this time, Adefovir difficile ortholate has low solubility in water, and NaCl, an inorganic salt produced by the reaction of acid and base used to neutralize each substance, has a very high solubility in aqueous solution. Ororate can be easily obtained in aqueous solution, and the neutralizing NaCl inorganic salt is dissolved in aqueous solution and can be easily removed.

At this time, the concentration of hydrochloric acid used is irrelevant to the concentration and the amount, but when using a high concentration of hydrochloric acid, the coating chamber of adefovir difficile occurs, and when using a low concentration of hydrochloric acid, excess water is used. This has the disadvantage of producing a large amount of waste water. In addition, the concentration of the aqueous sodium hydroxide solution is also irrelevant. However, it is necessary to neutralize the aqueous hydrochloric acid solution by using the same concentration of hydrochloric acid to be used to increase the purity and yield of adefovir difficyl ororate. Therefore, the concentrations of hydrochloric acid and sodium hydroxide to be used can be used at 0.1N ~ 6N, most preferably 1N ~ 2N concentration is used. It is preferable to use 1 to 5 equivalents in an equivalent ratio, and most preferably, 2.0 to 3.0 equivalents are used. If the amount is less than this, oral acid does not dissolve well in the sodium hydroxide aqueous solution, and more than this results in a large amount of waste water, which is not advantageous.

In addition, the amount of adefovir difficile and orroic acid used in the reaction is most preferably used in an equivalent ratio of 1: 1, and in the case where the ratio of adefovir difficile is higher than this, it leads to the loss of expensive adefovir difficile. If less than this, orotic acid may remain and be present as an impurity.

The reaction temperature in the reaction is most preferably 20 ~ 40 ℃, if it is lower than this problem of dissolution of adefovir difficile, if higher than this there is a fear that the coating of the adefovir difficile deviate there is no particular advantage. .

On the other hand, it has been recognized that tolerant variants of HBV may appear after continuous treatment with antiviral agents. Tolerability is most typically caused by enzymes used in the viral life cycle, and most typically in the case of HBV, by mutations in the genes that coat the DNA polymerase. Recently, the efficacy of a drug against HBV infection persists by administering this compound in parallel or alternating with a second, and possibly third, antiviral compound causing the mutation and other variations caused by the main drug, It is known that it can be augmented or preserved. Independently, the pharmacokinetics, biodistribution, or other variables of the drug may be altered by this combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy. The reason for this is that concurrent therapies cause multiple simultaneous stresses against the virus.

The anti-hepatitis B virus activity of the adefovir dipoxyl ororate salts provided herein can be increased by administering two or more of these nucleosides in parallel or alternately. The adefovir dipoxyl ororate salts provided in the present invention are anti-hepatitis β-L-2-hydroxymethyl-5- (cytosine-1-yl) -1,3-oxathioran (3TC), cis-2-hydride. Roxymethyl-5- (5-fluorocytosine-1-yl) -1,3-oxathiorane (FTC), β-L-2'-fluoro-5-methyl- arabinofranosyluridine (L -FMAU), β-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9- [4 -Hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] -6H-purin-6-one (entecavir), 9-((1R, 2R, 3S) -2,3-bis (hydroxy It may be administered in combination or alternately with one or more selected from methyl) cyclo-butyl) guanine (lobucavir), ganciclovir and ribavirin.

Compositions comprising a compound of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

The drug composition according to the present invention may conveniently use any route suitable for administration, for example, oral administration, topical administration, parenteral administration or inhalation administration, and preferably, orally. Typically, the compositions of the present invention can be obtained by standardized methods known in the art, using carriers in the prior art. Such methods include mixing, granulating and tabletting. It is well known to those skilled in the art that pharmaceutically acceptable carriers or excipients will depend on the amount of active ingredient to be mixed, the route of administration and other known factors. The composition comprises about 1 to 40% by weight, preferably 5 to 30% by weight of adefovir difficyl ororate as the active ingredient.

The adefovir dipoxyl orotate of the present invention is readily absorbed after oral administration and rapidly degrades to its parent compound, 9-[(phosphonomethoxy) ethyl] adenine (PMEA, adefovir). To date, the main formulations including adefovir difficile are suspensions, tablets and capsules.

Studies have shown that adefovir dipoxyl ororate is included in an aqueous suspension, and the bioactivity of adefovir is independent of the solubility of the drug. Thus, adefovir difficyl ororate in a suitable formulation is a tablet or capsule. The drug can be compressed into solid unit dosage forms such as pills, tablets, or mixed with a suitable pharmaceutically acceptable carrier followed by capsule processing. Additives according to the prior art, for example fillers, colorants and binders, can be added to the preparation of unit dosage forms such as tablets. Typically, dosage forms for treating AIDS comprise adefovir difficile ororate in an amount of 100 to 500 mg / unit, preferably 100 to 300 mg / unit. Formulations for the treatment of hepatitis B comprise adefovir difficile ororate in an amount of 1-100 mg / unit, preferably 5-40 mg / unit. According to the invention, the pharmaceutically acceptable carrier is an organic or inorganic carrier which can be administered together with the active ingredient, for solid pharmaceutical preparations, for example excipients, lubricants, binders and disintegrants, pharmaceuticals Acceptable additives such as colorants, sweeteners and the like.

As preferred excipients, lactose, sugar, D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC-Na), gum arabic , Dextrin, amylopectin, light anhydrous silicic acid, synthetic aluminum silicate, aluminum-magnesium silicate and the like. Preferred lubricants include magnesium stearate, calcium stearate, talcum powder and silica gel.

Preferred binders include α-starch, sucrose, glutin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sugar, D-mannitol, trehalose, dextrin, Amylopectin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), pyrrolidone and the like. Preferred disintegrants include lactose, sugar, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hard anhydrous silica acid and low-substituted hydroxypropyl cellulose. As a preferable coloring agent, water-soluble edible dye citric acid yellow, for example, edible red No. 2, edible yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2; Water-insoluble dyes such as the aluminum salts of the above-mentioned edible dye citric acid yellow; Natural dyes such as beta-carotene, chlorophyll and iron red. Preferred sweeteners include saccharin sodium, potassium glycyrrhetinate dibasic, aspartame and stevioside.

The adefovir dipoxyl ororate salts of the present invention may also contain other active substances that do not impair the desired action, or substances that complement the desired action, such as antibiotics, antifungal agents, anti-inflammatory agents, protease inhibitors, or other nucleoside or nonnucleoside antiviral agents. It can be mixed with. Solutions or suspensions used for oral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents, such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediaminetetraacetic acid; Buffers such as acetates, citrates or phosphates and tonic modifiers such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

When administered intravenously, the preferred carrier is physiological saline or phosphate buffered saline (PBS). In a preferred embodiment, the active compound is formulated into a controlled release formulation, including, for example, an implant and a microencapsulated dispensing system, with a carrier that will protect the compound against rapid removal from the body. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polyacetic acid. Methods of preparing such formulations will be apparent to those skilled in the art. The material can also be obtained commercially from Alza Corporation.

Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) are also preferred as pharmaceutically acceptable carriers.

They can be prepared according to methods known to those skilled in the art, for example as described in US Pat. No. 4,522,811. For example, liposome formulations may be dissolved in suitable lipids (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in the evaporated inorganic solvent and dried lipids on the container surface. It can be produced leaving a thin film of. An aqueous solution of the active compound or monophosphate, diphosphate, and / or triphosphate derivatives thereof is then introduced into the vessel. The vessel is then vortexed by hand to liberate the lipid material on the side of the vessel and to disperse the lipid aggregates, thereby forming a liposome suspension.

The present invention was confirmed that the new compound adefovir dipoxyl orotate and a method for preparing the same as an acid addition salt of adefovir difficile increased the solubility in water by about 100 times or more compared to adefovir difficile. In comparison with the hygroscopicity is not only stable to humidity, but also has the effect of having a constant crystallinity according to a simple manufacturing method.

Even in the flowability of the powder with respect to the adefovir difficile ororate powder of the present invention, while the adefovir difficile powder, which is an existing raw material, is a powder having a strong adhesion cohesiveness and a very poor flowability, the adefovir difficile olot of the present invention. The acid salt powder has improved flowability and markedly increased compressibility, which has good industrial properties for handling and preparing the material during pharmaceutical formulation processing.

In addition, the adefovir difficile ororate of the present invention is known as a vitamin having the effect of adefovir difficile as well as the anti-HBV drug effect of the liver function, and to help the recovery of addictive hepatic disorders, commonly used in the treatment of liver The drug effect of orotic acid is added to have a better therapeutic effect than the drug of adefovir difficile salt.

In addition, the production of adefovir difficile ororate of the present invention is an environmentally friendly manufacturing process by only reacting with water without using an organic solvent, and it is industrially inexpensive because it can exclude the manufacturing cost of wastewater treatment due to the use of an organic solvent. The advantage is that mass production is possible at a price.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples.

Example 1 Preparation of Adefovir Difficyl Orotate

300 ml of a 1N aqueous sodium hydroxide solution was added to a 1,000 ml reactor, and 17.4 g of orthoic acid was completely dissolved. Separately, 300 ml of 1N hydrochloric acid solution was added to a 500 ml reactor, and 50.1 g of adefovir difficile was completely dissolved. Adefovir difficile solution is slowly added dropwise to the orot acid solution at room temperature to form a white solid. After the dropwise addition is completed, the resulting crystals are stirred at room temperature for 1 hour and then filtered. Washing is done sufficiently with purified water. The filtered crystals were dried at 50 ° C. to obtain 60.7 g (90%) of white adefovir difficile ororate. mp = 179-185 ° C., ¹ H NMR (DMSO-d ₆ ) δ ppm 11.29 (br s, 1H, NH), 10.79 (br s, 1H, NH), 8.15 (s, 1H, N = CH-N), 8.09 (s, 1H, N = CH-N), 7.42 (br s, 2H, NH ₂ ), 5.97 (s, 1H, C = CH-C (= O)), 5.56 (s, 2H, O-CH ₂ -O), 5.52 (s, 2H, O-CH ₂ -O), 4.32 (t, 2H, N-CH ₂ -O, J = 1.3 Hz), 3.95 (d, 2H, O-CH ₂ -P , J = 1.9 Hz), 3.86 (t, 2H, CH ₂ -C H ₂ -O, J = 1.3 Hz), 1.12 (s, 18H, CH ₃ ). (See Figure 1)

Example 2: Preparation of Tablets Containing Adefovir Difficyl Orotate

Tablets containing the adefovir dipoxyl orotate of Example 1 were prepared according to the following formulation, each tablet containing 10 mg of adefovir dipoxyl orotate:

-Defovir difficile ororate 10mg

-Lactose 65mg

-25 mg of pregelatinized starch

-Croscarmellose Starch 3mg

0.25 mg of colloidal silicon dioxide

Magnesium Stearate 0.30mg

Adefovir dipoxyl orotate, lactose, pregelatinized starch and croscarmellose sodium were each passed through a 65-mesh screen for later use. Adefovir difficile ororate was weighed to the content described in the above formulation and mixed with other adjuvants in a manner that gradually increased the content. The mixture was passed through a 65-mesh screen three times. The angle of repose was measured to be less than 30 °. After the content was tested and weighed, tablets were prepared by directly compressing the mixture using a flat punch pin of 6.5 mm-diameter.

Example 3: Preparation of Capsules Containing Adefovir Difficyl Orotate

Capsules containing the adefovir dipoxyl orotate of Example 1 were prepared according to the preparation method described below, and each capsule contained 10 mg of adefovir dipoxyl orotate.

Adefovir difficile ororate 10mg

-Lactose 135mg

-25 mg of pregelatinized starch

-Croscarmellose Starch 3mg

0.25 mg of colloidal silicon dioxide

Magnesium Stearate 0.30mg

Adefovir difficile orotate, lactose, pregelled starch and croscarmellose sodium were each passed through a 65-mesh screen for later use. Adefovir difficile ororate was weighed to the amount described in the above formulation and mixed with other adjuvants in a manner that gradually increased the content. The mixture was passed through a 65-mesh screen three times. The angle of repose was measured to be less than 30 °. After the content was tested and the volume was determined, the mixture was No. A capsule was prepared in addition to 3 capsules.

1 is a diagram showing the ¹ H-NMR spectrum of adefovir difficile ororate.

Claims (7)

An adefovir difficyl ororate compound represented by the following formula (1). [Formula 1]

The method for producing the adefovir difficile ororate of claim 1, Dissolving orotic acid in an aqueous alkali solution; Dissolving adefovir difficile acid in aqueous acid solution; Mixing the two solutions to obtain adefovir difficile ororate; method of producing adefovir difficile ororate. The method of claim 2, The alkaline aqueous solution is a method for producing adefovir difficile ororate, characterized in that the aqueous sodium hydroxide solution. The method of claim 2, The acid aqueous solution is a method for producing adefovir difficile ororate, characterized in that the aqueous solution of hydrochloric acid. A pharmaceutical composition for the prophylaxis or treatment of human immunodeficiency virus (HIV) infection or hepatitis B virus (HBV) infection disease, comprising the adefovir difficile ororate salt of claim 1 as an active ingredient. A pharmaceutical composition for the prophylaxis or treatment of hepatitis B virus (HBV) infection disease, comprising an effective amount of adefovir difficile orotate of Formula 1, administered in combination with other anti-hepatitis agents. [Formula 1]

The method of claim 6, The anti-hepatitis agent is β-L-2-hydroxymethyl-5- (cytosin-1-yl) -1,3-oxathiolan (3TC), cis-2-hydroxymethyl-5- (5-fluoro Rositocin-1-yl) -1,3-oxathiorane (FTC), β-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU), β-D-2 , 6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9- [4-hydroxy-3- (hydroxy Methyl) -2-methylenecyclopentyl] -6H-purin-6-one (entecavir), 9-((1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclo-butyl) guanine (lobucavir ), Gancyclolovir (ganciclovir) and ribavirin (ribavirin) A pharmaceutical composition for the prevention or treatment of hepatitis B virus (HBV) infection disease, characterized in that at least one selected from the group consisting of.

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