The prolonged release granules containing stavudine

 

(57) Abstract:

Suggested dosage forms of stavudine extended release, including pellets obtained by extrusion-spheronization and covered with an insulating coating. Granules also have a coating for sustained release. The granules are obtained by mixing stavudine, spheronization agent, a suitable diluent, a stabilizing amount of magnesium stearate in the presence of limited amount of water needed for the process of extrusion-spheronization. In the scope of the invention also include hard gelatin capsules, containing in addition to the granules of stavudine, such granules that contain other therapeutic agents suitable for the treatment of retroviral infections. It was found that magnesium stearate, in contrast to other similar pharmaceutical additives, stabilizes stavudine from destruction caused by hydrolysis, protects the pellets from the color changes from yellow to brown. Granules of stavudine with stearate do not show a reduction in activity of stavudine due to hydrolysis, resulting from the method of obtaining. 5 N. and 28 C.p. f-crystals, 3 tables.

The level of technology

Stavudine (3'-deoxythymidin-the clients, infected with retroviruses. This compound, which is a nucleoside analog of reversibility transcriptase, and access is described, for example, in US 4978655 published 18.12.1990. It is known that stavudine is an effective treatment for infections caused by retroviruses, such as a virus murine leukemia and human immunodeficiency virus, i.e., HIV, HTLV III/LAV virus (AIDS virus). Since the introduction of stavudine has considerable commercial success.

In the treatment of HIV infection patients usually receive a combination of drugs. Therefore, patients usually make daily visits to a very large number of tablets. It is obvious that the decrease of the daily number of tablets even one pill can be essential for this patient. Ultimately reducing the number of tablets can lead to the relief of addiction the patient for the treatment of HIV, especially in the case of drugs, which can be assigned to a single daily dose. The appointment of a once-daily dose is important from the point of view of achieving improved receptivity of the patient, increasing the duration of maintaining the level of the drug in blood safety and convenience for the patient, and hence is portable is well absorbed in the upper intestine. Absorption in the colon is about half of the absorption in the small intestine. The optimal composition could provide a release of approximately 40% of stavudine for four hours and the remainder over the next twelve to twenty hours. 100 mg Dosage form of stavudine extended release, therefore, would provide the same bioavailability as the industrial 40 mg of immediate-release capsules taken twice a day. Therefore, the average expert in the art it is clear that stavudine could be applied in a single daily dose, if it had received a suitable composition of extended release. The problem is to obtain a suitable dosage forms of stavudine extended release is its sensitivity to moisture, which causes its hydrolysis, primarily to thymine. This sensitivity to moisture was not a problem for the production of commercially available dosage forms neprolongirovannymi release stavudine, as it is a dry granulate, enclosed in a hard gelatin capsule. However, for dosage forms of extended release usually requires significant difference is the consequently, medicines that are moisture-sensitive, such as stavudine, can cause significant problems when attempting to obtain these forms. In accordance with the present invention a method by which stavudine can be successfully included in the sustained release using standard techniques without significant loss of activity due to hydrolysis.

The invention

Proposed stable granules containing stavudine obtained using standard extrusion techniques/spheronization. Granules suitable for dosage forms for sustained release, can provide 24-hour level of stavudine in the blood after a single dose. The novelty of the composition of the granules in accordance with the present invention is that in the dry mixture included magnesium stearate in an amount sufficient to stabilize stavudine from hydrolysis during the subsequent process of obtaining granules. Hydrolysis of stavudine in composition is reflected in the decrease of activity and the changing colors of pellets, derived from it, i.e., the granules obtained in accordance with the invention, remain white, while the granules obtained by using the beginning of the applied insulating coating and then covered with a modified coating for release from polymeric barrier material, such as ethylcellulose, and a suitable plasticizer, which provides the release stavudine in time so that they will ensure the levels of stavudine in the blood for about 24 hours. A suitable number of such pellets enclosed in a standard hard gelatin capsules. Similar granules other compounds active against retroviruses, can also be included in these capsules, thus ensuring that long-term combination therapy for approximately 24 hours.

Detailed description of the invention

The study of a variety of standard dosage forms, extended release showed that the composition in the form of granules, as it turns out, is most suitable for stavudine. One of the main reasons for this is that, as stated above, it is usually used for the treatment of AIDS, in combination with other medicines for maximum antiretroviral effect. When using granules can be prepared separate granules of two or more medicines, which are then enclosed in a standard hard gelatin capsules. When such separate cooking excluded any possible manufacturing problems, kotoran is what was discovered that stavudine is usually absorbed through the gastrointestinal tract, as described above. Therefore, for prolonged release perfectly suitable form such as granules, which passed slowly through the system. In addition, because of the known forms of prolonged or neprolongirovannymi release granules have been shown to have more reproducible time of the passage of the gastrointestinal tract than larger dosage forms such as tablets.

A significant advantage of the dosage form of stavudine extended release is that a single daily dose increases the susceptibility of the patient, and smaller doses are ineffective. This is especially important when the treatment of AIDS, since the main goal of treatment is to maintain low or undetectable levels of the virus. Another advantage dosage forms for sustained release of such drugs, as stavudine, is the reduction of side effects as a result of increasing levels of drug in the blood, which may cause the use of individual doses too often for each other. A further advantage of the granules according to the present which decreases the possibility of a missed dose, what can happen, for example, if you are not careful chewing of solid tablets. Finally, because the majority of patients, AIDS patients often suffer from gastrointestinal disorders or diarrhea, pellets are the preferred dosage form, as they slowly pass through the small intestine and the rectum and therefore ensure a more steady level of medication in the blood. It was reported, for example, in Int. J. Pharm., Vol. 140 (AUG. 30), pages 229-235 (1996), what pills have a long residual time in the rectum compared to the pills.

Average expert in the art it is clear that there are several methods for producing granules containing the drug, which can be coated to provide prolonged release. Cover the drug or the application of a layer of sugar, grain, as well as direct production of rotary granulation are two such standard methods. However, both of these techniques involve significant contact with water, which can lead to the destruction of the drug, such as stavudine, which is relatively rapidly hydrolyzed upon contact with moisture and heat. Can be used other ways, ispolzuyuschei environment. Thus, it was found that the method of extrusion and spheronization is the preferred method, as it allows you to produce pellets with a high content of drug in a relatively short time with minimal contact with water, what is most important to stavudine.

Extrusion spheronization is a well-known method to obtain granules of medicines. This method essentially includes obtaining a mixture of known spheronization agent and other suitable dry excipients with the drug, wet granulating the mixture with a limited amount of water to obtain a wet powder mass, which ekstragiruyut through a standard extruder fitted with a suitable strainer with obtaining discrete extrudates. The extrudates are then transferred into spheronization in which they are cut and give them the form of discrete spherical granules which are then dried. Spheronization are commercially available equipment, well known to the average person skilled in the art. The final spherical particles can vary in size and degree of sphericity, depending on a number of factors, such as the amount of water in the wet powder, the configuration of the cards in speronis is obtained in this way, have from 0.5 to 1.5 mm in the greatest dimension. Such spherical particles are ideal for the application in the case of receiving the dosage forms of extended release in size and shape.

For the same reason, they also are easily in a standard empty gelatin capsules. It is clear that with such moisture-sensitive medication as stavudine, stage extrusion and spheronization should be performed quickly to minimize contact with water.

Although there are a number spheronization agents, well known to the average expert in the field of technology used to produce pellets by way of extrusion/spheronization, the most famous is microcrystalline cellulose. Other agents suitable for the methods of extrusion/spheronization include carboxymethylcellulose sodium and corn starch, however, the quality of these pellets is not as good as the quality obtained with the use of microcrystalline cellulose. Functions spheronization agent are providing plasticity to the composition that favors the formation of spherical granules, and maintaining the spanning properties, which gives the granules rigidity and integrity. Macii or combine it with a suitable diluent, usually lactose, more preferably Lactose Hydrous NF. Microcrystalline cellulose is commercially available from a number of sources and in various forms with different physical characteristics or properties. For example, various types of microcrystalline cellulose is available under the trademark Avicel from FMC Corporation. Typically, microcrystalline cellulose diluent, such as lactose, is used to obtain distributions for spheronization without any other standard additives, such as a standard tabletting lubricants, agents, giving fluidity and the like. In fact, production descriptions Avicel argues that the advantage of this product is that it can be used without such standard agents. Description of the application of microcrystalline cellulose for the extrusion and spheronization, as well as the composition containing microcrystalline cellulose and hydrocolloid can be found in US 5725886 owned by FMC Corporation.

Even the application of methods of extrusion and spheronization with minimal contact with water was not ideal for dosage forms of stavudine extended release because of its sklon is prohibited, that stavudine is possible to prepare granules, suitable for extrusion and spheronization, without any material damage during the inclusion in its membership of the stearate. This result is unexpected for two reasons. First, due to the properties of excipients used for obtaining such granulates, especially microcrystalline cellulose, and entities of the ways the average person skilled in the field of technology there is no reason to believe the obvious inclusion of a standard tabletting lubricant in the composition. Secondly, the stearate is effective for stabilization of stavudine in the granulate, while others like standard tabletting lubricants/AIDS, such as talc and colloidal amorphous silicone, does not have a stabilizing effect. Typically, the amount of magnesium stearate from about 0.5 to 3.0% by weight, preferably from about 1.4 to 1.7% by weight, of the weight of the present stavudine, is sufficient to ensure the stabilizing actions undertaken in accordance with the present invention. Magnesium stearate has an additional unexpected advantage in that it protects the pellets from the color changes from same Noli, obtained from compositions without him or with other standard tabletting lubricants.

Usually stavudine is from about 33 to about 67% by weight of the pellets obtained by extrusion and spheronization in accordance with the present invention. The advantage of this method is that it allows for high loading of drug in granules. The final dosage forms contain stavudine in various doses depending on the intended schema therapy. Typically, the granules containing the dose of stavudine on a 37.5, 50, 75 and 100 mg, respectively, can be enclosed in single hard gelatin capsule. The required number of stavudine combined with microcrystalline cellulose, a suitable diluent, such as lactose, preferably Lactose NF Water, and a stabilizing amount of magnesium stearate, thoroughly mixed and subjected to wet granulation with a minimum amount of water to give the desired granulate. The diluent required to obtain acceptable weight of the granules so that they could be enclosed in standard gelatin capsules using standard equipment for filling. Average expert in the field of the th lactose formulations. Such diluents include, for example, dicalcium phosphate, mannitol and corn starch. The granulate get in a standard mixer and then ekstragiruyut using Nica, Luwa or other standard extrusion equipment with getting extrudate, which is then placed in a standard spheronization equipment such as Caleva, Nica, Luwa, or other type, with the transformation of the extrudate into pellets with the desired range of particle size. The size of the proposed granules in accordance with the present invention can be, for example, from about 0.7 to about 1 mm in diameter.

Thus obtained granules can be dried pan dryer in a suitable kiln or fluid dryer. The resulting granules are covered with an insulating coating, using a standard film-forming agents such as hypromellose (receiver array), hydroxypropylcellulose (LDCs) and the like, in combination with agents against bonding to reduce the tendency of the pellets to the bonding in the coating process. Although in this case it is preferred talc, microcrystalline cellulose and magnesium stearate can also be used as agents against bonding. Usually the weight ratio of foaming agent to the edge rounding granules and isolates stavudine in granules from contact with the modified surface for release. The granules are then coated with a barrier or modified coating for release in order to achieve long-term dissolution and absorption within such period, to provide the level of stavudine in the blood within 24 hours. Usually a modified coating for release is from about 4 to about 6% by weight of the final granules. Modified coverage for the release contains a polymeric barrier material and a suitable plasticizer. Polymeric barrier material may be a suitable polymethacrylate, but preferably is a commercially available aqueous latex dispersion of ethyl cellulose. Suitable commercial products include ethyl cellulose, e.g., Surelease from use, which is available in combination with a plasticizer, and Aquacoat® from FMC Corporation, which is usually mixed with a suitable plasticizer. Preferred plasticizers include a mixture of acetylated monoglycerides, dibutylsebacate, triethylcitrate and the like. A suitable number of granules with modified surface for release and then sign into hard gelatin capsules of suitable size. Usually covered with granules contain from about 50 to about 67% by weight, preferably about 55% can be combined in the described hard gelatin capsules in combination with other drugs, suitable for the treatment of retroviral infections so that the level of this combination in the blood can be achieved within 24 hours using a single dose. Such combination therapy is preferred in the treatment of AIDS. These therapeutic agents include, for example, DDI(2',3'-deoxyinosine), dimethyl ether [3S-(3R*,8R*,9R*,12R*)]-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13-penthousesuitebarcelona acid, indinavir, lotensin and others, eligible or will become eligible for the treatment of retroviral infections. Such agents can be used in combinations of two or three for appropriate therapy and can be combined into hard gelatin capsules of suitable size. In the scope of the present invention includes combining these antiretroviral agents in doses so that the dose of two capsules should be taken once per day to ensure the effective dose combination. The ability of stavudine to form a stable granules in accordance with the present invention makes it possible to run such a combined therapy so that effective blood levels of the combination within 24 casamania of the invention are understood and can be easily carried out by a specialist in the art without going beyond the scope and essence of the invention, as explained above. The invention is further described in the following experimental examples.

Example 1

The prolonged release granules obtained from the following composition:

Ethyl cellulose aqueous dispersion, NF, produced as Aquacoat ECD from FMC Corporation, contains ethylcellulose, cetyl alcohol, sodium lauryl sulphate and water. Distilled acetylated monoglycerides produced by Eastman chemical Company and containing distilled acetylated monoglycerides, propylene glycol, propylgallate and citric acid.

Ingredients kernel thoroughly mixed and then kneaded in a planetary mixer with a quantity of water sufficient for the formation of wet mass. The wet mass is passed through Nica E 140 extruder getting extrudate approximately 0.8 mm in diameter. The extrudate is then passed through the Caleva spheronizer obtaining granules, which are dried at 65°C for 2 hours in flowing dryer. The dried granules are then treated to form an insulating coating by spraying an aqueous solution of hydroxypropylmethylcellulose, to which add talc to obtain a suspension. It is necessary to mix the suspension to prevent ostentation, consisting of distilled acetylated monoglycerides, as described above, and incubated for two hours in the oven. Aged pellets enclosed in gelatin capsules. Analysis of the pellets showed no significant reduction in activity of stavudine due to hydrolysis, resulting from the retrieval method.

Example 2

Pellets extended release get in accordance with the method of Example 1 from the following composition:

Analysis of the pellets showed no significant reduction in activity of stavudine in the production process.

Example 3

A mixture of granules of stavudine, obtained according to the procedure described in Examples 1 and 2, and similar granules containing antiretroviral drug didanosine(2',3'-deoxyinosine) and dimethyl ether [3S-(3R*,8R*,9R*,12R*)]-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13-penthousesuitebarcelona acid, enclosed in hard gelatin capsules. The latter granules and method of production thereof is generally the same as described in Examples 1 and 2. Granules and their contents are shown in Table 1. Values in each column presents represent the weight of the filler sooe, provided for the granules of stavudine, represents the weight of the filler 61 mg, of which 33 mg represents stavudine, and the remainder of the excipients. The total weight of the filler shown in the right column, is a drug plus excipients.

Example 4

Granules containing in each case, 67% by weight of stavudine and 10% by weight microcrystalline cellulose produced in accordance with the procedure of Examples 1 and 2. The compositions containing the following excipients are tested using known standards for yellowness (ASTM D>1925) and whiteness (Berger 59). The results are presented in Table 2.

Data from Table 2 clearly show that the granules obtained from the compositions according to the present invention, have excellent color both from the point of view of the white, and the absence of yellow.

Example 5

Granules are produced in accordance with the procedure of Examples 1 and 2 from the composition containing 60% by weight of stavudine, 25% by weight microcrystalline cellulose and 15% by weight of lactose. Such granules are obtained in accordance with the present invention, where 1% by weight of lactose substituted by magnesium stearate. The insulating coating is Opadry (use), which consists of hydroxypropyl in Examples 1 and 2. The pellets are stored in controlled conditions at 40°C and 75% relative humidity. Samples of pellets examined for the presence of a thymine at regular intervals. Found that the fracture mechanism of stavudine is the hydrolysis of b-glycosidic bonds between N-1 nitrogen of the pyrimidine bases and carbon unsaturated pentose group with the formation of thymine and unsaturated sugar. HPLC determination of thymine, therefore, is a reliable method of determining degradation of stavudine in time, as defined by the number of thymine is directly dependent on the number of destroyed stavudine. The results are presented in Table 3.

The data in Table 3 clearly show the unexpected stabilizing effect of magnesium stearate in the composition of the present invention to prevent the destruction of stavudine.

1. Extruded spheronization granules, including stavudine, spheronization agent and magnesium stearate in an amount sufficient to stabilize stavudine from destruction during the extrusion process-spheronization of about 0.5 to 3.0% by weight of stavudine.

2. Granules under item 1, containing from about 1.4 to 1.7% by weight of magnesium stearate by weight of the becoming of microcrystalline cellulose, carboxymethylcellulose sodium and corn starch.

4. Granules under item 3, characterized in that spheronization agent is a microcrystalline cellulose.

5. Granules under item 1, additionally containing a diluent.

6. Granules under item 5, characterized in that the diluent is chosen from lactose, dicalcium phosphate, mannitol and corn starch

7. Granules under item 1, additionally containing an insulating coating and coating for sustained release.

8. Granules under item 7, characterized in that the insulating cover includes a foaming agent and a substance against bonding, and the said coating for sustained release includes a polymeric barrier material and a plasticizer.

9. Granules under item 8, characterized in that the foaming agent is chosen from the group consisting of hydroxypropylmethylcellulose and dihydroxyprogesterone.

10. Granules under item 8, characterized in that the substance against the bonding selected from the group consisting of talc, microcrystalline cellulose and magnesium stearate.

11. Granules under item 8, characterized in that the polymeric barrier material vklyuchayuschaya.

13. Granules under item 8, wherein the plasticizer comprises acylated monoglycerides.

14. Extruded spheronization granules comprising (a) stavudine; (b) spheronization agent; (c) a diluent; (d) magnesium stearate in an amount sufficient to stabilize stavudine from destruction during the extrusion process-spheronization of about 0.5 to 3.0% by weight of stavudine; (e) an insulating coating; (f) coating for sustained release.

15. Granules on p. 14 containing from about 33 to 67% by weight of stavudine.

16. Granules under item 14, characterized in that spheronization agent selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl cellulose and corn starch.

17. Granules under item 14, characterized in that the diluent is chosen from the group consisting of lactose, dicalcium phosphate, mannitol and corn starch.

18. Granules under item 14, characterized in that spheronization agent is a microcrystalline cellulose; the diluent is a lactose; insulating cover includes a foaming agent and a substance against bonding; coating for sustained release includes incoordinating is a hypromellose, specified substance against bonding is a talc specified polymeric barrier material is ethylcellulose and the plasticizer includes distilled acetylated monoglycerides.

20. Pharmaceutical dosage form, representing a hard gelatin capsule, containing many granules in p. 15 or 19, to ensure the effective dose of stavudine.

21. The pharmaceutical dosage form according to p. 20, characterized in that the capsule further comprises granules, comprising, at least, the only other drug suitable for the treatment of retroviral infections.

22. The pharmaceutical dosage form according to p. 21, characterized in that these other drugs are selected from the group consisting of didanosine, dimethyl ether [3S-(3R*,8R*,9R*,12R*)]-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13 - penthousesuitebarcelona acid, indinavir and lodenosine.

23. The pharmaceutical dosage form according to p. 22, wherein the specified at least, the only other medication is a DDI.

24. Pharmaceutical is[3S-(3R*,8R*,9R*,12R*)]-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13-penthousesuitebarcelona acid; and (b) an optional another drug selected from the group consisting of didanosine and dimethyl ether [3S-(3R*,8R*,9R*,12R*)]-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13-penthousesuitebarcelona acid.

25. A method of treating a patient in need of therapeutic treatment of retroviral infections, including the introduction of the indicated patient a pharmaceutical dosage form, representing a hard gelatin capsule, containing many granules in p. 15 or 19, to ensure the effective dose of stavudine.

26. The method according to p. 25, characterized in that the capsule further comprises granules, comprising, at least, the only other drug suitable for the treatment of retroviral infections.

27. The method according to p. 26, characterized in that the at least one other ingredient selected from the group consisting of didanosine, dimethyl ether [3S-(3R*,8R*,9R*,12R*)]-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl}-2,3,6,10,13-penthousesuitebarcelona acid, indinavir and lodenosine.

28. The method according to p. 27, characterized in that the other medication is presented to the XI-4,11-dioxo-9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl)-2,3,6,10,13-penthousesuitebarcelona acid.

29. The method according to p. 28, characterized in that the other medication is a DDI.

30. A method of producing granules containing stavudine, including (a) formation of a wet mass of stavudine, spheronization agent, optionally, a diluent and magnesium stearate in an amount sufficient to stabilize stavudine from destruction during this process and comprising from about 0.5 to about 3.0 percent by weight of stavudine, and water enough to form a wet mass suitable for extrusion; (b) extruding the specified weight with obtaining extrudate, spheronization specified extrudate; (c) forming granules and drying of these granules.

31. The method according to p. 30 additionally includes the stage of formation of the insulating coating on top of these granules and the formation of the coating for sustained release over a specified insulating coating.

32. The method according to p. 31, characterized in that the specified spheronization agent is a microcrystalline cellulose, a specified diluent is a lactose specified insulating cover includes a foaming agent and a substance against bonding, and the said coating for p the persons under item 30, in which the formation of wet mass for extrusion at the stage a) is carried out by mixing stavudine, spheronization agent, optionally, a diluent, magnesium stearate and water, sufficient for the formation of wet mass suitable for extrusion.



 

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where X denotes a hydroxy-group; Y represents a group-COORAin which RArepresents hydrogen or ester residue, or denotes a group-CONRINRCin which RINand RCeach independently of one another denotes hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl, and1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or AND1denote optionally substituted indol-3-yl, or contains its tautomer, prodrug, pharmaceutically acceptable salt or hydrate, compounds of formulas I, II

where X, Y described above, AND1- optional replaced heteroaryl; Z1and Z2indicate the relationship; Z2means a connection, (ness.)alkylene, -CH(OH)-, -S-, -SO2-, -O - or-CO; Z4means a connection, (ness.)alkylene, (ness.)albaniles or-CO-; R1means neobyzantine substituted heterocycle, R2denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (ness.)allyloxycarbonyl, optionally substituted aryl, optionally substituted by alloctype, carboxy or halogen; R=0 or 1, with the exception of compounds in which (1) Y and/or AND1denotes optionally substituted indol-3-yl and (2) X denotes a hydroxy-group, Y represents 2-thienyl, AND1denotes a 1H-1,2,4-triazole-3-yl, Z1and Z3each denotes a bond, Z2denotes-NH-, R1denotes phenyl or para-tolyl and p=0; (3) X denotes a hydroxy-group, Y represents 4-methoxyphenyl, or 4-chlorophenyl, AND1means thiazol-5-yl, Z1, Z2, Z3and Z4each represents a bond, R1denotes phenyl, 4-methoxyphenyl or 4-chlorophenyl, R2denotes methyl and p=1; (4) X denotes hydroxyl, Y represents phenyl, 4-were, 4-bromophenyl or 4-chlorophenyl, AND1signifies imidazol-2-yl, Z1and Z3each denotes a bond, Z2denotes methylene, R1denotes phenyl, Z4denotes a bond, R2denotes 4-dimethylaminophenyl or 4-methoxyphenyl, and p=1; (5) X denotes hydroxyl, Y represents phenyl, 4-were-or 4-met is 1 denotes phenyl and p=0; (6) X denotes hydroxyl, Y represents-COORAwhere RAdenotes hydrogen or ethyl, AND1signifies 3-indolyl, imidazo[1,2-a]pyridine-3-yl or imidazo[2,1-b] thiazole-5-yl, Z1, Z2and Z3each represents a bond, R1denotes optionally substituted phenyl, and tautomer, prodrug, pharmaceutically acceptable salt or hydrate; various farmkompanijam, comprising as active ingredient the compound II, the drug compound having anti-HIV activity; the method of obtaining compounds of formula III

as well as the intermediate products of the formula

where Z2denotes a bond, -CO-, -O-, -CH2- or -(CH2)2and R1denotes phenyl, substituted with fluorine, and

where And denotes C-W, where W denotes hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N, Q denotes trail and L denotes ethoxypropan

The invention relates to new derivatives of thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione of General formula (I) or their pharmaceutically-acceptable salts, having immunosuppressive activity

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to peptides having the amino acid sequence of at least 5 amino acids are identical to part ner receptor, corresponding to amino acids 308-373 this receptor, excluding the peptide TEKKRRETVEREKE

The invention relates to biotechnology and is intended for use in the pharmaceutical industry for the production of a stable aqueous solution of genetically engineered interferon-alpha-two, not containing albumin for injection for treatment of various viral diseases and cancer

The invention relates to the field of biotechnology, specifically to means of stimulating preparirovanie damage cells, and may be used in therapy and cosmetology

The invention relates to the field of molecular biology, Virology and medicine

The invention relates to medicine, in particular Hepatology, Virology, and for the treatment of infections caused by hepatitis b virus

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to the field of veterinary Virology

The invention relates to the derivatives of purine, which has antiviral activity against human cytomegalovirus and human immunodeficiency virus type 1, of General formula:

where n = 0 to 4; m = 0 to 3; R1= N, HE or NH2; R2= HE, NH2, acetylamino or benzoylamine; R3= H or lower alkyl (C1-C4; R4= H, lower alkyl (C1-C4or phenyl; X = CH2, O, S, NH or C(O)O; and Y = CH2, CH=CH, C(O), or ordinary communication; Ar = phenyl, pyridyl, naphthyl or substituted phenyl of the formula

where independently R5-R9= alkyl1-C8cycloalkyl C5-C6, 1-substituted, allyl, phenyl, benzyl, F, Cl, Br, J, trifluoromethyl, alkoxy, C1-C5phenoxy, benzyloxy, benzoyloxy, cyano, carboxy, acetyl, or nitro, antiviral effect of the most active compounds against human cytomegalovirus in vitro manifests itself in concentrations of 0.01-0,0005M and is characterized by selectivity 1-400 thousand
The invention relates to medicine, namely to Pediatrics, and can be used for vaccination against pertussis, diphtheria and tetanus

The invention relates to medicine, namely to infectious diseases, in particular to the treatment of HFRS

The invention relates to the field of medicine and relates to a pharmaceutical composition having antiviral activity against herpes viruses and containing a pharmaceutically acceptable carrier and an active ingredient, which is an antagonist of bradykinin (R)-arginyl-(S)-arginyl-(S)-prolyl-(2S,4R)-oksipropil)glycyl-(S)-[3-(2-thienyl)alanyl]-(S)-seryl-(R)-[(1,2,3,4-tetrahydro-3-ethanolic)carbonyl]-(2S,3aS,7aS)-[(hexahydro-2-indolyl)carbonyl]-(S)-arginine in the form of N-acetate in the effective number of
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