Combination of anti-hiv inhibitors of reverse transcriptase and protease
SUBSTANCE: present invention refers to remedies and namely to anti-HIV combination and composition including (i) Tenofovir or its disoproxylfumarate derivate, (ii) Ritonavir and (iii) TMC114, which can be used for treatment or preventive treatment of HIV infection. Besides invention refers to the use of the above combination and treatment method of human HIV infection.
EFFECT: such combination of active components leads to the improved disposition profile.
14 cl, 1 ex
The present invention relates to anti-HIV combination of nucleoside reverse transcriptase inhibitor and two protease inhibitors.
Background of invention
Among anti-HIV drugs that have been developed, there are those that focus on the enzyme reverse transcriptase (RT) or protease enzyme, both of these enzymes necessary for viral replication. Examples of RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIS). Currently infected with HIV-patients are usually subjected to treatment using combinations of three drugs. Widely used modes, containing (at least) three NRTI; two NRTIs in combination with one or two protease inhibitors (PI); or two NRTIs in combination with NNRTIS. When using two or more PI in these combinations, one of the PI is often a ritonavir, administered at low subtherapeutic dose, which acts as an effective inhibitor that eliminates other PI mode, leading to a maximum suppression of the virus and therefore reducing contingency resistance.
Clinical studies have shown that a combination of three medicines data of anti-HIV drugs is much more effective to prevent the development of disease and death, than one drug is used alone or in combination of two medicines. In numerous studies of combinations of drugs with different combinations of such drugs, it was found that such combinations significantly reduce disease progression and mortality in HIV-infected people. Usually at the present time, the combination of anti-HIV medicines called HAART (highly active antiretroviral therapy (Highly Active Anti-Retroviral Therapy).
Specific nucleotide analog reverse transcriptase inhibitor, which was found to be effective in anti-HIV therapy, is a tenofovir, which is also used in the form of its prodrugs of getproxyport tenofovir.
Tenofovir is a nucleotide analogue of adenosine, commercially available at the present time and has activity against retroviruses. Getproxyport tenofovir (tenofovir DF) is a prodrug, oral injected once daily intravenous antiviral agent tenofovir (RMR). For the manifestation of antiviral activity requires that passed the hydrolysis of tenofovir DF with the formation of similar ANP, and then phosphorylation with the formation of the active diphosphate fragment [Arimilli et al. Antiviral Chemistry and Chmotherapy, 1997, 8:6 (557-564); Fridland et al. Antiviral Research 1997, 34]. After entering lymphocytes or macrophages prodrug quantitatively converted into the original analog tenofovir and undergoes phosphorylation with the formation of mono - and diphosphate metabolites. Cellular enzymes, which are responsible for the phosphorylation of this medicinal product are adenylatecyclase and nucleotidebinding [Robbins et al. Antimicrobial Agents and Chemotherapy, 1995, 39:10 (2304-2308); Robbins et al. Antimicrobial Agents and Chemotherapy, 1998, 42:3 (612-617)]. Unlike other nucleoside analogues such as zidovudine or stavudine, phosphorylation, both of which depend on the cell cycle, tenofovir effectively fosfauriliruetsa as in resting and exercising cycle development of peripheral blood lymphocytes
[Robbins et al., 1998]. Tenofovir can inhibit the replication of HIV-1 in cells of different types that can affect HIV, including primary human blood lymphocytes and macrophages [Perno et al. Antiviral Research, 1992 (289-304); Perno et al. Molecular Pharmacology, 1996, 50:2 (359-366)]. The main target of tenofovir diphosphate is a reverse transcriptase (RT). Tenofovir diphosphate is a competitive inhibitor include deoxyadenosines in proviral DNA chain at the stage of emergence. The inhibition of the RT of HIV-1 by means of tenofovir diphosphate is characterized by the inhibition constant, is estimated at approximately 0.9 µm, and, if the analog is included in the growing DNA chain of the virus, it can stop further elongation of the chain. Tenofovir inhibits RT virus much more effectively than it inhibits cellular DNA polymerase [Suo et al. Journal of Biological Chemistry, 1998, 273:42 (2750-2758)]. The concentration required for inhibition of replication of different chains of HIV-1 by 50% (AS) in these types of cells as lymphocytes and macrophages (MT-2, CEM, USN), ranges from 0.2 to 10 μm. The antiviral effect is achieved in non-toxic doses of tenofovir (index selectivity ranges from 100 to 2000). Tenofovir DF is currently available in the form of tablets of 300 mg to be taken once a day.
Tenofovir, usually used in combination with other anti-HIV medicines, in particular with one or more protease inhibitors, such as indinavir, atazanavir, ritonavir and ritonavir/lopinavir. The last is a combination of two protease inhibitors, which has been found to possess favorable pharmacokinetic profile when you share, compared with a profile of ritonavir, which is an inhibitor of the cytochrome
P450cyclooxygenase and increases the level of lopinavir in plasma. Tanaka and others (J.Clin.Pharmacy Therap., 1998, 23, 403-416) described some anti-HIV protease inhibitors, M. the metabolism which may depend on the isoform of cytochrome P 450. Hsu and others (Clin. Pharmacokinet., 1998, 35, 275-291) described the pharmacokinetics of ritonavir, including its effect on the isoenzymes of the cytochrome P450.
The combination of tenofovir with protease inhibitors usually leads to improved anti-HIV therapeutic efficacy, but between the drugs can be undesirable. For example, levels in plasma lopinavir, one of the two protease inhibitors in the above combination of lopinavir/ritonavir may decrease when the drug is combined with tenofovir. Thus, it was investigated the joint introduction of a mixture of lopinavir/ritonavir (400/100 mg twice daily for 14 days) and tenofovir (300 mg once daily) in 21 healthy volunteers. AUC, Cmax and Cmin of tenofovir were increased by 34%, 31% and 29%, respectively. Both AUC and Cmax for lopinavir was reduced by 15%, and Cmin of lopinavir there was no change. AUC and Cmax of ritonavir decreased by 24% and 28%, respectively, while 7% increase ritonavir Cmin (Viread SPC, 2002, Gilead Sciences International Ltd. Viread Product Information, 2002, Gilead Science Inc.).
A similar effect was observed in case of another protease inhibitor, namely ATV. Co-administration of ritonavir (100 mg once a day given with atazanavir and tenofovir (300 mg once daily) was investigated in 10 HIV+ men. In the presence of tenofovir was reduced the e AUC of ritonavir (7011 up 5217 ng/ml·h), Cmax (from 886 to 642 ng/ml) and Cmin (from 43 to 39 ng/ml). ATV concentrations were also decreased in the presence of tenofovir (pharmacokinetic parameters of atazanavir/ritonavir in combination with tenofovir in HIV-infected patients with multiple failures in the treatment of: pozyskiwanie PUZZLE2-ANRS 107 test. Taburet AM., Piketty C., Gerard L. et al. 10thConference on Retroviruses and Opportunistic Infections, Boston, February 2003, Abstract 537).
Held various other pharmacokinetic studies of combinations of getproxyport tenofovir, ritonavir and protease inhibitors such as atazanavir or saquinavir, as discussed below.
The pharmacokinetics of a mixture of atazanavir/ritonavir (300/100 mg once daily) with getproxyport tenofovir (300 mg once daily) was investigated in 10 HIV-1-infected patients. After adding getproxyport tenofovir duration as atazanavir and ritonavir decreased. Cmax ATV decreased from 5233±3033 to 3443±1412 ng/ml (mean±mean deviation), AUC was decreased from 53761±35255 to 39276±23034 ng/ml·h and Cmin decreased from 862±838 to 577±367 ng/ml (Taburet AM., Piketty C., Chazallon C, et al. Antimicrob Agents Chemother., 2004, 48:2091-2096).
The joint introduction of getproxyport tenofovir (300 mg once daily) was investigated in 18 HIV-1-infected individuals treated with the combination of saquinavir in the form of a solid is Oh gelatin capsules/ritonavir (1000/100 mg twice daily). Day 1 was given a 12-hour pharmacokinetic profile of saquinavir and ritonavir, then the mode was added getproxyport tenofovir, and sampling of blood was repeated on days 3 and 14. After adding getproxyport tenofovir concentrations of saquinavir and ritonavir in plasma did not differ significantly compared to day 1. Geometric mean ratio (95% confidence intervals for AUC on days 3 and 14 were 1,16 (0,97, 1,59) and 0.99 (0,87, 1,30) for saquinavir and 1.05 (0,92, 1,28) and 1.08 (0,97, 1,30) ritonavir (Boffito m, Back d, Stainsby-Tron m et al. Br. J.Clin. Pharmacol., 2005, 59: 38-42).
Co-administration of saquinavir in the form of hard gelatin capsules/ritonavir (1000/100 mg twice daily), separately and together with getproxyport tenofovir (300 mg once daily) was investigated in 40 healthy subjects. On the pharmacokinetics of tenofovir saquinavir/ritonavir did not significantly impacted (Cmin, Cmax and AUC were increased by 23%, 15% and 14%, respectively). The duration of action of ritonavir slightly increased; Cmin, Cmax and AUC were increased by 23%, 10% and 11%, respectively. Saquinavir Cmin moderately increased (47% increase); Cmax and AUC were increased by 22% and 29%, respectively. All subjects received SQV Cmin above 100 ng/ml (J. Zong,m Chittick G., Blum MR. et al. 44thInterscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-444).
Other pharmacokinetic studies the project for combinations of getproxyport TDF ritonavir and or fosamprenavir or atazanavir described respectively in points 10 and 16 in the proceedings of the 6thInternational Workshop on Clinical Pharmacology of HIV Therapy: April 28-30, 2005, Quebec, Canada.
From these studies it is clear that the concentration in the blood plasma lopinavir or atazanavir may decrease, which could lead to decreased efficacy of the corresponding component of the combination, which is usually undesirable.
Another protease inhibitor, which has been identified for clinical use, is a compound set forth in this description TMS, which is disclosed in the description of the international patent WO 95/06030 as the compound (4) and has the formula
Koh and others (Antimicrobial agents and Chemotherapy (2003), 7(10), 3123-3129) discuss antiretroviral activity TMS described as ones of the inhibitor of the protease of human immunodeficiency virus type 1 (HIV-1)containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl (bis-THF) and ISOStAR sulfonamida, which is extremely effective against laboratory strains of HIV-1 and primary clinical isolates (50% inhibitory concentration [IC50] approximately of 0.003 μm; IC90 approximately 0,009 μm) with minimal cytotoxicity (50% cytotoxic concentration for CD4+MT-2 is 74 microns).
In the description of the international patent WO 03/049746 describes the combination of therape is automatically effective amount hexahydrofuro[2,3-b]furnishing of HIV protease inhibitors, including TMS, and a therapeutically effective amount of an inhibitor of cytochrome P450for example ritonavir, ketoconazole, cimetidine or bergamottin.
Due to lower concentrations in plasma, marked for the above combinations of tenofovir/ritonavir with such protease inhibitors, such as lopinavir or atazanavir, there is a need in combination tenofovir/ritonavir/protease inhibitor, for which the concentration of protease inhibitor in plasma is not reduced to such an extent, as to the above-mentioned combinations.
The present invention is to develop a combination of tenofovir with ritonavir and additional protease inhibitor, which would lead to improved concentration in plasma of blood of the last of the protease inhibitor compared to discussed above combination of tenofovir/ritonavir/lopinavir.
The next task of the invention is to develop a combination of more than one therapeutically active antiretroviral medicines, where each of the active antiretroviral drug combinations could be put together in a formula.
Another object of the invention is to develop a combination of more than one therapeutically active antiretroviral, Lekarstvo the th means, where a therapeutically effective amount of each active antiretroviral drug combinations can be entered in one single pharmaceutical product.
All cited references are included in this description by reference.
Description of the invention
The authors of the present invention have found that the replacement of lopinavir in the above combination tenofovir/ritonavir/lopinavir protease inhibitor TMC 114, mentioned above, leads to improved pharmacokinetic profile.
Thus, the present invention relates to anti-HIV combination comprising (i) tenofovir or its getproxyport derivative, (ii) ritonavir and (iii) TMS.
The above combination will be referred to in the description as the combination according to the invention.
It is established that the application of TMS instead of lopinavir leads to a favourable improvement, from the point of view of concentration in the blood plasma of this protease inhibitor, with the introduction of this combination.
The following variant of implementation of the present invention relates to combinations according to the invention for use as a drug. In another embodiment, the combination according to the invention can be used for getting medicines for treatment or profilaktiki infection. The following variant of implementation relates to a method of treating or preventing HIV infection in humans, which includes an introduction to the human a therapeutically effective amount of a combination according to the invention.
The combination according to the invention is particularly useful for the treatment of various HIV infection, including AIDS and related clinical conditions such as associated with AIDS complex (ARC), progressive generalized lymphadenopathy (PGL) or AIDS-related neurological conditions such as multiple sclerosis. The combination according to the invention may be particularly useful for the treatment of HIV-infected patients who are not treated with drugs.
However, it should be understood that the specific dose level and frequency of dosage combinations according to the invention can vary for each patient and will depend on many factors, including the activity of the specific compound, the metabolic stability and length of action of the compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the particular condition, and the host undergoing therapy.
Typically for oral administration components of the combination is according to the invention will be entered in the following daily dosages: tenofovir - usually about 300 mg of getproxyport; ritonavir is usually from 100 to 1200 mg, preferably from 100 to 400 mg, and TMS - usually from 400 to 1200 mg
In the preferred embodiment, each of the components of the combination according to the invention can be incorporated into the same pharmaceutical form and should not be entered as a separate pharmaceutical form. Daily antiretroviral therapeutic amounts of the ingredients of this combination, thus obtained, one standard pharmaceutical forms then can be given as one standard dosage forms, or even in the form of a variety of standard dosage forms, as, for example, as two, three, four, five, or even more standard medicines.
Such a standard dosage forms may contain, for example, about 300 mg of getproxyport tenofovir; for example from 100 to 400 mg, preferably from 100 to 200 mg of ritonavir; and, for example, from 400 to 1200 mg TMS.
Thus, in one embodiment, the pharmaceutical composition includes a pharmaceutically acceptable carrier and as active ingredient combination according to the present invention.
Compound combinations according to the invention can be entered together, simultaneously or sequentially. Joint introduction is s can be carried out through the use of a single pharmaceutical preparation or separate pharmaceutical preparations. Usually the combination can be entered using local, oral, rectal, intravenous, subcutaneous or intramuscular routes. For first-line therapy of HIV infection, co-administration with the use of a single pharmaceutical preparation is preferred.
With this purpose, the composition comprising a combination according to the present invention or included in the single drug or obtained for the joint separate or sequential use, can be administered orally (including suspensions, capsules, tablets, sachets, solutions, suspensions, emulsions), parenteral (including subcutaneous, intravenous, intramuscular, intradermal injections, or infusion techniques), by inhalation spray (including nasal sprays) or rectal (including suppositories) in standard dosage forms, containing a suitable non-toxic pharmaceutically acceptable carriers, adjuvants and fillers.
The present invention also relates to pharmaceutical compositions in the form adapted for application to areas where they could have intercourse or similar sexual contact, such as the genitals, rectum, mouth, hands, lower abdomen, upper thigh, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and the image quality is as active ingredients an effective amount of a combination according to the present invention. As specially adapted compositions it is possible to mention all compositions usually employed for application to the vagina, rectum, mouth, and skin such as, for example, gels, jellies, creams, ointments, films, sponges, foams, vnutrivlagalischnye rings, caps for cervical suppositories for use in the rectum or vagina, vaginal or rectal or buccal tablets, means for rinsing the mouth. To obtain such pharmaceutical compositions an effective amount of each specific compounds combinations are used as the active ingredient, combined into a homogeneous mixture with a pharmaceutically acceptable carrier, where the carrier may take a wide variety of forms depending on the form of administration. To increase the length of time the preservation of such pharmaceutical compositions in the introduction may be favorable to include in the composition bioadhesive, in particular bioadhesive polymer. Bioadhesive can be defined as material that is associated with living biological surfaces, such as mucous membrane or skin tissue.
Thus, the present invention also relates to pharmaceutical compositions comprising pharmaceutically acceptable carrier and as active ingredient an effective amount is about each of the compounds of the present combination, characterized in that the pharmaceutical composition is bioadhesive at the application site. Preferably the application site is the vagina, rectum, mouth, or skin, the most preferred is the vagina.
Improved pharmacokinetic profile combinations according to the invention was demonstrated in a follow-up study on volunteers.
Methods:13 healthy volunteers randomly divided into 2 groups. 1 session, both groups received 300 mg TS/100 mg ritonavir for 6 days and a single dose (day 7) with the subsequent breeding season for at least 6 days.
In the 2nd session, both groups received 300 mg getproxyport tenofovir per day for 14 days. Additionally, group 1 received 300 mg TS/100 mg ritonavir, starting from the 8th day to 14th day, and group 2 received 300 mg TS/100 mg ritonavir, from day 1 to 7. TMS was administered as an oral solution.
The results:the average concentrations TMS in plasma tended to increase in the presence of tenofovir. The increase in average ratios of least-squares by 24%, 16% and 21% for Cmin, Cmax and AUC12 respectively were not statistically significant.
Co-administration of tenofovir did not affect the allocation of TMS with urine.
Approximately 7% of the total dose TMS was eliminated unchanged in the urine in the presence and in the absence of tenofovir.
The concentration in the blood plasma of tenofovir were increased when introduced together TMS/ritonavir. On the basis of the ratio of the average least-squares Cmin, Cmax and AUC24 for tenofovir were increased by 37%, 24% and 22%, respectively. These results were statistically significant. Excretion of unchanged tenofovir with urine during the period of time one dose was approximately 36% in the presence and in the absence of TMS/RTV. Introduction 300 mg TMS and 100 mg of ritonavir in healthy volunteers in combination with tenofovir or without TDF was well tolerated.
The results of this study show that the period of systemic effects of tenofovir in a joint introduction TMS/ritonavir increased by 22%. Tenofovir had no significant effect on the period TMS. It is noteworthy that the concentration in the blood plasma TMS was maintained during exposure to tenofovir compared with reduced levels of lopinavir noted in the discussion of the prior development of this field.
1. Anti-HIV combination comprising (i) tenofovir or its getproxyport derivative (i) with ritonavir and (iii) TMC114.
2. The combination according to claim 1, where the components of the combination are in the form of a single or separate pharmaceutical(s) song(s).
3. The combination according to claim 1, gdadataproxy tenofovir is part of the standard pharmaceutical dosage forms, containing approximately 300 mg of getproxyport of tenofovir on a standard dosage form.
4. Combination according to any one of the preceding paragraphs, where the RTV is part of the standard pharmaceutical dosage forms, containing from 100 to 400 mg of ritonavir on the standard dosage form.
5. The combination according to claim 1, where TMC114 is part of the standard pharmaceutical dosage forms, containing from 400 to 1200 mg TMS on a standard dosage form.
6. Pharmaceutical composition comprising a combination according to claim 1.
7. The combination according to claim 1 for use as a medicine.
8. The combination according to claim 7 for use for the prevention or treatment of HIV infection.
9. The use of a combination according to claim 1 to obtain drugs for prevention or treatment of HIV infection.
10. A method of preventing or treating HIV infection in humans, which includes the introduction of a specified person a therapeutically effective amount of a combination according to claim 1.
11. The method according to claim 10, where getproxyport tenofovir is administered in a daily dose of approximately 300 mg
12. The method according to claim 10, where the ritonavir is administered in a daily dose comprising from 100 to 400 mg
13. The method according to claim 10, where TMS is administered in a daily dose of 400 to 1200 mg
14. The method according to claim 10, where the combination is administered in the form of a pharmaceutical company who flies.
SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.
EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.
23 cl, 41 ex
SUBSTANCE: invention refers to medicine and pharmaceutics and concerns an inhibitor of propagation of the human immunodeficiency virus that is 4-nitro-6-trifluoromethyl-1,2,3-benzotritiol-1-oxide of formula .
EFFECT: inhibitor is characterised with high biological activity.
SUBSTANCE: invention concerns chemical-pharmaceutical industry, and concerns medicinal compound on the basis of glycyrrhizic acid derivatives, allowing to increase bioavailability of the bonds considerably and can be used in medicine, virology, pharmacology, for example as an inhibitor of human immunodeficiency virus reproduction. The medicinal compound for inhibition of human immunodeficiency virus reproduction includes sodium carbonate and glycyrrhizic acid derivatives, the mass parity as part of di - and tri glycyrrhizic acid nicotinates and sodium carbonate lies in the range from 1:1 to 1:3.
EFFECT: increase of biologically active component - admixtures of di - and tri glycyrrhizic acid nicotinates bioavailability.
3 ex, 3 tbl
SUBSTANCE: invention relates to novel diazaindoledicarbonylpiperazinyl compounds of formula I, including its pharmaceutically acceptable salts, which possess antiviral activity and can be used for HIV-infection treatment. In compounds of formula I Q represents , T represents -C(O)- or -CH(CN)-; R1 represents hydrogen; R3 represents hydrogen; R5 is independently selected from group including halogen, cyano, XR9 and B; R2 and R4 are absent; R6 represents hydrogen; -- represents carbon-carbon bond; -Y- is selected from group including , each of R10, R11, R12, R13, R14, R15, R16 and R17 represents H; R18 is selected from group including C(O)-phenyl, isoquinolyl, quinazolyl; D is selected from group including cyano, 5-member heteroaryl containing 3 heteroatoms selected from nitrogen and oxygen; A is selected from group including phenyl, pyridinyl; B is selected from group including -C(O)CH3; piperazinyl; 5-, 6-member heteroaryl containing 1-3 N atoms and possibly O atom; where said heteroaryl optionally is substituted with from one to three similar or different substituents selected from F; F is selected from group including (C1-6)alkyl, phenyl, pyridinyl, COOR26, -COR21, and -CONR24R25; where phenyl is optionally substituted with (C1-6)alkoxy, CF3, or halogen atom; R9, R24, R25 and R26 each is independently selected from group including hydrogen and (C1-6)alkyl; X represents O; R27 represents piperazinyl, N-methylpiperazinyl, or 3-pirazolyl. Invention also relates to pharmaceutical composition.
EFFECT: obtaining compounds and pharmaceutically acceptable salts, which possess antiviral activity and can be used for treatment of HIV infection.
19 cl, 50 dwg, 4 tbl, 43 ex
SUBSTANCE: invention relates to novel compounds of formula (I) to its salts, in which X is bivalent radical NR2, O; R1 is cyanogroup; n equals 1; R2 is: i) C1-10alkyl, substituted with aryl, where said aryl is substituted with radical -COOR4; or R2 is ii) C1-10alkyl, substituted with radical selected from -O-NR5a-C(=NR5b)-NR5cR5d, -NR7R8, radical
in which each Q1 independently is simple bond, -CH2-; each Q2 independently is O; each R4 independently is hydrogen; each R5a, R5b, R5c, R5d independently is hydrogen; R7 is C1-4alkyl; R8 is arylC1-4alkyl; R11 is aryl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, "Гет"2; each R12 independently is hydroxy, C1-4alkyl; R13a is C1-4alkyl; each R13b is C1-4alkyl; or R2 is iii) radical of formula:
CH2-CH2-(O-CH2-CH2)m-NRI7eR17b (b-5); where in radical (b-3) one of hydrogen atoms in -CpH2p- and one of hydrogen atoms in - CH(OR14)-CqH2q-, which are not part of R14, can be substituted with simple bond or C1-4alkandiyl group; p equals 1, 2 or 3; q equals 0, 1, 2 or 3; each m independently equals 1-10; each R independently is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; R15 is substituent selected from group consisting of NR16aR16, pyrrolidine, pyperidinyl, homopyperidinyl, piperazinyl, , 4-(C1-4alkyl)-piperazinyl, 4-(C1-4alkylcarbonyl)-piperazinyl, 4-(C1-4alkyloxycarbonyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl; R16a and R16b, independently on each other, are hydrogen, C1-6alkyl or C1-6alkyl, substituted with aryl; R17a and R17b, independently on each other, are hydrogen, C1-4alkyl; or R17a and R17b, together with nitrogen atom, to which they are bonded, form pyrrolidine, morpholinyl; each R18 independently is arylC1-4alkyl; R19 is hydrogen; R3 is nitrogroup; aryl is phenyl; "Гет"2 is piridyl. Invention also relates to pharmaceutical composition, to method of obtaining compound on any of ii 1-4, as well as to compounds of formula (IV-a), (IV-b),(V).
EFFECT: obtaining novel biologically active compounds possessing ability to inhibit HIV.
11 cl, 18 ex, 3 tbl
SUBSTANCE: invention is related to medicine, specifically to biologically active substance 1-hydroxy-2-imino-4-methyl-6-(1,1,4-trimethylpent-3-enyl)-cyclohex-3-en-1,3-dinitrile of formula 1: .
EFFECT: may be used as inhibitor of immunodeficiency virus reproduction.
SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts which are able to inhibit the replication of HIV-virus, to pharmaceutical composition thereof and to the method of inhibition of HIV-virus replication. formula (A) where R1 is hydrogen; R2 is OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is (CH2)bCOOR9 where b takes up the integer values from 1 to 5; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.
EFFECT: claimed compounds inhibit the replication of HIV-virus.
4 cl, 6 dwg, 7 ex
SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts possessing anti hiv-activity, to the pharmaceutical composition thereof and to the method of HIV-integrase inhibition. formula (A) where R1 is selected from the group consisting of the hydrogen and halogen; R2 is selected from the group consisting of the hydrogen and OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is COOR9; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.
EFFECT: claimed compounds possess anti HIV-activity.
5 cl, 6 dwg, 13 ex
SUBSTANCE: composition contains the compound blocking the cyclic state G1, and the antiviral agent that inhibits or reduces HIV penetration into mononuclear cells. The compound blocking the cyclic state G1 is chosen from the group consisting of sodium butyrate, afidicoline, olomucine, roscovitine, tocopherols, tocotrienols, hydroxyurea and rapamycine.
EFFECT: invention ensures reducing receptor site number for HIV penetration into T-cages and increasing in antiviral agent activity.
14 cl, 9 dwg, 9 ex
SUBSTANCE: invention relates to tetrahydrochinoline derivatives represented by general formula , where t is equal 0, 1 or 2; each R independently represents H, alkyl, alkenyl or cycloalkyl; n is equal 0; R is selected from group, consisting of H, alkyl, halogenalkyl, cycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5 or group - Racycloalkyl, and where R2 is not substituted with amine or alkylamine; each R4 independently represents halogen; m is equal 0, 1 or 2; each R5 independently represents H, alkyl, alkenyl, alkinyl, cycloalkyl; p is equal 0 or 1; y represents -NR10-, -O-, -S-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, -RaHetRaN(R10)2, -HetRaAy or -HetRaHet; each Ra independently represents alkylene, possibly suibstituted with one or more than one alkyl or hydroxyl, cycloalkylene, possibly substituted with one or more than one alkyl or hydroxyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl or -Ra-cycloalkyl; each Ay independently represents possibly substituted phenyl or naphtyl group; each Het independently represents possibly substituted 3-12-member mono- or polycyclic heterocyclyl group, containing as heteroatoms N, or 5-7-member possibly substituted heteroaryl group, containing as heteroatom N; or its pharmaceutically acceptable salts or ethers. Also described are methods of obtaining compounds of formula (I-G).
EFFECT: obtained are novel compounds, which demonstrate protective against HIV-infection effect on target-cells by means of specific binding with chemokine receptor and which influence binding of natural ligand or chemokine with target-cell receptor, such as CXCR4 and/or CCR5.
54 cl, 2 tbl, 90 ex
SUBSTANCE: group of inventions concerns medicine and covers normalisation of sleep/wakefulness cycle in a mammal, and also to increasing its cognitive function. It involves introduction of therapeutically effective amount of the compound chosen from the group including cytosine, cytidine, cytidine monophosphate, cytidine triphosphate, deoxycytidine monophosphate, deoxycytidine diphosphate or deoxycytidine triphosphate, cytidine diphosphate - choline, cytidine diphosphate sodium choline, uridine, uridine triphosphate, uridine diphosphate, uridine monophosphate and triacetyluridine. Said mammal does not suffer from insomnia.
EFFECT: offered methods reduce asthenia or fatigue during a day, improve sleep quality, besides, they can be used in treatment of somnipathies, including sleep apnea, periodic limb movements, a restless leg syndrome, narcolepsy and somnolency problem, or in increasing cognitive functions in the sleep deprived patients.
18 cl, 3 dwg
SUBSTANCE: application of the oxidised ATF form (o-ATF) as the antiangiogenic pharmacological agent, a therapeutic preparation for treatment of the tumours, including o-ATF with antitumoral substance and a therapeutic preparation for treatment of the atherosclerotic processes, containing o-ATF with antiatherosclerotic substances is offered. The agent is applicable for treatment of diseases, in whose beginning or advance the angiogenesis, such as diseases of eyes, atherosclerotic processes or tumours is involved.
EFFECT: maintenance of suppression of a proliferation of endothelial cells, or anti-angiogenic effect even in the presence of the endothelial factor of growth of vessels.
6 cl, 2 dwg, 2 ex
SUBSTANCE: invention refers to new compounds of formula I where R1 stands for H, CN, halogen, -COR2, -S(O)xR2, C1-C12alkyl, C2-C12alkenyl, C3-C8dicloalkyl, aryl group, heteroaryl group standing for 5- or 6-merous aromatic mono- or bicyclic heterocyclic group with 1-2 heteroatoms, chosen of N or S, C3-C8cycloalkyl-(C1-C3)alkyl or group aril-(C1-C3)alkyl; alkyl, alkenyl, cycloalkyl, aryl and heteroaryl groups can be optionally substituted with halogen, C1-C6alkyl, group-COR2; R2 stands for -N(R3,R3'), C1-C6alkyl, C3-C8cycloalkyl, aryl, heteroaryl which stands for 5- or 6-merous aromatic mono- or bicyclic heterocyclic group with 1-2 heteroatoms chosen of N, C3-C8cycloalkyl-(C1-C3) alkyl or aril-(C1-C3)alkyl; C1-C6alkyl, C3-C8cycloalkyl, aryl, heteroaryl can be optionally substituted with halogen, C1-C6alkyl; R3 and R3' independently stands for hydrogen or (C1-C3)alkyl; x stands for 0, 1 or 2; and also to their esters, hydrolyzed in physiological environment, and to their pharmaceutically acceptable salts. The invention also concerns a medical product.
EFFECT: production of new biologically active compounds active as COMT inhibitor.
17 cl, 19 ex, 1 tbl
SUBSTANCE: there is disclosed peritoneal dialysate containing adenosine triphosphate or its salt, and peritoneal dialysis method with using the present dialysate. Peritoneal dialysate is safe and causes less peritoneum damages as compared to the prior-knowledge dialysates.
EFFECT: peritoneal dialysate is safe for continuous long-term use in peritoneal dialysis.
16 cl, 4 ex, 5 dwg
SUBSTANCE: invention relates to field of veterinary. Method lies in the following: as complex preparation, dioxygen is introduced intramuscularly daily two times a day in dose 0.1 ml/kg of body weight during 3-7 days. In case of serious disease course preparation is introduces 5-7 days. To calves not more than 5 ml of preparation are introduced in the same place. To piglets not more than 2.5 ml of preparation are introduced in the same place.
EFFECT: method allows to increase efficiency of treating salmonellosis in young farm animals.
4 cl, 7 tbl, 2 ex
SUBSTANCE: invention relates to homeopathy and can be used as medicinal-preventive remedy for increasing physical activity, workability and stamina for all pathological states, accompanied by depression of bioenergetic processes. Homeopathic preparation, increasing physical activity, workability and stamina is characterised by representing 30 vol % solution of adenosindiphosphoric acid in homeopathic potency 30 CH. Preparation is taken in 20 drops of water-alcohol solution (30 vol %) dose one time a day half an hour before meal.
EFFECT: preparation stimulates natural regulatory mechanisms controlling bioenergetic processes without risk of doing harm by drug therapy.
SUBSTANCE: correction of pain syndrome accompanying severe psoriasis is ensured with skin irradiation within affected region or above inflammatory tissue using low intensity IR rays of CO2 laser. Laser wavelength is 10.6 mcm. Radiation power density in pulse-periodic regime is 0.015-1 Wt/cm2, radiation pulse duration is 0.5-10 mc, pulse window is 10-100 mc, and highly directional IR radiation divergence is 10-2 radians. While radiation, laser beam is moved on skin within affected region during 5-10 minutes, herewith zone exposure duration determined by laser beam diameter is 1-2 sec. Skin is preliminary coated with adenosine triphosphate with daily exposure within course of 10-15 days.
EFFECT: evident reparative analgesic effect, reduced time of hospital stay, prevention of complications.
SUBSTANCE: present invention pertains to ester lipids of halogenated adenine nucleotides with formula I, which can be used in treating cancerous diseases. (I), where R1 - C1-C20-alkyl, can be substituted with C1-C6-alkoxyl radical, C1-C6-alkylmercaptan radical, C1-C6-alkylsulfenyl or C1-C6-alkylsulfonyl groups, R2 - C1-C20-alkyl, which can be substituted with C1-C6-alkoxyl radical, C1-C6-alkylmercaptan radical or C1-C6-alkylsulfonyl group, R3 - amino group, X - sulphur atom, sulfenyl or sulfonyl group, Y - oxygen atom.
EFFECT: obtaining new biologically active compounds.
3 cl, 9 ex, 1 tbl
FIELD: medicine; cardiology.
SUBSTANCE: pharmaceutical composition contains agonist A2A receptor and at least, one base oil, and, at least, one cosolvent.
EFFECT: fast and maximum coronary vasodilatation in mammals without invoking related peripheral vasodilatation, elimination of multiple introduction.
26 cl, 8 ex, 3 tbl, 18 dwg
FIELD: medicine; obstetrics.
SUBSTANCE: physiotherapy with a running impulsive magnetic field of low frequency is performed. Manipulation is performed with 1.5 mT power of magnetic induction and 100 Hz frequency of following impulses. The method involves influencing paravertebrally on the level CVII-ThV with didymous solenoids of N-S polarity. The procedure lasts for 15 minutes within 7-10 days. The method also includes carring out intravenous injection of Riboxinum once a day and intaking infusion of hawthorn foetuses 3 times a day within 10 days.
EFFECT: method has no restrictions and eliminates syndromes of an undifferentiated dysplasia of a connecting tissue.
4 tbl, 1 ex
SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .
EFFECT: higher efficiency.
12 cl, 2 tbl, 50 ex, 1 dwg