Anti-hiv composition comprising imidazole derivatives

 

(57) Abstract:

Anti-HIV composition contains 2-carbamoylated-methyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H - imidazole or its pharmaceutically acceptable salt and a different one or more compounds having anti-HIV activity in a synergistic effective amount. As compounds with anti-HIV activity, use AZT, ddI, ddC, 3TC, saquinavir and/or foscarnet. New exhibiting a synergistic combination of compounds provides the reduction of side effects, such as toxicity. Also effectively inhibited the development of virus resistance to the drug that provides efficient and effective treatment of AIDS. 3 S. and 4 C.p. f-crystals, 4 Il., 18 table.

The technical field of the invention

The invention relates to pharmaceutical compositions containing two or more compounds having anti-HIV activity.

Background of the invention

AIDS (acquired immunodeficiency syndrome) is widely distributed in the world and is not treatable disease, which is caused by the human immunodeficiency virus (HIV). The research and development of therapeutic agents to combat E. the present examples of anti-HIV-songs that are already in use or have been clinically tested, are compositions, the main therapeutic agents which are nucleoside derivatives, such as acidogenicity (AZT), dideoxyinosine (ddI), dideoxycytidine (ddC), dideoxythymidine (d4T), 3'-thiacytidine (3TC), etc.

However, all these agents have serious side effects, such as pancreatitis, anemia, leukopenia, neutropenia, vomiting, aphagia, gastric disorders, Apama (anthema), insomnia, illusions, myospasm, dyspnea, dysuria, renal failure, hypacusia, etc. When using these agents raises a number of problems, such as the development of resistance to the drug with continued use and, as a consequence, degradation agents, etc.

To address these problems at the present time for treatment, as a rule, apply some anti-HIV songs.

In this case, it was found that the application of several compounds with anti-HIV activity, is characterized by synergism. Examples of synergistic combinations are the combination of 3TC with compounds with anti-HIV activity, is not the etc., described in JP-A-7508997, and similar combination with 3TC 11-cyclopropyl-5,11-dihydro-4-methyl-6N-dipyrido[3,3-b;21,31-e][1,4]diazepin-6-one, described in JP-A-7508998.

When using compounds with anti-HIV activity, marked by serious side effects, such as development of resistance to the drug, etc., There is a need to develop new, exhibiting synergistic combinations of compounds with anti-HIV activity, i.e., compositions containing these compounds as active substances.

Detailed description of the invention

According to the present invention it was found that the application of 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H-imidazole (designated hereinafter in the present description as CDIMA) or its pharmaceutically acceptable salt in combination with one or more compounds having anti-HIV activity, synergism is observed, leading to increased anti-HIV activity of each of them.

Therefore, one of the objects of the present invention is an anti-HIV composition comprising CDIMA or its pharmaceutically acceptable salt and one or more compounds having anti-HIV activity is their CDIMA or its pharmaceutically acceptable salt simultaneously or sequentially with one or more compounds possessing anti-HIV activity.

Another object of the present invention is the use of CDIMA or its pharmaceutically acceptable salts and compounds with anti-HIV activity in the manufacture of a medicinal product intended for the treatment or prevention of AIDS. In addition, the present invention relates to a method of inhibiting the reproduction of HIV in the result of the contact of the HIV virus with CDIMA or its pharmaceutically acceptable salt in combination with one or more compounds having anti-HIV activity. The present invention relates to the combination CDIMA or its pharmaceutically acceptable salt with one or more compounds having anti-HIV activity.

CDIMA used in the present invention, is described in WO 96/10019, and in the description of the synthesis and anti-HIV activity of the compounds.

Brief description of drawings

In Fig. 1 shows the correlation between the concentration of compounds with anti-HIV activity and toxicity (SS50in relation to the cell line CEM.

In Fig. 2 shows the correlation between the concentration of compounds with anti-HIV activity and toxicity (SS50in otnoshenii-activity, and growth inhibition (IC50) cell line CEM.

In Fig. 4 shows the correlation between the concentration of compounds with anti-HIV activity, and growth inhibition (IC50) cell line U937.

The preferred embodiment of the invention

In the context of the present description pharmaceutically acceptable salt CDIMA include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, Hydrobromic acid, etc., salts with organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, naphthalenesulfonate acid, camphorsulfonic acid, etc. and salts of alkali metals or alkaline earth metals, such as sodium, potassium, calcium, etc.

In the context of the present invention, the term "compound having anti-HIV activity" refers to any compounds with anti-HIV activity, without particular limitation is tazy, which is the nucleoside derivative, analog reverse transcriptase inhibitor non-nucleoside derivative, an inhibitor of HIV protease, an inhibitor of DNA polymerase, etc.

In the context of the present description analog reverse transcriptase inhibitor, which is a nucleoside derivative that includes AZT, ddI, ddC, d4T, 3TC, etc., and nucleoside reverse transcriptase inhibitors, non-nucleoside derivatives include compounds described in WO 96/10019, for example, 3-[5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H-imidazol-2-yl]propan-1-ol or 2-[5-(3,5-dichlorophenylthio)-1-ethyl-4-isopropyl-1H-imidazol-2-yl]ethanol, etc., an inhibitor of HIV protease include saquinavir, indinavir, ritonavir, nelfinavir, VX-478, etc. Other drugs having anti-HIV activity include, for example, foscarnet, therapeutic agent from cytomegalovirus rhinitis, possessing inhibitory activity against DNA polymerase and inhibitory activity against reverse transcriptase, etc., In particular, preferred are AZT, ddI, ddC, 3TC, saquinavir or foscarnet due to their high synergistic anti-HIV activity in combination with CDIMA. In particular, more preferred are AZT, ddI, ddC, saquinavir or poscar is that significantly inhibit the development of virus resistance to the drug.

Anti-HIV composition of the present invention can provide effective treatment of AIDS because it has synergy compared using each of compounds with anti-HIV activity as a single agent. Thus, in particular, due to the fact that anti-HIV composition of the present invention has a synergistic anti-HIV activity, as shown in the following experiments, the use of a lower dose than in the case of using each of compounds with anti-HIV activity as a single agent allows to achieve adequate anti-HIV activity, ensuring the reduction of side effects, such as toxicity, etc., the introduction of the compositions of the present invention, which contains each of the compounds having anti-HIV activity, in the amount equal dose when used as the sole agent that effectively inhibits the development of virus resistance to the medication and, obviously, provides efficient and effective treatment.

Thus, an anti-HIV composition of the present invention is an effective pharmaceutical composition as medicinal creditagency action CDIMA in combination with one or more other compounds, possessing anti-HIV activity. Thus, each active substance can be entered simultaneously in the form of a composition. Sequential introduction of each of the active substance with such periods of time when stored synergies, leads to a similar effect.

When applying anti-HIV composition of the present invention safe by introducing may be oral or parenteral. For oral administration, it can be used as a conventional preparative forms, such as tablets, granules, powder, capsules, pills, liquid solutions, syrups, preparations for transbukkalno injection, sublingual tablets, etc. For parenteral administration it preferably can be used in any preparative forms, such as injections, such as preparations for intramuscular injection, etc., in the form of a suppository, percutaneous, inhalation, etc., in particular, it is preferable to oral administration.

The pharmaceutical composition of the present invention can be manufactured by mixing effective amounts of active substances, if necessary, with medical auxiliaries suitable for the end primenalsa substances, solvents, etc., for Example, preparations for injection can be obtained by sterilization with suitable carriers.

In one of the embodiments of the invention as carriers may be mentioned lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose, etc., the group of binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc., leavening agents include carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar, nutriceuticals, etc. and the coating materials are talc, magnesium stearate, macrogol, etc., the Basics suppositories are cocoa butter, macrogol, methylcellulose, etc., In the manufacture of liquid drugs or emulsions, or suspensions for injection may be added conventional solubilizing agents, emulsifiers, stabilizers, preservatives, agents, regulatory isotonicity, and other agents. For oral administration can be added sweeteners, corrigentov etc.

As active ingredient an anti-HIV compositions of the present invention CDIMA can be combined with some of the MI or other compounds possessing anti-HIV activity as a single agent applied dose of each active ingredient is usually from 0.05 mg to 3000 mg per day, preferably from 0.1 mg to 1000 mg per day parenteral from 0.01 mg to 1000 mg per day, preferably from 0.05 mg to 500 mg per day.

In the case of the introduction of anti-HIV composition of the present invention, the dose of each active substance in the preparative form should be determined taking into account the patient's age and body weight, condition of the disease, route of administration, etc. But the amount of each active substance in the composition may be 0.1-1 in relation to the above, the applied dose of each of compounds with anti-HIV activity when they are used as a single agent.

Thus, in the case of the introduction of CDIMA and other compounds with anti-HIV activity together in the form of an anti-HIV composition of the present invention, the dose of each active ingredient may be in oral introduction of 0.005-3000 mg/day, preferably 0.01 to 1000 mg/day parenteral 0.001 to 1000 mg/day, preferably 0.005 to 500 mg/day. The composition may be applied once a day or several times a day Demo invention serves to further illustrate the invention and are not intended to limit its scope.

Experiment 1: Synergistic anti-HIV activity

Cell line Molt-4 human T cells, persistence infected with HIV-1 (clone 2 strain IIIB), were cultured in medium RPMI-1640, supplemented with 10% fetal calf serum, and the supernatant was filtered and after determining the titer of the virus was stored at -80oC.

Prepared a series of twofold dilutions CDIMA with concentrations from 10 ng/ml to of) 0.157 ng/ml and 0 ng/ml and a series of two-fold dilution with AZT concentrations from 100 ng/ml 0.4 ng/ml and 0 ng/ml the Combination of these two drugs were prepared by the method of "checkerboard" using a 96-well microplate. 50 μl of the above medium containing 105cells MT-4/ml was added into each well of 96-well microplate and to each well was added 50 μl of AZT, diluted two times the same environment. After 4 h, each well was added 50 μl of the culture supernatant of the above clone 2 strain of HIV-1 IIIB, at the same time, we also added 50 ál of diluted 2 times KLIMI, and then incubated in 5% CO2in thermostat at 37oWith in 5 days.

The titers of virus in the culture supernatant was calculated, using as indicator the activity of the reverse transcriptase of the virus, which determine the> 0.1% of Nonidet P-40, 10 mm dithiothreitol, 5 g/l poly(A), 5 μg/ml (dT)12-18and 1 µci of [3N]-dTTP, was added 10 μl of culture supernatant and incubated at 37oC for 3 hours the Reaction mixture was cooled on ice and transferred using the harvester cells on the filter type DEAE-Filtermat. The filter was washed with 5% Na2HPO412 H2O and water, and the radioactivity incorporated into DNA was determined using a scintillation counter type LKB Beta Plate, determining the activity of the reverse transcriptase of the virus.

There were three analysis and was calculated the average degree of inhibition (%) reverse transcriptase inhibitors when compared with the enzymatic activity in the absence of CDIMA and AZT. The results are shown in table 1.

Assuming that the inhibitory effect of the two compounds with anti-HIV activity was additive, used to calculate the degree of inhibition of the growth of the virus in all combinations of concentrations by the formula (I)

Z=X+Y(1-X), (I)

where Z denotes the degree of inhibition additive effect, X denotes the degree of inhibition when using CDIMA and Y denotes the degree of inhibition when using other compounds with anti-HIV activity. Aprimitive 99,65%, if the concentration CDIMA is 5 ng/ml, and the concentration of AZT - 0 ng/ml, the value of X is 99,63% and the value of Y is 43,43%, if the concentration CDIMA is 0 ng/ml, and the concentration of AZT - 0.8 ng/ml Then the degree of inhibition additive action of Z according to the formula (I) is 99.79%.

Then, as described above, calculates the difference between the measured values shown in table 1, and calculated by the degree of inhibition additive action. The results are shown in table 2, and the value of the confidence limits at the level of probability 99% are shown in table 3.

When the measured value is greater than the degree of inhibition additive effect, namely, the value in table 3 is greater than 0, it is considered that there is a synergism. The coefficient of synergism is defined as the total of the values greater than 0, in table 3.

According to the same method conducted analysis of the data obtained with the use of ddI, ddC, saquinavir and foscarnet instead of AZT.

Adding to the cells of saquinavir and foscarnet were performed at the same time as KLIMI, while infecting the virus. For combination with ddC, ddI and saquinavir concentrations CDIMA ranged from 5 ng/ml to 0.08 ng/ml at twice/ml in two-fold dilution and 0 ng/ml

Analysis of the results is given below. In tables 4-6 shows the results when using ddI, in tables 7-9 shows the results when using the ddC, in tables 10-12 shows the results when using saquinavir and in tables 13-15 shows the results when using foscarnet.

Analysis of all data was performed using software Mac Synergy II (Prichard, M. N. and S. Shipman Jr., Antiviral Res. 14: 181-206, 1990). In accordance with the guidance of the coefficient of synergy was evaluated as follows: if the ratio of synergy is 25-50, synergism is low, but pronounced (+), if the ratio of synergy is 50-100, the synergies are strong (++), and if the ratio of synergy greater than 100, the synergy is very high (+++).

Factors synergies with confidence limits at the confidence level of 99% and the evaluation results are shown in table 16.

Table 16 very high synergy CDIMA in combination with other compounds with anti-HIV activity.

Experiment 2: Cytotoxicity and inhibition of cell growth

To evaluate the cytotoxicity and testing of inhibiting the growth of cells used 96-well, PlusCode is kg/ml and a series of twofold dilutions of AZT at concentrations of 200 μg/ml to 0.18 μg/ml and 0 ng/ml and two drugs were combined method "chessboard".

Evaluation of cytotoxicity

Cell line SEM or cell line U937 were cultured in medium RPMI-1640, supplemented with 10% fetal calf serum. The cells were added into each well of 96-well flat-bottomed microplate based 1x104cells per well, and each well was added CDIMA and AZT, diluted with the same medium, according to the previously described method. The plates were incubated in an incubator with 5% CO2at 37oWith in 3 days and all wells were added 5 mg/ml MTT (bromide 3-{4,5-dimethylthiazol-2-yl}-2,5-diphenyltetrazolium) and 30 ál SFR and incubated for 1 h In the process of this incubation, the surviving cells were recovered MTT obtaining insoluble formazan. From all wells were selected 150 μl of culture supernatant and then add 150 ál of solution (isopropanol containing 10% Triton X-100 and 0.4% model HC1). Formazan was dissolved by shaking and measured the optical density at a wavelength of 560 nm (OD560using standard OP690. Determined the concentration that causes 50% cytotoxicity (SS50), these results are presented graphically in Fig. 1 and 2. In Fig. 1 shows the result using the cell line SEM, and Fig. 2 presents the result used in the 937 were cultured in medium RPMI-1640, supplemented with 10% fetal calf serum. The cells were added into each well of 96-well flat-bottomed microplate based 1x104cells per well, and each well was added CDIMA and AZT, diluted with the same medium, according to the previously described method. The plates were incubated in an incubator with 5% CO2at 37oC for 5 h and to each well was added with 0.2 µci of [3H]-thymidine and incubated for 24 h the Cells were collected using a harvester cells on the filter type DEAE. The radioactivity incorporated in the cells was measured using a scintillation counter type Beta Plate to determine cell growth. Expected concentration that causes 50% inhibition of uptake of [3H]-thymidine (IC50), these results are presented graphically in Fig. 3 and 4. In Fig. 3 presents the result using the cell line SEM, and Fig. 4 shows the result using the cell line U937.

It is evident from Fig. 1-4 can be seen that the combination of CDIMA with AZT has no synergies both in terms of cytotoxicity, and inhibition of cell growth.

Experiment 3: Suppression of occurrence of the variants of drug-resistant

Cell line Molt-4 human T cells, persiste orothy, the supernatant was filtered and after determining the titer of the virus was stored at -80oC.

1 ml of the above medium containing 106cell line M 8166, was introduced into each well of 12-well plates, were added 100 μl of the above clone 3 strain of HIV-1 IIIB and incubated for 2 h to virus infection. Cells were washed above the environment and to each well was added 4 ml of medium containing CDIMI or other compounds with anti-HIV activity, individually or in combination, and incubated in an incubator with 5% CO2at 37oC. CDIMI was added at a concentration of 1 ng/ml, a ddC was added at a concentration of 50 ng/ml, respectively, and the same concentrations of these compounds are used in combination thereof. Cells were perseval twice a week and if you watched the growth of the virus, the concentration of the drug was increased twice. When not watched the growth of the virus, the concentration of compounds with anti-HIV activity was maintained at the same level that was in the last culture.

The titer of virus was determined by the following method, using as a marker of the activity of the reverse transcriptase.

To 100 μl of reaction mixture containing 50 mm Tris-HCl, pH 8.3, 150 mm KCl, 10 mm, 10 μl of culture supernatant and incubated at 37oC for 3 hours the Reaction mixture was cooled on ice and transferred using the harvester cells on the filter type DEAE-Filtermat. The filter was washed with 5% PA2NRA412 H2O and water, and the radioactivity incorporated into DNA was measured using a scintillation counter type LKB Beta Plate, determining the activity of the reverse transcriptase of the virus.

If you watched the growth of viruses, the viruses were isolated and the conventional method were determined sensitivity to each applicable substance. The results are shown in table 17.

Table 17 shows that when using a combination of ddC and CDIMA did not observe the emergence of resistant variants.

Experiment 4: sensitivity of the virus to drugs by a combination of mutations to the drug resistance

Induced mutations in vitro in molecules cDNA clone HIV NL432 received various mutant clones of the gene reverse transcriptase inhibitors, for which it is known that they cause resistance to CDIMA or AZT. Mutant cDNA clones were transfectable cell line SW480. The obtained mutant virus-infected cell line MT-4 in the presence of drugs in the same way as described in experiment 1. After 4 days was determined by the growth of the virus, use the of the growth of viruses (EC50and 90% inhibition of growth of viruses (EC90). The results are shown in table 18.

Strains Y181C, F227C, L234I and V106A plus F227L resistant to KLIMI, was sensitive to AZT. Conversely, sensitivity to CDIMA resistant to AZT clones of strains D67N plus K70R and T215Y was equal to the sensitivity of the wild strain. Hence, it is clear that CDIMA and AZT do not cause cross-resistance.

The level of sensitivity of the strain T215Y plus L234I with as causing resistance to AZT mutation T215Y and causing resistance to CDIMA mutation L234I, and to KLIMI, and AZT was close to the sensitivity level of the wild strain, which indicates the transition from resistance to sensitivity. This result, obtained in vitro, shows that infected patients, which simultaneously impose CDIMA and AZT, the unlikely occurrence of variants resistant to KLIMI, and AZT.

Preparative form 1: Granules

Granules produced by homogeneous mixing of all of the following ingredients, granulation in the fluidized bed, drying and filtering.

CDIMA 20 mg

AZT - 25 mg

Starch 15 mg

Dakota 16 mg

Crystalline cellulose - 21 mg

the crystals produced by homogeneous mixing of all of the following ingredients and fill with a mixture of gelatin capsules.

KLIMI - 35 mg

ddI - 55 mg

Lactose - 96 mg

Nitroglycol starch - 13 mg

Magnesium stearate 1 mg

Total: 200 mg

Preparative form 3: Tablets

Tablets weighing 200 mg were produced by homogeneous mixing of all of the following ingredients, except magnesium stearate, and granulation followed by the addition of magnesium stearate.

KLIMI - 7 mg

ddC 10 mg

Lactose 100 mg

Crystalline cellulose - 75 mg

Talc 5 mg

Carboxymethylcellulose 2 mg

Magnesium stearate 1 mg

Total: 200 mg

Industrial applicability of the invention

As follows from the above experiments, an anti-HIV composition of the present invention in comparison with the introduction of each of compounds with anti-HIV activity, individually, has a strong synergy with activity, but does not show synergism in terms of cytotoxicity. Therefore, the composition is an effective pharmaceutical composition intended for the treatment and prevention of AIDS.

1. Anti-HIV composition comprising 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H-imidazole or its pharmaceutically n is the first number.

2. Anti-HIV composition under item 1, in which compounds with anti-HIV activity, show synergism in combination with 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H-imidazole or its pharmaceutically acceptable salt.

3. Anti-HIV composition under item 1, in which compounds with anti-HIV activity, in combination with 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H-imidazole or its pharmaceutically acceptable salt inhibit the emergence of drug resistance in viruses.

4. Anti-HIV composition under item 1, in which compounds with anti-HIV activity, are inhibitor reverse transferase, which is the nucleoside derivative, nucleoside reverse transferase, non-nucleoside derivative, and/or an inhibitor of HIV protease.

5. Anti-HIV composition under item 1 or 2, in which compounds with anti-HIV activity, are AZT, ddI, ddC, 3TC, saquinavir and/or foscarnet.

6. Method for the treatment and prevention of AIDS, including the introduction of a synergistically effective amount, simultaneously or sequentially, 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-from the multiple connections, possessing anti-HIV activity.

7. Combination containing 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine-4-yl)methyl-1H-imidazole or its pharmaceutically acceptable salt and a different one or more compounds having anti-HIV activity in a synergistic effective amount designed to produce drugs for the treatment or prevention of AIDS.

 

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