RU2188638C2 - Anti-hiv-composition containing imidazole derivatives - Google Patents

Abstract

FIELD: organic chemistry, medicine, virology, pharmacy. SUBSTANCE: anti-HIV- composition comprises 2-carbamoylhydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridine- 4-yl)-methyl-1H-imidazole or its pharmaceutically acceptable salt and distinct from its one or some compounds showing an anti-HIV-activity taken in synergetically effective amount. Preparations AZT, ddI, ddC, 3TC, saquinavir and/or foscarnet are used as compounds showing an anti-HIV-activity. A novel combination eliciting synergetic effect provides decrease of adverse effects, for example, toxicity. It inhibits also the development of viral drug resistance effectively that provides the efficient and effective treatment of patients with AIDS. EFFECT: enhanced effectiveness of composition and treatment. 6 cl, 4 dwg, 18 tbl

Description

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 widespread in the world and is a treatable disease caused by the human immunodeficiency virus (HIV). The research and development of therapeutic agents to combat this disease is conducted all over the world, but to date, satisfactory results have not been obtained. Currently, examples of anti-HIV compositions that are already in use or have been clinically tested are those whose main therapeutic agents are nucleoside derivatives, such as azidodeoxythymidine (AZT), dideoxyinosine (ddI), dideoxycytidine (ddC), dideoxyoxide dehydrotimidine (d4T) , 3'-thiacytidine (3TC), etc.

 However, all of these agents have serious side effects, such as pancreatitis, anemia, leukopenia, neutropenia, vomiting, aphagia, gastric upsets, anthema, insomnia, illusions, myospasm, shortness of breath, dysuria, renal failure, hypakusia, etc. When using these agents, a number of problems arise, such as the development of resistance of viruses to drugs with prolonged use and, as a result, a decrease in the effectiveness of agents, etc.

 In order to solve these problems, as a rule, several anti-HIV compositions are currently used for treatment.

 In this case, it was found that when using several compounds with anti-HIV activity, synergism is manifested. Examples of synergistic combinations are the combination of 3TC with compounds having anti-HIV activity, not nucleoside derivatives, such as {[(benzoxazol-2-yl) methyl] amino} -5-alkyl-6-alkyl-2- (1H) -pyridinone and the like described in JP-A-7508997, and a similar combination of 3TC with 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,3-b; 21,31-e ] [1,4] diazepin-6-one, described in JP-A-7508998.

 When using compounds with anti-HIV activity, serious side effects were noted, such as the development of drug resistance of viruses, etc. There is a need to develop new combinations exhibiting synergism 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 when using 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole (referred to as CDIMI hereinafter) or a pharmaceutically acceptable salt thereof in combination with one or more compounds having anti-HIV activity, synergism is observed, which leads to an increase in the anti-HIV activity of each of them.

 Therefore, one of the objects of the present invention is an anti-HIV composition comprising CDIMI or a pharmaceutically acceptable salt thereof and one or more compounds having anti-HIV activity. The present invention also relates to a method of treating or preventing AIDS, which comprises administering CDIMI or a pharmaceutically acceptable salt thereof simultaneously or sequentially with one or more compounds having anti-HIV activity.

 Another object of the present invention is the use of CDIMI or its pharmaceutically acceptable salt and compounds having anti-HIV activity in the manufacture of a medicament for the treatment or prevention of AIDS. In addition, the present invention relates to a method for inhibiting the propagation of HIV by contacting an HIV virus with CDIMI or a pharmaceutically acceptable salt thereof in combination with one or more compounds having anti-HIV activity. The present invention relates to a combination of CDIMI or a pharmaceutically acceptable salt thereof with one or more compounds having anti-HIV activity.

 CDIMI used in the present invention is described in WO 96/10019, and the synthesis and anti-HIV activity of the compound are described.

Brief Description of the Drawings
In FIG. Figure 1 shows the correlation between the concentration of a compound having anti-HIV activity and toxicity (CC ₅₀ ) for CEM cells.

In FIG. Figure 2 shows the correlation between the concentration of a compound having anti-HIV activity and toxicity (CC ₅₀ ) with respect to U937 cell line.

In FIG. Figure 3 shows the correlation between the concentration of a compound having anti-HIV activity and growth inhibition (IC ₅₀ ) of CEM cells.

In FIG. 4 shows a correlation between the concentration of a compound having anti-HIV activity and inhibition of growth (IC ₅₀ ) of U937 cell line.

Preferred Embodiment
In the context of the present description, pharmaceutically acceptable salts of CDIMI include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and the like, salts with organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluo sulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid and the like, 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” means any compounds having anti-HIV activity, without particular limitation, for example, antiviral compounds having anti-HIV activity, such as a nucleoside derivative reverse transcriptase inhibitor a non-nucleoside derivative reverse transcriptase inhibitor, an HIV protease inhibitor, a DNA polymerase inhibitor, and the like.

 In the context of the present description, a nucleoside derivative reverse transcriptase inhibitor includes AZT, ddI, ddC, d4T, 3TC and the like, and a non-nucleoside derivative reverse transcriptase inhibitor includes the compounds described in WO 96/10019, for example 3- [5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-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 and the like, the HIV protease inhibitor includes saquinavir, indinavir, ritonavir, nelfinavir, VX-478 and the like. Other drugs having anti-HIV activity include, for example, foscarnet, a cytomegalovirus rhinitis therapeutic agent having DNA polymerase inhibitory activity and reverse transcriptase inhibitory activity, etc. Particularly preferred are AZT, ddI, ddC, 3TC, saquinavir or foscarnet due to their high synergistic anti-HIV activity when combined with CDIMI. In particular, AZT, ddI, ddC, saquinavir or foscarnet are more preferred, and AZT, ddC or saquinavir are most preferred. Most preferred are AZT and ddC, which significantly inhibit the development of drug resistance in viruses.

 The anti-HIV composition of the present invention can provide an effective treatment for AIDS due to the fact that it has a synergy compared with the use of each compound having anti-HIV activity as the sole agent. So, in particular, due to the fact that the 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 compound having anti-HIV activity , as the sole agent, it is possible to achieve sufficient anti-HIV activity, while reducing side effects such as toxicity and the like. The administration of the composition of the present invention, which contains each compound having anti-HIV activity in an amount equal to the dose when used as the sole agent, effectively inhibits the development of drug resistance in viruses and, obviously, provides an effective and effective treatment.

 Thus, the anti-HIV composition of the present invention is an effective pharmaceutical composition as a medicament for treating or preventing AIDS.

 The present invention is distinguished by the synergistic effect of CDIMI in combination with one or more other compounds having anti-HIV activity. Thus, each active substance can be administered simultaneously in the form of a composition. The sequential administration of each active substance with such time intervals at which synergism is maintained leads to a similar effect.

 When using the anti-HIV composition of the present invention, the safe route of administration may be oral or parenteral. For oral administration, it can be used in the form of conventional formulations, such as tablets, granules, powder, capsules, pills, liquid solutions, syrup, buccal preparations, sublingual tablets, and the like. For parenteral administration, it can preferably be used in the form of any formulations, for example, preparations for injection, such as preparations for intramuscular injection and the like, in the form of a suppository, transdermally, in the form of inhalations, etc., in particular, it is preferable oral administration.

 The pharmaceutical composition of the present invention can be prepared by mixing an effective amount of the active ingredients, if necessary, with medical excipients suitable for the final formulation used, such as carriers, binders, wetting agents, disintegrants, lubricants, solvents and the like. For example, injection preparations can be obtained by sterilization with suitable carriers.

 In one embodiment of the invention, carriers may include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like, a group of binders includes methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone and the like, disintegrants carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar, sodium lauryl sulfate, and the like can serve, and lubricants include talc, magnesium stearate, macrogol, etc. . The basis of suppositories are cocoa butter, macrogol, methyl cellulose, etc. In the manufacture of liquid preparations or emulsions or suspensions for injection, conventional solubilizing agents, emulsifiers, stabilizers, preservatives, isotonicity agents, and other agents may be added. For oral administration, sweeteners, flavoring agents and the like may be added.

 As an active ingredient of the anti-HIV compositions of the present invention, CDIMI can be combined with one or more other compounds having anti-HIV activity.

 In the case of the introduction of CDIMI or other compounds with anti-HIV activity, as a single agent, the applicable dose of each active substance is usually from 0.05 mg to 3000 mg per day, preferably from 0.1 mg to 1000 mg per day, parenteral administration is 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 the anti-HIV composition of the present invention, the dose of each active substance in the formulation must be determined taking into account the patient’s age and body weight, disease status, route of administration, etc. However, the amount of each active substance in the composition may be 0, 1-1 with respect to the above applicable dose of each of the compounds having anti-HIV activity when they are used as a single agent.

 Thus, in the case of administration of CDIMI and other compounds having anti-HIV activity, together as an anti-HIV composition of the present invention, the dose of each active substance can be, when administered orally, 0.005-3000 mg / day, preferably 0.01- 1000 mg / day, with parenteral administration, 0.001-1000 mg / day, preferably 0.005-500 mg / day. The composition may be applied once a day or several times a day in divided doses.

Example
The description of the following examples and experiments of the present invention serves to further illustrate the invention in more detail and is not intended to limit its scope.

Experiment 1: Synergistic anti-HIV activity
Cells of the Molt-4 line of human T cells persistently infected with HIV-1 (clone 2 of strain IIIB) were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum, and the supernatant was filtered off and after determining the virus titer, stored at -80 ^o C.

A series of double dilutions of CDIMI with concentrations from 10 ng / ml to 0.157 ng / ml and 0 ng / ml and a series of double dilutions of AZT with concentrations from 100 ng / ml to 0.4 ng / ml and 0 ng / ml were prepared. The combination of these two drugs was prepared using the checkerboard method using 96-well microplates. 50 μl of the above medium containing 10 ⁵ MT-4 / ml cells was added to each well of 96-well microplates and 50 μl of AZT diluted twice with the same medium was added to each well. After 4 hours, 50 μl of the culture supernatant of the above clone 2 strain of HIV-1 IIIB was added to each well, at the same time 50 μl of 2-fold diluted CDIMI was also added, and then incubated in 5% CO ₂ in an incubator at 37 ^° C within 5 days.

Virus titers in the culture supernatant were calculated using virus reverse transcriptase activity as an indicator, which was determined by the following method:
To 100 μl of the reaction mixture containing 50 mM Tris-HCl, pH 8.3, 150 mM KCl, 10 mM MgCl ₂ , 0.1% Nonidet P-40, 10 mM dithiothreitol, 5 μg / L poly (A), 5 μg / ml (dT) _12-18 and 1 μCi [ ³ H] -dTTP, 10 μl of culture supernatant was added and incubated at 37 ^° C for 3 hours. The reaction mixture was cooled on ice and transferred using a cell harvester to a DEAE filter -Filtermat. The filter was washed with 5% Na ₂ HPO ₄ • 12 H ₂ O and water, and the radioactivity included in the DNA was determined using a LKB Beta Plate scintillation counter, determining the activity of the virus reverse transcriptase.

 Three analyzes were performed and the mean inhibition degree (%) of reverse transcriptase was calculated when compared with enzymatic activity in the absence of CDIMI and AZT. The results are shown in table 1.

Based on the assumption that the inhibitory effect of the two compounds with anti-HIV activity was additive, the degree of inhibition of virus growth was calculated at all combinations of concentrations according to the formula (I)
Z = X + Y (1-X), (I)
where Z denotes the degree of inhibition by the additive effect, X denotes the degree of inhibition when using CDIMI and Y denotes the degree of inhibition when using another compound having anti-HIV activity. For example, for the case where the concentration of CDIMI was 5 ng / ml, and AZT was 0.8 ng / ml, it can be seen from table 1 that the X value is 99.65% if the concentration of CDIMI is 5 ng / ml and the concentration of AZT - 0 ng / ml, the X value is 99.63% and the Y value is 43.43% if the concentration of CDIMI is 0 ng / ml and the concentration of AZT is 0.8 ng / ml. Then the degree of inhibition with the additive effect of Z according to formula (I) is 99.79%.

 Then, as indicated above, the difference was calculated between the measured values given in table 1, and the calculated degree of inhibition with the additive effect. The results are shown in table 2, and the value of confidence limits at a probability level of 99% are given in table 3.

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

 According to the same method, data obtained using ddI, ddC, saquinavir and foscarnet instead of AZT were analyzed.

 Addition of saquinavir and foscarnet to the cells was carried out at the same time as CDIMI when infected with the virus. For the combination with ddC, ddI and saquinavir, the concentrations of CDIMI were in the range from 5 ng / ml to 0.08 ng / ml at two dilutions and 0 ng / ml, and the concentrations of ddC, ddI, saquinavir and foscarnet were in the range from 500 ng / ml to 2 ng / ml with double dilution and 0 ng / ml.

 An analysis of the results is given below. Tables 4-6 show the results when using ddI, tables 7-9 show the results when using ddC, tables 10-12 show the results when using saquinavir and tables 13-15 show the results when using foscarnet.

 All data were analyzed using Mac Synergy II software (Prichard M. N. and Shipman C. Jr., Antiviral Res. 14: 181-206, 1990). According to the manual, the synergy coefficient was estimated as follows: if the synergy coefficient is 25-50, then the synergism is low, but pronounced (+), if the synergy coefficient is 50-100, then the synergy is expressed (++), and if the synergy coefficient greater than 100, then the synergy is very high (+++).

 Coefficients of synergy with confidence limits at a probability level of 99% and the evaluation results are shown in table 16.

 Table 16 shows a very high synergy of CDIMI in combination with other compounds with anti-HIV activity.

Experiment 2: Cytotoxicity and Inhibition of Cell Growth
To assess cytotoxicity and test inhibition of cell growth, 96-well flat-bottomed microplates were used. A series of double dilutions of CDIMI with concentrations from 50 μg / ml to 0.78 μg / ml and 0 μg / ml and a series of double dilutions of AZT with concentrations from 200 μg / ml to 0.18 μg / ml and 0 ng / ml and two were prepared the drugs were combined using the checkerboard method.

Cytotoxicity assessment
CEM cells or U937 cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. Cells were added to each well of a 96-well flat-bottom microplate at a rate of 1x10 ⁴ cells per well, and CDIMI and AZT diluted with the same medium were added to each well according to the previously described method. The plates were incubated in a thermostat with 5% CO ₂ at 37 ^° C for 3 days and 5 mg / ml MTT (3- {4,5-dimethylthiazol-2-yl} -2,5-diphenyltetrazolium bromide) was added to all wells ) and 30 μl of PBS and incubated for 1 h. During this incubation, the surviving cells restored MTT to obtain insoluble formazan. 150 μl of culture supernatant was taken from all wells and then 150 μl of solution (isopropanol containing 10% X-100 triton and 0.4% HC1) was added. Formazan was dissolved by shaking and absorbance was measured at a wavelength of 560 nm (OD ₅₆₀ ) using OD ₆₉₀ as standard. The concentration causing 50% cytotoxicity (CC ₅₀ ) was determined; these results are presented graphically in FIG. 1 and 2. In FIG. 1 shows the result using cells of the CEM line, and in FIG. 2 shows the result using cells of the U937 line.

Assessment of cell growth inhibition
CEM cells or U937 cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. Cells were added to each well of a 96-well flat-bottom microplate at a rate of 1x10 ⁴ cells per well, and CDIMI and AZT diluted with the same medium were added to each well according to the previously described method. The plates were incubated in a thermostat with 5% CO ₂ at 37 ^° C for 5 hours and 0.2 μCi [ ³ H] thymidine was added to each well and incubated for 24 hours. Cells were harvested using a cell harvester on a filter type DEAE. The radioactivity incorporated into the cells was measured using a Beta Plate type scintillation counter to determine cell growth. The concentration causing 50% inhibition of the absorption of [ ³ H] -thymidine (IC ₅₀ ) was calculated; these results are presented graphically in FIG. 3 and 4. In FIG. 3 shows the result using cells of the CEM line, and FIG. 4 shows the result using cells of the U937 line.

 From FIG. 1-4 it is seen that the combination of CDIMI with AZT is not synergistic both in terms of cytotoxicity and inhibition of cell growth.

Experiment 3: Inhibition of Drug Resistant Options
Cells of the Molt-4 line of human T cells persistently infected with HIV-1 (clone 3 of strain IIIB) were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum, the supernatant was filtered off and, after determining the titer of the virus, stored at -80 ^o FROM.

1 ml of the above medium containing 10 ⁶ cells of the M 8166 line was added to each well of 12-well plates, 100 μl of the above clone 3 of HIV-1 IIIB strain was added and incubated for 2 hours for virus infection. Cells were washed with the above medium and 4 ml of medium containing CDIMI or other anti-HIV compounds were added to each well, individually or in combination, and incubated in an incubator with 5% CO ₂ at 37 ^° C. CDIMI was added at a concentration of 1 ng / ml, and ddC was added at a concentration of 50 ng / ml, respectively, and the same concentrations of these compounds were used in combination. Cells were reseeded twice a week, and if virus growth was observed, the drug concentration was doubled. In the case when no virus growth was observed, the concentration of the compound having anti-HIV activity was maintained at the same level as in the last culture.

 Virus titer was determined by the following method using reverse transcriptase activity as a marker.

To 100 μl of the reaction mixture containing 50 mM Tris-HCl, pH 8.3, 150 mM KCl, 10 mM MgCl ₂ , 0.1% Nonidet P-40, 10 mM dinitrotreitol, 5 μg / L poly (A), 5 μg / ml (dT) _12-18 and 1 μCi [ ³ H] -dTTP, 10 μl of culture supernatant was added and incubated at 37 ^° C for 3 hours. The reaction mixture was cooled on ice and transferred using a cell harvester to a DEAE filter -Filtermat. The filter was washed with 5% Na ₂ HPO ₄ • 12 H ₂ O and water, and the radioactivity included in the DNA was measured using a LKB Beta Plate scintillation counter to determine the virus reverse transcriptase activity.

 If virus growth was observed, the viruses were isolated and the sensitivity to each active substance was determined using the usual method. The results are shown in table 17.

 From table 17 it is seen that when using a combination of ddC and CDIMI, the appearance of a stable variant was not observed.

Experiment 4: Changing the susceptibility of the virus to drugs through a combination of drug resistance mutations
In vitro mutations were induced in the cDNA molecules of the HIV clone NL432, and various mutant clones of the reverse transcriptase gene were obtained, for which it is known that they cause resistance to CDIMI or to AZT. Mutant cDNA clones transfected SW480 cells. The obtained mutant viruses infected cells of the MT-4 line in the presence of a drug, similarly to that described in experiment 1. After 4 days, virus growth was determined using reverse transcriptase activity as a marker. Concentrations causing 50% inhibition of virus growth (EC ₅₀ ) and 90% inhibition of virus growth (EC ₉₀ ) were determined. The results are shown in table 18.

 Strains Y181C, F227C, L234I, and V106A plus F227L, which are resistant to CDIMI, were sensitive to AZT. Conversely, the sensitivity to CDIMI resistant to AZT clones of strains D67N plus K70R and T215Y was equal to the sensitivity of the wild strain. It is clear from this that CDIMI and AZT do not cause cross-stability.

 The sensitivity level of strain T215Y plus L234I, which has both the T215Y mutation that determines resistance to AZT, and the L234I mutation that causes resistance to CDIM, and both the CDIMI and AZT resistance, is close to the sensitivity level of the wild strain, which indicates a transition from resistance to sensitivity. This in vitro result shows that in infected patients who are simultaneously administered with CDIMI and AZT, the emergence of variants resistant to both CDIMI and AZT is unlikely.

Formulation 1: Granules
Granules were made by uniformly mixing all of the ingredients below, fluidized bed granulation, drying and filtering.

CDIMI - 20 mg
AZT - 25 mg
Starch - 15 mg
Dactose - 16 mg
Crystalline Cellulose - 21 mg
Polyvinyl alcohol - 3 mg
Water - 30 mg
Total: - 130 mg
Formulation 2: Capsules
Capsules were made by uniformly mixing all of the ingredients below and filling with a mixture of gelatin capsules.

CDIMI - 35 mg
ddI - 55 mg
Lactose - 96 mg
Sodium Starch Glycolate - 13 mg
Magnesium Stearate - 1 mg
Total: - 200 mg
Formulation 3: Tablets
200 mg tablets were prepared by uniformly mixing all of the ingredients below, except magnesium stearate, and granulation, followed by magnesium stearate.

CDIMI - 7 mg
ddC - 10 mg
Lactose - 100 mg
Crystalline Cellulose - 75 mg
Talcum - 5 mg
Carboxymethyl cellulose - 2 mg
Magnesium Stearate - 1 mg
Total: - 200 mg
Industrial Applicability of the Invention
As follows from the above experiments, the anti-HIV composition of the present invention, in comparison with the administration of each of the compounds having anti-HIV activity, individually has a pronounced synergism with respect to activity, but does not show synergism with respect to cytotoxicity. Therefore, the composition is an effective pharmaceutical composition intended for the treatment and prevention of AIDS.

Claims (7)

 1. Anti-HIV composition containing 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole or a pharmaceutically acceptable salt thereof, and other than it one or more compounds having anti-HIV activity in an effective amount.  2. The anti-HIV composition according to claim 1, wherein the compounds having anti-HIV activity show synergism in combination with 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridine -4-yl) methyl-1H-imidazole or a pharmaceutically acceptable salt thereof.  3. The anti-HIV composition according to claim 1, wherein the compounds having anti-HIV activity, in combination with 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4 -yl) methyl-1H-imidazole or with its pharmaceutically acceptable salt inhibit the emergence of drug resistance in viruses.  4. The anti-HIV composition according to claim 1, wherein the compounds having anti-HIV activity are a reverse transferase inhibitor that is a nucleoside derivative, a reverse transferase inhibitor that is not a nucleoside derivative, and / or an HIV protease inhibitor.  5. The anti-HIV composition according to claim 1 or 2, wherein the compounds having anti-HIV activity are AZT, ddI, ddC, 3TC, saquinavir and / or foscarnet.  6. A method of treating and preventing AIDS, comprising administering a synergistically effective amount, simultaneously or sequentially, of 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole or its pharmaceutically acceptable salt and other than one or more compounds having anti-HIV activity.  7. A combination containing 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole or a pharmaceutically acceptable salt thereof and one or more compounds different from it having anti-HIV activity, in a synergistically effective amount, intended for the manufacture of a medicament for the treatment or prevention of AIDS.

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