MXPA00006441A - Pharmaceutical compositions and combinations for the treatment or prophylaxis of diseases related to vih and retrovirus - Google Patents

Abstract

The object of the present invention is directed to a pharmaceutical composition for the treatment or prophylaxis of diseases related to VIH and retrovirus;said composition comprises an effective quantity of a compound of the formula I. Wherein Ar represents aryl, which is substituted with halo, hydroxy or alkoxyl C1-6;A represents alkylene C1-6, alkenylene C2-6 or alkynylene C2-6, m is a whole number from 0 to 6 and B represents hydrogen, alkyl C1-6 or aryl, said aryl is substituted or not substituted with halo, hydroxy, alkyl C1-6, alkenyl C2-6 or alkynyl C2-6;or pharmaceutically accepted salts of the same, together with a pharmaceutically acceptable carrier. The invention also is directed to a pharmaceutical composition to be used in the inhibition of VIH and the reapplication of retrovirus comprising an effective quantity of a compound of the formula I. The invention moreover is directed to a combination of the formula I compound together with other antiviral agents.

Description

PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS FOR THE TREATMENT OR PROPHYLAXIS OF RELATED DISEASES TO HIV AND THE RETROVIRUS Description of the invention Field of the Invention The invention relates to a novel composition comprising a compound of the formula I. Said composition can be used in the treatment of diseases related to HIV and the retrovirus and in the inhibition of HIV and the replication of the retrovirus. In addition, said composition can optionally be combined with other antiviral agents.

Background of the Invention It is well known that human disorders of acquired immunodeficiency syndrome (AIDS) are caused by the human immunodeficiency virus (HIV). HIV, like other viruses, can not replicate itself if it does not occupy the biosynthesis apparatus of its infected host. The apparatus is reinforced to produce structural proteins of viral resistance. Said proteins are encoded by the genetic materials in the infected viral particles. However, like a retrovirus, the genetic material of HIV is RNA, rather than DNA as in the genome of host cells. Accordingly, the viral RNA must be converted to DNA and subsequently integrated into the genome of the host cells, so that the host cells can produce the desired viral proteins. The conversion of RNA to DNA is achieved through the use of reverse transcriptase (RT), which is contained in the viral particles infected together with the RNA. The reverse transcriptase exhibits three known enzymatic functions, for example, a DNA-dependent RNA polymerase, a ribonuclease and a DNA-dependent DNA polymerase. RT first functions as a DNA-dependent RNA polymerase to produce a copy of a DNA strand of viral RNA. And later, like a ribonuclease, RT releases the DNA produced from the original viral RNA and destroys the original RNA. Finally, as a DNA-dependent DNA polymerase, RT uses the first strand of DNA as a template to produce the second complementary strand of DNA. The two strands of double-stranded DNA are subsequently integrated into the genome of host cells by another enzyme called integrase.

It is known that many compounds can inhibit the enzymatic function of HIV reverse transcriptase. One class of known HIV-1 RT inhibitors are nucleoside analogs. This class includes zidovudine (ZDV, 2 ', 3'-dideoxyinosine (ddl) and 2 \ 3'-d¡deoxycytidine (ddC) .Another class is the non-nucleoside analogues.This class includes nevirapine, which is 11 - cyclopropyl-5, 11-dihydro-4-met? l-6H-dipyridino [3,2-b: 2 ', 3'-e] [1,4] diazepine-6-one Nevirapine non-nucleoside and other compounds especially suitable are described in U.S. Patent No. 5,336,972.

However, since HIV can easily develop resistance to known antiviral agents (e.g., protease inhibitors and reverse transcriptase inhibitors), the therapeutic effects of such agents are often less than expected. In addition, the essential doses for these agents result in side effects for most patients. The most common disadvantage is the toxicity for normal cells. Therefore, medical experts continually develop new antiviral agents and effective doses of them to obtain more effective treatments for diseases caused by HIV.

Recently, it has been found that integrases essential for viral replication may be the target for the development of another class of antiviral agents. It is especially potential to be used in the development of anti-HIV inhibitors. In HIV and other retroviruses, the integration of a DNA copy obtained from the RNA genome on the chromosome of host cells is essential for effective viral replication and virus multiplication. More specifically, the enzymes are sequentially carried out as follows: a dinucleotide unit is removed from the 3 'ends of the viral DNA (called "processing-3"'). The 3'-processed strands are transferred from the cytoplasm to the nucleus. The 3'-processed strands are incorporated into the corresponding host DNA in the nucleus via the 5-base pair print key (called "strand displacement"). On the other hand, integrase has not yet shown a similar function to human cells. Therefore, fatigue inhibitors may be useful for the treatment of retroviral infections.

Despite the fact that integrases play an important role in the retroviral life cycle, information concerning compounds with selective inhibition against HIV integrases is rarely reported. To date, the major classes of integrase inhibitors include DNA binding agents, topoisomerase inhibitors, aurintricarboxylic acid, fenetyl caffeic ester acid (CAPE) and catechols-bis and the like.

Many compounds have been reported to inhibit HIV integrases in biochemical tests. However, most of these compounds have little or no activity in tissue cultures and have no selectivity in their mechanisms of action. These results show that the compounds have no selectivity to eliminate the activation of the HIV integrases or that the inhibitory compounds of the HIV integrase can not enter the cells. Particularly, although most compounds exhibit inhibition activity of the integrases in enzymatic tests in vitro, it has not yet been demonstrated that said compounds have anti-HIV activity in vivo. For example, both actinomycin D and CAPE have in vitro activity of integrase inhibition. However, it has not been reported that they have anti-HIV activity.

The CAPE is the product of the propolis. It is known that CAPE has immunomodulatory, anti-inflammatory, anti-carcinogenic and anti-mitogenic properties. On the other hand, CAPE can selectively inhibit transformed and oncogene-transformed virus cells from rodents and human tumor cells including colon adenocarcinoma (HT-29), melanoma (HU-1, SK-MEL-28 and SK-MEL). -MO), human breast carcinoma (MCF-7) and Fischer rat embryo fibroblast (CREF) and the like. CAPE can also stop the growth of HL-60 cells in human leukemia and inhibit the synthesis of DNA, RNA and proteins in HL-60 cells. The activation of NF-Kappa B by tumor necrosis factor can be blocked by a dose of CAPE depending on the time of administration. CAPE can also be used as an inhibitor of lipoxygenase, carrying out antioxidant activity.

Summary of the Invention It is an object of the invention to provide a pharmaceutical composition for use for the treatment or prophylaxis of diseases related to HIV and retroviruses. It is also an object of the invention to provide a pharmaceutical composition for the inhibition of HIV and the viral replication of the retrovirus. It is further an object of the invention to provide a combination of the composition of the invention with known antiviral agents.

Brief Description of the Drawings Figure 1 depicts the cellular activities in tetrazolium microculture tests for 24 hours. Figure 2 depicts the cellular activities in the tetrazolium microculture tests for 48 hours. Figure 3 depicts the results of treatment of peripheral blood-infected mononuclear cells with (A) tropic macrophage (NL-43), (B) tropic T cells (JRCSF) and (C) dual tropical viruses (89.6), respectively with fenetyl caffeic ester acid in different concentrations. Figure 4 depicts the results of treatment of peripheral blood-infected mononuclear cells with (A) tropic macrophage (NL-43), (B) tropic T cells (JRCSF) and (C) dual tropical viruses (89.6), respectively with methyl caffeine in different concentrations. Figure 5 depicts the results of treatment of peripheral blood-infected mononuclear cells with (A) tropic macrophage (NL-43), (B) tropic T cells (JRCSF) and (C) dual tropical viruses (89.6), respectively in different concentrations.

Legends In Figures 3-5, (+) indicates maintaining the original concentration of the compound added after washing at the end of the infection. In Figures 3-5, (-) indicates removing the compound after washing.

In Figures 1-5, the vertical axis represents the concentrations (: M) of the compounds tested. In Figures 3-5, the horizontal axis represents the concentrations (unit) of the viral P24 antigen. In Figures 1-2, the horizontal axis represents the relative percentage.

Detailed Description of the Invention The object of the invention relates to the effects of the compounds of the formula I and the pharmaceutically acceptable salts thereof for use in the treatment or prophylaxis of diseases related to HIV and retroviruses. More specifically, the compounds of the formula I can be used in the treatment or prophylaxis of diseases such as acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC) and adult T cell leukemia. Therefore, the invention provides a pharmaceutical composition for the tracing or prophylaxis of diseases related to HIV and retroviruses, comprising an effective amount of the compound of formula I or Ar-A-C-0- (CH) m-B wherein Ar represents aryl, which is unsubstituted or substituted by halo, hydroxyl or alkoxyl A represents C1-6 alkylene, C2-6 alkenylene? C2-6 alkynylene; m is an integer from 0 to 6 and B represents hydrogen, C 1-6 alkyl or aryl, said aryl is unsubstituted or substituted by halo, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl C 2-6 alkynyl; or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier.

Preferred compounds of Formula I are those in which Ar represents phenyl or naphthyl, which is unsubstituted or substituted by halo, hydroxyl or Ci-β alkoxy; A represents C 1-4 alkylene C 2-4 alkenylene; m is an integer from 0 to 3 and B represents C 1-3 alkyl phenyl, said phenyl is unsubstituted or substituted by halo, hydroxyl or Ci-β alkyl; or pharmaceutically acceptable salts thereof.

The most preferred compounds of the formula I are those in which Ar represents phenyl, which is unsubstituted or substituted by halo, hydroxyl or methoxy; A represents C2-3 alkenylene is an integer from 0 to 2 and B represents methyl or phenyl; or pharmaceutically acceptable salts thereof.

The most preferred compounds of formula I are selected from the group consisting of: phenethyl caffeic ester acid (CAPE), phenethyl dimethyl caffeate (PEDMC), methyl caffeate (MC) and phenethyl 4-bromocynamic ester acid or pharmaceutically acceptable salts of the same.

It was found that the compounds of the formula I and the pharmaceutically acceptable salts thereof have a substantial inhibitory activity on the replication of HIV. In addition, retroviral and HIV integrases are highly homologous. Accordingly, the invention also provides a pharmaceutical composition for HIV inhibition and replication of the retrovirus, which comprises a compound of the formula I as defined above together with a pharmaceutically acceptable carrier.

The compound of formula I may have one or more chiral centers. Therefore, it has several stereoisomeric forms. That is, the compound of formula I includes all isomers.

The compound of the formula I and the starting materials for its preparation can be prepared by known processes, such as the methods described in the references (for example, He zhao ef al., J. Med. Chem. 1997, 40, 1186-1194 Chinthalapally B. Rao et al., Chem. Biol. Interactions, 84 (1992) 277-290, and the like). That is, the compounds of the formula I can be prepared by reactions noted in said references under the appropriate and known reaction disorders. The preparation can also be done by some of the known processes with minor modifications. However, such preparation is not described in detail in this document.

Nowadays, patients with AIDS are treated with cocktail therapies. However, HIV in some of the patients still developed resistance to known antiviral agents. Therefore effective treatments or prophylaxis can not be achieved. To achieve the effective treatment or prophylaxis of AIDS or related diseases and the inhibition of viral replications, it is necessary to use them in combination with other antiviral agents. Therefore, the invention provides a combination of a compound of formula I and one or more antiviral agents. The antiviral agents are selected from the group consisting of protease inhibitors such as indinavir, ritonavir or nelfinavir, nucleoside reverse transcriptase inhibitors such as zidovudine (ZDV), lamivudine (3TC), stavudine (d4T), 2 ', 3'-dideoxinosine (ddl) or 2 ', 3'-dideoxycytidine (ddC), non-nucleoside reverse transcriptase inhibitors such as nevirapine and integrase inhibitors.

It will be appreciated that the compounds of the combination can be administered simultaneously, either in the same or different pharmaceutical formulation or sequentially. If sequential administration exists, the delay in the administration of other active ingredients should not be at the expense of losing the advantage of a synergistic therapeutic effect of the combination of the active ingredients. It will also be understood that several of the active ingredients used in the combination of the invention or the physiologically functional derivatives of any of them, whether presented simultaneously or sequentially, may be administered individually or in multiples or in any combination thereof. The active ingredients in the combinations are preferably administered simultaneously or sequentially in separate pharmaceutical formulations, more preferably simultaneously.

While it is possible for the active ingredients of the combination to be administered as the unprocessed chemical, it is preferable to present them as a pharmaceutical formulation. The pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier (s) should be acceptable in the sense of being compatible with other ingredients of the formula and not deleterious to the excipient thereof. When the individual components of the combination are administered separately, each is generally presented as a pharmaceutical formulation.

It will be understood that administration of the combination of the invention by means of a single package to the patient or packs to the patient of each formulation, containing within a package inserted instructions to the patient for the correct use of the invention, is an additional desirable feature. of this invention.

The compound of the formula I and / or pharmaceutically acceptable salts thereof for use in the invention can form an appropriate dosage form in combination with at least one solid, liquid and / or semi-liquid excipient or adjuvant.

Useful excipients are organic or inorganic materials that are suitable for topical or parenteral (eg, oral) administration and are not interactive with the aforementioned compounds, eg, water, oils, benzylic alcohols, ethylene glycols, polyethylene glycols, gelatin, sugars such as lactose or starch, magnesium stearate, talc and petrolatum. In particular, tablets, pills, covered tablets, capsules, powders, particles, syrups and drops are for oral administrations; the suppositories are for rectal administrations; The solutions as well as suspensions, emulsions and injectable solutions are for parenteral administrations and ointments, creams or powders are for topical administrations. The compounds of the invention can also be lyophilized and subsequently used in the preparation of, for example, injectable solutions. These formulations can be sterilized and / or contain adjuvants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, stabilizers, colorants, flavoring agents and / or sweetening agents.

Since the administration of high doses of antiviral agents to patients can result in intoxication, the invention provides a pharmaceutical composition or combination comprising a safe and effective amount of a compound of formula I, wherein the effective and safe amount is from 0.1 to 1000: M, preferably from 100 to 400: M.

The specific dose level to be administered to an individual patient is determined by all possible factors, such as the activity of the specific compound employed, age, body weight, general health, sex, diet, mode and time. of administration, the rate of excretion, the drug combination, the severity of the disorder to be treated and the like. Oral administration is the preferred route of administration.

Example 1 Synthesis of Ester Fenetil 4-Bromocinnamic Acid The solution of 500 mg (1 eq.) Of 4-bromobenzyl aldehyde and 562 mg (2 eq.) Of malonic acid in 4 ml of pyridine were mixed and 266 ml of piperidine were added. The mixture was heated at 80 ° C for 2 hours and subsequently heated at 115 ° C for 8 hours. After cooling, the reaction mixture was poured into 250 ml of cold water. The solution was acidified slowly adding 10 ml of HCl. The crystals were separated by filtration and then washed 4 times with cold water. The crude acid was dissolved in an aqueous solution of NaOH (1: 20). The solution was filtered, diluted with 10 ml of cold water and acidified with 1: 1 HCl. The mixture was filtered, the crystals were washed with 20 ml of cold water and extracted with chloroform (Production 77%).

The 4-bromo-kinamic acid (1 eq.) Was placed together with 8 ml of CHC and SO2CI2 (3 eq.) The mixture was heated at 70 ° C for 7 hours and concentrated to hydrochloric acid.The hydrochloric acid was subsequently dissolved in CHCl3 (10 ml) and the solution was added dropwise to the mixture of phenylethyl alcohol (2 eq.) and pyridine (2 eq.) in 10 ml of CHCl3 for 5 minutes.The mixture was stirred for 30 minutes and purified with column chromatography to give fenetyl 4-bromocynamic acid ester (Production 88.6%).

Example 2 The cytotoxicities of Ester Fenetil Cafeico Acid (CAPE), Methyl Caffeate (MC) and Dimethyl Fenetil Cafeate (PEDMC) to Peripheral Blood Mononuclear Cells (PBMC).

In 24-well plates, the PBMC cells were exposed to various concentrations (0.1, 0.5, 1, 5, 10, 25, 50, 100, 200 and 400: M) of CAFÉ, MC and PEDMC for 48 hours. The viability of the cells was tested by the trypan blue dye exclusion method. More specifically, for the determination of the growth inhibitory effect of MC, CAPE and PEDMC, the cells were placed in 6-well plates with various sub-cytotoxic concentrations of these agents for 48 hours. The concentration of DMSO was adjusted to less than 0.5%. The cells of the quadrupled plates were washed once with Hank's Balanced Salt Solution (HBSS). In accordance with the process, the floating dead cells were separated from the living monolayer cells. Subsequently the cells were labeled with trypan blue and counted. The total number of viable cells in the control group considered with 100% viability and the cells treated with the agents were compared with the control group for the determination of% viability. The% viability of the cells treated with agents was calculated from the total number of viable cells in the control group and in the group treated with agents.

The results are shown in the following table. The viabilities of PBMC under treatments at high doses of CAPE, MC or PEDMC, even as high as 400: M, did not have substantial differences from those under treatments at low doses (for example, 0.1-10: M). The results indicate that the tested compounds do not cause cytotoxicity to the cells under said high dose.

Cytotoxicities of CAPE, MC and PEDMC to PBMC (the number of dead cells in a count of 400 cells is as follows and the numbers of dead cells in the control group being 9) concentration CAPE MC PEDMC s (: M)% The% of% numbers viability numbers feasibility numbers cell viability of dead dead cell cells in the in the counting count of 400 400 400 cells cells cells 400 8 392/391 7 393/391 6 394/391 (100.3%) (100.5%) (100.8%) 200 7 393/391 8 392/391 7 393/391 (100.5%) (100.3%) (100.5%) 100 11 389/391 7 393/391 10 390/391 (99.5%) (100.5%) (99.7%) 50 12 388/391 11 389/391 10 390/391 (99.2%) (99.5%) (99.7%) 5 395/391 11 389/391 8 392/391 (101%) (99.5%) (100.3%) 10 390/391 7 393/391 9 391/391 (99.7%) (100.5%) (100%) 10 390/391 9 391/391 11 389/391 (99.7%) (100%) (99.5%) 1 7 393/391 12 388/391 7 393/391 (100.5%) (99.2%) (100.5%) 0. 5 9 391/391 7 393/391 10 390/391 (100%) (100.5%) (99.7%) 0. 1 11 389/391 9 391/391 11 389/391 (99.5%) (100%) (99.5%) Example 3 The Cellular Activities in Tetrazolium Microculture Tests Cell activities were tested in accordance with the method described in Alley M.C. et al., Cancer Res. 1988; 48 (3): 589-601. The principle of the method resides in the fact that living cells can reduce MTT, for example, in 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (tetrazolium salt) to formazan crystal through the Dehydrogenase metabolism in Mitochondria. The crystal was dissolved in propanol and the OD values were determined at 570 nm. The OD values can indicate the numbers of the living cells. First the growth of cell conditions was observed. Cells were diluted at 2x104 cells / ml. A sample of 100: I taken by means of a micro pipette was placed on a 96-well plate. The plate was cultured for 24 hours at 37 ° C and 100: 1 of the compounds, which were prepared in medium, were added to each dish. After cultivation for 48 hours, the floating liquid was absorbed and 90: 1 / plate of medium and 10: 1 / plate of MTT solution were added. After cultivation for 4 hours, the floating liquid was absorbed and 100: 1 of DMSO and 10: 1 / dish were added. Each plate was mixed homogeneously. The absorbance was determined at 570 nm.

As shown in Figures 1 and 2, in the CAPE and the EC there are no substantial effects between the PEDMC, CAPE and EC. The results indicate that the cells are alive.

Example 4 P24 quantification for HIV and retrovirus-1 The PBMCs were treated with various concentrations of CAPE, MC and PEDMC provided in Example 2 and infected simultaneously with tropic macrophage (NL-43), tropic T cells (JRCSF) and macrophage and dual tropic HIV-1 isolated T cells ( 89.6). The next day, the added compounds were removed by washing methods or kept in the same concentration. The samples were divided into two groups and the cream of the culture medium was collected on the 3 and 7 days after infection, respectively. The use of the EIA P24 Reagent Kit from Abbott Laboratory compares the concentrations of the viral P24 antigen with or without the tested compounds.

As shown in Figures 3-5, CAPE, MC, and PEDMC have viral replications significantly inhibited. Especially, CAPE and MC in the concentration of 100: M or less, can inhibit 100% the viral replication of several of the isolates of HIV. When the concentration of the compounds tested gradually decreases, the inhibition of viral replication gradually decreases. On the other hand, the activities were not different from several of the HIV isolates (NL-43, JRCSF or 89.6). It is evident that the occurrence of inhibition can not be achieved in the connection stage but only after subsequent viral penetration. Given the above, the results showed that CAPE, MC and PEDMC can inhibit the replication of HIV isolates with different tropism.

The data are as follows: MTT 24 CAPE EC PEDMC 0.1 97.49 98.38 92.38 0.5 104.67 105.82 98.72 1 109.25 110.22 98.26 5 102.41 101.18 94.33 10 93.07 102.41 98.72 25 98.65 109.46 107.27 50 95.49 92.15 102.03 100 96.15 98.07 106.06 200 106.8 99.69 97.93 400 108.62 89.69 94.8 Figure 1! 4 h CAPE EC PEDMC 0.1 87.49 103.81 97.31 0.5 97.54 98.92 98.72 1 104.18 103.37 105.28 5 99.74 94.44 104.07 10 94.76 98.35 98.08 25 96.92 97.94 98.78 50 96.42 98.19 97.15 100 94.02 98.77 97.74 200 98.6 98.83 96.32 400 98. 102.07 93.76 Figure 2 CAPE NL43 (+) NL43 (-) CAPE JRCSF (+) JRCSF (-) CAPE 89.6 (+) 89.6 (-) 400 0 0 400 0 0 400 0 0 200 0 0 200 0 0 200 0 0 100 0 62.26 100 0 0 100 0 113.2 50 166.12 865.44 50 0 0 50 0 243.53 975.64 988.28 25 0 0 25 0 182.44 990.64 1000 10 642.72 34.42 10 230.32 255.21 1000 1000 5 965.62 1000 5 243.87 280.51 1 1000 1000 1 1000 1000 1 643.71 1000 0. 5 1000 1000 0.5 1000 1000 0.5 899.22 949.75 0. 1 1000 1000 0.1 1000 1000 0.1 1000 1000 Figure 3 MC NL43 (+) NL43 (-) MC JRCSF (+) JRCSF (-) MC 89.6 (+) 89.6 (-) 400 0 2.53 400 0 0 400 0 0 200 0 518.45 200 0 0 200 0 124.97 100 0 687.24 100 0 0 100 8.91 278.43 50 273.07 922.63 50 0 42.64 50 18.4 286.46 220.63 1000 25 2.33 786.67 25 5.2 504.42 1000 1000 10 2.53 828.46 10 14.36 624.39 1000 1000 5 58.13 1000 5 66.78 1000 1 1000 1000 1 1000 1000 1 149.67 966.67 0. 5 1000 1000 0.5 1000 1000 0.5 954.88 1000 0. 1 1000 1000 0.1 1000 1000 0.1 1000 1000 Figure 4 PEDMC NL43 (+) NL43 (-) PEDMC JRCSF (+) JRCSF (-) PEDMC 89.6 (+) 89.6 (-) 400 640.7 898.4 400 348.96 869.4 400 84.85 494.91 200 890.43 981.43 200 452.46 1000 200 187.69 539.82 100 1000 1000 100 892.45 1000 100 238.49 647 50 1000 1000 50 1000 1000 50 747.3 681.42 1000 1000 25 1000 1000 25 886.42 927.4 1000 1000 10 1000 1000 10 965.48 932.67 1000 1000 5 1000 1000 5 1000 1000 1 1000 1000 1 1000 1000 1 1000 1000 0. 5 1000 1000 0.5 1000 1000 0.5 1000 1000 0. 1 1000 1000 0.1 1000 1000 0.1 1000 1000 Figure 5

Claims (19)

CLAIMS 1. A pharmaceutical composition for the treatment or prophylaxis of diseases related to HIV and retroviruses or for inhibition of HIV and replication of retroviruses, comprising an effective amount of a compound of the formula IO ll wherein Ar represents aryl , which is unsubstituted or substituted by halo, hydroxyl or alkoxyl
1. A represents alkylene Ci-β, C2-6 alkenylene? C2-6 alkynylene; m is an integer from 0 to 6 and B represents hydrogen, Ci-β alkyl or aryl, said aryl is unsubstituted or substituted by halo, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl? C2-6 alkynyl; or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier.
2. 2. The pharmaceutical composition according to claim 1, wherein Ar represents phenyl or naphthyl, which is unsubstituted or substituted by halo, hydroxyl or C 1-6 alkyl alkoxy represents C 1-4 alkylene C 2-4 alkenylene is a whole number from 0 to 3 and B represents C 1-3 alkyl or phenyl, said phenyl is unsubstituted or substituted by halo, hydroxyl or C 1-6 alkyl.
3. 3. The pharmaceutical composition according to claim 2, wherein Ar represents phenyl, which is substituted with halo, hydroxyl or methoxy; A represents C2-3 alkenylene; m is an integer from 0 to 2 and B represents methyl or phenyl.
4. 4. The pharmaceutical composition according to claim 1, wherein the compounds of the formula I are selected from the group consisting of: phenethyl caffeic ester (CAPE), phenethyl dimethyl caffeate (PEDMC), methyl coffee (MC) and acid 4-bromocynamic phenethyl ester
5. 5. The pharmaceutical composition according to claim 1, wherein the diseases are such as the acquired immunodeficiency syndrome (AIDS), the AIDS-related complex (ARC) and the adult T-cleukemia.
6. 6. The pharmaceutical composition according to claim 1, wherein the effective amount of a compound of the formula I is 0.1-1000: M.
7. 7. The pharmaceutical composition according to claim 1, wherein the effective amount of a compound of the formula I is 100-400: M.
8. 8. A combination comprising an effective amount of a compound of the formula I O where Ar represents aryl, which is unsubstituted or substituted by halo, hydroxyl or alkoxyl A represents C1-6 alkylene, C2-6 alkenylene? C2-6alkynylene is an integer from 0 to 6 and B represents hydrogen, C1-6alkyl or aryl, said aryl is unsubstituted or substituted by halo, hydroxyl, C1-6alkyl, C2-6alkenyl or C2alkynyl -6; or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, with one or more antiviral agents.
9. 9. The combination according to claim 8, wherein Ar represents phenyl or naphthyl, which is unsubstituted or substituted by halo, hydroxyl or Ci-β alkoxy; A represents C1-4alkylene or C2-4alkenylene; m is an integer from 0 to 3 and B represents C 1-3 alkyl or phenyl, said phenyl is unsubstituted or substituted by halo, hydroxyl or C 1-6 alkyl.
10. 10. The combination according to claim 9, wherein Ar represents phenyl, which is unsubstituted or substituted by halo, hydroxyl or methoxy; A represents C2-3 alkenylene is an integer from 0 to 2 and B represents methyl or phenyl.
11. 11. The combination according to claim 8, wherein the compounds of the formula I are selected from the group consisting of: phenethyl caffeic ester (CAPE), phenethyl dimethyl caffeate (PEDMC), methyl coffee (MC) and ester acid 4-bromocynamic phenethyl.
12. 12. The combination according to claim 8, wherein the antiviral agents are selected from the group consisting of protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and integrase inhibitors.
13. 13. The combination according to claim 8, wherein the protease inhibitors are selected from the group consisting of indinavir, ritonavir and nelfinavir.
14. 14. The combination according to claim 8, wherein the inhibitors of the nucleoside reverse transcriptase are selected from the group consisting of zidovudine (ZDV), lamivudine (3TC), stavudine (d4T), 2 ', 3'-dideoxyinosine (ddl) ) and 2 ', 3'-dideoxycytidine (ddC).
15. 15. The combination according to claim 8, wherein the inhibitor of the non-nucleoside reverse transcriptase is nevirapine.
16. 16. The combination according to claim 8, wherein the effective amount of a compound of the formula I is 0.1-1000: M.
17. 17. The combination according to claim 8, wherein the effective amount of a compound of the formula I is 100-400: M.
18. 18. The combination according to claim 8, wherein the active components are administered simultaneously.
19. 19. The combination according to claim 8, wherein the active components are sequentially administered.