it has now been discovered , and this constitutes an aspect of the present invention , that diethyl -[ 6 -( 4 - hydroxycarbamoyl - phenylcarbamoyloxymethyl )- naphtalen - 2 - yl - methyl ]- ammonium chloride , preferably in monohydrate form , more preferably in monohydrate crystal form ( itf2357 , givinostat ), is capable of inducing the hiv - 1 gene expression , in the ach - 2 cell line , at a concentration preferably between 125 and 250 nm . itf2357 revealed to be non - mutagenic [ monzani , v m et al . presented at eurotox 2007 , 44 th congress of toxicology , poster g33 ]; therapeutic circulating concentrations between 125 and 250 nm may be easily obtained , in the clinical treatment , by administering 50 - 200 mg of itf2357 . the dosages within this range were used in numerous clinical studies and the detected toxic effects were extremely low ; an equivalent dose of 1 . 5 mg / kg / day was administered to children with systemic onset juvenile idiopathic arthritis ( sojia ) with encouraging results and without detection of any toxic effect [ vojinovic , j . et al . presented at the 72 nd annual meeting of the american college of rheumatology , san francisco , calif ., 29 oct . 2008 ]. it was thus found , and this is a second aspect of the invention , that some hdac inhibitors which are 4 - amino - n - hydroxy - benzamide derivatives ( which include itf2357 ) may be extremely effective at inducing the hiv gene expression at concentrations that do not reveal any considerable toxicity ; this seems to be in contrast with the previous opinions [ shehu - xhilaga , m . et al . aids 23 , 2047 ( 2009 )] which suggest that the two effects , hiv gene induction and toxicity , may depend on the same structural and / or mechanistic reasons . it has also been found , and this is a third aspect of the invention , that some of such 4 - amino - n - hydroxy - benzamide derivatives , capable of inhibiting hdac enzymes , are even more potent than itf2357 at inducing the hiv - 1 gene expression , in the ach - 2 cell line , at a concentration between 125 and 250 nm . purely by way of example , 4 -( 2 ( s )- benzoylamino - 3 - naphtalen - 2 - yl - propionylamino )- n - hydroxy - benzamide ( compound g ) and benzo [ 1 , 3 ] dioxole - 5 - carboxylic acid [ 1 ( s )-( 4 - hydroxycarbamoyl - phenylcarbamoyl )- 2 - naphtalen - 2 - yl - ethy ]- amide ( compound t ), both described in example 2 of the aforementioned wo 2006 / 003068 , induce , in ach - 2 cells , at 250 nm , an increase of the hiv expression 30 times higher with respect to the 15 times higher increase obtained with the same concentration of itf2357 . thus , the object of the present invention is represented by a compound of general formula i for use in the treatment of hiv infections , preferably hiv - 1 infections , x is o , ch or it is absent ; ar is aryl or saturated , unsaturated or partially unsaturated mono -, di -, tricyclic carbocyclic residue , or a saturated , unsaturated or partially unsaturated mono -, di -, tricyclic heterocyclic residue comprising one or more heteroatoms selected from among n , s and o ; said carbocyclic or heterocyclic aryl residue being optionally substituted with one or more identical or different halogens , c 1 - c 4 alkyl , c 1 - c 4 alkoxyl , c 1 - c 4 haloalkyl , alkylsulfonyl , cycloalkyl , ( cycloalkyl ) alkyl , alkanoyl , amino , ( c 1 - c 4 ) mono - or dialkylamino , ( c 1 - c 4 ) aminoalkyl mono - or disubstituted with c 1 - c 4 alkyl , carboxy , c 1 - c 4 alkoxylcarbonyl , mercaptoalkoxy , mercaptophenoxy , nitro , cyano , oxo , perfluoroalkoxy , perfluoroalkyl , phenyl , phenoxy , phenylalkoxy , benzoyloxy , phenylalkyl , benzoyl , phenylsulfonyl and hydroxy ; wherein r 1 is aryl , arylalkyl , linear or branched c 1 - c 4 alkyl , or saturated , unsaturated or partially unsaturated mono -, di -, tricyclic carbocyclic residue , or a saturated , unsaturated or partially unsaturated mono -, di -, tricyclic heterocyclic residue comprising one or more heteroatoms selected from among n , s and o ; said aryl , arylalkyl , linear or branched c 1 - c 4 alkyl , carbocyclic or heterocyclic residue optionally being selected , with one or more residues , mutually identical or different , from among : halogen , c 1 - c 4 alkyl , c 1 - c 4 alkoxyl , c 1 - c 4 haloalkyl , alkylsulfonyl , cycloalkyl , ( cycloalkyl ) alkyl , alkanoyl , amino , ( c 1 - c 4 ) mono - or dialkylamino , ( c 1 - c 4 ) aminoalkyl mono - or disubstituted with c 1 - c 4 alkyl , carboxy , c 1 - c 4 alkoxylcarbonyl , mercaptoalkoxy , mercaptophenoxy , nitro , cyano , oxo , perfluoroalkoxy , perfluoroalkyl , phenyl , phenoxy , phenylalkoxy , benzoyloxy , phenylalkyl , benzoyl , phenylsulfonyl and hydroxy . the compound of formula i is mainly intended for administration to a human , preferably to obtain a blood concentration between 125 and 250 nm ; preferably , such compound is administered at a dosage ranging from 50 to 200 mg / day , more preferably from 100 to 200 mg / day . according to an embodiment it is administered at a dosage ranging from 50 mg twice a day to 200 mg once a day . according to another embodiment , it is administered in combination and / or in temporal proximity with at least one anti - retroviral agent ; preferred anti - retroviral agents include nucleoside reverse transcriptase inhibitors , non - nucleoside reverse transcriptase inhibitors , protease inhibitors , fusion inhibitors , entry inhibitors , integrase inhibitors , co - receptor antagonists , viral adsorption inhibitors , viral specific transcription inhibitors and / or cyclin dependent kinase inhibitors ; the most preferred anti - retroviral agents being efavirenz , indinavir sulfate and / or raltegravir potassium . ach2 cells were obtained through aids research and reference reagent program , division of aids , national institute of allergy and infectious diseases , national institutes of health , bethesda , md . the cells were cultured in flasks , washed in rpmi and resuspended in rpmi / 10 % fcs at a concentration of 2 × 10 6 cells / ml . 250 μl of cells , 200 μl of media and 50 μl of hdac inhibitors solution at various concentrations ( from 0 to 250 nm ), containing 0 . 01 % dmso , were divided into aliquotes in a 48 - wells polystyrene tissue culture plate ( falcon , lincoln park , n . j .). after 24 hours of incubation at 37 ° c ./ 5 % co 2 , 50 μl of supernatant were removed for the cytotoxicity assay of the lactate dehydrogenase ( ldh ) and triton - x - 100 ( 0 . 5 % vol / vol final concentration ) were added to each culture . the p24 assays of the lysates were performed immediately . the cellular death as determined by the ldh activity after 24 hours was not considerably different in the cells exposed to hdac inhibitors with respect to the non - treated cells . p24 was measured using specific antibodies immobilized on magnetic beads as previously described [ nold m . f . et al . j . immunol . 181 , 557 ( 2008 )]. the levels of p24 for each experiment without hdac inhibitors were fixed at 1 . 0 and the increase values by the number of times for each experiment and each analogous were calculated . the results are shown in the table below . recombinant human enzymes were acquired from bps biosciences ( ca , usa ). isoforms of class i hdac1 , 2 , 3 ; hdac6 , 10 of class iib and class iv hdac11 were tested using the fluor - de - lys fluorogenic synthetic substrate ( enzo life sciences , plymouth meeting , pa .). isoforms of class iia hdac4 , 7 , 9 were tested using the boc - l - lys ( tfa )- mca ( tfal ) derivative , described as a specific substrate for these enzymes [ jones p . et al . bioorg med chem lett . 18 , 3456 ( 2008 )]. the recombinant human hdac8 assay was performed using hdac8 fluorimetric drug discovery kit ( enzo ) according to the manufacturer instructions . each inhibitor was dissolved in dmso and then further diluted in an assay buffer . concentrations of dmso lower than 0 . 5 % do not affect the activity of the assay . the assays were performed by pre - incubating each enzyme with the inhibitors for 15 minutes at 37 ° c . the reaction was started by adding the substrate at 37 ° c . and allowed to proceed for 60 minutes . the fluorescent signal was generated by adding 50 μl of a twice concentrated developer solution 2 ( enzo ) containing trichostatin a 4 μm . the generated fluorescence was detected at 355 nm ( excitation ) and 460 nm ( emission ) wavelengths . the results , expressed as ic 50 ( concentration required to reduce the enzymatic activity by 50 %), are shown in the table below ( the saha values were also measured and they are shown in the table ).
herein disclosed is a method for treating patients affected by hiv comprising administering n - hydroxy - benzamide - based histone deacetylase inhibitors , such as : diethyl -- naphtalen - 2 - yl - methyl ]- ammonium chloride ; 4 -- benzoylamino - 3 - naphtalen - 2 - yl - propionylamino )- n - hydroxy - benzamide ; and / or benzodioxole - 5 - carboxylic acid -- 2 - naphtalen - 2 - yl - ethyl ]- amide . such histone deacetylase inhibitors are administered in a dosage ranging from 50 to 200 mg / day , preferably from 100 to 200 mg / day , so as to obtain a blood concentration between 125 and 250 nm .