MXPA98008661A - Benzamide treatment of associated dementia the infection for the virus of the acquired immunodeficiency syndrome (human immunodeficiency virus) - Google Patents

Abstract

It is disclosed that benzamide-based compositions have activity as therapeutic and prophylactic agents in the treatment of conditions associated with infection by the HIV-1 virus, which are referred to in advanced stages as dementia associated with infection by HIV or dementia for V

Description

BENZAMIDE TREATMENT OF DEMENTIA ASSOCIATED WITH INFECTION WITH THE ACQUIRED IMMUNODEFICIENCY SYNDROME VIRUS (HUMAN IMMUNODEFICIENCY VIRUS 1) FIELD OF THE INVENTION - This invention relates to the treatment of dementia associated with infection by the AIDS virus (HIV-1). More particularly, it relates to compositions and methods for treating this condition prophylactically and therapeutically.

BACKGROUND INFORMATION This background information is divided into two parts. The first provides information about the condition treated by this invention, the dementia associated with infection by the AIDS virus. The second provides information regarding the benzamides and their use as medicaments, the benzamides being active agents used in the methods and compositions of this invention.

Dementia due to HIV (AIDS dementia complex) Acquired immunodeficiency syndrome (AIDS) is often accompanied by neurological complications in more advanced stages of the disease. Approximately one third of adults and a half of children with AIDS eventually have these complications. These neurological conditions involve a complex set of cognitive, motor, and behavioral dysfunctions that have been grouped with the names "AIDS dementia complex" (CDS) or more appropriately "dementia associated with HIV" or "HIV dementia". As much as 50% of infected children have neurological deficits manifested as important events of delayed development. Neurological diseases associated with HIV infection include ielopathy, peripheral neuropathy, and myopathy. The neuropathological alterations that accompany HIV infection in the CNS include pallor due to myelin, increased astrogliosis, loss of neurons and loss of dentrival arborization, as well as a decrease in the presynaptic area. The resulting neurological dysfunction can impair daily function, productivity at work and in severe cases require expensive institutional care. Although initial losses of mental capacity are not considered fully developed dementia, they nevertheless reflect neuronal damage associated with HIV-1. Currently there are no effective therapies for HIV dementia. "The drugs described herein should minimize the neuronic damage and prevent the advance of neuronal damage, thus allowing the prolonged functional capabilities of the affected individuals and consequently considerable savings for society.

In the United States alone, more than 1 million individuals are infected with HIV and approximately one third of this group has AIDS. Therefore, the possible population expected for a therapeutic treatment against HIV dementia is currently greater than 100,000 per year and the targeted population that would benefit significantly may be the prophylactic treatment against HIV dementia, about ten times that amount. The density of HIV dementia treatments is expected to grow as more effective therapies allow people with AIDS to live longer. There is no known cure for AIDS currently available and in the absence of effective treatment to completely eliminate the virus in individuals who suffer from it, it is unlikely that it will be available for a fully effective treatment for HIV dementia. Zidovudine (AZT) has been widely used to treat AIDS infection. Although there is now doubt as to the long-lasting effectiveness of this treatment due to the high frequency of mutation of the virus, there is nothing that AZT has been effective in the treatment of HIV dementia on a basis of ranuración. The neurological symptoms associated with HIV dementia have been treated with certain drugs. For example, the psychosis associated with HIV dementia has been treated with haloperidol and thioridazine. Olindone has been used in patients with psychotic and delirious dementia due to HIV. Methylfemidate has been used for the treatment of depression associated with HIV dementia. Electroconvulsive therapy has been used for stupor induced by HIV. All these treatments are used to improve the symptoms of HIV dementia. None treats HIV dementia itself. The envelope glocoprotein of HIV, gpl20, has been implicated in the pathogenesis of HIV dementia. It has been observed that this protein, which is abundantly secreted by infected cells, is neurotoxic to neurons in culture at extremely low concentrations, to impair learning, induce situkinase and reduce cerebral glucose utilization. Hill and others (Hill, JM, Mervis, RR, Avidor,., Moody, TW and Brenneman, DE (1993) Brain Res., 603: 22-233) have shown that newborn rats, administration of gpl20 causes morphological damage to the brain, as well as the delay in the development of complex motor behavior. There are no approved treatments available. Lipton has proposed the use of calcium channel antagonists and NMDA antagonists as possible therapies. Numerous calcium channel antagonists are available on the market, for example, nimodipine, but many companies are still studying clinically NMDA antagonists, mainly because of their remarkable use in populgia or chronic use in epilepsy or Parkinson's disease. It is known that amantadine, which exists in the market as anti-ral, possesses NMDA antagonist properties. There is a closer co-genus of amantadine in the European market, emantidine, and Lipton has proposed it as a possible alternative for the treatment of HIV dementia. Another agent that can be used for testing is nitroglycerin. Under certain circumstances, the NO generated by nitroglycerin can protect neurons from over-stimulation of NMDA receptors with the resulting exotoxicity of calcium and glutamate. However, the cardiovascular effects and the extremely erratic pharmacokinetics of nitroglycerin make this procedure seem problematic. The work related to the present invention, together with Robert Floyd, I, was discovered that certain nitron compounds will exhibit activity as anti-dementia agents by HIV. This separate invention is covered in another patent application filed concurrently with it.

Benzamides as medicaments The method of this invention for mitigating HIV dementia employs a family of benzamide analogs as the active agent. The Patent of E.U.A. No. 5,472,777, possessed in common, describes certain benzamides and their use in the treatment of neurological conditions. The application of the Patent Cooperation Treaty PCT / US96 / 0453S had in common, describes the compounds used herein and describes their use as pharmaceutical compositions for conditions that do not specifically include HIV dementia.

BRIEF DESCRIPTION OF THE INVENTION It has now been observed that certain benzamide compounds have activity in the treatment of the AIDS Dementia Complex (HIV dementia). This discovery may take the form of benzamide-based pharmaceutical compositions having activity against HIV dementia. These compositions include one or more of the acetamidobenzamide, inobenzamide or nitrobenzamide compounds of the Formula I as the active agent in a pharmaceutically acceptable carrier.

In formula I, R 'is a saturated alkyl of 3 to 5 carbon atoms, each R is independently -NH-CO-CH3, -NO2, and n is 1 or 2, with the following conditions: 1) when n is 1 and R is -NO2 at the 4-position of the ring, R 'is not terbutyl, iso-butyl or propyl; 2) when n is 1 and R is NO2 at the 2-position of the ring, R 'is not iso-butyl or propyl; 3) when n is 2 and R 'is tert-butyl and both Rs are -NO2, the R groups are not found in positions 3 and 5 of the ring. The vehicle is preferably an oral vehicle, but it can also be an injectable vehicle. These pharmaceutical compositions may exist in bulk form, but typically present in unit dosage form. In another aspect, this invention provides a therapeutic method for treating a patient suffering from HIV dementia. This method involves administering to the patient an effective amount for the treatment of HIV dementia of one or more of the pharmaceutical compositions just described. In another aspect, this invention provides a prophylactic method to protect a patient susceptible to HIV dementia. This method involves administering to the patient a prophylactic effective amount against HIV dementia of one more of the pharmaceutical compositions just described.

BRIEF DESCRIPTION OF THE DRAWINGS This invention will be described more fully with reference to the drawings in which: Figure 1 is a bar graph showing the protective effect of a benzamide in a culture test of cells related to HIV dementia. Figure 2 is a bar graph showing the protective effect of a benzamide in a culture test of cells related to HIV dementia. to Figure 3 is a bar graph showing the apoptosis response obtained in a cell aggregation test with a benzamide. Figure 4 is a graph of bioavailability of benzamide as a function of time.

DETAILED DESCRIPTION OF THE INVENTION Benzamides The treatment of this invention employs one or more benzamides as its active agent. This invention employs certain acetamidobenzamides, inobenzamides and nitrobenzaes as active pharmaceutical agents. The benzamides are described by the formula I. In this formula, R 'is a saturated alkyl of 3 to 5 carbon atoms and n is 1 or 2. The group (or groups) acetamido, amino or nitro, can be found in any part about the ring. Preferred embodiments include when n is 1 and the acetamido group is in the 2, 3 or 4 position of the ring and when n is 2 and in the acetamido groups they are in positions 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4, or 3 and 5 of the ring. With respect to the alkyl substituents, -R ', the compounds in which R' is an alkyl which does not have a hydrogen on the alpha carbon, that is, the carbon which binds to the ring nitrogen, are preferred. Some examples of these preferred R 'groups are tert-butyl or tert -amyl.

The acetamidobenzamides of Formula I of particular interest are: N-te r-bu ti 1 -aceta idobenzamide, N-iso-propyl-4-acetamidobenzamide, N-tert-amyl-4-acetamidobenzamide, N-tert-butyl- 3-acetamidobenzamide, and N-methylcyclopropyl-4-acetamidobenzamide, N-tert-butyl-4-acetamidobenzamide is the preferred idobenzamide acetamide. The aminobenzamides and nit robenzamides employed as active agents are described by the formula I, when R is an amino or nitro group. In this formula, R 'is the saturated alkyl of 3 to 5 carbon atoms and n is 1 or 2 subject to the same preferences for the substituents and their exposed positions with reference to the acetamidobenzamides and further subject to the conditions that 1) when n is 1 and R is -NO2 at the 4-position of the ring, R 'is not tert-butyl, iso-butyl or propyl; 2) n is 1 and n is -NO2 in the 2-position of the ring, R 'is not iso-butyl or propyl; and 3) when n 'is 2 and R' is tert-butyl and both Rs are -NO2, the R groups are not in positions 3 and 5 of the ring. The aminobenzamides and nitrobenzamides of Formula I of particular interest as active agents are: N-iso-propyl-n-trobenzamide, N-tert-butyl-3-nitrobenzamide, N-te r -butyl-2-n-trobenzamide, Nn- bu ti 1-4 -ni trobenzamide, Nn -propi 1-4 -ni trobenzamide, N- e r-bu ti 1-3, 5-di i trobenzamide, N -1 -mti lp rop i 1- -ni trobenzamide, N-tert-butyl-4-aminobenzamide and N-tert-butyl-3-aminobenzamide When a benzamide compound contains an amino group, such as is the case with N-tert-butyl-4-aminobenzamide, the amine functionality may be present as such or as salt. In the salt form, the amino is protonated to the cation form in combination with a pharmaceutically acceptable anion, such as chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, methanesulfonate, acetate, tartrate, oxalate, succinate or palmoate. When referring to this aminobenzamides, it is to be understood that these salts are also included. U.S. Patent No. 5,472,983, commonly owned, to which reference was made above, discloses several benzamides useful in the treatment of neurodegenerative diseases, based on their protective action in the MPTP mouse model of Parkinson's disease. The N-tert-butyl-4-acetamidobenzamide compound of the present invention is an in vivo biotransformation product of one of these benzamides (N-tert-butyl-4-nitrobenzamide) which has been found in the blood of rats and mice. which have been administered orally (N-tert-butyl-4-nitrobenzamide).

Mixtures of two or more of these materials can be used, if desired.

Pharmaceutical Compositions The benzamide compounds as pharmaceutical compositions suitable for oral or parenteral administration, for example as intravenous or intramuscular injection. The compositions for oral administration may take the form of liquid solutions or suspensions, powders, tablets, capsules or the like. In such compositions, the most usual nitrate is usually a minor component (from 0.1 to about 50% by weight) with the remainder being several carriers or carriers and processing aids useful in producing the desired dosage form. A liquid form can include a suitable aqueous or non-aqueous vehicle with pH regulators, suspension dispensing agents, colorants, flavors and the like. A solid form may include, for example, any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as algenic acid, Pri ogel or corn starch; a lubricant such as magnesium stearate; a slip agent such as colloidal silicon dioxide; a glycorant agent such as sucrose or saccharin; a flavoring agent such as peppermint, sugar, methyl salicylate or orange flavor. In the case of 'injectable compositions, are commonly based on injectable sterile saline solution or regular saline at their pH by phosphate or other injectable vehicles known in the art. Once again the active nitron is typically a less important component, often constituting about 0.05 to 10% by weight with the remainder being the injectable vehicle and the like. These components for orally administrable or injectable compositions are merely representative. Other materials as well as treatment techniques and the like are set forth in part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., Which is incorporated by reference. The compounds of the invention can also be administered in sustained release forms or by sustained release drug delivery systems. An "Assignment of Representative Retention Materials" can be found in the materials incorporated in Remington's Pharmaceutical Sciences.

Conditions treated and treatment regimens Conditions treated with benzamide-containing compositions generally include HIV dementia and the various symptoms that fall within the definition of HIV dementia. The formulations containing benzamide can be administered to achieve a therapeutic effect and decrease counteract the progression of HIV dementia or can be administered prophylactically to patients who do not yet exhibit dementia for HIV, or who are exposed to the HIV-1 virus. The benzamide-containing composition is administered in designated ways to procure the drug into the patient's bloodstream and through the blood-brain barrier to the patient's brain. An excellent way to do this is intravenous administration. The intravenous dose levels for treating these conditions range from about 0.01 mg / kg / hour, to about 10 mg / kg / hour all for about 1 to about 120 hours and especially 1 to 96 hours. A preload bolus of about 10 to about 500 mg can also be administered to achieve adequate levels of steady state. Other forms of parenteral administration, such as intramuscular injection, may also be used. In this case, similar dose levels are employed. Although parenteral administration is attractive from a drug delivery point of view, it must be recognized that the course of HIV infection can extend for many months even years, so that oral dosing may be preferred for patient comfort and tolerance. With oral dosing, 1 to 3 oral doses per day are each required from about 0.02 to about 50 mg / kg, with preferred doses being from about 0.04 to about 10 mg / kg. These same levels and dosing regimens would be used for prophylactic treatment. In any treatment regimen, the health care expert should evaluate the patient's condition and determine whether or not the patient benefits from benzamide treatment. Some degree of experimentation may be required to determine an optimal level and pattern of effectiveness. A positive dose response relationship has been observed. As such and bearing in mind the safety of side effects and the advantages of providing the application to the maximum possible improvement, it may be desirable in some cases to administer large amounts of benzamide, such as those described above.

Methods of Preparation of the Compounds The benzamide compounds employed herein can be prepared using commonly available and more readily available starting materials. A representative preparation process, which is illustrated with tert-butylamine, but which can be carried out by any alkylamine, involves the following reactions: NHC Í CHJJ J III wherein X is halogen, such as I, Br, F or Cl.

IV (C) 3 In step (A) N-tert-butylnitrobenzamides (III) are formed. This reaction should be carried out at temperatures below 10 ° C. This step (A) produces, as benzamides III, the compounds of the invention wherein R is -NO2. In step (B), the nitro groups in the mono- or di-nitro benzamide III are subjected to reduction. A suitable catalyst such as a heterogeneous platinum, iron oxide hydroxide, palladium or nickel catalyst, typically on a support or with hydrogen gas and a catalyst is commonly carried out with a reducing agent such as hydrazine. This step (B) produces as benzamides IV, the compounds of the invention wherein R is NH 2. In step (O) the aminobenzamides IV are converted to acetamidobenzamides V by reaction of an acetyl halide such as acetyl chloride. This reaction is carried out in the presence of a soft base and at low temperatures to environments such as -20 ° C to + 20 ° C. This produces the compounds of the invention wherein R is acetamido. Alternative synthetic schemes can also be used to prepare the compounds. Some of these alternative procedures are set forth below using N-tert-butyl-4-acetamidobenzamide as the representative compound. Other compounds can be prepared using alternative methods starting with the appropriate starting materials, such as 2- 3-amino- or nitro-benzonitrile or 2,3-2,4-, 2,5-, 2,6, 3,4- or 3,5-diamino or dini-ro-benzonitrile and the suitable alcohol (alternative procedure 1) or similarly substituted toluene compounds and appropriate alkylamine (alternative procedure 3).

Alternative procedure 1 This procedure begins with the acetylation, for example, of the 4-aminobenzonityl ryl (A) to the compound (B) using regular methods. The acid hydrolysis of tert-butanol in the presence of 4-acetamidobenzoni ryl (B), provides a viable synthetic route to N-te r -butyl-4-acetamidobenzamid.

Alternative procedure 2 Acetylation, using regular methods, of the inexpensive starting material PABA (C) provides an inexpensive method to produce 4-acetomidobenzoic acid (D). The conversion of (D) to the acid chloride (E) using regular methods (eg, SOCI2) and the subsequent amidation using regular methods, such as those previously described, produce N-tert-butyl-4-acetamidobenzamide as inexpensive starting materials.

Alternative method 3 Another method for the preparation of the compounds begins with acetylation, using regular methods, for example, from paratoluidine (F) to 4-acetamidotoluene (G). Synthetic intermediate compound (G) and 4-acetamidobenzoic acid (D) can be converted with common oxidizing agents (for example KMnO ^) and subsequently converted to N-tert-butyl-4-acetamidobenzamides as outlined in the alternative procedure 2.

EXAMPLES The invention will be described more broadly by the following examples. These are provided to illustrate several preferred embodiments of the invention, but are not to be construed as limiting their scope which are defined, in contrast, in the appended claims. Examples 1 to 19 demonstrate the preparation of acetamidobenzamides, as well as nitro- and aminobenzamides, which are representative of the benzamide compounds employed in the compositions and methods of this invention. Examples 20 and 24 demonstrate the preparation of pharmaceutical compositions based on the compounds. Next, the results of the biological tests that illustrate the activity of the compositions of the invention are provided.

EXAMPLE 1 Preparation of N-t-butyl-4-aminobenzamide Tert-butylamine (14.6 g, 0.200 mol) was stirred in ethyl acetate (150 ml, which was purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate and filtering through funnel filter paper) and cooled to 5 ° C with ice bath. 4-Nitrobenzoyl chloride (18.6 g, 0.100 mol) in purified ethyl acetate (75 ml) was added dropwise at a rate such that the temperature below 10 ° C was maintained. The ice bath was removed after complete addition of benzoyl chloride solution and the reaction was stirred for 4 hours. This reaction mixture was then filtered over a Büchner funnel, the filtrate was washed 3 times with 5% HCl, once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered through filter paper in the following manner. funnel and the solvent was extracted leaving the white crystalline product. The product was dried in a vacuum oven at 24 mm and 45 ° C for 14 hours. This procedure yielded 17.13 g of crystals of N-tert-butyl-4-nit robenzamide (4% yield), 162-163 ° C. Nuclear magnetic resonance of protons (89.55 MHZ in CDCI3) showed obstructions at 8,257 ppm (d, 8.8 Hz, 2H, 3,5-aryl-H); 7.878 ppm (d, 8.8 Hz, 2H; 2,6-aryl-H) 6.097 ppm (bs, 1H; n-H); 1,500 ppm (s, 9h; te r-butyl-H). Palladium on carbon (5%, 75 mg) was added to N-tert-butyl-4-nitrobenzamide (5 g, 22.5 mmol) in 95% ethanol at 55 ° C. A solution of hydrazine (1.2 ml) in ethanol in 95% (10 ml) was measured dropwise over 30 minutes and more Pd / c (75 mg) was added. The reaction was refluxed for 3 hours, hydrazine (0.5 g) in 95% ethanol (5 ml) was added, and the reaction was refluxed for another hour. The reaction was filtered over a Büchner funnel, the volume of the solvent was reduced in vacuo and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and the solvent was removed, leaving 3.90 g of N-te? -butyl-4-aminobenzamide (90% yield) melting point 125-127 ° C Proton NMR at 90 MHZ. (in CDCl 3) showed absorbances at 7,290 ppm (wH, d, 8.8 Hz, 2,6-aryl-H); 6.368 ppm (2H, d, 8.8 Hz, 3.5-aryl-H); 5.45 ppm (1 H, bs; NHC = 0); 3.727 ppm (2H, bs; aryl-NH2); 1,186 ppm (9 H, s; t-butyl-H).

EXAMPLE 2 Preparation of N-e-r-butyl-4-acetamidobenzamide Acetyl chloride (0.45 g, 5.7 mmol) in ethyl acetate (25 mL) was added dropwise to N-tert-butyl-4-aminobenzamide (1.0 g, 5.2 mmol) and triethylamine (0.58 g, 5.7 mmol) in ethyl acetate at 3 ° C at a rate such that they were kept at a temperature below 10 ° C. The reaction was allowed to warm to room temperature, stirred 1 hour and washed with 5% HCl. Recrystallization from the aceto gave 1.08 g of N-tert-butyl-4-acetamidobenzamide (89% yield), melting point 119-121 ° C. Proton NMR at 90 MHz (in DMS0-d6) will provide absorbances at 9.726 ppm (1H, bs, N-H); 7.715 ppm (4H, dd, 4.4 Hz, aryl-H); 7.295 ppm (1 H, bs; NH); 2844 pp, (3H, s; CH3CO); 1448 ppm (9H, s; t-butyl-H).

EXAMPLE 3 Preparation of N-tert-butyl-3-nitrobenzamide N-tert-butyl-3- a-inobenza ida and N-tert-butyl-3-acetamidobenzamide The amination procedures of the example are sealed 1 using 3-not robenzoyl chloride instead of 4-nitrobenzoyl chloride. This gave N-tert-butyl-3-nit robenza ida with 92% yield, melting point 123-125 ° C. Proton NMR (in CDCI3) revealed absorptions at 8,517 ppm (2-aryl-H, s, 1H); 8.337 ppm (4-aryl-H, d, 8.8 Hz, ÍH); 8.121 ppm (6-aryl-H, d, 6. 4 Hz, 1H); 7.618 ppm (5-aryl-H, m, ÍH); 6.032 ppm (N-H, bs, ÍH); 1484 ppm (t-butyl-H, s, 9 H). The reduction of hydrazine catalyzed by iron (III) oxide-hydroxide produced N-tei-util-3-aminobenzamide with 53% yield, mp 118-120 ° C. Proton NMR (in CDCl 3) revealed absorbances at 7,088 ppm (4-6-aryl-H, m, 3 H); 6,794 ppm (2-aryl-H, s, ÍH); 5,902 ppm (N-H, bs, ÍH); 3.145 ppm (aryl-N-H, bs, 2H); 1458 ppm (t-butyl-H, s, 9 H). Acetylation of N-te r -butyl-3-aminobenzamide as described in example 2 gave N-tert-buty -3-acetaminobenzamide in 75% yield, mp 194-195 ° C. Proton NMR (in CDCl 3) revealed absorptions at 7,778 ppm (4-6-aryl-H, m, 3 H); 7,392 ppm (2-aryl-H, s, ÍH); 6.08 ppm (N-H, bs, 1H); 2174 ppm (acetyl-CH 3, s, 9H); 1,500 ppm (t-butyl-H, s, 9 H).

EXAMPLE 4 Preparation of N-tert-butyl-2-nor robenzamide and N-tert-butyl-2-acetamidobenzamide The method of Example 3 is repeated using the 2-nitrobenzoyl chloride in the amination step. This produces N-tert-butyl-2-nitrobenzamide. The reduction of nitrobenzamide with hydrazine produces N-te r-bu i1-2-aminobenzamide. The acetylation of the aminobenzamide produces N-tert-butyl-2-acetamidobenzamide.

EXAMPLE 5 Preparation of N-Isopropyl-4-nitrobenzamide and N-iso-propyl-4-acetamidobenza ida The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and iso-propyl-aane in the amination step. This produces N-iso-propyl-4-nor robenzamid. The reduction of nitrobenzamide with hydrazine produces N-iso-propi 1-4-aminobenzamide. The acetylation of the aminobenzamide produces N-iso-p ropil-4-acetamidobenzamide.

EXAMPLE 6 Preparation of N-ter-amyl-4-nitrobenzamide and N-ter-amyl-4-aceta-idobenzamide The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and t r -amyl amine in the amination step. This produces N-ter-amyl-4-nit robenzamide. The reduction of nitrobenzamide with hydrazine produces N-te r-amyl-4-aminobenzamide. The acetylation of the aminobenzamide produces N-ter-ami 1- acetamidobenzamide.

EXAMPLE 7 Preparation of N-iso-butyl-4-acetamic-obenzamide The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and iso-butylamine in the amination step. This produces N-iso-butyl-4-nitrobenzamide. The reduction of nitrobenzamide with hydrazine produces N-tert-butyl-2-aminobenzamide. The acetylation of the aminobenzamide produces N-iso-butyl-4-acetamidobenzamide.

EXAMPLE 8 Preparation of N-n-butyl-4-nitrobenzamide and N-n-butyl-4-acetamidobenzamide The method of Example 3 is repeated using the 4-n-trobenzoyl chloride and n-butylamine in the amination step. This produces N-n-butyl-4-nit robenzamide. The reduction of nitrobenzamide with hydrazine produces N-n-bu il-4-aminobenzamide. The acetylation of the aminobenzamide produces N-n-buty 1-4-cetami-obenzamide.

EXAMPLE 9 Preparation of N-n-propyl-4-nitrobenzamide and N-n-propyl-4-acetamidobenzamide The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and n-propylamine in the amination step. This produces N-n-butyl-4-nitrobenzamide. The reduction of nitrobenzamide with hydrazine produces N-n-propy1-aminobenzamide. The acetylation of the aminobenzamide produces N-n-propi 1-4 -acetamidobenzamide.

EXAMPLE 10 Preparation of N-l.2-di-netylpropyl-4-nitrobenzanide and N-l, 2-dimethyl-propyl-4-acetamidobenzamide The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and 1,2-dimethylpropylamine in the amination step. This produces N-l, 2-dimethylpropyl-4-nitrobenzamide. The reduction of nitrobenzamide with hydrazine produces N-1, 2-dimethyl ti lp rop i 1- -aminobenzamide. The acetylation of the aminobenzamide produces N-l, 2-dimet i lpropi 1-4 -acetamidobenzamide.

EXAMPLE 11 Preparation of N-n-pentyl-4-nor robenzamide and N-n-penfyl-4-acetamidobenzamide The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and n-pentylamine in the amination step. This produces N-n-pentyl-4-nitrobenzamide. The reduction of nitrobenzamide with hydrazine results in N-n-pen thi-4-aminobenzamide. The acetylation of the aminobenzamide produces N-n-penti 1-4 -acetamidobenzamide.

EXAMPLE 12 Preparation of N-2-methylbutyl-4-nor robenzamide and N-2-methylbutyl-4-acetamidobenzamide The method of Example 3 is repeated using the 4-nitrobenzoyl chloride and 2-methylbutylamine in the amination step. This produces N-2-methylbutyl-4-nitrobenzamide. The reduction of nitrobenzamide with hydrazine produces N-2-methylbutyl-4-aminobenzamide. The acetylation of the aminobenzamide produces N-2-methylbutyl-4-acetamidobenzamide.

EXAMPLE 13 Preparation of N-n-pentyl-2-nitrobenzamide and N-n-pentyl-2-acetamidobenzamide The method of Example 3 is repeated using the 2-nit robenzoyl chloride and n-pentylamine in the amination step. This produces N-n-pentyl-2-nitrobenzamide. The reduction of nitrobenzamide with hydrazine results in N-n-penti 1-2 -aminobenzamide. The acetylation of the aminobenzamide produces N-n-penti 1-2-acetamidobenzamide.

EXAMPLE 14 Preparation of N-te r -butyl -2, 3-diacetamidobenzamide The method of Example 3 is repeated using the 2,3-dinitrobenzoyl chloride in the amination step. This produces N-te r-butyl -2, 3-dini t robbery gone. The reduction of nitrobenzamide with hydrazine produces N-tert-butyl-2,3-diaminobenzamide. The acetylation of the aminobenzamide produces N-tei-butyl-2,3-diacetamidobenzamide.

EXAMPLE 15 Preparation of N-ter-amyl-2,4-diacetamidobenzamide The method of Example 3 is repeated using the 2,4-dinitrobenzoyl chloride and ter-a-amine amine in the amination step. This produces N-ter-amyl-2,4-dinitrobenzamide. The reduction of nitrobenzamide with hydrazine p results in N-te r-amyl -2, -diaminobenzamide. The acetylation of the aminobenzamide produces N-ter-amyl-2,4-diacetamidobenzamide.

EXAMPLE 16 Preparation of N-tert-butyl-2,5-diacetamidobenzamide The method of Example 3 is repeated using the 2,5-dinitrobenzoyl chloride in the amination step. This produces N-te r-butyl -2,5-di or trobenzamide. The reduction of nitrobenzamide with hydrazine produces N-te r -butyl -2,5-diaminobenzamide. The acetylation of the aminobenzamide produces N-tert-butyl-2,5-diacetamidobenzamide.

EXAMPLE 17 Preparation of N-te r -butyl -2,6-diacetamidobenzamide The method of Example 3 is repeated using the 2,6-dinitrobenzoyl chloride in the amination step. This produces N-te r -butyl -2,6-di ni t robenzamide. The reduction of nitrobenzamide with hydrazine produces N-tert-butyl-2,6-diaminobenzamide. The acetylation of the aminobenzamide produces N-tert-butyl-2,6-diacetamidobenzamide.

EXAMPLE 18 Preparation of N-tert-butyl-3,4-diacetamidobenzamide The method of Example 3 is repeated using the 3,4-dinitrobenzoyl chloride in the amination step. This produces N-tert-butyl-3, -di or trobenzamide. The reduction of nitrobenzamide with hydrazine p results in N-te r -butyl-3,4-diaminobenzamide. The acetylation of the aminobenzamide produces N-tert-buyl-3,4-di-acetamidobenzamide.

EXAMPLE 19 Preparation of N-tert-butyl-3., 5-diacetamidobenzamide The method of Example 3 is repeated using the 3,5-dinitrobenzoyl chloride in the amination step. This produces N-te r -butyl-3,5-dinitidene robenzamide. The reduction of the nor robenzamide with hydrazine produces N-te r-butyl-3,5-diaminobenzamide. The acetylation of the aminobenzamide produces N-tert-butyl 1-3, 5-diacetamidobenzamide.

PREPARATION OF PHARMACEUTICAL COMPOSITIONS EXAMPLE 20 The compound of Example 1 is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A minor amount of magnesium stearate is added as a lubricant. With the mixture, tablets of 240-270 mg (80-90 mg of active benzamide) are formed in a tableting press. If these tablets were administered to a patient suffering from HIV dementia on a daily regimen, three times a day or three times a day would reduce the progression of the patient's disease.

EXAMPLE 21 The compound of Example 2 is mixed as a dry powder with a starch diluent in an approximate weight ratio of 2: 1. The mixture is introduced into 250 mg capsules (125 mg of active benzamide). If these capsules were administered to a patient susceptible to dementia due to HIV on a daily regimen, twice a day or three times a day, it would diminish or prevent the attack of dementia by HIV.

EXAMPLE 22 The compound of Example 3 is suspended in an aqueous medium provided with sweetened flavor at a concentration of about 50 mg / ml. If 5 ml of this liquid material were administered to a patient suffering from dementia due to HIV in a daily regimen, twice a day or three times a day, the progress of the patient's disease would decrease.

EXAMPLE 23 The compound of Example 4 is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. The lower amount of magnesium stearate is added as a lubricant. With the mixtures tablets of 450-900 mg (150-300 mg of active benzamide) are formed in a tableting press. If these tablets were administered to a patient suffering from HIV dementia in a daily regimen of twice a day or three times a day, the progression of the patient's disease would decrease.

EXAMPLE 24 The compound of Example 14 is dissolved in an injectable aqueous medium of sterile saline buffered in its pH at a concentration of about 5 mg / ml. If 50 ml of this liquid material is administered to a patient suffering from dementia due to HIV in a daily regimen, twice a day or three times a day this dose would decrease the progress of the patient's disease. It will be appreciated that any of the compounds of formula I could be extended in any of these representative formulations and that any of these formulations could be administered in any of these ways, in order to treat any of the HIV dementia conditions described herein. specification.

BIOLOGICAL TESTS Two nerve cell culture systems were used in these tests to determine the efficacy of the N-tert-butyl-4-acetamidobenzamide ("compound I") in the reversal of neurotoxicity that mimic that observed with HIV dementia. In both trials. Human nerve cell cultures are obtained either as double layer (neurons on a layer of astrocytes) or three-dimensional model (aggregate of brain cells). TNF-α (100 pg / ml) was used as the neurotoxin and the duration of the 72-hour incubation. A considerable body of evidence supports the notion that the TNF-a is one of the neurotoxins responsible for HIV dementia. TNF-α brain concentrations are elevated in the gray matter of patients with AIDS and with mild dementia due to HIV (Achi, C, Heyes, MP, Wiley, CA (1993) Quantitation of human immunodeficiency virus, immune activation facyors, and quinolinic acid in AIDS brains, J Clin Invest 91: 2769-2775). The distribution of messenger RNA expressing TNF-a in the brain shows a similar pattern (W Sselingh, SL, Power, C, Glass, JD, Tyor, WR and others (1993) Int racereberal cytokine essenger RNA expression in here network immuniodeficiency syndrome Dementia, Annals of Neurology, 33: 576-582). Gelbard and others have shown that HIV-1 infected monkeys in culture with astroglial cells produce sufficient TNF-α levels to cause neurotoxicity (>200 pg / ml). Gelbard, HA, Dzenko, KA, DiLoreto, D, delCero, C, delCerro, M, Epstein, LG (1994). The neurotoxic effects of the a factor of fearful necrosis in primary human neuronal cultures are measured by activation of the AMPA glutamate receptor subtype (Implications for AIDS neuropathogenesis, Dev Neurosci, 15: 417-422). It has been reported that TNFa-a causes its neutoxicity by inducing apoptosis (Sel aj, K, Raine, CS, Farocq, M, Norton, WT, Brosnan, CF (1991) Cytokine cytoxicity against oligodendrocytes.) Apoptosis induced by Lymphotosins, J Im one, 147: 1522-1529). Recently, he demonstrated that gp 120 exerts toxic effects through the induction of IL-6 and TNF-a (Yeung, MC, Pulliam, L., Lau, AS (1995).) The envelope protein gp 120 of HIV is toxic to human brain cell cultures by induction interleukin-6 and factor a of the necrotic fear, AIDS, 9: 137-143.

Procedure for brain aggregates Brain cell aggregates were prepared with second-trimester abortion tissue as previously described (Pulliam L., Berens, ME, Rosenblum, ML 1988. A normal human brain cell aggregate model for nerobiological studies, J Neurosci Res 21 : 521-530). In summary, human brain tissue is dissociated gradually within 16 and 18 weeks of gestation through naylon sieves to obtain individual cells. Approximately 4 x 107 cells within 4 ml DME supplemented with 0.6% dextrose, 50 mg / ml gentamicin and 10% FCS are distributed in 25 ml DeLong flasks. The aggregates are rotated constantly and incubated at 37 ° C in a 10% CO2 atmosphere. After 2-3 days, the aggregates are transferred to 50 ml flasks and 50 ml of DME supplemented with 15% FCS (half exchanges) are added. Each bottle contains several thousand aggregates from which a sample can be taken over time. 5 ml of medium are exchanged on alternating days in the culture. After 10-12 days in culture, samples are taken for histology and the tripanicidal blue exclusion is performed to determine the weakness. The samples are analyzed for HIV, hepatitis A, B, C and ichroplasma. The aggregates remain viable for approximately 40 days in culture. The aggregates of cerebellar cells are differentiated and again of taking samples because they express nerve cell markers for their identification. The aggregates of brain cells contain all the cells of the CNS-approximately 40% of neurons, 40% of astrocytes, 10% of oligodendrocytes with myelin and 10% of icrogliocytes. The apoptosis / death of the nerve cells was measured by the Elisa technique of DNA fermentation according to the instructions of the manufactures (Boehringher Mannheim).

Double-layer procedure of nerve cells Brain aggregates were prepared as described above. Several aggregates are placed in each receptacle of a multi-receptacle chamber (Numc) coated slide of Cell TAK (Collaborative Research) at a concentration of 20 ug / ml. The cells move out of the brain aggregates over the course of three days. The astrocytes form a single layer with neurons in the upper part and icrocytes (<1%) / oligodendrocytes (<1%) rare. These crops are confluent in the course of a week. Simple layers can be maintained for up to three weeks. The characterization of cell types is determined using immunohistochemistry and the specific inolases of antibody neurons (NSE, Dako) for neurons and the glibibiarial glial acid protein (GFAP, Dako) for the identification of astrocytes. A confocal microscope was used to visualize and identify neurons and astrocytes by size and shape. Neuronal viability was determined by exposing the cameras with different treatments and without them to AO and ethidium bromide (EtBr). The amounts of 3 neurons and total cells were determined by staining of AO with visual confirmation by phase microscope. The cell road numbering was performed by computerized software at the time of the microscopy; In addition, a visual impression of the observed fields always accompanied the data.

EXPERIMENTAL DESIGN # of experiment System TNF-a (pg / ml) Compound (μM) 1 Double layers 0 0 nerve cells 0 100 100 0 100 100 2 C Caappaass ddoobblleess 0 0 0 nerve cells 100 0 100 100 3 A Aggrreeggaaddoo 0 0 0 Cerebral 0 100 100 0 100 100 I The p-compound is N-te r -butyl-4-acetamidobenzamide Resul ates Experiment 1 (Figure 1): This was an experiment - with double layers of human nerve cells. The N-tert-butyl-r-acetamidobenzamide ("compound I") showed certain toxicities in relation to the comparison pattern. The treatment contains TNF-a produced a high degree of cell death, more than 61%. the COM N-tet-butyl-4-acetamidobenzamide treatment produced considerable protection. Experiment 2 (figure 2): This experiment was a repetition of experiment 1 using the different brain preparation. The results essentially duplicated those of the first experiment, except that the treatment contains TNF-α resulting in less neurological toxicity. Experiment 3 (FIG. 3): This experiment used human brain aggregates. In this experiment, apoptosis / cell death was measured by an immunoassay for the quantification of DNA fragments associated with cytoplasmic histone. In this experiment, treatments with N-tert-butyl-4-acetamidobenzamide produced considerable protection both with and without TNF-a treatments. The bars of figure 4 represent the average of the duplicate experiments. The error bars in this figure express the individual values. Physical / chemical parameters N-tert-butyl-4-acetamidobenzamide was studied for certain physical / chemical properties that suggest the inconvenience of its application. The following results were obtained: N-tert-butyl-4- acetated idobenzamide t? / 2 (min) in aqueous HCl solution (pHl) 3000 Octanol-water separation 31 This shows that N-tert-butyl-4- Acetamidobenzamide is lipophilic and is slowly extracted from the body. N-tert-butyl-4-acetamidobenzamide is a compound of particular interest for HIV dementia because, at least in the rat, it exhibits excellent brain distribution, bioavailability and far-kinetic profile. N-tei-butyl-4-acetamidobenzamide is also significantly stable at a pH commonly observed in the stomach.

Brain penetration of N-te r -butyl--acetamidobenzamide Following an oral dose of 30 mg / kg, blood and brain samples from the same animals were analyzed for N-tert-butyl-4-acetamidobenzamide a 4 and 8 hours after the dose with the following results: Time after concentration Concentration of the mean blood brain dose (hours) (μg / g) + / -SEM (μg / 9) + / -SEM 4 4 8 8..99 ++ // - 33..22 43 +/- 7.9 8 9.1 +/- 1.7 39 +/- 4.2 Absolute bioavailability of the oral suspension of N-tert-butyl-4-acetamidobenzamide The bioavailability of N-tert-butyl-4-acetamidobenzamide was determined by comparing the area under the curve (AUC) followed by a dose of 20 mg / kg of the benzamide dissolved in 1% methylcellulose. The blood concentrations were determined at 0, 0.083, 0.15, 0.5, 1.2, 4, 8 and 24 hours after the dose (intravenous) or 0, 0.5, 1.2, 4 and 8 hours after the dose (oral), and the ABCs were determined. Four animals were dosed orally and dosed to 4 animals intravenously.

Via ABC mean +/- SEM Bioavailability (μg hr mi-1) absolute Intravenous 252 +/- 73 Oral 130 +/- 33 52% The pharacokinetic profile of a dose of 30 mg / kg can be found in Figure 4 to Sprague Dawley rats. The apparent Ti 2 for N-tert-butyl-4-acetamidobenzamide in the experiment was 8 hours, a very long ti / 2 for a drug in a rat - for prediction of a once-a-day dosage if it was dosed N -ter-butyl-4-acetamidobenzamide in man. Such a dosage regimen would be a significant therapeutic advantage in the clinic.

Other brain aggregation studies Other studies were conducted as follows: Experiment No. gpl20 (ng / ml) TNF-a (ng / ml) Compound (μM) 0 0 1 0.1 1 0. 3 1 3.0 0 - 0 1 - 3 1 The test compound is N-ter-butyl- 4-acetamidobenzamide As shown in the following table, experiment 4 revealed that at unexpectedly low concentrations, Nt r -butyl-4-acetamidobenzamide provided complete protection and human brain aggregates from DNA fermentation, a measure of apoptosis, induced by 1 ng of TNF-a. A certain degree of dose proportionality was observed. The results at all concentrations of the test compounds are statistically significant at < 0.05 by Student's t-test of the single group of TNF, but, of the groups treated with the compounds, only the group of TNF test compounds ± 0.3 μM is statistically significant from the other two treatment groups.

TABLE RESULTS OF EXPERIMENT 4 F ragmentation of DNA (Absorbency Experiment ± SF.n = 3)% Protection Comparison pattern 0.663 ± 0.048 - - TNF only 1.592 ± 0.156 - -TNF + 0.1 μM compound 0.955 ± 0.101 78 TNF + 0.3 μM compound 0.835 ± 0.051 90 TNF + 3.0 μm compound 0.801 ± 0.123 90 1 The test compound is N-tert-butyl-4-acetamidobenzamide.

The above data suggest that protection with apoptosis can be achieved at concentrations of approximately 1 μM and less. A concentration of 1 μM of N-tert-butyl-4-acetamidobenzamide is in the order of 0.2 μg / ml. To achieve this concentration in the brain of a rat, a blood concentration of only 1 μg / ml would be required based on the brain / blood ratio data presented above. If a certain degree of dose proportionality is observed with lower doses of N-tert-butyl-4-acetamidobenzamide, a dose of 6 mg / kg to the rats should achieve this concentration even 24 hours after the dose (minimum value ). Using differences in blood flow in the liver to achieve drug separation in rats from man as described in Pulliam, L. Herndier, B. McGrath, MS (1992) Purified Trichosanthin (GLQ223R)) exacerbation of indirect HIV- associated neurotoxicity in vitro, AIDS, 5: 1237-1242, it would be predicted that a dose of 1.5 mg / kg to man would achieve 24 hours after the dose the desired concentration of one μM in the brain for protection against apoptosis. In harmony with the previous results, N-tert-butyl-4-acetamidobenzamide also provided complete protection in human brain aggregates against the toxicity induced by 1 ng of TNF-a, although the concentration of benzamine needed was considerably higher than the one obtained to avoid DNA fermentation. These data are as follows: Release of LDH Absorbency Experiment ± SD (n =)% Protection Comparison pattern 0.875 ± 0.022 - -TNF only 1.071 ± 0.036 - - TNF + 0.1 μM of compound 1.114 ± 0.023 0 TNF + 0.3 μM of compound 0.103 ± 0.034 0 TNF + 3.0 μm of compound 0.864 ± 0.028 100 1 The test compound is N-tert-butyl-4-acetamidobenzamide.

Experiment 5 In this experiment, N-tert-butyl-4-acetamidobenzamide provided significant protection in human brain aggregates against cellular toxicity induced by an ng of gpl20. The difference in absorbance was statistically significant for all the groups at p < 0.003.

Experiment Release of LDH Abso rbancia% ± SD (n =) Protection Patterns of comparison 0.328 ± 0.011 gpl20 0.575 ± 0.008 gp! 20 + 3.0 μM of compound1 0.427 ± 0.034 60% 1 The test compound is N-tert-butyl-4-acetamidobenzamide There was no evidence in that DNA fragmentation experiment induced at this concentration of gpl20.

Experiment 6 Using procedures essentially the same as those described above to determine the release of LDH induced by TNF, the programmed cell death analysis (PMC) will be performed by ELISA using standardized equipment (Boehringer Mannheim) .. The results were as follows: Experiment 6A PMC Comparison pattern 0 ± 0.359 TNF-a 1.18 ± 0.759 TNF-a + 10.0 μM compound 1.15 ± 0.125 TNF-a + 10.0 μM compounds 1,021 ± 0.099 TNF-a + 10.0 μM compound3 0.34 ± 0.029 1 The test compound is N-tert-butyl-4-acetamidobenzamide. 2 The test compound is N-tert-butyl-4-aminobenzamide. 3 The test compound is N-te r-amyl- -acetamidobenzamide Experiment 6B PMC Control 0 ± 0.69 TNF-a 1.16 ± 0.088 TNF-a + 10.0 μM compound 1.05 ± 0.043 TNF-a + 10.0 μM compound2 1.567 ± 0.026 TNF-a + 10.0 μM of compound3 0.671 ± 0.043 1 The test compound is N-tert-butyl-4-acetamidobenzamide. 2 The test compound is N-tert-butyl-4-aminobenzamide. 3 The test compound is N-ter-amyl-4-acetamidobenzamide Experiment 6C _ PMC Control 0 ± 0.032 TNF-a 0.674 ± 0.058 TNF-a + 10.0 μM of compound * 0.565 ± 0.042 * The test compound is N-tert-butyl-4-acetamidobenzamide.

Experiment 6D PMC Control 0 ± 0.018 TNF-a 0.531 ± 0.034 TNF-a + 10.0 μM of compound * 0.016 ± 0.03 * The test compound is N-tert-butyl-4-acetamidobenzamide.

The data from the 6A-D experiments demonstrate that the various benzamides of this invention provided protection in human brain aggregates against the toxicity induced by 1 ng of TNF-α as measured by PMC analysis.

In vivo tests In order to determine the effectiveness of this procedure to treat the CDS, a series of biological tests were carried out in vivo. Test in vivo Material and methods used. N-methyl-D-glucamide-dithiocarboamate was obtained (MGD) Sodium and Nitron, PBN, from 0MRF Spin Trap Source, Oklahoma City, Oklaho a. Gpl20 was obtained from Intracel Corporation, Cambridge, Massachusetts. These materials were used in the following preliminary test: Treatment of animals: Newborn Sprague-Dawley rats (16 siblings) were divided into four groups.

Starting on day one after birth until day 6, newborns received 60 μl of subcutaneous injections of the following treatments. Group 1: saline regulated in its pH by phosphate (PBS), Group 2: 5 ng of gpl20 in PBS, Group 3: 5 ng of gpl20 plus PBN (50 mg / kg) in PBS, and Group 4: PBN (50 mg / kg) in PBS. The rats were weighed daily and the amount of PBN injected was adjusted accordingly. Behavioral evaluations: The time required to perform the two important cases of development was measured in order to determine the adverse effects on the administration of gp! 20 in the development of behavior as reported by Hill and others and in order to determine the possible protective action of the PBN on these parameters. The behavioral parameters studied were surface bindings (the animal placed head down on a screen tilted at 45 ° will turn and rise). These two tests have been shown to be the most sensitive tests for the assessment of the neurological disorder caused by the treatment with gpl20. further, can be examined with sufficient anticipation in the life of the animal (day 3 for the end rezamiento on the surface and day 6 for the negative geotaxis), so that its determination will not interfere with the trapping of NO in the brain that is performed at the end of the first week of the animal's life. The animals were tested and the time required for straightening on the surface on day 3 and on day 4 after birth, immediately before receiving the injections on those days, and on day 6 (2 hours after of the last injection received by the animals) as well as on day 7 (20 hours after the last injections) regarding the time required to perform the negative geotaxis. The angle chosen for the assembly used for the negative geotaxis was reduced from 45 ° (the angle used by Hill and others) to 35 °, since according to the experimental setup used, the animals were not able to remain on the screen adjusted to 45 degrees. ° and it slid down before being able to make an attempt to turn upwards.

B test in vivo Protection of N-tei-butyl-4-acetamidobenzamide against the behavioral changes induced by gp! 20 The surprising results obtained with PBN drove the preliminary experiments with N-tert-butyl-4-acetamidobenzamide in the same model. The results suggest that N-tei-butyl-4-acetamidobenzamide is effective as demonstrated by the data shown below obtained in newborns who had been administered gpl20 at 10 ng - per dose starting with the 3-day-old animals . N-tert-butyl-4-acetamidobenzamide was given at an oral dose of 35 mg / kg 2 hours before administering gpl20. Treatment with N-tert-butyl-4-acetamidobenzamide and gpl20 continued daily. The negative geotaxis test was conducted on day 6.

Negative Geotaxis (sec) Treatment 3 after the last dose of gpl20 (day 6) Vehicle 8.80 ± 3.74 gpl20 18.0 ± 13.8 gpl20 + Compound * 8.29 ± 3.94 Compound1 8.56 ± 5.11 1 The p-compound compound is N-te i -butyl-4-acetamidobenzamide, The data suggest that N-te r -butyl-4-acetamidobenzamide had a protective effect. t REFERENCES Other references of interest include: Lipton, SA, Gendelman, HE (1995) Dementia associated with the acquired immunodeficiency syndrome, New England Journal of Medicine, 332 (14): 934-940. Simpson, DM, Tagliati, M (1994) Neurologic anifestations of HIV infection, Ann Intern Med, 121 (10): 769- 785. 0 Lipton, SA (1994) Neuronal injury associated with HIV-1 and potential treatment with calcium channel and NMDA antagonists, Dew Neurosci, 16 (3-4): 145-151. Danysz, W, Parsons, CG, Bresink, I, Quack, G (1995) Glutamate in CNS disorders, Drug News and Perspectives, 8: 261-5 277. Lipton, SA, Choi, YB, Pan, ZH, Lei, SZ , Chen, HSV et al. (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds, Nature, 364: 626-632. 0 Dawson, VL, Dawson, TM, Uhl, GR, Synder, SH (1993) Human immunodeficiency virus type I coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures, Proc Nati Acad Sci, 90: 3256-3259. Mollace, V, Colasanti, M, Persichini, Bagetta, G, 5 Lauro, GM, Nistico, G (1993) HIV pgl20 glycoprotein sti ulates the inducible isofor of NO synthase in human cultured astrocytoma cells, Biochem Biophys Res Comm 194: 439- 445 Schutz, JB, Henshaw, R, Siwek, D, Jenkins, BG, Ferrante, RJ, Cipolloni, PB, Kowall, NW, Rosen BR and Beal, MF (1995) Involvement of free radicals in excitotoxicity in-vivo. J. Neurochem. 64: 2239-2247. Winrow, VR. Winyard, PG, Morris, CJ, Blake, DR (1993) Free radicáis in inflammation: Second essayers and mediators of tissue destruction, Br Med Bull 49: 506-522. Lafon-Cazal, M, Pietri, S, Culcasi, M, Bockaert, J (1993) NMDA-dependent superoxide production and neurotoxicity, Nature, 364: 535-537. Olanow, CW (1992) An introduction to the free radical hypothesis in parkinson's disease, Annals of Neurology, 32 (supplement): 53-59. Floyd, R.A. and Carney, J., Nitrone radical traps (NRTs) protect in experimental neurodegenerative diseases, in Neoprotective approaches to the treatment of Parkinson's disease and other neurodegenerative disorders (Olanow, CW Jenner, P. and Youssim, Eds.) Academic Press, New York, New York, in print. Cao, X. and Phillis, J.W. (1994) a-Phenyl-N-tert-butyl-nitrone Reduces Cortical Infarct and Edema in Rats Subjected to Focal Ischemia. Brain Res. 644: 267-272 Zhao, W., Pahlmark, K., Smith, M.-J., and Siesjo, Bl (1994) Delayed treatment with the spin aphenyl-n-tert-butyl not spoiled (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats. Acta Physiol. Scad. 152: 349-350. Olive r, CN, Starke-Reed, PE. Stadt an, ER, Carney, JM and Floyd, RA (1990) Oxidative datum to brain proteins, loss of gluta ine synthetase activity and production of free radicals during ischemia induced injury to gerbil brain. Proc. Nati Acad. Sci. USA 87: 5144-5147. Carney, JM, Starke-Reed, PE 01 i see, CN, Landrum, RW, Chenge, MS, Wu, JF and Floyd, RA (1991) Reversal or age- related increase in brain protein oxidation in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-a-phenylnitrone.

Proc. Nati Acad. Sci., 88: 3633-3636. McKechnie, K, Fur an, BL, Paratt, JR (1986) Modification by oxygen free radical scavengers of metabolic and cardiovascular effects of endotoxin infusion in conscious rats, Circulatory Shock, 19: 429-439. Hamburge, SA, McCay, PB (1989) Endotoxin-induced mortality in rats is reduced by nitrones, Circulatory Shock, 29: 329-384. Pogrebniad, HW, Merino, MJ, Hahn, SM, Mitchell, JB, Pass, Hl (1992) Spin trap salvage from endotoxemia: The role of cytokine down regulation, Surgery, 112: 130-139.

Edamatsu, R, Mori, A., Packer, L (1995) The spin trap N-tert-a-phenyl-butylnitrone prolongs the life span of the senescence accelerated mouse, Biochem Biophys Res Comm 211: 847-849. Achim, C, Heyes, MP, Wiley, CA (1993) Quantitation of human immunodefficiency vires, immune activation facyors, and quinolinic acid in AIDS brains, J Clin Invest 91: 2769-2775. Wesselingh, SL, Power, C, Glass, JD, Tyor, WR and others (1993) Intrace reberal cytodine essenger RNA expression in here network immuniodeficiency syndro e dementia, Annals of Neurology, 33: 576-582. Gelbard, HA, Dzenko, KA, Diloret, D, delCero, C, delCero, M, Epstein, LG (1994) Neurotoxic effects of tumor necrosis factor alpha in primary human neural cultures are mediated by activation of the glutamate AMPA receptor subtype: Implications for AIDS neropathogenesis, Dev Neurosci, 15: 417-422. Selmaj, K, Raine, CS, Farocq, M, Norton, WT, Brosnan, CF (1991) Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced "by Lymphotoxins, J Im unol, 147: 1522-1529, Yeung, MC, Pulliam, L., Lau, AS (1995) The"? IV envelope protein gp 120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-a, AIDS, 9: 137-143.

Pulliam L., Berens, ME, Rosenblu, ML 1988. A normal human brain cell aggregate model for neurobiological studies, J Neurosci Res 21: 521-530. Pulliam, L, West, D, Haigwood, N, Swanson, TA (1993) HIV-1 envelope gp 120 alters astrocytes in human brain cultures, AIDS Research and Human Retroviruses, 9: 439-444. Pulliam, L., Herndier, B, McGrath, MS (1991) Furified trichosanthin (GLQ223R) exacerbation of indirect HlV-associated neurotoxicity in vitro, AIDS, 5: 1237-1242. Robinson, C (1995) N-acetylcysteine, Drugs of the Future, 20 (6): 559-563. Sandstrom, PA, Roberts, B, Folks, TM, Buttke, TM (1993) HIV gene expression enhances T-cell susceptibility to hydrogen peroxide induced apoptosis, AIDS Res Hum Retroviruses, 9: 1107-1113. Staal, RJ, Roederer, M, Raju, PA, Anderson, MT et al. (1993) Antioxidants inhibit simulation of HIV transcription, AIDS Res Hum Retroviruses, 9: 299-306. Floyd, RA, Watson, JJ, Wong, PK (1984) Sensitive assay of hudroxyl free radical formation utilizing high pressure liquid chromatography and electrochemical detection of phenoi and salicylate hydroxylation products, J Biochem Biophys Methods, 10: 221-235. Floyd, RA, Henderson, R, Watson, JJ, Wong, PK (1986) Use of salicylate with high pressure liquid chromatography and electrochemical detection (LCED) as a sensitive measure of tt hydroxyl free radicals in adriamycin treated rats, Free Radical Biol Med , 2: 13-18.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for treating HIV dementia comprising a benzamide compound of the formula: 10 (R), • CONHR 'I fr

Where R 'is a saturated alkyl of 3 to 5 carbon atoms, face R is independently -NO2 or -NH2 or NHCOCH3, and n is 1 or 2, with the following conditions: 1) when n is 1 and R is - NO2 at the 4-position of the ring, R 'is not ter-butyl, iso-butyl or propyl; 2) when n is 1 and R is -NO2 at position 2 of the 20 ring, R 'is not iso-butyl or propyl; and 3) when n is 2 and R 'is tert-butyl and both Rs are -NO2, of the R groups are not in the 3 and 5 positions of the ring; in a pharmaceutically acceptable vehicle. 2.- The pharmaceutical composition in accordance with the 25 claim 1, further characterized in that the benzamide compound is an acetamidobenzamide of the formula: wherein R 'is a saturated alkyl of 3 to 5 carbon atoms and n is 1 or 2.

3. The pharmaceutical composition according to claim 2, further characterized in that n is 1.

4. The pharmaceutical composition in accordance with claim 3, further characterized in that R 'is tert-butyl.

5. The pharmaceutical composition according to claim 3, further characterized in that R 'is ter-amyl.

6. The pharmaceutical composition according to claim 3, further characterized in that the benzamide compound is N-tert-butyl-4-acetamidobenzamide.

7. The pharmaceutical composition according to claim 1, further characterized in that the vehicle is an oral vehicle.

8. The pharmaceutical composition according to claim 1, further characterized in that the vehicle is an injectable vehicle.

9. The use of a benzamide compound according to claims 1-6, for the preparation of a medicament for treating HIV dementia.

10. - The use according to claim 9, further characterized in that the treatment is therapeutic.

11. The use according to claim 9, further characterized in that the treatment is prophylactic.