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WO1997038684A1 - Traitement par benzamides de la demence associee a l'infection par le virus du sida (vih-1) - Google Patents

Traitement par benzamides de la demence associee a l'infection par le virus du sida (vih-1) Download PDF

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Publication number
WO1997038684A1
WO1997038684A1 PCT/US1997/006351 US9706351W WO9738684A1 WO 1997038684 A1 WO1997038684 A1 WO 1997038684A1 US 9706351 W US9706351 W US 9706351W WO 9738684 A1 WO9738684 A1 WO 9738684A1
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Prior art keywords
butyl
tert
acetamidobenzamide
hiv
dementia
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PCT/US1997/006351
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English (en)
Inventor
William Garland
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Centaur Pharmaceuticals, Inc.
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Publication date
Application filed by Centaur Pharmaceuticals, Inc. filed Critical Centaur Pharmaceuticals, Inc.
Priority to NZ332438A priority Critical patent/NZ332438A/en
Priority to BR9708720-3A priority patent/BR9708720A/pt
Priority to AU27322/97A priority patent/AU720578B2/en
Priority to APAP/P/1998/001368A priority patent/AP898A/en
Priority to EP97921220A priority patent/EP0912171A1/fr
Publication of WO1997038684A1 publication Critical patent/WO1997038684A1/fr
Priority to IS4868A priority patent/IS4868A/is

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol

Definitions

  • This invention relates to the treatment of dementia associated with AIDS virus (HIV-1) infection. More particularly it concerns compositions and methods for prophylactically or therapeutically treating this condition.
  • HIV-1 AIDS virus
  • This Background Information section is divided into two parts. The first provides information on the condition being treated by this invention, the dementia associated with AIDS virus infection. The second provides information concerning benzamides and their use as medicaments, benzamides being the active agents employed in the methods and compositions of this invention.
  • HIV Dementia (AIDS Dementia Complex)
  • AIDS Acquired Immune Deficiency syndrome
  • ADC AIDS Dementia Complex
  • HV-associated dementia HIV dementia
  • the neuropathological alterations that accompany HIV infection in the CNS include myelin pallor, increased astrogliosis, neuronal loss, and loss of dendritic arborization as well as a decrease in the presynaptic area. Resulting neurologic dysfunction can impair daily function, work productivity and in severe cases mandate expensive institutional care. Although early losses in mental capacity are not considered full-blown dementia, they nevertheless reflect neuronal damage associated with HIV-1. At present there are no effective therapies for HIV-dementia. The medicaments described herein should minimize the neuronal damage and prevent the progression of neuronal damage thus allowing extended functional capabilities of the affected individuals and hence considerable savings to society.
  • HIV dementia In the United States alone, over 1 million individuals are infected with HIV and approximately one third of this group have AIDS. Thus, the potential target population for an anti-HIV dementia therapeutic treatment is currently greater than 100,000 patients/year and the target population which would acutely benefit from a prophylactic HIV dementia treatment some ten times that. The need for treatments of HIV dementia is expected to grow as more effective therapies allow persons with AIDS to live longer.
  • Zidovudine has been used extensively to treat the AIDS infection. Although there is now doubt as to the long term effectiveness of this treatment because of high mutational frequency of the virus there is no doubt that AZT has been effective in treating HIV dementia on a short-term basis.
  • the neurological symptoms associated with HIV dementia have been treated with certain drugs. For instance, the psychosis associated with HIV dementia has been treated with haloperidol and thioridazine. Molindone has been used for psychotic and delirious HIV dementia patients. Methylphenidate has been used for treatment of depression associated with HIV dementia.
  • Electro-convulsive therapy has been used for HIV-induced stupor. All of these treatments serve to ameliorate symptoms of HIV dementia. None treat HIV dementia, itself.
  • the envelope glycoprotein of HIV, gpl20 has been implicated in the pathogenesis of HIV dementia. This protein which is shed abundantly by infected cells has been found to be neurotoxic to neurons in culture at extremely low concentrations, to impair learning, to induce cytokines, and to reduce cerebral glucose utilization. Hill et al. (.Hill, J.M., Mervis, R.R. , Avidor, R. , Moody, T.W. and Brenneman, D.E. (1993) Brain Res. , 603:222-233.) have shown that in neonatal rats, administration of gpl20 causes morphological damage to the brain as well as retardation of the development of complex motor behaviors.
  • the NO generated from the nitroglycerin can protect neurons from overstimulation of the NMDA receptors with the resulting calcium and glutamate excitotoxicity.
  • cardiovascular effects and the extremely erratic pharmacokinetics of nitroglycerin make this approach seem problematic.
  • HIV gpl20 glycoprotein stimulates the inducible isoform of NO synthase in human cultured astrocytoma cells, Biochem Biophys Res Comm 194: 439-445.
  • NRTs Nitrone radical traps
  • N-tert- ⁇ -phenyl-butylnitrone prolongs the life span of the senescence accelerated mouse, Biochem Biophys Res Comm 211: 847-849.
  • HIV envelope protein gpl20 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor- ⁇ , AIDS, 9: 137-143.
  • HIV-1 envelope gpl20 alters astrocytes in human brain cultures, AIDS Research and Human Retroviruses, 9: 439-444.
  • HIV gene expression enhances T-cell susceptibility to hydrogen peroxide induced apoptosis, AIDS Res Hum Retroviruses, 9: 1107-1113.
  • Antioxidants inhibit simulation of HIV transcription, AIDS Res Hum Retroviruses, 9: 299-306.
  • benzamide-based pharmaceutical compositions having activity against HIV-dementia. These compositions include one or more of the acetamidobenzamide, aminobenzamide or nitrobenzamide compounds of Formula I as active agent in a pharmaceutically acceptable carrier.
  • R' is a saturated alkyl of from 3 to 5 carbon atoms, each R is independently -NH-CO-CH 3 , -NO 2 or -NH 2 , and n is 1 or 2, with the foUowing provisos: 1) when n is 1 and R is -NO 2 at the 4 position of the ring, R' is not tert-butyl, w ⁇ -butyl, or propyl; 2) when n is 1 and R is -NO 2 at the 2 position of the ring, R' is not wo-butyl or propyl; and 3) when n is 2 and R' is tert- butyl and both Rs are -NO 2 , the R groups are not at the 3 and 5 positions of the ring.
  • the carrier is preferably an oral carrier but can be an injectable carrier as well.
  • These pharmaceutical compositions can be in bulk form but more typically are presented in unit dosage form.
  • this invention provides a therapeutic method for treating a patient suffering from HIV-dementia. This method involves administering to the patient an effective HIV-dementia-treating amount of one or more of the pharmaceutical compositions just described.
  • this invention provides a prophylactic method for protecting a patient susceptible to HIV-dementia. This method involves administering to the patient an effective HIV-dementia prophylactic amount of one or more of the pharmaceutical compositions just described.
  • Fig. 1 is a bar graph showing the protective effect of a benzamide in a HIV-dementia related cell culture test.
  • Fig. 2 is a bar graph showing the protective effect of a benzamide in a HIV-dementia related cell culture test.
  • Fig. 3 is a bar graph showing apoptosis response observed in a cell aggregation test with a benzamide.
  • Fig. 4 is a plot of bioavailability of benzamide as a function of time.
  • the Benzamides The treatment of this invention employs one or more benzamides as its active agent.
  • This invention employs certain acetamidobenzamides, aminobenzamides and nitrobenzamides as active pharmaceutical agents.
  • the benzamides are described by Formula I. In this formula, R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2.
  • the acetamido, amino or nitro group may be found anywhere on the ring. Preferred embodiments include when n is 1 and the acetamido group is at the 2, 3 or 4 position of the ring and when n is 2 and the acetamido groups are at the 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4, or 3 and 5 positions of the ring.
  • R ⁇ compounds wherein R' is an alkyl which does not have a hydrogen on the alpha carbon, that is, the carbon which bonds to the nitrogen of the ring are preferred.
  • R' groups are tert-butyl and tert-amyl.
  • Acetamidobenzamides of Formula I of particular interest are: N-tert-buty 1-4-acetamidobenzamide , N-w ⁇ -propyl-4-acetamidobenzamide, N-tert-amyl-4-acetamidobenzamide,
  • N-tert-butyl-4-acetamidobenzamide is the most preferred acetamidobenzamide.
  • the aminobenzamides and nitrobenzamides employed as active agents are described by Formula I when R is an amino or nitro group.
  • R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2 subject to the same preferences for substituents and their positions set forth with reference to the acetamidobenzamides and further subject to the provisos that 1) when n is 1 and R is -NO 2 at the 4 position of the ring, R' is not tert-butyl, iso ⁇ butyl, or propyl; 2) when n is 1 and R is -NO 2 at the 2 position of the ring, R' is not w ⁇ -butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are -NO 2 , the R groups are not at the 3 and 5 positions of the ring
  • the amine functionality can be present as such or as a salt.
  • the amino is protonated to the cation form in combination with a pharmaceutically acceptable anion, such as chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, methane sulfonate, acetate, tartrate, oxalate, succinate, or palmoate.
  • the compound N-tert-butyl-4-acetamidobenzamide 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 to which N-tert-butyl-4-nitrobenzamide has been administered orally.
  • compositions are prepared by reacting two or more of these materials together.
  • the benzamide compound(s) is formulated into pharmaceutical compositions suitable for oral or parenteral, e.g. intravenous or intramuscular injection administration.
  • the compositions for oral administration can take the form of liquid solutions or suspensions, powders, tablets, capsules or the like.
  • the nitrone or its salt is usually a minor component (0.1 to say 50% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • a liquid form may include a suitable aqueous or nonaqueous vehicle with buffers, suspending 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 alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, sugar, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • injectable compositions they are commonly based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Again the active nitrone is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in the incorporated materials in Remington's Pharmaceutical Sciences.
  • the conditions treated with the benzamide-containing compositions generally include HIV dementia and the various symptoms which fall within the HIV dementia definition.
  • the benzamide-containing formulations can be administered to achieve a therapeutic effect and slow or counteract the progression of HIV dementia or they can be administered prophylactically, to patients not yet exhibiting HIV dementia but exposed to the HIV-1 virus.
  • the benzamide-containing composition is administered in manners designed to get the drug into the patient's bloodstream and across the blood-brain barrier into the patient's brain.
  • One excellent mode for accomplishing this is intravenous administration. Intravenous dose levels for treating these conditions range from about 0.01 mg/kg/hour to about 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 1 to 96 hours.
  • a preloading bolus of from about 10 to about 500 mg may also be administered to achieve adequate steady state levels.
  • Other forms of parenteral administration such as intramuscular injection can be used, as well. In this case, similar dose levels are employed. While parenteral administration is attractive from a drug delivery point of view, it should be recognized that the course of HIV infection can stretch over many months or even years so oral dosing may be preferred for patient convenience and tolerance. With oral dosing, one to three oral doses per day, each from about 0.02 to about 50 mg/kg are called for with preferred doses being from about 0.04 to about 10 mg/kg. These same dosing levels and regimens would be used for prophylactic treatment as well.
  • the health care professional should assess the patient's condition and determine whether or not the patient would benefit from benzamide treatment. Some degree of experimentation to determine an optimal doing level and pattern may be called for.
  • benzamide compounds employed herein can be prepared using commonly available starting materials and readily achievable reactions.
  • X is halo such as I, Br, F or Cl.
  • step (A) the N-terr-butyl nitrobenzamides (III) are formed. This reaction should be carried out at temperatures below 10°C.
  • This step (A) yields as benzamides III, the compounds of the invention where R is -NO 2 .
  • step (B) the nitro groups in the mono- or di-nitro benzamide III are subjected to reduction.
  • a reducing agent such as hydrazine
  • an appropriate catalyst such as a heterogeneous platinum, iron oxide hydroxide, palladium or nickel catalyst, typically on a support, or with hydrogen gas and a catalyst.
  • step (B) yields as benzamides IV, the compounds of the invention where R is NH 2 .
  • step (C) the amino-benzamides IV are converted to acetamidobenzamides V by reaction with an acetyl halide such as acetylchloride. This reaction is carried out in the presence of a mild base and at low to ambient temperatures such as - 20°C to + 20°C. This yields the compounds of the invention where R is acetamido.
  • Alternate synthetic schemes may also be used to prepare the compounds. Examples of these alternate routes are set forth below using N-terr-butyl-4- acetamidobenzamide as the representative compound. Other compounds may be prepared using these alternate methods by starting with appropriate starting materials, such as 2- or 3- amino- or nitro-benzonitrile or 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- diamino- or dinitro-benzonitrile and the appropriate alcohol (Alternate Route 1) or similarly substituted toluene compounds and the appropriate alkyl amine (Alternate Route 3).
  • appropriate starting materials such as 2- or 3- amino- or nitro-benzonitrile or 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- diamino- or dinitro-benzonitrile and the appropriate alcohol (Alternate Route 1) or similarly substituted toluene compounds and the appropriate alkyl amine (Alternate Route 3).
  • Another method for the preparation of the compounds begins with acetylation, using standard methods, of, for example, paratoluidine (F) to 4- acetamidotoluene (G).
  • the synthetic intermediate (G) may be converted to 4- acetamidobenzoic acid (D) with common oxidizing agents (e.g. , KMnO 4 ) and subsequently transformed to N-tert-butyl-4-acetamidobenzamide as outlined in Alternate Route 2.
  • 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 to 24 demonstrate the preparation of pharmaceutical compositions based on the compounds. Thereafter biological test results illustrating the activity of the compositions of the invention are provided.
  • Example 1 Preparation of N-tert-butyl-4-aminobenzamide tert-Butyl amine (14.6 g, 0.200 mole) was stirred in ethyl acetate (150 mL, purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and filtering through fluted filter paper) and cooled to 5° C with an ice bath.
  • 4- nitrobenzoyl chloride (18.6 g, 0.100 mole) in purified ethyl acetate (75 mL) was added dropwise at such a rate to maintain the temperature below 10° C. The ice bath was removed upon complete addition of benzoyl chloride solution and the reaction stirred for 4 hours.
  • Proton nuclear magnetic resonance (89.55 MHz in CDC1 3 ) showed abso ⁇ tions 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, IH; N-H); 1.500 ppm (s, 9H; tert-butyl H).
  • N-rert-butyl-2-acetamidobenzamide The method of Example 3 is repeated using 2-nitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2-nitrobenzamide.
  • Example 3 The method of Example 3 is repeated using 4-nitrobenzoyl chloride and w ⁇ -propyl amine in the amidation step. This yields N-w ⁇ -propyl-4- nitrobenzamide.
  • Example 6 Preparation ofN-tert-amyl-4-nitrobenzamide and N-tert-am y 1-4-acetam idoben zam i de The method of Example 3 is repeated using 4-nitrobenzoyl chloride and terr-amyl amine in the amidation step. This yields N-tert-amyl-4- nitrobenzamide.
  • Example 7 Preparation of N-/w-butyl-4-acetamidobenzamide The method of Example 3 is repeated using 4-nitrobenzoyl chloride and w ⁇ -butyl amine in the amidation step. This yields N-w ⁇ -butyl-4- nitrobenzamide.
  • Example 8 Preparation of N-n-butyl-4-nitrobenzamide and N-/ ⁇ -butyl-4-acetamidobenzamide The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-butyl amine in the amidation step. This yields N-n-butyl-4-nitrobenzamide.
  • Example 9 Preparation of N-n-propyl-4-nitrobenzamide and N-n-propyl-4-acetamidobenzamide The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-propyl amine in the amidation step. This yields N-n-propyl-4- nitrobenzamide.
  • Example 10 Preparation of N-1.2-dimethylpropyl-4-nitrobenzamide and N- 1.2-dimethylpropyl-4-acetamidobenzamide The method of Example 3 is repeated using 4-nitrobenzoyl chloride and 1,2-dimethylpropyl amine in the amidation step. This yields N-1, 2- dimethylpropyl-4-nitrobenzamide.
  • Example 11 Preparation of N-n-pentyl-4-nitrobenzamide and N-n-pentyl-4-acetamidobenzamide
  • the method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-pentyl amine in the amidation step. This yields N-n-pentyl-4-nitrobenzamide.
  • Reduction of the nitrobenzamide with hydrazine yields N-n-pentyl-4- aminobenzamide.
  • Acetylation of the aminobenzamide yields N-n-pentyl-4- acetamidobenzamide.
  • Example 3 The method of Example 3 is repeated using 4-nitrobenzoyl chloride and 2-methylbutyl amine in the amidation step. This yields N-2-methylbutyl-4- nitrobenzamide.
  • Example 3 The method of Example 3 is repeated using 2-nitrobenzoyl chloride and n-pentyl amine in the amidation step. This yields N-n-pentyl-2-nitrobenzamide.
  • Example 14 Preparation of N-tert-butyl-2.3-diacetamidobenzamide The method of Example 3 is repeated using 2,3-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2,3-dinitrobenzamide. Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-2,3- diaminobenzamide!
  • Example 3 The method of Example 3 is repeated using 2,5-dinitrobenzoyl chloride in the amidation step. This yields N-te/ ⁇ -butyl-2,5-dinitrobenzamide.
  • Example 17 Preparation of N-tert-butyl-2.6-diacetamidobenzamide The method of Example 3 is repeated using 2,6-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2,6-dinitrobenzamide. Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-2,6- diaminobenzamide .
  • Example 19 Preparation of N-tert-butyl-3.5-diacetamidobenzamide The method of Example 3 is repeated using 3,5-dinitrobenzoyl chloride in the amidation step. This yields N-terr-butyl-3,5-dinitrobenzamide.
  • Example 20 The compound of Example 1 is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240- 270 mg tablets (80-90 mg of active benzamide) in a tablet press. If these tablets were administered to a patient suffering from HIV dementia on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
  • Example 21 The compound of Example 2 is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active benzamide). If these capsules were administered to a patient susceptible to coming down with HIV dementia on a daily, twice daily or thrice daily regimen they would slow or prevent the onset of the HIV dementia.
  • Example 22 The compound of Example 3 is suspended in a sweetened flavored aqueous medium to a concentration of approximately 50 mg/mL. If 5 mLs of this liquid material was administered to a patient suffering from HIV dementia on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
  • Example 23 The compound of Example 4 is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450- 900 mg tablets (150-300 mg of active benzamide) in a tablet press. If these tablets were administered to a patient suffering from HIV dementia on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
  • Example 24 The compound of Example 14 is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml. If 50 mLs of this liquid material was administered to a patient suffering from HIV dementia on a daily, twice daily or thrice daily regimen this dose would slow the progress of the patient's disease.
  • HTV-1 infected monocytes in culture with astroglial cells produce concentrations ( >200 pg/ml) of TNF- ⁇ sufficient to cause neurotoxicity.
  • Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: Implications for AIDS neuropathogenesis, Dev Neurosci, 15: 417-422.
  • TNF- ⁇ is reported to cause its neurotoxicity by inducing apoptosis.
  • Brain cell aggregates were prepared from second trimester abortion tissue as previously described. Pulliam L., Berens, ME, Rosenblum, ML
  • Brain cell aggregates contain all the cells of the CNS- approximately 40% neurons, 40% astrocytes, 10% oligodendrocytes with myelin and 10% microglia. Neural cell apoptosis/death was measured by DNA fragmentation Elisa technique according to manufactures directions (Boehringher Mannheim).
  • Brain aggregates were prepared as described above. Several aggregates are placed in each well of a multi-well chamber slide (Nunc) coated with Cell TAK (Collaborative Research) at a concentration of 20 ug/ml. Cells migrate from the brain aggregates within 3 days. Astrocytes form a monolayer with neurons on top and rare microglia ( ⁇ 1 %)/oligodendrocytes ( ⁇ 1 %). These cultures are confluent within 1 week. Monolayers can be maintained for up to three weeks. Characterization of cell types is determined by using immunohistochemistry and the antibodies neuron specific enolase (NSE, Dako) for neurons and glial fibrillary acidic protein (GFAP, Dako) for the identification of astrocytes.
  • NSE neuron specific enolase
  • GFAP glial fibrillary acidic protein
  • Test compound is N-te/ ⁇ -butyl-4-acetamidobenzamide.
  • N-terr-butyl-4-acetamidobenzamide was studied to determine physical/chemical properties which suggest its suitability for this application. The following results were obtained:
  • N-terf-butyl-4-acetamidobenzamide is lipophilic and slowly cleared from the body.
  • N-tert-butyl-4-acetamidobenzamide is a compound of particular interest for HIV dementia because, at least in the rat, it shows excellent brain distribution, bioavailability and pharmacokinetic profile.
  • N-tert-butyl-4-acetamidobenzamide is also significantly stable at a pH commonly observed in the stomach. Brain penetration of N-tert-butyl-4-acetamidobenzamide
  • the absolute bioavailability of N-tert-butyl-4-acetamidobenzamide in rats was determined by comparing the area under the curve following a 20 mg/kg dose of the benzamide dissolved in 1 % methyl cellulose. Blood concentrations were determined at either 0, 0.083, 0.15, 0.5, 1, 2, 4, 8 and 24 hours post- dose (IV) or 0, 0.5, 1 , 2, 4 and 8 hour post-dose (oral), and the AUCs determined. Four animals were dosed orally and 4 animals were dosed IV.
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • a l ⁇ M concentration of N-tert-butyl-4-acetamidobenzamide is in the order of 0.2 ⁇ g/ml. To achieve this concentration in rat brain would require a blood concentration of only 1 ⁇ g/ml based on the brain/blood ratio data presented previously. If some degree of dose proportionality is found with lower doses of N-tert-butyl-4-acetamidobenzamide, a 6 mg/kg dose to rats should achieve this concentration even at 24 hours post-dose (trough value).
  • N-terr-butyl-4-acetamidobenzamide also provided complete protection in human brain aggregates from toxicity induced by 1 ng TNF- ⁇ , although the concentration of the benzamide needed was considerably higher than that found to prevent DNA fragmentation.
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • N-terr-butyl-4-acetamidobenzamide provided significant protection in human brain aggregates from cell toxicity induced by 1 ng gpl20.
  • the difference in absorbance was statistically significant for all groups at p ⁇ 0.003.
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • PCD programmed cell death
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • Test compound is N-rert-butyl-4-aminobenzamide.
  • Test compound is N-tert-amyl-4-acetamidobenzamide.
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • Test compound is N-tert-butyl-4-aminobenzamide,
  • Test compound is N-tert-amyl-4-acetamidobenzamide.
  • Test compound is N-isopropyl-4-acetamidobenzamide.
  • Test compound is N-isopropyl-4-acetamidobenzamide.
  • Sodium N-methyl D-glucamine dithiocarbamate (MGD) and the nitrone, PBN, were obtained from OMRF Spin Trap Source, Oklahoma City, Oklahoma.
  • gpl20 was obtained from Intracel Co ⁇ oration, Cambridge, Massachusetts. These materials were used in the following preliminary test: Treatment of Animals: Sprague-Dawley neonatal rats (sixteen siblings) were divided into four groups. Starting at day one after birth until day six, the neonates received 60 ⁇ l subcutaneous injections of the following treatments.
  • Group 1 phosphate buffer-saline (PBS), Group 2: 5 ng gpl20 in PBS, Group 3: 5 ng gpl20 plus PBN (50 mg/kg) in PBS, and Group 4: PBN (50 mg/kg) in PBS. Rats were weighed daily and the amount of PBN injected was adjusted accordingly.
  • PBS phosphate buffer-saline
  • Group 2 5 ng gpl20 in PBS
  • Group 3 5 ng gpl20 plus PBN (50 mg/kg) in PBS
  • Group 4 PBN (50 mg/kg) in PBS. Rats were weighed daily and the amount of PBN injected was adjusted accordingly.
  • the angle chosen for the setting used for negative geotaxis was decreased from 45° (the angle used by Hill et al) to 35° since under the experimental setting employed, animals were not able to stay on the screen set at 45° and would slide down before being able to make an attempt to turn upward.
  • Test compound is N-tert-butyl-4-acetamidobenzamide.
  • the data suggests N-tert-butyl-4-acetamidobenzamide had a protective effect.

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Abstract

L'invention concerne des compositions à base de benzamides ayant une activité en tant qu'agents thérapeutiques et prophylactiques dans le traitement des pathologies associées à l'infection par le VIH-1, désignées dans les stades avancés par le terme de démence associée à l'infection par le VIH-1 ou d'encéphalopathie du VIH.
PCT/US1997/006351 1996-04-17 1997-04-17 Traitement par benzamides de la demence associee a l'infection par le virus du sida (vih-1) WO1997038684A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
NZ332438A NZ332438A (en) 1996-04-17 1997-04-17 Use of acetamido, amino or nitro substituted benzamide derivatives for treating of dementia associated with AIDS virus (HIV-1) infection
BR9708720-3A BR9708720A (pt) 1996-04-17 1997-04-17 Composição farmacêutica e processo para o tratamento de demência por hiv.
AU27322/97A AU720578B2 (en) 1996-04-17 1997-04-17 Benzamide treatment of dementia associated with AIDS virus (HIV-1) infection
APAP/P/1998/001368A AP898A (en) 1996-04-17 1997-04-17 Benzamidine treatment of dementia associated with Aids Virus (HIV-1) infection.
EP97921220A EP0912171A1 (fr) 1996-04-17 1997-04-17 Traitement par benzamides de la demence associee a l'infection par le virus du sida (vih-1)
IS4868A IS4868A (is) 1996-04-17 1998-10-16 Meðhöndlun á vitglöpum tengdum sýkingum af völdumalnæmisveirunnar (HIV-1) með bensamíði

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AP (1) AP898A (fr)
AU (1) AU720578B2 (fr)
BR (1) BR9708720A (fr)
CA (1) CA2252403A1 (fr)
IS (1) IS4868A (fr)
NZ (1) NZ332438A (fr)
OA (1) OA10901A (fr)
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WO2003068171A2 (fr) 2002-02-13 2003-08-21 Creagri, Inc. Procede et composition pour le traitement d'une inflammation et de troubles neurologiques associes au sida
JP2017109982A (ja) * 2015-12-11 2017-06-22 ロート製薬株式会社 アントラニルアミド誘導体およびそれを含有するｔｌｒ３が関与する疾患の治療剤

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WO1996031462A1 (fr) * 1995-04-03 1996-10-10 Centaur Pharmaceuticals, Inc. Benzamides destines au traitement de troubles neuro-degeneratifs

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WO2003068171A2 (fr) 2002-02-13 2003-08-21 Creagri, Inc. Procede et composition pour le traitement d'une inflammation et de troubles neurologiques associes au sida
JP2017109982A (ja) * 2015-12-11 2017-06-22 ロート製薬株式会社 アントラニルアミド誘導体およびそれを含有するｔｌｒ３が関与する疾患の治療剤

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NZ332438A (en) 2001-02-23
AP9801368A0 (en) 1998-12-31
IS4868A (is) 1998-10-16
BR9708720A (pt) 2000-01-04
CN1218399A (zh) 1999-06-02
EP0912171A1 (fr) 1999-05-06
AU720578B2 (en) 2000-06-08
AU2732297A (en) 1997-11-07
AP898A (en) 2000-11-17
TW412421B (en) 2000-11-21
CA2252403A1 (fr) 1997-10-23

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