WO2004108076A2 - Composes de benzamide anti-vih - Google Patents

Composes de benzamide anti-vih Download PDF

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Publication number
WO2004108076A2
WO2004108076A2 PCT/US2004/015791 US2004015791W WO2004108076A2 WO 2004108076 A2 WO2004108076 A2 WO 2004108076A2 US 2004015791 W US2004015791 W US 2004015791W WO 2004108076 A2 WO2004108076 A2 WO 2004108076A2
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WIPO (PCT)
Prior art keywords
alkyl
formula
compound
cycloalkyl
hiv
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PCT/US2004/015791
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English (en)
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WO2004108076A3 (fr
Inventor
Vassilios Papadopoulos
Janet Greeson
Laurent Lecanu
Original Assignee
Samaritan Pharmaceuticals, Inc.
Georgetown University
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Application filed by Samaritan Pharmaceuticals, Inc., Georgetown University filed Critical Samaritan Pharmaceuticals, Inc.
Priority to CA002527211A priority Critical patent/CA2527211A1/fr
Priority to EP04752748A priority patent/EP1631289A4/fr
Priority to JP2006514907A priority patent/JP2006526633A/ja
Priority to AU2004244982A priority patent/AU2004244982A1/en
Publication of WO2004108076A2 publication Critical patent/WO2004108076A2/fr
Priority to PCT/US2005/014131 priority patent/WO2005112922A2/fr
Priority to US11/292,797 priority patent/US20060194814A1/en
Publication of WO2004108076A3 publication Critical patent/WO2004108076A3/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • HIV human immunodeficiency virus
  • Current therapeutic strategies for AIDS include protease inhibitors, nucleoside analog reverse transcriptase inhibitors, non- nucleoside analog reverse transcriptase inhibitors, fusion inhibitors and also the highly toxic hydroxyurea (Yarchoan R et al. (1986) Lancet 1(8481): 575-580; Richards AD et al.
  • the invention provides a method to prevent viral replication by blocking or inhibiting the ability of viruses, such as retroviruses, including HIV, to infect mammalian cells in vitro or in vivo.
  • the present invention provides a method for treatment of a mammal threatened or afflicted by an infectious pathogen, such as a bacteria or virus, by administering to said mammal an effective amount of a compound of formula I: wherein: a) R 1 , R 2 , R 3 , R 4 and R 5 are individually H, OH, halo, (C 1 -C 6 )alkyl, ( - C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl((C 1 -C 6 )alkyl), (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C C ⁇ alkanoyl, halo(C 1 -C 6
  • (Alk) is (C C 4 )alkyl, such as -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 - or -(CH 2 ) 4 -.
  • 1, 2 or 3 of R 1 , R 2 and R 3 is H.
  • R 6 and R 7 are individually H, (C ⁇ -C 4 )alkyl (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl or benzyl.
  • X 1 is NO 2 .
  • each of R 4 and R 5 is (C ⁇ -C 6 )alkyl or (C 3 -C 6 )cycloalkyl.
  • R 1 , R 2 or R 3 is (C ⁇ -C 6 )alkoxy.
  • p is 1.
  • Het is heteroaryl, e.g., lH-indol-3-yl, indan-3-yl or 1H- imidazol-4-yl.
  • the invention also provides a pharmaceutical composition, such as a unit dosage form, comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, which optionally can include one or more anti-HIV agents of one or more of the classes of anti-HIV agents referenced herein above, and can optionally include stabilizers, preservatives, and absorption control agents.
  • a pharmaceutical composition such as a unit dosage form, comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, which optionally can include one or more anti-HIV agents of one or more of the classes of anti-HIV agents referenced herein above, and can optionally include stabilizers, preservatives, and absorption control agents.
  • the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the infectivity of a pathogenic agent or microorganism such as a virus or a retrovirus toward mammalian cells is implicated and inhibition of its infectivity is desired comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula I for use in medical therapy (e.g., for use in treating a mammal infected, e.g., with a retrovirus such as HIV), as well as the use of a compound of formula I for the manufacture of a medicament useful for the treatment of infection in a mammal, such as a human.
  • the invention also provides a method for binding a compound of formula
  • Cells comprising a compound of formula I as a ligand bound to receptor sites can be used to measure the selectivity of test compounds for specific receptors on or in cell walls, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions dependent on cell wall permeability, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent.
  • the invention also provides novel compounds of formula I, as well as, processes and intermediates disclosed herein that are useful for preparing compounds of formula (I) or salts thereof. Many of the compounds of formula I are also useful as intermediates in the preparation of compounds of formula I.
  • Figure 1 depicts the chemical structure of SPO 1 , SPO 10 and SP 100.
  • FIG 2 panels A-C are graphs depicting the inhibitory effect of SPOl, SP010 and SP100 on the HIV-1 IIIB strain replication in HeLa cells. Compounds were tested either alone or in a formulation (1 A, 010A or 100 A) 3TC, ddl and AZT are known anti- viral compounds.
  • Figure 3 panels A-C are graphs depicting the inhibitory effect of 24- hour SPOl, SP010 and SP100 premedication on the HIV-1 IIIB strain replication in HeLa cells. Compounds were tested in a formulation (01A, 010A or 100A).
  • Figure 4 are graphs depicting the inhibitory effect of 48- hour SPOl, SP010 and SP100 premedication on the HIV-1 IIIB strain replication in HeLa cells.
  • FIGS. 1 panels A-C are graphs depicting the inhibitory effect of SPOl, SPOl A and SP010 on the multi-drug resistant HIN MDR-769 strain replication in HeLa cells.
  • Figure 6 is a reaction scheme for the synthesis of SPOl 0.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C ⁇ -C )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • (C ⁇ -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 3 -C 6 )cycloalkyl(C 1 - C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclo ⁇ ropylethyl, 2-cyclobutylethyl, 2-cyclo ⁇ entylethyl, or 2-cyclohexylethyl;
  • heterocycloalkyl and heterocycloalkylalkyl includes the foregoing cycloalkyl wherein the
  • retrovirus includes, but is not limited to, the members of the family retroviridae, including alpharetroviruses (e.g., avian leukosis virus), betaretroviruses (e.g., mouse mammary tumor virus), gammaretroviruses (e.g., murine leukemia virus), deltaretroviruses (e.g., bovine leukemia virus), epsilonretroviruses (e.g., Walley dermal sarcoma virus), lentiviruses (e.g., HFV- 1) and spumaviruses (e.g., human spumavirus).
  • alpharetroviruses e.g., avian leukosis virus
  • betaretroviruses e.g., mouse mammary tumor virus
  • gammaretroviruses e.g., murine leukemia virus
  • deltaretroviruses e.g., bovine leukemia virus
  • methods generally applicable to peptide synthesis can be employed to prepare compounds of formula I. For example, see published PCT application WO 02/094857, U.S. Pat. No. 6,043,218, 6,407,211 and 5,583,108.
  • a compound of formula Ila is prepared as shown in Scheme 2, below. Scheme 2.
  • an N-protected aminoalkyl derivative of formula III where PG is an amino protecting group (e.g., tert-butoxycarboyl (BOC), benzyloxycarbonyl (CBZ), benzyl, and the like) is prepared by reacting a compound of formula 1 with a compound of formula 4: PG-NH-CH[(CH 2 ) n Het]X (4) where X is carboxy ( — COOH) or a reactive carboxy derivative, e.g., acid halide.
  • the reaction conditions employed depend on the nature of the X group.
  • X is a carboxy group
  • the reaction is carried out in the presence of a suitable coupling agent (e.g., N,N-dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, and the like) in a suitable organic solvent (e.g., methylene chloride, tetrahydrofuran, and the like) to give an amide intermediate.
  • a suitable coupling agent e.g., N,N-dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, and the like
  • a suitable organic solvent e.g., methylene chloride, tetrahydrofuran, and the like
  • X is an acid derivative such as an acid chloride
  • the reaction is carried out in the presence of a suitable base such as triethylamine, pyridine in an organic solvent (e.g., methylene chloride, dichloroethane, N,N-dimethylformamide, and the like) to give an amide intermediate.
  • a suitable base such as triethylamine, pyridine
  • organic solvent e.g., methylene chloride, dichloroethane, N,N-dimethylformamide, and the like
  • compounds of formula 4 which are N-protected, heterocyclic or heteroaryl ⁇ -amino acids or are derived therefrom, are either commercially available or they can be prepared by methods well known in the field of organic chemistry.
  • both natural and unnatural amino acids useful in the present invention are commercially available from vendors such as Sigma- Aldrich and Bachem. Examples of natural amino acids are tryptophan and histidine.
  • Unnatural amino acids include, 3-(indan-3-yl)-2-amino ⁇ ropanoic acid, 3- (morpholin-l-yl)-2-aminopropanoic acid, 3-(piperidin-l-yl)-2-aminopropanoic acid, 3-(piperazin-l-yl)-2-aminopropanoic acid, 3-(pyridin-2-yl)-2- aminopropanoic acid, 4-(pyridin-2-yl)-2-aminobutanoic acid, 4-(imidazol-2-yl)- 2-aminobutanoic acid, 4-(benzofuran-2-yl)-2-aminobutanoic acid; 3-(l,3- dithian-2-yl)-2-aminopropanoic acid and the like.
  • a suitable chlorinating agent e.g., oxyalyl chloride, thionyl chloride and the like
  • a suitable organic solvent such as methylene chloride and the like.
  • Method (b) is particularly ssuuiittaabbllee ffoorr pprreeppaaririnng compounds of Formula Ila wherein R 5 X contains an amido or a carbonyl group.
  • compounds of formula 6 which can also be used to introduce the moiety [X 1 (R 1 )(R 2 )(R 3 )Ph]C(O) into the compound of formula I are commercially available or can be prepared by methods well known in the art.
  • arakyl halides and arakyl acids such as benzyl bromide, 3,4- dichlorobenzyl bromide, phenylacetic acids and 2-phenylpropionic acids are commercially available.
  • Piperazines and homopiperazines of formula 7 such as piperazine, 2 or 3- methylpiperazines and homopiperazine are commercially available. Piperazines 7 can also be prepared by following the procedures described in the European Pat. Pub. No. 0 068 544 and U.S. Pat. No. 3,267,104.
  • a compound of Formula (I) can be prepared, either:
  • Ar — C(O)L wherein L is a leaving group under acylating conditions, such as a halo (particularly Cl or Br) or imidazolide.
  • Suitable solvents for the reaction include aprotic polar solvents (e.g., dichloromethane, THF, dioxane and the like).
  • a non-nucleophilic organic base e.g., triethylamine or pyridine, preferably pyridine
  • Suitable solvents for the reaction are tetrahydrofuran, dioxane and the like; or (iii) reacting a compound of formula Ila, or a compound of formula H 2 NCH- ((Alk)Het)C(O)Ot-Bu (8) with a compound of formula ArCHO in the presence of NaCNBH , followed by hydrolysis of the ester group, if present.
  • a compound of formula Ila or a compound of formula H 2 NCH- ((Alk)Het)C(O)Ot-Bu (8)
  • a compound of formula ArCHO a compound of formula ArCHO in the presence of NaCNBH , followed by hydrolysis of the ester group, if present.
  • Many alpha- amino acid t-butyl esters are commercially available, e.g., from Bachem.
  • R 1 in formula I, above is H, (C 2 -
  • a specific value for R 2 is H.
  • a specific value for R 3 is H.
  • a specific value for X 1 is NO 2 .
  • a specific value for N(R 6 )(R 7 ) is amino, diethyl amino, dipropylamino, cyclohexylamino, or propylamino.
  • a specific value for (Alk) is -(CH 2 )-.
  • a specific value for R 4 is CH 3 .
  • a specific value for R 5 is cyclopropyl.
  • Another preferred group of compounds are compounds of formula I which are 4-N-alkanoylpiperazin-l-yl-carbonylalkylbenzamides.
  • a preferred compound of the invention is SP10 (Fig. 1).
  • administration of the compounds as salts maybe appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate:, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium or lithium
  • alkaline earth metal for example calcium or magnesium
  • zinc salts can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by inhalation or insufflation.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules as powders, pellets or suspensions or may be compressed into tablets.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules as powders, pellets or suspensions or may be compressed into tablets.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices, such as patches, infusion pumps or implantable depots.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection, infusion or inhalation can include sterile aqueous solutions or dispersions.
  • Sterile powders can be prepared comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate, cellulose ethers, and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) of formula I in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently administered in unit dosage form; for example, containing 5 mg to as much as 1-3 g, conveniently 10 to 1000 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M.
  • This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline.
  • a 0.05 to 5% solution of the active ingredient optionally in saline.
  • a compound of formula I can be dissolved in about 125-500 ml of an intravenous solution comprising, e.g., 0.9% NaCl, and about 5-10% glucose.
  • Such solutions can be infused over an extended period of up to several hours, optionally in conjunction with other anti-viral agents, antibiotics, etc.
  • the active ingredient can also be orally administered as a bolus containing about 1- 100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • a compound of the invention to act as an antiviral agent may be determined using pharmacological models which are well known to the art, or using tests described below.
  • the following illustrate representative pharmaceutical dosage forms, containing a compound of formula I, for therapeutic or prophylactic use in humans.
  • the above formulations may be prepared by conventional procedures well known in the pharmaceutical art.
  • Example 1 Synthetic protocol for the compound SP010 A. [ 1 -( 1 H-indol-3 -ylmethyl -2-(3 -methyl-piperazin- 1 -yl)-2-oxo-ethyll carbamic acid terbutyl ester (B .
  • Boc-L-Tryptophan (A) (4.556 g; 15 mmol) was dissolved in CH 2 C1 2 (DCM) (60 ml), l,l'-carbonyldirmidazole (GDI) (2.513 g, 15.5 mmol) was added and then the reaction mixture was stirred at RT for 100 min.
  • 2-Methylpiperazine (1.502 g; 15 mmol) was added and stirring was continued at RT for 6 more hours.
  • 1,2-Dichloroethane (DCE) (15 ml) was added and the organic solution was washed with 5% aq. Na 2 CO , 3% aq. HC1 and water, respectively.
  • the GenPhar (Mt. pleasant, SC) AV-FinderTM-HIV Drug Discovery Assay was used, that consists of two components: (1) a cloned, continuous-passage HeLa cell line containing an HIV- 1 tat-activated molecular switch and a Green Fluorescent Protein reporter gene and (2) a recombinant adenovirus (rAd) vector containing the genes for all three of the HIV-1 receptor/co-receptors (CD4, CXCR4, and CCR5) to transduce into HeLa cells and convert them into highly susceptible HIV-1 indicator cells for use in the assay.
  • the indicator cells over-express the HIV-1 receptor genes and are readily infected with any HIV-1 strain or isolate.
  • Detector plates are set up at day 1 by adding HeLa cells (3000/well) to the adenovirus AD-3R in DMEM containing CCS in 96-well plates and to incubate at 37°C under 95% humidity and 5% CO 2 for 2 days. Without premedication, at day 3, HIV-1 IIIB (200IP/well) and increasing concentrations of procaine, procainamide (both from Aldrich-Sigma), SP 10, or reference compounds (AZT, ddl, 3TC) were added and incubated overnight. At day 4, the medium was replaced by fresh medium containing the corresponding concentration of the compounds of interest. The infectivity was assessed by measuring the fluorescence on each well at day 7 nm).
  • Procaine HC1 was used either alone dissolved in water (SPOl) or in an Anticort-like formulation (SPOl A) containing zinc sulfate heptahydrate and ascorbic acid at the ratio of about 26-27 (26.6)1111 -2 (1.6) (for example 200 mg procaine HC1 with 7.5 mg of zinc sulfate heptahydrate and 12.5 mg of ascorbic acid; Xu, J. et al. J Pharmacol. Exper. Ther. 2003 307:1148-1157) (Samaritan Pharmaceuticals) . B. Results
  • SP10 was obtained from Comgenex (Budapest, Hungary). Compounds were dissolved in water or when indicated in the Anticort-like formulation (SPOl A, SP100A, SP10A).
  • SP10A were found to be more potent that ddl at concentrations up to 1 ⁇ M (Fig. 2B), inhibiting viral replication by 40%.
  • Fig. 2B concentrations up to 1 ⁇ M
  • the strongest inhibition was observed at 0.01 ⁇ M inhibiting by 55.60+2.12% and 50.20+1.70% (p>0.001) respectively the viral replication compared to 26.37 ⁇ 26.11 % (p ⁇ 0.05) inhibition observed by ddl.
  • Fig. 4A Forty-eight hours pretreatment with SPOl inhibited by 75% HIV replication at all concentrations tested (Fig. 4A). Under the same protocol AZT inhibited the HIV replication in a dose-dependent manner with an IC50 of 30 nM. 48 hours pretreatment with SP01A also inhibited viral replication (Fig. 4B) and the same was true for SP010 which inhibited with an IC50 of 0.01 nM (Fig. 4C). 4. Effect on HIV MDR 769 viral replication. Effects without premedication.
  • AZT was not effective in inhibiting the HIV MDR 769 strain replication (Fig. 5 A,B,C).
  • SPOl inhibited by 75% the HIV MDR 769 viral replication at concentrations up to 1 nM. At higher concentrations the compound was not effective.
  • SPOl A effectively inhibited the MDR HIV strain replication at all concentrations tested, reaching up to 80% inhibition.
  • SPO 10 also inhibited the replication of the MDR HIV strain although with a maximal efficacy reaching 50%.
  • Procaine HC1 Capsules of 200 mg Procaine HC1 were supplied by Samaritan Pharmaceuticals in a formulation containing procaine HC1, zinc sulfate heptahydrate (to decrease the rate of absorption of procaine), ascorbic acid (as an antioxidant), potassium benzoate, and disodium phosphate and sodium sorbate as a preservative.
  • the dose was determined by prior studies of the bioavailability of procaine HC1 and the doses used in previous studies of procaine HC1 in the treatment of depression in elderly persons (Whalen et al. J. Clin. Epidemiol. 199447: 537-546; Cohen et al., Psychosomatics 1974 15: 15-19; Sakalis et al. Current Therapeutic Research 191 16: 59-63).
  • Eligible patients were > 18 years, HIV-1 positive (cohorts A, B, C, D); on stable triple antiretroviral regimen for the preceding 8 weeks; with current CD4 counts >200/mm 3 .
  • Viral load was measured by NASBA Assay (Using Nuclisens assay from Organon Technica®) with a lower limit of detection of 50 copies/ml, banked samples were stored at -70°C. 6.
  • PCRI all measures
  • PCRII only viral load less than 400 copies/ml
  • Ancova adjusted for baseline value.
  • Procainamide (SP100) and SP010 reduce HIV-1 IIIB replication in human cells with an efficacy higher than AZT, ddl or 3TC.
  • an inhibition of HIV-1 IIIB replication by these compounds was observed up to 50% with concentrations in the nanomolar range and there was not a major difference between the compounds dissolved in water compared to those dissolved in the Anticort formulation (SPOl A, SPOIOA and SP100A).
  • SPOl A, SPOIOA and SP100A Surprisingly, within the range of 1 nM to 1 ⁇ M, SPO 10 displayed a higher efficacy than ddl in inhibiting viral replication.
  • the HeLa cells were pre-medicated for 24 hours with the different compounds in Anticort-like solution before the virus was added.
  • the effect obtained was much stronger than without pre-medication and with concentrations in the picomolar range.
  • the curve plateau was at more than 63% inhibition for SP01A, 52% for SPOIOA whereas it was around 32% for AZT.
  • SP100A was less effective than AZT.
  • the anti-viral activity of SPOIOA peaked up to 65% inhibition of the replication at 30 pM, and below 60 % for SP01A whereas at the same concentration the inhibitory effect of AZT did not reach 30 %.
  • procaine and procaine based compounds containing or derived from the SPOl, SPO 10 and SP100 compounds reduce the HIV virus replication by modifying the cholesterol content of the cell membrane, rendering it much more difficult, even impossible, for the virus to entry and infect the cell.
  • the data herein demonstrates the ability of procaine, procainamide and the benzamide derivative SP010 to provide new anti-retro viral therapy efficaciuous either alone or in combination with HAART and mega HAART therapies.

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Abstract

La présente invention concerne une méthode thérapeutique de prévention ou de traitement d'une condition ou d'un symptôme pathologique chez un mammifère, tel qu'un homme, pour lequel l'infectivité d'un pathogène tel qu'un rétrovirus à l'égard des cellules de mammifère est impliquée et pour lequel l'inhibition de ladite infectivité est désirée. Cette méthode consiste à administrer à un mammifère nécessitant un tel traitement, une quantité efficace d'un dérivé N-benzamide d'un amide pipérazinyle d'un amino de ce dernier qui présente une infectivité pathogène, y compris ses sels pharmaceutiquement acceptables.
PCT/US2004/015791 2003-06-02 2004-05-20 Composes de benzamide anti-vih WO2004108076A2 (fr)

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CA002527211A CA2527211A1 (fr) 2003-06-02 2004-05-20 Composes de benzamide anti-vih
EP04752748A EP1631289A4 (fr) 2003-06-02 2004-05-20 Composes de benzamide anti-vih
JP2006514907A JP2006526633A (ja) 2003-06-02 2004-05-20 抗ｈｉｖ性ベンズアミド化合物
AU2004244982A AU2004244982A1 (en) 2003-06-02 2004-05-20 Anti-HIV benzamide compounds
PCT/US2005/014131 WO2005112922A2 (fr) 2004-04-22 2005-04-22 Composes benzamide
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016276A3 (fr) * 2003-08-05 2005-07-07 Samaritan Pharmaceuticals Inc Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase
WO2006085890A2 (fr) * 2004-04-05 2006-08-17 Samaritan Pharmaceuticals, Inc. Composes de quinuclidine anti-vih

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GB1279843A (en) * 1969-05-23 1972-06-28 Science Union & Cie Benzamidoethyl-piperazines and process for their preparation
JP2769578B2 (ja) * 1989-10-13 1998-06-25 大塚製薬株式会社 バソプレシン拮抗剤
DE4302485A1 (de) * 1993-01-29 1994-08-04 Merck Patent Gmbh Piperazinderivate
US6339087B1 (en) * 1997-08-18 2002-01-15 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
IL125658A0 (en) * 1997-08-18 1999-04-11 Hoffmann La Roche Ccr-3 receptor antagonists
GB0030306D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds
US20020119979A1 (en) * 2000-10-17 2002-08-29 Degenhardt Charles Raymond Acyclic compounds and methods for treating multidrug resistance
EP1628660A4 (fr) * 2003-06-02 2010-06-02 Samaritan Pharmaceuticals Inc Methodes et compositions permettant de moduler les taux de cortisol serique

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Title
See references of EP1631289A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016276A3 (fr) * 2003-08-05 2005-07-07 Samaritan Pharmaceuticals Inc Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase
WO2006085890A2 (fr) * 2004-04-05 2006-08-17 Samaritan Pharmaceuticals, Inc. Composes de quinuclidine anti-vih
WO2006085890A3 (fr) * 2004-04-05 2006-12-07 Samaritan Pharmaceuticals Inc Composes de quinuclidine anti-vih
JP2007531792A (ja) * 2004-04-05 2007-11-08 サマリタン，ファーマスーティカルス，インク． 抗ｈｉｖキヌクリジン化合物

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EP1631289A2 (fr) 2006-03-08
EP1631289A4 (fr) 2010-06-02

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