WO1995023134A1 - Benzonitriles therapeutiques - Google Patents

Benzonitriles therapeutiques Download PDF

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Publication number
WO1995023134A1
WO1995023134A1 PCT/GB1995/000376 GB9500376W WO9523134A1 WO 1995023134 A1 WO1995023134 A1 WO 1995023134A1 GB 9500376 W GB9500376 W GB 9500376W WO 9523134 A1 WO9523134 A1 WO 9523134A1
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WO
WIPO (PCT)
Prior art keywords
benzonitrile
compound
amino
formula
thio
Prior art date
Application number
PCT/GB1995/000376
Other languages
English (en)
Inventor
Joseph Howing Chan
Original Assignee
The Wellcome Foundation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Wellcome Foundation Limited filed Critical The Wellcome Foundation Limited
Priority to JP7522198A priority Critical patent/JPH09509423A/ja
Priority to AU17141/95A priority patent/AU1714195A/en
Priority to EP95909037A priority patent/EP0746542A1/fr
Publication of WO1995023134A1 publication Critical patent/WO1995023134A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • the present invention relates to certain arylthiobenzonitrile compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy, particularly for the prophylaxis or treatment of viral infections and inflammation.
  • Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first 'reverse transcribe' the RNA of their genome into DNA ('transcription' conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the viral genome may be incorporated into the host cell genome, allowing it to take advantage of the host cell's transcription/translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus producing mechanism may persist for the life of the cell.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immune Deficiency Syndrome
  • AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections.
  • Characteristically, AIDS is associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the OKT 4 surface marker. HIV is cytopathic and appears to preferentially infect and destroy T-cells bearing the OKT 4 marker and it is now generally recognised that HIV is the aetiological agent of AIDS.
  • PCT patent application WO 92/06683 discloses certain diphenylsulfides having anti- retrovirus activity.
  • 2-Amino-6-[(3,4-dichlorophenyl)thio]benzonitrile and 2-amino-6-(phenylthio)benzonitrile have been described as chemical intermediates with no reference to any medical uses (Ashton, W.T. et al., J. Med. Chem., 1973, 16(11), 1233-7 and Harris, N.V. et al., J. Med. Chem., 1990, 33(1), 434-4).
  • R is hydrogen, nitro, trifluoromethyl, halogen (for example, fluorine, chlorine, bromine or iodine), carboxy, C 1-4 carboxamido, nitrile, C 1-4 alkanoyl (for example methanoyl), C 1-4 alkylsulfonyl (for example methylsulfonyl), C 1-4 alkylsulfinyl (for example methylsulfinyl), trifluoromethylsulfonyl, trifluoromethylsulfinyl, C 2-7 alkenyl (for exampl ethenyl) or C 2-7 alkynyl (for example ethynyl).
  • halogen for example, fluorine, chlorine, bromine or iodine
  • carboxy for example methanoyl
  • C 1-4 alkylsulfonyl for example methylsulfonyl
  • C 1-4 alkylsulfinyl for example
  • R 1 and R 2 which may be the same or different, are hydrogen or C 1-4 alkyl (for example, methyl); m is 0, 1 or 2; and n is 1 to 5 (when n is greater than 1, R may be the same or different); provided that when R 1 and R 2 are both hydrogen, and m is 0,
  • R is not hydrogen
  • R is not 3,4-dichloro; or a physiologically functional derivative thereof.
  • R is hydrogen, nitro, trifluoromethyl, halogen, carboxy, carboxamide, nitrile, C 1-4 alkanoyl (for example methanoyl), C 1-4 alkylsulfonyl (for example methylsulfonyl), C 1-4 alkylsulfinyl ( for example methylsulfinyl), trifluoromethylsulfonyl or trifluoromethylsulfinyl.
  • Preferred compounds of formula (I) include those wherein n is 1 or 2, ring A is 3-substituted or 3,5-disubstituted and m is 2.
  • Preferred compounds of formula (I) include:
  • Compounds of the invention are useful in the treatment or prophylaxis of HIV infections. Compounds of the invention also have anti-inflammatory properties.
  • the compounds according to the invention for use in therapy, more particularly for use as an antiviral agent, for example, for the prophylaxis or treatment of a retrovirus infection such as an HIV infection.
  • the present invention further includes:
  • a method for the prophylaxis or treatment of a viral infection in an infected host for example, a mammal including a human, which comprises administering to said host a therapeutically effective non-toxic amount of a compound according to the invention.
  • the viral infection is a retrovirus infection such as an HIV infection.
  • the present invention further includes:
  • a method for the prophylaxis or treatment of inflammation in an affected host for example, a mammal including a human, which comprises administering to said host a therapeutically effective non-toxic amount of a compound according to the invention.
  • inflammation it is meant the reactive state of hyperemia and exudation from blood vessels, with consequent redness, heat, swelling and pain, which a tissue undergoes in response to physical or chemical injury or bacterial or viral invasions.
  • the compounds according to the invention are useful for treating inflammatory conditions associated with disorders such as arthritis, tendinitis, synovitis, bursitis and inflammatory bowel disease.
  • AIDS Acquired Immune Deficiency Syndrome
  • ARC AIDS-related complex
  • PDL progressive generalised lymphadenopathy
  • Kaposis sarcoma thrombocytopenic purpura
  • AIDS related neurological conditions such as multiple sclerosis or tropical paraparesis and also anti-HIV antibody-positive and HIV-positive conditions including AIDS asymptomatic patients.
  • physiologically functional derivative means any physiologically acceptable salt, ester, amide or salt of such ester, of a compound of formula (I) or a solvate of any thereof, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
  • a physiologically functional derivative is within the scope of the invention.
  • esters of the compounds of formula (I), wherein R is hydroxyl included within the scope of the invention as physiologically functional derivatives include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C 1-4 alkyl, or C 1-4 alkoxy or amino); sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); amino acid esters (for example, L-valyl or L-i
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises an optionally substituted phenyl group.
  • Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable amides of the compounds of the invention are those derivatives wherein an amino group is present in the form of an amide, e.g., -NHCOR where in R is C 1-6 alkyl, trihalomethyl (e.g., trifluoromethyl) or aryl (e.g., phenyl optionally substituted by halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro or hydroxyl).
  • R is C 1-6 alkyl, trihalomethyl (e.g., trifluoromethyl) or aryl (e.g., phenyl optionally substituted by halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro or hydroxyl).
  • Examples of pharmaceutically acceptable salts of the compounds of the invention and physiologically acceptable derivatives thereof include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C 1-4 alkyl).
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C 1-4 alkyl).
  • Pharmaceutically acceptable salts include salts of organic carboxylic acids such as acetic, fumaric, citric, lactic, tartaric, maleic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, fumaric, citric, lactic, tartaric, maleic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric
  • salts of the compounds of the invention will be pharmaceutically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • the compounds according to the invention may be employed alone or in combination with other therapeutic agents for the treatment of HIV infections, such as Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for example zidovudine, zalcitabine, didanosine, lamivudine, stavudine, S-chloro-2'-3'-dideoxy-3'-fluorouridine and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, non-NRTIs for example nevirapine and a-APA, HIV-proteinase inhibitors for example saquinavir and VX-478, other anti-HIV agents for example soluble CD4, immune modulators for example interleukin ⁇ , erythropoietin, tucaresol and interferons for example a-interferon.
  • NRTIs Nucleoside Reverse Transcriptase Inhibitors
  • the present invention further provides pharmaceutical formulations of the compounds according to the invention, also referred to herein as active ingredients, which may be administered for therapy to a mammal including a human ("the recipient") by any suitable route appropriate to the clinical condition to be treated; suitable routes include oral, rectal, nasal, topical (including buccal, sublingual and transdermal), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition, weight, age and sex of the recipient, the nature of the infection and the chosen active ingredient.
  • the amount of a compound of the invention required for the treatment of the above named viral infections will depend on a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician.
  • a suitable dose for the treatment of each of the above named viral infections in a human subject is in the range 3.0 to 120 mg per kilogram body weight of the recipient per day, preferably in the range 6 to 90 mg per kilogram body weight per day and most preferably in the range 15 to 60 mg per kilogram body weight per day.
  • the desired dose is preferably presented as two, three, four, five, six, or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing from 10 to 1500 mg, preferably from 20 to 1000 mg, most preferably from 50 to 700 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the dose may be administered as a continuous infusion.
  • the formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and, optionally, one or more other therapeutic agents.
  • Each carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Formulations of the invention include those suitable for administration by any of the aforementioned routes which may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary, or paste or may be contained within liposomes.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (for example, povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxmethyl cellulose), or a surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile or to be soluble or effervescent when added to liquid. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for oral use may also include buffering agents designed to neutralize stomach acidity.
  • buffers may be chosen from a variety of organic or inorganic agents such as weak acids or bases admixed with their conjugated salts.
  • a capsule may be made by filling a loose or compressed powder on an appropriate filling machine, optionally with one or more additives.
  • suitable additives include binders such as povidone; gelatin, lubricants, inert diluents and disintegrants as for tablets.
  • Capsules may also be formulated to contain pellets or discrete sub-units to provide slow or controlled release of the active mgredient. This can be achieved by extruding and spheronising a wet mixture of the drug plus an extrusion aid (for example microcrystalline cellulose) plus a diluent such as lactose.
  • the spheroids thus produced can be coated with a semi-permeable membrane (for example ethyl cellulose, Eudragit WE30D) to produce sustained release properties.
  • compositions for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • a formulation may comprise a dressing such as a bandage or adhesive plaster impregnated with active ingredients and optionally one or more excipients or diluents.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain the active compound 1) in an optionally buffered, aqueous solution of 2) dissolved in an adhesive or 3) dispersed in a polymer.
  • a suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%.
  • the active compound may be delivered from the patch by ionophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w, preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base or as a water-in-oil base.
  • the aqueous phase of the cream base may include, for example, at least 40-45% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulphoxide and related analogues.
  • the oily phase of an emulsion formulation according to the invention may comprise merely an emulsifier (otherwise known as an emulgent), but desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which act. as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, arid the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulphate.
  • the choice of suitable oih or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • a suitable carrier especially an aqueous solvent.
  • the ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored material, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert material such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or higher fatty alcohol (e.g. hard wax, European Pharmacopoeia) or triglycerides and saturated fatty acids (e.g. Witepsol).
  • a suitable base comprising for example cocoa butter or higher fatty alcohol (e.g. hard wax, European Pharmacopoeia) or triglycerides and saturated fatty acids (e.g. Witepsol).
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds of formula (I) may be produced by various methods known in the art of organic chemistry in general. Starting materials are either known or readily available from commercial sources or may themselves be produced by known and conventional techniques.
  • the present invention further includes a process for the preparation of a compound of formula (I) or a physiologically functional derivative thereof.
  • n and R are as defined for formula (I)
  • a reducing agent such as SnCl 2 in concentrated HCl
  • b) (wherein one of R 1 or R 2 is C 1-4 alkyl and the other is hydrogen, or both R 1 and R 2 are C 1-4 alkyl) by alkylation of a corresponding compound of formula (I) (wherein both R 1 and R 2 are hydrogen), for example,
  • (i) by monoalkylation may be effected by first converting the amino group into an amide, such as trifluoromethyl amide, followed by alkylation of the amide and hydrolysis of the resulting product using a standard procedure to give the desired monoalkylated product; or
  • a compound of formula (II) may be prepared by reacting a compound of formula (III)
  • R n is as defined for formula (I) with 2,6-dinitrobenzonitrile, commercially available or prepared in accordance with the method described in Harris, N.V. et al., J. Med. Chem., 1990, 33(1), 434-44, with a base such as K 2 CO 3 in a suitable solvent such as N,N-dimemylformamide.
  • Compounds of formula (III) may be obtained commercially, for example, from Aldrich, Milwaukee, WI 53233 ,USA. They may also be prepared by conventional methods well known to a skilled person or readily available from the chemical literature, for example, J. Org. Chem., 1969, 34, 1463.
  • esters of compounds of formula (I) may be prepared by esterification of compounds of formula (II) prior to reduction, using conventional methods known in the art. Such methods include, for example, the use of an appropriate acid halide or anhydride.
  • the compounds of formula (I) may be converted into pharmaceutically acceptable amides by reaction with an appropriate acylating agent, for example, an acid halide or anhydride serving to acylate the phenyl amino group.
  • an appropriate acylating agent for example, an acid halide or anhydride serving to acylate the phenyl amino group.
  • Acyl groups may be removed selectively from one or other of the hydroxyl and/or. amino groups.
  • treatment of the acylated compound under acidic conditions e.g. with a Lewis acid, such as zinc bromide in methanol, removes an N-acyl group and treatment of a diacylated compound under alkaline conditions, e.g. with sodium methoxide, removes a hydroxyl acyl group to yield an N-amide.
  • the compounds of formula (I), including esters and amides thereof, may be converted into pharmaceutically acceptable salts in a conventional manner.
  • the salts may be obtained by treatment with an appropriate acid.
  • the salts may be obtained by treatment with a base.
  • An amide, ester or salt of a compound of formula (I) may be converted into the parent compound, for example, by hydrolysis.
  • active ingredient' as used in the examples means a compound of the invention or a physiologically functional derivative or a pharmaceutically acceptable salt or a solvate of any thereof.
  • Ci4HnN2 ⁇ 2SBr C, 47.88; H, 3.16; N, 7.98; S, 9.13; Br, 22.75. Found: C, 47.93; H, 3.11; N, 97.99; S, 9.21; Br, 22.79.
  • Example 25 Tablet Formulations The following formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by the addition of magnesium stearate and compression.
  • formulations, D and E are prepared by direct compression of the admixed ingredients.
  • the lactose in formulation E is of the direct compression type (Dairy Crest - "Zeparox").
  • the formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.
  • a capsule formulation is prepared by admixing the ingredients of Formulation D in Example 2 above and filling the mixture into a two-part hard gelatin capsule.
  • Formulation B (infra) is prepared in a similar manner.
  • Capsules of formulation D are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
  • Formulation E Controlled Release Capsule
  • the following controlled release capsule formulation is prepared by extruding ingredients (a), (b) and (c) using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets are then coated with the release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mg/capsule
  • the active ingredient is dissolved in most of the water at 35°C-40°C and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or sodium hydroxide as appropriate.
  • the batch is then made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.
  • the active ingredient is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is filtered through a sterile micropore filter and sealed in sterile 3 ml amber glass vials (type 1).
  • the active ingredient is dissolved in a mixture of the glycerol and most of the purified water.
  • An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavor.
  • the volume is made up with purified water and mixed well.
  • the active ingredient is used as a powder wherein at least 90% of the particles are of 631m diameter or less.
  • Witepsol H15 One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum.
  • the active ingredient is sifted through a 200 ⁇ m sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
  • the entire suspension is passed through a 250 ⁇ m stainless steel screen and, with continuous stirring, allowed to cool to 40°C. At a temperature of 38°C to 40°C, 2.0g of the mixture is filled into suitable 2 ml plastic moulds. The suppositories are allowed to cool to room temperature.
  • Anti-HIV activity of compounds of formula (I) was determined using the method of Averett D.R., 1989, J. Virol. Methods, 23, pp263-276, by measuring the ability of the compound to reverse the cytopathic effect of HIV infection. This was determined by a quantitative assessment of cell growth monitored at the fifth day post infection by a propidium iodide dye uptake test.
  • MT4 cells were incubated with 100XTCID 50 of HIV- 1 (strain 3B) or HIV-2 (strain ZY) for one hour prior to addition of the compound in six different concentrations varying from 2 to 200 ⁇ M. The cells were allowed to incubate for five days at 37°C.
  • NP-40 a detergent
  • Cell number was determined using a method which measures the fluorescence of a dye (propidium iodide) which binds to DNA. Since the amount of DNA is directly proportional to cell number, this fluorescence assay is an indication of cell growth. While uninfected cells double in cell number several times during the five days duration of the assay, HIV-infected cells grow very little, if at all. A compound which reverses the cytopathic effect of HIV would allow for rapid cell growth, approaching that of the mock-infected cells.
  • IC 50 i.e. as the inhibitory concentration that would produce a 50% decrease in the HIV-induced cytopathic effect. This effect is measured by the amount of compound required to restore 50% of the cell growth of HIV-infected MT4 cells, compared to uninfected MT4 cell controls.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés arylthiobenzonitriles de la formule (I) ou dérivé physiologiquement acceptable de ceux-ci, dans laquelle R représente hydrogène, nitro, trifluorométhyle, halogène, carboxy, carboxyamido C1-4, nitrile, alcanoyle C1-4, alcoylsulfonyle C1-4, alcoylsulfinyle C1-4, trifluorométhylsulfonyle, trifluorométhylsulfinyle, alcényle C2-7 ou alcynyle C2-7; R1, R2, m et n ont les notations données dans la description. L'invention se rapporte également aux formulations pharmaceutiques contenant ces composés, aux procédés de préparation de ceux-ci ainsi qu'à l'utilisation desdits composés dans la thérapie et le traitement ou la prophylaxie d'une infection ou d'une inflammation par VIH.
PCT/GB1995/000376 1994-02-23 1995-02-23 Benzonitriles therapeutiques WO1995023134A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7522198A JPH09509423A (ja) 1994-02-23 1995-02-23 治療用ベンゾニトリル
AU17141/95A AU1714195A (en) 1994-02-23 1995-02-23 Therapeutic benzonitriles
EP95909037A EP0746542A1 (fr) 1994-02-23 1995-02-23 Benzonitriles therapeutiques

Applications Claiming Priority (2)

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GB9403408.9 1994-02-23
GB9403408A GB9403408D0 (en) 1994-02-23 1994-02-23 Therapeutic benzonitriles

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WO1995023134A1 true WO1995023134A1 (fr) 1995-08-31

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EP (1) EP0746542A1 (fr)
JP (1) JPH09509423A (fr)
AU (1) AU1714195A (fr)
GB (1) GB9403408D0 (fr)
WO (1) WO1995023134A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0702008A2 (fr) * 1994-07-05 1996-03-20 Sumitomo Seika Chemicals Co., Ltd. Procédé pour la préparation de 1,2-benzisothiazol-3-ones
WO2000059878A2 (fr) * 1999-04-02 2000-10-12 Icos Corporation Inhibiteurs de la liaison de lfa-1 a des icams icams et lieurs utilisations

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034263A2 (fr) * 1980-01-25 1981-08-26 The Dow Chemical Company Benzonitriles substitués et compositions pour l'inhibition de virus
WO1992000952A1 (fr) * 1990-07-10 1992-01-23 Janssen Pharmaceutica N.V. Derives de benzeneacetamide inhibiteurs du vih
WO1992006683A1 (fr) * 1990-10-22 1992-04-30 Research Corporation Technologies, Inc. Composes d'aryle et d'heteroaryle presentant une activite contre un retrovirus
EP0507488A1 (fr) * 1991-03-27 1992-10-07 Merck & Co. Inc. Inhibiteurs de transcriptase inverse de HIV-1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034263A2 (fr) * 1980-01-25 1981-08-26 The Dow Chemical Company Benzonitriles substitués et compositions pour l'inhibition de virus
WO1992000952A1 (fr) * 1990-07-10 1992-01-23 Janssen Pharmaceutica N.V. Derives de benzeneacetamide inhibiteurs du vih
WO1992006683A1 (fr) * 1990-10-22 1992-04-30 Research Corporation Technologies, Inc. Composes d'aryle et d'heteroaryle presentant une activite contre un retrovirus
EP0507488A1 (fr) * 1991-03-27 1992-10-07 Merck & Co. Inc. Inhibiteurs de transcriptase inverse de HIV-1

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ASHTON, W.T. ET AL.: "Synthesis of 5-Substituted Quinazolines as Potential Antimalarial Agents", J. MED. CHEM., vol. 16, no. 11, pages 1233 - 1237 *
HARRIS, N.V. ET AL.: "Antifolate and Antibacterial Activities of 5-Substituted 2,4-Diaminoquinazolines", J. MED. CHEM., vol. 33, no. 1, pages 434 - 444 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0702008A2 (fr) * 1994-07-05 1996-03-20 Sumitomo Seika Chemicals Co., Ltd. Procédé pour la préparation de 1,2-benzisothiazol-3-ones
EP0702008A3 (fr) * 1994-07-05 1996-10-16 Sumitomo Seika Chemicals Procédé pour la préparation de 1,2-benzisothiazol-3-ones
US5633384A (en) * 1994-07-05 1997-05-27 Sumitomo Seika Chemicals Co., Ltd. Method for producing 1,2-benzisothiazol-3-ones
US5773626A (en) * 1994-07-05 1998-06-30 Sumitomo Seika Chemicals Co., Ltd. Method for producing 1,2-benzisothiazol-3-ones
EP1081141A1 (fr) * 1994-07-05 2001-03-07 Sumitomo Seika Chemicals Co., Ltd. Procédé pour la préparation de 1,2-benzisothiazol-3-ones
WO2000059878A2 (fr) * 1999-04-02 2000-10-12 Icos Corporation Inhibiteurs de la liaison de lfa-1 a des icams icams et lieurs utilisations
WO2000059878A3 (fr) * 1999-04-02 2001-08-09 Icos Corp Inhibiteurs de la liaison de lfa-1 a des icams icams et lieurs utilisations

Also Published As

Publication number Publication date
AU1714195A (en) 1995-09-11
JPH09509423A (ja) 1997-09-22
EP0746542A1 (fr) 1996-12-11
GB9403408D0 (en) 1994-04-13

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