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WO2000048998A1 - Amino(thio)phénols et leur utilisation thérapeutique - Google Patents

Amino(thio)phénols et leur utilisation thérapeutique Download PDF

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Publication number
WO2000048998A1
WO2000048998A1 PCT/GB2000/000484 GB0000484W WO0048998A1 WO 2000048998 A1 WO2000048998 A1 WO 2000048998A1 GB 0000484 W GB0000484 W GB 0000484W WO 0048998 A1 WO0048998 A1 WO 0048998A1
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Prior art keywords
alkyl
disease
compound
aryl
heteroaryl
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English (en)
Inventor
Andrew Sharpe
Hannah Jayne Kendall
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Darwin Discovery Ltd
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Darwin Discovery Ltd
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Priority to AU25574/00A priority Critical patent/AU2557400A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to novel amino(thio)phenol (and phenol ether) compounds and to their formulation and use as pharmaceuticals.
  • WO-A-9631476 and WO-A-9640636 disclose aromatic ethers having therapeutic utility, as inhibitors of tumour necrosis factor (TNF) and phosphodiesterases (PDE). Other such compounds and their uses are described in US-A-5804588, and in WO-A- 9924404 (published 20 May 1999). Summary of the Invention
  • This invention provides novel compounds having therapeutic utility, in particular for the treatment of disease states associated with proteins which mediate cellular activity, for example by inhibiting TNF and/or PDE IV.
  • the compounds are of formula (i):
  • Rj is alkyl optionally substituted with one or more halogens
  • R 2 is COjRj, COR, , CONRjR,,, or S(O) p R,;
  • R 3 is H or alkyl
  • R 4 is H or alkyl
  • Rs is aryl or heteroaryl either of which may be substituted at any position with (one or more) substituents R M or alkyl-R 14 ;
  • Re is H or alkyl
  • R 7 is OR u> NR 15 Ri 2 , CN, COjRu, CONR ⁇ or COR ls ;
  • R g is R, 3 optionally substituted with R 7 ;
  • R j , and R ⁇ 0 are the same or different and are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl, or represents a heterocyclic ring optionally substituted with alkyl, arylalkyl or heteroarylalkyl;
  • R u is H, alkyl (optionally substituted with one or more halogens), cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • Rj 2 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl, alkylsulphonyl, arylsulphonyl, heteroarylsulphonyl or heterocyclosulphonyl;
  • R 13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • R 14 is alkyl, aryl, heteroaryl, heterocyclo, SO 2 N 9 R K ,, OR n , halogen, CN, NR, 5 R 12 , COR ls or S(O) p R u ;
  • R 1$ is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • This invention provides also a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically- acceptable salt thereof.
  • X is preferably O. - g is preferably H.
  • Rj is preferably phenyl, pyrimidinyl, pyridyl or pyridyl-N-oxide, any of which may be substituted at any position with (one or more) substitutents R 14 (in which R 14 is alkyl optionally substituted with one or more halogens, halogen, OR u or CN).
  • Suitable pharmaceutically-acceptable salts are pharmaceutically-acceptable base salts and pharmaceutically-acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically- acceptable base salts include metal salts, such as alkali metal salts, for example sodium salts, or organic amine salts such as that provided with ethylenediamine.
  • acid addition salts include pharmaceutically-acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphate, ⁇ -ketoglutarate, ⁇ -glycerophosphate and glucose- 1 -phosphate.
  • the pharmaceutically-acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence ofone or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers, and diastereoisomers and mixtures including racemic mixtures thereof.
  • alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 carbon atoms.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described, and thioalkyl means an alkyl-S- group.
  • Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of 3 to 10 carbon atoms.
  • the cyclic alkyl may optionally be partially unsaturated.
  • Aryl indicates mono- or multicyclic carbocyclic radicals containing 6 to 10 carbon atoms.
  • Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein.
  • Heteroaryl means a 5 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Heterocyclo means a 4 to 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Heteroarylalkyl means a heteroaryl-alkyl- group and heterocycloalkyl means a heterocycloalkyl- group.
  • Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described.
  • Heteroarylcarbonyl means a heteroaryl-CO- group and heterocyclocarbonyl means a heterocyclo-CO- group.
  • Arylsulphonyl means an aryl-SO 2 - group in which the aryl group is as previously described.
  • Heteroarylsulphonyl means a heteroaryl-SO 2 - group and heterocyclosulponyl means a heterocyclo-SO 2 - group.
  • Alkoxycarbonyl means an alkoxy-CO- group in wich the alkoxy group is as previously desribed.
  • Alkylsulphonyl means an alkyl-SO 2 - group in which the alkyl group is as previously described.
  • Carbonyl oxygen means a -CO- group.
  • Heterocyclic ring means a 4 to 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • the invention further provides a process for the preparation of a compound of formula (i), in which and p are as defined above.
  • functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such circumstances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, T W Greene or Chem. Ber. (1925), 58, 44.
  • the process for preparing compounds of formula (i) in which R 7 contains an -OH comprises deprotecting (for example by hydrogenolysis or hydrolysis) a compound of formula (i) in which R 7 contains an appropriate -OP wherein P represents a suitable protecting group (e.g. benzyl or acetyl).
  • P represents a suitable protecting group (e.g. benzyl or acetyl).
  • a process for the preparation of a compound of formula (i) comprises reaction of an appropriate carboxylic acid of formula (ii) with a suitable amine of formula (i ⁇ )
  • Ri.-Rg represent Ri-Rg as defined in relation to formula (i) or a group convertible to R Rg respectively.
  • the reaction of a carboxyuc acid of formula (ii) with an amine of formula ( ⁇ i) may be carried out under suitable conditions known to those skilled in the art.
  • the carboxyuc acid is converted into an acid chloride, mixed anhydride or other activated intermediate prior to reaction with an amine of formula (iii).
  • the reaction with the amine of formula (iii) is carried out in the presence of a suitable base, for example an amine base such as triethylamine, preferably in an appropriate solvent such as dichloromethane. In some cases a stronger base, such as sodium hydride, and a polar solvent such as dimethylformamide, will be required.
  • Carboxylic acids of formula (ii) are either commercially available, previously described compounds or are prepared using standard conditions known to those skilled in the art.
  • a carboxylic acid of formula (ii) is conveniently prepared from a compound of formula (iv), either by formylation to provide an aldehyde of formula (v) followed by oxidation to provide the acid of formula (ii), or by bromination to provide a bromide of formula (vi) followed by carboxylation to provide an acid of formula (ii).
  • Formylation of a compound of formula (iv) may be carried out under any standard conditions known to those skilled in the art, for example by using phosphorus oxychloride and dimethylformamide at elevated temperature.
  • Oxidation of an aldehyde of formula (v) may be carried out using any appropriate conditions known to those skilled in the art, for example by using sodium chlorite and sodium phosphate in water/t-butanol in the presence of an acid scavenger such as 2-methyl-2-butene.
  • Bromination of a compound of formula (iv) can be carried out using standard conditions, for example by using bromine in an appropriate solvent such as methanol.
  • Carboxylation of a bromide of formula (vi) can conveniently be achieved by the use of an organometal catalyst, such as a palladium catalyst in the presence of an appropriate base in a suitable solvent.
  • a compound of formula (iv) may be commercially available, a previously described compound or may be prepared using standard conditions known to those skilled in the art. Procedures for their preparation are described in Bull. Soc. Chim. Fr. (1974), 2628.
  • Amines of formula ( ⁇ i) are either commercially available or are prepared using standard conditions known to those skilled in the art.
  • Compounds of formula (i) in which R 3 and R 4 are both H may be prepared by the acid-mediated ring opening of a benzoxazole of formula (vii) as shown in the following scheme and described in Chem. Ber. (1925) 58, 44.
  • Q represents a suitable substituent such that COQ represents R 2 or may be converted to R 2 .
  • Benzoxazoles of formula (v ⁇ ) may be prepared as described in WO-A-9822460.
  • R 3 and /or R 4 are alkyl
  • This transformation may be carried out using appropriate alkylation conditions known to those skilled in the art, for example by the use of an alkyl halide and appropriate base, such as sodium hydride, in a suitable solvent such as THF.
  • TNF-mediated disease or disease states any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophUic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative co ⁇ tis, Crohn's disease, reperfiision injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia.
  • PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication.
  • PDE IV inhibitors may be useful in the treatment of tarditive dyskinesia, ischaemia and Huntingdon's disease.
  • PDE IV inhibitors may have utility as gastroprotectants.
  • a special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
  • TNF release inhibitors are useful in the treatment of viral infections.
  • viruses contemplated for treatment here are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF release inhibitors of Formula (i).
  • viruses include, but are not limited to HTV-l, HIV-2 and HTV-3, cytomegalo virus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not ⁇ mited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HTV), which comprises administering to such mammal an effective TNF release-inhibiting amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
  • HTV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not ⁇ mited to fe ⁇ ne immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis v ⁇ us, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will e ⁇ cit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of formula (i) are preferably in pharmaceutically-acceptable form.
  • pharmaceutically-acceptable form is meant, inter alia, a pharmaceutically-acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically- acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • pharmaceutically-acceptable encompasses materials suitable for both human and veterinary use.
  • a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may be administered/jer se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically- acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, and a pharmaceutically- acceptable carrier.
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroUdone; fillers for example microcrystal ⁇ ne cellulose, lactose, sugar, maize- starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically-acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroUdone
  • fillers for example microcrystal ⁇ ne cellulose, lactose, sugar, maize- starch, calcium phosphate, sorbitol or glycine
  • So ⁇ d oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups or e ⁇ xirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such Uquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, non- aqueous vehicles (which may include edible o ⁇ s), for example almond oil, fractionated coconut o ⁇ , oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbit
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 ⁇ m, such as from 0.1 to 50 ⁇ m, preferably less than 10 ⁇ m, for example from 1 to 10 ⁇ m, 1 to 5 ⁇ m or from 2 to 5 ⁇ m.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprena ⁇ ne, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprena ⁇ ne, isoetharine, salbutamol, phenylephrine and ephedrine
  • corticosteroids such as prednisolone
  • adrenal stimulants such as ACTH
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomp ⁇ shed by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the compositions may contain from 0.1% to 99% by weight, preferably from 10- 60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (i), or if appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceuticaUy-acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emoUients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceuticaUy-acceptable salt thereof, are conventional formulations weU known in the art, for example, as described in standard text books such as Harry's Cosmeticology pub ⁇ shed by Leonard Hill Books,
  • the compound of formula (i), or if appropriate a pharmaceutically- acceptable salt thereof, wiU compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • the dose of the compound used in the treatment of the invention will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and the relative efficacy of the compound.
  • suitable unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 tunes a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70 kg adult is in the range of about 0.1 to 1000 mg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg day, and such therapy may extend for a number of weeks or months.
  • the following Examples illustrate the invention.
  • the aqueous layer was acidified to pH3 with 2M hydrochloric acid and extracted with ethyl acetate (150ml). Separation of the organic layer, drying over magnesium sulphate, filtering and removal of the solvent in vacuo afforded the title compound as an off-white so ⁇ d (0.47g).
  • TLC R f 0.37 (50% ethyl acetate in hexane).
  • the assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (I) are standard assay procedures as disclosed by Schil ⁇ ng et al, Anal. Biochem. 216:154 (1994), Thompson and Strada, Adv. Cycl. Nucl. Res. 8:119 (1979) and Gristwood and Owen, Br. J. Pharmacol. 87:91P (1986).
  • PMBC's peripheral blood mononuclear cells
  • abi ⁇ ty of compounds of formula (i) to inhibit TNF production in human peripheral blood mononuclear cells (PMBC's) is measured as follows. PMBC's are prepared from freshly taken blood or "Bufiy coats" by standard procedures. Cells are plated out in RPMI1640 +1% foetal calf serum in the presence and absence of inhibitors. Lipopolysaccharide (endotoxin) (100 ng/ml) is added and cultures are incubated for 22 h at 37°C in an atmosphere of 95% air/5% CO 2 . Supernatants are tested for TNF ⁇ by enzyme-linked immunosorbent assay, using commerciaUy available kits.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés présentant un utilisation thérapeutique comme inhibiteurs du PDE et du TNF et de formule (i) dans laquelle R1 est alkyle facultativement substitué par un ou plusieurs halogènes, R2 est carboxylate, carboxamide, sulfinyle ou sulfonyle; R3, R4 et R6 sont chacun H ou alkyle; R5 est aryle ou hétéroaryle facultativement substitué; et X est O ou S.
PCT/GB2000/000484 1999-02-19 2000-02-14 Amino(thio)phénols et leur utilisation thérapeutique Ceased WO2000048998A1 (fr)

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AU25574/00A AU2557400A (en) 1999-02-19 2000-02-14 Amino(thio)phenols and their therapeutic use

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GB9903919.0 1999-02-19
GBGB9903919.0A GB9903919D0 (en) 1999-02-19 1999-02-19 Aminophenols and their therapeutic use

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056988A1 (fr) * 2000-02-01 2001-08-09 Kirin Beer Kabushiki Kaisha Composes contenant de l'azote et possedant une activite d'inhibition des kinases, et medicaments comprenant ces composes
WO2008026687A1 (fr) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031476A1 (fr) * 1995-04-07 1996-10-10 Rhone-Poulenc Rorer Limited Hydroxyethers aromatiques
WO1996040636A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. Derives de diethers de catechol utilises comme agents pharmaceutiques
WO1999024404A1 (fr) * 1997-11-07 1999-05-20 Amgen Inc. Composes pyridine substitues presentant une action anti-inflammatoire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031476A1 (fr) * 1995-04-07 1996-10-10 Rhone-Poulenc Rorer Limited Hydroxyethers aromatiques
WO1996040636A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. Derives de diethers de catechol utilises comme agents pharmaceutiques
WO1999024404A1 (fr) * 1997-11-07 1999-05-20 Amgen Inc. Composes pyridine substitues presentant une action anti-inflammatoire

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056988A1 (fr) * 2000-02-01 2001-08-09 Kirin Beer Kabushiki Kaisha Composes contenant de l'azote et possedant une activite d'inhibition des kinases, et medicaments comprenant ces composes
US7217722B2 (en) 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
WO2008026687A1 (fr) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé

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