WO1998043953A1 - Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur - Google Patents

Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur Download PDF

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Publication number
WO1998043953A1
WO1998043953A1 PCT/EP1998/001845 EP9801845W WO9843953A1 WO 1998043953 A1 WO1998043953 A1 WO 1998043953A1 EP 9801845 W EP9801845 W EP 9801845W WO 9843953 A1 WO9843953 A1 WO 9843953A1
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Prior art keywords
compound
hydroxy
phenyl
ethylamino
alkyl
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PCT/EP1998/001845
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English (en)
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David Norman Deaton
Robert Blount Mcfadyen
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Glaxo Group Limited
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Priority to AU72125/98A priority Critical patent/AU7212598A/en
Publication of WO1998043953A1 publication Critical patent/WO1998043953A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/68—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C229/70—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/47—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having at least one of the sulfo groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system

Definitions

  • This invention relates to a new class of chemical compounds and to their use in medicine.
  • the invention concerns novel naphthalene derivatives, methods for their preparation, pharmaceutical compositions containing them and their use as selective agonists at atypical beta-adrenoceptors (also known as beta-3- adrenoceptors).
  • beta-adrenoceptors also known as beta-3- adrenoceptors.
  • Such receptors have been described for example by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309- 319 (1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).
  • Phenethanolamine derivatives having activity at atypical beta-adrenoceptors are disclosed in, for example, European
  • Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline. Subtypes of the adrenoceptors, c ⁇ -, ⁇ 2 -, ⁇ 1 -, ⁇ 2 - and ⁇ 3 -(atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not ⁇ 3 ) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors. Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract.
  • Atypical beta-ad renoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents.
  • Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiatherosclerotic agents, and as being useful in the treatment of glaucoma.
  • the invention therefore provides, in a first aspect, compounds of formula (I):
  • R 1 represents a phenyl, naphthyl, phenoxymethyl, thiazolyl, pyridyl or pyrmidyl group, optionally substituted by one or more substituents selected from halogen, hydroxy, C-j ⁇ alkoxy, C ⁇ alkyl, nitro, cyano, hydroxy methyl, trifluoromethyl, NR°R7, R2 represents hydrogen or C ⁇ alkyl;
  • R represents hydrogen or C1.4 alkyl
  • R 4 represents CO2R 6 or SO3H
  • R5 represents one or more groups independently selected from hydrogen, C-
  • R6 and R? independently represent hydrogen or C-
  • N(R ⁇ ) and R 4 are separated by at least 4 ring carbon atoms
  • R 1 represents a phenyl, naphthyl, pyridyl or pyrmidyl group, optionally substituted by one or more substituents selected from halogen, hydroxy, C- ⁇ alkoxy, C-j_6alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, NR 6 R 7 , and NHSO2R 6 ;
  • R2 represents hydrogen or C ⁇ _ ⁇ alkyl
  • R3 represents hydrogen or C-j_4 alkyl
  • R 4 represents CO2R 6 or SO3H
  • R5 represents one or more groups independently selected from hydrogen, C ⁇ . 6 a 'kyl, halogen, trifluoromethyl and C ⁇ . ⁇ alkoxy; n represents an integer from 1-6; R6 and R 7 independently represent hydrogen or C-j_4 alkyl; or pharmaceutically acceptable derivatives thereof.
  • the term 'alkyl' as used herein respectively contains the appropriate indicated number of carbon atoms and appropriately includes straight chained alkyl groups, typically methyl and ethyl groups, and straight chain and branched propyl and butyl groups.
  • the term 'alkoxy * includes both straight and branched chain groups.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • R 1 represents phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C ⁇ alkoxy, C ⁇ alkyl, nitro, cyano, hydroxymethyl and trifluoromethyl.
  • R 1 represents phenyl substituted by a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group, which atom or group is preferably located in the meta position. More preferably R 1 represents phenyl substituted by a chlorine atom located in the meta position.
  • R 2 is suitably hydrogen or methyl.
  • R 3 is suitably hydrogen or methyl.
  • R 3 is preferably hydrogen.
  • R 4 is suitably CO2H, or SO3H. Preferably, R 4 is CO2H.
  • R 5 is suitably hydrogen.
  • a further preferred subgroup of the present invention is represented by a compound of formula (lb):
  • R2 represents hydrogen or C ⁇ alkyl
  • R 4 represents CO2H or SO3H; or pharmaceutically acceptable derivatives thereof.
  • the above compounds of formula (I) may contain optically active centres.
  • the individual, isolated isomers and mixtures thereof, including racemates, are all within the scope of the present invention.
  • mixtures of diastereomers of compounds of formula (I) may be obtained, which are enriched with greater than or equal to 80% by weight of one diastereomer.
  • Particularly preferred compounds of formula (I) are those wherein the asymmetric carbon atoms in the - CH(OH)- group and the -CH(R 2 )- group are both in the (R)-configuration.
  • Suitable compounds of formula (I) of the invention include:
  • Preferred compounds of the invention include: 5- ⁇ 2R-[2-(3-Chloro-phenyl)-2R-hydroxy-ethylamino]-propylamino ⁇ -naphthalene-2- carboxylic acid; and pharmaceutically acceptable derivatives thereof.
  • a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds of formula (I).
  • pharmaceutically acceptable derivatives are compounds modified at the carboxyl function, hydroxyl functions or at amino groups.
  • Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) are pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene- p- sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR 4 + (where R is C ⁇ alkyl) salts.
  • the compounds of formula (I) act as agonists at atypical beta -adrenoceptors and as such are useful in the treatment of clinical conditions susceptible to amelioration by administration of an atypical beta-ad renoceptor agonist.
  • Such conditions include hyperglycaemia, obesity, hyperlipemia, irritable bowel syndrome and its associated pain, motility dysfunction, excessive gastrointestinal secretion, non-specific diarrhoea, neurogenic inflammation, regulation of intraocular pressure, triglyceridemia, diabetes, e.g. non-insulin-dependent diabetes mellitus (NIDDM or
  • Type II such as obese NIDDM and non-obese NIDDM, diabetic complications such as retinopathy, nephropathy, neuropathy, cataracts, coronary heart diseases and arteriosclerosis, osteoporosis; and gastrointestinal disorders, particularly inflammatory gastrointestinal disorders. They are also of use in increasing the high- density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum, especially human blood serum, and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They also may be useful for the treatment of hyperinsulinaemia, depression, muscle wasting, and urinary incontinence.
  • HDL high- density-lipoprotein
  • the present invention provides, as a further aspect, a method of treatment of a mammal, including man, suffering from condition susceptible of amelioration by an atypical beta-ad renoceptor agonist which method comprises administering to the subject an effective amount of a compound of general formula (I) or a pharmaceutically acceptable derivative thereof.
  • References in this specification to treatment include prophylactic treatment as well as the alleviation of symptoms.
  • the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition susceptible of amelioration by an atypical beta-adrenoceptor agonist.
  • a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) or excipient(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compounds for use according to the present invention may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose).
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. ?
  • lecithin or acacia lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
  • preservatives e.g. methyl or propyl-p- hydroxybenzoates or sorbic acid
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds according to the present invention may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Suitable therapeutic ingredients which may be formulated with compounds of the invention, together with one or more pharmaceutical carriers or excipients, include ingredients which may be used in the same clinical conditions as those listed herein for atypical beta-adrenoceptor agonists. Such ingredients may include, for example, PPAR-gamma agonists.
  • a proposed dose of the compounds according to the present invention for administration to a human is 0.1 mg to 1g, preferably to 1mg to 100mg of the active ingredient per unit dose, expressed as the weight of free base.
  • the unit dose may be administered, for example, 1 to 4 times per day.
  • the dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the compounds of the invention may be prepared by any of the processes known in the art for the preparation of similar compounds.
  • compounds of formula (I) may be prepared from of a compound of formula (II):
  • R 4 is CO2R 6 or SO3H and R 6 is C-
  • an acid e.g. aqueous hydrochloric acid in a suitable solvent such as dioxane.
  • compounds of formula (I) may be prepared from other compounds of formula (I).
  • a compound of formula (I) where R6 is H may be prepared from a compound of formula (I) where R ⁇ is C-j_6 alkyl by hydrolysis, e.g. base hydrolysis with a reagent such as lithium hydroxide in a solvent such as tetrahydrofuran.
  • R 4 is CO2R 6 or SO3H and R 6 is C-
  • step (C) the preparation of compounds of formula (II), as defined above, followed by step (A) may be combined without purification of intermediate products.
  • R$ and n are defined above and R6 is a C-j ⁇ alkyl group, by reaction with benzylamine and cesium carbonate in the presence of a suitable catalyst/catalysts, e.g. (R)-(+)-2,2 , -bis(diphenylphosphino)-1,1'-binaphthyl and tris(dibenzylideneacetone) dipalladium(O), followed by suitable reduction, e.g. hydrogenation, of the benzyl group.
  • a suitable catalyst/catalysts e.g. (R)-(+)-2,2 , -bis(diphenylphosphino)-1,1'-binaphthyl and tris(dibenzylideneacetone) dipalladium(O)
  • a compound of formula (IV) which is a 5-amino-2-naphthoate ester may be obtained from a compound of formula (VI)
  • R 5 and n are defined above and P 3 represents a suitable primary nitrogen protecting group, e.g. an isoindole, by reaction with carbon monoxide, under pressure and at elevated temperature, e.g. 100°C, in the presence of a suitable catalyst or catalysts such as palladium (II) acetate and 1,1'-bis(diphenylphosphino)- ferrocene and lithium chloride, in a suitable solvent such as triethylamine and methanoi, followed by deprotection of the amino protecting group under suitable conditions, e.g. hydrazine in methanoi at elevated temperature.
  • a suitable catalyst or catalysts such as palladium (II) acetate and 1,1'-bis(diphenylphosphino)- ferrocene and lithium chloride
  • a compound of formula (VI) may be prepared from the corresponding 5-amino-2- naphthol by sequential reaction with a suitable reagent such as phthallic anhydride in a suitable solvent such as N,N-dimethylacetamide followed by reaction with trifluoromethanesulfonic anhydride and triethylamine in a suitable solvent such as dichloromethane.
  • a suitable reagent such as phthallic anhydride in a suitable solvent such as N,N-dimethylacetamide
  • trifluoromethanesulfonic anhydride and triethylamine in a suitable solvent such as dichloromethane.
  • Suitable reducing agents of use in the reactions include hydrogen in the presence of a catalyst, such as a noble metal catalyst, for example palladium, platinum or platinum oxide, Raney-nickel or hydride reducing agents such as borohydrides, for example sodium borohydride sodium triacetoxyborohydride or sodium cyanoborohydride.
  • a catalyst such as a noble metal catalyst, for example palladium, platinum or platinum oxide, Raney-nickel or hydride reducing agents such as borohydrides, for example sodium borohydride sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example 'Protective Groups in Organic Chemistry' Ed. J. F. W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by Theodora W Greene and P M G Wuts (John Wiley and Sons 1991).
  • Conventional amino protecting groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N- benzyloxycarbonyl or t-butoxycarbonyl.
  • Conventional oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl, or tert-butyldimethylsilyl; alkylethers such as tetrahydropyranyl, or tert-butyl; or esters such as acetate.
  • alky silyl groups such as trimethylsilyl, or tert-butyldimethylsilyl
  • alkylethers such as tetrahydropyranyl, or tert-butyl
  • esters such as acetate.
  • Atypical beta-adrenoceptor agonists are compounds which demonstrate a pharmacological response mediated at atypical beta-adrenoceptors. This activity has been be measured as the ability to stimulate lipolysis by rat adipocytes at sub- micromolar concentrations, in a response that is resistant to blockade by standard beta-adrenoceptor blocking drugs such as propranolol.
  • Another useful means of identifying an atypical beta-adrenoceptor agonist involves the measurement of agonist activity at atypical beta-adrenoceptors in the rat isolated lower oesophagus.
  • a compound of general formula (I) for use according to the present invention has an equipotent molar ratio (EPMR) relevant to isoprenaline of less than 30.
  • EPMR equipotent molar ratio
  • the rat oesophagus assay is based upon that described by Ford et. al., Br. J. Pharmacol., 105(suppl.), 235p, 1992.
  • a particularly useful method for determining agoinst activity at human atypical beta- adrenoceptors involves the use of Chinese hamster ovarian (CHO) cells transfected with the human beta-3-adrenoceptor according to Method 1.
  • the cell lines may also be transfected with human beta-1- and beta-2- adrenoceptor in a similar manner to provide a method of determining the selectivity of the compounds of the invention at the three receptors.
  • H ⁇ 3 CHO cells are grown in DMEM/F12 (with pyroxidine-HCI, 15 mM HEPES, L-glutamine), supplanted with 10% heat-inactivated FBS, 500 ⁇ g/ml G418, 2 mM L-gluatmine, 100 units penicillin G and 100 ⁇ g streptomycin sulfate.
  • the medium is aspirated from each well, and replaced with 180 ⁇ l DMEM/F12 with 500 mM IBMX. Antagonists, if required, are added at this stage. The plate is then placed back in the incubator for 30min. Drugs are then added to the wells (20 ⁇ l, 100x required final concentration) for 60 min. Responses were determined by measuring cAMP levels of a 20 ul sample of extracellular media using a scintillation proximity based radio-immunoassay (NEN Flashplates).
  • CHO-6CRE-luciferase cell lines which stably express h ⁇ 3 receptors are seeded at 30,000 cells/well for 24 hr in DMEM/F12 containing 10% FBS. Media is removed from the cells and replaced with DMEM/F12 buffer (180 ⁇ l) containing 300 mM IBMX and 1 mM ascorbic acid for 30 min prior to addition of compound. Vehicle or agonist (20 ⁇ l) is added and incubated at 37°C for 60 minutes. At the end of the incubation period, samples of extracellular media are removed for direct assay in cAMP Flashplates (NEN).
  • EPMR EC 30 agonist /EC 30 isoprenaline wherein EC 30 is the molar concentration of agonist which produces 30% of the maximum possible response for that agonist.
  • compounds selective for atypical beta-adrenoceptors should preferably be a minimum of 10-30 times less potent than isoprenaline at ⁇ or ⁇ 2 -adrenoceptors and, more preferably, 300-1000 times less potent than isoprenaline at ⁇ or ⁇ 2 - adrenoceptors.
  • the compounds of the present invention have been determined to be highly selective for this receptor compared to the ⁇ or ⁇ 2 -adrenoceptors.
  • HPLC characterisation was carried out where specified using a Dynamax-60A C18 83-201 -C, 25cm x 4.6mm column, eluting with 5-40% CH 3 CN in H 2 0 with 0.1 % TFA buffer, with a programme time of 30.0 min and flow rate of 1.5ml_. min). Retention times are expressed as t r in minutes. Optical rotation values are expressed as [ ]__ values.
  • Mass spectra were obtained using electrospray (positive or negative ion) analysis.
  • Ci8HifjN02Br requires C 61.39, H 2.86, N 3.98% from 6-bromo-2-naphthalenamine (9.50 g) (Journal of Organic Chemistry, 25, 214 1960).
  • Trifluoromethanesulfonic anhydride (10.09 mL) was added dropwise under nitrogen to a slurry of 2-(6-hydroxy-1-naphthyl)-1H-isoindole-1 ,3(2H)-dione (14.46 g) in dichloromethane (200 mL) containing triethylamine (13.9 mL) at -78 °C. After 2 h, 1
  • Methyl 6-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)-2-naphthoate A solution of 2-(6-bromo-2-naphthyl)-1H-isoindole-1 ,3(2/-/)-dione (3.52 g), palladium (II) acetate (111 mg), 1 ,1'-bis(diphenylphosphino)-ferrocene (554 mg), lithium chloride (1.271 g), triethylamine (6.97 mL), and methanoi (8.10 mL) in N,N- dimethylformamide (50 mL) was stirred in a Parr bomb at 100 °C under 30 psi of carbon monoxide for 3 h.
  • 5-Benzylamino-naphthalene-2-carboxylic acid methyl ester was obtained by collecting the resulting yellow solid (4.86g) and rinsing with tetrahydrofuran. Additional product (2.40 g) was obtained by washing the filtrate with water, concentrating and triturating the residue with diethyl ether.
  • the filter plug was extracted with ethyl acetate/methanol (10:1). These extracts were combined and washed with saturated aqueous sodium bicarbonate. Precipitated solids were drawn off with the aqueous layer. The pH of the filtrate was then adjusted to a value of ca. 8 with 1 M aqueous sodium hydroxide solution, and the resulting cloudy mixture was extracted with ethyl acetate. The extracts were combined with those from the filter plug, dried (magnesium sulfate), and concentrated to afford the title compound (1.62 g).
  • Diisobutylaluminum hydride (4 mL, 1.5 M in toluene) was added dropwise under nitrogen to a solution of methyl (2S)-2-(fetf-butoxycarbonyl)[(2R)-2-[tetf- butyl(dimethyl)silyl]oxy-2-(3-chlorophenyl)ethyl]aminopropanoate (1.28 g) in toluene (20 mL) at -78 °C. The resulting colorless solution was stirred at this temperature for 90 min, before a saturated aqueous solution of Rochelle's salt (20 mL) was added dropwise.
  • the resulting mixture was allowed to warm to room temperature, and was then filtered through celite, rinsing with water (50 mL) and ethyl acetate.
  • the filtrate was separated into its two layers, and the aqueous layer was extracted with ethyl acetate.
  • the extracts were combined with the organic layer of the filtrate, washed with saturated aqueous sodium chloride solution (20 mL), dried (magnesium sulfate), and concentrated to afford the title compound as a colorless oil (1.08 g).
  • Methyl 6-amino-2-naphthoate (201 mg) was dissolved in a 0.14 M solution of ⁇ 2R- (tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)-ethyl]- aminojpropionaldehyde in 1 ,2-dichloroethane (12.0 mL) under nitrogen.
  • Acetic acid 87 ⁇ L
  • 4 A molsieves (4 beads) were added, and the mixture was stirred for 25 min.
  • the mixture was extracted with toluene, and the organic layer was dried (magnesium sulfate) and concentrated to a dark oil, which was purified by chromatography on silica gel with chloroform:methanol:water (60:30:4) to give the blocked compound as an oil (0.105g).
  • the oil was dissolved in 1 , 4- dioxane (4mL) and 4N hydrochloric acid was added. The resulting mixture was stirred at room temperature for 18 hours. It was then neutralized with ammonium hydroxide and concentrated.
  • Tablets may be prepared by the normal methods such as direct compression or wet granulation.
  • the tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques.
  • suitable film forming materials such as hydroxypropyl methylcellulose, using standard techniques.
  • the tablets may be sugar coated.
  • Compression weight 90.0 * of a grade suitable for direct compression The active ingredient is passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmeliose sodium and magnesium stearate. The resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 5.5mm, flat bevelled edge punches. mg/tablet
  • the active ingredient is passed through a 60 mesh sieve, and blended with the lactose, pregelatinised starch and magnesium stearate.
  • the resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 7.5mm normal concave punches.
  • This may be either a sucrose or sucrose free presentation.
  • the active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.
  • the hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation.
  • the resultant solufion is adjusted to volume and mixed.
  • the syrup is clarified by filtration.
  • the active ingredient is dissolved in a suitable volume of Sodium Chloride Injection BP, the pH of the resultant solution is adjusted to pH3.5 with dilute hydrochloric acid BP then the solution is made to volume with sodium chloride injection BP and thoroughly mixed.
  • the solution is filled into Type I clear glass 5ml ampoules which are sealed under a headspace of air, by fusion of the glass then sterilised by autoclaving at 120 ⁇ for not less than 15 minutes.
  • Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient.
  • suitable buffer salts may be used.
  • the solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass.
  • the injection is sterilised by heating in an autoclave using one of the acceptable cycles.
  • the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.
  • the solufion may be packed under an inert atmosphere of nitrogen or other suitable gas.
  • a suspension of the active ingredient in molten Witepsol is prepared and filled using suitable machinery, into 1g size suppository moulds.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule (I) dans laquelle les groupes N(R?3) et R4¿ sont séparés par au moins 4 atomes de carbone de noyau; R1 représente un groupe phényle, naphtyle, phénoxyméthyle, thiazolyle, pyridyle ou pyrimidyle éventuellement substitué par un ou plusieurs substituants sélectionnés dans halogène, hydroxy, alkoxy C¿1?-C6, alkyle C1-C6, nitro, cyano, hydroxyméthyle, trifluorométhyle, NR?6R7¿ et NHSO2R6; R2 représente hydrogène ou alkyle C¿1?-C6; R?3¿ représente hydrogène ou alkyle C¿1?-C4; R?4¿ représente CO¿2R?6 ou SO¿3H; R?5 représente un ou plusieurs groupes indépendamment sélectionnés dans hydrogène, alkyle C¿1?-C6, halogène, trifluorométhyle et alkoxy C1-C6; n représente un entier de 1 à 6; R?6 et R7¿ indépendamment représentent hydrogène ou alkyle C¿1?-C4; ou leurs dérivés acceptables sur le plan pharmaceutique, des procédés servant à les préparer, ainsi que leur utilisation afin de traiter des états susceptibles d'être améliorés par un agoniste atypique de bêta-adrénorécepteur.
PCT/EP1998/001845 1997-04-02 1998-03-31 Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur WO1998043953A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72125/98A AU7212598A (en) 1997-04-02 1998-03-31 Naphthalenesulphonic or carboxylic acids and their use as atypical beta-adrenoceptor agonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9706707.8 1997-04-02
GBGB9706707.8A GB9706707D0 (en) 1997-04-02 1997-04-02 Chemical compounds

Publications (1)

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WO1998043953A1 true WO1998043953A1 (fr) 1998-10-08

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PCT/EP1998/001845 WO1998043953A1 (fr) 1997-04-02 1998-03-31 Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur

Country Status (7)

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AR (1) AR012209A1 (fr)
AU (1) AU7212598A (fr)
GB (1) GB9706707D0 (fr)
HR (1) HRP980171A2 (fr)
MA (1) MA26478A1 (fr)
PE (1) PE62299A1 (fr)
WO (1) WO1998043953A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006527290A (ja) * 2003-06-11 2006-11-30 ビーエーエスエフ　アクチェンゲゼルシャフト 結晶化調節剤としてのキナルジン誘導体およびナフタリン誘導体の使用
US7705028B2 (en) 2005-12-19 2010-04-27 Glaxosmithkline Llc Farnesoid X receptor agonists
US20180261886A1 (en) * 2015-09-21 2018-09-13 Commissariat A L'energie Atomique Et Aux Energies Alternatives Electrolyte for electrochemical generator

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0543662A2 (fr) * 1991-11-20 1993-05-26 Sankyo Company Limited Dérivés d'aminoalcohol aromatique avec propriétés antidiabétiques et antiobésité, leur préparation et utilisation thérapeutique
WO1995001170A2 (fr) * 1993-07-01 1995-01-12 Glaxo Group Limited Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux
WO1995033724A1 (fr) * 1994-06-09 1995-12-14 Glaxo Group Limited Derives phenethanolamine et leur utilisation en tant qu'agonistes atypiques du recepteur adrenergique beta

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0543662A2 (fr) * 1991-11-20 1993-05-26 Sankyo Company Limited Dérivés d'aminoalcohol aromatique avec propriétés antidiabétiques et antiobésité, leur préparation et utilisation thérapeutique
WO1995001170A2 (fr) * 1993-07-01 1995-01-12 Glaxo Group Limited Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux
WO1995033724A1 (fr) * 1994-06-09 1995-12-14 Glaxo Group Limited Derives phenethanolamine et leur utilisation en tant qu'agonistes atypiques du recepteur adrenergique beta

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006527290A (ja) * 2003-06-11 2006-11-30 ビーエーエスエフ　アクチェンゲゼルシャフト 結晶化調節剤としてのキナルジン誘導体およびナフタリン誘導体の使用
JP4790604B2 (ja) * 2003-06-11 2011-10-12 ビーエーエスエフ ソシエタス・ヨーロピア 結晶化調節剤としてのキナルジン誘導体およびナフタリン誘導体の使用
US7705028B2 (en) 2005-12-19 2010-04-27 Glaxosmithkline Llc Farnesoid X receptor agonists
US8158665B2 (en) 2005-12-19 2012-04-17 Glaxosmithkline Llc Farnesoid X receptor agonists
US20180261886A1 (en) * 2015-09-21 2018-09-13 Commissariat A L'energie Atomique Et Aux Energies Alternatives Electrolyte for electrochemical generator
US10833368B2 (en) * 2015-09-21 2020-11-10 Commissariat A L'energie Atomique Et Aux Energies Alternatives Electrolyte for electrochemical generator

Also Published As

Publication number Publication date
MA26478A1 (fr) 2004-12-20
AU7212598A (en) 1998-10-22
GB9706707D0 (en) 1997-05-21
PE62299A1 (es) 1999-07-07
HRP980171A2 (en) 1998-12-31
AR012209A1 (es) 2000-09-27

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