WO1995007909A1 - Carboxylates d'alkyl-1-alkyl-4-hydroxy-2-oxo-1,8-naphtyridine-3 en tant qu'agents antirhumatismaux - Google Patents

Carboxylates d'alkyl-1-alkyl-4-hydroxy-2-oxo-1,8-naphtyridine-3 en tant qu'agents antirhumatismaux Download PDF

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Publication number
WO1995007909A1
WO1995007909A1 PCT/EP1994/002993 EP9402993W WO9507909A1 WO 1995007909 A1 WO1995007909 A1 WO 1995007909A1 EP 9402993 W EP9402993 W EP 9402993W WO 9507909 A1 WO9507909 A1 WO 9507909A1
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formula
compound
group
previously defined
compounds
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Bernard John Armitage
Julie Carolyn Gill
Bruce William Leslie
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Abbott GmbH and Co KG
Boots Co PLC
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Knoll GmbH
Boots Co PLC
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Priority to AU76950/94A priority Critical patent/AU7695094A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to therapeutic agents and, in particular, to substituted alkyl l-alkyl-4- hydroxy-2-oxo-l, 8-naphthyridine-3-carboxylates, to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic activity as anti-rheumatic agents.
  • Rheumatoid arthritis is currently treated with anti-inflammatory agents, which alleviate the symptoms but do not affect the progression of the condition, or with disease-modifying antirheumatic drugs e.g. gold compounds, D-penicillamine, sulphasalazine, azathioprine and methotrexate.
  • disease-modifying antirheumatic drugs e.g. gold compounds, D-penicillamine, sulphasalazine, azathioprine and methotrexate.
  • most disease-modifying antirheumatic drugs are associated with side-effects, often of a serious nature. This means that such drugs are often only used as a last resort in the most serious cases. Consequently a need exists for a less toxic, disease-modifying, antirheumatic drug which may be administered orally.
  • EP 452,873 discloses the use of substituted 1-aryl- 1, 8-naphthyridine-3-carboxamides of formula A
  • R- j _ represents an alkyl group (optionally substituted) , an alkenyl group or an aryl group
  • R2 represents hydrogen, an alkyl group (optionally substituted) or an aryl group
  • R3 represents hydrogen or an acyl group, which allegedly possess analgesic, antiinflammatory, central nervous system depressant and diuretic effects.
  • R- j _ represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl etc;
  • R2 represents hydrogen, a C ⁇ - / _ alkyl group, a C3_g alkenyl group or a C _g alkynyl group;
  • R3 and R4 independently represent hydrogen or a C- [ __4 alkyl group and/or salts thereof.
  • Ethyl 4-hydroxy-l, 7- dimethyl -2-oxo-l, 2 -dihydro- 1 , 8 -naphthyridine-3 - carboxylate is one of fourteen compounds specifically exemplified. The use of these compounds as anti ⁇ allergic agents is also disclosed. There is no suggestion in this document that the compounds have any anti-rheumatic activity.
  • US 4,215,123 discloses a method of treating peptic ulcers comprising the administration of a compound of formula D
  • R- j _ represents hydrogen, a C- ] __g alkyl group, a C- j _g aralkyl group etc;
  • R 2 represents hydrogen, a C 2 _7 alkoxycarbonyl group, carboxy, carbamoyl, c 2-7 N " alkylcarbamoyl etc;
  • R 4 is hydrogen or a C ⁇ _ alkyl group and R 5 and Rg are independently hydrogen or a C ⁇ _g alkyl group or alkali metal salts thereof.
  • Ethyl 4-hydroxy- 1, 7-dimethyl-2-oxo-1, 2-dihydro-l, 8-naphthyridine-3- carboxylate and ethyl l-ethyl-4-hydroxy-2-oxo-l,2- dihydro-1,8-naphthyridine-3-carboxylate are specifically exemplified. There is no suggestion in this document that the compounds have any anti-rheumatic activity. In addition ethyl 4-hydroxy-l-methyl-2-oxo-l,2-dihydro-l, 8- naphthyridine-3-carboxylate is disclosed without any pharmacological activity in J. Med. Chem. 1987, 30, 2270, in which the structure activity relationships of these compounds are discussed.
  • the present invention provides compounds of formula I
  • R ⁇ _ represents a C- ] __g alkyl group optionally substituted by one or more hydroxy groups
  • R 2 represents a C 2 _g alkoxycarbonyl group
  • R3, R ⁇ and R5 independently represent hydrogen, halo, a halogenated C- j __g alkyl group in which at least one halogen atom is attached to the carbon atom which is attached to the naphthyridine ring, or a halogenated c l-6 a l ⁇ - o ⁇ y group in which at least one halogen atom is attached to the carbon atom which is attached to the oxygen atom of the alkoxy group; provided that at least one of R3, R4 and R5 represents a group other than hydrogen.
  • a group containing a chain of 3 or more carbon atoms may be straight or branched, for example, propyl includes n-propyl and isopropyl and butyl includes n-butyl, sec-butyl, isobutyl and tert-butyl.
  • the total number of carbon atoms is specified for certain substituents, for example 2 _ alkoxycarbonyl refers to an alkoxycarbonyl group having from two to six carbon atoms.
  • the term "halo" covers fluoro, chloro or bromo.
  • a compound of formula I will generally exist in equilibrium with its other tautomeric forms. It is to be understood that all tautomeric forms of the compounds of formula I, as well as mixtures thereof, are included within the scope of the present invention.
  • R ] _ represents a C 1-4 alkyl group optionally substituted by one or more hydroxy groups (for example R- j _ represents methyl, ethyl, propyl, butyl, hydroxymethyl, 2- hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl) ;
  • R 2 represents a C 2 _g alkoxycarbonyl group (for example ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentoxycarbonyl) ;
  • R represents halo (for example bromo, chloro or fluoro) , a perhalo - ] __ 4 alkyl group (for example trifluoromethyl or pentafluoroethyl) or a perhalo C --. alkoxy group (for example trifluoromethoxy or pentafluoroethoxy) .
  • _ represents methyl, 2-hydroxyethyl or propyl. More preferably R represents methyl.
  • R 2 represents a 2 _ alkoxycarbonyl group. More preferably R represents ethoxycarbonyl.
  • R3 represents fluoro, chloro or bromo. More preferably R represents chloro or fluoro. Most preferably R3 represents chloro.
  • Another preferred group of compounds of formula I is represented by formula II in which, R- j _ represents a c l-6 a l ⁇ l group; R 2 represents a C 2 _g alkoxycarbonyl group; and R3 represents halo.
  • a compound of formula I or a salt thereof contains a single chiral centre (for example when R- ⁇ represents sec-butyl) it may exist in two enantiomeric forms .
  • the present invention includes individual enantiomers and mixtures of those enantiomers. The enantiomers may be obtained by methods known to those skilled in the art.
  • Such methods typically include resolution via formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; resolution via formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer by reaction with an enantiomer-specific reagent, for example, enzymatic esterification, oxidation or reduction, followed 'by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of formula I or a salt thereof contains more than one chiral centre it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example, chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of formula I or II and mixtures thereof.
  • Some compounds of formula I may exist in the form of solvates, for example, hydrates, which also fall within the scope of the present invention.
  • the compounds of formula I may form organic or inorganic salts, for example, the compounds of formula I may form acid addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulphuric acid, hydriodic acid, maleic acid, acetic acid, succinic acid, benzoic acid, pamoic acid, palmitic acid, dodecanoic acid and acidic amino acids such as glutamic acid.
  • Some compounds of formula I may form base addition salts, for example, with alkali metal hydroxides for example sodium hydroxide, with aminoacids for example, lysine or arginine or with organic bases, for example meglumine.
  • salts may be used in therapy in place of the corresponding compounds of formula I.
  • Such salts are prepared by reacting the compound of formula I with a suitable acid or base in a conventional manner.
  • Such salts may also exist in form of solvates (for example, hydrates) .
  • Certain compounds of formula I or salts thereof may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • the present invention also provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
  • Such pharmaceutical formulations may be used in the treatment of rheumatic diseases for example rheumatoid arthritis or osteoarthritis.
  • the term "active compound” denotes a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a local and/or systemic effect.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
  • compositions of the invention may contain 0.1-99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
  • compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.
  • Tablets may be prepared from a mixture of the active compound with fillers such as lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethyl- cellulose phthalate.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
  • the tablets and capsules may conveniently each contain 0.1 to 1000 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg or 800 mg) of the active compound.
  • Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example sunflower oil.
  • the active compound may be formulated into granules with or without additional excipients.
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion.
  • the granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
  • compositions for topical administration are also preferred compositions of the invention.
  • the pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
  • a suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using surfactants.
  • An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax.
  • a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water.
  • Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with hard fat, synthetic glycerides or polyethylene glycol bases.
  • compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
  • compositions of the invention suitable for inhalation via the mouth and/or the nose are the known pharmaceutical forms for such administration, for example aerosols, nebulised solutions or powders.
  • Metered dose systems known to those skilled in the art, may be used.
  • compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwashes or rinses.
  • the compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion, or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be a) liquid such as an oily solution or suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or b) solid in the form of an implanted support for example of a synthetic resin of waxy material for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients, for example, a non-steroidal antiinflammatory agent e.g. ibuprofen, S (+) -ibuprofen, flurbiprofen or S(+)- flurbiprofen, an analgesic or an antipyretic agent.
  • a non-steroidal antiinflammatory agent e.g. ibuprofen, S (+) -ibuprofen, flurbiprofen or S(+)- flurbiprofen
  • analgesic e.g. a non-steroidal antiinflammatory agent
  • analgesic or an antipyretic agent e.g. ibuprofen, S (+) -ibuprofen, flurbiprofen or S(+)- flurbiprofen
  • the compounds of formula I and pharmaceutically acceptable salts thereof are indicated for use as medicaments.
  • compounds of formula I are indicated for use as anti-rheumatic agents by their activity demonstrated by means of tests on standard laboratory animals. Such tests include, for example, the oral administration of compounds of formula I to mice with experimental antigen-induced arthritis.
  • Compounds of formula I are suitable for use in treating rheumatic diseases for example rheumatoid arthritis, osteoarthritis, osteoporosis, crystal arthropathies (e.g. gout), reactive arthritis, ankylosing spondylitis or psoriatic arthropathy. It is believed that compounds of formula I and pharmaceutically acceptable salts thereof are disease-modifying antirheumatic agents.
  • Compounds of formula I may also be suitable for the treatment of diseases of the oral cavity for example periodontitis, gingivitis and alveolar bone resorption.
  • the present invention also includes a method of treating rheumatic diseases, particularly rheumatoid arthritis and osteo-arthritis, comprising the administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
  • Compounds of formula I may also be administered in a prophylactic manner to mammals, particularly humans who have been identified as being susceptible to arthritic diseases.
  • a suitable dose for oral administration to mammals is generally within the range 0.01-80 mg/kg/ day, more usually 0.2-40 mg/kg/day given in single or divided doses.
  • a suitable dose is generally within the range 0.001-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses or by continuous infusion.
  • a suitable preparation for topical administration generally contains the active ingredient within the range 0.01-20% by weight, more usually 0.05-5% by weight. Oral administration is preferred.
  • compositions containing, a therapeutically effective amount of a compound of formula I may be used to treat rheumatic diseases such as rheumatoid arthritis and osteoarthritis.
  • the amount of the compound of formula I administered per day is in the range 0.1 to 6000 mg.
  • R- j _, R 2 , R3, R and R5 are as previously defined and R- j _ Q represents cyano or a group of formula COR- ] _- j _ in which R- ] _- ] _ represents a leaving group, for example halo, a C- j __g alkoxy group, an aryloxy group, an arylalkoxy
  • 25 represent a saturated 3-7 membered heterocyclic ring optionally containing sulphur, oxygen or an additional nitrogen atom, wherein the ring is optionally substituted by one or more C- j __4 alkyl groups), in the presence of a base, for example sodium hydride or sodium ethoxide, in the presence of an inert organic liquid which is preferably a solvent for the compound of formula III, for example ethanol, tetrahydrofuran or N,N-dimethylformamide, at a temperature in the range -50 to 250°C, preferably in the range -15 to 150°C, optionally followed by hydrolysis when R- ⁇ Q represents cyano and optionally followed by acidification.
  • a base for example sodium hydride or sodium ethoxide
  • an inert organic liquid which is preferably a solvent for the compound of formula III, for example ethanol, tetrahydrofuran or N,N-dimethylformamide
  • R j _, R , R3, R4 and R5 are as previously defined and R ] _ represents a group of formula i n which R- is as previously defined, for example by heating, at a temperature in the range 30-250°C preferably in the presence of an inert organic liquid which is preferably a solvent for the compound of formula IV, for example N,N-dimethylformamide.
  • R 2 is as previously defined and R- j _4 represents a group of formula COR- in which R- j _ ] _ is as previously defined, for example by reacting together at a temperature in the range 0-150°C, preferably in the presence of a base, for example sodium ethoxide, in the presence of an inert organic liquid which is preferably a solvent for the reactants, for example N,N-dimethylformamide, and then heating at a temperature in the range 0-250°C, optionally followed by hydrolysis when R-
  • _o represents cyano and optionally followed by acidification.
  • R 14 is the same as group R 2 .
  • R 2 is as previously defined and represents a group of formula COR- ⁇ in which R- ⁇ is as previously defined, for example by reacting together at a temperature in the range 0-150°C, preferably in the presence of a base, for example sodium hydride, in the presence of an inert organic liquid which is preferably a solvent for the reactants, for example N,N-dimethylformamide, and then heating at a temperature in the range 0-250°C, optionally followed by acidification.
  • R- j _ is the same as group R 2 •
  • a base for example sodium hydride
  • an organic liquid which is preferably a solvent for the compound of formula IX, for example N, - dimethylformamide, at a temperature in the range 0-150°C optionally followed by acidification.
  • R- j _, R 2 , R3, R4 and R5 are as previously defined and R- [ _4 represents hydrogen, with a compound of formula Y ] _COY in which Y-
  • R 2 , R , R4 and R5 are as previously defined, with an alkylating agent of formula R- ⁇ X in which R- j _ is as previously defined and X represents a leaving group, for example chloro, bromo or iodo.
  • R- j _ is as previously defined and X represents a leaving group, for example chloro, bromo or iodo.
  • Compounds of formula III may be prepared by reacting a compound of formula V with a compound of formula VI at a temperature in the range -50 to 150°C, preferably in the presence of an organic liquid which is preferably a solvent for the compound of formula V.
  • Compounds of formula IV may be prepared by reacting a compound of formula V with a compound of formula VI in the presence of a base, for example sodium hydride or sodium ethoxide, in the presence of an organic liquid, preferably a solvent for compounds of formula V, at a temperature in the range -50 to 150°C.
  • a base for example sodium hydride or sodium ethoxide
  • an organic liquid preferably a solvent for compounds of formula V
  • Compounds of formula IV may also be prepared by reacting a compound of formula VII with a compound of formula VI in the presence of a base, for example sodium hydride or sodium ethoxide, in the presence of an organic liquid, preferably a solvent for compounds of formula V, at a temperature in the range -50 to 150°C.
  • a base for example sodium hydride or sodium ethoxide
  • an organic liquid preferably a solvent for compounds of formula V
  • R 2 is as previously defined and when n is 1 then M ⁇ represents Li or MgX, in which X represents bromo, chloro or iodo, and when n is 2 then M- j _ represents Cd, optionally in the presence of a transition metal or a transition metal salt, by methods known to those skilled in the art, optionally followed by hydrolysis when R- ⁇ Q represents cyano.
  • the therapeutic activity of the compounds of the present invention has been demonstrated by tests which , include the oral administration of the compounds to mice with experimental antigen-induced arthritis.
  • the compounds showed activity in the following test.
  • mice Female BALB/c mice, 8 weeks of age were used: each control group contained either 35, 60 or 80 mice and each test group contained either 13, 15 or 20 mice respectively.
  • the mice were sensitised by subcutaneous injection into the flank or nuchal area with an emulsion (0.1 ml) consisting of a solution of methylated bovine serum albumin (m-BSA) (0.1 mg) in sterile aqueous sodium chloride solution (0.05 ml; 0.15 M) and Freund's Complete Adjuvant (0.05 ml) containing, in total, killed Mycobacterium tuberculosis (0.075 mg) .
  • m-BSA methylated bovine serum albumin
  • each mouse was injected intraperitoneally with an aqueous suspension of heat killed Bordetella pertussis (0.05 ml; 2 x 10 y organisms). Identical injections were administered after 7 days. After a further 14 days the left knee-joint of each mouse was injected with a solution of m-BSA (0.1 mg) in aqueous sodium chloride solution (0.01 ml; 0.15 M) (intra-articular challenge). This procedure induced a chronic erosive arthritis restricted to the challenged joint.
  • test compounds were suspended in a vehicle of aqueous carboxymethyl cellulose solution (0.25% w/v) containing TWEEN®80 (1.5% w/v) at varying dosages and 0.1 ml was administered to each test mouse by gastric intubation.
  • vehicle aqueous carboxymethyl cellulose solution (0.25% w/v) containing TWEEN®80 (1.5% w/v) at varying dosages and 0.1 ml was administered to each test mouse by gastric intubation.
  • the control mice received the vehicle with no test compound.
  • Administration occurred daily for 28 days commencing 14 days after intra-articular challenge. After 42 days the test was terminated and the animals were killed using a rising concentration of carbon dioxide and the arthritic hind leg removed.
  • the femur and tibia were cut midway along their length and the knee-joint trimmed free of skin and musculature.
  • the arthritic joints were placed in perforated plastic holders and fixed in 10% formol saline for at least 48 hours. They were then decalcified in 5% formic acid for 72 hours with constant agitation (replacing the formic acid after the first 24 hours) , washed in water, dehydrated in alcohol and embedded in paraffin wax.
  • the joints were sectioned in the sagittal plane at 5 ⁇ m and stained with Van Gieson's stain. Each joint was sectioned at two levels.
  • the severity of arthritis was assessed by examination of the prepared sections. Synovitis and pannus formation were graded on a 0-5 scale, by a skilled operator, according to the degree of synovial lining cell hypertrophy and hyperplasia, infiltration of the synovium by lymphocytes, plasma cells, monocytes/macrophages, fibroblasts and polymorpho- nuclear (PMN) leukocytes and the degree of pannus formation. Erosions of cartilage and bone were also graded on a 0-5 scale, by a skilled operator, the score reflecting the proportion of articular surface eroded as well as the depth of the erosions. Using the combined data the drug effects were expressed as the percentage change in the mean scores for synovitis and erosions compared to those of the control group. The data were then analysed using the Mann-Whitney U-test.
  • the invention is illustrated by the following non- limitative Examples in which parts and percentages are by weight and compositions of mixed solvents are given by volume. Novel compounds were characterised by elemental analysis and one or more of the following spectroscopic techniques: nuclear magnetic resonance, infra-red and mass spectroscopy.
  • IMS industrial methylated spirit
  • DMF N,N- dimethylformamide
  • Active 3/3 at 30 mg/kg; Active 2/2 at 10 mg/kg; Active 2/3 at 3 mg/kg.
  • Ethyl 6-chloro-4-hydroxy-l-methyl-2-oxo-1 , 2- dihydro-1, 8-naphthyridine-3-carboxylate was also prepared by reacting ethyl malonyl chloride (2.41 g) with ethyl 5-chloro-2- (methylamino)nicotinate (3.43 g) in ether (150 ml) containing triethylamine (1.62 g) in a similar manner to Example 1 and then dissolving the residue, obtained after work-up, in ethanol (40 ml) and then adding this solution to a solution of sodium (1.30 g) in ethanol (100 ml) at ambient temperature and then working up as in Example 1 after stirring for 1 hour at ambient temperature.
  • Examples 2-4 were prepared in a similar manner to
  • Example 1 by reacting a compound of formula V, in which
  • R and R5 each represent hydrogen and R- R and R-J_Q are as given in Table 1, with ethyl malonyl chloride (VI), as summarised in Table 1.
  • Et ethyl
  • S solvent
  • a diethyl ether
  • b dichloromethane
  • Vol volume
  • EMC ethyl malonyl chloride
  • Wt weight
  • the dichloromethane layer was separated and the aqueous layer extracted with dichloromethane.
  • the combined dichloromethane layers were evaporated to give ethyl 5-chloro-2- (methylamino) nicotinate, m.p. 80-81°C (after recrystallisation from ethanol) .
  • method 3 may be employed for converting the acid into the ester.
  • Tablets are prepared from the following ingredients .
  • Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with magnesium stearate and the rest of the starch. The mixture is then compressed in a tableting machine to give tablets containing 10 mg of active compound.
  • Tablets are prepared by the method of the previous Example.
  • the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1).
  • suppositories 100 parts by weight of active compound is incorporated in 1300 parts by weight of semi-synthetic glycerides as the suppository base and the mixture formed into suppositories each containing 100 mg of active ingredient.
  • Example Z In the preparation of capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 50 mg of active ingredient.
  • Example Z In the preparation of capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 50 mg of active ingredient.
  • Example Z Example Z
  • the active compound is incorporated into the base by thorough homogenization until the drug is evenly distributed.
  • the ointment is packed into 10 g amber jars with screw-capped lined lids.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de formule (I) ainsi qu'à leurs sels acceptables sur le plan pharmaceutique. Dans cette formule, R1 représente un groupe alkyle C1-6 substitué le cas échéant par un ou plusieurs groupes hydroxy; R2 représente un groupe alcoxycarbonyle C2-6; et R3, R4 et R5 représentent indépendamment hydrogène, halo, un groupe alkyle C1-6 halogéné dans lequel au moins un atome d'halogène est attaché à l'atome de carbone, lequel est attaché au noyau naphtyridine, ou un groupe alcoxy C1-6 halogéné dans lequel au moins un atome d'halogène est attaché à l'atome de carbone, lequel est attaché à l'atome d'oxygène du groupe alcoxy; à condition qu'au moins un des R3, R4 et R5 représente un groupe autre qu'hydrogène. Les composés de l'invention sont des agents antirhumatismaux. L'invention se rapporte également aux compositions contenant ces composés ainsi qu'aux procédés de production de ceux-ci.
PCT/EP1994/002993 1993-09-14 1994-09-07 Carboxylates d'alkyl-1-alkyl-4-hydroxy-2-oxo-1,8-naphtyridine-3 en tant qu'agents antirhumatismaux Ceased WO1995007909A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76950/94A AU7695094A (en) 1993-09-14 1994-09-07 Alkyl-1-alkyl-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylat es as anti-rheumatic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939318931A GB9318931D0 (en) 1993-09-14 1993-09-14 Therapeutic agents
GB9318931.4 1993-09-14

Publications (1)

Publication Number Publication Date
WO1995007909A1 true WO1995007909A1 (fr) 1995-03-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002993 Ceased WO1995007909A1 (fr) 1993-09-14 1994-09-07 Carboxylates d'alkyl-1-alkyl-4-hydroxy-2-oxo-1,8-naphtyridine-3 en tant qu'agents antirhumatismaux

Country Status (5)

Country Link
AU (1) AU7695094A (fr)
GB (1) GB9318931D0 (fr)
IL (1) IL110862A0 (fr)
WO (1) WO1995007909A1 (fr)
ZA (1) ZA947044B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011199A1 (fr) * 1994-10-06 1996-04-18 Knoll Aktiengesellschaft Derives de naphtyridinone
WO1996011198A1 (fr) * 1994-10-06 1996-04-18 Knoll Aktiengesellschaft Derives de naphtyridine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128649A (en) * 1977-06-29 1978-12-05 Sandoz, Inc. 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters
US4215123A (en) * 1979-05-07 1980-07-29 American Home Products Corporation Antisecretory 4-oxy-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives
EP0018735A1 (fr) * 1979-04-18 1980-11-12 American Home Products Corporation Dérivés de la 1,8-naphtyridine, leur préparation, compositions pharmaceutiques les contenant
EP0452873A1 (fr) * 1990-04-16 1991-10-23 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 2-oxo-(1,8-naphtyridine)
WO1993013097A1 (fr) * 1991-12-23 1993-07-08 The Boots Company Plc Derives de naphtyridine antirhumatismaux

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128649A (en) * 1977-06-29 1978-12-05 Sandoz, Inc. 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters
EP0018735A1 (fr) * 1979-04-18 1980-11-12 American Home Products Corporation Dérivés de la 1,8-naphtyridine, leur préparation, compositions pharmaceutiques les contenant
US4215123A (en) * 1979-05-07 1980-07-29 American Home Products Corporation Antisecretory 4-oxy-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives
EP0452873A1 (fr) * 1990-04-16 1991-10-23 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 2-oxo-(1,8-naphtyridine)
JPH04217981A (ja) * 1990-04-16 1992-08-07 Kyowa Hakko Kogyo Co Ltd １，８−ナフチリジン−２−オン誘導体
WO1993013097A1 (fr) * 1991-12-23 1993-07-08 The Boots Company Plc Derives de naphtyridine antirhumatismaux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 16, no. 560 (C - 1008) 2 December 1992 (1992-12-02) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011199A1 (fr) * 1994-10-06 1996-04-18 Knoll Aktiengesellschaft Derives de naphtyridinone
WO1996011198A1 (fr) * 1994-10-06 1996-04-18 Knoll Aktiengesellschaft Derives de naphtyridine
US5712286A (en) * 1994-10-06 1998-01-27 Knoll Aktiengesellschaft Naphthyridine derivatives
US5854257A (en) * 1994-10-06 1998-12-29 Knoll Aktiengesellschaft Naphthyridinone derivatives

Also Published As

Publication number Publication date
IL110862A0 (en) 1995-01-24
ZA947044B (en) 1995-03-14
AU7695094A (en) 1995-04-03
GB9318931D0 (en) 1993-10-27

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