WO1995007909A1 - Alkyl-1-alkyl-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylates as anti-rheumatic agents - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof in which R1 represents a C1-6 alkyl group optionally substituted by one or more hydroxy groups; R2 represents a C2-6 alkoxycarbonyl group; and R3, R4 and R5 independently represent hydrogen, halo, a halogenated C1-6 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 C1-6 alkoxy 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; are disclosed, which are antirheumatic agents. Compositions containing these compounds and processes to make them are also disclosed.

Description

Al yl-l-a1kyl-4-hydroxy-2-oxo-l,8-naphthyr1d1ne-3-carboxylates as ant1-rheumatic agents

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. However, 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

in which X represents hydrogen, a ^.g alkyl group, aralkyl, aryl, an aromatic heterocyclic group etc. and Y represents a single bond or alkylene, as antiinflammatory agents which are useful in the treatment of rheumatoid arthritis. Japanese Patent Application 52-116495 (1977) discloses compounds of formula B

in which 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 and R3 represents hydrogen or an acyl group, which allegedly possess analgesic, antiinflammatory, central nervous system depressant and diuretic effects. There is no suggestion in this document that the compounds have any disease-modifying anti-rheumatic activity.

US 4,128,649 discloses compounds of formula C

wherein 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

wherein R-_j_ represents hydrogen, a C-_]__g alkyl group, a C-_j _g aralkyl group etc; R₂ represents hydrogen, a C₂_7 alkoxycarbonyl group, carboxy, carbamoyl, ^c2-7 ^N" alkylcarbamoyl etc; R₄ is hydrogen or a C^_ alkyl group and R₅ 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

and pharmaceutically acceptable salts thereof in which R→_ represents a C-_]__g alkyl group optionally substituted by one or more hydroxy groups;

R₂ represents a C₂_g alkoxycarbonyl group; and

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 ^cl-6 ^al^-^oχy 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.

It will be understood that 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.

A preferred group of compounds of formula I is represented by formula II

R-

and pharmaceutically acceptable salts thereof in which 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) ;

R₂ represents a C₂_g alkoxycarbonyl group (for example ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentoxycarbonyl) ; and

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) .

Preferably R-_|_ represents methyl, 2-hydroxyethyl or propyl. More preferably R represents methyl.

Preferably R₂ represents a ₂_ alkoxycarbonyl group. More preferably R represents ethoxycarbonyl.

Preferably 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 ^cl-6 ^al^ l group; R₂ represents a C₂_g alkoxycarbonyl group; and R3 represents halo.

Specific compounds of formula I are:

ethyl 6-chloro-4-hydroxy-l-methyl-2-oxo-l, 2-dihydro-l, 8 naphthyridine-3-carboxylate; ethyl 6-fluoro-4-hydroxy-l-methyl-2-oxo-l, 2-dihydro-l, 8- naphthyridine-3-carboxylate; ethyl 6-chloro-4-hydroxy-l- (2-hydroxyethyl) -2-oxo-l, 2- dihydro-1, 8-naphthyridine-3-carboxylate; and ethyl 6-chloro-4-hydroxy-2-oxo-l-propyl-1, 2-dihydro-l, 8- naphthyridine-3-carboxylate;

and pharmaceutically acceptable salts thereof

When 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. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation processes described above, at least one further step will subsequently be required to liberate the desired enantiomeric form. Alternatively, specific 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.

When 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. It will be appreciated that such salts, provided they are pharmaceutically acceptable 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.

As used hereinafter, the term "active compound" denotes a compound of formula I or a pharmaceutically acceptable salt thereof. In therapeutic use, 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. Thus 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. The 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.

Similarly, 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.

In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.

In the compositions of the present invention 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.

The compounds of formula I and pharmaceutically acceptable salts thereof are indicated for use as medicaments. In particular 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.

Accordingly, in a further aspect, 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.

Whilst the precise amount of active compound administered will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history and always lies within the sound discretion of the administering physician, a suitable dose for oral administration to mammals, including humans, 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. For parenteral administration, 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.

The pharmaceutical 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. In such treatment the amount of the compound of formula I administered per day is in the range 0.1 to 6000 mg.

In yet another aspect, the present invention

5 provides the use of a compound of formula I in the manufacture of a medicament for use in the treatment of a rheumatic disease such as rheumatoid arthritis and osteoarthritis.

Processes for the preparation of compounds of

10 formula I will now be described. These processes form a further aspect of the present invention. The processes listed are preferably carried out at atmospheric pressure unless otherwise stated.

Compounds of formula I may be prepared by cyclising 15 a compound of formula III

in which R-_j_, R₂, 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

20. group, a ^cl-6 alkanoyloxy group, a (^1-6 alkoxy)carbonyloxy group, an amino group of formula ^NR12^R13 ^^{n w}hich ^Ri2 ^an^ R]_3 independently represent hydrogen or a C_]__ alkyl group or R-_j_ and R-_j_3 together with the nitrogen atom to which they are attached

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.

Compounds of formula I may be prepared by cyclising a compound of formula IV

in which R-_j_, R , R3, R4 and R5 are as previously defined and R_]_ represents a group of formula

iⁿ 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.

Compounds of formula I may be prepared by condensing a compound of formula V

in which R_l7 R3, R4, R₅ and R-J__Q are as defined previously with a compound of formula VI

^R2^CH2^R14 VI

in which R₂ 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. Preferably R₁₄ is the same as group R₂.

Compounds of formula I may be prepared by reacting a compound of formula VII

R-

in which R-^, R3, R4 and R5 are as previously defined with a compound of formula VI R₂CH₂R₁ VI

in which R₂ 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. Preferably R-_j_ is the same as group R₂ •

Compounds of formula I may be prepared by cyclising a compound of formula IX

in which

are as previously defined, optionally in the presence of a base, for example sodium hydride, preferably in the presence of 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.

Compounds of formula I may be prepared by reacting a compound of formula IX

in which R-_j_, R₂, R3, R4 and R5 are as previously defined and R-_[_4 represents hydrogen, with a compound of formula Y_]_COY in which Y-_|_ represents halo, alkoxy (optionally substituted by halo) , aryloxy, arylalkoxy, cyano or a group of formula ^NR15^R16 (in which R-^ and R 16 independently represent a C-^.g alkyl group or R-^ and R-_j_g together with the nitrogen atom to which they are attached represent a saturated 3-7 membered heterocyclic ring) and Y₂ represents halo, alkoxy (optionally substituted by halo) , aryloxy or arylalkoxy, for example Y-_]_COY₂ is ethyl chloroformate or diethyl carbonate, optionally in the presence of a base, for example sodium hydride or triethylamine, preferably in the presence of an inert organic liquid which is preferably a solvent for the compound of formula IX, for example N,N- dimethylformamide, at a temperature in the range 0-150°C.

Compounds of formula I may be prepared by reacting a compound of formula XII

in which R₂, 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. It will be appreciated by those skilled in the art that an O- alkylated or an ,0,N-dialkylated product may be obtained in this process from which the desired compound may be obtained by chromatography. The undesired __\, ]_{- dialkylated product may be converted into the N- alkylated product by methods known to those skilled in the art, e.g. by hydrolysis. Alternatively the 0- alkylated product may be converted into the N-alkylated product by heating.

Compounds of formula II may be prepared by methods analogous to those described for the preparation of compounds of formula I.

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.

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. Compounds of formulae V, VI, and VII may be prepared by methods known to those skilled in the art.

Compounds of formula IX may be prepared by reacting a compound of formula X

^Rl

in which R-_j_, 3 R4 R5, R_]_g and R→^^ are as defined previously with a compound of formula XI

<^R2^CH2>n^Ml ^XI

in which R₂ 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.

Compounds of formula X and XI may be prepared by methods known to those skilled in the art. For example, compounds of formula X may be prepared from compounds of formula V.

Compounds of formula XII may be prepared by methods analogous to those described for the preparation of compounds of formula I by reaction of compounds of formulae III, IV, V, VII and IX in which R-_j_ represents

^' hydrogen. Certain intermediate compounds of formulae III, IV,

V, VII, IX, X and XII are believed to be novel. All novel compounds herein form a further aspect of the invention.

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.

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) . Simultaneously 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.

The 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. 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 μm 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.

Those compounds which induced a statistically significant suppression of erosions or synovitis at a dosage of 100 mg/kg or below were deemed to be active. The results obtained are given in the Examples. Preferred compounds induce a statistically significant suppression of erosions.

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.

In the Examples the following abbreviations are used: IMS = industrial methylated spirit and DMF = N,N- dimethylformamide.

Unless otherwise stated, the starting materials used in the Examples are commercially available and may be obtained by reference to the Fine Chemicals Directory.

EXAMPLE 1

Ethyl malonyl chloride (21.45 g) was added dropwise with stirring to a mixture of methyl 5-chloro-2-

(methylamino)nicotinate (27.3 g) in diethyl ether (1 1) and triethylamine (14.4 g) . The mixture was stirred for

17 hours at ambient temperature. Diethyl ether (500 ml) was added and the mixture was stirred for a further 2 hours and then filtered. The filtrate was evaporated to dryness and the residue was dissolved in ethanol

(200 ml) with warming. This ethanolic solution was added to a solution of sodium (6.6 g) dissolved in ethanol (500 ml) . The mixture was stirred for 2 hours at ambient temperature, diluted with water (1250 ml) and acidified to pH 1 with concentrated hydrochloric acid.

This mixture was stirred for 1 hour and then filtered. The residue was washed with water, dried and recrystallised from ethyl acetate/petroleum ether, b.p. 40-60°C to give ethyl 6-chloro-4-hydroxy-l-methyl-2-oxo- 1, 2-dihydro-1, 8-naphthyridine-3-carboxylate, m.p. 134- 137°C.

Active 3/3 at 30 mg/kg; Active 2/2 at 10 mg/kg; Active 2/3 at 3 mg/kg.

EXAMPLE IA

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

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. TABLE 1

Et = ethyl; S = solvent; a = diethyl ether; b = dichloromethane; Vol = volume; EMC = ethyl malonyl chloride; Wt = weight

EXAMPLE 2

Ethyl 6-fluoro-4-hydroxy-l-methyl-2-oxo-l,2-dihydro-l, 8- naphthyridine-3-carboxylate, .p. 117-119°C.

Active 1/3 at 30 mg/kg; Active 2/2 at 10 mg/kg.

EXAMPLE 3

Ethyl 6-chloro-4-hydroxy-l- (2-hydroxyethyl) -2-oxo-l,2- dihydro-1,8-naphthyridine-3-carboxylate, m.p. 171-172°C (after recrystallisation from ethyl acetate) .

Weakly active 1/1 at 30 mg/kg.

EXAMPLE 4

Ethyl 6-chloro-4-hydroxy-2-oxo-l-propyl-l,2-dihydro-l, 8- naphthyridine-3-carboxylate, m.p. 139-142°C (after trituration with petroleum ether b.p. 40-60°C.

Weakly active 1/1 at 30 mg/kg.

PREPARATION OF STARTING MATERIALS

METHOD 1

a) 5-Chloro-2-hydroxynicotinic acid (m.p. 257-260°C) was prepared by chlorination of 2-hydroxynicotinic acid using sodium hypochlorite solution as described in Synthetic Communications .19., p 553 (1989) .

b) Thionyl chloride (10 ml) was added dropwise over 30 minutes to 5-chloro-2-hydroxynicotinic acid (2.0 g) with stirring. DMF (0.6 ml) was then added dropwise and the mixture was boiled under reflux for 2 hours. After cooling, excess thionyl chloride was removed under reduced pressure and the residue was cooled in an ice bath with stirring while water (20 ml) was added dropwise over 10 minutes. The mixture was stirred for a further 30 minutes and then filtered to give 2,5- dichloronicotinic acid, m.p. 148-152°C.

c) A mixture of 2, 5-dichloronicotinic acid (15.0 g) and 33% methylamine in ethanol (50 ml) was heated at 100°C in a pressure vessel for 7 hours and then cooled and evaporated to dryness. The residue was dissolved in water and acidified to pH 3 with concentrated hydrochloric acid. The mixture was filtered and the solid obtained was triturated with dichloromethane and then filtered to give 5-chloro-2- (methylamino)nicotinic acid, m.p. 277-280°C (after recrystallisation from IMS) .

d) A mixture of the amino acid from c) (8.98 g) and saturated ethanolic hydrogen chloride (200 ml) was boiled under reflux while distilling the solvent through an extraction thimble containing molecular sieves. After two days approximately 150 ml of solvent was distilled off and replaced with fresh ethanolic hydrogen chloride. The molecular sieves were also replaced with fresh molecular sieves. The mixture was boiled under reflux for 24 hours, then cooled to give a gelatinous mixture which was filtered. The filtrate was evaporated to dryness, and the residue diluted with water and poured into a solution of potassium carbonate (29 g) in water (200 ml) . The mixture was extracted with dichloromethane and filtered. 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 2

a) A mixture of 2-chloronicotinic acid (120 g) and 33% methylamine in ethanol (400 ml) was heated at 100°C in a pressure vessel with stirring for 18 hours. The mixture was cooled and diluted with water (250 ml) . The ethanol was removed under reduced pressure and aqueous residue was filtered. The filtrate was acidified to pH 5 with concentrated hydrochloric acid and then filtered to produce a solid. The solid was collected by filtration and recrystallised from IMS to give 2-

(methylamino) icotinic acid hemihydrochloride hemihydrate, m.p. 240-242°C.

b) 2- (Methylamino)nicotinic acid hemihydrochloride hemihydrate (87.97 g) was added to glacial acetic acid

(3.5 1) and the mixture stirred at ambient temperature.

Chlorine gas was bubbled through the mixture for 90 minutes until the mixture was saturated. The mixture was stirred for 5 hours at ambient temperature and left to stand for 64 hours. The mixture was filtered and the collected solid was washed with diethyl ether and dried to give 5-chloro-2- (methylamino) nicotinic acid hydrochloride, m.p. 254-258°C. c) The product from b) (78.6 g) was stirred in methanol (1 1) which was saturated with hydrogen chloride gas for 20 hours. The mixture was then boiled under reflux for 4 hours. Additional methanol (500 ml) saturated with hydrogen chloride was added and the mixture was heated under reflux with stirring for 3 days and then cooled. Hydrogen chloride gas was bubbled through the mixture until saturation was reached and the mixture was boiled under reflux for a further 24 hours and then concentrated under reduced pressure to approximately 250 ml. This residue was poured carefully into saturated potassium carbonate solution (1 1) and then additional solid potassium carbonate was added until the mixture was basic. The mixture was filtered to give a solid which was recrystallised from methanol to give methyl 5-chloro-2- (methylamino)nicotinate, m.p. 91-92°C.

METHOD 3

a) Chloroacetonitrile (4.55 g) was added dropwise with stirring at 0°C to a solution of 5-chloro-2-

(methylamino)nicotinic acid (10.0 g) and triethylamine (5.75 g) in acetone (100 ml) . The mixture was then boiled under reflux for 18 hours. The mixture was hot filtered and the filtrate evaporated to dryness to give a residue which was triturated with water and filtered to give cyanomethyl 5-chloro-2- (methylamino)nicotinate, m.p. 108-110°C.

b) The product from a) (11.4 g), triethylamine (1.0 g) and methanol (100 ml) were boiled under reflux for 6 hours. The mixture was cooled and filtered to give methyl 5-chloro-2- (methylamino)nicotinate, m.p. 91-94°C. Methyl 5-fluoro-2- (methylamino) icotinate

a) A mixture of 2-chloro-5-fluoronicotinic acid (12.31 g) [prepared as described in J. Chemical and Engineering Data, 1972, YJ_, p515] in methylamine/ethanol (55 ml, 33% solution) was heated in a pressure vessel at 100°C for 20 hours. The mixture was cooled and evaporated under reduced pressure. Water (50 ml) was added to the residue and this mixture was acidified to pH 3 with concentrated hydrochloric acid. The mixture was filtered to give 5-fluoro-2- (methylamino)nicotinic acid.

b) Chloroacetonitrile (3.35 ml) was added dropwise to a stirred mixture of 5-fluoro-2- (methylamino)nicotinic acid (8.0 g) , triethylamine (7.0 ml) and dry acetone (80 ml) at 0°C with stirring. The mixture was boiled under reflux for 18 hours and then hot filtered. The filtrate was cooled and the solvent removed under reduced pressure to give a residue which was triturated with water, then filtered and dried to give cyanomethyl 5-fluoro-2- (methylamino)nicotinate.

c) The product from b) (6.8 g) , triethylamine

(0.65 ml) and methanol (70 ml) were boiled under reflux for 6 hours. The solvent was removed under reduced pressure to give an oil which solidified on scratching. The solid was triturated with ether and filtered to give methyl 5-fluoro-2- (methylamino)nicotinate. A further crop of product was obtained by evaporating the filtrate, triturating the residue with hot petroleum ether b.p. 40-60°C and then evaporating the petroleum ether filtrate. Methyl 5-chloro-2- (2-hydroxyethylamino)nicotinate

a) A mixture of 2, 5-dichloronicotinic acid (15.07 g) and ethanolamine (30 ml) was heated in a small pressure vessel at 100°C for 18 hours. The mixture was allowed to cool and then poured into ice water and acidified with concentrated hydrochloric acid. The precipitate was collected by filtration to give 5-chloro-2- (2- hydroxyethylamino)nicotinic acid, m.p. 226-228°C.

b) A mixture of the acid from a) (14.3 g) , triethylamine (7 ml) and acetone (100 ml) was stirred at

0°C while chloroacetonitrile (4.9 ml) was added dropwise with stirring. The mixture was allowed to warm up to ambient temperature and then boiled under reflux for 18 hours. The mixture was evaporated to dryness under reduced pressure and the residue diluted with water and then extracted with ethyl acetate to give an oil which was dissolved in methanol (100 ml) and triethylamine

(1 ml) . The mixture was boiled under reflux for 5 hours, then cooled and evaporated to dryness under reduced pressure to give a residue which was triturated with water and the solid obtained was collected by filtration. The solid was stirred in dilute sodium bicarbonate solution and filtered to give methyl 5-chloro-2- (2 -hydroxyethylamino ) nicotinate, m.p. 110-112°C.

Methyl 5-chloro-2-propylaminonicotinate

a) A mixture of 2, 5-dichloronicotinic acid (15.0 g) and propylamine (30 ml) was heated at 100°C in a pressure vessel for 18 hours. The mixture was cooled and poured onto ice water. The mixture was acidified with concentrated hydrochloric acid and filtered to give 5-chloro-2-propylaminonicotinic acid dihydrochloride, m.p. 214-216°C.

b) A mixture of the acid from a) (1.55 g) and methanol

(100 ml) saturated with gaseous hydrogen chloride was boiled under reflux for 64 hours, then cooled and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate (200 ml) and washed with dilute sodium bicarbonate solution and then with water.

The solvent was removed under reduced pressure to give methyl 5-chloro-2-propylaminonicotinate as a yellow oil.

Alternatively, method 3 may be employed for converting the acid into the ester.

PHARMACEUTICAL EXAMPLES

Example U

In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 10 mg active compound.

Example V

Tablets are prepared from the following ingredients .

Parts by Weight

Active compound 10 Lactose 190

Maize starch 22

Polyvinylpyrrolidone 10

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.

Example W

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).

Example X

In the preparation of 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 Y

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

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.

Active compound 0.1 g White soft paraffin to 10 g

Claims

1. Compounds of formula I

^Rl

and pharmaceutically acceptable salts thereof in which R-_]_ represents a C^.g alkyl group optionally substituted by one or more hydroxy groups;

R₂ represents a C₂_ alkoxycarbonyl group; and

R , R and R5 independently represent hydrogen, halo, a halogenated -_j__ 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 ^cl-6 alkoxy 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, R and R5 represents a group other than hydrogen.

2. Compounds according to claim 1 represented by formula II

OH

II

N N O I

Ri and pharmaceutically acceptable salts thereof in which R-_|_ represents a C-_j__4 alkyl group optionally substituted by one or more hydroxy groups;

R₂ represents a C₂_g alkoxycarbonyl group; and

R3 represents halo, a perhalo C-_j__4 alkyl group or a perhalo C-_j__ alkoxy group.

3. Compounds according to claim 1 represented by formula II

in which R-_j_ represents a C-_[__g alkyl group; R₂ represents a C₂_g alkoxycarbonyl group; and R3 represents halo.

4. Compounds according to claim 2 in which R-_j_ represents methyl, 2-hydroxyethyl or propyl.

5. Compounds according to claim 2 in which R₂ represents a C _4 alkoxycarbonyl group.

6. Compounds according to claim 2 in which R3 represents fluoro, chloro or bromo.

7. A compound of formula I as claimed in claim 1 selected from:

ethyl 6-chloro-4-hydroxy-l-methyl-2-oxo-l, 2-dihydro-l, 8 naphthyridine-3-carboxylate; ethyl 6-fluoro-4-hydroxy-l-methyl-2-oxo-1,2-dihydro-l, 8- naphthyridine-3-carboxylate;

ethyl 6-chloro-4-hydroxy-l- (2-hydroxyethyl) -2-oxo-l,2- dihydro-1, 8-naphthyridine-3-carboxylate; and

ethyl 6-chloro-4-hydroxy-2-oxo-l-propyl-l,2-dihydro-l,8- naphthyridine-3-carboxylate;

and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as claimed in any one of claims 1-7 together with a pharmaceutically acceptable diluent or carrier.

9. The use of a compound of formula I as claimed in any one of claims 1-7 as a medicament.

10. The use of a compound of formula I as claimed in any one of claims 1-7 in the treatment of rheumatic diseases.

11. The use of a compound of formula I as claimed in any one of claims 1-7 in the manufacture of a medicament for use in the treatment of rheumatic diseases.

12. A method of treating rheumatic diseases comprising the administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 to a mammal in need thereof.

13. A process to prepare a compound of formula I according to claim 1 comprising:

a) cyclising a compound of formula III

in which R-_j_, R , R3, R4 and R5 are as previously defined and R-_]__Q represents cyano or a group of formula COR- in which R-_[_ represents a leaving group, in the presence of a base, in the presence of an inert organic liquid, at a temperature in the range -50 to 250°C, optionally followed by hydrolysis when R-J__Q represents cyano and optionally followed by acidification; or

b) cyclising a compound of formula IV

in which R^, R , R3, R4 and R₅ are as previously defined and R₁₄ represents a group of formula COR-_j^ iⁿ which R- is as previously defined, by heating, at a temperature in the range 30-250°C; or

c) condensing a compound of formula V

in which R-_j_, R3, R4, R5 and R-_j_ø are as defined previously with a compound of formula VI

R₂CH₂R_{14 VI}

in which R₂ is as previously defined and R-^ represents a group of formula COR- in which R-^ is as previously defined, by reacting together at a temperature in the range 0-150°C, in the presence of a base, in the presence of an inert organic liquid and then heating at a temperature in the range 0-250°C, optionally followed by hydrolysis when R_]_ø represents cyano and optionally followed by acidification; or

d) reacting a compound of formula VII

in which R-_j_, R , R and R5 are as previously defined with a compound of formula VI

R₂CH₂R_{14 VI} in which R is as previously defined and

represents a group of formula COR- in which R-^ is as previously defined, by reacting together at a temperature in the range 0-150°C, in the presence of a base, in the presence of an inert organic liquid and then heating at a temperature in the range 0-250°C, optionally followed by acidification; or

e) cyclising a compound of formula IX

in which R-_j_, R , R3, R4, R₅ and R-_j_₄ are as previously defined, optionally in the presence of a base, in the presence of an organic liquid at a temperature in the range 0-150°C optionally followed by acidification; or

f) reacting a compound of formula IX

1

in which R_1# R₂, R , R₄ and R5 are as previously defined and R₁₄ represents hydrogen, with a compound of formula Y-_j_COY₂ in which Y-_j_ represents halo, alkoxy (optionally substituted by halo) , aryloxy, arylalkoxy, cyano or a group of formula NR₁₅R-_|_g (in which R₁₅ and R_]_g independently represent a C-_j__g alkyl group or R^ and R-_j_g together with the nitrogen atom to which they are attached represent a saturated 3-7 membered heterocyclic ring) and Y₂ represents halo, alkoxy (optionally substituted by halo) , aryloxy or arylalkoxy, optionally in the presence of a base, in the presence of an inert organic liquid at a temperature in the range 0-150°C; or

g) reacting a compound of formula XII

H

in which R₂, 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.