WO1995030676A1

WO1995030676A1 - Antirheumatic 1-alkyl-4-hydroxy-3-(thien-3-yl) 1,8-naphthyridin-2(1h)-ones

Info

Publication number: WO1995030676A1
Application number: PCT/EP1995/001579
Authority: WO
Inventors: Julie Carolyn Gill; Bruce William Leslie
Original assignee: Knoll Aktiengesellschaft
Priority date: 1994-05-10
Filing date: 1995-04-26
Publication date: 1995-11-16
Also published as: AU2408495A; GB9409264D0; IL113538A0

Abstract

Compounds of formula (I) including pharmaceutically acceptable salts thereof in which R1 represents a C1-6 alkyl group; R2 represents thien-3-yl; and R3 represents halo, are disclosed, which are antirheumatic agents. Compositions containing these compounds and processes to make them are also disclosed.

Description

ANTIRHEUMATIC l-ALKYL-4-HYDR0XY-3-(THIEN-3-YL) 1,8-NAPHTHYRIDIN-2(1H)-0NES

The present invention relates to therapeutic agents and, in particular, to substituted 1-alkyl-4-hydroxy-3- (thien-3-yl) -1, 8-naphthyridin-2 ( IE) -ones, to processes 5 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

10 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,

15 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.

20 US 4,492,702 discloses that compounds of formula A

wherein X is CH or N;

R_]_ represents inter alia 2- 3- or 4-pyridinyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, or 2- or 3-furanyl; R2 represents inter alia hydrogen or hydroxyalkyl having from 2 to 6 carbon atoms;

Y represents inter alia hydrogen, hydroxy, halogen, etc; Z represents inter alia hydrogen; are useful in the treatment of allergic reactions. There is no suggestion in this document that these compounds have any disease-modifying antirheumatic activity.

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; R 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 these compounds have any disease-modifying antirheumatic activity.

The present invention provides compounds of formula I

including pharmaceutically acceptable salts thereof in which

Rι_ represents a C-_]__g alkyl group; R2 represents thien-3-yl; and R3 represents halo.

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.

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.

Preferably R_]_ represents a C-_j__4 alkyl group (for example methyl, ethyl, propyl or butyl). More preferably R^ represents methyl.

Preferably R3 represents fluoro, chloro or bromo. More preferably R3 represents chloro or fluoro. Most preferably R represents chloro.

A specific compound of formula I is: 6-chloro-4-hydroxy-1-methyl-3- (thien-3-yl) -1, 8- naphthyridin-2- (1H) -one

including pharmaceutically acceptable salts thereof.

When a compound of formula I contains a single chiral centre (for example when R-_j_ 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, a 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.

Some compounds of formula I, including pharmaceutically acceptable salts thereof, 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, or with aminoacids for example, lysine or arginine. 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 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 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. In therapeutic use, the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally, intra-articularly 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 g. 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 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 including 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 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 0.01-100 mg/kg/ day, more usually 0.2-50 mg/kg/day given in single or divided doses. For parenteral administration, a suitable dose is generally within the range 0.001-100 mg/kg/day, more usually 0.2-50 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 7000 mg.

In yet another aspect, the present invention provides the use of a compound of formula I in the manufacture of a medicament for use in the treatment of rheumatic diseases such as rheumatoid arthritis and osteoarthritis.

Processes for the preparation of compounds of 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 a compound of formula III

in which R^_, R2 and R3 are as previously defined and R-J_Q represents cyano or a group of formula COR-^ in which R_]__]_ represents a leaving group, for example halo, a C-_|__ alkoxy group, a ^ci-6 alkanoyloxy group, a ( C -_ζ alkoxy) carbonyloxy group, an amino group of formula NR-L2^R13 (iⁿ which R-ι_2 and R-_j_3 independently represent hydrogen or a C^_g alkyl group) , 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 tetrahydrofuran or N,N-dimethylformamide, at a temperature in the range 0-250°C, preferably in the range 20-150°C, optionally followed by hydrolysis when

R 10 represents cyano, optionally followed by acidification.

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

in which R-_|_, R2 and R are as previously defined and R-^ represents a group of formula COR-_j__]_ in which R-J_-J_ 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-dimethy1formamide.

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

in which R-_j_, R3 and R^_Q 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, 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-dimethyIformamide, and^" then heating at a temperature in the range 0-250°C, optionally followed by hydrolysis when R-J__Q represents cyano, optionally followed by acidification.

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

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

R₂CH₂R₁₄ VI

in which R and R-^ are as previously defined, preferably in the presence of a base e.g. sodium hydride, at a temperature in the range from 0°C to 150°C, preferably from 60°C to 130°C, optionally^' in the presence of an inert organic liquid, which is preferably a solvent for VI and VII, followed by acidification e.g. with hydrochloric acid.

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

in which R-_j_, R , 3 and R-_j_4 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,N-dimethyIformamide, at a temperature in the range 0-250°C optionally followed by acidification.

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. Preferably the compound of formula VI is converted into the corresponding anion by treatment with the base prior to reaction with the compound of formula V. Alternatively a salt of the anion from VI, e.g. the sodium salt, may be used.

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

in which R-_]_, R3 , R_]_Q and R-^ are as defined previously with a compound of formula XI

(R₂CH₂)_nM₁ XI in which R2 is as previously defined and when n is 1 then _j 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 (for example copper) or a transition metal salt, by methods known to those skilled in the art, optionally followed by hydrolysis when R₁₀ 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.

Certain intermediate compounds of formulae III, IV, VII and IX 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 60 ^"or 80 mice and each test group contained either 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 celiulose 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. PREPARATION OF STARTING MATERIALS

Methyl 5-chloro-2- (methylamino)nicotinate

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 JL9_, 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 ) nico inic 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. The residue 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.

EXAMPLE 1

Ethyl (thien-3-yl)acetate (5.0 g) was added to a suspension of sodium hydride (2.4 g of a 60% dispersion in mineral oil) in dry 1,4-dioxane (30 ml) under nitrogen with stirring. A solution of methyl 5-chloro- 2- (methylamino)nicotinate (5.96 g) in 1,4-dioxane

(50 ml) was added to the suspension with stirring. The mixture was stirred and heated at 100°C for 20 hours.

The mixture was cooled and filtered. The residue was washed with 1,4-dioxane, dried and then dissolved in water (200 ml) . The aqueous solution was treated with charcoal, filtered and then the filtrate was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and then triturated with hot IMS, allowed to cool and filtered. The solid obtained was dried to give 6-chloro-4-hydroxy- 1-methy1-3- (thien-3-yl) -1, 8-naphthyridin-2 (1H) -one, m.p. 292-295°C.

Active at ≥IO mg/kg in the Mouse Arthritis Test.

EXAMPLE 2

Sodium hydride (688 mg of a 60% dispersion in mineral oil) was washed with petroleum ether b.p. 40-60°C (25 ml) and then dissolved in ethanol

(50 ml) . This solution was added to a stirred suspension of 6-chloro-4-hydroxy-l-methyl-3- (thien-3- yl) -1, 8-naphthyridin-2 (1H) -one (5.03 g) in absolute ethanol (300 ml) which was boiling under reflux. After the addition the mixture was boiled under reflux for 0.5 hours and then left to stand at ambient temperature overnight. The mixture was evaporated to dryness under reduced pressure to give 6-chloro-4-hydroxy-l-methyl-3- (thien-3-yl) -1, 8-naphthyridin-2 (IH) -one sodium salt .0.6 hydrate .0.6 C₂H₅OH, m.p. >300°C.

EXAMPLE 3

6-Chloro-l-ethyl-4-hydroxy-3- (thien-3-yl) -1,8- naphthyridin-2 (IH) -one is prepared in a similar manner to Example 1.

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 polyvinylpyrrolidone and water. 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

Compounds of formula I

including pharmaceutically acceptable salts thereof in which

R-_j_ represents a C-_j__g alkyl group;

R₂ represents thien-3-yl; and

R3 represents halo.

2. A compound according to claim 1 which is 6-chloro- 4-hydroxy-l-methyl-3- (thien-3-yl) -1, 8-naphthyridin-2- (lH)-one including pharmaceutically acceptable salts thereof .

3. A pharmaceutical composition comprising a therapeutically acceptable amount of a compound of formula I as claimed in claim 1 or claim 2 together with a pharmaceutically acceptable diluent or carrier.

4. The use of a compound of formula I as claimed in either claim 1 or claim 2 as a medicament.

5. The use of a compound of formula I as claimed in either claim 1 or claim 2 in the treatment of rheumatic diseases.

6. A method of treating rheumatic diseases comprising the administration of a therapeutically effective amount of a compound of formula I according to claim 1 to a mammal in need thereof.

7. The use of a compound of formula I as claimed in claim 1 in the manufacture of a medicament for use in the treatment of rheumatic diseases.

8. A process to prepare a compound of formula I as claimed in claim 1 comprising:

a) cyclising a compound of formula III

in which R-^, R₂ and R3 are as previously defined and R-JΛ 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 0-250°C, optionally followed by hydrolysis when R-^ _Q represents cyano, optionally followed by acidification; or

b) cyclising a compound of formula IV

3V

in which R-^ , R₂ and R are as previously defined and R₁₄ represents a group of formula COR-^ in which R-^ is as previously defined, at a temperature in the range 30-250°C in the presence of an inert organic liquid; or

c) condensing a compound of formula V

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

R₂CH₂R₁₄ VI

in which R₂ is as previously defined and R^ represents a group of formula COR-J_-J_ in which R-^ is as previously defined, 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-, represents cyano, optionally followed by acidification; or

d) reacting a compound of formula VII

R- in which R-_|_ and R3 are as previously defined with a compound of formula VI

^R2^CH2^R14 VI

in which R₂ and R-_j_₄ are as previously defined, in the presence of a base at a temperature in the range from 0°C to 150°C optionally in the presence of an inert organic liquid; or

e) cyclising a compound of formula IX

in which R_j, R₂, R3 and R-_[_₄ are as previously defined in the presence of a base, in the presence of an organic liquid at a temperature in the range 0-250°C optionally followed by acidification.