WO2000018731A1

WO2000018731A1 - Novel compounds

Info

Publication number: WO2000018731A1
Application number: PCT/SE1999/001631
Authority: WO
Inventors: David Cheshire; Mark Furber
Original assignee: Astrazeneca Ab
Priority date: 1998-09-25
Filing date: 1999-09-17
Publication date: 2000-04-06
Also published as: SE9803279D0; EP1115401A1; AU1192200A

Abstract

The invention relates to novel pyridyl derivatives (I), their use as medicaments, pharmaceutical formulations including them and methods for their preparation. In said formula, R is hydrogen, chloro or fluoro, or a salt or solvate thereof.

Description

NOVEL COMPOUNDS

This invention relates to novel pyridyl derivatives, their use as medicaments, pharmaceutical formulations including them and methods for their preparation.

PCT patent application PCT/SE98/00575 discloses certain pyridine alkanol derivatives and their activity as mast cell antagonists.

It has now surprisingly been found that certain compounds within the scope of PCT/SE98/00575, but not specifically disclosed therein, exhibit advantageous pharmacokinetic and physical properties such as solubility.

In a first aspect the present invention therefore provides a compound of formula (I) or a salt thereof:

(D

wherein;

R is hydrogen, chloro or fluoro or a salt or solvate thereof.

Suitably R is hydrogen, chloro or fluoro, preferably R is hydrogen.

Suitably the right hand pyridyl group can be attached to the neighbouring phenyl ring at the 2-, 3- or 4-positions. The sulfonamide group can then be attached to any free position of the pyridyl ring, preferably the sulfonamide is para with respect to the phenyl group. Preferably these groups are attached as shown below:

Particularly preferred compounds of the invention include: 6-[2-Chloro-4-(2-hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide, 6-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide, (2R)-5-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)benzene]pyridine-2-sulfonic acid amide, or salts or solvates thereof.

Compounds of the invention can form pharmaceutically acceptable solvates and salts. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, trifluoroacetic and methanesulphonic acids. Compounds of the invention may also form alkali metal salts such as magnesium, sodium, potassium and calcium salts.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

Preferably the compounds of formula (I) have the following stereochemistry:

According to the invention there is also provided a process for the preparation of compounds of formula (I) as hereinbefore defined which comprises:

(a) reaction of a compound of formula (LT):

(π)

with a compound of formula (ILT):

cm)

1 " in which R is as defined in formula (I), R is a hydroxy protecting group, and one of R R is triflate or halo and the other is B(OH)₂, or ZnHal, or

(b) reaction of a compound of formula (IV), where R⁴ is a suitable protecting group such as tertiary butyl, with a suitably protected and activated derivative of 4-(3-pyridyl)-

-1,2-butanediol;

or

(c) preparation of compounds of formula (I) from a compound of formula (V):

in which R as defined in process (a) by reaction with a compound of formula (IN), and optionally thereafter process (a) to (c):

• removing any protecting groups

• forming a pharmaceutically acceptable salt or solvate.

Reaction of compounds of formulae (LI) and (III) can be carried out under the conditions of the Suzuki reaction (Synthetic Communications 11(7), 513-519, 1981) for example at 100 °C in the presence of a suitable catalyst and base (e.g. tetrakis(triphenylphosphine)- palladium(O) and aqueous sodium carbonate) in a suitable solvent (e.g. ethanol/toluene).

Process (b) is caσied out at elevated temperature, for example at about 60°C, in the presence of suitable base (e.g. cesium carbonate) and an appropriate organic solvent (e.g. dimethylformamide). Suitably protected and activated derivative of 4-(3-pyridyl)- -1,2-butanediol for example the compound (VI):

Processes (c) is carried out under the conditions of the Mitsonobu reaction, for example at approximately 0-25°C in the presence of diethyl azodicarboxylate and triphenylphosphine in an appropriate solvent (e.g. toluene).

Compounds of formula (HI) wherein R² is B(OH)₂, can be prepared from a compound in which R is bromine or iodine by, for example, treatment with n-butyllithium and tri- isopropylborate in an appropriate solvent (e.g. tetrahydrofuran), at low temperature (e.g. - 78°C). Compounds of formula (LI) R" is bromine or iodine can be prepared from compounds of formula (VI) as defined above by reaction with a compound of formula (VLI), in which R² is bromine or iodine

under the conditions described for process b.

Compounds of formula (V) can be prepared by reduction of a compound of formula (VIII)

in which R is as defined above using conventional procedures, for example hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate, followed by debenzylation using conventional methods such as those described in Protective Groups in Organic Synthesis', 2^nd Edition, T.W. Greene & P.G.M. Wuts, Wiley-Interscience (1991).

Compounds of formula (VET) can be prepared by the reaction of compound (LX):

reported by Reetz et. al. Angew. Chem. SuppL, (1983), 151 1.) with a compound of formula (X):

in which M is lithium, sodium, potassium, MgX or ZnX, where X is halogen, optionally in the presence of additives such as boron trifluoride.

Compounds of formula (IX) and (X) can be prepared using known methods or are available commercially. It will be appreciated by those skilled in the art that in the process described above the functional groups of intermediate compounds may need to be protected by protecting groups.

Functional groups which it is desirable to protect include hydroxy and sulfonamide. Suitable protecting groups for hydroxy include organosilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydro- pyranyl. A suitable protecting group for sulfonamide would be tertiary butyl. The protection and deprotection of functional groups may take place before or after a reaction step.

The use of protecting groups is fully described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1991).

Novel intermediates form a further aspect of the invention.

Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.

The compounds of the invention are useful because they possess pharmacological activity and more particularly activity in the modulation of inflammatory and allergic conditions, for example as shown in the test described below. The compounds of the invention inhibit the activation of a range of cell types from haematopoetic lineage, including mast cells, neutrophils and eosinophils. In a further aspect the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory, auto-immune, proliferative and hyper-proliferative diseases. _

The compounds of the invention are also indicated in the treatment and prevention of allergic, inflammatory or auto-immune conditions of the lung, including reversible obstructive airways diseases which includes asthma (e.g. bronchial, allergic, intrinsic asthma, extrinsic and chronic asthma), and associated manifestations of the disease (late responses, hyper-responsiveness), also farmer's lung and related diseases, fibrosis, ideopathic interstitial pneumonia, chronic obstructive airways disease (COPD), bronchiectasis, cystic fibrosis, eosinophilic pneumonias, adult respiratory distress syndrome (ARDS), emphysema and alveolitis, for example cryptogenic fibrosing alveolitis.

Further, the compounds of the invention are indicated in the treatment or prevention of allergic, inflammatory or auto-immune conditions in the nose including all conditions characterised by inflammation of the nasal mucous membrane such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, scrofulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis. Of particular interest are allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever). The compounds are also indicated for the treatment of nasal polyps and allergic menifestations of the nasopharynx other than those described hereintofore.

The compounds of the invention are also indicated the treatment or prevention of allergic, inflammatory or auto-immune conditions of the eye such as conjunctivitis (allergic, acute, vernal, of hay fever, chronic), inflammation disorders of the eyelids, cornea, uveal tract and retina.

The compounds of the invention are also indicated in the treatment and prevention of allergic, inflammatory and auto-immune conditions of the gastrointestinal tract such as food allergy and food intolerance, ulcerative colitis, Crohn's disease, irritable bowel disease, gastric ulcers, and food related allergic diseases which have symptomatic manifestations remote from the gastrointestinal tract, for example migraine, rhinitis and eczema.

The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory or auto-immune conditions of the skin such as psoriasis, atopical _ dermatitis, contact dermatitis/dermatitis herpetiformis, erythema nodosum, urticaria, cutaneous eosinophilias, acne, Alopecia areata, eosinophilic fascitis dermatomyositis, photoallergic sensitivity and periodontal disease.

The compounds of the invention are therefore indicated for use in the treatment or prevention of allergic, inflammatory or auto-immune conditions of the joints and connective tissue, including osteoarthritis, rheumatoid arthritis, systemic lupus erythematosis, vasculitis, Wegener's granulomatosis, polyarthritis nodosa, bursitis, tendonitis, gout, Behcet's syndrome, ankylosing sponditis, Reiter's syndrome and psoriatic arthritis.

The compounds of the invention are indicated in the treatment and prevention of allergic, inflammatory, and auto-immune conditions of the circulatory system including atheroma, reperfusion injury (e.g. on angioplasty), myocardial infarction, thrombosis and vascular and tissue damage caused by ischaemic disease or injury.

The compounds of the invention are indicated in the treatment and prevention of allergic, inflammatory or auto-immune conditions of the CNS including Parkinson's disease, Alzheimers and other dementias, stroke and subarachnoid haemorrhage. The compounds of the invention are indicated in the treatment and prevention of inflammatory conditions of the liver for example hepatitis, cirrhosis and glomerulonephritis.

The compounds of the invention are indicated in the treatment and prevention of allergic, inflammatory or auto-immune conditions of the bladder and uro-genital tract including cystitis.

The compounds of the invention are indicated in the treatment and prevention of tumours and other proliferative diseases. Of particular interest amongst the above indications is use of the compounds of the invention in a reversible obstructive airways disease, most particularly asthma and especially the treatment and prophylaxis of asthma and rhinitis.

According to a further aspect of the invention there is thus provided the use of a compound of formula I, as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of the above diseases, in particular reversible obstructive airways disease.

Administration of the compounds of the invention may be topical (for example by inhalation to the lung). The compounds of the invention may be inhaled as a dry powder which may be pressurised or non-pressurised.

In non-pressurised powder compositions, the active ingredient in finely divided form may be used in admixture with a larger sized pharmaceutically acceptable inert carrier.

The composition may alternatively be pressurised and contain a compressed gas, e.g. nitrogen, or a liquefied gas propellant. In such pressurised compositions, the active ingredient is preferably finely divided. The pressurised composition may also contain a surface active agent. The pressurised compositions may be made by conventional methods. The compounds of the invention may be administered systemically (for example by oral administration to the gastrointestinal tract). The active ingredient may be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract.

Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin.

According to a further aspect of the invention there is provided a pharmaceutical composition including a compound of formula I or a salt or solvate thereof as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable doses for such oral administration are in the range from 0.03 to 30 mg kg^" day^" , for example 0.3 mg kg^"1 day^'1. According to a further aspect of the present invention, there is provided a method of treatment or prophylaxis of a reversible obstructive airways disease, in particular asthma, which method comprises administration of a therapeutically effective amount of a compound of formula I as hereinbefore defined, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to, the disease.

It will be understood by those skilled in the art tat certain functional groups in the compounds of the invention may be protected using appropriate protecting groups as hereinbefore described to form "protected derivatives" of compounds of the invention. All protected derivatives of compounds of formula I are included within the scope of the invention.

The invention is illustrated by the following Examples.

Example 1

6-[2-Chloro-4-(2-hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-suIfonic acid amide

a) (2R, 3E/Z)-4-(3-Pyridyl)-l,2-0-wopropyIidenebut-3-en-l,2-diol

A solution of n-butyllithium (2.5 M in hexanes; 100 ml) was added dropwise to a stirred suspension of 3-pyridylmethyltriphenylphosphonium chloride hydrochloride (53.39 g, J. Med. Chem. 1986, 29, 1461) in tetrahydrofuran (50 ml) at -40 °C. The resulting mixture was stirred at room temperature for 30 minutes and was then cooled to -70 °C. A solution of 2,3-O-(S)-wøpropylidene-L-glyceraldehyde (15.2 g) (ex Oxford Asymmetry; see Organic Synthesis (1995) 72, 1 ) in tetrahydrofuran (10 ml) was added. The resulting mixture was stirred and allowed to reach room temperature over 3 hours. The mixture was poured into brine (500 ml) and extracted into ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as an oil (21.2 g). MS (El) 205 (M)⁺

Η NMR (CDC1₃) major Z-diastereomer 8.53(2H, d); 7.61(1H, dt); 7.29(1H, dd); 6.67(1H, d); 5.85(1H, dd); 4.83(1H, q); 4.16(1H, t); 3.71(1H, t); 1.49(3H, s); 1.39(3H, s).

b) (2R)-4-(3-Pyridyl)-l,2-0-wopropylidenebutane-l,2-diol

A solution of (2R, 3E/Z)-4-(3-pyridyl)-l,2-O-wopropylidenebut-3-en-l,2-diol (21.2 g, Example la)) in ethyl acetate (200 ml) was hydrogenated for 2 hours at 3 atmospheres pressure using palladium on carbon (10%, 0.5 g) as catalyst. The reaction was filtered through celite® and the residue washed with ethyl acetate. The combined filtrate and washings were concentrated under reduced pressure and the residue obtained purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as an oil (20.5 g). MS (ESI) 208 (M + H)⁺ Η NMR (CDC1₃) 8.48-8.45(2H, m); 7.52(1H, dt); 7.23(1H, dd); 4.10(1H, quintet);

4.04(1H, t); 3.55(1H, t); 2.84-2.64(2H, m); 1.94-1.80(2H, m); 1.44(3H, s); 1.36(3H, s). c) (2R)-4-(3-Pyridyl)-l,2-butanediol

(2R)-4-(3-Pyridyl)-l,2-O-wopropylidenebutane-l,2-diol (20.4 g, Example lb)) was dissolved in hydrochloric acid (2M, 100 ml) and was stirred for 40 minutes. The mixture s was neutralised with saturated aqueous sodium hydrogencarbonate solution and was concentrated under reduced pressure. The residue obtained was triturated with ethyl acetate and filtered. The residue was washed with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting o with ethyl acetate : methanol (9: 1) to give the sub-title compound as an oil (16.4 g).

MS (APCI) 168 (M + H)⁺

1H NMR (CDC1₃) 8.44-8.40(2H, m); 7.54(1H, d); 7.22(1H, dd); 3.73-3.67(lH, m); 3.65(1H, dd); 3.48(1H, dd); 2.90-2.70(2H, bm); 2.87-2.68(2H, m); 1.84-1.67(2H, m).

5 d) (2R)-4-[2-(3-Pyridyl)ethyI]-l,3-dioxin-2-one

A solution of (2R)-4-(3-pyridyl)-l,2-butanediol (0.42 g, Example lc)) and 1 , l'-carbonyldi- imidazole (0.49 g) in chloroform (15 ml) was heated at reflux for 20 minutes. The reaction was cooled and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with methanol : dichloromethane (1 : 19) to give the sub- 0 title compound as an oil (0.35 g). MS (APCI) 194 (M + H)⁺

1H NMR (CDC1₃) 8.52-8.49(2H, m); 7.53(1H, d); 7.26(1H, dd); 4.73^.66(1H, m); 4.54 (1H, dd); 4.09 (1H, dd); 2.94-2.88 (1H, m); 2.86-2.72 (1H, m); 2.17-2.09 (1H, m); 2.02- 1.97 (lH, m). 5 e) (2R)-3-[4-(4-Bromo-3-chloro-phenoxy)-3-(tert-butyl-dimethylsilyloxy)-butyI]- pyridine

(2R)-4-[2-(3-Pyridyl)ethyl]-l,3-dioxin-2-one (Example Id, 2.41 g), 3-chloro-4- 0 bromophenol (3.74 g) and cesium carbonate (6.5 g) were heated together at 100°C in dry dimethylformamide (30 ml) for 10 hours. The mixture was cooled, poured into water (200 ml) and extracted into ethyl acetate (3x50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue (2.8 g) was dissolved in dry dichloromethane (30 ml) and treated with imidazole (1.36 g) and tert-butyl- dimethylsilyl chloride (1.51 g). The resulting mixture was stirred at room temperature for 20 hours, poured into water (100 ml) and extracted into diethyl ether (3x50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (1-2 to 1-1) to afford the sub-title compound (3.7 g) as an oil.

MS (APCI) 472 (M+H)⁺

1H NMR (CDC1₃) 8.47 (1H, d); 8.45 (1H, dd); 7.52-7.46 (2H, m); 7.22-7.19 (1H, m); 6.98 (1H, d); 6.68 (1H, dd); 4.1 1-4.06 (1H, m); 3.89-3.81 (2H, m); 2.80-2.65 (2H, m); 2.05-1.86 (2H, m); 0.92 (9H, s); 0.20 (3H, s); 0.10 (3H, s).

f) 4-[2-(tert-ButyI-dimethyl-silyloxy)-4-pyridin-3-yl]-2-chloro-benzeneboronic acid

To a solution of (2R)-3-[4-(4-Bromo-3-chloro-phenoxy)-3-(tert-butyl-dimethylsilyloxy)- butyl] -pyridine (Example le, 3 g) and the tπ^'-isopropylborate (4.41 ml) in tetrahydrofuran (100 ml) at -78°C was added the t-BuLi (1.7M in hexanes, 7.9 ml) over about 10 minutes. The reaction was stirred for 3h at -78°C . and then quenched at this temperature with saturated ammonium chloride solution (100 ml). The mixture was warmed up to room temperature, extracted with Ethyl acetate (3 times 100 ml), and the organic layers dried over anhydrous magnesium sulfate. The crude material was purified on a silica gel column (ethyl acetate then dichloromethane: methanol / 9: 1) to afford the sub-title compound as a white glass (2.4 g, 87%).

MS (APCI) 436 (MH⁺) Η NMR (DMSO-d6/D₂O) 8.44(1H, d); 8.40(1H, dd); 7.64(1H, ddd); 7.38(1H, d); 7.32(1H, dd); 6.91(1H, d); 6.85(1H, d); 4.05-3.95(2H, m); 3.90-3.80(lH, m); 2.80- 2.60(2H, m); 1.90-1.70(2H, m); 0.87 (9H, s); 0.09(3H, s); 0.05 (3H, s). g) 6-[2-ChIoro-4-(2-hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide

A mixture of 4-[2-(tert-butyl-dimethyl-silyloxy)-4-pyridin-3-yl]-2-chloro-phenylboronic acid (Example If, 1.00 g), 2-bromo-pyridine-5-sulfonamide (0.82g), ethanol (15 ml), 2M sodium carbonate solution (3.2 ml) and tetrakistriphenylphosphine palladium (0) (0.10 g) were combined in that order then heated in a sealed tube at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue taken in water (5 ml), extracted with ethyl acetate (3 times, 10 ml) and the combined organic layers dried over anhydrous magnesium sulfate. The solution was filtered, concentrated under vacuum and the crude material purified by column chromatography over silica eluting with ethyl acetate : hexane (1 : 1) to give a solid. This material was dissolved in methanol (10 ml) and treated with 2M hydrochloric acid (10 ml). After 3 hours, the methanol was removed under reduced pressure and the solution neutralised with solid sodium hydrogen carbonate. The aqueous phase was then extracted with ethyl acetate (3 times 10 ml), the combined organic layers dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound as a white solid.

MS (APCI) 434 (M+H)+ 1H NMR (DMSO-d6) 9.03(1H, d); 8.47(1H, d); 8.40(1H, dd); 8.24(1H, dd); 7.87(1H, d); 7.70-7.60(3H, m); 7.56(1H, d); 7.31(1H, dd); 7.19 (1H, d); 7.08(1H, dd); 5.10 (1H, d); 4.05-3.90(2H, m); 3.85-3.75(lH, m); 2.90-2.60(2H, m); 1.90-1.65(2H, m).

Example 2

6-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide

a) (2R)-l-(4-Bromophenoxy)-4-(3-pyridyl)butan-2-ol

Cesium carbonate (8.1 g) and 4-bromophenol (6.05 g) were added to a solution of (2R)-4- [2-(3-pyridyl)ethyl]-l,3-dioxin-2-one (4.8 g, Example Id) in dry dimethylformamide

(50 ml) and heated at 100 °C for 16 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with acetone : isohexme ( 1 : 1 ) to gi ve the sub-title compound as a beige solid (6.42 g).

MS (APCI) 322/324 (M + H)⁺

Η NMR (CDC1₃) 8.50(1H, d); 8.45(1H, dd); 7.55(1H, dt); 7.35(2H, d); 7.25-7.20(lH, m); 6.80-6.75(2H, m); 4.10-3.90(2H, m); 3.85(1H, dd); 2.95-2.90(lH, m); 2.85-2.75(lH, m); 2.65(1H, s); 1.90-1.80(2H, m).

b) (2R)-l-(4-Bromophenoxy)-4-(3-pyridyl) -2-(tert-butyldimethylsiIyloxy) butane tert-Butyldimethylsilylchloride (3.75 g) and imidazole (1.69 g) were added to a solution of (2R)-l-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (4 g, Example 2a) in dichloromethane. The mixture was stirred for 16 hours at room temperature. The white precipitate was collected by filtration and the filtrate concentrated under reduced pressure to give the subtitle compound as an oil (5.4 g).

MS (APCI) 436/438 (M + H)⁺

1H NMR (CDC1₃) 8.50(1H, d); 8.45(1H, dd); 7.55(1H, dt); 7.35(2H, dd); 7.25-7.20(lH, m); 6.80-6.75(2H, dd); 4.15-4.05(1H, m); 3.90-3.75(2H, m); 2.95-2.80(2H, m); 2.0- 1.90(2H, m); 0.95-0.9(9H, m); 0.15-0.10(6H, m).

c) (2R)-4-[4-(3-pyridyl)-2-(tørt-butyIdimethyIsilyloxy)butoxy]benzene boronic acid

A solution of n-butyllithium (2.5 M in hexanes, 6.9 ml) was added dropwise to a stirring solution of (2R)-l-(4-bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (1.50 g, Example 2b) and tri-zsopropyl borate (4.3 ml) in tetrahydrofuran (200ml) at -70 °C. After the addition was complete the reaction mixture was allowed to warm to room temperature. After 1 hour water (200 ml) and ethyl acetate (200 ml) were added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. This was partly purified by column chromatography over silica eluting with dichloromethane then ethyl acetate then methanol to give the sub-title compound as a glass (2 g).

MS (APCI) 402 (M + H)⁺

Η NMR (CDC1₃) 8.60(1H, d); 8.55(1H, dd); 7.95(2H, d); 7.60(1H, d); 7.30 (1H, dd); 6.90(2H, d ); 4.15-4.05(1H, m); 3.95-3.80(2H, m); 2.95-2.70(2H, m); 2.05-1.80(2H, m); 0.95-0.9(9H, m); 0.15-0.10(6H, m).

d) 6-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide

Prepared as for example lg) employing (2R)-4-[4-(3-pyridyl)-2- (tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (Example 2c, 0.143g), 2-bromo- pyridine-5-sulfonamide (0.092 g), ethanol (3 ml), 2M sodium carbonate solution (0.5 ml) and tetrakistriphenylphosphine palladium (0) (0.010 g) to afford the title compound as a white solid (0.066g).

MS (APCI) 400 (M+H)+

Η NMR (DMSO-d6) 8.97 (1H, d); 8.47 (1H, d); 8.40 (1H, dd); 8.2-8.1 (3H, m); 7.66 (1H, dd); 7.58 (1H, bs); 7.31(1H, dd); 7.10 & 7.07 (2H, d); 5.12 & 5.10 (1H, d); 3.97 (2H, d); 3.9(1H, bm); 2.95-2.80 (2H, dm); 2.0-1.8 (2H, dm).

Example 3 (2R)-5-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)benzene]pyridiπe-2-suIfonic acid amide

a) 5-Bromopyridine-2-thiol 1 ,2-Propanediol (125 ml) was degassed for 40 minutes, then 2,5-dibromopyridine (5 g) and sodium hydrogen sulfide (7.85 g) were added. The mixture was heated at 165 C under nitrogen for 4 hours, cooled, and concentrated under reduced pressure. The residue was dissolved in water (250 ml) and neutralised to pH7 with acetic acid. The resultant yellow solid was filtered off and dried in vacuo to yield the sub-title compound (3.35 g). MS (APCI) 192 (M+H)+ b) 5-bromopyridine-2-sulfonic acid amide.

5-bromopyridine-2-thiol (Example 3a, 1 g) was suspended in concentrated hydrochloric acid (8 ml) and cooled to 10°C. Excess chlorine gas was bubbled through the suspension for 30 minutes. The mixture was then poured into ice/water (10 ml) and the resultant solid filtered off. This was dissolved in tetrahydrofuran (20 ml) and aqueous ammonia solution (12 ml) was added. The mixture was stirred under nitrogen at room temperature for 1.5 hours then concentrated under reduced pressure to yield the sub-title compound as a solid (1.23 g).

MS (APCI) 235 (M-H)+ 1H NMR (DMSO-d6) 8.88-8.87(lH, d); 8.35-8.31(lH, dd); 7.89-7.85(lH, d); 7.59(2H, br s).

c) (2R)-5-{4-[2-(tert-Butyldimethylsilyloxy)-4-pyridin-3-ylbutoxy]benzene}-pyridine- 2-sulfonic acid amide. (2R)-4-[4-(3-Pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (Example 2c, 0.25g), 5-bromopyridine-2-sulfonic acid amide (Example 3a, 0.22g), tetrakis(triphenylphosphine)-palladium (0) (0.025g), 2M aqueous sodium carbonate (0.5 ml) and ethanol (5 ml) were heated together in a sealed tube at 100°C for 30 hours. The reaction mixture was then cooled, poured into water (100 ml) and extracted into ethyl acetate (3 x 150 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the sub-title compound (0.217g). MS (APCI) 514 (M+H)+

d) (2R)-5-[4-(2-Hydroxy-4-pyridin-3-ylbutoxy)-benzene]pyridine-2-sulfonic cid amide.

(2R)-5- { 4-[2-(tert-Butyldimethylsilyloxy)-4-pyridin-3-ylbutoxy]-benzene } -pyridine-2- sulfonic acid amide (Example 3c, 0.217g), 2N hydrochloric acid (16 ml) and methanol (40 ml) were stirred together under nitrogen at room temperature for 20 hours. The mixture was then concentrated under reduced pressure and the residue dissolved in aqueous ammonia solution and extracted into ethyl acetate (3 x 150 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with 5% methanol in ethyl acetate to give the title compound as a solid (139 mg). MS (APCI) 400 (M+H)+

1H NMR (DMSO-d6) 8.99(1H, d); 8.47 (1H, d); 8.41-8.39(1H, dd); 8.29-8.26(lH, dd); 7.96-7.93(lH, d); 7.78-7.74(2H, d); 7.67-7.64(lH, d); 7.48(2H, s); 7.33-7.30(lH, m); 7.11- 7.09(2H, d); 5.10-5.08 (1H, d); 3.97-3.95 (2H, d); 3.83-3.78(lH, m); 2.85-2.65 (2H, m), 1.88-1.70 (2H, m).

Pharmacological activity

The pharmacological activity of the compounds of the invention may be tested by the method of E. Wells et al, 'Characterization of primate bronchoalveolar mast cells: II — inhibition of histamine, LTC₄ and PGD release from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells', J. Immunol., vol. 137, 3941, 1986.

The compounds exemplified were tested and found to inhibit histamine release at a concentration of less than 10^"4 M (IC ₀).

Claims

1. A compound of formula (I):

(I)

wherein; R is hydrogen, chloro or fluoro or a salt or solvate thereof.

2. A compound according to claim 1 having the following stereochemistry:

3. A compound according to claim 1 or 2 in which R is hydrogen.

4. A compound according to any one of claims 1 to 3 in which the sulfonamide group is para with respect to the phenyl group.

5. A compound according to claim 1 which is;

6-[2-Chloro-4-(2-hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide, 6-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide, (2R)-5-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)benzene]pyridine-2-sulfonic acid amide, or salts or solvates thereof.

6. A compound according to any one of claims 1 to 5 for use in therapy.

7. Use as claimed in claim 6, wherein the disease is asthma or rhinitis.

8. A pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof as defined in any one of claims 1 to 5 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A method of treatment or prophylaxis of a reversible obstructive airways disease, in particular asthma, which method comprises administration of a therapeutically effective amount of a compound of formula I as hereinbefore defined, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to, the disease.

10. A process for the preparation of a compound of formula (I) which comprises: (a) reaction of a compound of formula (H):

(ID

with a compound of formula (III):

(HI)

in which R is as defined in formula (I), R¹ is a hydroxy protecting group, and one of R²/R³ is triflate or halo and the other is B(OH)₂, or ZnHal, or

(b) reaction of a compound of formula (IV), where R >4 i •s a suitable protecting group, with a suitably protected and activated derivative of 4-(3-pyridyl)-l,2-butanediol;

or

(c) preparation of compounds of formula (I) from a compound of formula (V):

in which R¹ as defined in process (a) by reaction with a compound of formula (IV), and optionally thereafter process (a) to (c):

• removing any protecting groups

• forming a pharmaceutically acceptable salt or solvate.