WO2000018730A1

WO2000018730A1 - Novel compounds

Info

Publication number: WO2000018730A1
Application number: PCT/SE1999/001632
Authority: WO
Inventors: David Cheshire; Michael Stocks
Original assignee: Astrazeneca Ab
Priority date: 1998-09-25
Filing date: 1999-09-17
Publication date: 2000-04-06
Also published as: SE9803280D0; AU1192300A; EP1115706A1

Abstract

The invention relates to novel pyridyl derivatives (I), their use as medicaments, pharmaceutical formulations including them and methods for their preparation, wherein: R is hydrogen, chloro or fluoro; and N is 0, 1, or 2 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 WO 97/20815 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 WO 97/20815, but not specifically disclosed therein, exhibit advantageous pharmacokinetics, for example an increased half-life.

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

(D wherein; R is hydrogen or fluoro; and n is 0, 1 or 2 or a salt or solvate thereof.

Suitably R is hydrogen or fluoro, preferably R is fluoro. Preferably the fluoro group is ortho with respect to the sulfonamide group.

Preferably n is 1.

Particularly preferred compounds of the invention include: (2R)-3-Fluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide,

(2R)-2,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, (2R)-2-Fluoro-4'-(2hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, (2R)-3,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, (2R)- 4'-(2-Hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, or salts and 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:

Compounds of formula (I) can be prepared according to the procedures outlined in WO 97/20815. Preferred processes include:

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

(ID

with a compound of formula (HI):

(HI)

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 R is a suitable protecting group such as tert. 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 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.

Reaction of compounds of formulae (II) and (HI) can be carried out under the conditions of the Suzuki reaction (Synthetic Communications 1 1(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 carried 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 (H) wherein R² is B(OH) , can be prepared from a compound in which R² 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 (II) R" is bromine or iodine can be prepared from compounds of formula (VI) as defined above by reaction with a compound of formula (VII), in which R 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 (VET)

in which R¹ 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 ,nⁿd^α Edition, T.W. Greene & P.G.M. Wuts, Wiley-Interscience (1991).

Compounds of formula (VIE) can be prepared by the reaction of compound (DC):

reported by Reetz et. al. Angew. Chem. SuppL, (1983), 1511.) 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 (DC) and (X) can be prepared using known methods or are commercially available. 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 alveolrtis.

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^"1 day^"1, 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 that 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 (2R)-3-Fluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide

a) (2R, 3E/Z)-4-(3-Pyridyl)-l,2-0-isopropylidenebut-3-en-l,2-diol A solution of π-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-C7-(S)- _'opropylidene-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-PyridyI)-l,2- -wopropylidenebutane-l,2-dioI

A solution of (2R, 3E/Z)-4-(3-pyridyl)-l,2-0-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-Pyr_dyl)-l,2-butanediol

(2R)-4-(3-Pyridyl)-l,2-0-._-σpropylidenebutane-l,2-diol (20.4 g, Example lb)) was dissolved in hydrochloric acid (2M, 100 ml) and was stirred for 40 minutes. The mixture 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 with ethyl acetate : methanol (9: 1) to give the sub-title compound as an oil (16.4 g). MS (APCI) 168 (M + H)⁺

Η 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).

d) (2R)-4-[2-(3-Pyridyl)ethy_]-l,3-dioxin-2-one A solution of (2R)-4-(3-pyridyl)-l,2-butanediol (0.42 g, Example lc)) and 1,1'- carbonyldiimidazole (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-title compound as an oil (0.35 g). MS (APCI) 194 (M + H)⁺

Η NMR (CDC1₃) 8.52-8.49(2H, m); 7.53(1H, d); 7.26(1H, dd); 4.73-4.66(lH, 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).

e) (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 : wøhexane (1 : 1) to give the sub-title compound as a beige solid (6.42 g) . m.p. 68-69°C

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).

f) (2R)-l-(4-Bromophenoxy)-4-(3-pyridyl) -2-(tert-butyIdimethylsilyIoxy) 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 le) 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); O.15-0.10(6H, m).

g) (2R)-4-[4-(3-Pyridyl)-2-(tert-butyldimethylsily_oxy)butoxy]benzene boronic acid

A solution of n-butyllithium (2.5 M in hexanes, 6.9 ml) was added dropwise to a stirred solution of (2R)- 1 -(4-bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (1.50 g, Example If) and trϋsopropyl 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).

h) 2-Fluoro-4-bromobenzenesulfonamide

A solution of sodium nitrite (4.36g) in water (35ml) was added dropwise over two hours to a stirred slurry of 4-bromo-2-fluoroaniline (lOg) in concentrated (twelve molar) HC1 (20ml) at below 5°C (ice/methanol bath used). Magnesium chloride (8.52g) was added portionwise over one hour such that the reaction temperature did not exceed 8°C. The reaction mixture was poured into acetic acid saturated with sulfur dioxide (37ml) containing cupric chloride (copper (II) chloride, 2.83g) and stirred. An exothermic, effervescent reaction occured and the temperature of the reaction mixture rose to 30°C. After 30 minutes, the reaction mixture was poured into brine and extracted into ethyl acetate three times. The combined organic extracts were washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100ml) and 0.880 sp.gr. ammonia (100ml) was added and the reaction stirred one hour. The product was extracted into ethyl acetate three times and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was washed with 4: 1 isohexane / diethyl ether and dried to give the sub-title compound as brown solid (9.4g). MS (gems) 253/255 (M)⁺ Η NMR (DMSO) 7.83 (1H, m); 7.70-7.76 (3H, m); 7.61(1H, m)

i) (3R)-3-[3-(tert-Butyl-dimethylsilyIoxy)-4-(4'-fluoro-3'-methyl-biphenyl-4-yloxy)- butyl]-pyridine

Prepared from (2R)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (Example lg, 0.250g), 4-bromo-2-fluorobenzenesulfonamide (Example lh), 0.237g), tetra/ ytriphenylphosphine palladium (0) (0.018g), aqueous 2 molar sodium carbonate (0.72ml) and ethanol (3ml). The reaction was refluxed in a sealed Wheaton vial for twelve hours at 90°C. After cooling, brine was added to the reaction mixture and the product was extracted into ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered through a pad of silica (isolute syringe) and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and purified by normal phase hplc, eluting with a gradient of 0 to 10% ethanol in dichloromethane to give the sub-title compound as a white solid (0.29 lg). MS (APCI+) 531.0 (M+H)⁺ (APCI-) 529.1 (M-H)^"

j) (2R)-3-Fluoro-4'-(2-hydroxy-4-pyridin-3-y_-butoxy)-biphenyl-4-sulfonic acid amide

(3R)-3-[3-(tert-Butyl-dimethylsilyloxy)-4-(4'-fluoro-3'-methyl-biphenyl-4-yloxy)-butyl]- pyridine (Example li, 0.29 lg), methanol (3ml) and two molar hydrochloric acid (2ml) was stirred for four hours at room temperature. The reaction mixture was neutralised with aqueous sodium bicarbonate and the product extracted into ethyl acetate three times. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. Trituration with diethyl ether resulted in the isolation of a white solid (0.099g).

MS (APCI)+ 417 (M+H)⁺ Η NMR (DMSO) 8.47 (1H, s); 8.40 (1H, m); 7.83-7.61 (8H, m); 7.31 (1H, m); 7.06

(2H, d); 5.08 (1H, d); 3.95 (2H, d); 3.80 (1H, m); 2.84-2.63 (2H, m), 1.95-1.71 (2H, m).

The hydrochloride salt was prepared in a similar manner from (3R)-3-[3-(tert-Butyl- dimethylsilyloxy)-4-(4'-fluoro-3'-methyl-biphenyl-4-yloxy)-butyl]-pyridine (Example li, 0.935g), the hydrochloride salt being filtered from the reaction mixture, washed with diethyl ether and dried to afford the title compound as a white solid (0.802g). MS (APCI)⁺ 417 ((M-HC1)+H)⁺

Η NMR (DMSO) 8.81(1H, d); 8.73 (1H, dd); 8.42 (1H, dt); 7.93 (1H, dd); 7.81 (1H, t); 7.74-7.61 (6H, m); 7.06 (2H, d); 3.96 (2H, d); 3.80-3.76 (1H, m); 3.05-2.2.85 (2H, m): 2.01-1.75 (2H, m). Example 2

(2R)-2,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide.

a) 4-Bromo-2,5-difluorobenzenesulfonamide.

Ammonium hydroxide (5 ml) was added to a solution of 2,5-difluoro-4- bromophenylsulfonyl chloride (4.3 g) in tetrahydrofuran (20 ml) at room temperature and stirred for lOminutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and the residue triturated with 20% diethyl ether in wohexane to give the sub-title compound as a solid (4.3 g).

MS (El) 271/273 (M⁺)

Η NMR (CDC1₃) 7.69(1H, t); 7.50(1H, dd); 5.17(2H, s)

b) (2R)-2,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide.

(2R)-4-[4-(3-Pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (0.25g, Example lg)), 4-bromo-2,5-difluoro-benzenesulfonamide (0.25g, Example 2a), 2M aqueous sodium carbonate (0.72ml) and tetracz^'_^,(triphenylphosphine) palladium (0)

(0.018g) in ethanol was heated at 90 °C for 10 hours. After cooling, the suspension was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give a colourless oil. 2M Hydrochloric acid (5 ml) was added to a solution of the oil in methanol (7 ml) and stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ether and water. The aqueous layer was basified and extracted with ethyl acetate (3x). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a cream powder

(0.09 g). MS (APCI) 435[M+H]⁺

ΗNMR(DMSO-D6) 8.46(1 H, d); 8.40(1 H, dd); 7.83(2H, s); 7.67-7.56(5H, m); 7.33- 7.29(1H, m); 7.08(2H, d); 5.09(1H, d); 3.96(2H, d); 3.83-3.40(lH, m); 2.86-2.63(2H, m); 1.89-1.68(2H, m).

Example 3

(2R)-2-Fluoro-4'-(2hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide. Hydrochloride salt.

a) 4-Bromo-3-fluorobenzenesulfonamide

4-Bromo-3-fluoroaniline (3.49 g, WO9216519) was suspended in concentrated hydrochloric acid (30 ml) and stirred at room temperature for 17 hours. The suspension was cooled to -5 °C and a solution of sodium nitrite (1.42 g) in water (15 ml) was added dropwise at such a rate to maintain the temperature below 0 °C. Magnesium chloride (2.94 g) was added portionwise maintaining the temperature below 0 °C. The resulting mixture was added with stirring to a saturated solution of sulfur dioxide in acetic acid (40 ml), containing cupric chloride (0.98 g) at room temperature. The mixture was stirred at room temperature for 60 minutes, poured into brine and extracted with ethyl acetate. The combined extracts were washed with saturated sodium hydrogen carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an amber oil. The residue was dissolved in tetrahydrofuran (100 ml) and ammonia (0.880, 100ml) was added. The resulting mixture was stirred for 30 minutes and concentrated to afford an aqueous residue which was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined extracts dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was triturated with etheπisohexane (1 :4) and filtered to give the sub-title compound as a pale cream solid (3.47 g).

MS(APCI) 256[M+H]⁺ 'HNMR(DMSO-Do) 7.58(2H, s); 7.62-7.61(lH, m); 7.75-7.72(lH, m); 7.99-7.96(lH, m).

b) (2R)-2-Fluoro-4'-(2-hydroxy-4-pyridin-3-yI-butoxy)-biphenyl-4-sulfonic acid amide. Hydrochloride salt.

(2R)-4-[4-(3-Pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (0.25 g, Example lg), 4-bromo-3-fluorobenzenesulfonamide (0.24 g, Example 3a), 2M aqueous sodium carbonate (0.72 ml) and tetra .i^,(triphenylphosphine)palladium (0) (0.018 g) in ethanol (3 ml) was heated at 90 °C for 10 hours. After cooling, the suspension was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with a gradient of 20-50% ethyl acetate in isohexane to give a white solid. 2M Hydrochloric acid (5 ml) was added to a solution of the solid in methanol (7 ml) and stirred at room temperature for 18 hours. The white precipitate was filtered off, washed with water then ether and dried under vacuum to give the title compound as a white powder. (0.12 g).

MS(APCI) 417[M+H-HC1]⁺

'HNMR(DMSO-D6) 8.82(1H, d); 8.74(1H, dd); 8.43(1H, d); 7.95-7.91(lH, m); 7.75- 7.69(3H, m); 7.53(4H, s); 7.07(2H, d); 3.96(2H, d); 3.84-3.80(lH, m); 3.05-2.86(2H, m); 1.95-1.74(2H, m).

Example 4

(2R)-3,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yI-butoxy)-biphenyI-4-sulfonic acid amide

a) 4-B romo-2,6-difluorobenzenesulf onamide

Prepared by the method as described in Example lh) from 4-bromo-2,6-difluoroaniline (8.35g), concentrated hydrochloric acid (20ml, 12M), sodium nitrite (3.32g dissolved in 20ml water), 6.50g magnesium chloride, acetic acid saturated with sulfur dioxide (50ml), cuprous chloride (CuCl , 2.17g), tetrahydrofuran ( 100ml) and 0.880 sp.gr. ammonia (100ml). The sub-title compound was obtained as a beige solid (6.35g).

MS (APCI)+ 271/272/273/274 (M)⁺

Η NMR (DMSO) 8.07 (2H, bs); 7.69 (2H, m).

b) (3R)-3-[3-(tert-Butyl-dimethylsilyloxy)-4-(3',5'-difluoro-4'-methyl-biphenyl-4- yloxy)-butyl] -py ridine

Prepared according to the method described in Example li from (2R)- 4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (Example lg, 0.250g), 4-bromo-2,6-difluorobenzenesulfonamide, (Example 4a, 0.254g), tetrα/αstriphenylphosphine palladium (0) (0.018g), aqueous 2 molar sodium carbonate (0.72ml) and ethanol (3ml). The reaction was refluxed in a sealed Wheaton vial for ten hours at 90°C. After cooling, brine was added to the reaction mixture and the product was extracted into ethyl acetate three times. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 2: 1 isohexane/acetone to give the subtitle compound as a foam (0.21 lg). Not characterised. Used directly in next step.

c) (2R)-3,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-suIfonic acid amide

Prepared according to the method described in example 3b from (3R)-3-[3-(tert- butyldimethylsilyloxy)-4-(3',5'-difluoro-4'-methyl-biphenyl-4-yloxy)-butyl]-pyridine , (Example 4b, 0.21 lg), methanol (3ml) and 2M aqueous hydrochloric acid (2ml). The reaction was stirred sixteen hours at room temperature and then concentrated under reduced pressure. Water was added to the residue and the resulting solution was neutralised by the addition of aqueous sodium bicarbonate solution. The product was extracted into ethyl acetate and filtered through a pad of silica (isolute syringe), eluting with methanol. The title compound was obtained as a white solid (0.082g). MS (APCI)+ 435.0/436.0/437.0 (M+H)⁺ Η NMR (DMSO) 8.47 (1H, m); 8.40 (1H, m), 7.96 (2H, s); 7.77 (2H, d); 7.76-7.57 (3H, m); 7.31 (1H, m); 7.05 (2H, d); 5.08 (1H, d); 3.96 (2H, d); 3.80 (1H, m); 2.81-2.68 (2H, m); 1.86-1.71 (2H, m).

Example 5

(2R)- 4'-(2-Hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide. Hydrochloride salt.

Prepared according to the method described in Example li) from (2R)- 4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzene boronic acid (Example lg, 0.265g), 4-bromobenzenesulfonamide (0.312g), tetra/αstriphenylphosphine palladium (0) (0.020g), aqueous 2 molar sodium carbonate (0.66ml) and ethanol (3ml) with heating at 90°C for 4 hours. After work-up, the residue was purified by normal phase hplc, eluting with a gradient of 0 to 5% ethanol in dichloromethane. The white solid obtained was dissolved in methanol (5ml) and stirred with two molar hydrochloric acid (2ml) overnight at room temperature. The hydrochloride salt was filtered from the reaction mixture, washed with diethyl ether and dried to give the title compound as a white solid (0.06g).

MS (APCI) 399 ((M-HC1)+H)+ 1H NMR (DMSO-d6) 8.82(1H, d); 8.74(1H, d); 8.43(1H, d); 7.93(1H, q); 7.85(2H, dd); 7.80(2H, dd); 7.67(2H, dd); 7.38(2H, s); 7.05(2H, dd); 3.94(2H, d); 3.83-3.80(lH, m); 3.05-2.95(lH, m); 2.93-2.81(lH, m); 1.98-1.90(1H, m); 1.87-1.76(1H, 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 PGD₂ 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 (IC₅₀).

Claims

1. A compound of formula (I):

(D

wherein; R is hydrogen or fluoro; and n is 0, 1 or 2 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 fluoro.

4. A compound according to claim 3 in which the fluoro group is ortho with respect to the sulfonamide group.

5. A compound according to claim 1 which is;

(2R)-3-Fluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, (2R)-2,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide,

(2R)-2-Fluoro-4'-(2hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, (2R)-3,5-Difluoro-4'-(2-hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-sulfonic acid amide, (2R)- 4'-(2-Hydroxy-4-pyridin-3-yl-butoxy)-biphenyl-4-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 comprisesError! Switch argument not specified.: (a) reaction of a compound of formula (II):

(π)

with a compound of formula (HI):

(DI) in which R is as defined in formula (I), R¹ is a hydroxy protecting group, and one of R7R is triflate or halo and the other is B(OH)₂, or ZnHal, or

(b) for compounds of formula (I), where R and R" are both hydrogen, reaction of a compound of formula (IV), where R⁴ is 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.