The mast cell, by virtue of its capacity to release a variety of pro-inflammatory mediators, proteases and cytokines, its abundant expression of the high-affinity receptor for immunoglobulin E, FcsRI, and its proximity to blood vessels, mucosal surfaces, nerves and smooth muscle, has had a long association with allergic diseases, such as rhinitis and asthma. The mast cells are central to the initiation of the early phase of the allergic inflammatory response (type I hypersensitivity) by releasing e. g. histamine, leukotrienes, platelet activating factor and prostaglandins. More recent clinical studies have demonstrated that activated mast cells express CD40L, an important cell surface ligand expressed by T-cells and critically involved in T/B cell interactions leading to immunoglobulin (IgE) production. Furthermore, activated human mast cells produce and release factors (e. g. IL-3,4,5,6,8,13 and TNFa) thought to be involved in upregulating and maintaining the chronic inflammation.

It is therefore expected that inhibitors of mast cells will be useful for the treatment of allergic diseases. W097/20815, W098/42669, W098/42670 and W098/43971 disclose various pyridine derivatives which are said to be mast cell inhibitors. A series of structurally distinct compounds have now been found to act as mast cell inhibitors and are expected to be particularly useful for the treatment of allergic diseases, especially rhinitis.

In a first aspect the present invention therefore provides a compound of formula (I): where W is oxygen or sulfur; X is a C, 6 alkyl or C24 alkylenyl group; Y is a bond or a C,, 0 alkyl chain optionally substituted by one or more fluorine atoms, and optionally interrupted by one or more oxygen atoms, and

R'is hydrogen or C, 6 alkyl; R2 is phenyl, C, alkyl, a 5-7 membered saturated ring optionally containing 1 or 2 heteroatoms or NHCo2R3 where R3 is C, 4 alkyl; and pharmaceutically acceptable salts and solvates thereof, provided that when Y is a bond, R2 is not Cl 6 alkyl.

Alkyl groups, whether alone or as part of another group, can be straight chained or branched.

The group W can be oxygen or sulfur. Preferably W is oxygen.

Suitably X is a Cl4 alkyl or C26 alkylenyl group 4, preferably X is CH2CH2 or CH=CH.

Suitably Y is a bond or a C1-10 alkyl chain optionally substituted by one or more fluorine atoms, and optionally interrupted by one or more oxygen atoms. Preferably Y is a bond when Ruz ils phenyl or cycloalkyl or Y together with R2 forms an octyl group. When R2 is a 5-7 membered saturated ring optionally containing 1 or 2 heteroatoms examples include morpholine, piperidine and piperazine rings, preferably morpholine.

Suitably R'is hydrogen or C14 alkyl, preferably R'is hydrogen.

Preferably the naphthyl substituent is in the following position: Preferred compounds of the invention include: (2R)3-[6-(2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]- N-octyl-acrylamide, (2R)3-[6-(2-Hydroxy-4-pyridin-3-yl-butaxy)-naphthalen-2-yl]- N-octyl-propionamide, (2R)3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-phenyl- acrylamide, (2R)3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-phenyl- propionamide,

(2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N- (4-phenyl-butyl)- propionamide, (2R) N-Cyclohexyl-3- [6- (2-hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]- propionamide, (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N- (3-morpholin-4-yl- propyl)-propionamide, (2R) (10- {3- [6-(2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-propio nylamino}- decyl)-carbamic acid tert-butyl ester, and pharmaceutically acceptable salts 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: Certain compounds of the invention and intermediates to the compounds of the invention can be prepared using procedures disclosed or analogous to those described in W097/20815, W098/42669, W098/42670 and W098/43971. In particular a compound of formula (I) can be prepared by reacting a compound of formula (II):

where W and X are as defined in formula (I), with a compound of formula (III): where Y, Rl and R2 are as defined in formula (I), or reacting a compound of formula (IV): where W is as defined in formula (I) and Ris halogen with a compound of formula (V): where Y, R'and W are as defined in formula (I) or are protected derivatives thereof and X is C26 alkenyl, and thereafter, optionally if appropriate and in any order: * removing any protecting groups . converting a compound of formula (I) into a further compound of formula (I)

* forming a pharmaceutically acceptable salt.

Compounds of formula (II) can be reacted with compounds of formula (III) using standard conditions for forming amide bonds which are known in the art and exemplified herein.

Compounds of formula (IV) can be reacted with compounds of formula (V) using standard conditions. Preferably compounds of formulae (IV) and (V) are reacted in the presence of a palladium catalyst ate elevated temperature as exemplified herein.

A compound of formula (I) can be converted into a further compound of formula (I) using known procedures. For example, a compound of formula (I) where X is C26 alkenyl can be converted into a compound of formula (I) where X is alkyl by hydrogenation.

Certain groups in intermediate compounds may need to be protected before reaction of the intermediates. 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).

Intermediate compounds of formulae (II), (III), (IV) and (V) can be prepared using known methods such as those disclosed in W097/20815, W098/42669, W098/42670 and W098/43971. All 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 herein.

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 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 different types of rhinitis.

Administration of the compounds of the invention is preferably by a topical route, for example by inhalation to the lung or more preferably by topical administration to the nose.

The compounds of the invention may be inhaled as a dry powder from an inhaler 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 administration are in the range from 0.001 to 30 mg kg-'day-', for example 0.1 mg kg''day'.

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.

The invention is illustrated by the following examples.

Example 1 (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-octyl-a crylamide A mixture of (2R) 1- (6-Bromo-naphthalen-2-yloxy)-4-pyridin-3-yl-butan-2-ol (0.200g; see Example 1 of International Patent Application WO 98/42669), N-Octyl-acrylamide (0.996g), palladium acetate (0.012g), tri-o-tolylphospine (0.033g) and triethylamine (0.23ml) in acetonitrile (2 ml) were heated at 80°C in a sealed tube for 16 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with ethylacetate followed by ethylacetate/methanol (20: 1) to give the title compound (0.21g).

'H NMR (CDC13) 8.52 (1H, d); 8.45 (1H, dd); 7.74 (1H, s); 7.72 (1H, d); 7.62 (1H, d); 7.60-7.54 (3H, m); 7.23 (1H, dd); 7.09 (1H, dd); 7.02 (1H, d); 6.48 (1H, d); 6.08 (1H, t); 4.10-3.94 (3H, m); 3.39 (2H, q); 2.98-2.76 (2H, m); 1.93 (2H, m); 1.58 (2H, m); 1.41-1.19 (10H, m); 0.87 (3H, t).

Example 2 (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-octyl-p ropionamide To a solution of (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-octyl- acrylamide (0.154g; Example 1) in methanol (10ml) and dimethylformamide (0.5ml) was added 10% palladium on carbon (0.021g). The mixture was hydrogenated at 1 atm for 18 hours. The reaction mixture was filtered through Celite# to remove catalyst and the filter cake was washed with methanol. The combined solutions were concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with ethylacetate/methanol (20: 1) to give (0.127g).

'H NMR (CDC13) 8.54 (1H, d); 8.47 (1H, d); 7.67 (1H, dd); 7.59 (1H, d); 7.57 (1H, s); 7.31 (1H, dd); 7.24 (1H, dd); 7.13 (1H, dd); 7.09 (1H, d); 5. 30 (1H, t); 4.08 (2H, m); 3.98 (1H, dd); 3.19 (2H, q); 3.10 (2H, t); 2.99-2.77 (2H, m); 2.53 (2H, t); 1.95 (2H, m); 1.37 (2H, m); 1.32-1.12 (10H, m); 0.88 (3H, t).

Example 3 (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-phenyl- acrylamide Prepared according to method described in Example 1 from (2R) 1-(6-Bromo-naphthalen- 2-yloxy)-4-pyridin-3-yl-butan-2-ol (0.200g; see Example 1 of International Patent Application WO 98/42669), N-Acryloyl aniline (0.795g), palladium acetate (0.012g), tri-o- tolylphospine (0.033g) and triethylamine (0.23ml) in acetonitrile (2 ml) were heated at 80°C in a sealed tube for 16 hours. Purified by flash chromatography over silica gel eluting with ethylacetate to give the title compound (0.11 g).

'H NMR (CDC13) 8.32 (1H, d); 8.26 (1H, dd); 7.76 (1H, s); 7.71 (1H, d); 7.64 (1H, d); 7.62-7.52 (SH, m); 7.26-7.15 (3H, m); 7.09-6.96 (3H, m); 6.65 (1H, d); 3.97-3.87 (3H, m); 2.89-2.62 (2H, m); 1.85 (2H, m) Example 4 (2R) 3-[6-(2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-ph enyl- propionamide Prepared according to method described in Example 2 from (2R) 3- [6- (2-Hydroxy-4- pyridin-3-yl-butoxy)-naphthalen-2-yl]-N-phenyl-acrylamide (0.18g, Example 3) in methanol (20ml) and dimethylformamide (3.5ml) with 10% palladium on carbon (0.040g) . Purified by preparative HPLC (CH3CN+0. 1% TFA: H20+0.1% TFA) (40: 60) to give (0.15g).

'H NMR (CDCl3) 8.52 (1H, s); 8.47 (1H, d); 7.66 (2H, dd); 7.60 (1H, s); 7.58 (1H, d); 7.43 (2H, d); 7.23 (1H, dd); 7.36-7.21 (3H, m); 7.15-7.06 (3H, m); 4.06-3.94 (3H, m); 3.18 (2H, t); 2.98-2. 76 (2H, m); 2.73 (2H, t); 2.04-1.82 (2H, m).

Example 5 (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N- (4-phenyl-butyl)- propionamide (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-propionic acid (0.065g, see Example 9 of International Patent Application WO 98/42669), 0- (7-azabenzotriazol-lyl)- 1,1,3,3-tetramethyluronium hexafluorphosphate (HATU) (0.068g) and diisopropylethylamine (DIEA) (PH 7) were dissolved in dichloromethane (3ml). After 30

min 4-Phenyl-butylamine (0.032ml) was added and the mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane : methanol (95: 5) to give the title compound (0.024g).

'H NMR (CDCl3) 8.54 (1H, d); 8.47 (1H, dd); 7.66 (2H, dd); 7.61 (1H, dt); 7.57 (1H, s); 7.31 (1H, dd); (3H, m); 7.20-7.08 (SH, m); 4.06 (2H, m); 3.97 (1H, dd); 3.22 (2H, q); 3.10 (2H, t); 3.00-2.78 (2H, m); 2.53 (2H, t); 2.52 (2H, t); 2.04-1.77 (3H, m); 1.56- 1.36 (4H, m).

Example 6 (2R) N-Cyclohexyl-3- [6- (2-hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]- propionamide Prepared according to the method in Example 5 from (2R) 3- [6- (2-Hydroxy-4-pyridin-3- yl-butoxy)-naphthalen-2-yl]-propionic acid (0.150g, see Example 9 of International Patent Application WO 98/42669), 0- (7-azabenzotriazol-lyl)-1, 1, 3,3-tetramethyluronium hexafluorphosphate (HATU) (0.156g) and diisopropylethylamine (DIEA) (PH 7) were dissolved in dichloromethane (4ml). After 30 min Cyclohexylamine (0.047ml) was added and the mixture stirred at room temperature for 2 hours. Purified by column chromatography over silica eluting with dichloromethane: methanol (90: 10) and by preparative HPLC (CH3CN+0.1% TFA: H20+0.1% TFA) (38: 62) to give the title compound (0.060g).

'H NMR (CDC13) 8.54 (1H, d); 8.48 (1H, dd); 7.67 (2H, t); 7.60 (1H, dt); 7.58 (1H, s); 7.32 (1H, dd); 7.24 (1H, dd); 7.14 (1H, dd); 7.10 (1H, m); 4.09 (2H, m); 3.99 (1H, dd); 3.75 (1H, m); 3.10 (2H, t); 2.99-2.77 (2H, m); 2.50 (2H, t); 2.04-1.84 (2H, m); 1.82 (2H, d); 1.67-1.53 (6H, m); 1.39-1.25 (2H, m); 1.10 (1H, m); 1.04-0.92 (2H, m) Example 7 (2R) 3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yl]-N- (3-morpholin-4-yl- propyl)-propionamide Prepared according to the method in Example 5 from (2R) 3- [6- (2-Hydroxy-4-pyridin-3- yl-butoxy)-naphthalen-2-yl]-propionic acid (0.150g, see Example 9 of International Patent Application WO 98/42669), 0- (7-azabenzotriazol-lyl)-1, 1, 3,3-tetramethyluronium

hexafluorphosphate (HATU) (0.156g) and diisopropylethylamine (DIEA) (PH 7) were dissolved in dichloromethane (4ml) and dimethylformamide (2ml). After 60 min 3- Morpholin-4-yl-propylamine (0.061ml) was added and the mixture was stirred at room temperature for 15 hours. Purified by column chromatography over silica eluting with dichloromethane: methanol (90: 10) and by preparative HPLC (CH3CN+0.1% TFA: H20+0.1% TFA) (26: 74) to give the title compound (0.060g).

'H NMR (CD30D) 8.80 (1H, d); 8.69 (1H, d); 8.57 (1H, dt); 8.01 (1H, dd); 7.70 (2H, d); 7.60 (1H, s); 7.35 (1H, dd); 7.22 (1H, d); 7.15 (1H, dd); 4.10-3.96 (3H, m); 3.88 (2H, d); 3.62 (2H, t); 3.18 (2H, t); 3.16-2.98 (6H, m); 2.67-2.51 (6H, m); 2.17-1.92 (2H, m); 1.68 (2H, m).

Example 8 (2R) (10- {3- [6- (2-Hydroxy-4-pyridin-3-yl-butoxy)-naphthalen-2-yll-propionyl amino}- decyl)-carbamic acid tert-butyl ester Prepared according to the method in Example 5 from (2R) 3- [6- (2-Hydroxy-4-pyridin-3- yl-butoxy)-naphthalen-2-yl]-propionic acid (O. 1 OOg, see Example 9 of International Patent Application WO 98/42669), 0- (7-azabenzotriazol-lyl)-1, 1, 3,3-tetramethyluronium hexafluorphosphate (HATU) (0.104g) and diisopropylethylamine (DIEA) (PH 7) were dissolved in dichloromethane (4ml) and dimethylformamide (2ml). After 30 min (10- Amino-decyl)-carbamic acid tert-butyl ester (0.074mg) was added and the mixture stirred at room temperature for 1 hour. Purified by preparative HPLC (CH3CN+0.1% TFA: H20+0.1% TFA) (25: 75 to 45: 55) to give the title compound as trifluoroacetic acid salt. The salt was converted to free base with dichloromethane/saturated sodium hydrogen carbonate.

'H NMR (CDCl3) 8.54 (1H, s); 8.47 (1H, d); 7.66 (2H, t); 7.61 (1H, dt); 7.57 (1H, s); 7.31 (1H, dd); 7.26 (1H, dd); 7.13 (1H, dd); 7.09 (1H, d); 4.10-4.03 (2H, m); 3.99 (1H, dd); 3.18 (2H, q); 3.10 (4H, m); 3.01-2.77 (2H, m); 2.53 (2H, t); 2.03-1.86 (2H, m); 1.45 (9H, s); 1.40-1.08 (16H, m).

Pharmacological data Allergic rhinitis model Anaesthetised guinea-pigs, sensitised to produce IgE antibodies, are exposed to allergen (ovalbumin, OA) by intranasal administrations (lOul per nostril). For evaluation of the early allergic reaction (EAR) the experiments are terminated 20 min after challenge. A lavage of the nasal cavitites is performed. For evaluation of the late allergic reaction (LAR) the termination time is 5-8 h after challenge.

Clinical relevant read outs in lavage fluid and nasal tissue are: EAR LAR Mucosal exudation Mucosal exudation Histamine Histamine Leukotrienes Leukotrienes Inflammatory cells (eosinophils) Pretreatments with compounds are performed by single or repeteated intranasal administrations 30 min to 5h prior to allergen challenge.

Ref.: I. Erjefalt et. al., Am Rev Respir Dis Vol 148. pp 695-701,1993