EP1115705A1 - Novel compounds - Google Patents

Novel compounds

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Publication number
EP1115705A1
EP1115705A1 EP99952851A EP99952851A EP1115705A1 EP 1115705 A1 EP1115705 A1 EP 1115705A1 EP 99952851 A EP99952851 A EP 99952851A EP 99952851 A EP99952851 A EP 99952851A EP 1115705 A1 EP1115705 A1 EP 1115705A1
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EP
European Patent Office
Prior art keywords
compound
formula
compounds
salt
rhinitis
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99952851A
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German (de)
French (fr)
Inventor
David Cheshire
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1115705A1 publication Critical patent/EP1115705A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms

Definitions

  • This invention relates to novel pyridyl derivatives, their use as medicaments, pharmaceutical formulations including them and methods for their preparation.
  • PCT Patent Application PCT/SE98/00423 discloses certain pyridine alkanol derivatives having activity as mast cell antagonists.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • the compound 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 and methanesulphonic acids.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric 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.
  • the compound of formula (I) has the stereochemistry shown below:
  • the compound of formula (I) can be prepared using the methods described in PCT/SE98/00423.
  • the invention also provides a process for the preparation of compounds of formula (I) as hereinbefore defined which comprises: (a) reaction of a compound of formula (II):
  • R is a suitable protecting group such as tertiary butyl (b) reaction of ( ⁇ )-3-(2-oxiranylethyl)pyridine or ⁇ -(chloromethyl)-3-pyridinepropanol either with a compound of formula (IV):
  • R is as defined above and M is Li, Na, K or MgHal where Hal is halogen, for example at ambient or elevated temperature in a suitable solvent such as dimethylformamide or tetrahydrofuran; or with a compound of formula (U) as defined above in the presence of a base such as sodium hydroxide in a suitable solvent such as aqueous ethanol, or and optionally thereafter (a) or (b):
  • reaction can be carried out in a solvent such as chloroform at elevated temperature, preferably at reflux temperature.
  • 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.
  • Suitable protecting groups for sulfonamide include alkyl groups, in particular tertiary butyl.
  • the protection and deprotection of functional groups may take place before or after a reaction step.
  • Novel intermediates form a further aspect of the invention.
  • the compound 6-(2-hydroxy-4-pyridin-3-yl-butoxy)-naphthylene-2-sulfonyl tert-butylamide forms an 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.
  • 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 (AR-DS), emphysema and alveolitis, for example cryptogenic fibrosing alveolitis.
  • asthma e.g. bronchial, allergic, intrinsic asthma, extrinsic and chronic asthma
  • associated manifestations of the disease late responses, hyper-responsiveness
  • fibrosis e.g. bronchial, allergic, intrinsic asthma, extrinsic and chronic asthma
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compressed gas e.g. nitrogen
  • a liquefied gas propellant e.g. a liquefied gas propellant
  • 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.
  • 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.
  • 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 3 mg kg "1 day “1 .
  • 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 hydrochloride salt was formed by dissolving the free base in hot methanol (50 ml) and adding 6N ethanolic hydrogen chloride. The resulting white solid was filtered off and dried in vacuo
  • the hydroxy- naphthalene (2) (36g, 0.13mol) was added to the filtrate, washed in with NMP (42ml), followed by cesium carbonate (18g, O.O ⁇ mol) also washed in with NMP (42ml).
  • the reaction was heated at 100°C for approximately 20 hours, and then cooled to ambient temperature.
  • 2M HCl (aq ) (481ml) was added cautiously, producing an exotherm of approximately 15°C and vigorous effervescence.
  • Water (IL) was added and the solution was extracted into ethyl acetate (3x800ml).
  • the aqueous layer was basified using 2M NaOH (842ml) and the product was extracted into ethyl acetate (3x800ml).
  • 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: L — inhibition of histamine, LTC and PGD 2 release from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells', J. Immunol., vol. 137, 3941, 1986.
  • the compound exemplified were tested and found to inhibit histamine release at a concentration of less than 10 "4 M (IC 50 ).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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

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/SE98/00423 discloses certain pyridine alkanol derivatives having activity as mast cell antagonists.
It has now surprisingly been found that a compound within the scope of PCT/SE98/00423 but not specifically disclosed therein exhibits advantageous pharmacokinetics and physical properties. For example, the compound had improved physical properties which led to a reduced plasma binding in blood and increased systemic exposure.
In a first aspect the present invention therefore provides a compound of formula (I) or a salt thereof:
(I)
The compound 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 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 compound of formula (I) has the stereochemistry shown below:
The compound of formula (I) can be prepared using the methods described in PCT/SE98/00423.
Therefore the invention also provides a process for the preparation of compounds of formula (I) as hereinbefore defined which comprises: (a) reaction of a compound of formula (II):
(H)
with a compound of formula (DI):
where R is a suitable protecting group such as tertiary butyl (b) reaction of (±)-3-(2-oxiranylethyl)pyridine or α-(chloromethyl)-3-pyridinepropanol either with a compound of formula (IV):
where R is as defined above and M is Li, Na, K or MgHal where Hal is halogen, for example at ambient or elevated temperature in a suitable solvent such as dimethylformamide or tetrahydrofuran; or with a compound of formula (U) as defined above in the presence of a base such as sodium hydroxide in a suitable solvent such as aqueous ethanol, or and optionally thereafter (a) or (b):
• removing any protecting groups, and/or • forming a pharmaceutically acceptable salt.
Reaction of compounds of formulae (LI) and (LU) can be carried out the presence of a suitable base in an inert solvent at elevated temperature, for example using cesium carbonate in dimethylformamide at about 100°C.
Compounds of formula (II) can be prepared by treating compounds of formula (V):
(V)
with l,l'-carbonyldiimidazole. The reaction can be carried out in a solvent such as chloroform at elevated temperature, preferably at reflux temperature.
Compounds of formula (IN) and (V) are commercially available or can be prepared using known techniques. 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. Suitable protecting groups for sulfonamide include alkyl groups, in particular 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. In particular the compound 6-(2-hydroxy-4-pyridin-3-yl-butoxy)-naphthylene-2-sulfonyl tert-butylamide forms an 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 (AR-DS), 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, especially the treatment and prophylaxis of asthma and rhinitis.
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 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)-6-(2-Hydroxy-4-pyridin-3-ylbutoxy)naphthalene-2-sulfonamide, hydrochloride salt
a) 6-Hydroxynaphthalene-2-sulfonic acid tert-butyl amide
A solution of 2-naphthol-6-sulfonic acid, sodium salt (10 g) in dry dimethylformamide (100 ml) was cooled to 5°C and thionyl chloride (10 ml) was added drop wise. The mixture was allowed to warm to room temperature and stirred for 30 minutes. tert-Butylamine (40 ml) was then added to the reaction dropwise and the mixture stirred under nitrogen for 5hours. The mixture was then poured into 2N hydrochloric acid (500 ml) and extracted into ethyl acetate (3x300 ml). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica, eluting with wohexane/ethyl acetate (2:1) to give the sub-title compound as a solid (lg). MS (APCI) 278 (M-H)+
1H NMR (DMSO-d6) 10.17(1H, s); 8.28 (1H, s); 7.99-7.96(lH, d); 7.86-7.82(lH, AB); 7.74-7.71(lH, AB); 7.47(1H, s); 7.21-7.17(2H, m); 1.08(9H, s).
b) (2R, 3 /Z)-4-(3-Pyridyl)-l,2-0-wopropylidenebut-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 2,3-0-(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).
c) (2R)-4-(3-Pyridyl)-l,2-0-wopropylidenebutane-l,2-diol
A solution of (2R, 3E/Z)-4-(3-pyridyl)-l,2-0-wσpropylidenebut-3-en-l,2-diol (21.2 g, Example lb) 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)+ 1H 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).
d) (2R)-4-(3-PyridyI)-l,2-butanediol
(2R)-4-(3-Pyridyl)-l,2-0-.-?opropylidenebutane-l,2-diol (20.4 g, Example c) 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)+ 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).
e) (2R)-4-[2-(3-Pyridyl)ethyI]-l,3-dioxin-2-one A solution of (2R)-4-(3-pyridyl)- 1 ,2-butanediol (0.42 g, Example d) and 1 , 1 '-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 subtitle 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).
f) (2R)-6-(2-Hydroxy-4-pyridin-3-ylbutoxy)naphthalene-2-sulfonic acid tert-butyl amide.
A mixture of (2R)-4-[2-(3-pyridyl)ethyl]-l,3-dioxin-2-one (Example le, 1.33 g), 6- hydroxynaphthalene-2-sulfonic acid ten- butyl amide (Example la, 1.6 g), cesium carbonate (2.25 g) and dimethyl formamide (25 ml) were heated together at 100°C, under nitrogen, for 20 hours. The mixture was then cooled, poured into water (200 ml) and extracted into ethyl acetate (3 x 200 ml). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the sub-title compound (1.17 g). MS (APCI) 429 (M+H)+
Η NMR (CDC13) 8.54-8.53(lH, d); 8.49-8.46(lH, dd); 8.36(1H, s); 7.87-7.80(3H, m); 7.59-7.56(lH, m); 7.27-7.15(3H, m); 4.53(1H, s); 4.13-4.01(3H, m); 2.96-2.75(2H, m); 2.46(1H, s); 1.98-1.93(2H, m); 1.24(9H, s).
g) (2R)"6-(2-Hydroxy-4-pyridin-3-yIbutoxy)naphthalene-2-sulfonic acid amide, hydrochloride salt (2R)-6-(2-Hydroxy-4-pyridin-3-ylbutoxy)naphthalene-2-sulfonic acid tert-butyl amide (Example If, 1.17 g), trifluoroacetic acid (12 ml) and dry dichloromethane (12 ml) were stirred together at room temperature, under nitrogen, for 20 hours. The reaction mixture was then concentrated under reduced pressure. To the residue was added methanol (5 ml) and aqueous ammonia solution (5 ml, 10%w/v) and the mixture stirred for 10 minutes. The methanol was removed in vacuo and the resulting aqueous solution was extracted into ethyl acetate (3 x 50 ml), dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica, eluting with 2% methanol in dichloromethane to give the title compound as its free base.
MS (APCI) 373 (M+H)+
Η NMR (DMSO-d6) 8.48-8.47(lH, d); 8.41-8.38 (IH, dd); 8.33(1H, d); 8.05-8.02(lH, d); 7.98-7.95(lH, d); 7.83-7.82(lH, d); 7.80-7.79(lH, d); 7.69-7.65(lH, m); 7.43-7.42 (IH, d); 7.35-7.28 (4H, ); 5.14-5.12 (IH, d); 4.06-4.04 (2H, d); 3.89-3.84 (IH, m); 2.87-2.64 (2H, m); 1.94-1.71 (2H, m).
The hydrochloride salt was formed by dissolving the free base in hot methanol (50 ml) and adding 6N ethanolic hydrogen chloride. The resulting white solid was filtered off and dried in vacuo
MS (APCI) 373 (M+H-HC1)+
1H NMR (DMSO-d6) 8.82(1H, s); 8.73-8.72 (IH, d); 8.42-8.39(lH, d); 8.33(1H, s); 8.06- 7.80(4H, m); 7.44-7.43(1H, d); 7.36(2H, s); 7.31-7.27(1H, dd); 4.07-4.05(2H, d); 3.92- 3.85(1H, m); 3.04-2.84 (2H, m); 2.03-1.77 (2H, m).
Example 2
6-(2-hydroxy-4-pyridin-3-yl-butoxy)-naphthylene-2-sulfonyl t'ert-butylamide (alternative procedure)
4-(2-Pyridin-3-yl-ethyl)-[l,3]dioxolan-2-one oxalate (36.6g, 0.13mol) was dissolved in 290ml NMP. Imidazole (18g, 0.26mol) was added and the line washed with NMP (12ml). The reaction was stirred at rt for 2 hours. The resulting insoluble imidazole oxalate salt was removed by filtration and the cake washed with NMP (3x20ml). The hydroxy- naphthalene (2) (36g, 0.13mol) was added to the filtrate, washed in with NMP (42ml), followed by cesium carbonate (18g, O.Oόmol) also washed in with NMP (42ml). The reaction was heated at 100°C for approximately 20 hours, and then cooled to ambient temperature. 2M HCl(aq) (481ml) was added cautiously, producing an exotherm of approximately 15°C and vigorous effervescence. Water (IL) was added and the solution was extracted into ethyl acetate (3x800ml). The aqueous layer was basified using 2M NaOH (842ml) and the product was extracted into ethyl acetate (3x800ml). This solution was concentrated to give a brown oil, which was washed with water (1800ml) and ethyl acetate (200ml) to remove residual NMP, and extracted into ethyl acetate (2x400ml). The ethyl acetate solution was dried and concentrated to yield the desired sulphonamide naphthalene alcohol product (3) (46g, 84%) as a foam. LC MS : mass 429.1 (M+) HPLC Purity : 89.6% Η NMR : δH 1.15 (9H, s, NH(CH3)3), δH 1.9 (2H, m, PyCH2CH3), δH 2.7 (2H, m, PyCH2CH2), δH 3.9 (IH, m, PyCH2CH2CHOH), δH4.06 (2H, d, J5.9,
PyCH2CH2CH(OH)CH2), δH 5.2 IH, d, J7.4, PyCH2CH2CH(OH)), δH 7.27, (IH, m, NpH), δH7.29, (IH, m, PyH), δH 7.4 (IH, d, J2.2, NpH), δH7.5 (IH, S, SO2NH(CH3)3), δπ 7.65 (IH, d, J7.8, PyH), δH 7.8, (IH, dd, J8.8, J1.4, NpH), δH 7.9 (IH, d, J8.9, NpH), δH 8.06 (IH, d, J8.8, NpH), δH8.3, (IH, d, J1.2, NpH), δH 8.4 (IH, dd, J4.5, J1.3, PyH), δπ 8.49 (IH, d, J2.5, PyH)
(2R)-6-(2-Hydroxy-4-pyridin-3-ylbutoxy)naphthalene-2-sulfonamide hydrochloride salt
6-(2-hydroxy-4-pyridin-3-yl-butoxy)-naphthylene-2-sulfonyl tert-butylamide (46g,
0.1 lmol) was suspended in MeOH (370ml) and concentrated HCl (185ml) was added. The solution was heated at reflux for 18 hours and then allowed to cool to it. The solid crystalline product began to precipitate from the reaction mixture at approximately 40°C. Ethyl acetate (400ml) was added and the slurry was allowed to stir for 2 hours to remove any trace of the regioisomer (6). The product was collected by filtration and dried in a vacuum oven to yield the desired AR-C125630AA (4) (29g, 66%). LC/MS : mass 373.1 (M+) HPLC Purity : 99.8%
1H NMR : δH 1.97 (2H, m, PyCH2CH2), δH 3.9 (2H, m, PyCH2), δH 3.9 (IH, m, PyCH2CH2CH(OH)), δH 4.1 (2H, d, J6.7, CH(OH)CH2), δn 7.2 (IH, d, J7.4, NpH), δπ 7.4 (2H, s, SO2NH2), δH 7.5 (IH, s, NpH) δH7.8 (IH, d, J7.4, PyH) δn 8.0 (2H, m, PyH+NpH), δH 8.05 (IH, d, J7.8, NpH), δH 8.3 (IH, s, NpH), δH 8.5 (IH, d, J7.4, NpH), δH 8.8 (IH, d, J6.7, PyH), δπ 8.9 (IH, s, PyH)
6-(2-Hydroxy-4-pyridiπ-3-ylbutoxy)naphthaIene-2-sulfonamide
(2R)-6-(2-Hydroxy-4-pyridin-3-ylbutoxy)naphthalene-2-sulfonamide hydrochloride salt (158g, 0.39mol) was suspended in methanol (IL). 1M NaOH (406ml, 0.39mol, 1 molar equivalent) was added and the whole stirred at rt for 2 hours. Water (1375ml) was added to the resulting slurry and the mixture stirred for a further hour. The crystalline product was isolated by filtration and the cake washed with 9: 1 water: methanol (680ml). The white crystalline product was then dried in a vacuum oven to yield AR-C125630XX (5) (140g, 97%)
LC/MS : 373 mass (M+) HPLC Purity : 99.8% Η NMR : δH 1.9 (2H, m, PyCH2CH2), δH 2.7 (2H, m, PyCH2), δH 3.88 (IH, m,
CH(OH)H), δH 4.06 (2H, d, J7.4, CH(OH)CH2), δH 5.1 (IH, d, J6.2, CH(OH)), δH 7.3 (IH, dd, J2.8, J6.5, NpH), δH 7.3 (IH, d, J2.1, PyH), δH 7.35 (2H, s, NH2), δH 7.45 (IH, d, J2.5, NpH), δH 7.7 (IH, d, J6.1, PyH), δH 7.83 (IH, d, J2.2, J8.8, NpH), δH 7.95 (IH, d, J8.5, NpH,), δH 8.0 (IH, d, J8.4, NpH), δu 8.35 (IH, d, Jl.l, NpH), δH 8.4 (IH, d, J3.1, PyH), δH 8.5 (lH, d, J1.0, PyH)
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: L — inhibition of histamine, LTC and PGD2 release from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells', J. Immunol., vol. 137, 3941, 1986.
The compound exemplified were tested and found to inhibit histamine release at a concentration of less than 10"4 M (IC50).

Claims

Claims
1. A compound of formula (I) or a salt or solvate thereof:
2. A compound according to claim 1 which is:
(2R)-6-(2-hydroxy-4-pyridin-3-ylbutoxy)naphthalene-2-sulfonic acid amide, or a salt or solvate thereof.
3. A compound according to claim 1 or 2 for use in therapy.
4. Use according to claim 3 wherein the disease is asthma or rhinitis.
5. A pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof as defined in claim 1 or 2 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
6. 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.
7. A process for the preparation of compounds of formula (I) which comprises: (a) reaction of a compound of formula (II):
(ID with a compound of formula (HI):
where R is a suitable protecting group, or
(b) reaction of (±)-3-(2-oxiranylethyl)pyridine or α-(chloromethyl)-3-pyridinepropanol either with a compound of formula (IV):
where R is as defined above and where M is Li, Na, K or MgHal where Hal is halogen; or with a compound of formula (H) as defined above in the presence of a base, and optionally thereafter (a) or (b):
• removing any protecting groups, and/or
• forming a pharmaceutically acceptable salt.
8. A compound of formula (DT) as defined in claim 7.
9. 6-(2-hydroxy-4-pyridin-3-yl-butoxy)-naphthylene-2-sulfonyl tert-butylamide:
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