EP1115401A1 - Neue verbindungen - Google Patents

Neue verbindungen

Info

Publication number
EP1115401A1
EP1115401A1 EP99969715A EP99969715A EP1115401A1 EP 1115401 A1 EP1115401 A1 EP 1115401A1 EP 99969715 A EP99969715 A EP 99969715A EP 99969715 A EP99969715 A EP 99969715A EP 1115401 A1 EP1115401 A1 EP 1115401A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
compounds
hydroxy
pyridine
Prior art date
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.)
Withdrawn
Application number
EP99969715A
Other languages
English (en)
French (fr)
Inventor
David AstraZeneca R&D Charnwood CHESHIRE
Mark AstraZeneca R&D Charnwood Furber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1115401A1 publication Critical patent/EP1115401A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached

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/SE98/00575 discloses certain pyridine alkanol derivatives and their activity as mast cell antagonists.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • R is hydrogen, chloro or fluoro or a salt or solvate thereof.
  • R is hydrogen, chloro or fluoro, preferably R is hydrogen.
  • the right hand pyridyl group can be attached to the neighbouring phenyl ring at the 2-, 3- or 4-positions.
  • the sulfonamide group can then be attached to any free position of the pyridyl ring, preferably the sulfonamide is para with respect to the phenyl group.
  • these groups are attached as shown below:
  • Particularly preferred compounds of the invention include: 6-[2-Chloro-4-(2-hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide, 6-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)-benzene]-pyridine-3-sulfonic acid amide, (2R)-5-[4-(2-Hydroxy-4-pyridin-3-yl-butoxy)benzene]pyridine-2-sulfonic acid amide, or salts or solvates thereof.
  • Compounds of the invention can form pharmaceutically acceptable solvates and salts.
  • the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, trifluoroacetic and methanesulphonic acids.
  • 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.
  • the compounds of formula (I) have the following stereochemistry:
  • 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
  • Reaction of compounds of formulae (LI) and (III) can be carried out under the conditions of the Suzuki reaction (Synthetic Communications 11(7), 513-519, 1981) for example at 100 °C in the presence of a suitable catalyst and base (e.g. tetrakis(triphenylphosphine)- palladium(O) and aqueous sodium carbonate) in a suitable solvent (e.g. ethanol/toluene).
  • a suitable catalyst and base e.g. tetrakis(triphenylphosphine)- palladium(O) and aqueous sodium carbonate
  • a suitable solvent e.g. ethanol/toluene
  • Process (b) is ca ⁇ ied 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).
  • suitable base e.g. cesium carbonate
  • organic solvent e.g. dimethylformamide
  • 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).
  • an appropriate solvent e.g. toluene
  • R is as defined above using conventional procedures, for example hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate, followed by debenzylation using conventional methods such as those described in Protective Groups in Organic Synthesis', 2 nd Edition, T.W. Greene & P.G.M. Wuts, Wiley-Interscience (1991).
  • M is lithium, sodium, potassium, MgX or ZnX, where X is halogen, optionally in the presence of additives such as boron trifluoride.
  • 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.
  • 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.
  • 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.
  • asthma e.g. bronchial, allergic, intrinsic asthma, extrinsic and chronic asthma
  • associated manifestations of the disease late responses, hyper-responsiveness
  • COPD chronic obstructive airways disease
  • COPD chronic obstructive airways disease
  • ARDS adult
  • 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.
  • the compounds of the invention are indicated in the treatment and prevention of tumours and other proliferative diseases.
  • a reversible obstructive airways disease most particularly asthma and 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.
  • 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 " day " , for example 0.3 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 mixture was warmed up to room temperature, extracted with Ethyl acetate (3 times 100 ml), and the organic layers dried over anhydrous magnesium sulfate.
  • the crude material was purified on a silica gel column (ethyl acetate then dichloromethane: methanol / 9: 1) to afford the sub-title compound as a white glass (2.4 g, 87%).
  • the reaction mixture was concentrated under reduced pressure, the residue taken in water (5 ml), extracted with ethyl acetate (3 times, 10 ml) and the combined organic layers dried over anhydrous magnesium sulfate.
  • the solution was filtered, concentrated under vacuum and the crude material purified by column chromatography over silica eluting with ethyl acetate : hexane (1 : 1) to give a solid.
  • This material was dissolved in methanol (10 ml) and treated with 2M hydrochloric acid (10 ml). After 3 hours, the methanol was removed under reduced pressure and the solution neutralised with solid sodium hydrogen carbonate.
  • the aqueous phase was then extracted with ethyl acetate (3 times 10 ml), the combined organic layers dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound as a white solid.
  • 5-bromopyridine-2-thiol (Example 3a, 1 g) was suspended in concentrated hydrochloric acid (8 ml) and cooled to 10°C. Excess chlorine gas was bubbled through the suspension for 30 minutes. The mixture was then poured into ice/water (10 ml) and the resultant solid filtered off. This was dissolved in tetrahydrofuran (20 ml) and aqueous ammonia solution (12 ml) was added. The mixture was stirred under nitrogen at room temperature for 1.5 hours then concentrated under reduced pressure to yield the sub-title compound as a solid (1.23 g).
  • 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, LTC 4 and PGD release from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells', J. Immunol., vol. 137, 3941, 1986.
  • the compounds exemplified were tested and found to inhibit histamine release at a concentration of less than 10 "4 M (IC 0 ).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
EP99969715A 1998-09-25 1999-09-17 Neue verbindungen Withdrawn EP1115401A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9803279 1998-09-25
SE9803279A SE9803279D0 (sv) 1998-09-25 1998-09-25 Novel compounds
PCT/SE1999/001631 WO2000018731A1 (en) 1998-09-25 1999-09-17 Novel compounds

Publications (1)

Publication Number Publication Date
EP1115401A1 true EP1115401A1 (de) 2001-07-18

Family

ID=20412738

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99969715A Withdrawn EP1115401A1 (de) 1998-09-25 1999-09-17 Neue verbindungen

Country Status (4)

Country Link
EP (1) EP1115401A1 (de)
AU (1) AU1192200A (de)
SE (1) SE9803279D0 (de)
WO (1) WO2000018731A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1187617E (pt) 1999-06-18 2004-06-30 Alcon Mfg Ltd Metodo para seleccionar a concentracao de um farmaco antipatico anti-histaminico pela determinacao da taxa de actividade superficial do farmaco

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ323521A (en) * 1995-12-06 1999-10-28 Astra Pharma Prod Compounds for treating reversible obstructive airway disease or allergic conditions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0018731A1 *

Also Published As

Publication number Publication date
SE9803279D0 (sv) 1998-09-25
AU1192200A (en) 2000-04-17
WO2000018731A1 (en) 2000-04-06

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