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WO2003007939A1 - Derives azetidine et leurs utilisations en tant qu'antagonistes de recepteur ccr3 - Google Patents

Derives azetidine et leurs utilisations en tant qu'antagonistes de recepteur ccr3 Download PDF

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Publication number
WO2003007939A1
WO2003007939A1 PCT/EP2002/007925 EP0207925W WO03007939A1 WO 2003007939 A1 WO2003007939 A1 WO 2003007939A1 EP 0207925 W EP0207925 W EP 0207925W WO 03007939 A1 WO03007939 A1 WO 03007939A1
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alkyl
alkoxy
substituted
formula
halogen
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PCT/EP2002/007925
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English (en)
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Gurdip Bhalay
Trevor John Howe
Darren Mark Le Grand
Clive Victor Walker
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Novartis Ag
Novartis Pharma Gmbh
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Publication of WO2003007939A1 publication Critical patent/WO2003007939A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • This invention relates to organic compounds, their preparation and their use as pharmaceuticals.
  • Ar 1 is phenyl substituted by one or more halogen atoms
  • Ar 2 is phenyl optionally substituted by one or more substitutuents selected from halogen, cyano, hydroxy, nitro, Q-Q-alkyl, Q-Q-haloalkyl, Q-Q-alkoxy, Q-Q-alkoxycarbonyl or di(Q-Q-alkyl)aminocarbonylrnetho ⁇ y;
  • R 1 is hydrogen or Q-Q-alkyl optionally substituted by hydroxy, Q-Q-alkoxy, acyloxy, halogen, carboxy, Q-Q-alkoxycarbonyl, -N(R 2 )R 3 , -CON(R 4 )R 5 or by a monovalent cyclic organic group having 3 to 15 atoms in the ring system;
  • R 2 and R 3 are each independently hydrogen or Ci-Cg-alkyl, or R 2 is hydrogen and R 3 is hydroxy-Q-Q-alkyl, acvl, -S0 2 R 6 or -CON(R 4 )R 5 , or R 2 and R 3 together with the nitrogen atom to which they are attached denote a 5 -or 6-membered heterocyclic group;
  • R 4 and R 5 are each independently hydrogen or Q-Q-alkyl, or R 4 and R 5 together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group;
  • R 6 is rQ-alkyl, Q-Q-haloalkyl, or phenyl optionally substituted by Q-Q-alkyl;
  • X is -C(-sO)-, -O- or -CH 2 -; and n is 1, 2, 3 or 4.
  • Q-Q-alkyl denotes straight chain or branched Q-Cg-alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, or straight or branched octyl.
  • Q-Q-alkyl is Q-Q-alkyl.
  • Q-Q-alkoxy denotes straight chain or branched Q-Q-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy.
  • Q-Q-alkoxy is Q-Q-alkoxy.
  • Q-Q-haloalkyl denotes C Cg-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms.
  • Acyl denotes alkylcarbonyl, for example Q-Q-alkylcarbonyl where Q-Cg- alkyl may be one of the Q-Q-alkyl groups hereinbefore mentioned, optionally substituted by one or more halogen atoms; cycloalkylcarbonyl, for example Q-Q-cycloalkylcarbonyl where Q-Q-cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6- membered heterocyclylcarbonyl having one or two hetero atoms selected from nitrogen, oxygen and sulfur in the ring, such as furylcarbonyl or pyridylcarbonyl; arylcarbonyl, for example Q-Qo-arylcarbonyl such as benzoyl; or aralkylcarbonyl, for example Q to Qo-ary
  • Acyloxy denotes alkylcarbonyloxy, for example Q-Q-alkylcarbonyloxy where Q-Cg-alkyl may be one of the Q-Q-alkyl groups hereinbefore mentioned, optionally substituted by one or more halogen atoms; cycloalkylcarbonyloxy, for example Q-Q- cycloalkylcarbonyloxy where Q-Q-cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6- membered heterocyclylcarbonyloxy having one or two hetero atoms selected from nitrogen, oxygen and sulfur in the ring, such as furylcarbonyloxy or pyridylcarbonyloxy; arylcarbonyloxy, for example Q-Qo- arylcarbonyloxy such as benzoyloxy; or aralkylcarbonyloxy,
  • Halogen as used herein may be fluorine, chlorine, bromine or iodine; preferably it is fluorine, chlorine or bromine.
  • Q-Q-alkoxycarbonyl denotes Q-Q-alkoxy as hereinbefore defined attached through the oxygen atom to a carbonyl group.
  • Di-(Q-Q-alkyl)aminocarbonylmethoxy denotes aminocarbonylmethoxy disubstituted on the amino nitrogen atom by Q-Q-alkyl as hereinbefore defined, the two Q-Q-alkyl groups being the same or different.
  • the phenyl group may be substituted by one, two or three, preferably one or two halogen atoms, preferably selected from fluorine and chlorine atoms.
  • one halogen substituent it is preferably para to the indicated group X.
  • two or three halogen substituents preferably one is para to the indicated group X and at least one of the others is ortho to the para-halogen substituent.
  • Ar 2 as substituted phenyl may, for example, be substituted by one, two, three, four or five, preferably by one, two or three, of the abovementioned substituents.
  • Ar 2 may alternatively be, for example, disubstituted phenyl in which the substituents are preferably selected from halogen, cyano, hydroxy, nitro, Q-Q-alkoxy, di(Q- C 4 -alkyl)aminocarbonylmethoxy, Q-Q-alkyl and Q-Q-haloalkyl, especially two halogen substituents (same or different halogen), two Q-Q-alkoxy groups, two Q-Q-alkyl groups, two Q-Q-haloalkyl groups, one halogen and one cyano, one halogen and one Q-Q-alkoxy, one halogen and one nitro, one halogen and one hydroxy, one halogen and one Q-Q- haloalkyl, one cyano and one Q-Q-alkoxy, one hydroxy and one CrQ-alkyl, or one hydroxy and one Q-Q-alkoxy group.
  • substituents are preferably selected from
  • Ar 2 may alternatively be, for example, trisubstituted phenyl in which the substituents are preferably selected from halogen, hydroxy, Q-Q-alkoxy and Q-Q- alkoxycarbonyl, especially three halogen substituents (same or two or three different halogens), or two Q-Q-alkoxy and one halogen, hydroxy or Q-Q-alkoxycarbonyl.
  • Ar 2 may alternatively be, for example, penta-substituted phenyl in which the substituents are preferably halogen, especially fluorine.
  • Ar 2 is phenyl substituted by one or more substitutents selected from cyano, halogen, Q-Q-alkoxy or di(Q-C 4 -alkyl)aminocarbonylmethoxy.
  • R 1 as optionally substituted Q-Q-alkyl is preferably optionally substituted Q-Q-alkyl, especially Q-Q-alkyl or substituted methyl or ethyl.
  • R 1 is substituted by a cyclic organic group, the latter may be a carbocycUc or heterocyclic group, for example a Q-Q 5 -carbocyclic group or a 5- to 7-membered heterocyclic group having one or more, preferably one, two or three, ring hetero atoms selected from nitrogen, oxygen and sulfur.
  • the Q-Q 5 -carbocyclic group may be, for example, a cycloaliphatic group having 3 to 8 carbon atoms, preferably Q - or Q - cycloalkyl such as cyclopentyl, methylcyclopentyl or cyclohexyl.
  • the Q-Q 5 -carbocyclic group may alternatively be, for example, a Q-Q5 aromatic group, such as phenyl, which is unsubstituted or substituted by CrCg-alkyl, Q-Q-alkoxy, halogen, cyano, -CON(R 4 )R 5 , - S0 2 N(R 4 )R 5 or CrQ-alkylsulfonylamino where R 4 and R 5 are as hereinbefore defined.
  • the heterocyclic group may have one nitrogen, oxygen or sulfur atom in the ring or it may have two nitrogens, or one oxygen and one or two nitrogens, or one sulfur and one or two nitrogens in the ring.
  • the heterocyclic group is preferably a heterocyclic aromatic group, especially a 5- or 6- membered heterocyclic group such as furyl, imidazolyl, thiazolyl or pyridyl.
  • Preferred embodiments include those in which R 1 is hydrogen or Q-Q-alkyl substituted by hydroxy or Q-Q-alkoxy.
  • Ar 1 is phenyl substituted by fluorine or chlorine para to the indicated group X, and optionally further substituted by fluorine or chlorine meta to the group X;
  • R 1 is hydrogen or Q-Q-alkyl substituted by hydroxy
  • the compounds represented by formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohaUc acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxyUc acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxyUc acids such as maleic acid or succinic acid, aromatic carboxyUc acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalen
  • Compounds of formula I which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I by known salt-forming procedures.
  • R 1 is other than hydrogen
  • the carbon atom to which R 1 is attached in formula I is asymmetric, in which case the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
  • the invention embraces both individual optically active R and S isomers as well as mixtures, e.g.racemic or diastereomeric mixtures, thereof.
  • the invention also provides a process for the preparation of compounds of formula I which comprises
  • Process step (i) may be effected using known methods, for example by reacting a compound of formula II with an acid halide, particularly acid chloride, of the acid of formula HI using known amide-forming procedures.
  • the compound of formula II is reacted with a free carboxyUc acid of formula HI, for example using known procedures, such as reaction in the presence of a tertiary amine and a peptide coupUng agent such as a phosphonium salt, 2- (1H benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate or diisopropylcarbodiimide; this reaction may be carried out in an inert organic solvent, for example a halohydrocarbon such as dichloromethane; the reaction temperature is conveniently from 0 to 40°C, preferably ambient temperature.
  • a halohydrocarbon such as dichloromethane
  • R 1 , R 1 , Y and n are as hereinbefore defined, with the proviso that when R 1 contains a reactive functional group such as a hydroxy group, the reactive group may be in protected form, for example a hydroxy group protected as a tert-butoxy group, R 7 is hydrogen or an amine-protective group, for example a tert-butoxycarbonyl group, and Y is halogen and, where R 7 is a protective group, replacing R 7 in the product by hydrogen, and, where R 1 in the product contains a protected functional group, replacing the protecting group by hydrogen.
  • R 7 is hydrogen
  • reaction between a compound of formula V and a salt of a compound of formula VI may be effected by the procedures described in US 4559349.
  • reaction between compounds of formulae V and VI may be effected using known methods, for example in the presence of a tertiary organic base such as triethylamine or 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU), conveniently in an inert organic solvent, for example a polar solvent such as dimethylformamide, the reaction temperature suitably being from 0 to 40°C, preferably ambient temperature.
  • a protective group R 7 by hydrogen may be effected using known procedures; for example, where R 7 is tert-butoxycarbonyl, by treatment with a carboxylic acid such as trifluoroacetic acid.
  • R 1 Replacement of a protecting group in R 1 may be affected using known procedures, for example, when R 1 contains a hydroxy group protected as an ether group, such as tert-butoxy, by treatment with HBr in a carboxylic acid such as acetic acid; when R 7 is a protective group, this treatment also replaces R 7 by hydrogen.
  • the protecting groups may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, Second Edition, 1991, which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
  • R 9 is a protecting group
  • R 9 in the product by hydrogen may be carried out in an inert organic solvent such as DMF. Suitable reaction temperatures may be from 20°C to 150°C, conveniently from 50 to 70°C.
  • the replacement of R 9 by hydrogen may be affected using known procedures, for example where R 9 is benzhydryl by reacting the product of the reaction of the compound of formula VI and Ar 1 -OH with 1-chloroethyl chloroformate, a suitable reaction tempterature being 10-30°C, conveniently at room temperature.
  • N-dimethylhydroxylamine hydrochloride in the presence of a peptide coupling agent such as di-imidazol-1-yl-methanone, conveniently in an inert organic solvent such as THF, suitably at reflux temperature.
  • a peptide coupling agent such as di-imidazol-1-yl-methanone
  • Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystalUzation.
  • Compounds of formula I can be recovered from reaction mixtures and purified in a conventional manner.
  • Isomers, such as enantiomers may be obtained in a conventional manner, e.g. by fractional crystallization or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • Compounds of formula I in free or pharmaceutically acceptable salt form hereinafter referred to alternatively as agents of the invention, are useful as pharmaceuticals.
  • the invention also provides a compound of formula I in free or pharmaceutically acceptable salt form for use as a pharmaceutical.
  • the agents of the invention act as CCR-3 receptor antagonists, thereby inhibiting the infiltration and activation of inflammatory cells, particularly eosinophils, and inhibiting allergic response.
  • the inhibitory properties of agents of the invention can be demonstrated in the following assay:
  • the effect of agents of the invention on the binding of human eotaxin to human CCR-3 is determined.
  • Recombinant cells expressing human CCR-3 are captured by wheatgerm agglutinin (WGA) polyvinyltoluidene (PVT) SPA beads (available from Amersham), through a specific interaction between the WGA and carbohydrate residues of glycoproteins on the surface of the cells.
  • WGA wheatgerm agglutinin
  • PVT polyvinyltoluidene
  • SPA beads available from Amersham
  • Assay Buffer 5.96 g HEPES and 7.0 g sodium chloride are dissolved in distilled water and 1M aqueous CaCl 2 (1 mL) and 1M aqueous MgCl 2 (5 mL) are added. The pH is adjusted to 7.6 with NaOH and the solution made to a final volume of 1 L using distilled water. 5 g bovine serum albumin and 0.1 g sodium azide are then dissolved in the solution and the resulting buffer stored at 4°C. A CompleteTM protease inhibitor cocktail tablet (available from Boehringer) is added per 50 mL of the buffer on the day of use.
  • a CompleteTM protease inhibitor cocktail tablet available from Boehringer
  • Tris-base (2.42g) is dissolved in distilled water, the pH of the solution is adjusted to 7.6 with hydrochloric acid and the solution is diluted with distilled water to a final volume of IL.
  • the resulting buffer is stored at 4°C.
  • a CompleteTM protease inhibitor cocktail tablet is added per 50 mL of the buffer on the day of use.
  • rat basophil leukemia (RBL-2H3) cells stably expressing CCR3 are removed from tissue culture flasks using enzyme-free cell dissociation buffer and resuspended in phosphate-buffered saline.
  • the cells are centrifuged (800 g, 5 minutes), the pellet resuspended in ice-cold homogenisation buffer using 1 mL homogenisation buffer per gram of cells and incubated on ice for 30 minutes.
  • the cells are homogenised on ice with 10 strokes in a glass mortar and pestle.
  • the homogenate is centrifuged (800 g, 5 minutes, 4°C), the supernatant further centrifuged (48,000 g, 30 minutes, 4°C) and the pellet redissolved in Homogenisation Buffer containing 10% (v/v) glycerol.
  • the protein content of the membrane preparation is estimated by the method of Bradford (AnaLBiochem. (1976) 72:248) and aliquots are snap frozen and stored at -80°C.
  • the assay is performed in a final volume of 250 ⁇ L per well of an Optiplate (ex Canberra Packard). To selected wells of the Optiplate are added 50 ⁇ L of solutions of a test compound in Assay Buffer containing 5 % DMSO (concentrations from O.OlnM to 10 uM). To determine total binding, 50 ⁇ L of the Assay Buffer containing 5 % DMSO is added to other selected wells. To determine non-specific binding, 50 ⁇ L of lOOnM human eotaxin (ex R&D Systems) in Assay Buffer containing 5 % DMSO is added to further selected wells.
  • the compounds of the Examples hereinbelow have IQ 0 values below l ⁇ M in the above assay.
  • the compounds of Examples 11, 16, 17 and 18 have IQ 0 values of 32nM, 7nM, InM, and 9nM respectively.
  • the inhibitory properties of agents of the invention on binding of the alpha-1 adrenergic receptor can be determined in the following assay: Cerebral cortices from male Sprague-Dawley rats (175-200 g) are dissected and homogenised in 10 volumes of ice cold 0.32 M sucrose (containing ImM MgCl 2 dihydrate and ImM K 2 HP0 4 ) with a glass/teflon homogeniser. The membranes are centrifuged at 1000 x g for 15 min., the pellet discarded and the centrifugation repeated.
  • the supernatants are pooled and centrifuged at 18,000 x g for 15 min.
  • the pellet is osmotically shocked in 10 volumes of water and kept on ice for 30 min.
  • the suspension is centrifuged at 39,000 x g for 20 min., resuspended in Krebs-Henseleit buffer pH 7.4 (1.17mM MgS0 4 anhydrous, 4.69 mM KCl, 0.7mMK 2 HPO 4 anhydrous, O.llM NaCl, 11 mM D-glucose and 25 mM NaHC0 3 ) containing 20mM Tris, and kept for 2 days at -20°C.
  • the membranes are then thawed at 20- 23°C, washed three times with Krebs-Henseleit buffer by centrifugation at 18,000 x g for 15 min., left overnight at 4°C and washed again three times.
  • the final pellet is resuspended with a glass/teflon homogeniser in 125mL/100 membranes in the same buffer.
  • a sample is taken to determine the protein concentration (using the Bradford Assay with gamma globulin as the standard) and the remainder aliquoted and stored at -80°C.
  • the resulting membranes are subjected to a radioligand binding assay.
  • the assay is conducted in triplicate using 96 well plates containing [ 125 Ij-HEAT (Amersham) (40pM, K d : 58.9 ⁇ 18.7 pM), unlabelled test compound and membrane (57.1 ⁇ g mL) to yield a final volume of 250 ⁇ L (assay buffer containing 50 mM Tris-base and 0.9% (w/v) NaCl, pH 7.4).
  • the plates are incubated at 37°C for 60 min., after which rapid vacuum filtration over Whatman GF/C 96 well filter plates is carried out.
  • Each plate is then washed three times with 10ml of ice cold assay buffer using a Brandel Cell harvester (Gaithersburg, MD). Following drying of the plates for 3 h. at 50°C, 40 ⁇ L of Microscint 20 is added to each well, the plates incubated at room temperature for a further 20 min. and the retained radioactivity quantified in a Packard Topcount NXT scintillation counter.
  • test compounds are dissolved initially in 100 % DMSO and diluted with assay buffer to the required concentrations to yield 1 % (v/v) DMSO.
  • the concentration of test compound at which 50% inhibition occurs (IQo) is determined from concentration-inhibition curves in a conventional manner.
  • agents of the invention are useful in the treatment of conditions mediated by CCR-3, particularly inflammatory or allergic conditions. Treatment in accordance with the invention may be symptomatic or prophylactic. Accordingly, agents of the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, bronchial hyperreactivity, remodelUng or disease progression.
  • Inflammatory or obstructive airways diseases to which the present invention is appUcable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, excercise-induced asthma, occupational asthma and asthma induced following bacterial or viral infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome".)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is appUcable include acute lung injury (ALI), acute/adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently
  • agents of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophiUa, in particular eosinophil related disorders of the airways (e.g.
  • morbid eosinophiUc infiltration of pulmonary tissues including hyper- eosinophiUa as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to L ⁇ ffler's syndrome, eosinophiUc pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophiUa), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophiUc granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • Agents of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, e.g.
  • atrophic, chronic, or seasonal rhinitis inflammatory conditions of the gastrointestinal tract, for example inflammatory bowel disease such as ulcerative coUtis and Crohn's disease, diseases of the bone and joints including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and systemic sclerosis, and other diseases such as athersclerosis, multiple sclerosis, diabetes (type I), myasthenia gravis, hyper IgE syndrome and acute and chronic allograft rejection, e.g. following transplantation of heart, kidney, liver, lung or bone marrow.
  • inflammatory bowel disease such as ulcerative coUtis and Crohn's disease
  • diseases of the bone and joints including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and systemic sclerosis
  • other diseases such as athersclerosis, multiple sclerosis, diabetes (type I), myasthenia gravis, hyper IgE syndrome and acute and chronic allograft
  • an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. a mouse or rat model, of airways inflammation or other inflammatory conditions, for example as described by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renzi et al, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. CUn. Invest. (1995) 96:2924-2931; and Cernadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8.
  • the agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • An agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone, LTB4 antagonists such as those described in US 5451700, LTD4 antagonists such as montelukast and zafirlukast, and PDE4 inhibitors such as Ariflo ® (GlaxoSmith Khne), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Arofylline (Almirall Prodesfarma) and PD189659 (Parke-Davis).
  • steroids in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone
  • LTB4 antagonists such as those described in US 5451700
  • LTD4 antagonists
  • bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide, and beta-2 adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and, especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of PCT International Publication No. WO00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula
  • Co-therapeutic antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride.
  • Combinations of agents of the invention and steroids, beta-2 agonists, PDE4 inhibitors or LTD4 antagonists may be used, for example, in the treatment of COPD or, particularly, asthma.
  • Combinations of agents of the invention and antichoUnergic or antimuscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists may be used, for example, in the treatment of asthma or, particularly, COPD.
  • agents of the invention with anti-inflammatory drugs are those with other anatagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H- benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4- aminium chloride (TAK-770), CCR-5 antagonists described in US6166037 (particularly claims 18 and 19), WO00/66558 (particularly claim 8), and WO00/665
  • the invention also provides a method for the treatment of a condition mediated by CCR-3, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof an effective amount of a compound of formula I in a free or pharmaceutically acceptable salt form as hereinbefore described.
  • the invention provides the use of a compound of formula I, in free or pharmaceutically acceptable salt form, as hereinbefore described for the manufacture of a medicament for the treatment of a condition mediated by CCR-3, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topicaUy to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • any appropriate route e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topicaUy to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound of formula I in free or pharmaceutically acceptable salt form, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • the composition may contain a co-therapeutic agent such as an anti-inflammatory bronchodilatory or antihistamine drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal deUvery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol (preferably with a HFA propellant such as HFA134a or HFA227) or other atomizable or dry powder formulations.
  • the invention includes (A) an agent of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form, (B) an inhalable medicament comprising an agent of the invention in inhalable form; (C) a pharmaceutical product comprising such an agent of the invention in inhalable form in association with an inhalation device; and (D) an inhalation device containing an agent of the invention in inhalable form.
  • A an agent of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form
  • B an inhalable medicament comprising an agent of the invention in inhalable form
  • C a pharmaceutical product comprising such an agent of the invention in inhalable form in association with an inhalation device
  • an inhalation device containing an agent of the invention in inhalable form.
  • Dosages of agents of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.01 to 30 mg/kg while for oral administration suitable daily doses are of the order of 0.01 to 100 mg/kg.
  • a suspension of sodium hydride (60% dispersion, 0.228g, 5.7mmol) in dry DMF (20ml) is treated with 4-fluorophenol (0.70g, 6.29mmol). Effervescence is allowed to subside and the resultant mixture is treated with methanesulfonic acid l-benzhydryl-azetidin-3-yl ester (1.81g, 5.71mmol) and the reaction heated to 60°C for 2.5 days. The mixture is cooled and poured into iced water and extracted with diethylether. The organic phase is washed with brine, dried with magnesium sulfate and evaporated.
  • 3-(4-chloro-phenoxy)-azetidine hydrochloride (0.068g, 0.37mmol), prepared analogously to 3- (4-fluorophenoxy)-azetidine hydrochloride, is dissolved in saturated aqueous sodium bicarbonate (10ml) and the solution extracted with dichloromethane (2x10ml). The combined organic phase is dried (MgS0 4 ) and evaporated and re-dissolved in DMF (3ml).
  • the solution is treated with triethylamine (0.063ml, 0.45mmol) and ((S)-l-tert-butoxymethyl-3-iodo- propyl)-carbamic acid benzyl ester (0.164g, 0.40mmol) and stirred for 2 days at room temperature.
  • the mixture is diluted with aqueous NaHC0 3 and ethyl acetate (10ml) and extracted with more ethyl acetate (2x10ml) which is dried (MgS0 4 ) and evaporated to afford the crude product as an oil.
  • reaction mixture is evaporated in vacuo and the crude product is partitioned between ethyl acetate (20ml) and aqueous NaHC0 3 (20ml).
  • the aqueous layer is extracted with ethyl acetate (20ml) and the combined organic layers washed with aqueous NaHC0 3 (40ml), brine (40ml), dried (MgS0 4 ) and evaporated.
  • Example 8 is prepared analogously to Example 16.
  • a solution of azetidin-3-yl-(4-fluoro-phenyl)-methanone hydrochloride (0.5g, 2.84mmol), prepared from (l-benzhydryl-azetidin-3-yl)-(4-fluoro-phenyl)-methanone using a procedure analogous to that used for preparation of 3-(4-fluorophenoxy)azetidine hydrochloride, in dry acetonitrile (15ml) is treated with triethylamine (0.59ml, 4.25 mmol) followed by 3- bromopropylamine hydrobromide (0.75g, 3.40mmol). The resultant suspension is heated to 70°C for 1.5hours and the solvents removed in vacuo.
  • the reaction mixture is evaporated and the crude residue dissolved in ethyl acetate which is washed with aqueous NaHC0 3 (x3), brine (xl), dried (MgS0 4 ) and evaporated.
  • the product is partly purified by flash silica chromatography (ethyl actetate:hexane, 1:1 followed by ethyl acetate:methanol, 4:1 gradient elution) to afford a mixture of acylated products.
  • the mixture is dissolved in methanol (2ml) / water (0.5ml) and treated with K 2 C0 3 (0.082g, 0.059mmol) and stirred at room temperature for 0.75 hours.
  • Examples 1 and 3 are prepared analogously to Example 14.
  • Acetic acid (S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-l-yl]-butyl ester hydrobromide is prepared analogously to (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-l-yl]-butan-l-ol hydrobromide ( intermediate in Example 16).
  • the product is isolated as the O-acetyl derivative (as characterised by *H NMR) and is used directly.
  • the reaction mixture is evaporated and the crude residue dissolved in ethyl acetate which is washed with aqueous NaHC0 3 (x3), brine (xl), dried (MgS0 4 ) and evaporated.
  • the crude product is treated with methanol and filtered.
  • the filtrate is treated with siUca, evaporated and the crude adsorbed product purified by flash silica chromatography (ethyl actetate:hexane, 1:1 followed by ethyl acetate and then ethylacetate:methanol, 9:1 gradient elution) to afford a mixture of acylated products as an oil.

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Abstract

L'invention concerne des composés de formule (I) sous forme libre ou saline, dans laquelle Ar?1, Ar2, R1¿, X et n sont définis dans les revendications. Elle concerne aussi des compositions qui contiennent ces composés, des procédés de préparation de ces composés et leur utilisation en tant que médicaments.
PCT/EP2002/007925 2001-07-17 2002-07-16 Derives azetidine et leurs utilisations en tant qu'antagonistes de recepteur ccr3 WO2003007939A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003077907A1 (fr) * 2002-03-15 2003-09-25 Novartis Ag Utilisation de derives d'azetidine en tant qu'antagonistes du recepteur ccr3
WO2005026113A1 (fr) * 2003-09-15 2005-03-24 Novartis Ag Derives d'azetidine 1, 3-disubstitues a utiliser en tant qu'antagonistes du recepteur ccr3 dans le traitement de maladies inflammatoires et allergiques
US7485732B2 (en) 2003-06-11 2009-02-03 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
AU2005270308B2 (en) * 2004-08-10 2009-10-22 Novartis Ag Azetidine derivatives as CCR-3 receptor antagonists
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
WO2021152488A1 (fr) 2020-01-29 2021-08-05 Novartis Ag Méthodes de traitement d'une maladie inflammatoire ou obstructive des voies respiratoires à l'aide d'un anticorps anti-tslp

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WO2000031032A1 (fr) * 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de derives de pyrrolidine-ccr-3
WO2000058305A1 (fr) * 1999-03-26 2000-10-05 Astrazeneca Ab Nouveaux composes
WO2000069820A1 (fr) * 1999-05-14 2000-11-23 Combichem, Inc. Derives d'amine cycliques et leurs utilisations
WO2002030899A1 (fr) * 2000-10-09 2002-04-18 Novartis Ag Amides n-(4-aryloxypiperidine-1-ylalkyl) cinnamiques utilises comme antagonistes du recepteur ccr3
WO2002030898A1 (fr) * 2000-10-09 2002-04-18 Novartis Ag Amides n-(4-aryloxypiperidin-1-ylalkyl)cinnamiques utilises comme antagonistes du recepteur ccr33

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2000031032A1 (fr) * 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Antagonistes du recepteur de derives de pyrrolidine-ccr-3
WO2000058305A1 (fr) * 1999-03-26 2000-10-05 Astrazeneca Ab Nouveaux composes
WO2000069820A1 (fr) * 1999-05-14 2000-11-23 Combichem, Inc. Derives d'amine cycliques et leurs utilisations
WO2002030899A1 (fr) * 2000-10-09 2002-04-18 Novartis Ag Amides n-(4-aryloxypiperidine-1-ylalkyl) cinnamiques utilises comme antagonistes du recepteur ccr3
WO2002030898A1 (fr) * 2000-10-09 2002-04-18 Novartis Ag Amides n-(4-aryloxypiperidin-1-ylalkyl)cinnamiques utilises comme antagonistes du recepteur ccr33

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003077907A1 (fr) * 2002-03-15 2003-09-25 Novartis Ag Utilisation de derives d'azetidine en tant qu'antagonistes du recepteur ccr3
US7288537B2 (en) 2002-03-15 2007-10-30 Novartis Ag Azetidine derivatives as CCR-3 receptor antagonists
US7485732B2 (en) 2003-06-11 2009-02-03 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
US7906503B2 (en) 2003-06-11 2011-03-15 Merck Sharp & Dohme Corp. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
WO2005026113A1 (fr) * 2003-09-15 2005-03-24 Novartis Ag Derives d'azetidine 1, 3-disubstitues a utiliser en tant qu'antagonistes du recepteur ccr3 dans le traitement de maladies inflammatoires et allergiques
JP2007505080A (ja) * 2003-09-15 2007-03-08 ノバルティス アクチエンゲゼルシャフト 炎症性およびアレルギー性疾患の処置における、ｃｃｒ−３受容体アンタゴニストとして使用するための１，３−二置換アゼチジン誘導体
JP2010265278A (ja) * 2003-09-15 2010-11-25 Novartis Ag 炎症性およびアレルギー性疾患の処置における、ｃｃｒ−３受容体アンタゴニストとして使用するための１，３−二置換アゼチジン誘導体
AU2005270308B2 (en) * 2004-08-10 2009-10-22 Novartis Ag Azetidine derivatives as CCR-3 receptor antagonists
US7691841B2 (en) 2004-08-10 2010-04-06 Novartis Ag Azetidine derivatives as CCR-3 receptor antagonist
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
WO2021152488A1 (fr) 2020-01-29 2021-08-05 Novartis Ag Méthodes de traitement d'une maladie inflammatoire ou obstructive des voies respiratoires à l'aide d'un anticorps anti-tslp

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