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WO2005092860A1 - Composes servant au traitement de maladies - Google Patents

Composes servant au traitement de maladies Download PDF

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Publication number
WO2005092860A1
WO2005092860A1 PCT/IB2005/000669 IB2005000669W WO2005092860A1 WO 2005092860 A1 WO2005092860 A1 WO 2005092860A1 IB 2005000669 W IB2005000669 W IB 2005000669W WO 2005092860 A1 WO2005092860 A1 WO 2005092860A1
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WIPO (PCT)
Prior art keywords
hydroxy
phenyl
hydroxymethyl
ethyl
pyridin
Prior art date
Application number
PCT/IB2005/000669
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English (en)
Inventor
Alan Daniel Brown
Mark Edward Bunnage
Paul Alan Glossop
Kim James
Charlotte Alice Louise Lane
Russell Andrew Lewthwaite
David Anthony Price
Original Assignee
Pfizer Limited
Pfizer Inc
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Publication of WO2005092860A1 publication Critical patent/WO2005092860A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • This invention relates to ⁇ 2 agonists of general formula:
  • Adrenoceptors are members of the large G-protein coupled receptor super-family.
  • the adrenoceptor subfamily is itself divided into the ⁇ and ⁇ subfamilies with the ⁇ sub-family being composed of at least 3 receptor subtypes: ⁇ 1 , ⁇ 2 and ⁇ 3.
  • These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals.
  • ⁇ 2 adrenergic ( ⁇ 2) receptors are mainly expressed in smooth muscle cells (e.g.
  • ⁇ 3 adrenergic receptors are mainly expressed in fat tissues (therefore ⁇ 3 agonists could potentially be useful in the treatment of obesity and diabetes) and ⁇ 1 adrenergic receptors are mainly expressed in cardiac tissues (therefore ⁇ 1 agonists are mainly used as cardiac stimulants).
  • the pathophysiology and treatments of airway diseases have been extensively reviewed in the literature (for reference see Barnes, P.J. Chest, 1997, 111 :2, pp 17S-26S and Bryan, S.A. et al, Expert Opinion on investigational drugs, 2000, 9:1 , pp25-42) and therefore only a brief summary will be included here to provide some background information.
  • Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti- cholinergics and ⁇ 2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD).
  • Treatment guidelines for these diseases include both short and long acting inhaled ⁇ 2 agonists. Short acting, rapid onset ⁇ 2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy. Bronchodilation is mediated via agonism of the ⁇ 2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation.
  • ⁇ 2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins.
  • LTD4 leukotriene D4
  • acetylcholine acetylcholine
  • bradykinin acetylcholine
  • prostaglandins histamine and endothelins.
  • ⁇ 2 receptors are so widely distributed in the airway
  • ⁇ 2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that ⁇ 2 agonists may stabilize mast cells.
  • the inhibition of the release of bronchoconstrictor substances may be how ⁇ 2 agonists block the bronchoconstriction induced by allergens, exercise and cold air.
  • ⁇ 2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction.
  • ⁇ 2 adrenoceptors are also expressed in other organs and tissues and thus ⁇ 2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • ⁇ 2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at ⁇ 2 adrenoreceptors expressed outside the airways (muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class. Accordingly, there is still a need for novel ⁇ 2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics or duration of action.
  • the present invention relates to novel ⁇ 2 agonists.
  • the invention relates to the compounds of general formula (1 ):
  • R 1 and R 2 are independently selected from H and C- 1 -C 4 alkyl;
  • - n 0, 1 or 2;
  • - Q 1 is a group selected from,
  • - A is selected from: o C 3 -C-io cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms, and being optionally substituted with one hydroxy group a 5 to 6 membered heterocyclic group, optionally aromatic, containing one or two heteroatoms selected from O, N or S, optionally substituted by one or two substituents selected from C ⁇ - C 4 alkyl, benzyl and cyclopropylmethyl or;
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, C ⁇ -C alkyl, OR 9 , SR 9 , SOR 9 , SO 2 R 9 , halo, CN, CF 3 , OCF 3 , S0 2 NR 9 R 10 , COOR 9 , CONR 9 R 10 , NR 9 R 10 , NHCOR 10 and phenyl optionally substituted with OH; - R 9 and R 10 are the same or different and are selected from H or C 1 -C 4 alkyl,
  • R 11 is selected from H or OH
  • the compounds of formula (1) are agonists of the ⁇ 2 receptors, that are particularly useful for the treatment of ⁇ 2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.
  • C 1 -C alkyl and C ⁇ -C alkylene denote a straight-chain or branched group containing 1 , 2, 3 or 4 carbon atoms.
  • C-i-Ce alkyl denotes a straight-chain or branched group containing 1 , 2, 3, 4, 5 or 6 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in 0-(C -C 4 )alkyl radicals, S-(Cr)
  • suitable (C- ⁇ -C )alkyl radicals are methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, fe/f-butyl....
  • suitable 0-(CrC 4 )alkyl radicals are methoxy, ethoxy, n-propyloxy, /so-propyloxy, n-butyloxy, /so-butyloxy, sec-butyloxy and te/f-butyloxy....
  • the C 3 -C-io cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo[3.1.1 ]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane.
  • Preferred cycloalkyl groups are cyclohexyl and adamantyl.
  • Non limitative examples of "5 to 6 membered heterocyclic group, optionally aromatic, containing one or two heteroatoms selected from O, N or S" are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furanyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl and pyrimidyl.
  • said heterocyclic group contains one nitrogen, two nitrogens or one nitrogen and one oxygen atom.
  • Preferred aromatic 5 to 6 membered heterocyclic groups are pyrazolyl and pyridyl.
  • Preferred non aromatic 5 to 6 membered heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl and piperazinyl.
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
  • the compounds of the formula (1 ) can be prepared using conventional procedures such as by the following illustrative methods in which Q 1 , Q 2 , R 1 , R 2 , A and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
  • the amide derivatives of the formula (1 ) may be prepared by coupling an acid of formula (2):
  • the coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, ⁇ /'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g.
  • a conventional coupling agent e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, ⁇ /'-dicyclohexylcarbodiimide
  • a catalyst e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole
  • a tertiary amine base e.g.
  • the reaction may be undertaken in a suitable solvent such as pyridine, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
  • Said amines are either commercially availabl e or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc...) from commercially available mate rial.
  • the acid of formula (2) may be prepared from the corresponding ester of formula (4):
  • Ra is a suitable acid protecting group, prefe rably a (C ⁇ -C )alkyl group, which includes, but is not limited to, methyl and ethyl , according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule.
  • the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g.
  • the ester of formula (4) may be prepared b ⁇ t reaction of an amine of formula (5) :
  • Ra and n are as previously defined and Rb and Rc represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Rc may be ⁇ -methylbenzyl), provided that the bonds between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book Protective Groups in Organic Synthesis Third Edition by T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1999.
  • the amine of formula (7) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (8):
  • Ra, Rb, Rc and n are as previously defined.
  • a suitable reducing agent e.g. sodium cyanoborohydride of formula NaCNBH 3 or sodium triacetoxyborohydride of formula Na(OAc) 3 BH
  • a drying agent e.g. molecular sieves, magnesium sulfate
  • an acid catalyst e.g. acetic acid
  • the reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours.
  • a solvent such as tetrahydrofuran or dichloromethane
  • the resulting product is then converted to the hydrochloride salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (7) as a single diastereomer.
  • a suitable solvent or mixture of solvents e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol
  • Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent.
  • the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu 3 SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-o/ ⁇ o-tolylphosphine of formula Pd(OAc) 2 /P(o- Tol) 3 ) in a non-polar solvent (e.g.
  • the reaction is carried out at a temperature comprised between 80°C and 110°C for 6 to 16 hours.
  • the aryl halide of formula (9) may be obtained by esterification of the corresponding acid of formula (10): wherein Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule.
  • the acid of formula (10) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 10°C and 40°C (room temperature) for 8 to 16 hours.
  • the acid of formula (10) is a commercial product.
  • the amine of formula (5), where R 1 and R 2 are both C 1 -C 4 alkyl, may be prepared according to the following scheme: Scheme 1
  • activated alkyl organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li
  • Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e .g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks.
  • the resulting amino acid is then esterified using the method described herein to give the amine of formula (5).
  • bromo amine e.g. acetonitrile, chloroacetonitrile
  • an acid e.g. sulphuric acid, acetic acid
  • the resulting bromo amine (15) is treated with a suitable palladium catalyst (e.g. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (100°C) and pressure (100psi) to give the ester of formula (5).
  • a suitable palladium catalyst e.g. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
  • a solution of the olefin of formula (16) in a suitable solvent e.g. methanol, ethanol, ethyl acetate
  • a palladium catalyst e.g. 10% palladium on charcoal
  • elevated pressure e.g. 60 psi
  • the alkene of formula (16) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (17):
  • the aryl halide (17) is coupled with a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh 3 ) 4 , palladium acetate/tri-o/f/70-tolylphosphine of formula Pd(OAc) 2 /P(o-tol) 3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCI 2 ) in a suitable solvent (e.g.
  • a suitable palladium catalyst e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh 3 ) 4 , palladium acetate/tri-o/f/70-tolylphosphine of formula Pd(OAc) 2 /P(o-tol) 3 or (dipheny
  • ketone of formula (17) is a commercial product.
  • a compound of formula (1 ) may be prepared by reaction of a bromide of formula (6) and an amine of formula (18):
  • R 1 , R 2 , Q 1 and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
  • the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, ⁇ /-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.
  • the amide of formula (18) may be prepared by coupling an acid of formula (19) incorporating a suitable amine protecting group P1 :
  • the coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, ⁇ /'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. ⁇ /-methylmorpholine, triethylamine or diisopropylethylamine).
  • a conventional coupling agent e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, ⁇ /'-dicyclohexylcarbodiimide
  • a catalyst e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-
  • the reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
  • a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate
  • Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc ..) from commercially available material.
  • the acid of formula (19) may be prepared from the corresponding ester of formula (5).
  • the acid of formula (19), where R 1 and R 2 are both C C 4 alkyl, may be prepared from the ester (5) incorporating a suitable amine protecting group P1 either before or after the acid formation:
  • Ra is a suitable acid protecting group, preferably a (C- ⁇ -C )alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule.
  • the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.
  • aqueous acid or base e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide
  • solvent or mixture of solvents e.g. water, 1 ,4-dioxan, tetrahydrofur
  • R 1 , R 2 and Ra are as previously defined.
  • the acid of formula (20) is preferentially reduced to the corresponding alcohol (21 ) in the presence of the ester.
  • This may be performed by formation of the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.
  • Said primary alcohol of formula (21) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with an appropriate amine nucleophile.
  • the preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine.
  • nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to furnish the amine.
  • alkylamines such as benzylamine or allylamine
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W. Greene and P. G. M Wuts (Protective Groups in Organic Synthesis, John
  • Q 2 is a single bond.
  • A is selected from morpholinyl, pyrrolidinyl, piperidyl, piperazinyl or pyrazolyl, optionally susbstituted by a methyl group.
  • A is selected from pyrazolyl optionally substituted by one or two C C 4 alkyl groups.
  • Q 1 is *-NR 8 -Q 3 .
  • Q 1 is a group selected from,
  • R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl
  • - Q 1 is a group selected from,
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, C- J -C 4 alkyl, OR 9 , SR 9 , SOR 9 , S0 2 R 9 , halo, CN, CF 3 , OCF 3 , S0 2 NR 9 R 10 , COOR 9 , CONR 9 R 10 , NR 9 R 10 , NHCOR 10 and phenyl optionally substituted with OH; - R 9 and R 10 are the same or different and are selected from H or C- ⁇ -C 4 alkyl and,
  • Q 1 is a group *-NH-Q 2 -A, wherein A is cyclohexyl or adamantyl.
  • Q 1 is
  • R 3 , R 4 , R5 and R 6 are H.
  • Q 1 is a group *-NH-Q 2 -A, wherein A is a group
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from
  • R 9 and R 10 are the same or different and are selected from H or C1-C 4 alkyl. More preferably, Q 1 is a group *-NH-Q 2 -A, wherein A is a group
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from
  • Q 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, or -C(CH 3 ) 2 -, preferably -CH 2 -.
  • R 1 is H or C 1 -C 4 alkyl and R 2 is C C 4 alkyl. More preferably, R 1 is H or CH 3 and
  • R 2 is CH 3 .
  • n is 1.
  • R 1 is H and R 2 is CH 3 and n is 1.
  • R 1 is CH 3
  • R 2 is CH 3
  • n is 1.
  • Pharmaceutically acceptable salts of the compounds of formula (1 ) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate, sacchar
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be* formed, for example, hemisulphate and hemicalcium salts.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation i n the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solve nt molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of formula (1) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula
  • 'pro-drugs' of the compounds of formula (1 ) are also within the scope of the invention.
  • certain derivatives of compounds of formula (1 ) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1 ) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1 ) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include:
  • the compound of formula (1) contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ ), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1 ) is/are replaced by (Ci-C-io)alkanoyl.
  • metabolites of compounds of formula (1 ) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include (i) where the compound of formula (1 ) contains a methyl group, an hydroxymethyl derivative thereof (-CH 3 -» -CH 2 OH):
  • Compounds of formula (1 ) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (1 ) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1 ) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (1 ) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).
  • the (R,R)-stereoisomer of the formula below, wherein R 1 is hydrogen and R 2 is C C 4 alkyl, preferably methyl, and n and Q 1 are as defined above, is generally preferred:
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (1 ) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and "125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phospho rus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (1 ), for example, t ose incorporating a radioactive isotope, are useful in drug and/or substrate tis sue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for exam pie, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (1 ) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de-acetone, d 6 -DMSO.
  • the compounds of formula (1 ), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the ⁇ 2 receptor is involved or in which agonism of this receptor may induce benefit, in particular the allergic and non-allergic airways diseases but also in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001 ).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1 ), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
  • Some components of the formulation may perform more than one function.
  • the compound of formula (1 ) may be water-soluble or insoluble.
  • a water- soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of formula (1 ) may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (1 ) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug- coated stents and poly( ⁇ 7-lactic-coglycolic)acid (PGLA) microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (1 ), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 0.001 mg to 10mg of the compound of formula (1 ).
  • the overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of formula (1 ) are particularly suitable for an administration by inhalation
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1 ) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 5000mg depending, of course, on the mode of administration.
  • an intravenous daily dose may only require from 0.001 mg to 40mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the compounds of the formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof can also be used as a combination with one or more additional therapeutic agents to be co-adrninistered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough.
  • the second and more additional therapeutic agents may also be a compound of the formula (1 ), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more ⁇ 2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
  • the terms "co-administration”, “co-administered” and “in combination with”, referring to the compounds of formula (1 ) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following: • simultaneous administration of such combination of compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient, • substantially simultaneous administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient, • sequential administration of such combination compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said
  • Histamine receptor antagonists including H1 and H3 antagonists
  • PDE inhibitors e.g. PDE3, PDE4 and PDE5 inhibitors
  • COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs),
  • Anti-tumor necrosis factor (anti-TNF- ⁇ ) agents (m) Anti-tumor necrosis factor (anti-TNF- ⁇ ) agents, (m)Adhesion molecule inhibitors including VLA-4 antagonists,
  • Modulators of the NF ⁇ pathway e.g. IKK inhibitors
  • modulators of cytokine signalling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor
  • cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or,
  • LTRAs Leukotriene antagonists
  • ipratropium salts namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepin
  • the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of : • asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whez infant syndrome and bronchiolytis, • chronic or acute bronchoconstriction, chronic bronchocons
  • a still further aspect of the present invention relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug having a ⁇ 2 agonist activity.
  • the present inventions concerns the use of the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of ⁇ 2- mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
  • the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (1 ), or a pharmaceutically acceptable salt, derived form or composition thereof.
  • the present invention provides a particularly interesting method for the treatment of a ⁇ 2-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising admidministering said mammal with an effective amount of a compound of formula (1 ), its pharmaceutically acceptable salts and/or derived forms.
  • a compound of formula (1 ) its pharmaceutically acceptable salts and/or derived forms.
  • Acetyl chloride (12.5 ml, 175 mmol) was added to a suspension of 2,2'-(1 ,3- phenylene)diacetic acid (50.0 g, 260 mmol) in ethanol (500 ml) and the resulting solution heated to reflux for 16 hours. The reaction was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between saturated sodium hydrogencarbonate (300 ml) and ethyl acetate (500 ml). The organic phase was washed with water (200 ml), saturated sodium chloride (300ml), dried (Na 2 S0 4 ) and the solvent removed in vacuo to give the title compound as a pale yellow oil (63.5 g).
  • Tributyltin methoxide 28.3 mL, 98 mmol
  • the product of preparation 8 (15.0 g, 65mmol)
  • isopropenyl acetate (10.8 mL, 98 mmol)
  • palladium(ll)acetate 750 mg, 3.30 mmol
  • tri-ott/70-tolylphosphine 2.0 g, 6.5 mmol
  • the reaction was diluted with ethyl acetate (150 mL) and 4M aqueous potassium fluoride solution (90mL), and stirred for 15 minutes.
  • the title compound was prepared from the product of preparation 11 and 2,2- dimethyl-6-oxiranyl-4H-[1 ,3]dioxino[5,4-b]pyridine, using a method similar to that of preparation 6, as a brown oil (1.35 g, 42 %).
  • Example 1 ⁇ /-(3,4-Dichlorobenzyl)-2-(3- ⁇ 2-[2-hydroxy-2-(5-hydroxy-6- hydroxymethylpyridin-2-yl)ethylamino]-2-methylpropyl ⁇ phenyl)acetamide
  • the title compound was prepared from the product of preparation 13 and 2- aminomethylphenol, using a method similar to that of example 1 , as a pale yellow foam (28 mg).
  • Example 7 W-(3,4-Dimethylbenzyl)-2-(3- ⁇ (2/?)-2-[2-hydroxy-2-(5-hydroxy-6- hydroxymethyl-pyridin-2-yl)ethylamino]propyl ⁇ phenyl)acetamide
  • Example 8 W-(2,5-Dimethylbenzyl)-2-(3- ⁇ (2 ?)-2-[2-hydroxy-2-(5-hydroxy-6- hydroxymethylpyridin-2-yl)ethylamino]propyl ⁇ phenyl)acetamide
  • the title compound was prepared from the product of preparation 13 and 2- ethoxybenzylamine, using a method similar to that of example 1.
  • Example 11 ⁇ .-(3,4-Dichlorobenzyl)-2-(3- ⁇ (2f?)-2-[2-hydroxy-2-(5-hydroxy- 6-hydroxymethyl-pyridin-2-yl)ethylamino]propyl ⁇ phenyl)acetamide
  • the title compound was prepared from the product of preparation 13 and 3,4- dichlorobenzylamine, using a method similar to that of example 1.
  • Example 12 W-(2-Chloro-6-fluorobenzyl)-2-(3- ⁇ (2R)-2-[2-hydroxy-2-(5- hydroxy-6-hydroxymethylpyridin-2-yl)ethylamino]propyl ⁇ phenyl)acetamide
  • the title compound was prepared from the product of preparation 13 and 2- chloro-6-fluorobenzylamine, using a method similar to that of example 1.
  • the ability of the compounds of the formula (1 ) to act as potent ⁇ 2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips.
  • Guinea-pig trachea Guinea-pig trachea
  • the strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 ⁇ M Indomethacin (Sigma I7378), 10 ⁇ M Guanethidine (Sigma G8520) and 10 ⁇ M Atenolol (Sigma A7655), heated at 37°C and gassed with 95% 0 2 /5% C0 2 , before applying an initial tension of 1 g.
  • the preparations are allowed to equilibrate for a further 30- 45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals.
  • the organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception of when a beta-2 agonist according to the present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period.
  • a peristaltic pump system pump flow rate 7.5 ml / minute
  • isoprenaline (Sigma I5627) to establish a maximal response in terms of inhibition of the contractile EFS response.
  • the isoprenaline is then washed out over a period of 40 minutes.
  • a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration. The concentration range used is 1 e"9 to 1 e /3 e" ⁇ M.
  • Beta-2 agonist responses are expressed as percentage inhibition of the EFS response.
  • Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1.
  • the EC 50 value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect.
  • Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC 50 beta-2 agonist)/(EC50 Isoprenaline).
  • Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective ⁇ 2 antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.
  • the agonist potency for the ⁇ 2 receptor of the compounds of the formula (1 ) may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC 50 ) for the ⁇ 2 receptor.
  • CHO Choinese Hamster Ovary cells recombinantly expressing the human ⁇ 2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOh ⁇ 2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 ⁇ g/ml geneticin (Sigma, G7034) and 10 ⁇ g/ml puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.

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Abstract

La présente invention porte sur des composés représentés par la formule (1) ainsi que sur des procédés de préparation de dérivés, sur des intermédiaires intervenant dans la préparation de ces dérivés, sur des compositions contenant ces dérivés ainsi que sur les utilisations de ces dérivés. Les composés de cette invention sont utilisés pour un grand nombre de maladies, de troubles et d'états, en particulier pour des maladies, troubles et états inflammatoires, allergiques et respiratoires.
PCT/IB2005/000669 2004-03-23 2005-03-11 Composes servant au traitement de maladies WO2005092860A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP04290770.9 2004-03-23
EP04290770 2004-03-23
US62502104P 2004-11-03 2004-11-03
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WO2009087224A1 (fr) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
EP2280006A1 (fr) 2005-08-08 2011-02-02 Pulmagen Therapeutics (Synergy) Limited Composition pharmaceutique pour inhalation comprenant un oxazole ou thiazole antagoniste du récepteur m3 muscarinique
EP2281813A1 (fr) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Dérivés de bicyclo[2.2.1]hept-7-ylamine et leurs utilisations
EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
WO2011051671A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminopyridine comme inhibiteurs de la kallicréine
WO2011051672A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
WO2012034091A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions à titre d'inhibiteurs de trk
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
WO2012116217A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composés et compositions en tant qu'inhibiteurs de trk

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MA44037B1 (fr) * 2016-06-06 2020-03-31 Arena Pharm Inc Modulateurs du récepteur adrénergique bêta 3 utile dans le traitement ou la prévention de troubles associés à ceux-ci

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US4908386A (en) * 1985-10-15 1990-03-13 Glaxo Group Limited Ethanolamine derivatives
EP0842924A1 (fr) * 1996-11-14 1998-05-20 Pfizer Inc. Pyridines en tant qu'intermédiaires de synthèse pour certain agonistes du récepteur bêta-adrénergique
WO2003042164A1 (fr) * 2001-11-13 2003-05-22 Theravance, Inc Agonistes arylaniline des recepteurs adrenergiques $g(b)2
WO2004100950A1 (fr) * 2003-05-15 2004-11-25 Pfizer Limited Derives de (2-hydroxy-2-(4-hydroxy-3-hydoxymethylphenyl)-ethylamino)-propylphenyle utilises comme beta2 agonistes

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2280006A1 (fr) 2005-08-08 2011-02-02 Pulmagen Therapeutics (Synergy) Limited Composition pharmaceutique pour inhalation comprenant un oxazole ou thiazole antagoniste du récepteur m3 muscarinique
EP2281813A1 (fr) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Dérivés de bicyclo[2.2.1]hept-7-ylamine et leurs utilisations
EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
WO2009087224A1 (fr) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
US9078885B2 (en) 2008-08-07 2015-07-14 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
US8815837B2 (en) 2008-08-07 2014-08-26 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
US8362064B2 (en) 2008-12-30 2013-01-29 Pulmagen Theraputics (Inflammation) Limited Sulfonamide compounds for the treatment of respiratory disorders
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2011051672A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
WO2011051671A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminopyridine comme inhibiteurs de la kallicréine
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
WO2012034091A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions à titre d'inhibiteurs de trk
WO2012116217A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composés et compositions en tant qu'inhibiteurs de trk

Also Published As

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TW200533351A (en) 2005-10-16
NL1028599C2 (nl) 2006-01-03
AR048322A1 (es) 2006-04-19
PA8627001A1 (es) 2006-05-16
NL1028599A1 (nl) 2005-09-26

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