WO2005092861A1 - Derives de quinolinone compositions pharmaceutiques contenant ces derives et utilisation de celles-ci - Google Patents

Derives de quinolinone compositions pharmaceutiques contenant ces derives et utilisation de celles-ci Download PDF

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Publication number
WO2005092861A1
WO2005092861A1 PCT/IB2005/000536 IB2005000536W WO2005092861A1 WO 2005092861 A1 WO2005092861 A1 WO 2005092861A1 IB 2005000536 W IB2005000536 W IB 2005000536W WO 2005092861 A1 WO2005092861 A1 WO 2005092861A1
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WIPO (PCT)
Prior art keywords
hydroxy
ethyl
oxo
amino
dihydroquinolin
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PCT/IB2005/000536
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English (en)
Inventor
Alan Daniel Brown
Paul Alan Glossop
Charlotte Alice Louise Lane
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Pfizer Limited
Pfizer Inc.
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Priority claimed from EP04290667A external-priority patent/EP1574501A1/fr
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO2005092861A1 publication Critical patent/WO2005092861A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • 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

Definitions

  • This invention relates to ⁇ 2 agonists of general formula:
  • R 1 , R 2 , n and Q 1 have the meanings indicated below, and to processes 5 for the preparation of, compositions containing and the uses of such derivatives.
  • 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 sub- 0 types: ⁇ 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. vascular, bronchial, uterine or intestinal smooth muscles), whereas ⁇ 3 adrenergic receptors are mainly expressed in fat tissues (therefore ⁇ 3 agonists could
  • ⁇ 1 adrenergic receptors are mainly expressed in cardiac tissues (therefore ⁇ 1 agonists are mainly used as cardiac stimulants).
  • 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).
  • COPD chronic obstructive airways disease
  • 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 prostaglandins
  • histamine and endothelins 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. Furthermore, ⁇ 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.
  • 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.
  • 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.
  • WOOO/75114 discloses compounds active as ⁇ 2 agonist, of formula:
  • EP147719 discloses ⁇ 2 agonists of formula
  • the invention relates to the compounds of general formula (1):
  • R 1 and R 2 are independently selected from H and C-i-C alkyl
  • - Q 1 is a group selected from:
  • Q 2 is a C ⁇ -C alkylene
  • R 8 is H or C ⁇ -C 4 alkyl
  • A is pyridyl, C 3 -C 7 cycloalkyl, adamantyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl or a group
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, C ⁇ - C 4 alkyl, OR 9 , SR 9 , halo, CN, CF 3 , OCF 3 , SO 2 NR 9 R 10 , CONR 9 R 10 , NR 9 R 10 , NHCOR 10 and phenyl;
  • R 9 and R 10 are the same or different and are selected from H or C ⁇ -C alkyl and the * represent the attachment point to the carbonyl group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.
  • 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 ⁇ -C 4 alkyl and C ⁇ -C 4 alkylene denote a straight-chain or branched group containing 1 , 2, 3 or 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in O-(C- t -C 4 )alkyl radicals, S-(C- ⁇ -C )alkyl radicals etc... .
  • suitable (C C )alkyl radicals are methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, fetf-butyl....
  • O-(C ⁇ -C 4 )alkyl radicals are methoxy, ethoxy, n-propyloxy, /so-propyloxy, n-butyloxy, /so-butyloxy, sec-butyloxy and fe/ -butyloxy....
  • C 3 -C 7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a preferred cycloalkyl group is cyclohexyl.
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
  • R 1 , R 2 , Q 1 , and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
  • the compounds of the formula (1 ) may be prepared by deprotection of the protected compound of formula (2):
  • R 1 , R 2 , Q 1 , and n are as previously defined and PG represents a suitable alcohol protecting group, typically a silyl group such as tbutyldimethylsilyl (TBDMS) or trimethylsilyl (TMS), and preferably TBDMS.
  • TDMS tbutyldimethylsilyl
  • TMS trimethylsilyl
  • the deprotection may be carried out according to the methods described in standard text-books such as "Protective Groups in Organic Synthesis" by T.W.Greene, A.Wiley-lnterscience Publication, 1981.
  • PG represents TBDMS
  • compound of formula (2) is treated with 10-18 eq ammonium fluoride in aqueous methanol, at about 45°C for between 18 and 42 hours.
  • the amide derivatives of formula (2) may be prepared by coupling an acid of formula (3):
  • 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
  • the acid of formula (3) is treated with an excess of amine of formula (4), (4') or (4") (1.2-2.1 eq), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.2-1.4 eq), 1-hydroxybenzotriazole hydrate (1.1-1.4eq) and triethylamine (2-3 eq) in N,N-dimethylformamide for a period of 18 hours.
  • Said amine (4), (4') or (4" 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 (3) may be prepared from the corresponding ester of formula (5) :
  • Ra is a suitable acid protecting group, typically benzyl or a (C- ⁇ -C )alkyl group and preferably a (C ⁇ -C 4 )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
  • ester of formula (5) is treated with an excess of lithium or sodium hydroxide (3-5eq) in aqueous dioxan or tetrahydrofuran for about 18 hours.
  • the ester of formula (5) may be prepared by deprotection of the compound of formula (6):
  • PG represents a suitable alcohol protecting group, typically benzyl or acetate, and preferably benzyl.
  • the deprotection may be carried out according to the methods described in standard text-books such as "Protective Groups in Organic Synthesis” by T.W.Greene, A.Wiley-lnterscience Publication, 1981.
  • compound of formula (6) is hydrogenated in the presence of 10% palladium on charcoal in ethanol or methanol as solvent at 60 psi of H 2 , for up to 40 hours at room temperature.
  • compound of formula (6) is treated with 20% palladium on charcoal, an excess of ammonium formate in ethanol at 80°C for about 1 hours.
  • the compound of formula (6) may be prepared by reaction of an arnine of formula (7) :
  • PG and PG are as previously defined.
  • the amine of formula (7) is reacted with a bromide of formula (8) at 90 °C for between 18 and 48 hours, in the absence of solvent.
  • the bromide of formula (8) may be prepared by analogy with the methods of Iwakuma et. al. (EP 147719) or Moran et. al. (WO 03/042160).
  • the amine of formula (7) may be pre ared as either the (R) or (S) enantiomer from the corresponding protected amine of formula (9) :
  • Ra, R 1 , R 2 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 (7) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book T.W. GREENE, Protective Groups in Organic Synthesis , A. Wiley-lnterscience Publication, 1981.
  • the amine of formula (9) is treated with 20% palladium hydroxide on charcoal and an excess of ammonium formate in ethanol at room temperature for about 2 hours.
  • the amine of formula (9) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (10):
  • the reaction is generally performed in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours.
  • 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 (9) as a single diastereomer.
  • the ketone of formula (10) may be prepared by palladium mediated coupling of an aryl halide of formula (11 ):
  • Ra and n are as previously defined and HAL represents a halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent.
  • the aryl halide of formula (11 ) 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-ot ⁇ o-toIylphosphine of formula Pd(OAc) 2 /P(o- Tol) 3 ) in a non-polar solvent (e.g. toluene, benzene, hexane).
  • a suitable palladium catalyst palladium acetate/ tri-ot ⁇ o-toIylphosphine of formula Pd(OAc) 2 /P(o- Tol) 3
  • a non-polar solvent e.g. toluene, benzene, hexane.
  • the reaction is carried out at a temperature comprised between 80°C and 110°C
  • the aryl halide of formula (11) may be obtained by esterification of the corresponding acid of formula (12):
  • 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 (12) 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 up to 16 hours.
  • the acid of formula (12) is a commercial product.
  • the amide of formula (13) is treated with a small excess of thiourea in acetic acid and ethanol at the reflux temperatu re of the reaction for about 16 hours, followed by treatment of the product with ethanolic hydrogen chloride for 16 hours at the reflux temperature of the reaction.
  • the amide of formula (13) may be prepared from the alcohol of formula (14):
  • CICH 2 CN chloroacetonitrile
  • the alcohol of formula (14) is treated with an excess of chloroacetonitrile in acetic acid and sulphuric acid at between 0°C and room temperature for about 5 hours.
  • the alcohol of formula (14) may be prepared from the ester of formula (15):
  • Rd represents a suitable acid protecting group, typically benzyl or a (C C ) alkyl group, which includes, but is not limited to, methyl or 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 is reacted with a suitable organometallic reagent, (e.g. R 2 Li, R 2 MgBr) in a suitable solvent such as tetrahydrofuran or ether.
  • ester of formula (15) is treated with an excess of CH 3 MgBr in ether at between 0°C and room temperature for about 2 hours.
  • the acid of formula (15) may be prepared by partial hydrolysis of the diester of formula (16):
  • Rd is as previously defined, and are preferably the same, by analogy with the method of Vander Elst et. al. Int. J. Peptide Protein Res. 29, 1987, 331- 346.
  • the diester of formula (16) is treated with ethanolic hydrochloric acid in dioxan in the presence of 2 eq of the diacid of formula (17), at the reflux temperature of the reaction for 18 hours.
  • the diester of formula (16) may be prepared by esterification of the corresponding diacid of formula (17):
  • the acid of formula (17) is treated with catalytic acetyl chloride in an alcoholic solvent of formula RdOH, wherein Rd is as previously defined, at the reflux temperature of the reaction for about 18 hours.
  • the acid of formula (17) is commercially available.
  • Ra are as previously defined.
  • ester of formula (20) is reacted with an "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li) to give the corresponding tertiary alcohol of formula (19) using the method described above.
  • Said tertiary alcohol of formula (19) is then treated with an alkyl nitrile
  • the resulting bromo amine (18) is treated with a suitable palladium catalyst (e.g. [1 ,1'-bis(diphenylphophino)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 (7).
  • a suitable palladium catalyst e.g. [1 ,1'-bis(diphenylphophino)ferrocene]dichloropalladium(ll)
  • a solution of the olefin of formula (21 ) 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 (21 ) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (22):
  • the aryl halide (22) 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 ) , palladium acetate/tri-orfbo-tolylphosphine of formula Pd(OAc) 2 /P(o-tol) 3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCI 2 ) in a sutiable solvent (e.g. acetonitrile, N, /V-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 40°C and 1 10°C for 8 to 24 hours.
  • a suitable palladium catalyst e.g. tetrakis(triphenylphosphine)pal
  • the ketone of formula (22) is a commercial product.
  • the acid of formula (23) is preferentially reduced to the corresponding alcohol (24) 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 (24) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile.
  • the preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine.
  • Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to furnish the amine of formula (7), where R 1 and R 2 are both H.
  • the compounds of formula (1) wherein the dashed line is a bond can be reduced to a compound of formula (1 ) wherein the dashed line doesn't represent a bond, according to processes well known to the man skilled in the art. For example, it may be hydrogenated using 10% palladium on carbon catalyst at 30°C for 48 hours under one atmosphere of hydrogen.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
  • Q 1 is a group *-NH-Q 2 -A, wherein A is cyclohexyl.
  • A is adamantyl.
  • Q 1 is
  • R 3 , R 4 , R 5 and R 6 are H.
  • Q 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 C 1 -C 4 alkyl.
  • 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 H, CH 3 , OCH 3 , OCH 2 -CH 3 , SCH 3 , halo, CF 3 and phenyl provided at least 2 of R 3 to R 7 are equal to H. More preferably, Q is a group *-NH-Q -A, wherein A is a group
  • R 3 , R 4 , R 5 , R and R 7 are the same or different and are selected from H, CH 3 , OCH 3 , OCH 2 -CH 3) CI, F, CF 3 and phenyl provided at least 3 of R 3 to R 7 are equal to H.
  • Q 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, or -CH 2 -C(CH 3 ) 2 -, preferably -CH 2 -.
  • R 1 is H or C ⁇ -C 4 alkyl and R 2 is d-C 4 alkyl. More preferably, R 1 is H or CH 3 and R 2 is CH 3 or CH 2 CH 3 .
  • n 0 or 1.
  • R 1 is H and R 2 is CH 3 or CH 2 CH 3 and n is 1.
  • R 1 is CH 3
  • R 2 is CH 3
  • n is 1.
  • the compounds of formula (1 ) wherein the dashed line represents a bond, such as in the formula below, are preferred:
  • 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/hydr
  • 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 in 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.
  • '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 solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • '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, pro drugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (1).
  • '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 carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1 ) is replaced by (C-i-CsJalkyl;
  • the compound of formula (1 ) contains an alcohol functionality (- OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1 ) is replaced by (CrC 6 )alkanoyloxymethyl; and (iii) where 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 (C 1 -C ⁇ 0 )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
  • the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR 1 R 2 -> -NHR 1 or -NHR 2 ); (iv) where the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR 1 -> -NH 2 ); (v) where the compound of formula (1 ) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and (vi) where the compound of formula (1 ) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -> COOH).
  • 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 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
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • 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 reagent ⁇ in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -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 typicality 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 stimul ting 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 prog rammed 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) micro spheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical fo rmulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, i mplants, 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 micronee>dle 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 electro-hydrodynamics 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 comminut ing method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminut ing 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//I to 100//I.
  • 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 incl ude 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.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • 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 container, divided bottle, or divided foil packet An example of such 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-administered 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.
  • the second and more therapeutic agents will be selected from a different class of therapeutic agents.
  • co-administration means, 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,
  • each part may be administered by either the same or different route.
  • Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to :
  • LTRAs Leukotriene antagonists
  • Histamine receptor antagonists including H1 and H3 antagonists
  • muscarinic M3 receptor antagonists or anticholinergic agents (e) muscarinic M3 receptor antagonists or anticholinergic agents, (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,
  • COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs)
  • NSAIDs non-selective and selective COX-1 or COX-2 inhibitors
  • Oral and inhaled glucocorticosteroids such as DAGR (dissociated agonists of the corticoid receptor)
  • dopamine receptors e.g. D2 agonists
  • Modulators of the NFic ⁇ pathway e.g. IKK inhibitors
  • modulators of cytokine signalling pathyways 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
  • glucocorticosteroids in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or
  • ipratropium salts namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine
  • ipratropium salts namely bromide
  • tiotropium salts namely bromide
  • oxitropium salts namely bromide, perenzepine, and telenzepine
  • the compounds of formula (1 ) have the ability to interact with the ⁇ 2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the ⁇ 2 receptor plays in the physiology of all mammals.
  • a further aspect of the present invention relates to the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the ⁇ 2 receptor is involved. More specifically, 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, in
  • obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper- reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension,
  • COPD chronic osinophilic pneumonia
  • COPD chronic obstructive pulmonary disease
  • COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD
  • COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacer
  • bronchitis of whatever type, etiology, or pathogenesis in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,
  • bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
  • a still further aspect of the present invention also 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. More precisely, 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.
  • the crude product (89.2g) was triturated with a mixture of dichloromethane and methanol (1 :1 , 2 ml/g) for 90 minutes.
  • the solid was filtered and washed with dichloromethane (53ml).
  • the solid was then heated in a mixture of dichloromethane (39ml) and methanol (8ml) for 2 hours under reflux, cooled to room temperature and stirred for 1 hour. Filtration of the solid followed by washing with dichloromethane: methanol (9:1 , 30ml) afforded the title compound as a pale brown solid, 37.15 g.
  • Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromo- phenyl)-acetic acid (20. Og, 93mmol) in methanol (500ml) at 0°C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane, dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the title compound as a colourless oil, 20.6g.
  • 2,2'-(1 ,3-Phenylene)diacetic acid (10. Og, 51 mmol) was dissolved in ethanol (100ml) and the solution treated dropwise with catalytic acetyl chloride (2.5ml). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated under reduced pressure. The residue was taken up in ethyl acetate (100ml) and washed with sodium bicarbonate solution (3x50ml) and brine (3x50ml). The organic phase was dried (MgSO 4 ) and concentrated under reduced pressure. The residue was triturated with pentane to yield the title product, 11.8g.
  • Methyl magnesium chloride (51 ml of a 3M solution in tetrahydrofuran, 153mmol) was added dropwise to a stirred solution of preparation 9 (11.6g, 51 mmol) (International Journal of Peptide and Protein Research, 1987, 29(3), 331 ) in tetrahydrofuran (300ml) at 0°C under nitrogen. The reaction was allowed to warm to room temperature overnight with the formation of a thick white precipitate and then water (50ml) and 2N hydrochloric acid (80ml) were cautiously added.
  • the orange oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 98:2:0.2) to afford the title compound as an orange oil, 2.17g.
  • the residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0.2 to 95:5:0.5) to afford the title compound as a yellow foam, 1.31 g.
  • Lithium hydroxide solution (4.23ml, 1 M, 4.23mmol) was added to a solution of the compound from preparation 21 (1.11g, 2.16mmol) in tetrahydrofuran (10ml) and the reaction stirred at room temperature for 18 hours. Tic analysis showed starting material remaining, so additional lithium hydroxide (2.1ml, 1 M, 2.1 mmol) was added and the reaction stirred for a further 18 hours at room temperature and at 45°C for a further 5 hours. The mixture was acidifed by the addition of 1 M hydrochloric acid (6.33ml), then concentrated under reduced pressure to remove tetrahydrofuran. The remaining aqueous solution was decanted off, and the residue azeotroped with methanol to afford the title compound as a brown foam, 1.1g.
  • the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99.8:0:0.2 to 94.8:4:0.2). The resulting oil was azeotroped with ether to afford the title compound as a foam.
  • Methylmagnesium bromide (3M solution in diethylether, 51.6ml, 155mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0g, 70mmol) in dry diethylether (200ml) at 0°C. The resulting mixture was left for 3 hours, then cooled to 0°C and slowly quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried (sodium sulfate). The yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol (90:5:5 by volume to afford a pale yellow oil, 13.26g.
  • the product containing, basic washings were evaporated under reduced pressure to afford the title compound as a pale yellow oil, 1.1g.
  • the product containing, basic washings from the first SCX Isolute® ion-exchange cartridge were evaporated under reduced pressure and the residue purified by column chromatography on silica gel using pentane:ethyl acetate (1 :1 ) to ethyl acetate to dichloromethane:methanol:0.88 ammonia (85:15:1 ) as eluant to afford additional title compound as a pale yellow oil, 4.8g (5.9g in total).
  • 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 Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO 2 asphyxi ation and exsanguination from the femoral artery and the trachea is isolated.
  • Four preparations are obtained from each animal, starting the dissection immed ⁇ ately below the larynx and taking 2.5 cm length of trachea.
  • the piece of trachea is opened by cutting the cartilage opposite the trachealis muscle, then transverse sections, 3-4 cartilage rings wide, are cut.
  • the resulting strip preparations are suspended in 5 ml organ baths using cotton threads tied through the upper and lower cartilage bands.
  • the strips are equilibrated, un-tensioned, for 20 min utes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 ⁇ M Indomethiacin (Sigma I7378), 10 ⁇ M Guanethidine (Sigma G8520) and 10 ⁇ M Atenolol (Si ⁇ ma A7655), heated at 37°C and gassed with 95% O 2 /5% CO 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. Changes in tension are recorded and monitored via standard isometric transducers coupled to a data-collection system (custom-designed at Pfizer). Following the tensioning equilibration, the tissues are subjected to electrical field stimulation (EFS) using the following parameters : 10 s trains every 2 minutes, 0.1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts) continuously throughout the length of the experiment. EFS of post-ganglionic cholinergic nerves in the trachea results in monophasic contractions of the smooth muscle and twitch height is recorded.
  • EFS electrical field stimulation
  • 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 accord ing 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
  • 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 5 o 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). Confirmation of beta-2 mediated functional activity
  • 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 concerne des composés représentés par la formule (I) et des processus de préparation d'intermédiaires utilisés dans la préparation de compositions contenant ces dérivés ainsi que des procédés d'utilisation de ces compositions. Les composés de cette invention conviennent pour de nombreuses maladies, pathologies et états, en particulier des maladies, des pathologies et des états inflammatoires, allergiques et respiratoires.
PCT/IB2005/000536 2004-03-11 2005-03-01 Derives de quinolinone compositions pharmaceutiques contenant ces derives et utilisation de celles-ci WO2005092861A1 (fr)

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EP04290667A EP1574501A1 (fr) 2004-03-11 2004-03-11 Dérivés de quinoléinone, compositions pharmaceutiques les contenant et leur usage
US59179104P 2004-07-27 2004-07-27
US60/591,791 2004-07-27

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Cited By (27)

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WO2007102771A1 (fr) * 2006-03-08 2007-09-13 Astrazeneca Ab Nouveaux composés
WO2007106016A1 (fr) * 2006-03-14 2007-09-20 Astrazeneca Ab Dérivés de benzothiazole en tant qu'agonistes de l'adrénorécepteur bêta2
JP2008056680A (ja) * 2004-03-23 2008-03-13 Pfizer Inc アドレナリン受容体として有用なホルムアミド誘導体
US7612084B2 (en) 2006-03-20 2009-11-03 Pfizer Inc Amine derivatives for the treatment of asthma and COPD
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010123766A1 (fr) 2009-04-23 2010-10-28 Theravance, Inc. Composes diamides ayant un antagoniste du recepteur muscarinique et une activite agoniste des recepteurs adrenergiques beta2
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
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
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
WO2012168359A1 (fr) 2011-06-10 2012-12-13 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste d'un récepteur muscarinique et agoniste d'un récepteur bêta2 adrénergique
WO2014086927A1 (fr) 2012-12-06 2014-06-12 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste du récepteur muscarinique et agoniste du récepteur bêta2 adrénergique
WO2014086924A1 (fr) 2012-12-06 2014-06-12 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste du récepteur muscarinique et agoniste du récepteur bêta2 adrénergique
WO2016128456A1 (fr) 2015-02-12 2016-08-18 Chiesi Farmaceutici S.P.A. Composés présentant une activité d'antagonistes de récepteur muscarinique et d'agonistes de récepteur bêta 2 adrénergique
WO2016193241A1 (fr) 2015-06-01 2016-12-08 Chiesi Farmaceutici S.P.A. Composés ayant une activité d'antagoniste des récepteurs muscariniques et d'agoniste des récepteur adrénergiques bêta 2
WO2017093208A1 (fr) 2015-12-03 2017-06-08 Chiesi Farmaceutici S.P.A. Composés ayant une activité d'antagoniste des récepteurs muscariniques et d'agoniste des récepteurs adrénergiques bêta2
WO2018011090A1 (fr) 2016-07-13 2018-01-18 Chiesi Farmaceutici S.P.A. Composés d'hydroxyquinolinone ayant une activité d'antagoniste des récepteurs muscariniques et d'agoniste des récepteurs adrénergiques bêta2

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JP2008056680A (ja) * 2004-03-23 2008-03-13 Pfizer Inc アドレナリン受容体として有用なホルムアミド誘導体
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
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
WO2007102771A1 (fr) * 2006-03-08 2007-09-13 Astrazeneca Ab Nouveaux composés
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
WO2007106016A1 (fr) * 2006-03-14 2007-09-20 Astrazeneca Ab Dérivés de benzothiazole en tant qu'agonistes de l'adrénorécepteur bêta2
US7612084B2 (en) 2006-03-20 2009-11-03 Pfizer Inc Amine derivatives for the treatment of asthma and COPD
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
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
US8362064B2 (en) 2008-12-30 2013-01-29 Pulmagen Theraputics (Inflammation) Limited Sulfonamide compounds for the treatment of respiratory disorders
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010123766A1 (fr) 2009-04-23 2010-10-28 Theravance, Inc. Composes diamides ayant un antagoniste du recepteur muscarinique et une activite agoniste des recepteurs adrenergiques beta2
EP3210981A1 (fr) 2009-04-23 2017-08-30 Theravance Respiratory Company, LLC Composés de diamide contenant une activité d'antagoniste du récepteur muscarinique et d'agoniste du récepteur adrénergique bêta 2
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
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
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
WO2012168359A1 (fr) 2011-06-10 2012-12-13 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste d'un récepteur muscarinique et agoniste d'un récepteur bêta2 adrénergique
WO2014086924A1 (fr) 2012-12-06 2014-06-12 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste du récepteur muscarinique et agoniste du récepteur bêta2 adrénergique
WO2014086927A1 (fr) 2012-12-06 2014-06-12 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste du récepteur muscarinique et agoniste du récepteur bêta2 adrénergique
EP3345904A1 (fr) 2012-12-06 2018-07-11 Chiesi Farmaceutici S.p.a. Composés dotés de l'antagoniste de récepteur muscarinique et activité d'agoniste de récepteur adrénergique bêta2
WO2016128456A1 (fr) 2015-02-12 2016-08-18 Chiesi Farmaceutici S.P.A. Composés présentant une activité d'antagonistes de récepteur muscarinique et d'agonistes de récepteur bêta 2 adrénergique
WO2016193241A1 (fr) 2015-06-01 2016-12-08 Chiesi Farmaceutici S.P.A. Composés ayant une activité d'antagoniste des récepteurs muscariniques et d'agoniste des récepteur adrénergiques bêta 2
WO2017093208A1 (fr) 2015-12-03 2017-06-08 Chiesi Farmaceutici S.P.A. Composés ayant une activité d'antagoniste des récepteurs muscariniques et d'agoniste des récepteurs adrénergiques bêta2
WO2018011090A1 (fr) 2016-07-13 2018-01-18 Chiesi Farmaceutici S.P.A. Composés d'hydroxyquinolinone ayant une activité d'antagoniste des récepteurs muscariniques et d'agoniste des récepteurs adrénergiques bêta2

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