EP1727789A2 - Dérivés béta-2 agonistes de la phényléthanolamine - Google Patents

Dérivés béta-2 agonistes de la phényléthanolamine

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Publication number
EP1727789A2
EP1727789A2 EP05708731A EP05708731A EP1727789A2 EP 1727789 A2 EP1727789 A2 EP 1727789A2 EP 05708731 A EP05708731 A EP 05708731A EP 05708731 A EP05708731 A EP 05708731A EP 1727789 A2 EP1727789 A2 EP 1727789A2
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EP
European Patent Office
Prior art keywords
hydroxy
phenyl
ethyl
hydroxymethyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP05708731A
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German (de)
English (en)
Inventor
Alan Daniel Pfizer Global Res.and Developm BROWN
Mark Edward Pfizer Global Res.and Devel. BUNNAGE
Paul Alan Pfizer Global Res.and Develop. GLOSSOP
Kim Pfizer Global Research and Development JAMES
Charlotte Alice Luise Pfizer Global Res. LANE
Russell Andrew Pfizer Global Res.and LEWTHWAITE
Graham Pfizer Global Research and Develop. LUNN
David Anthony Pfizer Global Res.and Devel. PRICE
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Pfizer Ltd
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Pfizer Ltd
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Priority claimed from EP04290725A external-priority patent/EP1577291A1/fr
Priority claimed from GB0425064A external-priority patent/GB0425064D0/en
Application filed by Pfizer Ltd filed Critical Pfizer Ltd
Priority to EP05708731A priority Critical patent/EP1727789A2/fr
Publication of EP1727789A2 publication Critical patent/EP1727789A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • 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
    • 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
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 sub- 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.
  • ⁇ 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).
  • 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, duration of action and/or pharmacodynamic properties.
  • the present invention relates to novel ⁇ 2 agonists.
  • EP 0654534 B1 and EP0939134 B1 disclose a process for the preparation of compounds of formula (XI):
  • These compounds are disclosed as anti-obesity and anti-diabetic agents having specific ⁇ 3 activity.
  • EP0236624 discloses compounds of formula
  • the invention relates to compounds of general formula (1 ):
  • R 1 and R 2 are independently selected from H and C ⁇ -C 4 alkyl, n is 0, 1 or 2, and,
  • Q 1 is a group selected from:
  • Q is a single bond or a C ⁇ -C 4 alkylene
  • R 8 is H or C ⁇ -C 4 alkyl, p is 1 or 2, and
  • A is a C3-C1 0 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably by 1 , 2, 3 or 4 carbon atoms, O-phenyl-pyrazolyl, 5 to 10 membered heterocyclic group, optionally aromatic, comprising one, two, three or four heteroatoms selected from O, S or N, optionally substituted with C r C 4 alkyl or 0-C- ⁇ -C 4 alkyl, or a group of formula
  • 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 , SOR 9 , S0 2 R 9 , halo, CN, CF 3 , OCF 3 , phenyl, O-phenyl, S- phenyl, SO 2 -morpholinyl, O-(CH 2 ) 3 -pyrrolidinyl, COOR 9 , S0 2 NR 9 R 10 , CONR 9 R 10 , NR 9 R 10 and NHCOR 10 ;
  • R 9 and R 10 are the same or different and are selected from H or C ⁇ -C 4 alkyl and the * represents the attachment point to the carbonyl group;
  • Q 1 is * -NH-CrC 4 alkyl, or * -N(R 8 )-Q 2 -A where A is - C 3 -C1 0 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms,
  • heterocyclic group optionally aromatic, comprinsing one, two, three or four heteroatoms selected from O, S or N optionally substituted with C C alkyl or 0-C C 4 alkyl, said heterocyclic group being other than pyridyl,
  • 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, and show good potency, in particular when administered via the inhalation route.
  • the term "potent" means that the compounds of formula (1 ) show an agonist potency for the ⁇ 2 receptor, which is less than 10 nM as measured by the cell-based assay described herein.
  • the compounds of the invention are selective agonists of the ⁇ 2 receptor.
  • the compounds of the invention show an agonist potency for the ⁇ 2 receptor, which is at least about 100-fold higher as for the ⁇ 3 receptor and at least about 500-fold higher as for the ⁇ 1 receptor.
  • C ⁇ -C alkyl and C 1 -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 0-(C-i-C )alkyl radicals, S-(CrC 4 )alkyl radicals etc... .
  • suitable (CrC )alkyl radicals are methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, terf-butyl....
  • O-(C-i-C 4 )alkyl radicals are methoxy, ethoxy, n-propyloxy, /so-propyloxy, ⁇ -butyloxy, /so-butyloxy, sec-butyloxy and terf-butyloxy....
  • the C 3 -C 10 cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms include 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.
  • Examples of 5 to 10 membered heterocyclic group, optionally aromatic, comprinsing one, two, three or four heteroatoms independently selected from O, S or N are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, oxadiazolyl, triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyl, quinoxalyl, phthalazinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisox
  • Preferred heterocyclic groups are pyrrolidinyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoimidazolyl and benzofuranyl.
  • heterocyclic group contains 1 or 2 heteroatoms selected from O, S or N. More preferably said heterocyclic group contains one or two nitrogen atoms.
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
  • the amide derivatives of the formula (1 ) may be prepared by coupling an acid of formula (2):
  • R 8 , Q 2 , A, p and R 3 to R 6 are as previously defined for compounds of formula (1).
  • 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, /V-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. /V-methylmorpholine, triethylamine or diisopropylethylamine).
  • a conventional coupling agent e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, /V-dicyclohexylcarbodiimide
  • a catalyst e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- aza
  • 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.
  • 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, protection, deprotection etc..) from commercially available material.
  • the acid of formula (2) may be prepared from the corresponding ester of formula (4):
  • Ra is a suitable acid protecting group, 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. water, 1 ,4-dioxan, tetrahydro
  • the ester of formula (4) may be prepared by reaction of an amine of formula (5) :
  • the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethyl sulphoxide, toluene, ⁇ /, ⁇ /-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.
  • a solvent or mixture of solvents e.g. dimethyl sulphoxide, toluene, ⁇ /, ⁇ /-dimethylformamide, acetonitrile
  • a suitable base e.g. triethylamine, diisopropylethylamine, potassium carbonate
  • the bromide of formula (6) may be prepared from the ester of formula
  • the alcohol of formula (7) may be prepared as either the (R) or (S) enantiomer according to methods well described in the literature (Tetrahedron Letters 1994, 35(50), 9375).
  • the amine of formula (5) may be prepared as either the (R) or (S) enantiomer from the corresponding protected amine of formula (8) :
  • Ra and n are as previously defined and Rb and Re represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Re may be ⁇ -methylbenzyl), provided that the bonds between N and Rb and N and Re 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 T.W. GREENE, Protective Groups in Organic Synthesis , A. Wiley-lnterscience Publication, 1981.
  • the amine of formula (8) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (9):
  • Ra, Rb, Re and n are as previously defined.
  • the reaction of the ketone of formula (9) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH 3 or sodium triacetoxyborohydride of formula Na(OAc) 3 BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic acid) to give the amine of formula (8) as a mixture of diastereomers.
  • 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 (8) as a single diastereomer.
  • 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 (10) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula BusSnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-ort ⁇ o-tolylphosphine of formula Pd(OAc) 2 /P(o- T0 3 ) in a non-polar solvent (e.g. toluene, benzene, hexane).
  • a suitable palladium catalyst palladium acetate/ tri-ort ⁇ o-tolylphosphine of formula Pd(OAc) 2 /P(o- T0 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 for 6 to 16 hours.
  • the aryl halide of formula (10) may be obtained by esterification of the corresponding acid of formula (11 ):
  • 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 (11 ) 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 (11) is a commercial product.
  • R , R and Ra are as previously defined.
  • ester of formula (12) 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 (13) using the method described above.
  • an "activated” alkyl organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li
  • acetonitrile e.g. acetonitrile, chloroacetonitrile
  • an acid e.g. sulphuric acid, acetic acid
  • the resulting amino acid is then esterified using the method described herein to give the amine of formula (5).
  • R 1 , R 2 and Ra are as previously defined.
  • ester of formula (14) 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 (15) using the method described above.
  • an "activated" alkyl organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li
  • the resulting bromo amine (16) 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 (17) 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 (17) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (18):
  • the aryl halide (18) 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-ort 70-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.
  • a suitable palladium catalyst e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh 3 ) 4 , palladium acetate/tri-ort 70-tolylphosphine of formula Pd(OAc) 2 /P(o-tol) 3 or (diphenyl
  • acetonitrile N, ⁇ /-dimethylformamide, toluene
  • a base such as triethylamine
  • the ketone of formula (18) is a commercial product.
  • R 1 , R 2 and Ra are as previously defined.
  • the acid of formula (19) is preferentially reduced to the corresponding alcohol (20) 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 (20) 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.
  • 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.
  • R Ra, Rb, Re, n and Qi are as previously defined.
  • the acid of formula (21 ) is obtained by hydrolysis of the ester of formula (8). This is achieved 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, tetrahydrofuran/water
  • Amide of formula (22) is prepared by coupling of acid (21 ) with a suitable amine of formula (3), (3') or (3").
  • the coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 2-chloro-1 ,3-dimethylimidazolidinum hexafluorophosphate, 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. /V-methylmorpholine, triethylamine or N,N-diisopropylethylamine).
  • a tertiary amine base e.g. /V-methylmorpholine, triethylamine or N,N-diisopropylethylamine.
  • 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 amine (3), (3') or (3" 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, protection, deprotection etc) from commercially available material.
  • the amine of formula (23) can be prepared 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.
  • a suitable solvent e.g. methanol, ethanol, ethyl acetate
  • a suitable hydrogen donor such as ammonium formate or formic acid
  • a suitable palladium catalyst e.g. 20% palladium hydroxide on charcoal
  • amine (23) and bromide (6) can be heated together, optionally in the presence of a suitable solvent (e.g. toluene or xylene) and a suitable tertiary amine base (e.g. V-methylmorpholine, triethylamine or N,N-diisopropylethylamine) at elevated temperature, for 18-48 hours.
  • a suitable solvent e.g. toluene or xylene
  • a suitable tertiary amine base e.g. V-methylmorpholine, triethylamine or N,N-diisopropylethylamine
  • 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- Interscience Publication, 1981 ) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • R 1 and R 2 are independently selected from H and C C 4 alkyl
  • Q is a group selected from:
  • Q is a single bond or a C C alkylene
  • R 8 is H or C C 4 alkyl, p is 1 or 2, and
  • A is a C3-C10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, pyridyl, or a group of formula
  • 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 , SOR 9 , SO 2 R 9 , halo, CN, CF 3 , OCF 3 , COOR 9 , SO 2 NR 9 R 10 , CONR 9 R 10 , NR 9 R 10 , NHCOR 10 ;
  • R 9 and R 10 are the same or different and are selected from H or d-C 4 alkyl and the * represent the attachment point to the carbonyl group;
  • Q 1 is * -NH-C ⁇ -C 4 alkyl, or * -N(R 8 )-Q 2 -A where A is C 3 -C 10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, and/or, 2) when one of R 1 and R 2 is H, the other is not CH 3
  • a preferred * -NH-C C 4 alkyl is NH-isopropyl.
  • Preferred compounds of formula 1 are those wherein Q 1 is *-N(R 8 )-Q 2 -A where A is C 3 -C10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably cyclohexyl, or adamantyl.
  • n is 1
  • Q 2 is CH 2 or a bond
  • A is C 3 -C 10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably cyclohexyl, or adamantyl.
  • n is 0 and Q 1 is a group of formula or * -N(R ⁇ 8X )-Q -A, wherein Q is a single bond or a C ⁇ -C alkylene, R is H and A is naphthyl or
  • 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 and the * represent the attachment point to the carbonyl group.
  • R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
  • A is a group of formula
  • R 3 , R 4 , R 5 , R 6 and R 7 are selected from H, C ⁇ -C 4 alkyl, OR 9 , SR 9 , CI, F, CF 3 , OCF 3 , COOR 9 , S0 2 NR 9 R 10 , and at least 2 of R 3 to R 7 represent H, wherein R 9 and R 10 are the same or different and are selected from H or C ⁇ -C alkyl.
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, CH 3 , OH, OCH 3 , SCH 3 , OCH 2 CH 3 , CI, F, CF 3> OCF 3 , COOH, SO 2 NH 2 , and at least 2 of R 3 to R 7 represent H.
  • R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, CH 3 , OH, OCH 3 , OCH 2 CH 3 , CI, F, CF 3 , OCF 3 , COOH, S0 2 NH 2 , and at least 3 of R 3 to R 7 are represent H.
  • R 8 is H, methyl or ethyl, more preferably H.
  • Q 2 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -C(CH 3 ) 2 - CH 2 -, -CH 2 -C(CH 3 )2-, and -CH(CH 3 )-.
  • n is 0 or 1.
  • R 1 and R 2 are both CH 3 or, R 1 is H and R 2 is CH 3 or CH 2 -CH 3 or, R 1 and R 2 are both H.
  • the compounds of formula (1 ) may also be optionally transformed into pharmaceutically acceptable salts.
  • these pharmaceutically acceptable salts of the compounds of the formula (1 ) include the acid addition and the base salts (including disalts) 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.
  • Pharmaceutically acceptable salts of compounds of formula (1 ) may be prepared by one or more of three methods: (i) by reacting the compound of formula (1 ) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (1 ) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
  • 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.
  • 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 solvent 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:
  • 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
  • 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 cisltrans (or Z/E) isomers are possible. Where the compound contains, for example, a keto orstructural isomers are interconvertible via a low oxime group or an aromatic moiety.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.
  • a single compound may exhibit more than one type of isomerism.
  • Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counterion is optically active for example, d-lactate or /-lysine, or racemic, for example, c//-tartrate or /-arginine.
  • Cisltrans 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.
  • 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).
  • n and Q 1 are as defined above for compounds of formula (1 ).
  • 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 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (1) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • 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 reagents 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 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.
  • the compounds of formula (1) and their pharmaceutically acceptable salts and derived forms as mentioned above can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy and/or prophylaxis. They can be administered per se, in mixtures with one another or in the form of pharmaceutical preparations which as active constituent contain an efficacious dose of at least one compounds of formula (1 ), its pharmaceutically acceptable salts and/or derived forms, in addition to customary pharmaceutically innocuous excipients and/or additives.
  • the compounds of formula (1 ), their pharmaceutically acceptable salts and/or derived forms may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.
  • the compounds of formula (1 ), their pharmaceutically acceptable salts and/or derived forms may be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.
  • 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, intrasternal, 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 PGLApoly(o7-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.
  • 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.
  • 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/vl.
  • 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.
  • 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.
  • kits suitable for coadministration of the 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.
  • 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 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.
  • co-administration As used herein, 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:
  • 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
  • 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, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whez infant syndrome and bronchiolytis,
  • 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.
  • 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.
  • Example 1 ⁇ /-cycloheptyl-2- ⁇ 3-[(2R)-2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3. (hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 7 ⁇ -(cyclopentylmethyl)-2- ⁇ 3-[(2R)-2-( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 10 ⁇ /-(cyclohexylmethyl)-2- ⁇ 3-[(2R)-2-( ⁇ (2/?)-2-hydroxy.2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 12 V-(cycloheptylmethyl)-2- ⁇ 3-[(2r?)-2-( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 13 ⁇ -1 -adamantyl-2- ⁇ 3-[(2R)-2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 14 *V-(1 -adamantylmethyl)-2- ⁇ 3-[(2R)-2-( ⁇ (2R)-2-hydiOxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 15 ⁇ /-2-adamantyl-2- ⁇ 3-[(2r?)-2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 19 *V-(2-cyclohexylethyl)-2- ⁇ 3-[(2R)-2.( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide
  • Example 21 ⁇ /-(2,6-dimethoxybenzyl)-2- ⁇ 3-[2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy- 3-(hydroxymethyl)phenyl]ethyl ⁇ amino)-2-methylpropyl]phenyl ⁇ acetamide
  • Example 23 4- ⁇ (1R)-2-[(2- ⁇ 3-[2-(3,4-dihydrolsoquinolin-2(1r/)-yl)-2- oxoethyl]phenyl ⁇ -1 ,1 -dimethylethyl)amino]-1 -hydroxyethyl ⁇ -2- (hydroxymethyl)phenol
  • Example 25 ⁇ -(2,6-dichlorobenzyl)-2- ⁇ 3-[2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)-2-methylpropyl]phenyl ⁇ acetamide
  • Example 33 ⁇ -[2-(4-chlorophenyl)ethyl]-3- ⁇ 2-[(2R)-2-hydroxy-2-(4-hydroxy- 3-hydroxy-methylphenyl)ethylamino]-2-methylpropyl ⁇ benzamide
  • Example 35 3- ⁇ 2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)- ethylamino]-2-methyl-propyl ⁇ - ⁇ /-[2-(4- trifluoromethylphenyl)ethyl]benzamide
  • Example 36 /V-[2-(3,4-dichlorophenyl)ethyl]-3- ⁇ 2-[(2R)-2-hydroxy-2-(4- hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methyl-propyl ⁇ -benzamide
  • Example 38 3- ⁇ 2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl- phenyl)ethylamino]-2-methyl-propyl ⁇ - ⁇ /-(2-naphthalen-2-yl-ethyl)benzamide
  • Example 39 *V-(1 ,1 -dimethyl-2-phenylethyl)-3- ⁇ 2-[(2R)-2-hydroxy-2-(4- hydroxy-3-hydroxy-methylphenyl)-ethylamino]-2-methylpropyl ⁇ benzamide
  • Example 45 ⁇ /-(2,3-dihydro-1 H-inden-2-yl)-2- ⁇ 3-[2-( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)ethyl]phenyl ⁇ acetamide
  • Example 52 ⁇ -[2-(4-chlorophenyl)ethyl]-3-[(2R)-2-( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]benzamide
  • Example 60 ⁇ /-(4-chlorobenzyl)-3-[(2R)-2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]benzamide
  • Example 62 ⁇ -[4-(aminosulfonyl)benzyl]-3-[(2R)-2-( ⁇ (2R)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]benzamide
  • Example 65 Compound was further purified by trituration with diethyl ether.
  • Example 72 Purified by column chromatography using an ISCO ® silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 100:0 to 90:10:1
  • Example 75 Purified by column chromatography using a 4g RediSep ® silica cartridge, eluting with, dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 , followed by ethyl acetate:methanol:0.88 ammonia, 100:0:0 to 80:20:2
  • Example 78 Crude compound was further purified by trituration with diethyl ether
  • the title compound was prepared from 3-[2-( ⁇ (2R)-2- ⁇ [fert- butyl(dimethyl)silyl]oxy ⁇ -2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)-2- methylpropyl]- -[2-(4-chlorophenyl)ethyl]- ⁇ /-ethylbenzamide (preparation 110), using a similar method to example 33, as a colourless solid in 61% yield.
  • the title compound was prepared from 2- ⁇ 3-[2-( ⁇ (2R)-2- ⁇ [terf- butyl(dimethyl)silyl]oxy ⁇ -2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)-2- methylpropyl]phenyl ⁇ -/V-(3-pyrrolidin-1 -ylpropyl)acetamide (preparation 109), using a similar method to that of example 33.
  • the crude residue was further purified by column chromatography on Biotage ® amino silica gel, eluting with dichloromethane:methanol, 80:20, to afford the title compound as a colourless gum in 54% yield.
  • reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 91 :9:1 , followed by trituration with diethyl ether, to afford the title compound in 50% yield, 45mg.
  • examples: 89, 90 and 91 were warmed at 50°C for 18 hours.
  • Example 102 ⁇ 2-[2-(trifluoromethyl)phenyl]ethyl ⁇ amine can be prepared as described in WO 2003093231
  • Example 106 4-[[4-(2-aminoethyl)phenyl]sulfonyl]- morpholine is commercially available from Scientific Exchange Product List (K-046583)
  • Example 107 amine precursor (2-(2-aminoethyl)-6-chlorophenol) can be prepared as described in DE1959898
  • Example 108 crude compound was purified by HPLC using a Phenomenex Luna C18 system, eluting with water/acetonitrile/trifluoroacetic acid (5:95:0.1 ):acetonitrile, 95:5 to 5:95, to isolate the trifluoroacetic acid salt of the desired product.
  • Example 109 and 110 crude compound was purified by HPLC using a Phenomenex Luna C18 system, eluting with water/0.1 % formic acid:acetonitrile/0.1 % formic acid, 85:15 to 15:85
  • the title compound was prepared from 3- ⁇ 3-[2-( ⁇ (2R)-2- ⁇ [fert- butyl(dimethyl)silyl]oxy ⁇ -2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl ⁇ amino)-2- methylpropyl]phenyl ⁇ -/V-(3,4-dichlorobenzyl) propanamide (preparation 145), using a method similar to that of example 113, as a white foam in 71% yield.
  • Example 131 amine precursor (4-(2-amino-1 ,1-dimethylethyl)phenol) can be prepared as described in Ada Chem.Scand. 8, 1203, 1207; 1954
  • reaction mixture was then concentrated in vacuo, re-dissolved in dimethylsulfoxide (300 /L) and stirred for 30 minutes at room temperature.
  • the mixture was diluted with further dimethylsulfoxide (50 ⁇ L) and water (100 ⁇ L), stirred for one minute at room temperature and then purified by HPLC using a Phenomenex Luna C18 system, eluting with water/acetonitrile/diethylamine (5:95:0.05):acetonitrile, 95:5 to 5:95, to afford the desired compound.
  • xampe -e y- -p enypropyamne can e prepare as escr e n d. Med.
  • Example 141 6-methoxy-3-pyridineethanamine can be prepared as described in Drug Design and Discovery, 10, 35; 1993
  • Example 146: 5-Quinolineethanamine can be prepared as described in J. Med. Chem., 28, 1803-10; 1985
  • reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97:3:0.3, by volume) to give the title compound (12.1g) as a white oil.
  • Tributyltin methoxide 28.3 ml, 98mmol
  • preparation 28 (15.0g, 65mmol)
  • isopropenyl acetate (10.8ml, 98mmol)
  • palladium(ll)acetate 750mg, 3.30mmol
  • tri-otffto-tolylphosphine 2.0g, 6.5mmol
  • the reaction was diluted with ethyl acetate (150ml) and 4M aqueous potassium fluoride solution (90ml) and stirred for 15 minutes.
  • the mixture was filtered through arbocel and the organic phase separated and reduced in vacuo.
  • 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 (13.26 g).

Abstract

La présente invention concerne des composés représentés par la formule (I), des processus de préparation d'intermédiaires utilisés dans la préparation de composition contenant ces dérivés et, des processus d'utilisation de ceux-ci. Les composés de cette invention conviennent pour de nombreuses maladies, de nombreux troubles et de nombreuses pathologies, en particulier des maladies, des troubles et des pathologies inflammatoires, allergiques et respiratoires.
EP05708731A 2004-03-17 2005-03-10 Dérivés béta-2 agonistes de la phényléthanolamine Withdrawn EP1727789A2 (fr)

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EP04290725A EP1577291A1 (fr) 2004-03-17 2004-03-17 Dérivés béta-2 agonistes de la phényléthanolamine
US59179004P 2004-07-27 2004-07-27
GB0425064A GB0425064D0 (en) 2004-11-12 2004-11-12 Compounds useful for the treatment of diseases
EP05708731A EP1727789A2 (fr) 2004-03-17 2005-03-10 Dérivés béta-2 agonistes de la phényléthanolamine
PCT/IB2005/000640 WO2005090287A2 (fr) 2004-03-17 2005-03-10 Composes convenant pour le traitement de maladies

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GB0425054D0 (en) * 2004-03-23 2004-12-15 Pfizer Ltd Formamide derivatives for the treatment of diseases
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
GB0601951D0 (en) 2006-01-31 2006-03-15 Novartis Ag Organic compounds
ES2320961B1 (es) * 2007-11-28 2010-03-17 Laboratorios Almirall, S.A. Derivados de 4-(2-amino-1-hidroxietil)fenol como agonistas del receptor adrenergico beta2.
PL2231642T3 (pl) 2008-01-11 2014-04-30 Novartis Ag Pirymidyny jako inhibitory kinazy
JP5801997B2 (ja) 2009-07-07 2015-10-28 ファイザー・リミテッドＰｆｉｚｅｒ Ｌｉｍｉｔｅｄ 薬品の組合せを吸入するための投薬ユニット、投薬ユニットのパック、および吸入器
US8637516B2 (en) 2010-09-09 2014-01-28 Irm Llc Compounds and compositions as TRK inhibitors
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
CA2828219A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composes et compositions en tant qu'inhibiteurs de trk
CN116033893A (zh) 2020-06-26 2023-04-28 迈兰制药英国有限公司 包含5-[3-(3-羟基苯氧基)氮杂环丁烷-1-基]-5-甲基-2,2-二苯基己酰胺的制剂

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LU85856A1 (fr) * 1984-04-17 1986-06-11 Glaxo Group Ltd Composes de phenethanolamine
GB8528633D0 (en) * 1985-11-21 1985-12-24 Beecham Group Plc Compounds
OA11558A (en) * 1999-12-08 2004-06-03 Advanced Medicine Inc Beta 2-adrenergic receptor agonists.
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EP1497261B1 (fr) * 2002-04-25 2007-12-19 Glaxo Group Limited Derives de la phenethanolamine
EP1477167A1 (fr) * 2003-05-15 2004-11-17 Pfizer Limited Dérivés de [(2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino)-propyl] phenyl come agonistes de beta2

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EA200601510A1 (ru) 2007-04-27
JP2007529501A (ja) 2007-10-25
WO2005090287A3 (fr) 2006-02-16
AU2005223488A1 (en) 2005-09-29
WO2005090287A2 (fr) 2005-09-29
JP4054366B2 (ja) 2008-02-27
BRPI0508927A (pt) 2007-08-14

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