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WO2011048409A1 - Dérivés d'amine cyclique ayant une activité agoniste de récepteur adrénergique bêta-2 et antagoniste de récepteur muscarinique - Google Patents

Dérivés d'amine cyclique ayant une activité agoniste de récepteur adrénergique bêta-2 et antagoniste de récepteur muscarinique Download PDF

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WO2011048409A1
WO2011048409A1 PCT/GB2010/051751 GB2010051751W WO2011048409A1 WO 2011048409 A1 WO2011048409 A1 WO 2011048409A1 GB 2010051751 W GB2010051751 W GB 2010051751W WO 2011048409 A1 WO2011048409 A1 WO 2011048409A1
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alkyl
group
optionally substituted
compound
pharmaceutically acceptable
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PCT/GB2010/051751
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English (en)
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David Keith Donald
Andrew Stephen Robert Jennings
Nicholas Charles Ray
Fabien Roussel
Jonathan Mark Sutton
Patrizia Tisselli
Michelle Wilson
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Astrazeneca Ab
Pulmagen Therapeutics (Synergy) Limited
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Priority claimed from GB0918322A external-priority patent/GB0918322D0/en
Priority claimed from GBGB1009803.6A external-priority patent/GB201009803D0/en
Application filed by Astrazeneca Ab, Pulmagen Therapeutics (Synergy) Limited filed Critical Astrazeneca Ab
Publication of WO2011048409A1 publication Critical patent/WO2011048409A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to cyclic amine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing such pharmaceutical compositions, their use in therapy, and intermediates for use in their preparation.
  • bronchodilators Muscarinic- receptor antagonists (anti-cholinergics) are bronchodilators that exert their efficacy by reducing vagal cholinergic tone, the main reversible component of airway constriction in COPD.
  • ⁇ -adrenoceptor agonists are also bronchodilators due to their ability to functionally antagonise the bronchoconstrictor responses to a range of mediators, including
  • a single molecule possessing activities at muscarinic and ⁇ 2 - receptors may provide additional benefits to COPD patients in terms of efficacy and side-effect profile over either single agent.
  • a molecule possessing dual activity may also offer benefits in terms of ease-of-use and patient compliance over coadministration of the single therapies.
  • a single agent may also be beneficial from the perspective of formulation compared to two separate compounds, also offering the potential, if combined with another therapeutic, for triple action therapies.
  • ArCH 2 CH 2 NH- represents a ⁇ -adrenoceptor binding group
  • R 1 is selected from the following;
  • Ci_ 6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted by up to three Ci_ 3 alkyl chains and two such chains may be joined to form a C 3 _ 8 cycloalkyl ring; or wherein said alkyl group is substituted by up to two cycloalkyl or cycloalkylalkyl groups each comprising up to six carbon atoms;
  • n 0, 1, 2 or 3;
  • n 1 , 2, 3 or 4; provided that m + n is greater than or equal to 2;
  • R 2 , R 2 , R 3 , R 3 , R 4 , R 4 , R 5 , and R 5 are each independently, hydrogen or Ci_ 6 alkyl;
  • R 6 is a Ci_8 alkyl group optionally substituted by up to 3 substituents selected from halogen, Ci_ 6 alkyl, OR 10 , Ci_6 alkylS(O) 0 - 2 , NR 8 R 9 , OC(0)(Ci_ 6 alkyl), or C 3 _ 8 cycloalkyl
  • R 6 is a Ci_g alkyl group substituted by an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S; or R 6 is a C 3 _ 9 cycloalkyl group (wherein one or two of the ring carbon atoms can be replaced by O, S or N) and optionally substituted by up to 3 substituents independently selected from halogen, Ci_6 alkyl, OR 10 , Ci_ 6 alkylS(O) 0 - 2 , NR 8 R 9 , OC(0)(Ci_ 6 alkyl), and an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non- aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S; or R 6 is a C7-9 bicycloalkyl group optionally substituted by up to 3 substituents independently selected from halogen
  • R 7 is selected from hydrogen, -OR 10 , halogen, -CF 3 , -NR 8 R 9 , -NHS0 2 R u , -C(0)NR 8 R 9 or -CH 2 OR 10 ;
  • G represents a group comprising a straight or branched hydrocarbyl chain of up to 9 carbon atoms
  • up to three carbon atoms of the chain may be replaced by groups independently selected from O, NR 10 , S, S(O), S(0) 2 , C(0)0, OC(O), NR 10 C(O),
  • up to six carbon atoms of the chain may form part of an aryl, heteroaryl, fused bicyclic, alicyclic, or heteroaliphatic ring having up to four heteroatoms
  • the chain may comprise up to two of such rings each selected independently; wherein the chain may additionally comprise up to three carbon-carbon double bonds; and wherein the chain may additionally comprise up to three carbon-carbon triple bonds;
  • T is selected from an optionally substituted aryl group or an optionally substituted 5- or 6- membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S, or Ci_ 6 alkyl or C3-8 cycloalkyl or a hydrogen atom;
  • R 8 and R 9 are independently hydrogen or Ci_ 6 alkyl, or R 8 and R 9 may be joined together to form a heterocyclic ring comprising up to 9 ring atoms and optionally containing a further heteroatom selected from O, N or S;
  • R 10 and R 10 independently represent hydrogen, Ci_ 6 alkyl or C3-6 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_ 6 alkoxy;
  • R 11 represents Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, wherein the Ci_ 6 alkyl and C 3 _6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxy or Ci_ 6 alkoxy;
  • R 12 and R 13 are independently hydrogen, Ci_ 6 alkyl, an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S
  • t 1-3;
  • u is 2-4;
  • ⁇ -adrenoceptor binding group we mean a group capable of binding a ⁇ - adrenergic receptor; such as for example as outlined in the review article " ⁇ -adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, B.E. Main, pi 87 (Pergamon Press). Such groups are also known from, for example in WO/2005092841 ,
  • Examples of the group Ar in such convenient ⁇ -adrenoceptor binding groups include
  • a 1 , A 2 , A 3 and A 4 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0) 2 A 8 , NA 9 S(0) 2 A 10 , C(0)NA n A 12 , NA 13 C(0)A 14 , Ci_ 6 alkyl,
  • Ci_6 alkoxy C(0)(Ci_ 6 alkyl) or C(0)OCi_ 6 alkyl
  • a 3 can also be CH 2 OH, NHCHO, NHC(0)OCi_ 6 alkyl, NHC(0)Ci_6 alkyl,
  • a and ⁇ 2 ⁇ A are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0) 2 A 8 , NA 9 S(0) 2 A 10 , C(0)NA n A 12 , NA 13 C(0)A 14 , Ci_ 6 alkyl,
  • Ci_6 alkoxy C(0)(Ci_ 6 alkyl) or C(0)OCi_ 6 alkyl
  • a 5 , A 6 , A 7 , A 9 , A 11 , A 12 , A 13 , A 14 are independently, hydrogen, Ci_ 6 alkyl;
  • a 15 or A 1 1 0 6 are independently, hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl;
  • a and A 1 ' are, independently, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl;
  • the Ar rou is selected from:
  • a 1 , A 2 , and A 4 are, independently, hydrogen, halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy;
  • a 3 can be CH 2 OH, NHCHO, NHS(0) 2 NA 15 A 16 or NHS(0) 2 A 17 ;
  • a 1A and A 2A are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0) 2 A 8 , NA 9 S(0) 2 A 10 , C(0)NA n A 12 , NA 13 C(0)A 14 , Ci_ 6 alkyl,
  • Ci_6 alkoxy C(0)(Ci_ 6 alkyl) or C(0)OCi_ 6 alkyl
  • a 15 or A 16 are independently selected from hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl;
  • a 17 is Ci_6 alkyl or C 3 _ 6 cycloalkyl;
  • Ci_ 6 alkyl examples include Ci_ 4 alkyl and Ci_ 2 alkyl.
  • C 3 _ 6 cycloalkyl examples include C 3 _ 5 cycloalkyl and C 3 _ 4 cycloalkyl.
  • Ci_ 6 alkoxy examples include Ci_ 4 alkoxy and Ci_ 2 alkoxy.
  • Ar group is selected from:
  • Ar group is selected from:
  • R 1 is a hydrogen atom or a Ci_ 6 alkyl group; more conveniently R 1 is methyl, ethyl or isopropyl;
  • R 1 is a C 3"8 cycloalkyl group; more conveniently R 1 is cyclopropyl, cyclobutyl or cyclopentyl;
  • R 1 is a group -C 1-6 alkyl - C3-8 cycloalkyl; more conveniently R 1 is -CH 2 - c Pr or -CH 2 - c Bu;
  • R 1 is a Ci_ 6 alkyl-0-Ci_6 alkyl group; more conveniently R 1 is a group - -CH 2 CH 2 -0-Ci_6 alkyl.
  • alkyl group (as defined) is substituted by up to three Ci_3 alkyl chains any given carbon atom in the group may be substituted by 1 , 2 or 3 Ci_ 3 alkyl chains as appropriate.
  • n and n are both 1 ;
  • T is an aryl group; more conveniently T is phenyl.
  • T is a heteroaryl group; more conveniently T is a 5-membered heteroaryl group such as a thienyl or thiazoloyl group.
  • T is a Ci_ 6 alkyl group
  • T is a hydrogen atom.
  • T is a phenyl group.
  • the group G is a C 2 _ 4 alkylene group; more conveniently G is a group -(CH 2 ) 2 - or a group -(CH 2 ) 3 -;
  • G is a group -C 2 _ 4 alkylene-N(R 10 )C(O)-;
  • G is a group -(CH 2 ) 2 - or a group -(CH 2 ) 3 -.
  • group G is attached to the phenyl ring in one of two regioisomeric positions:
  • R 4 , R 4 ', R 5 and R 5 ' are each hydrogen or Ci_6alkyl
  • R 4 , R 4 ', R 5 and R 5 ' are each hydrogen or methyl; more conveniently the groups are each hydrogen.
  • R 6 is a Ci_g alkyl group
  • R 6 is a Ci_g alkyl group optionally substituted by a C3-8 cycloalkyl group, such as cyclopentylmethyl or cyclopentyl-1 -ethyl, said cycloalkyl group optionally substituted by up to two Ci_ 6 alkyl groups, more preferably by up to two Ci_ 2 alkyl groups, or by up to two halogen atoms, such as fluoro;
  • R 6 is a Ci_g alkyl group optionally substituted by a Ci_g cycloalkyl group, wherein said cycloalkyl group has one of the carbon atoms replaced by -O- or -S-;
  • R 6 is a Ci_g alkyl group substituted by -0-Ci_ 6 alkyl or -S-Ci_ 6 alkyl or by up to three halogen atoms;
  • R 6 is a C 3 _9 cycloalkyl group; more conveniently R 6 is a cyclopentyl or cyclohexyl or cycloheptyl group, said cycloalkyl group optionally substituted by up to two Ci_6 alkyl groups, more preferably by up to two Ci_ 2 alkyl groups, or by up to two halogen atoms, such as fluoro;
  • R 7 is a group -OR 10 ; more conveniently R 7 is -OCH 3 or -OH; even more conveniently R 7 is -OH
  • Each exemplified compound of the invention represents a particular and independent aspect of the invention. It will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • the present invention encompasses the replacement of any quaternary carbon by a silicon atom for example as disclosed in "Silicon switches of Marketed Drugs: Mini-reviews in Med. Chem.”, 2006, 6, 1169-1177.
  • aryl means an aromatic carbocyclic ring system containing one or more rings.
  • exemplary aryl rings are phenyl and naphthyl.
  • heteroaryl denotes a group or part of a group comprising an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which up to four of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl,
  • the heteroaryl group may be substituted by one or more substituent groups.
  • the heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.
  • alkyl groups and moieties may be straight or branched chain and include, for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl or fert-butyl.
  • 'C 1-8 alkyl' means a straight or branched chain alkyl group having from one to eight carbon atoms; similarly 'C 1-6 alkyl' means a straight or branched alkyl chain having from one to six carbon atoms.
  • Cycloalkyl groups are monocyclic, for example cyclopentyl or cyclohexyl.
  • 'C 3 _g cycloalkyl' means a cycloalkyl group having from three to eight carbon atoms'.
  • cyclic groups referred to above namely, aryl, heteroaryl and cycloalkyl, are unsubstituted or substituted by one or more of the same or different substituent groups.
  • substituent groups include -CI, -F, -CH 3 , -OCH 3 , -OH, -CN, -COOCH 3 , -CONH 2 , -SO 2 NH 2 , -S0 2 N(CH 3 ) 2 . More generally the substituents can be divided into two classes:
  • a first class of substituent includes acyl (e.g. -COCH 3 ), alkoxy (e.g., -OCH 3 ), alkoxycarbonyl (e.g. -COOCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfmyl (e.g. -SOCH 3 ), alkylsulfonyl (e.g. -S0 2 CH 3 ), alkylthio (e.g. -SCH 3 ), -NH 2 , aminoacyl (e.g. -CON(CH 3 ) 2 ), aminoalkyl (e.g. -CH 2 NH 2 ), cyano, dialkylamino (e.g. -N(CH 3 ) 2 ), halo, haloalkoxy (e.g.
  • haloalkyl e.g. -CF 3
  • alkyl e.g. -CH 3 or -CH 2 CH 3
  • -OH e.g. -CHO
  • aminoacyl e.g. -CONH 2 , -CONHCH 3
  • aminosulfonyl e.g. -S0 2 NH 2 , - S0 2 NHCH 3
  • acylamino e.g. -NHCOCH 3
  • sulfonylamino e.g. -NHS0 2 CH 3
  • a second class of substituent includes arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph), aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl, cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy, the cyclic part of any of which being optionally substituted by any of the first class of substituent referred to above (for example alkoxy, haloalkoxy, halogen, alkyl and haloalkyl).
  • arylalkyl e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph
  • aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl, cyclic amine e.g. morpholine
  • Alkyl, alkoxy and alkenyl groups may be optionally substituted. Suitable optional substituent groups for alkyl and alkenyl include alkoxy (e.g., -OCH 3 ), alkylamino (e.g. -
  • alkylsulfmyl e.g. -SOCH 3
  • alkylsulfonyl e.g. -S0 2 CH 3
  • alkylthio e.g. -SCH 3
  • aminoalkyl e.g. -CH 2 NH 2
  • arylalkyl e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph
  • cyano dialkylamino (e.g. -N(CH 3 ) 2 )
  • halo haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g.
  • alkoxy examples include alkylamino (e.g. -NHCH 3 ), alkylsulfmyl (e.g. -SOCH 3 ), alkylsulfonyl (e.g. -S0 2 CH 3 ), alkylthio (e.g. -SCH 3 ), -NH 2 , aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or
  • -OCHF 2 haloalkyl
  • alkyl e.g. -CH 3 or -CH 2 CH 3
  • -OH e.g. -CHO
  • -N0 2 e.g. -N0 2 .
  • Alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfmyl
  • alkylsulfonyl e.g. -S0 2 CH 3
  • alkylthio e.g. -SCH 3
  • -NH 2 aminoalkyl
  • arylalkyl e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph
  • cyano dialkylamino (e.g. -N(CH 3 ) 2 ), halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g. -CF 3 ), alkyl (e.g. - CH 3 or -CH 2 CH 3 ), -OH, -CHO, and -N0 2 .
  • a group may be optionally substituted with up to three substituents, the group may be unsubstituted or substituted; when substituted the group will generally be substituted with one, two or three substituents.
  • a hydroxyl moiety will not be attached to a carbon atom which is adjacent to a nitrogen atom, another oxygen atom or a sulfur atom.
  • Compounds of formula (1) may be prepared from compounds of formula (2) by initial acetal hydrolysis using a suitable acid in the presence of water, for example tosic acid monohydrate, in a solvent such as THF or an acetic acid/water mixture, followed by reaction with a compound of formula (9) or a salt thereof where Ar is defined as for formula (I):
  • This reaction is carried out in the presence of a suitable reducing agent such as a metal borohyride, especially sodium triacetoxyborohydride in a variety solvents or solvent mixtures such as NMP/water or DMF/water mixtures.
  • a suitable reducing agent such as a metal borohyride, especially sodium triacetoxyborohydride
  • solvents or solvent mixtures such as NMP/water or DMF/water mixtures.
  • This reaction is carried out in the presence of a suitable coupling reagent, examples of which include HATU and T3P in the presence or absence of a base such as DIPEA, in a solvent such as DMF.
  • a suitable coupling reagent examples of which include HATU and T3P in the presence or absence of a base such as DIPEA, in a solvent such as DMF.
  • a suitable reducing agent such as a metal borohydride or hydrogen gas in the presence of a metal catalyst, in an apposite solvent such as methanol.
  • Compounds of formula (11) are known or readily prepared by known methods.
  • Compounds of formula (3) may be prepared from compounds of formula (4) by a three step procedure: a) Simultaneous removal of the boc-group and deprotection of the tert-butyl ester by usual methods for example an acid such as TFA in a solvent such as DCM; b) Debenzylation using standard procedures such as hydrogen gas in the presence of a metal catalyst, especially palladium hydroxide on carbon, in a suitable solvent such as ethanol; c) Reductive amination with a suitable carbonyl compound (examples of which include formaldehyde or acetone) or alkylation with a suitable alkylating agent (e.g. ethyl bromide) under standard conditions known for these reactions.
  • a suitable carbonyl compound examples of which include formaldehyde or acetone
  • alkylating agent e.g. ethyl bromide
  • benzyltrimethylammonium hydroxide in a suitable solvent for example acetonitrile or toluene.
  • Compounds of formula (5), where q > 1, may be prepared from compounds of formula (6) by reaction with benzyl bromide in the presence of a suitable base such as caesium carbonate in a solvent such as DMF.
  • Compounds of formulae (6) and (7) may be prepared from compounds of formula (8) by reacting with a strong acid such as triflic acid in the presence of compounds of formulae (12) and (13) in a suitable solvent such as nitrobenzene.
  • Compounds of formula (14) represent compounds of formula (I) where R , R , R , R 3 , R 4 , R 4 , R 5 and R 5 are hydrogen, R 7 is -OH and where G is a group -C 2-4 alkylene- NR 10 C(O)- wherein R 10 , R 1 , R 6 , Ar, T, n and m are as defined for formula (I).
  • Compounds of formula (14) may be prepared from compounds of formula (15) using analogous methods to those described for the preparation of compounds of formula (1) from compounds of formula (3).
  • This reaction is carried out in the presence of a suitable coupling reagent, examples of which include HATU and T3P in the presence or absence of a base such as DIPEA, in a suitable solvent such as DMF.
  • a suitable coupling reagent examples of which include HATU and T3P in the presence or absence of a base such as DIPEA, in a suitable solvent such as DMF.
  • Compounds of formula (19) may be prepared from compounds of formula (20), wherein PG 1 is a suitable protecting group (for example benzyloxycarbamate or phthalimide), and tert-butyl acrylate in the presence of a suitable base for example sodium hydride or benzyl trimethylammonium hydroxide in a suitable solvent such as THF or toluene.
  • PG 1 is a suitable protecting group (for example benzyloxycarbamate or phthalimide)
  • tert-butyl acrylate in the presence of a suitable base for example sodium hydride or benzyl trimethylammonium hydroxide in a suitable solvent such as THF or toluene.
  • Compounds of formula (17) may be prepared from compounds of formula (18) by reaction with an aqueous base such as lithium hydroxide in the presence of a co-solvent such as dioxane at a temperature between ambient and the boiling point of the mixture.
  • Compounds of formula (18) may be prepared from compounds of formula (8) by reaction with methyl 4-hydroxybenzoate in the presence of a strong acid such as triflic acid in a suitable solvent such as nitrobenzene.
  • Compounds of formulae (6) and (18) may be prepared from compounds of formula (20) (wherein PG 2 is a suitable protecting group) by reaction with a fo ' s-alkylating agent of formula (25) (wherein LG 2 are suitable leaving groups e.g. chloride) in the presence of a base such as sodium hydride in a suitable solvent such as DMF; followed by the appropriate method for the removal of PG 2 .
  • Compounds of formula (20) may be prepared from compounds of formula (21) by use of various standard reduction protocols ( J. Med. Chem. 1989, 32, 2357-2362) or from compounds of formula (24) (wherein LG 1 is a suitable leaving group e.g. chloride) by reaction with a suitable nucleophilic form of T via standard procedures or via palladium mediated couplings (c.f. Eur. J. Org. Chem. 2008, 28, 4824-4827)
  • T is a heterocyclic group
  • compounds of formula (22) wherein PG 2 is a suitable protecting group
  • PG 2 is a suitable protecting group
  • Compounds of formula (23) may be prepared from compounds of formula (24) (wherein LG 1 is a suitable leaving group e.g. chloride) by reaction with a cyanide source e.g. sodium cyanide in a suitable solvent such as DMF.
  • LG 1 is a suitable leaving group e.g. chloride
  • the compounds of formula I have activity as pharmaceuticals, in particular as dual adrenergic ⁇ receptor agonists and anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonists, in particular M3 antagonists.
  • Diseases and conditions which may be treated with the compounds of formula (I) and their pharmaceutically acceptable salts include:
  • obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
  • COPD chronic obstructive pulmonary disease
  • lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;
  • SARS coronavirus
  • osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated
  • spondarthropathy septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including
  • dermatomyositits and polymyositis dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget's
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
  • the present invention provides a compound of formula (I) or a
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly
  • the invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions,
  • Hydro fluoroalkane aerosols and dry powder formulations for example,
  • formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ , and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C8-C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
  • Suitable carriers are sugars, for example, lactose, glucose, raffmose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the present invention and salts thereof may be used in the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease
  • the compounds of the invention may be combined with the following agents: non-steroidal anti-inflammatory agents
  • NSAIDs non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically
  • piroxicam diclofenac
  • propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen
  • fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as
  • phenylbutazone phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes);
  • methotrexate methotrexate
  • leflunomide hydroxychloroquine
  • d-penicillamine d-penicillamine
  • auranofm other parenteral or oral gold preparations
  • analgesics diacerein
  • intra-articular therapies such as hyaluronic acid derivatives
  • nutritional supplements such as glucosamine.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a
  • composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed above.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin- like growth factor type I (IGF-1); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-a) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R) or T-Lymphocytes (CTLA4-Ig, HuMax 11-15).
  • B- Lymphocytes such as CD20 (rituximab), MRA-aIL16R) or T-Lymphocytes (CTLA4-Ig, HuMax 11-15).
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 - C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591,
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c;
  • benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, PvO-245913, iralukast (CGP 45715A), and BAY x 7195.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2
  • adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,
  • xylometazoline hydrochloride tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • Another systemic or topically- applied anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline;
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • thrombolytic or an anticoagulant such as a platelet aggregation inhibitor.
  • an anticoagulant such as a platelet aggregation inhibitor.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agent-s sodium valproate
  • paracetamol paracetamol
  • non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase);
  • - or B.sub2. -receptor antagonist for example colchicine;
  • anti-gout agent for example colchicine;
  • xanthine oxidase inhibitor for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • growth hormone secretagogue for example transforming growth factor (TGF );
  • PDGF platelet-derived growth factor
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.subl .
  • NKP-608C SB-233412 (talnetant) or D-4418
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API or STATS
  • GR-receptor glucocorticoid receptor
  • the present invention provides a combination (for example for the treatment of CO
  • GR-receptor a non-steroidal glucocorticoid receptor
  • a PDE4 inhibitor including an inhibitor of the isoform PDE4D
  • chemokine receptor function such as a CCR1 receptor
  • a steroid such as budesonide
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin,
  • cyclophosphamide nitrogen mustard, melphalan, chlorambucil, busulphan or a
  • nitrosourea an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5a-reductase such as finasteride;
  • an antioestrogen for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab
  • a farnesyl transferase inhibitor for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
  • an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3
  • an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ⁇ 3 function or an angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ 3 function or an angiostatin
  • a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or
  • an agent used in an immunotherapeutic approach for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, for example an acid addition salt such as a hydrochloride (for example a dihydrochloride), hydrobromide (for example a dihydrobromide),
  • a pharmaceutically acceptable salt thereof for example an acid addition salt such as a hydrochloride (for example a dihydrochloride), hydrobromide (for example a dihydrobromide),
  • trifluoroacetate for example a di-trifluoroacetate
  • sulphate for example a di-trifluoroacetate
  • phosphate for example a di-trifluoroacetate
  • acetate fumarate
  • maleate tartrate
  • lactate citrate
  • pyruvate succinate
  • oxalate methanesulphonate or p- toluenesulphonate.
  • NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5mm inverse detection triple resonance TXI probe operating at 400MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300MHz or a Bruker Avance 600 (600 MHz), a Bruker DRX 500 (500 MHz) or a Varian Unitylnova 500 MHz, 400 MHz or 300 MHz instrument. Shifts are given in ppm relative to tetramethylsilane. NMR analysis of compounds purified by HPLC showed various amounts of formic acid equivalents.
  • Purification by chromatography refers to purification using the CombiFlash ® Companion purification system or the Biotage SPl purification system. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
  • TLC thin layer chromatography
  • MS ionization method Electrospray (positive and negative ion).
  • MS ionization method Electrospray (positive and negative ion).
  • MS ionisation method Electrospray (positive ion).
  • MS ionisation method Electrospray (positive ion).
  • AIBN (2,2'-azobis(2-methylproprionitrile)
  • Boc anhydride di-fert-butyl dicarbonate
  • CDI ⁇ , -carbonyldiimidazole
  • DIPEA diisopropylethylamine
  • HATU O-(7-azabenzotriazol- 1 -yl)-N,N,N'N -tetramethyluroniumhexafluoro- phosphate
  • NMP N-methyl-pyrrolidinone
  • pTS A ara-toluenesulphonic acid
  • the title compound can be prepared from Intermediate 6 using similar methods to those used for Intermediates 7 and 8, respectively.
  • reaction mixture was filtered through Celite ® and concentrated in vacuo then purified on an SCX-2 cartridge (eluting with MeOH, then 2 M NH 3 in MeOH) to give the title compound as a colourless oil (18.6 g, 98%>).

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Abstract

La présente invention concerne des composés de formule (I) ayant des activités sur les récepteurs muscarinique et β2 (MABA) pour utilisation en thérapie.
PCT/GB2010/051751 2009-10-20 2010-10-18 Dérivés d'amine cyclique ayant une activité agoniste de récepteur adrénergique bêta-2 et antagoniste de récepteur muscarinique WO2011048409A1 (fr)

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GB0918322A GB0918322D0 (en) 2009-10-20 2009-10-20 Compounds 814
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012168349A1 (fr) 2011-06-10 2012-12-13 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste des récepteurs muscariniques et une activité agoniste des récepteurs adrénergique bêta-2
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
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
CN108125953A (zh) * 2017-12-27 2018-06-08 湖北工业大学 芳香酯类化合物用于制备抗adv-7病毒药剂

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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
US9012644B2 (en) 2011-06-10 2015-04-21 Chiesi Farmaceutici S.P.A. Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity
WO2012168349A1 (fr) 2011-06-10 2012-12-13 Chiesi Farmaceutici S.P.A. Composés ayant une activité antagoniste des récepteurs muscariniques et une activité agoniste des récepteurs adrénergique bêta-2
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
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
EA032937B1 (ru) * 2015-02-12 2019-08-30 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Соединения, обладающие активностью антагонистов мускариновых рецепторов и агонистов бета-2 адренергических рецепторов
AU2016217955B2 (en) * 2015-02-12 2020-03-05 Chiesi Farmaceutici S.P.A. Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity
CN107207473A (zh) * 2015-02-12 2017-09-26 奇斯药制品公司 具有毒蕈碱受体拮抗剂和β2肾上腺素能受体激动剂活性的化合物
US9579314B2 (en) 2015-02-12 2017-02-28 Chiesi Farmaceutici S.P.A. Compounds having muscarinic receptor antagonist and BETA2 adrenergic receptor agonist activity
JP2018510137A (ja) * 2015-02-12 2018-04-12 シエッシ ファーマスーティシ エス．ピー．エー． ムスカリン受容体拮抗薬およびβ２アドレナリン受容体作動薬活性を有する化合物
TWI703138B (zh) * 2015-02-12 2020-09-01 義大利商吉斯藥品公司 具有蕈毒鹼受體拮抗劑及β２腎上腺素受體促效劑活性之化合物
US10004728B2 (en) 2015-02-12 2018-06-26 Chiesi Farmaceutici S.P.A. Compounds having muscarinic receptor antagonist and BETA2 adrenergic receptor agonist activity
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
CN107207473B (zh) * 2015-02-12 2020-07-07 奇斯药制品公司 具有毒蕈碱受体拮抗剂和β2肾上腺素能受体激动剂活性的化合物
EA032937B9 (ru) * 2015-02-12 2019-11-27 Chiesi Farm Spa Соединения, обладающие активностью антагонистов мускариновых рецепторов и агонистов бета-2 адренергических рецепторов
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
CN108125953B (zh) * 2017-12-27 2019-10-08 湖北工业大学 芳香酯类化合物用于制备抗adv-7病毒药剂
CN108125953A (zh) * 2017-12-27 2018-06-08 湖北工业大学 芳香酯类化合物用于制备抗adv-7病毒药剂

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