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WO2006016245A1 - Antagonistes des récepteurs muscariniques - Google Patents

Antagonistes des récepteurs muscariniques Download PDF

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Publication number
WO2006016245A1
WO2006016245A1 PCT/IB2005/002306 IB2005002306W WO2006016245A1 WO 2006016245 A1 WO2006016245 A1 WO 2006016245A1 IB 2005002306 W IB2005002306 W IB 2005002306W WO 2006016245 A1 WO2006016245 A1 WO 2006016245A1
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formula
compound
alkyl
aralkyl
alkenyl
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PCT/IB2005/002306
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English (en)
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Mohammad Salman
Pakala Kumara Savithru Sarma
Atul Kondaskar
Anita Chugh
Suman Gupta
Naresh Kumar
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Ranbaxy Laboratories Limited
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Publication of WO2006016245A1 publication Critical patent/WO2006016245A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system

Definitions

  • the present invention generally relates to muscarinic receptor antagonists, which are useful in the treatment of various diseases of the respiratory, urinary or gastrointestinal systems mediated through muscarinic receptors.
  • the invention also relates to processes for preparing such muscarinic receptor antagonists and pharmaceutical compositions thereof.
  • the invention further relates to methods of treating diseases mediated through muscarinic receptors.
  • Muscarinic receptors G Protein Coupled Receptors (GPCRs) are composed of a family of 5 receptor sub-types (M 1 , M 2 , M 3 , M 4 and M 5 ) and are activated by acetylcholine neurotransmitters. These receptors are widely distributed on various organs and tissues and can be critical to maintaining central and peripheral cholinergic neurotransmission. Regional distribution of these receptor sub-types in the brain and other organs has been documented.
  • the Mi subtype is located primarily in neuronal tissues, for example, cereberal cortex and autonomic ganglia; the M 2 subtype is mainly present in the heart where it mediates cholinergically induced bradycardia; and the M 3 subtype is located predominantly on smooth muscle and salivary glands. It also has been reported that modulating muscarinic receptor subtypes by ligands have biological potential in different disease conditions, for example, Alzheimer's disease, pain, urinary disease condition and chronic obstructive pulmonary disease.
  • M 2 and M 3 receptors generally mediate direct contractile effects of acetylcholine in the vast majority of smooth muscle tissues.
  • M2 receptors cause smooth muscle contraction indirectly by inhibiting sympathetically (/3-adrenoreceptor)-mediated relaxation.
  • Compounds that act as antagonists of muscarinic receptors have been used to treat certain disease states associated with improper smooth muscle function, as well as treat cognitive and neurodegenerative disorders, for example, Alzheimer's disease.
  • Cyclohexylmethylpiperidinyl-triphenylpropioamide derivatives have been disclosed as selective M 3 antagonist discriminating against the other receptor subtypes.
  • Certain 1-cycloalkyl-l -hydroxy- l-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds have been described as having antimuscarinic activity. Further, antimuscarinic activity has been disclosed for certain substituted 7-amino-l-hydroxy-5- heptyn-2-ones and related compounds.
  • R k can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Ri can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl; m can be 0 to 2; and
  • Q can be alkyl, alkenyl or alkynyl
  • R 3 and R 4 can each independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl; wherein R 5 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NR p R q (wherein R p and R q can each independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or R p and Rq can be together joined to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl; and
  • R 6 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl. Such compounds can include one or more of the following embodiments.
  • R 1 can be hydrogen, (Ci-C 6 )-alkyl, (C 2 -Ce)-alkenyl, (C 3 -Ce)-alkynyl, cycloalkyl, aryl or aralkyl; and Q can be lower alkyl, lower alkenyl or lower alkynyl.
  • muscarinic receptors comprising administering to an animal or human in need thereof therapeutically effective amounts of one or more compounds of Formula I:
  • R k can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Ri can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl; m can be 0 to 2; and
  • Q can be alkyl, alkenyl or alkynyl
  • Re can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl.
  • Such methods can include one or more of the following embodiments.
  • the one or more compounds of Fo ⁇ nula I can be administered orally or parenterally.
  • Ri can be hydrogen, (Ci-C6)-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, cycloalkyl, aryl or aralkyl; and Q can be lower alkyl, lower alkenyl or lower alkynyl.
  • the diseases or disorders can be one or more of respiratory
  • Formula IX system diseases or disorders can be bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis; the urinary system diseases or disorders can be selected from urinary incontinence or lower urinary tract symptoms (LUTS); and the gastrointestinal system disorders or diseases can be selected from irritable bowel syndrome, obesity, diabetes or gastrointestinal hyperkinesis.
  • COPD chronic obstructive pulmonary disorders
  • LUTS urinary incontinence or lower urinary tract symptoms
  • gastrointestinal system disorders or diseases can be selected from irritable bowel syndrome, obesity, diabetes or gastrointestinal hyperkinesis.
  • R 5 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NR p R q (wherein R p and Rq can each independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or Rp and Rq can be together joined to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl).
  • reaction of the compound of Formula II with a compound of Formula III in step i) can be carried out in the presence of one or more reducing agents.
  • Reducing agents used in this step can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • reaction of the compound of Formula IV with a compound of Formula V in step ii) can be carried out in the presence of one or more reducing agents.
  • Reducing agents used in this step can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • the deprotection of the compound of Formula VT in step iii) can be carried out in the presence of one or more deprotecting agents.
  • Deprotecting agents used in this step can be palladium on carbon in the presence of hydrogen gas, palladium on carbon in ammonium formate solution or mixtures thereof.
  • reaction of a compound of Formula VII with a compound of Formula VIII can be carried out in the presence of one or more bases.
  • Bases use in this step can be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • the protecting group can be alkyl, tosyl, mesyl, aralkyl or acyl and the halogen can be Cl, Br or I.
  • R n can be alkyl, alkenyl or alkynyl
  • hal can be halogen
  • the protecting group can be alkyl, tosyl, mesyl, aralkyl or acyl and the halogen can be Cl, Br or I.
  • the reaction of the compound of Formula X with the compound of Formula XI in step i) can be carried out in the presence of one or more organic bases and in the presence of one or more reducing agents.
  • the reaction of the compound of Formula XII and the compound of Formula V in step ii) can be carried out in the presence of one or more organic bases and in the presence of one or more reducing agents.
  • Organic solvents in steps i) or ii) can be dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof.
  • Reducing agents in steps i) and ii) can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • the deprotection reaction in step iii) can be carried out the presence of one or more deprotecting agents.
  • Deprotecting agents can be palladium on carbon in the presence of hydrogen gas, palladium on carbon in ammonium formate solution or mixtures thereof.
  • reaction of the compound of Formula XIV with the compound of Formula VIII in step iv) can be carried out in the presence of one or more bases.
  • Bases can be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • Rk can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl
  • Formula XII (wherein P can be a protecting group, for example, alkyl, tosyl, mesyl, aralkyl or acyl);
  • hal can be halogen
  • R p and R q can each independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or R p and R q can be together joined to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl) to form a compound of Formula XV.
  • the protecting group can be alkyl, tosyl, mesyl, aralkyl or acyl and the halogen can be Cl, Br or I.
  • the reaction of the compound of Formula XVI with the compound of Formula XVII in step i) can be carried out in the presence of one or more bases.
  • Bases can be pyridine, triethylamine, N-methyl morpholine, diisopropylethylamine or mixtures thereof.
  • reaction of the compound of Formula XII with the compound of Formula V in step iii) can be carried out in the presence of one or more reducing agents.
  • Reducing agents can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • the deprotection of the compound of Formula XIII in step iv) can be carried out in the presence of one or more deprotection agents.
  • Deprotecting agents can be selected from palladium on carbon in the presence of hydrogen gas, palladium on carbon in ammonium formate or mixtures thereof.
  • the reaction of the compound of Formula XIV with the compound of Formula VIII I step v) can be carried out in the presence of one or more bases.
  • Bases can be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • compositions comprising one or more compounds described herein and one or more pharmaceutically acceptable carriers.
  • R k can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Ri can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl;
  • m can be 0 to 2;
  • Q can be alkyl, alkenyl or alkynyl
  • R 3 and R 4 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl; wherein
  • R 5 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NR p R q (wherein R p and R q can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or R p and R q can be together joined to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl; and
  • R 6 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl.
  • Ri can be hydrogen, (C r C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, cycloalkyl, aryl or aralkyl; and Q is lower alkyl, lower alkenyl or lower alkynyl.
  • Exemplary compounds include, for example,
  • kits for the treatment or prophylaxis of diseases or disorders of the respiratory, urinary and gastrointestinal systems, wherein the diseases or disorders can be mediated through muscarinic receptors comprising administering to an animal or a human in need thereof effective amounts of one or more compounds of
  • compounds of Formula I can be administered orally or parenterally.
  • R 1 can be hydrogen, (CrC ⁇ -alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, cycloalkyl, aryl or aralkyl; and Q can be lower alkyl, lower alkenyl or lower alkynyl.
  • methods for the treatment or prophylaxis of diseases or disorders associated with muscarinic receptors comprising administering to an animal or human in need thereof effective amounts of one or more compounds of Formula I.
  • compounds of Formula I can be administered orally or parenterally.
  • Ri can be hydrogen, (Ci-C ⁇ )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, cycloalkyl, aryl or aralkyl; and Q can be lower alkyl, lower alkenyl or lower alkynyl.
  • the compounds of Formula I can be administered orally or parenterally.
  • Ri can be hydrogen, (Ci-C ⁇ )-alkyl, (C 2 -Ce)-alkenyl, (C 3 -C 6 )-alkynyl, cycloalkyl, aryl or aralkyl; and Q can be lower alkyl, lower alkenyl or lower alkynyl.
  • the respiratory system diseases or disorders can be bronchial asthma, chronic obstructive pulmonary disorders (COPD), or pulmonary fibrosis; and the urinary disorder can be urinary incontinence or lower urinary tract symptoms (LUTS).
  • the gastrointestinal system disorder or disease can be irritable bowel syndrome, obesity, diabetes or gastrointestinal hyperkinesis.
  • the present invention also relates to processes for preparing compounds of
  • R n can be alkyl, alkenyl or alkynyl
  • R n can be alkyl, alkenyl or alkynyl
  • hal can be halogen
  • the protecting group can be alkyl, tosyl, mesyl, aralkyl or acyl and the halogen can be Cl, Br or I.
  • the organic solvent in steps i) and ii) can be dichloromethane, dichloroethane, chloroform or carbon tetrachloride and the reducing agent in steps i) and ii) can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • the organic solvent in step iii) can be methanol, ethanol, propanol, isopropylalcohol or mixtures thereof, and the one or more deprotecting agents in step iii) can be palladium on carbon in the presence of hydrogen gas or palladium on carbon in ammonium formate solution.
  • the organic solvent in step iv) can be dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof, and the base in step iv) can be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • the present invention further relates to processes for preparing compounds of Formula XV
  • R k can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl
  • R n can be alkyl, alkenyl or alkynyl
  • the protecting group can be alkyl, tosyl, mesyl, aralkyl or acyl and the halogen can be Cl, Br or I.
  • the organic solvent in steps i) and ii) can be dichloromethane, dichloroethane, chloroform or carbon tetrachloride and the reducing agent in steps i) and ii) can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • the organic solvent in step iii) can be methanol, ethanol, propanol, isopropylalcohol or mixtures thereof, and the one or more deprotecting agents in step iii) can be palladium on carbon in the presence of hydrogen gas or palladium on carbon in ammonium formate solution.
  • the organic solvent in step iv) can be dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof, and the base in step iv) can be triethylamine, pyridine, N- methylmorpholine, diisopropylethylamine or mixtures thereof.
  • the present invention further relates to processes for preparing compounds of Formula XV:
  • R k can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl
  • OHC-R n Formula V (wherein R n can be alkyl, alkenyl or alkynyl) in the presence of an organic solvent and one or more reducing agents to form compounds of Formula XIII;
  • hal can be halogen
  • the protecting group can be alkyl, tosyl, mesyl, aralkyl or acyl and the halogen can be Cl, Br or I.
  • the organic solvent in step i) can be chloroform, benzene, toluene or mixtures thereof, and the base in step i) can be pyridine, triethylamine, N-methyl morpholine, diisopropylethylamine or mixtures thereof.
  • the organic solvent in step ii) can be acetonitrile, dichloromethane, tetrahydrofuran, dioxane or mixtures thereof.
  • the organic solvent in step iii) can be dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof, and the reducing agent in step iii) can be sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • the organic solvent in step iv) can be methanol, ethanol, propanol, isopropylalcohol or mixtures thereof and the one or more deprotecting agents in step iv) can be palladium on carbon in the presence of hydrogen gas or palladium on carbon in ammonium formate.
  • the organic solvent in step v) can be dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof
  • the base in step v) can be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • the present invention also relates to compounds prepared by the above processes.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising compounds of Formula I together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a diluents or excipients.
  • the present invention encompasses muscarinic receptor antagonists, which can be useful as safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.
  • the present invention also encompasses processes for synthesizing such muscarinic receptor antagonists.
  • the present invention also encompasses pharmaceutical compositions containing such muscarinic receptor antagonists together with pharmaceutically acceptable carriers and optionally included excipients or diluents.
  • Such pharmaceutical compositions can be useful for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.
  • the present invention also encompasses the enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds, as well as metabolites having the same type of activity, and pharmaceutical compositions thereof.
  • Other aspects will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention.
  • R k can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Ri can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl (preferably, the alkyl lower (Ci-C 6 ) alkyl, the alkenyl can be lower (C 2 -C 6 ) alkenyl, and the alkynyl can be lower (C 3 -C 6 ) alkynyl); m can be an integer from 0 to 2;
  • Q can be alkyl, alkenyl or alkynyl, preferably lower alkyl, lower alkenyl or lower alkynyl;
  • R 5 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NR p Rq (wherein R p and Rq can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl; R p and R q also can join together to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl; and
  • R 6 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl. The following definitions apply to terms as used herein.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR a -, wherein R a can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl.
  • This term can be exemplified by groups, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR a -, wherein R a can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF 3 , cyano, ⁇ NR p R q , -0-C(O)NR p R q (wherein Rp and Rq are the same as defined earlier) and -SO 2 R 66 (where R 66 is same as defined earlier).
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR a -, where R a can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF 3 , -NRpR q , -C(O)NR p R q , -NHC(O)NR p R q , -C(O)NR p R q (wherein R p and R q are the same as defined earlier), cyano, or S(O) m R 66 (wherein m is an integer from 0-2 and R 66 is same as defined earlier).
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, andbicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • alkoxy refers to the group O-alkyl, wherein alkyl can be defined hereinabove.
  • alkyl refers to aryl linked through an alkyl (wherein alkyl can be defined hereinabove) portion and the alkyl portion contains from 1-6 carbon atoms and aryl can be defined herein below.
  • aryl herein refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • the aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. Groups, for example, phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic or tricyclic aromatic group having from 8 to 14 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phen
  • Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl.
  • the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring.
  • the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl and the like.
  • heteroarylalkyl refers to a heteroaryl (wherein heteroaryl can be defined hereinabove) linked through alkyl (wherein alkyl can be defined hereinabove) portion and the alkyl portion contains 1-6 carbon atoms.
  • heterocyclylalkyl refers to heterocyclyl (wherein heterocyclyl can be defined hereinabove) linked through alkyl (wherein alkyl can be defined hereinabove) portion and the alkyl portion contains 1-6 carbon atoms.
  • protecting group can be used herein to refer to known moieties that have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified, may be used with groups, for example, hydroxy, amino, carboxy and other groups that are disclosed in T.W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis," 2 nd ED, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference.
  • the species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting group utilized is not critical so long as the derivatized moiety/moieties is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • methods for the treatment or prophylaxis of diseases or disorders of the respiratory, urinary and gastrointestinal systems, wherein the diseases or disorders can be mediated through muscarinic receptors, comprising administering to an animal or a human in need thereof therapeutically effective amounts of one or more compounds of Formula I.
  • provided herein are methods for the treatment or prophylaxis of diseases or disorders associated with muscarinic receptors comprising administering to an animal or human in need thereof therapeutically effective amounts of one or more compounds of Formula I.
  • Respiratory system diseases or disorders include, but are not limited to bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, and the like; urinary system which induce such urinary disorders as urinary incontinence, lower urinary tract symptoms (LUTS), and the like.
  • Gastrointestinal system disorders or diseases include, but are not limited to, irritable bowel syndrome, obesity, diabetes or gastrointestinal hyperkinesis.
  • provided herein are processes for preparing compounds of Formula I described herein.
  • the compounds described exhibit significant potency in terms of their activity, as determined by in vitro receptor binding and functional assays and in vivo experiments using anaesthetized rabbits. Compounds with in vitro activity were tested for in vivo activity.
  • Compounds herein can have potent muscarinic receptor antagonists with high affinity towards M 2 and/or M 3 receptors with M 5 sparing activity. Therefore, pharmaceutical compositions for the treatment or prophylaxis of diseases or disorders associated with muscarinic receptors are encompassed.
  • compounds herein can be administered orally or parenterally.
  • the compounds of the present invention can be prepared by techniques known to one of ordinary skill in the art.
  • the compounds described herein can be prepared by the processes described herein.
  • the various synthetic steps described herein may be performed in any alternate sequence or order to form the compounds described.
  • Compounds of Formula IX may be prepared, for example, by the reaction sequence as shown in Scheme I.
  • compounds of Formula II (wherein R 2 can be hydrogen, alkyl or alkoxy) can be reacted with compounds of Formula III (wherein P can be a protecting group, for example, alkyl, tosyl, mesyl, aralkyl or acyl) to form compounds of Formula IV by reductive amination.
  • This reaction can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more reducing agents, for example, sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • Compounds of Formula IV can react with compounds of Formula V (wherein R n can be alkyl, alkenyl or alkynyl) to form compounds of Formula VI by reductive animation.
  • the reductive animation in this step can be carried out in one or more organic solvents, for example, dichloroethane, dichloromethane, chloroform, carbon tetrachloride or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more reducing agents, for example, sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • Compounds of Formula VI can be deprotected to form compounds of Formula VII.
  • the deprotection in this step can be carried out in one or more organic solvents, for example, methanol, ethanol, propanol, isopropylalcohol or mixtures thereof.
  • the deprotection can also be carried out in the presence of one or more deprotecting agents, for example, palladium on carbon in the presence of hydrogen gas, palladium on carbon in ammonium formate solution or mixtures thereof.
  • hal can be halogen (e.g., Cl, Br, I)
  • This reaction can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more bases, for example, triethyl amine, pyridine, N- methylniorpholine, diisopropylethylamine or mixtures thereof.
  • Particular compounds include, for example: N- ⁇ [(l ⁇ ,5 ⁇ ,6 ⁇ )-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methyl ⁇ -l,2,3,4- tetrahydronaphthalen-2-amine (Compound No. 1),
  • Compounds of Formula XV may be prepared, for example, by the reaction sequence as depicted in Scheme II.
  • Rk can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl
  • P can be a protecting group, for example, alkyl, tosyl, mesyl, aralkyl or acyl
  • compounds of Formula XII by reductive amination.
  • This reaction can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more reducing agents, for example, sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • Compounds of Formula XII can be reacted with compounds of Formula V (wherein R n can be alkyl, alkenyl or alkynyl) to form compounds of Formula XIII by reductive amination.
  • This reaction can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more reducing agents, for example, sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • Compounds of Formula XIII can be deprotected to form compounds of Formula XIV.
  • the deprotection reaction can be carried out in one or more organic solvents, for example, methanol, ethanol, propanol, isopropylalcohol or mixtures thereof.
  • the deprotection reaction can also be carried out in the presence of one or more deprotecting agents, for example, palladium on carbon in the presence of hydrogen gas, palladium on carbon in ammonium formate solution or mixtures thereof.
  • This reaction can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more bases, for example, triethyl amine, pyridine, diisopropylethylamine, N-methylmorpholine or mixtures thereof.
  • X XIIVV Compounds of Formula XV may also be prepared, for example, by the reaction sequence as depicted in Scheme III.
  • Rk can be cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl
  • compounds of Formula XVlI wherein L can be mesyl or tosyl and hal can be halogen (e.g., Cl, Br, I)) to form compounds of Formula XVIII.
  • This reaction can be carried out in one or more organic solvents, for example, chloroform, benzene, toluene or mixtures thereof, and in the presence of one or more bases, for example, pyridine, triethylamine, N-methyl morpholine, diisopropylethylamine or mixtures thereof.
  • organic solvents for example, chloroform, benzene, toluene or mixtures thereof
  • bases for example, pyridine, triethylamine, N-methyl morpholine, diisopropylethylamine or mixtures thereof.
  • Compounds of Formula XVTII can be reacted with compounds of Formula III to form compounds of Formula XII (wherein P can be a protecting group, for example, alkyl, tosyl, mesyl, aralkyl or acyl).
  • the reaction can be carried in one or more organic solvents, for example, acetonitrile, dichloromethane, tetrahydrofuran, dioxane or mixtures thereof.
  • Compounds of Formula XII can be reacted with compounds of Fonnula V (wherein R n can be alkyl, alkenyl or alkynyl) to form compounds of Formula XIII by reductive animation.
  • the reductive animation can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof.
  • the reductive animation can also be carried out in the presence of one or more reducing agents, for example, sodium triacetoxyborohydride, sodium cyanoborohydride or mixtures thereof.
  • Compounds of Formula XIII can be deprotected to form compounds of Formula
  • the deprotection reaction can be carried out in one or more organic solvents, for examples, methanol, ethanol, propanol, isopropylalcohol or mixtures thereof.
  • the deprotection reaction can also be carried out in the presence of one or more deprotecting agents, for example, palladium on carbon in the presence of hydrogen gas, palladium on carbon in ammonium formate or mixtures thereof.
  • the reaction can be carried out in one or more organic solvents, for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more bases, for example, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • salts include pharmacologically acceptable salts, for example inorganic acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate) and organic acid salts (for example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate).
  • inorganic acid salts for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate
  • organic acid salts for example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate.
  • carboxyl groups When carboxyl groups are present as substituents in the described compounds, they may be in the form of an alkaline or alkali metal salt (for example, sodium, potassium, calcium, magnesium, and the like).
  • alkaline or alkali metal salt for example, sodium, potassium, calcium, magnesium, and the like.
  • compositions described herein comprise therapeutically effective amounts of one or more compounds described herein formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating materials or formulation auxiliaries of any type.
  • Solid form preparations for oral administrations include, but are not limited to, capsules, tablets, pills, powders, granules, or suppositories.
  • active compounds can be mixed with one or more inert, pharmaceutically acceptable excipient or carrier, for example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for example, starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof); binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, a agar-agar, calcium carbonate, potato starch, alginic acid, silicates, sodium carbonate or mixtures thereof; absorption accelerators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol, monostearate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium la
  • the dosage form also may comprise one or more buffering agents.
  • Solid preparations of tablets, capsules, pills or granules can be prepared using one or more coatings or shells, for example, enteric coatings and other coatings well known to one of ordinary skill in the art.
  • Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • active compounds can be mixed with water or one or more other solvents, solubilizing agents or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example, cottonseed, groundnut, corn, germ, olive, castor, sesame oil or mixtures thereof), glycerol, and fatty acid esters of sorbitan or mixtures thereof.
  • Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.
  • compositions may be in unit dosage form.
  • the preparation may be subdivided into unit doses containing appropriate quantities of active components.
  • Unit dosage forms can be packaged preparations, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachets, tablets, gel creams or any combination and number of any packaged forms.
  • Formulations described herein may be formulated so as to provide immediate, sustained, or delayed release of active ingredients after administration to a patient by employing procedures well known to one of ordinary skill in the art.
  • Examples of compounds described herein include, but are not limited to, the compound listed in Table I below.
  • compounds described herein may be administered to a patient, for example, a human or animal, for oral or parenteral treatment, as well as any other suitable routes of administration.
  • the pharmaceutical compositions described herein can be produced and administered in dosage units, wherein each unit containing certain amounts of one or more compounds described herein and/or one or more physiologically acceptable addition salts thereof. Dosages may be varied over wide limits as the compounds are effective at low dosage levels and substantially free of toxicity.
  • Compounds described may be administered in low micromolar concentrations, which is therapeutically effective, and dosages may be increased as desired up to the maximum dosage tolerated by the patient, as can readily be determined without undue experimentation by one of ordinary skill in the art.
  • Compounds described herein can be produced and formulated in all their forms, for example, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts, as well as metabolites having similar activity.
  • Pharmaceutical compositions comprising compounds of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable carriers and optionally one or more excipients can also be formulated.
  • Solvents used in the following examples were dried using various drying reagents according to procedures described in the literature and well known to one of ordinary skill in the art.
  • IR spectra were recorded as nujol mulls or a thin neat film on a Perkin Elmer Paragon IR instrument, and Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian XL-300 MHz instrument using tetramethylsilane as an internal standard.
  • the organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to furnish crude product.
  • the crude compound was purified by column chromatography using 1-10 % methanol in chloroform solvent mixture as eluent to furnish the title compound (0.7 g, 57%).
  • Ammonium formate (0.35g, 5.61 mmol) was added to a mixture of the compound N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-propyl-l,2,3,4-tetrahydronaphthalen- 2-amine (0.7 g, 1.87 mmol) and palladium on carbon (25 mg) in 15 mL methanol at 40 0 C and the reaction mixture was refluxed for 3 hours. Methanol was removed under reduced pressure and the residue was diluted with 50 mL water, acidified with hydrochloric acid and extracted with dichloromethane (25 mL).
  • Dimethylaminopyridine (0.0 Ig) was added to a solution of the compound N-(3- azabicyclo[3.1.0]hex-6-ylmethyl)-N- ⁇ ropyl- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine (0.2g, 0.7 mmol) in dichloromethane (10 mL), triethylamine (0.14 g, 1.4 mmol) and the reaction mixture was cooled to 0 0 C. Trifluoromethane sulfonyl chloride (0.18g, 1.05 mmol) was added drop wise to the reaction mixture followed by stirring at room temperature for 12 hours.
  • Dimethylaminopyridine (0.0 Ig) was added to a solution of N-(3- azabicyclo[3.1.0]hex-6-ylmethyl)-N-propyl- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine (0.2g, 0.7 mmol) in dichloromethane (10 mL) and triethylamine (0.14 g, 1.4 mmol). The solution was cooled to 0 0 C. Benzyloxyacetyl chloride (0.146g, 0.78 mmol) was added dropwise to the reaction mixture followed by stirring at room temperature for 12 hours.
  • Triethylamine (0.14 g, 1.4 mmol) was added to a solution of N-(3- azabicyclo[3.1.0]hex-6-ylmethyl)-N-propyl-l,2,3,4-tetrahydronaphthalen-2-amine (0.2 g, 0.7 mmol) in dichloromethane (10 mL).
  • Triphosgene (O.lg, 0.35 mmol) was added at 0 0 C and stirred the reaction mixture for 30 minutes.
  • Morpholine (0.07 g, 0.77 mmol) was added dropwise to the reaction mixture followed by stirring at room temperature for 12 hours.
  • Compound ⁇ o.6 (Compound ⁇ o.6) described below can be prepared by using 7-methoxy-N- ⁇ [(l ⁇ ,2 ⁇ ,6 ⁇ )- 3 -azabicyclo[3.1.0]hex-6-yl]methyl ⁇ -N-propyl- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine in place of ⁇ (S-azabicyclotS.l.OJhex- ⁇ -ylmethy ⁇ -N-propyl-l ⁇ jS ⁇ -tetrahydronaphthalen ⁇ - amine, respectively, as applicable in each case.
  • Example 7 Synthesis of tartarate salt ofN-f3-azabicyclo[3.1.0]hex-6- ⁇ lmethylV7- methoxy-N-propyl-1,2 J ⁇ -tetrahydronaphthaIen-2-amine (Compound No. 10)
  • Step a N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-7-methoxy-N-propyl- 1 ,2,3,4- tetrahydronaphthalen-2-amine
  • Step b Tartarate salt of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-7-methoxy-N-propyl- 1 ,2 ,3 ,4-tetrahydronaphthalen-2-amine
  • step (ii) The solid was washed with ether (3 x 20 mL) to yield a crude compound.
  • the crude compound was further purified by dissolving in methanol (15 mL), basified with 10 % aqueous sodium hydroxide (10 mL) and extracted with dichloromethane (25 mL). The organic layer was separated, washed, dried, and concentrated to yield the free base.
  • the solid free base was then subjected to step (i) above. In particular, the free base was redissolved in ethanol (25 mL), solid L-(+) tartaric acid (2.95 mmol) was added and the reaction mixture was heated and refluxed for 1 hour.
  • Affinities of test compounds for M 2 and M 3 muscarinic receptor subtypes were determined by [ 3 H]-N-methylscopolamine binding studies using rat heart and submandibular gland respectively as described in Moriya et al., Life Sci., 64(25):2351- 2358 (1999) with minor modifications.
  • specific binding of [ 3 H] NMS was also determined using membranes from Chinese hamster ovary (CHO) cells expressing cloned human m 1; m 2 , m 3 , In 4 and m 5 receptors. Selectivities were calculated from Ki values obtained on these human cloned membranes.
  • the tissues were homogenized in 10 volumes of homogenizing buffer, the homogenate was filtered through two layers of wet gauze and the filtrate was centrifuged at 500 g for 10 minutes. The supernatant was subsequently centrifuged at 40,00Og for 20 minutes. The pellet thus obtained was resuspended in homogenizing buffer (HEPES 2OmM, 1 OmM EDTA, pH 7.4) and were stored at -70 0 C until the time of assay.
  • HEPES 2OmM homogenizing buffer
  • Ligand binding assay The compounds were dissolved and diluted in DMSO.
  • the membrane homogenates 150-250 ⁇ g protein/well for rat membrane preparation and 5- lO ⁇ g/well for recombinant membrane preparation) were incubated in 250 ⁇ L of assay volume (HEPES 20 roM, pH 7.4) at 24-25 0 C for 3hours. Non-specific binding was determined in the presence of 1 ⁇ M atropine.
  • the incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac). The filters then were washed with ice-cold 5OmM Tris HCl buffer (pH 7.4). The filter mats were dried and bound radioactivity retained on filters was counted.
  • the IC50 & Kd were estimated by using the non-linear curve fitting program using Graph Pad Prism software.
  • the value of inhibition constant Ki was calculated from competitive binding studies by using the Cheng & Prusoff equation (Biochem Pharmacol, 22:3099-3108 (1973)),
  • Ki IC 50 /(1+L/Kd)
  • the bladder was cut into longitudinal strips (3 mm wide and 5-6 mm long) and mounted in 10 mL organ baths at 30 0 C, with one end connected to the base of the tissue holder and the other end connected through a force displacement transducer. Each tissue was maintained at a constant basal tension of 1 g and allowed to equilibrate for 1.5 hours during which the Tyrode buffer was changed every 15-20 minutes. At the end of equilibration period the stabilization of the tissue contractile response was assessed with l ⁇ mol/L of Carbachol until a reproducible response is obtained. Subsequently, a cumulative concentration response curve to Carbachol (10 " mol/L to 3 X 10 mol/L) was obtained. After several washes, once the baseline was achieved, a cumulative concentration response curve was obtained in presence of NCE (NCE added 20 minutes prior to the second cumulative response curve.
  • ED50 values were calculated by fitting a non-linear regression curve (Graph Pad Prism).
  • the described compounds exhibited the following: a) pKi values for M 2 muscarinic receptor subtype were from about 6 to about 8.1 in rats; and pKi values for M 3 muscarinic receptor subtype were from about 6 to about 8 in rats b) pKi values for M 2 muscarinic receptor subtype were from about 7.6 to about 8.6 in humans; and pKi values for M 3 muscarinic receptor subtype were from about 7.9 to about 8.4 in humans.
  • pKi values for M 5 muscarinic receptor subtype were from about 5.7 to about 6.7 in humans.

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Abstract

La présente invention concerne d'une façon générale des antagonistes des récepteurs muscariniques, lesquels antagonistes sont utiles dans le traitement de différentes maladies des systèmes respiratoire, urinaire ou gastro-intestinal médiées par les récepteurs muscariniques. L'invention concerne également des procédés servant à préparer de tels antagonistes des récepteurs muscariniques et des compositions pharmaceutiques de ceux-ci. L'invention concerne en outre des procédés de traitement de maladies médiées par les récepteurs muscariniques.
PCT/IB2005/002306 2004-08-05 2005-08-03 Antagonistes des récepteurs muscariniques WO2006016245A1 (fr)

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WO2007039884A1 (fr) 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited Dérivés de 3 -azabicyclooctane en tant qu’antagonistes de récepteurs muscariniques
WO2007110782A1 (fr) 2005-12-30 2007-10-04 Ranbaxy Laboratories Limited Antagonistes des récepteurs muscariniques
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
EP2280006A1 (fr) 2005-08-08 2011-02-02 Pulmagen Therapeutics (Synergy) Limited Composition pharmaceutique pour inhalation comprenant un oxazole ou thiazole antagoniste du récepteur m3 muscarinique
EP2281813A1 (fr) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Dérivés de bicyclo[2.2.1]hept-7-ylamine et leurs utilisations
WO2011051672A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
WO2011051671A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminopyridine comme inhibiteurs de la kallicréine
WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2280006A1 (fr) 2005-08-08 2011-02-02 Pulmagen Therapeutics (Synergy) Limited Composition pharmaceutique pour inhalation comprenant un oxazole ou thiazole antagoniste du récepteur m3 muscarinique
EP2281813A1 (fr) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Dérivés de bicyclo[2.2.1]hept-7-ylamine et leurs utilisations
WO2007039884A1 (fr) 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited Dérivés de 3 -azabicyclooctane en tant qu’antagonistes de récepteurs muscariniques
WO2007110782A1 (fr) 2005-12-30 2007-10-04 Ranbaxy Laboratories Limited Antagonistes des récepteurs muscariniques
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
US8815837B2 (en) 2008-08-07 2014-08-26 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
US9078885B2 (en) 2008-08-07 2015-07-14 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
US8362064B2 (en) 2008-12-30 2013-01-29 Pulmagen Theraputics (Inflammation) Limited Sulfonamide compounds for the treatment of respiratory disorders
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
WO2011051672A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
WO2011051671A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminopyridine comme inhibiteurs de la kallicréine
WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire

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