WO2006035280A1 - Antagonistes des recepteurs muscariniques - Google Patents

Antagonistes des recepteurs muscariniques Download PDF

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WO2006035280A1
WO2006035280A1 PCT/IB2005/002831 IB2005002831W WO2006035280A1 WO 2006035280 A1 WO2006035280 A1 WO 2006035280A1 IB 2005002831 W IB2005002831 W IB 2005002831W WO 2006035280 A1 WO2006035280 A1 WO 2006035280A1
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compound
formula
alkyl
cycloalkyl
alkenyl
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PCT/IB2005/002831
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WO2006035280A8 (fr
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Mohammad Salman
Anita Mehta
Naresh Kumar
Kirandeep Kaur
Arundutt Viswanatham Silamkoti
Bruhaspathy Miriyala
Shelley Aeron
Anita Chugh
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/24—Camphidines

Definitions

  • the present invention generally relates to muscarinic receptor antagonists, which 5 are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors.
  • the invention also relates to the process for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and the methods for treating diseases mediated through muscarinic receptors.
  • Muscarinic receptors as members of the G Protein Coupled Receptors are composed of a family of 5 receptor sub-types (Mi, M 2 , M 3 , M 4 and M 5 ) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple G Protein Coupled Receptors. These receptors are widely distributed on multiple G Protein Coupled Receptors. These receptors are widely distributed on multiple G Protein Coupled Receptors (GPCRs) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple GPCRs.
  • the Mj subtype is located primarily in neuronal tissues such as cereberal cortex and autonomic ganglia
  • the M 2 subtype is present mainly in the heart where it mediates cholinergically induced bradycardia
  • M 2 receptors outnumber M 3 receptors by a proportion of approximately 4 to 1.
  • M 3 receptors mediate the 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.
  • U.S. Patent Nos. 6,174,900, 6,130,232 and 5,948,792; WO 93/16018 and WO96/33973 are other references of interest; compounds disclosed in WO 97/45414 are 1 ,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives; US Patent No. 5,397,800 discloses l-azabicyclo[2.2.1]heptanes. US Patent No.5, 001,160 describes l-aryl-l-hydroxy-l-substituted-3-(4-substituted-l-piperazinyl)-2- propanones.
  • WO 99/43657 describes 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptors antagonists.
  • WO 01/090082 describes substituted 1-amino-alkyl lactams and their use as muscarinic receptor antagonists.
  • WO 01/47893 describes azabicycloctane derivatives useful in the treatment of cardiac arrhythmias.
  • WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas.
  • WO 01/42212 describes carbamate derivatives.
  • WO 01/90081 describes amino alkyl lactam.
  • WO 02/53564 describes novel quinuclidine derivatives.
  • WO 02/00652 describes carbamates derived from arylalkyl amines.
  • WO 02/06241 describes l,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives.
  • U.S. application No. 20030105071 describes thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonic receptors and transporters, and method of use thereof.
  • WO 03/033495 describes quinuclidine derivatives and their use as M 2 and/or M 3 muscarinic receptor antagonists.
  • US2003/0171362 describes amino-tetralin derivatives as muscarinic receptor antagonists.
  • US2003/0162780 describes 4-piperidinyl alkyl amine derivatives as muscarinic receptor antagonists.
  • US 5,179,108 disclose derivatives of 4- (aminomethyl) piperidine and their therapeutic applications.
  • WO 03/048125 discloses aminotetralin derivatives as muscarinic receptor antagonists.
  • WO 03/048124 discloses 4- piperidinyl alkylamine derivatives as muscarinic receptor antagonists.
  • WO 2004/052857 and WO 04/004629 disclose 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists.
  • WO 04/005252 discloses azabicyclo derivatives as muscarinic receptor antagonists.
  • WO 04/014853, WO 04/067510 and WO 04/014363 disclose derivatives of 3,6-disubstituted azabicyclohexane useful as muscarinic receptor antagonists.
  • WO 04/056810 discloses xanthine derivatives as muscarinic receptor antagonists.
  • WO 04/056811 discloses flaxavate derivatives as muscarinic receptor antagonists.
  • WO 04/056767 discloses 1 -substituted-3 -pyrrolidine derivatives as muscarinic receptor antagonists.
  • WO 04/018422 disclose fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
  • J.Med.Chem., 44, p. 984 describes cyclohexylmethylpiperidinyl- triphenylpropioamide derivatives as selective M 3 antagonist discriminating against the other receptor subtypes.
  • J.Med.Chem., 36 > P- 610 (1993) describes the synthesis and antimuscarinic activity of some 1-cycloalkyl-l -hydroxy- l-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds.
  • 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. Also provided are processes for synthesizing such compounds.
  • compositions containing such compounds are provided together with acceptable carriers, excipients or diluents which can be useful for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.
  • 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 are also provided, as well as pharmaceutical compositions comprising the compounds, their metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
  • ⁇ _y represents a nitrogen-containing ring having from 5 to 9 carbon atoms and T is a bridging group selected from the group consisting of -(CH 2 V, -CH(Q)CH 2 -, - CH 2 CH(Q)CH 2 -, -CH(Q)-, -CH 2 -O-CH 2 - or -CH 2 -NH-CH 2 -), where n is an integer selected from 0-3 (wherein when n is zero then T represents a direct bond);
  • Y is alkylene, alkenylene, alkynylene or no atom;
  • X is -NH or oxygen;
  • R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroarylalkyl or heterocyclylalkyl.
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, -NR p R q (wherein R p and R q are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl).
  • R w is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl or heteroarylalkyl;
  • Q is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as 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.
  • alkylene refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., -CH 2 CH 2 CH 2 and -CH(CH 3 )CH 2 ) 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. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkenylene unless otherwise specified, refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 6 carbon atoms with cis, trans or geminal geometry.
  • alkenylene In the event that alkenylene is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
  • the alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • alkynylene refers to a diradical of a triply- unsaturated hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that alkynylene is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom.
  • the alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I.
  • 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 olef ⁇ nic 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, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • Cycloalkylalkyl refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
  • alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
  • aralkyl refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like.
  • 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, and the like.
  • Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.
  • Heteroarylalkyl refers to heteroaryl (wherein heteroaryl is same as defined earlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6.
  • Heterocyclylalkyl refers to heterocyclyl (wherein heterocyclyl is same as defined earlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6.
  • “Acyl” refers to -C(O)R” wherein R" is selected from the group hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
  • protecting groups refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule.
  • protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found 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 groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease or disorder is mediated through muscarinic receptors includes administration of at least one compound having the structure of Formula I.
  • a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder associated with muscarinic receptors comprising administering to a patient in need thereof, an effective amount of a muscarinic receptor antagonist compound as described above.
  • a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory system such as 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), etc.; and gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein the disease or disorder is associated with muscarinic receptors.
  • a disease or disorder of the respiratory system such as 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), etc.
  • gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein the disease or disorder is associated with muscarinic receptors
  • the compounds described herein 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.
  • the compounds that were found active in vitro were tested in vivo.
  • Some of the compounds are 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 possible treatment for the disease or disorders associated with muscarinic receptors are provided.
  • the compounds can be administered orally or parenterally.
  • the compounds of the present invention may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention.
  • the compounds of the present invention may be prepared by the processes described herein, these processes are not the only means by which the compounds described may be synthesised. Further, the various synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds.
  • the compounds of Formulae VI and VIII can be prepared for example, by the reaction sequence as depicted in Scheme I, thus a compound of Formula II can be reacted with a compound of Formula III (wherein Ri is the same as defined earlier and hal is Br, Cl or I) to give a compound of Formula IV, which can undergo a cyclodehydration reaction to give a compound of Formula V, which can undergo a reduction to give a compound of Formula VI, which can be reacted with a compound of Formula VII (wherein R k is optionally substituted alkyl or aryl and hal is the same as defined above) to give a compound of Formula VIII.
  • reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in the presence of a base, for example, sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate.
  • a base for example, sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate.
  • the compound of Formula IV undergoes cyclodehydration to give compound of Formula V in the presence of a Lewis acid, for example, phosphorous oxychloride, zinc chloride or phosphorous pentachloride with dehydrating agent, for example, phosphorous pentaoxide in an organic solvent, for example, xylene or toluene.
  • a Lewis acid for example, phosphorous oxychloride, zinc chloride or phosphorous pentachloride with dehydrating agent, for example, phosphorous pentaoxide in an organic solvent, for example, xylene or toluene.
  • the reduction of a compound of Formula V to give a compound of Formula VI can be carried out in an organic solvent, for example, ethanol, methanol, propanol or isopropylalcohol with a reducing agent, for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride or palladium on carbon with hydrogen gas.
  • a reducing agent for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride or palladium on carbon with hydrogen gas.
  • the compound of Formula VI is reacted with a compound of Formula VII to give a compound of Formula VIII in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbontetrachloride in the presence of a base, for example, triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine.
  • the compounds of Formulae XI and XII can be prepared for example by the reaction sequence as depicted in Scheme II.
  • the reactions of a compound of Formula VI with a compound of Formula VII and a compound of Formula IX to give a compound of Formula X can be carried out in an organic solvent, for example, acetonitrile, acetone, ethanol or isopropylalcohol in the presence of a base, for example, triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine.
  • an organic solvent for example, acetonitrile, acetone, ethanol or isopropylalcohol
  • a base for example, triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine.
  • compound of Formula X can be prepared by reacting a compound of Formula VI with appropriate isocyanate or by using carbonyldiimidazole in place of chloroformates of Formula VII.
  • the deprotection of a compound of Formula X (when P is aralkyl) to give a compound of Formula XI can be carried out in an organic solvent, for example, dichloroethane, methanol, ethanol, propanol or isopropylalcohol in the presence of a deprotecting agent, for example, palladium on carbon, platinum on carbon, ⁇ -chloro ethylchloroformate or 1 , 1 , 1 -trichloro ethylchloroformate.
  • an organic solvent for example, dichloroethane, methanol, ethanol, propanol or isopropylalcohol
  • a deprotecting agent for example, palladium on carbon, platinum on carbon, ⁇ -chloro ethylchloroformate or 1 , 1 , 1 -trichloro ethylchloroformate.
  • an organic solvent for example, methanol, ethanol, propanol or isopropylalcohol in the presence of methanolic or etheral hydrochloric acid, solution of hydrochloric acid in ethyl acetate or trifluoroacetic acid.
  • an organic solvent for example, methanol, ethanol, propanol or isopropylalcohol or by hydrobromic acid (45% w/v solution in acetic acid).
  • N-alkylation of a compound of Formula XI to give a compound of Formula XII can be carried out in the presence of a base, for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate or sodium bicarbonate.
  • a base for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate or sodium bicarbonate.
  • Representative compounds which may be prepared following Scheme II include:
  • the compounds of Formulae XIV and Formula XV can be prepared, for example by the reaction sequence as depicted in Scheme III.
  • a compound of Formula VIII can be reacted with a compound of Formula XIII (wherein n is the same as defined earlier and X is -NH or O) to give a compound of Formula XIV, which can undergo deprotection to give a compound of Formula XV.
  • reaction of a compound of Formula VIII with a compound of Formula XIII (when X is oxygen) to give a compound of Formula XIV can be carried out in an organic solvent, for example, toluene, benzene or xylene in the presence of a base, for example, sodium hydride, lithium hydride, butyl lithium or lithium diisopropylamide.
  • organic solvent for example, toluene, benzene or xylene
  • a base for example, sodium hydride, lithium hydride, butyl lithium or lithium diisopropylamide.
  • reaction of a compound of Formula VIII with a compound of Formula XIII (when X is -NH) to give a compound of Formula XIV can be carried out in an organic solvent, for example, dimethylsulphoxide or dimethylformamide in the presence of a base, for example, diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine.
  • a base for example, diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine.
  • amines can be converted to corresponding tartarate salts by using tartaric acid in ethanol or hydrochloride salts with ethanolic hydrochloric acid solution in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • the compounds described herein may be administered to an animal for treatment orally, or by a parenteral route.
  • the pharmaceutical compositions described herein can be produced and administered in dosage units, each unit containing a certain amount of at least one compound described herein and/or at least one physiologically acceptable addition salt thereof.
  • the dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity.
  • the compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
  • the compounds described herein can be produced and formulated as their enantiomers, diastereomers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as metabolites having the same type of activity.
  • Pharmaceutical compositions comprising the molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipient can also be produced.
  • Step d Ethyl-l-phenyI-3,4-dihydro-2(lH)-carboxylate
  • triethylamine (1.75 g, 17.34 mmol)
  • ethylchloroformate (1.850 g, 17.052 mmol)
  • the reaction mixture was stirred at room temperature for 48 hours and the resulting reaction mixture was washed with water followed acidifying it with hydrochloric acid (IN).
  • the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 4.7 g.
  • Step a N-3-azabicyclo[3.1.0]hex-6-yl-l-phenyl-3,4-dihydroisoquinoline-2(l ⁇ ) carboxamide
  • Membrane preparation Submandibular glands and heart were isolated and placed in ice cold homogenising buffer (HEPES 2OmM, 1OmM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenised in 10 volumes of homogenising buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 500g for lOmin. The supernatant was subsequently centrifuged at 40,00Og for 20 min. The pellet thus obtained was resuspended in assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -7O 0 C until the time of assay.
  • HEPES 2OmM, 1OmM EDTA, pH 7.4 ice cold homogenising buffer
  • the bladder was cut into longitudinal strips (3mm wide and 5-6 mm long) and mounted in 10 ml organ baths at 30° 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 1/2 hour during which the Tyrode buffer was changed every 15-20 min. At the end of equilibration period the stabilization of the tissue contractile response was assessed with l ⁇ mol/L of Carbachol till a reproducible response is obtained. Subsequently a cumulative concentration response curve to carbachol (10 "9 mol/L to 3 X 10 "4 mol/L) was obtained. After several washes, once the baseline was achieved, cumulative concentration response curve was obtained in presence of NCE (NCE added 20 min. prior to the second cumulative response curve.
  • ED 50 values were calculated by fitting a non-linear regression curve (Graph Pad Prism).
  • the above specified compounds showed pK; values for M 2 receptors from about 13,800 nM to about 700 nM, for example, from about 10,000 nM to about 700 nM, or from about 1000 nM to about 700 nM.
  • the above specified compounds showed pIQ values for M 3 receptors in the range of from about 4200 nM to about 65 nM, for example, from about 1000 nM to about 65 nM, or from about 270 nM to about 65 nM.

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Abstract

La présente invention concerne, de manière générale, des antagonistes des récepteurs muscariniques de formule (I), lesquels sont utiles, entre autres, pour le traitement de diverses maladies des systèmes respiratoire, urinaire et gastro-intestinal médiées par des récepteurs muscariniques. L'invention concerne également le procédé de préparation des composés selon l'invention, des compositions pharmaceutiques contenant lesdits composés, ainsi que les méthodes de traitement de maladies médiées par des récepteurs muscariniques. Dans la formule (I), On représente un cycle contenant de l'azote présentant entre 5 et 9 atomes de carbone et T représente un groupe de pontage sélectionné dans le groupe comprenant (CH2)n-, -CH(Q)CH2-, -CH2CH(Q)CH2-, -CH2-O-CH2- ou -CH2-NH-CH2-), n est un entier sélectionné compris entre 0 et 3 (lorsque n est égal à zéro, alors T représente une liaison directe) ; Y représente alkylène, alcénylène, alkynylène ou aucun atome ; X représente NH ou oxygène.
PCT/IB2005/002831 2004-09-27 2005-09-26 Antagonistes des recepteurs muscariniques WO2006035280A1 (fr)

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EP2420237A1 (fr) 2010-08-11 2012-02-22 Ville Takio Dérivés fluorés d'isoquinoléines endogènes pour leur utilisation dans le traitement de maladies liées aux passages d'isoquinoline endogène
US8476297B2 (en) 2007-12-04 2013-07-02 Amgen Inc. TRP-M8 receptor ligands and their use in treatments
WO2019152809A1 (fr) 2018-02-02 2019-08-08 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
WO2020252222A1 (fr) * 2019-06-12 2020-12-17 Arkuda Therapeutics Modulateurs de la progranuline et leurs procédés d'utilisation
US11299481B2 (en) 2017-10-20 2022-04-12 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11352344B2 (en) 2017-10-31 2022-06-07 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4

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WO2004056811A1 (fr) * 2002-12-23 2004-07-08 Ranbaxy Laboratories Limited Derives de flavaxate comme antagonistes de recepteurs muscariniques

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WO2004018422A1 (fr) * 2002-08-23 2004-03-04 Ranbaxy Laboratories Limited Derives d'azabicyclo(3.1.0)hexanes 3,6-disubstitues contenant fluoro et sulfonylamino, utilises comme antagonistes des recepteurs de muscarine
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8476297B2 (en) 2007-12-04 2013-07-02 Amgen Inc. TRP-M8 receptor ligands and their use in treatments
EP2420237A1 (fr) 2010-08-11 2012-02-22 Ville Takio Dérivés fluorés d'isoquinoléines endogènes pour leur utilisation dans le traitement de maladies liées aux passages d'isoquinoline endogène
US11299481B2 (en) 2017-10-20 2022-04-12 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11820757B2 (en) 2017-10-20 2023-11-21 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11352344B2 (en) 2017-10-31 2022-06-07 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
WO2019152809A1 (fr) 2018-02-02 2019-08-08 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
JP2021513519A (ja) * 2018-02-02 2021-05-27 ヴァンダービルト ユニバーシティー ムスカリン性アセチルコリン受容体ｍ４のアンタゴニスト
EP3746421A4 (fr) * 2018-02-02 2021-10-27 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
US11414406B2 (en) 2018-02-02 2022-08-16 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
WO2020252222A1 (fr) * 2019-06-12 2020-12-17 Arkuda Therapeutics Modulateurs de la progranuline et leurs procédés d'utilisation
CN113950477A (zh) * 2019-06-12 2022-01-18 阿库达医疗公司 颗粒体蛋白前体调节剂和其使用方法

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