WO2006117754A1 - 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives as muscarinic receptor antagonists - Google Patents

3,6-disubstituted azabicyclo [3.1.0] hexane derivatives as muscarinic receptor antagonists Download PDF

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WO2006117754A1
WO2006117754A1 PCT/IB2006/051368 IB2006051368W WO2006117754A1 WO 2006117754 A1 WO2006117754 A1 WO 2006117754A1 IB 2006051368 W IB2006051368 W IB 2006051368W WO 2006117754 A1 WO2006117754 A1 WO 2006117754A1
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compound
methyl
hydroxy
azabicyclo
hex
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PCT/IB2006/051368
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French (fr)
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Mohammad Salman
Naresh Kumar
Kirandeep Kaur
Shelly Aeron
Pakala Kumara Savithru Sarma
Sankaranarayanan Dharmarajan
Anita Mehta
Anita Chugh
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Ranbaxy Laboratories Limited
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Priority to US11/913,599 priority Critical patent/US20080319043A1/en
Priority to EP06728107A priority patent/EP1888525A1/en
Publication of WO2006117754A1 publication Critical patent/WO2006117754A1/en

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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

Definitions

  • This invention generally relates to muscarinic receptor antagonists which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors.
  • the invention relates to derivatives of azabicyclo compounds, including, for example, 6- substituted azabicyclo[3.1.0] hexanes, as well as pharmaceutical compositions containing such compounds and methods of 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 (M 1 , M 2 , M 3 , M 4 and M 5 ) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The 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 such as cereberal cortex and autonomic ganglia
  • the M 2 subtype is present mainly in the heart where it mediates cholinergically induced bradycardia
  • the M 3 subtype is located predominantly on smooth muscle and salivary glands ⁇ Nature, 323, p.411 (1986); Science, 237, p.527 (1987)).
  • Muscarinic agonists such as muscarine and pilocarpine and antagonists such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds, making it difficult to assign specific functions to the individual receptors.
  • classical muscarinic antagonists such as atropine are potent bronchodilators, their clinical utility is limited due to high incidence of both peripheral and central adverse effects such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc.
  • 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.
  • 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 2 is straight or branched alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heteroaryl wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heteroaryl are optionally substituted with one or more substituents selected from alkyl, hydroxy or halogen.
  • R 3 is aryl or heteroaryl wherein the said aryl or heteroaryl are optionally substituted with one or more groups selected from alkyl, hydroxy or halogen;
  • R 5 is hydrogen or alkyl
  • R w is H or methyl
  • n, i, j are integer from 0-2.
  • a method for treatment or prophylaxis of a disease or disorder of the respiratory, urinary and gastrointestinal systems in an animal or a human suffering therefrom, 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 were found to be potent muscarinic receptor antagonists with high affinity towards M 3 receptors. 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 processes described herein, such 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 in order to give the desired compounds.
  • reaction of a compound of Formula II (when M is hydrogen) with a compound of Formula III (when Z is -NR 5 and Pi is H) to give a compound of Formula IV can be carried out in an organic solvent, for example, dimethylformamide, tetrahydrofuran, dioxane, chloroform or diethylether, in the presence of a base, for example, N- methylmorpholine, pyridine, triethylamine or diisopropylethylamine, with a condensing agent, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide.
  • organic solvent for example, dimethylformamide, tetrahydrofuran, dioxane, chloroform or diethylether
  • a base for example, N- methylmorpholine, pyridine, triethylamine or diisopropylethyl
  • reaction of a compound of Formula II (when M is hydrogen) with a compound of Formula III (when Z is oxygen and Pi is hal (Br, Cl or I), mesyl or tosyl) to give a compound of Formula IV can be carried out in an organic solvent, for example, toluene, benzene or xylene, in the presence of a base, for example, l,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, triethylamine or diisopropylethylamine.
  • an organic solvent for example, toluene, benzene or xylene
  • a base for example, l,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, triethylamine or diisopropylethylamine.
  • reaction of a compound of Formula II (when M is alkyl) with a compound of Formula III (when Z is oxygen and Pi is H) to give a compound of Formula IV can be carried out in an organic solvent, for example, tetrahydrofuran, diethyl ether, dioxane or dimethylformamide in the presence of a base, for example, butyl lithium, lithium diisopropyl amide, sodium hydride or diisopropylethylamine.
  • organic solvent for example, tetrahydrofuran, diethyl ether, dioxane or dimethylformamide
  • a base for example, butyl lithium, lithium diisopropyl amide, sodium hydride or diisopropylethylamine.
  • reaction of a compound of Formula II (when M is alkyl) with a compound of Formula III (when Z is -NR 5 and Pi is H) to give a compound of Formula IV can be carried out in an organic solvent, for example, tetrahydrofuran, diethyl ether, dioxane or dimethylformamide, in the presence of a reducing agent, for example, diisobutyl aluminum.
  • organic solvent for example, tetrahydrofuran, diethyl ether, dioxane or dimethylformamide
  • the deprotection of a compound of Formula IV (when P is benzyl) to give a compound of Formula V can be carried out in an organic solvent, for example, methanol, ethanol, propanol or isopropylalcohol, with a deprotecting agent, for example, palladium on carbon in the presence of hydrogen gas or palladium on carbon with a source of hydrogen gas such as ammonium formate, cyclohexene or formic acid.
  • an organic solvent for example, methanol, ethanol, propanol or isopropylalcohol
  • a deprotecting agent for example, palladium on carbon in the presence of hydrogen gas or palladium on carbon with a source of hydrogen gas such as ammonium formate, cyclohexene or formic acid.
  • an organic solvent for example, methanol, ethanol, propanol or isopropylalcohol
  • a strong acid for example, hydrochloric acid, trifluoroacetic acid in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol, diethylether, tetrahydrofuran or dichloromethane.
  • the compound of Formula V is reacted with R k -R c (when R c is -CHO) to give a compound of Formula VI in an organic solvent for example, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, chloroform or carbon tetrachloride, in the presence of, for example, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • an organic solvent for example, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, chloroform or carbon tetrachloride, in the presence of, for example, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the compound of Formula V is reacted with R k -R c (when R c is -CH 2 hal) to give a compound of Formula VI in an organic solvent, for example, dimethylformamide acetonitrile, dichloromethane, dichloroethane or chloroform, in the presence of a base, for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate or sodium bicarbonate.
  • an organic solvent for example, dimethylformamide acetonitrile, dichloromethane, dichloroethane or chloroform
  • a base for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate or sodium bicarbonate.
  • the compound of Formula IX can be prepared by following the procedure as depicted in, for example, Scheme II.
  • a compound of Formula II can be reacted with a compound of Formula VII (wherein Fi is mesyl, tosyl, triflyl or hal (Br, Cl or I); Q, R w , n and P are the same as defined earlier) to give a compound of Formula VIII, which can undergo deprotection to give a compound of Formula IX.
  • reaction of a compound of Formula II with a compound of Formula VII to give a compound of Formula VIII can be carried out in an organic solvent, for example, toluene or xylene in the presence of a base, for example, N-methylmorpholine, pyridine, triethylamine or diisopropylethylamine.
  • organic solvent for example, toluene or xylene
  • a base for example, N-methylmorpholine, pyridine, triethylamine or diisopropylethylamine.
  • the compounds of Formula XI can be prepared by following, for example, the reaction procedure as depicted in Scheme III.
  • a compound of Formula V can be reacted with a compound of Formula X (wherein P 2 is -Omesyl or -Otosyl) to give a compound of Formula XI (wherein R 1 , R 2 , R3, Z, Q, R w and n are the same as defined earlier), which can be deprotected to give a compound of Formula XII.
  • reaction of a compound of Formula V with a compound of Formula X to give a compound of Formula XI can be carried out in an organic solvent, for example, acetonitrile, dichloromethane, carbon tetrachloride or chloroform, in the presence of a base, for example, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
  • organic solvent for example, acetonitrile, dichloromethane, carbon tetrachloride or chloroform
  • a base for example, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
  • the deprotection of a compound of Formula XI to give a compound of Formula XII can be carried out with a strong acid, for example, hydrochloric acid, trifluoroacetic acid, in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol, diethylether, tetrahydrofuran or dichloromethane.
  • a strong acid for example, hydrochloric acid, trifluoroacetic acid
  • organic solvent for example, methanol, ethanol, propanol, isopropylalcohol, diethylether, tetrahydrofuran or dichloromethane.
  • salts examples include pharmacologically acceptable salts such as inorganic acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), 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 included in the Formula I as substituents, they may be present 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.
  • 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.
  • the examples mentioned below demonstrate general synthetic procedures, as well as specific preparations of particular compounds. The examples are provided to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
  • Step b [2-(Benzyloxy)-5-methylphenyl](hydroxy)phenyl acetic acid.
  • Step c Hydroxy (2-hydroxy-5-methylphenyl) phenyl acetic acid.
  • methanol 25 ml
  • palladium on carbon 100 g, 10 %
  • anhydrous ammonium formate 450 mg
  • the resulting reaction mixture was refluxed for 30 minutes followed by cooling it to room temperature.
  • the reaction mixture was filtered through a bed of hyflo, washed with methanol, ethyl acetate and water.
  • the filtrate was concentrated under reduced pressure.
  • the residue thus obtained was diluted with water and pH of the resulting solution was adjusted to 14 with IN sodium hydroxide. It was extracted with ether.
  • the aqueous layer was acidified and extracted with ethylacetate.
  • the organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 320 mg.
  • Step b S-Cyclohexyl-l-hydroxy-l-phenylpropanoic acid
  • Step b Methoxy(4-methyl phenyl) phenylacetic acid
  • Step a 2-(Bromomethyl)-6-methylpyridine
  • phosphorous bromide 2.2 g
  • the solvent was evaporated under reduced pressure and the aqueous layer was extracted with dichloromethane.
  • the organic layer was collected and washed with 10% sodium hydroxide solution, water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure.
  • the residue thus obtained was purified by column chromatography using 10% ethyl acetate in hexane to furnish the title compound.
  • Step b 2-Cyclohexyl-2-hydroxy-iV-( ⁇ 3-[(6-methyl pyridin-2-yl)methyl]-3-azabicyclo [3.1.0]hex-6-yl ⁇ methyl)-2-phenyl acetamide
  • Step b Methyl ⁇ -fCtert-butoxycarbony ⁇ aminoJpyridine-l-ylJcarboxylate
  • Step e Tert-butyl (6- ⁇ [6-Cyclohexyl(hydroxy)phenylacetyl]amino ⁇ methyl)-3- azabicyclofS.l.OJhex-S-ylJmethyllpyridin-l-y ⁇ carbamate
  • N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2- hydroxy-2-penylacetamide (disclosed in WO 04/005252) (1.19 g) in acetonitrile (30 ml), was added the compound obtained from step d above (1.32 g) and potassium carbonate
  • EXAMPLE 11 Synthesis of tartarate salt of N-(3-azabicvclor3.L01hex-6-ylmethyl)-3- hydroxy-N-methyl-3,3-diphenylpropanamide (Compound No. 37)
  • Step a N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-N-methyl-3,3-diphenyl propionamide
  • Step b Tartarate salt of ⁇ 3-azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-iV-methyl- 3,3-diphenylpropanamide
  • Membrane preparation Submandibular glands and heart were isolated and placed in ice- cold homogenizing buffer (HEPES 2OmM, 1OmM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenized in 10 volumes of homogenizing buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 500 g for 10 min. The supernatant was subsequently centrifuged at 40,000 g for 20 min. The pellets thus obtained were resuspended in assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -70 C until the time of assay.
  • HEPES 2OmM, 1OmM EDTA, pH 7.4 ice- cold homogenizing buffer
  • 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 m 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 until a reproducible response was 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.
  • the contractile results were expressed as % of control E max.
  • Ki for rat M3 receptors of between about 1000 and about 0.1 nM, for example, between about 200 and about 0.1 nM, or for example between about 50 and about 0.1 nM, or for example between about 15 and about 0.1 nM, or for example between about 8 and about 0.1 nM, or for example between about 1 and about 0.1 nM.
  • Ki for rat M2 receptors of between about 1000 and about 0.15 nM, for example, between about 200 and about 0.15 nM, or for example between about 50 and about 0.15 nM, or for example between about 15 and about 0.15 nM, or for example between about 8 and about 0.15 nM, or for example between about 1 and about 0.15 nM.
  • the compounds described herein displayed selectivity (Ki for rat M3 receptors/Ki for rat M2 receptors) of between about 0.3 and about 310, for example between about 10 and about 310, or for example between about 30 and about 310, or for example between about 60 and about 310.
  • Particular compounds displayed Ki for human M3 receptors of between about 113 and about 0.03 nM, for example, between about 15 and about 0.03 nM, or for example between about 7 and about 0.03 nM, or for example between about 0.5 and about 0.03 nM, or for example between about 0.15 and about 0.03 nM.
  • Particular compounds displayed Ki for human M3 receptors of between about 113 and about 0.03 nM, for example, between about 15 and about 0.03 nM, or for example between about 7 and about 0.03 nM, or for example between about 0.5 and about 0.03 nM, or for example between about 0.15 and about 0.03 nM.
  • Particular compounds displayed Ki for human M3 receptors of between about 113 and about 0.03 nM, for example, between about 15 and about 0.03 nM, or for example between about 7 and about 0.03 nM, or for example between about 0.5 and about 0.03 nM, or for example between about 0.15 and about 0.03 nM.
  • Particular compounds displayed Ki for
  • Ki for rat M2 receptors of between about 760 and about 24 nM, for example, between about 550 and about 24 nM, or for example between about 100 and about 24 nM, or for example between about 50 and about 24 nM.
  • the compounds described herein displayed selectivity (Ki for human M3 receptors/Ki for human M2 receptors) of between about 1.8 and about 140, for example between about 7 and about 140, or for example between about 40 and about 140.

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Abstract

The present invention generally relates to muscarinic receptor antagonists, which 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 prepration of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and the methods for treating diseases mediated through muscarinic receptors.

Description

3,6-DISUBSTITUTED AZABICYCLO [3.1.0] HEXANE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS
Field of the Invention This invention generally relates to muscarinic receptor antagonists which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. Specifically, the invention relates to derivatives of azabicyclo compounds, including, for example, 6- substituted azabicyclo[3.1.0] hexanes, as well as pharmaceutical compositions containing such compounds and methods of treating diseases mediated through muscarinic receptors.
Background of the Invention
Muscarinic receptors as members of the G Protein Coupled Receptors (GPCRs) are composed of a family of 5 receptor sub-types (M1, M2, M3, M4 and M5) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor sub-types in the brain and other organs has been documented. For example, the Mi subtype is located primarily in neuronal tissues such as cereberal cortex and autonomic ganglia, the M2 subtype is present mainly in the heart where it mediates cholinergically induced bradycardia, and the M3 subtype is located predominantly on smooth muscle and salivary glands {Nature, 323, p.411 (1986); Science, 237, p.527 (1987)).
A review in Current Opinions in Chemical Biology, 3, p. 426 (1999), as well as in Trends in Pharmacological Sciences, 22, p. 409 (2001) by Eglen et. al., describes the biological potentials of modulating muscarinic receptor subtypes by ligands in different disease conditions, such as Alzheimer's Disease, pain, urinary disease condition, chronic obstructive pulmonary disease, and the like.
A review in /. Med. Chem., 43, p. 4333 (2000), by Felder et. al. describes therapeutic opportunities for muscarinic receptors in the central nervous system and elaborates on muscarinic receptor structure and function, pharmacology and their therapeutic uses. The pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists are presented in a review in Molecules, 6, p. 142 (2001). Birdsall et. al. in Trends in Pharmacological Sciences, 22, p. 215 (2001) have also summarized the recent developments on the role of different muscarinic receptor subtypes using different muscarinic receptor of knock out mice.
Muscarinic agonists such as muscarine and pilocarpine and antagonists such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds, making it difficult to assign specific functions to the individual receptors. Although classical muscarinic antagonists such as atropine are potent bronchodilators, their clinical utility is limited due to high incidence of both peripheral and central adverse effects such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc. Subsequent development of the quarterly derivatives of atropine such as ipratropium bromide are better tolerated than parenterally administered options, but most of these are not ideal anti-cholinergic bronchodilators, due to lack of selectivity for muscarinic receptor sub-types, resulting in dose-limiting side-effects such as thirst, nausea, mydriasis and those associated with the heart such as tachycardia mediated by the M2 receptor.
Annual Review of Pharmacological Toxicol, 4J_, p. 691 (2001), describes the pharmacology of the lower urinary tract infections. Although anti-muscarinic agents such as oxybutynin and tolterodine that act non-selectively on muscarinic receptors have been used for many years to treat bladder hyperactivity, the clinical effectiveness of these agents has been limited due to the side effects such as dry mouth, blurred vision and constipation. Tolterodine is considered to be generally better tolerated than oxybutynin. (Steers et. al., in Curr. Opin. Invest. Drugs, 2, 268; Chappie et. al., in Urology, 55, 33; Steers et al., Adult and Pediatric Urology, ed. Gillenwatteret al., pp 1220-1325, St. Louis, MO; Mosby. 3rd edition (1996)).
There remains a need for development of new highly selective muscarinic antagonists, which can interact with distinct subtypes, thus avoiding the occurrence of adverse effects. Compounds reported as having antagonistic activity against muscarinic receptors have been described in Japanese patent application Laid Open Number 92921/1994 and 135958/1994; WO 93/16048; U.S. Patent No. 3,176,019; GB 940,540; EP 0325 571; WO 98/29402; EP 0801067; EP 0388054; WO 9109013; U.S. Patent No. 5,281,601. Also, U.S. Patent Nos. 6,174,900, 6,130,232 and 5,948,792; WO 97/45414 are related to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives; WO 93/16018 and WO96/33973 are other references of interest.
A report in /. Med. Chem., 44, p. 984 (2002), describes cyclohexylmethyl piperidinyl triphenylpropioamide derivatives as selective M3 antagonist discriminating against the other receptor subtypes.
Summary of the Invention
In one aspect, there are provided 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.
In another aspect, pharmaceutical 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. 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.
In accordance with one aspect, there are provided compounds having the structure of Formula I:
Figure imgf000005_0001
Formula I and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein Ri is hydrogen or alkyl;
R2 is straight or branched alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heteroaryl wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heteroaryl are optionally substituted with one or more substituents selected from alkyl, hydroxy or halogen. R3 is aryl or heteroaryl wherein the said aryl or heteroaryl are optionally substituted with one or more groups selected from alkyl, hydroxy or halogen;
W = -(CH2),; Q = -(CH2)j; X is oxygen or -N(Rs)-; R4 is hydrogen, straight or branched alkyl, straight or branched alkenyl, aralkyl or heteroarylalkyl wherein the said aralkyl or heteroarylalkyl is further substituted with alkyl, -NH2 or alkoxycarbonylamino;
R5 is hydrogen or alkyl; Rw is H or methyl; and n, i, j are integer from 0-2.
In accordance with a second aspect, there is provided a method for treatment or prophylaxis of a disease or disorder of the respiratory, urinary and gastrointestinal systems in an animal or a human suffering therefrom, wherein the disease or disorder is mediated through muscarinic receptors. The method includes administration of at least one compound having the structure of Formula I. In accordance with a third aspect, there is provided 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. In accordance with a fourth aspect, there is provided 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.
In accordance with a fifth aspect, there are provided processes for preparing the compounds as described above. 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 were found to be potent muscarinic receptor antagonists with high affinity towards M3 receptors. Therefore, pharmaceutical compositions for the possible treatment for the disease or disorders associated with muscarinic receptors are provided. In addition, the compounds can be administered orally or parenterally.
Detailed Description of the Invention 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. In addition, although the compounds of the present invention may be prepared by processes described herein, such 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 in order to give the desired compounds. Scheme I
condensation
Figure imgf000007_0001
Figure imgf000007_0002
Formula I Formula I Formula IV
deprotection
Figure imgf000007_0003
The compounds of Formula IV, V and VI can be prepared by the reaction procedure as depicted, for example, in Scheme I, thus a compound of Formula II (wherein M is alkyl or hydrogen; R1, R2, R3 and W are the same as defined earlier) can be reacted with a compound of Formula III (wherein Z is oxygen or -NR5 (wherein R5 is the same as defined earlier); Pi is hal (Cl, Br or I), mesyl, tosyl or H; Q, Rw and n are the same as defined earlier and P is benzyl, -C(=O)OtBu or -Ct=O)OCH2C6H5) to give a compound of Formula IV, which can undergo deprotection to give a compound of Formula V, which can undergo N-derivatization with a compound of Formula Rc-Rk [wherein Rc is CHO or CH2hal (hal is Br, Cl or I) and Rk is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroarylalkyl, or heteroaryl] to give a compound of Formula VI.
The reaction of a compound of Formula II (when M is hydrogen) with a compound of Formula III (when Z is -NR5 and Pi is H) to give a compound of Formula IV can be carried out in an organic solvent, for example, dimethylformamide, tetrahydrofuran, dioxane, chloroform or diethylether, in the presence of a base, for example, N- methylmorpholine, pyridine, triethylamine or diisopropylethylamine, with a condensing agent, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide.
The reaction of a compound of Formula II (when M is hydrogen) with a compound of Formula III (when Z is oxygen and Pi is hal (Br, Cl or I), mesyl or tosyl) to give a compound of Formula IV can be carried out in an organic solvent, for example, toluene, benzene or xylene, in the presence of a base, for example, l,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, triethylamine or diisopropylethylamine.
The reaction of a compound of Formula II (when M is alkyl) with a compound of Formula III (when Z is oxygen and Pi is H) to give a compound of Formula IV can be carried out in an organic solvent, for example, tetrahydrofuran, diethyl ether, dioxane or dimethylformamide in the presence of a base, for example, butyl lithium, lithium diisopropyl amide, sodium hydride or diisopropylethylamine.
The reaction of a compound of Formula II (when M is alkyl) with a compound of Formula III (when Z is -NR5 and Pi is H) to give a compound of Formula IV can be carried out in an organic solvent, for example, tetrahydrofuran, diethyl ether, dioxane or dimethylformamide, in the presence of a reducing agent, for example, diisobutyl aluminum.
The deprotection of a compound of Formula IV (when P is benzyl) to give a compound of Formula V can be carried out in an organic solvent, for example, methanol, ethanol, propanol or isopropylalcohol, with a deprotecting agent, for example, palladium on carbon in the presence of hydrogen gas or palladium on carbon with a source of hydrogen gas such as ammonium formate, cyclohexene or formic acid.
The deprotection of a compound of Formula IV (when P is -C(=O) OCH2C6H5) to give a compound of Formula V can be carried out in an organic solvent, for example, methanol, ethanol, propanol or isopropylalcohol, in the presence of methanolic or ethanolic potassium hydroxide.
The deprotection of a compound of Formula IV (when P is -C(=O)OtBu) to give a compound of Formula V can be carried out with a strong acid, for example, hydrochloric acid, trifluoroacetic acid in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol, diethylether, tetrahydrofuran or dichloromethane.
The compound of Formula V is reacted with Rk-Rc (when Rc is -CHO) to give a compound of Formula VI in an organic solvent for example, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, chloroform or carbon tetrachloride, in the presence of, for example, sodium cyanoborohydride or sodium triacetoxyborohydride. The compound of Formula V is reacted with Rk-Rc (when Rc is -CH2hal) to give a compound of Formula VI in an organic solvent, for example, dimethylformamide acetonitrile, dichloromethane, dichloroethane or chloroform, in the presence of a base, for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate or sodium bicarbonate.
Illustrative compounds which can be prepared following, for example, Scheme I include:
N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-phenyl-2-(2-thienyl)acetamide (Compound No. 1), N- [(3 -Benzyl-3-azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-2-phenyl-2-(2- thienyl)acetamide (Compound Νo.2),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)2-thienylacetate (Compound No. 3),
N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-phenyl-2-(3-thienyl)acetamide (Compound No. 5),
N- [(3 -Benzyl-3-azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-2-phenyl-2-(3 - thienyl)acetamide (Compound No. 6),
Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2- hydroxy-2-(2-thienyl)acetamide (Compound No. 7), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenyl-2-(3- thienyl)acetamide (Compound No. 8),
Tartarate salt of N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-cyclopentyl-2-hydroxy-2-(2- thienyl)acetamide (Compound No. 9),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2,2-di-2-thienylacetamide (Compound No. 10),
N- [(3 -Benzyl-3-azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-N-methyl-2-phenyl-2-(2- thienyl)acetamide (Compound No. 11),
N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -2-cyclopentyl-2-hydroxy-N-methyl-2- (2-thienyl)acetamide (Compound No. 12), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-(4- methylphenyl)-2-(2-thienyl)acetamide (Compound No. 13), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(4-methylphenyl)2-thienylacetate (Compound No. 14),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(di-2-thienyl)acetate (Compound No. 15), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-(4-methylphenyl)-2-(2- thienyl)acetamide (Compound No. 16),
Tartarate salt of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-(2- thienyl)acetamide (Compound No. 17),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2-phenyl-2-(2-thienyl)acetamide (Compound No. 18),
2-Hydroxy-N-[(3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-phenyl-2-(2- thienyl)acetamide (Compound No. 19),
N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-(4-fluorophenyl)-2-hydroxy-2- phenylacetamide (Compound No. 20), N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-(4-methylphenyl)-2- phenylacetamide (Compound No. 21),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl 3-hydroxy-3,3-diphenylpropanoate (Compound No. 22),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-3-hydroxy-N-methyl-3,3- diphenylpropanamide (Compound No. 23),
^[(S-Benzyl-S-azabicyclofS.l.OJhex-o-y^methylJ-S-hydroxy-S^-diphenylpropanamide (Compound No. 24),
(3 -Methyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl hydroxy (3 -methylphenyl)phenylacetate (Compound No. 25), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-(2-hydroxy-5- methylphenyl)-2-phenylacetamide (Compound No. 26),
3-Azabicyclo[3.1.0]hex-6-ylmethyl hydroxy [bis(3-methylphenyl)]acetate (Compound No.
27),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-bis(3-methylphenyl)acetamide (Compound No. 28),
N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-2,2-bis(3 - methylphenyl)acetamide (Compound No. 29),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-N-methyl-2,2-bis(3-methylphenyl) acetamide (Compound No. 30), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-methoxy-2,2-diphenylacetamide (Compound No. 32),
N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-methoxy-2,2-diphenylacetamide (Compound
No. 33), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-methoxy-N-methyl-2,2- diphenylacetamide (Compound No. 34),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-3,3-diphenylpropanamide (Compound No. 36),
Tartarate salt of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-N-methyl-3,3- diphenylpropanamide (Compound No. 37),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-methoxy-N-methyl-2,2-diphenylacetamide (Compound No. 38),
N-3-Azabicyclo[3.1.0]hex-6-yl-2-methoxy-2,2-diphenylacetamide (Compound No. 39),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-methoxy-2,2-diphenylacetamide (Compound No. 40),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-methoxy-2-(4-methylphenyl)-2- phenylacetamide (Compound No . 41 ) ,
3-Azabicyclo[3.1.0]hex-6-ylmethyl diphenyl(propoxy)acetate (Compound No. 42),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-N-methyl-2,2-diphenyl-2-propoxyacetamide (Compound No. 43),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2,2-diphenyl-2-propoxyacetamide (Compound
No. 44),
2-Hydroxy-N-methyl-2,2-diphenyl-N-{ [3-(2-thienylmethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl} ace tamide (Compound No. 45), 3-Azabicyclo[3.1.0]hex-6-ylmethyl hydroxy[bis(4-methylphenyl)]acetate (Compound No. 46),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2,2-bis(4-fluorophenyl)-2-hydroxy-N- methylacetamide (Compound No. 47),
N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-N-methyl-2,2-bis(4- methylphenyl)acetamide (Compound No. 48),
N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-N-ethyl-2-hydroxy-2,2-diphenylacetamide (Compound No. 49) 2-Cyclohexyl-2-hydroxy-N-( { 3 -[(6-methylpyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6- yl}methyl)-2-phenylacetamide (Compound No. 50),
2-Cycloheptyl-2-hydroxy-2-phenyl-N-{ [3-(pyridin-2-ylmethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl Jacetamide (Compound No. 55), 2-Cyclopentyl-2-hydroxy-N-({3-[(6-methylpyridin-2-yl)methyl]-3-azabicyclo[3.1.0]hex- 6-yl}methyl)-2-phenylacetamide (Compound No. 56),
(3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclopentyl(hydroxy) phenylacetate (Compound No. 58),
(3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclohexyl(hydroxy) phenylacetate (Compound No. 59),
N-[(3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2-hydroxy-2- phenylacetamide (Compound No. 60),
N-[(3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclohexyl-2-hydroxy-2- phenylacetamide (Compound No. 61), (3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(diphenyl)acetate (Compound No. 62),
Tartarate salt of N-[(3-benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2- cyclohexyl-2-hydroxy-2-phenylacetamide (compound No. 63),
(2-Methyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl cyclohexyl(hydroxy)phenylacetate (Compound No. 64),
Tartarate salt of [3-(4-methylpent-3-en-l-yl)-3-azabicyclo[3.1.0]hex-6-yl]methyl cyclopentyl(hydroxy)phenylacetate (Compound No. 68),
Tartarate salt of [3-(l-phenylethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl cyclohexyl(hydroxy)phenylacetate (Compound No. 69), Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclobutyl-2- hydroxy-2-phenylacetamide (Compound No. 70),
2-Hydroxy-N-{ [3-(3-methylbut-2-en-l-yl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}-2,2- diphenylacetamide (Compound No. 71),
2-Hydroxy-N- { [3 -(4-methylpent-3 -en- 1 -yl)-3-azabicyclo [3.1.0]hex-6-yl]methyl } -2,2- diphenylacetamide (Compound No. 72),
2-Cycloheptyl-2-hydroxy-2-phenyl-N-{ [3-(pyridin-3-ylmethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl Jacetamide (Compound No. 73),
2-Cycloheptyl-2-hydroxy-2-phenyl-N-{ [3-(pyridin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl Jacetamide (Compound No. 74), 2-Cyclopentyl-2-hydroxy-N-[(3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2- phenylacetamide (Compound No. 75),
2-Cyclopentyl-2-hydroxy-2-phenyl-N-{ [3-(2-phenylethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl Jacetamide (Compound No. 76), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cycloheptyl-2 -hydroxy -2- phenylacetamide (Compound No. 77),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclohexyl-2-hydroxy-N-methyl-2- phenylacetamide (Compound No. 78),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2,2- diphenylacetamide (Compound No. 79),
N-{ [3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}-2-cyclohexyl- 2-hydroxy-2-phenylacetamide (Compound No. 80),
2-Cyclopentyl-2-hydroxy-2-phenyl-N-{ [3-(2-thienylmethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl Jacetamide (Compound No. 81), 2-Cyclohexyl-2-hydroxy-2-phenyl-N-{ [3-(2-phenylethyl)-3-azabicyclo[3.1.0]hex-6- yl] methyl Jacetamide (Compound No. 82),
N-( { 3 - [2-( 1 ,3 -Benzodioxol-5-yl)ethyl] -3 -azabicyclo [3.1.0]hex-6-yl }methyl)-2- cycloheptyl-2-hydroxy-2 -phenylacetamide (Compound No. 83),
2-Cycloheptyl-N-({3-[2-(2,3-dihydro-l-benzofuran-5-yl)ethyl]-3-azabicyclo[3.1.0]hex-6- yl}methyl)-2-hydroxy-2-phenylacetamide (Compound No. 84),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-3-methyl-2- phenylpentanamide (Compound No. 85),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2-methoxy-2- phenylacetamide (Compound No. 86), Tartarate salt of [3-(3-methylbut-2-en-l-yl)-3-azabicyclo[3.1.0]hex-6-yl]methyl cyclopentyl(hydroxy)phenylacetate (Compound No. 87),
[3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl cyclopentyl (hydroxy )phenylacetate (Compound No. 88),
Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclohexyl-2- hydroxy-N-methyl-2 -phenylacetamide (Compound No. 89),
Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl- 2,2-diphenylacetamide (Compound No. 90),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-3-cyclohexyl-2-hydroxy-2- phenylpropanamide (Compound No. 91), 2-Cyclopentyl-N-{ [3-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}-2- hydroxy-2-phenylacetamide (Compound No. 92),
N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-cyclohexyl-N-ethyl-2 -hydroxy -2- phenylacetamide(Compound No. 93), N-3-azabicyclo[3.1.0]hex-6-yl-2-cyclohexyl-N-ethyl-2 -hydroxy-2-phenylacetamide (Compound No. 94),
Tartarate salt of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclopentyl(hydroxy)2- thienylacetate (Compound No. 95),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-3,3,3-trifluoro-2-hydroxy-2- phenylpropanamide (Compound No. 96),
(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl 2-hydroxy-2-phenylpent-4-ynoate (Compound No. 97),
N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-2-phenylpent-4-ynamide (Compound No. 98), [3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicyclo [3.1.0] hex-6-yl]methyl cyclohexyl(hydroxy)phenylacetate (Compound No. 99),
2-Hydroxy-2,2-diphenyl-N-{ [3-(2-phenylethyl)-3-azabicyclo[3.1.0]hex-6-yl] methyl Jacetamide (Compound No. 100),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-3-methyl-2- phenylbutanamide (Compound No. 101),
N-( { 3 -[2-( 1 ,3 -Benzodioxol-5-yl)ethyl] -3 -azabicyclo[3.1.0]hex-6-yl } methyl)-2- cyclopentyl-2-hydroxy-N-methyl-2-phenylacetamide (Compound No. 102),
Tartarate salt of N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2- hydroxy-N-methyl-2-phenylacetamide (Compound No. 103), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-2- ylacetamide (Compound No. 104),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenyl-2- pyridin-3-ylacetamide (Compound No. 105),
2-Hydroxy-N-methyl-N-{ [3-(4-methylpent-3-en-l-yl)-3-azabicyclo[3.1.0]hex-6- yl]methyl}-2,2-diphenylacetamide (Compound No. 106),
N-( { 3 -[2-( 1 ,3 -Benzodioxol-5-yl)ethyl] -3-azabicyclo [3.1.0]hex-6-yl } methyl)-2-hydroxy-N- methyl-2,2-diphenylacetamide (Compound No. 107),
N-({3-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}methyl)-2- hydroxy-N-methyl-2,2-diphenylacetamide (Compound No. 108), N- { 3 -Azabicyclo [3.1.0]hex-6-ylmethyl } -N-methyl-2,2-diphenylpropanamide (Compound No. 109),
N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-N-methyl-2-phenylhex-4- enamide (Compound No. 110), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-3- ylacetamide (Compound No. Il l),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenylhex-4-enamide (Compound No. 112),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenyl-2- propoxyacetamide (Compound No. 113),
3-Azabicyclo[3.1.0]hex-6-ylmethyl (AE ά4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 114),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (AE ά4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 115), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (2R or2S)-hydmxy(A- methylphenyl)phenylacetate (Compound No. 116),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-2-ylacetate (Compound No. 117),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-3-ylacetate (Compound No. 118),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenylpropanamide (Compound No. 119), and re/t-butyl 6-({ [(4£)-2-hydroxy-2-phenylhex-4-enoyl]oxy}methyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (Compound No. 120).
Scheme Il
Figure imgf000016_0001
Formula I -ormula VII Formula VIII
deprotection
Figure imgf000016_0002
Formula IX
The compound of Formula IX can be prepared by following the procedure as depicted in, for example, Scheme II. Thus a compound of Formula II can be reacted with a compound of Formula VII (wherein Fi is mesyl, tosyl, triflyl or hal (Br, Cl or I); Q, Rw, n and P are the same as defined earlier) to give a compound of Formula VIII, which can undergo deprotection to give a compound of Formula IX.
The reaction of a compound of Formula II with a compound of Formula VII to give a compound of Formula VIII can be carried out in an organic solvent, for example, toluene or xylene in the presence of a base, for example, N-methylmorpholine, pyridine, triethylamine or diisopropylethylamine.
The deprotection of a compound of Formula VIII to give a compound of Formula IX can be carried out following the procedure as described, for example, for the synthesis of compound of Formula V from a compound of Formula IV in Scheme I.
Illustrative compounds which can be prepared following, for example, Scheme II include:
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)3-thienylacetate (Compound No. 4),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl methoxy(diphenyl)acetate (Compound No. 31), and 3-Azabicyclo[3.1.0]hex-6-ylmethyl methoxy(diphenyl)acetate (Compound No. 35).
Figure imgf000017_0001
The compounds of Formula XI can be prepared by following, for example, the reaction procedure as depicted in Scheme III. Thus a compound of Formula V can be reacted with a compound of Formula X (wherein P2 is -Omesyl or -Otosyl) to give a compound of Formula XI (wherein R1, R2, R3, Z, Q, Rw and n are the same as defined earlier), which can be deprotected to give a compound of Formula XII.
The reaction of a compound of Formula V with a compound of Formula X to give a compound of Formula XI can be carried out in an organic solvent, for example, acetonitrile, dichloromethane, carbon tetrachloride or chloroform, in the presence of a base, for example, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
The deprotection of a compound of Formula XI to give a compound of Formula XII can be carried out with a strong acid, for example, hydrochloric acid, trifluoroacetic acid, in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol, diethylether, tetrahydrofuran or dichloromethane.
Illustrative compounds which can be prepared following, for example, Scheme III include:
N-({ 3 -[(6-Aminopyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6-yl } methyl)-2- cyclopentyl-2-hydroxy-2-phenylacetamide (Compound No. 51),
N-({ 3-[(6-Aminopyridin-2-yl)methyl]-3-azabicyclo[3.1.0]hex-6-yl }methyl)-2-cyclohexyl- 2-hydroxy-2-phenylacetamide (compound No. 52), Tartarate salt of N-dS-tCo-aminopyridin^-y^methyll-S-azabicyclofS.l.OJhex-o- yl}methyl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide (compound No. 53),
Tartarate salt of N-dS-tCό-aminopyridin^-y^methyll-S-azabicyclotS.l.OJhex-ό- yl}methyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (Compound No. 54), N-( { 3 - [(6-Aminopyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6-yl } methyl)-2-hydroxy- 2,2-diphenylacetamide (Compound No. 57),
Terf-butyl (6-{ [6-({ [cyclohexyl(hydroxy)phenylacetyl]amino}methyl)-3-azabicyclo [3.1.0]hex-3-yl]methyl}pyridin-2-yl)carbamate (Compound No. 65),
Tert-buty\ (6-{ [6-({ [hydroxy(diphenyl)acetyl]amino}methyl)-3-azabicyclo[3.1.0]hex-3- yl]methyl}pyridin-2-yl)carbamate (compound no. 66), and
Terf-butyl (6-{ [6-({ [cyclopentyl(hydroxy)phenylacetyl]amino}methyl)-3- azabicyclo[3.1.0]hex-3-yl]methyl}pyridin-2-yl)carbamate (Compound No. 67).
In the above scheme, where specific bases, condensing agents, protecting groups, deprotecting agents, solvents, catalysts, temperatures, etc. are mentioned, it is to be understood that other bases, condensing agents, protecting groups, deprotecting agents, solvents, catalysts, temperatures, etc. known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs. Suitable salts of the compounds represented by the Formula I were prepared so as to solubilize the compound in aqueous medium for biological evaluations, as well as to be compatible with various dosage formulations and also to aid in the bioavailability of the compounds. Examples of such salts include pharmacologically acceptable salts such as inorganic acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic acid salts (for example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate). When carboxyl groups are included in the Formula I as substituents, they may be present in the form of an alkaline or alkali metal salt (for example, sodium, potassium, calcium, magnesium, and the like). These salts may be prepared by various techniques, such as treating the compound with an equivalent amount of inorganic or organic, acid or base in a suitable solvent.
Because of their valuable pharmacological properties, 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. The examples mentioned below demonstrate general synthetic procedures, as well as specific preparations of particular compounds. The examples are provided to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
EXPERIMENTAL
Various solvents, such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexanes, and dichloromethane, were dried using various drying reagents according to procedures described in the literature. IR spectra were recorded as nujol mulls or a thin neat film on a Perkin Elmer Paragon instrument, Nuclear Magnetic Resonance (NMR) were recorded on a Varian XL-300 MHz instrument using tetramethylsilane as an internal standard. General Procedure Synthesis of Ethyl phenyl (hydroxy)2-pyridylacetate
A solution of 2-bromo pyridine (3g, 18.98 mmol) in diethylether (50 ml) was cooled at - 78° C followed by the addition of n-butyl lithium. The reaction mixture was stirred at room temperature for 50 minutes. The resulting reaction mixture was added to a solution of ethyl oxo(phenyl)acetate (3.71 g, 20.88 mmol) in diethyl ether (50 ml) which was cooled at -78 0C. The reaction mixture was stirred at same temperature for 40 minutes which was subsequently warmed at room temperature. The mixture was stirred at room temperature for overnight, which was subsequently quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 12 % ethyl acetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 1.2 g.
Synthesis of cyclopentyl (hydroxy)2-thienylacetic acid Step a: Ethyl oxo(2-thienyl)acetate
A solution of thiophene (3 g, 35.65 mmol), ethyl oxalylchloride (4.86 g, 35.65 mmol) in dichloromethane (100 ml) was cooled in an ice bath to -5 0C. A suspension of aluminum chloride (4.75 g, 35.65 mmol) in dichloromethane (100 ml) was added dropwise over a period of IVi hour to the reaction mixture and stirred for 1 hour at room temperature. To it was added dilute hydrochloric acid (100 ml). The organic layer was separated, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 2 % ethyl acetate in hexane solvent mixture to furnish the title compound. Yield: 2.5 gm Step b: Ethyl cyclopentyl (hydroxy)2-thienylacetate
A solution of cyclopentyl bromide (2.91 g, 19.56 mmol) in tetrahydrofuran was added to a suspension of magnesium (0.46 g, 19.56 mmol) in tetrahydrofuran dropwise and stirred the reaction mixture at room temperature for 2 hour. The reaction mixture was cooled in an ice bath followed by the addition of a compound obtained from step a above (2.4 g, 13.043 mmol) diluted in tetrahydrofuran. The resulting reaction mixture was stirred for 1 hour in ice bath and then at room temperature for overnight. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 640 mg.
Step c: Cyclopentyl (hydroxy)2-thienylacetic acid
A solution of a compound obtained from step b above (640 mg) in ethanol (20 ml) and potassium hydroxide (13.513 mmol) was stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was diluted with water and extracted with dichloromethane. The aqueous layer was basified with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 20 % ethyl acetate in hexane solvent mixture to furnish the little compound. Yield: 400 mg. 1H NMR (CDCl3): 7.24-7.23 (m, IH), 7.16-7.15 (m, IH), 7.00-6.90 (m, IH), 3.3-2.82 (bs, IH), 2.70-2.62 (m, IH), 1.78-1.26 (m, 8H).
Analogs of cyclopentyl (hydroxy)2-theinylacetic acid described below, were prepared similarly. Hydroxy(phenyl)2-thienyl acetic acid
Hydroxy(phenyl)3-thienyl acetic acid
Hydroxy(di-2-thienyl) acetic acid
Hydroxy(4-methylphenyl)2-thienyl acetic acid
(4-Fluorophenyl)(hydroxy)phenyl acetic acid Hydroxy(4-methylphenyl)phenyl acetic acid Synthesis of hydroxy(di-4-methylphenyl) acetic acid and hvdroxy(di-4-fluorophenyl) acetic acid
The title compound was prepared following the procedure described in Journal of American Chemical Society, 1953, 75, pg. 2654-2657.
Synthesis of 2-cylobutyl-2-hvdroxy-2-phenyl acetic acid, 2-cylopentyl-2-hydroxy-2- phenyl acetic acid, 2-cylohexyl-2-hvdroxy-2 -phenyl acetic acid and 2-cyloheptyl-2- hydroxy-2-phenyl acetic acid
The title compounds were prepared following the procedure described in Journal of Organic Chemistry, 2000, 65, pg. 6283-6287.
Synthesis of 3-hydroxy-3,3-diphenyl propanoic acid Step a: Ethyl 3-hydroxy-3,3-diphenyl propanoate
To activated zinc dust (706 mg) was added a solution of benzophenone (2 g) and bromoethyl acetate (1 ml) in dry ether (5 ml) dropwise followed by the addition of a small crystal of iodine. The suspension was warmed to 40 0C for 3-4 hours followed by cooling it to 0 0C. To it was added sulphuric acid (10 %) and extracted with ethyl acetate. The combined organic layer was washed with sulphuric acid (10 %) water, brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 5 % ethyl acetate in hexane. Yield: 2.2 g.
Step b: 3-Hydroxy-3,3-diphenylpropanoic acid
To a cold of solution of the compound obtained from step a above (2.1 g) in methanol, was added aqueous solution of potassium hydroxide and warmed the resulting reaction mixture to room temperature and then refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was taken in water and washed with ethyl acetate. Aqueous layer was neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated under reduced pressure to furnish the title compound. Yield: 1.5 g. 1H NMR (DMSO-de): 7.45 (m, 4H), 7.27 (m, 4H), 7.16 (m, 2H), 3.27 (s, 2H); IR (KBr): 3478, 1687.8 cm"1; m.p: 217-2200C.
Synthesis of hvdroxy(2-hvdroxy-5-methylphenyl) phenyl acetic acid Step a: Ethyl [2-(benzyloxy)-5-methyl phenyl](hydroxy)phenylacetate.
A solution of l-(benzyloxy)-2-bromo-4-methylbenzene (2 g) in dry tetrahydrofuran (2 ml) was cooled to -78°C under nitrogen atmosphere followed by the addition of butyl lithium (6.73 ml) and stirred for 1 hour. To it was added a solution of ethyl oxo(phenyl) acetate (1.92 g) in dry tetrahydrofuran and stirred the reaction mixture for 1 hour at room temperature. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 2 % ethyl acetate in hexane solvent mixture to furnish the title compound. Yield: 2 g. Step b: [2-(Benzyloxy)-5-methylphenyl](hydroxy)phenyl acetic acid.
A solution of the compound obtained from step a above (2 g) in ethanol (10 ml) and potassium hydroxide (1.5 g) was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was diluted with water and extracted with dichloromethane. The aqueous layer was basified with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 20 % ethyl acetate in hexane solvent mixture to furnish the title compound. Yield: 500 mg.
Step c: Hydroxy (2-hydroxy-5-methylphenyl) phenyl acetic acid. To a solution of the compound obtained from step b above (500 mg) in methanol (25 ml), was added palladium on carbon (100 g, 10 %) under nitrogen atmosphere and anhydrous ammonium formate (450 mg) with constant stirring. The resulting reaction mixture was refluxed for 30 minutes followed by cooling it to room temperature. The reaction mixture was filtered through a bed of hyflo, washed with methanol, ethyl acetate and water. The filtrate was concentrated under reduced pressure. The residue thus obtained was diluted with water and pH of the resulting solution was adjusted to 14 with IN sodium hydroxide. It was extracted with ether. The aqueous layer was acidified and extracted with ethylacetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 320 mg.
1H NMR δ: 7.37 (m, 6H), 7.21-7.06 (m, 2H), 3.5 (bs, IH), 2.33 (s, 3H).
Synthesis of 3 -cyclohexyl-2-hydroxy-2 -phenyl propanoic acid Step a: Ethyl S-cyclohexyl-l-hydroxy-l-phenylpropanoate
To a solution of the compound ethyl mandalate (4 g) in tetrahydrofuran (20 ml), was added lithium diisopropyl amide (4 eq.) and stirred at -78 0C for 30 minutes. The reaction mixture was subsequently stirred at 0 0C for approximately 2 hours and then at room temperature for 1 hour. The reaction mixture was cooled to -78 0C and cyclohexylmethyl bromide (5.84 g) in tetrahydrofuran was added. The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for overnight. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound.
Yield = 2.55 g.
Step b: S-Cyclohexyl-l-hydroxy-l-phenylpropanoic acid
To a solution of the compound obtained from step a above (0.93 g) in methanol (5 ml) was added aqueous potassium hydroxide (10 ml) and stirred at room temperature for overnight. The solvent was concentrated under reduced pressure and the residue thus obtained was diluted with water and extracted with dichloromethane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to furnish the title compound. Yield = 780 mg. 1H NMR (CDCl3):δ 7.26 (m, 2H), 7.30 (m, 3H), 2.15 (m, IH), 1.98 (m, IH), 1.76 (m, IH), 1.61 (m, 2H), 1.25-0.93 (m, 5H); IR (KBr): 3435 and 1721 cm"1; m.p.: 138-139.5°C
The analog of 3-cyclohexyl-2-hydroxy-2-phenyl propanoic acid, described below was prepared similarly.
2-Hydroxy-2-phenylpent-4ynoic acid.
Synthesis of 2-chloromethyl-5-methyl pyridine hydrochloride To 2-hydroxymethyl-5-methyl-pyridine (123 mg, 1 mmol) in chloroform at 0 0C, thionyl chloride (2.5 mmol) was added slowly and stirred at 0 0C overnight. The solvent was evaporated under reduced pressure and the residue thus obtained was crystallized using hexane.
Synthesis of 3-benzyl-2-methyl-3-aza-bicyclor3.1.01-hex-6-yl methanol and 3-benzyl-2- methyl-3-aza-bicyclor3.1.01-hex-6-yl methylamine
The title compound was prepared following the procedure as described in EP 0413455A2
Synthesis of S-benzy-S-azabicvclorS.l.Olhex-ό-yl-amine The title compound was prepared following the procedure described in EP 0413455.
Synthesis of S-benzyl-S-azabicyclorS.l.Oihex-ό-yl-methyl amine
The title compound was prepared following the procedure described in EP 0413455, U.S. Patent No. 2,490,714 and Synlett. 1097-1102 (1996).
Synthesis of 3-benzyl-6-hvdroxymethyl-3-azabicyclo(3.1.0)hexane. The title compound was prepared following the procedure described in EP 0413455.
Synthesis of 2 -hydroxy -2,2-diphenyl acetic acid
The title compound was prepared following the procedure described in Vogel's text book of practical organic chemistry page 1046 (5th ED), /. Am. Chem. SoC175, 2654 (1953) and EP 613232.
Synthesis of methoxy (4-methylphenyl) phenylacetic acid Step a: Methyl methoxy (4-methylphenyl) phenyl acetate A solution of compound methyl hydroxy (4-methylphenyl) phenyl acetate (2.9 g) in dimethyl formamide (30 ml) was added dropwise to a suspension of sodium hydride (543 mg) in dimethylformamide (543 mg) at 0 0C and warmed the reaction mixture to room temperature. The reaction mixture was stirred for 1 hour, which was subsequently cooled to 0 0C followed by the addition of methyl iodide (0.85 ml). The reaction mixture was again stirred for 45 minutes at the 0 0C and then at room temperature for overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 10 % ethyl acetate in hexane solvent mixture to furnish the title compound. Yield: 2.1 g.
Step b: Methoxy(4-methyl phenyl) phenylacetic acid
Solution of the compound obtained from step a above (2.1 g) in methanol (50 ml) containing methanolic potassium hydroxide (40 %, 13 ml) was refluxed for 3 hours and then stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was diluted with water and washed with dichloromethane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. Yield: 1.5 g.
1H NMR δ: 7.47-7.16 (m, 9H), 3.13 (s, 3H), 2.36 (s, 3H). IR: 1713.3 cm-
Analogs of methoxy (4-methylphenyl) phenylacetic acid described below, were prepared similarly, Methoxy(diphenyl) acetic acid. Propoxy(diphenyl) acetic acid.
Synthesis of S-benzyl-N-ethyl-S-azabicvclorS.l.Olhexan-ό-amine
To a solution of tetrahydrofuran at -78 0C was added lithium aluminium hydride (0.76 g) followed by the addition of a solution of S-benzyl-N-acetyl-S-azabicycloP.l.OJhexan-ό- amine (2.3 g) in tetrahydrofuran. The reaction mixture was warmed to room temperature and then refluxed for overnight. The reaction mixture was cooled in dry ice-acetone bath and quenched by addition of methanol followed by aqueous ammonium chloride solution. The reaction mixture was warmed to room temperature and washed with ethyl acetate. The organic layer was concentrated and purified with column chromatography using dichloromethane in triethyl amine (99:1) as eluent.
1H NMR(CDCl3): δ 7.19-7.31 (m, 5H), 3.5 (s, 2H), 2.95 (d, J=9Hz, 2H), 2.65-2.73 (q, 2H), 2.47 (s, IH), 2.39 (d, J=9Hz, 2H), 1.29 (s, 2H), 1.06-1.11 (t, 3H).
Scheme I
EXAMPLE 1: Synthesis of N-(3-benzyl-3-azabicyclor3.1.01hex-6-yl)-2-hvdroxy-2- phenyl-2-(2-thienyl)acetamide (Compound No. 1)
A solution of hydroxy(phenyl)2-thienylacetic acid (0.35 g, 1.49 mmol) and 3-benzyl-3- azabicyclo[3.1.0]hexan-6-amine (0.308 g, 1.639 mmol) in dimethylformamide (5 ml) was cooled in an ice bath followed by the addition of hydroxybenzotriazole (0.22 g, 1.039 mmol) and N-methylmorpholine (0.301 g, 2.98 mmol). The resulting reaction mixture was stirred in ice bath for 1 hour. l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.284 g, 1.49 mmol) was added followed by stirring in ice bath for 1 hour and then at room temperature for overnight. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 30% ethylacetate in hexane solvent mixture as eluent. Yield = 460 mg.
1H NMR (CDCl3): δ 7.43-7.20 (m, HH), 6.95-6.94 (d, 2H), 6.24 (s, IH), 4.1 (bs, IH), 3.53 (s, 2H), 3.11-3.05 (m, 3H), 2.37-2.35 (m, 2H), 1.49 (m, 2H); IR (DCM): 1659.3 cm" \ rn.p.: 125-126.5°C
Analogs of N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-phenyl-2-(2- thienyl)acetamide (Compound No. 1) described below, were prepared similarly,
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2-phenyl-2-(2- thienvDacetamide (Compound No. 2) 1H NMR (CDCl3): δ 7.51-7.48 (m, 2H), 7.34-7.23 (m, 9H), 7.00-6.95 (m, 2H), 6.35 (bs, IH), 4.1 (bs, IH), 3.57 (s, 2H), 3.19-3.14 (m, 2H), 2.94-2.87 (m, 2H), 2.34-2.31 (m, 2H), 1.47 (m, IH), 1.32 (s, 2H).
N-(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)-2-hvdroxy-2-phenyl-2-(3-thienyl)acetamide (Compound No. 5)
1H NMR (CDCl3): δ 7.41-6.95 (m, 13H), 6.31 (s, IH), 3.8 (bs, IH), 3.55 (s, 2H), 3.13-3.08 (m, 3H), 2.40-2.37 (d, 2H), 1.42 (m, 3H); IR (DCM): 1658 cm"1.
N- [(3 -Benzyl-3-azabicvclo [3.1.01hex-6-yl)methyll -2-hydroxy-2-phenyl-2-(3 -thienyl) acetamide (Compound No. 6)
1H NMR (CDCl3): δ 7.46-6.99 (m, 13H), 6.39 (bs, IH), 4.01 (bs, IH), 3.59 (s, 2H), 3.18- 3.14 (m, 2H), 2.97-2.94 (m, 2H), 2.37-2.34 (m, 2H), 1.29-1.26 (m, 3H); IR (DCM): 1661 cm" . N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-N-methyl-2-phenyl-2-(3- thienvDacetamide (Compound No. 8)
1H NMR (CDCl3): δ 7.408-7.14 (m, 13H), 6.2 (bs, IH), 3.59 (s, 2H), 3.40 (m, 2H), 3.1 (m, 2H), 2.94 (m, 2H), 2.59 (s, 3H), 1.28 (m, 3H); IR (DCM): 1631 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2,2-di-2-thienylacetamide (Compound No. 10)
1H NMR (CDCl3): δ 7.32-7.17 (m, 6H), 6.97-6.8 (m, 5H), 6.01 (bs, IH), 4.8 (bs, IH), 3.59 (s, 2H), 3.19-3.11 (m, 2H), 2.97-2.87 (m, 2H), 2.37-2.34 (m, 2H), 1.302-1.26 (m, 3H); IR (DCM): 1663 cm"1.
N- [(3 -Benzyl-3 -azabicyclo [3.1.01hex-6-yl)methyll -2-hydroxy-N-methyl-2-phenyl-2-(2- thienvDacetamide (Compound No. 11)
1H NMR (CDCl3): δ 7.44-7.28 (m, 10H), 6.97-6.96 (m, 3H), 3.59 (s, 2H), 3.39 (m, 2H), 3.1 (m, 2H), 2.95 (m, 2H), 2.66 (s, 3H), 1.41 (m, 3H); IR (DCM): 1634 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclopentyl-2 -hydroxy -N-methyl-2- (2-thienyl)acetamide (Compound No. 12)
1H NMR (CDCl3): δ 7.28-7.21 (m, 6H), 7.015-7.007 (m, IH), 6.93-6.90 (m, IH), 5.76 (s, IH), 3.56 (s, 2H), 3.42-2.90 (m, 8H), 2.32 (m, 2H), 1.65-0.88 (m, 1 IH); IR (DCM): 1625 cm"1.
N-r(3-Benzyl-3-azabicyclor3.1.01hex-6-yl)methyll-2-hvdroxy-N-methyl-2-(4- methylphenyl)-2-(2-thienyl)acetamide (Compound No. 13) 1H NMR (CDCl3): δ 7.35-7.13 (m, 10H), 6.97-6.95 (m, 2H), 6.17 (bs, IH), 3.60-2.67 (m, HH), 2.34 (m, 5H), 1.23 (m, 3H); IR (DCM): 1633 cm"1. N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2-(4-methylphenyl)-2-(2- thienvDacetamide (Compound No. 16)
1H NMR (CDCl3): δ 7.38-6.94 (m, 12H), 6.37 (bs, IH), 3.59 (s, 2H), 3.18-3.14 (m, IH), 2.97-2.87 (m, 3H), 2.36-2.33 (m, 5H), 1.30-1.25 (m, 3H).
N-(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)-2-(4-fluorophenyl)-2-hvdroxy-2- phenylacetamide (Compound No. 20)
1H NMR (CDCl3): δ 7.40-7.20 (m, 12H), 6.98 (m, 2H), 6.38 (bs, IH), 3.55 (s, 2H), 3.13 (bs, IH), 3.10 (m, 2H), 2.38 (m, 3H), 1.48 (m, 2H); m/z: 417 (M++l).
N-(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)-2-hvdroxy-2-(4-methylphenyl)-2- phenylacetamide (Compound No. 21)
1H NMR (CDCl3): δ 7.40-7.12 (m, 14H), 6.31 (bs, IH), 3.79 (bs, IH), 3.57 (s, 2H), 3.11 (m, 3H), 2.41 (m, 2H), 2.33 (s, 3H), 1.50 (m, 2H); m/z: 413 (M++l).
^[(S-Benzyl-S-azabicvclorS.l.Olhex-ό-vDmethyll-S-hvdroxy-N-methyl-S.S- diphenylpropanamide (Compound No. 23)
1H NMR (CDCl3): δ 7.41-7.15 (m, 15H), 6.78 (bs, IH), 3.57 (m, 2H), 3.20 (m, 4H), 3.00 (m, 3H), 2.88 (m, 2H), 2.37-2.26 (m, 2H), 1.33-1.27 (m, 2H), 1.15 (m, IH); IR: 3331 and 1619 cm"1; m/z: 441.5 (M++l).
^[(S-Benzyl-S-azabicvclorS.l.Olhex-ό-vDmethyll-S-hvdroxy-S.S-diphenylpropanamide (Compound No. 24)
1H NMR (CDCl3): δ 7.42-7.15 (m, 15H), 5.8 (bs, IH), 3.59 (s, 2H), 3.08 (s, 2H), 2.95 (m, 4H), 2.32 (m, 2H); IR: 3320 and 1666 cm"1; m/z: 427.4 (M++l). N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2-(2-hvdroxy-5- methylphenvD-2-phenylacetamide (Compound No. 26)
1H NMR (CDCl3): δ 7.30 (m, HH), 7.05 (m, IH), 6.94 (m, IH), 6.82 (m, IH), 3.59 (s, 2H), 3.3-3.12 (m, 2H), 2.96 (m, 2H), 2.37 (m, 2H), 2.26 (s, 3H), 1.49 (m, IH), 1.33 (m, 2H); m/z: 443.3 (M++l); IR: 3400 and 1648 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2,2-bis(3-methylphenyl) acetamide (Compound No. 29)
1H NMR (CDCl3): δ 7.21 (m, 13H), 6.32 (bs, IH), 4.0 (bs, IH), 3.57 (s, 2H), 3.16 (m, 2H), 22..9933 ((mm,, 22HH))., 2.32 (m, 8H), 1.46 (m, IH), 1.28 (m, 2H); IR: 3403 and 1658.8 cm"1; m/z: 441 (M++l).
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-methoxy-2,2-diphenylacetamide (Compound No. 32) 1H NMR (CDCl3): δ 7.43 (m, 3H), 7.28 (m, 12H), 3.55 (s, 2H), 3.10 (m, 2H), 3.00 (s, 3H), 2 2..9933 ((mm,, 22HH)),, 22.31 (m, 2H), 1.43 (m, IH), 1.31 (m, 2H); IR: 3424 and 1674 cm"1; m/z: 427.4 (M++l).
N-(3-Benzyl-3-azabicyclor3.1.01hex-6-yl)-2-methoxy-2,2-diphenylacetamide (Compound No. 33)
1H NMR (CDCl3): δ 7.44-7.24 (m, 15H), 3.55 (s, 2H), 3.08 (m, 3H), 3.00 (s, 3H), 2.38 (m, 2H), 1.52 (m, 2H), 1.29 (m, IH); m/z: 413.4 (M++l); IR (KBr): 3338 and 1660 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-methoxy-N-methyl-2,2- diphenylacetamide (Compound No. 34)
1H NMR (CDCl3): δ 7.49 (m, 5H), 7.20 (m, 10H), 3.57 (s, 2H), 3.34 (m, 5H), 2.92 (m,
2 2HH)),, 22..S8i5 (s, 3H), 2.33 (m, 2H), 1.41 (m, 2H), 0.88 (m, IH); IR: 1641 cm"1; m/z: 441.5
(M++l). N-(3-benzyl-3-azabicvclor3.1.01hex-6-yl)-N-ethyl-2-hvdroxy-2,2-diphenylacetamide (Compound No. 49)
1H NMR (CDCl3): δ 7.31 (m, 15H), 6.09 (bs, IH), 3.50 (m, 2H), 3.06 (m, 5H), 2.40 (m, 2H), 1.60 (m, 4H), 1.30 (m, IH), 0.88 (m, IH); IR: 3358 and 1628 cm"1; m/z: 427 (M++l).
(3-Benzyl-2-methyl-3-azabicvclor3.1.01hex-6-yl)methyl cvclohexyl(hvdroxy) phenylacetate (Compound No. 59)
1HNMR (CDCl3): δ 7.65 (m, 2H), 7.29 (m, 8H), 4.2-3.86 (m, 3H), 3.71 (bs, IH), 3.13 (m, IH), 2.84 (m, IH), 2.68 (m, IH), 2.28 (m, 2H), 1.74-1.05 (m, 16H); MS: 434 (M++l). IR: 3509 and 1720 cm"1.
N-r(3-Benzyl-2-methyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclopentyl-2-hvdroxy-2- phenylacetamide (Compound No. 60)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.30 (m, 8H), 6.6 (bs, IH), 3.94 (m, IH), 3.5-3.2 (m, 2H), 3.15-2.8 (m, 5H), 2.5 (m, IH), 1.75-1.1 (m, 14H); IR (KBr): 3410 and 1655 cm"1.
N-r(3-Benzyl-2-methyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclohexyl-2-hvdroxy-2- phenylacetamide (Compound No. 61)
1HNMR (CDCl3): δ 7.59 (m, 2H), 7.46 (m, 4H), 7.29 (m, 4H), 7.08 (bs, IH), 4.10 (m, 2H), 3.50 (m, 2H), 3.07 (m, 3H), 2.39 (m, IH), 2.2 (m, IH), 2.0-1.75 (m, 7H), 1.45-1.1 (m, 8H), 0.88 (m, IH); IR (KBr): 3407 and 1656 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvcloheptyl-2 -hydroxy -2- phenylacetamide (Compound No. 77) 1HNMR (CDCl3): δ 7.59 (m, 2H), 7.30 (m, 8H), 6.65 (bs, IH), 3.58 (s, 2H), 3.10-2.91 (m, 6H), 2.62 (m, IH), 2.33 (m, 2H), 1.69-1.10 (m, HH); MS: 432 (M++l); IR: 3413 and 1654 cm"1. N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclohexyl-2-hvdroxy-N-methyl-2- phenylacetamide (Compound No. 78)
1HNMR (CDCl3): δ 7.28 (m, 10H), 4.02 (m, IH), 3.51-2.77 (m, 9H), 2.41 (m, 2H), 1.82- 1.1 (m, 13H); MS: 433 (M++l); IR: 3422 and 1621 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-N-methyl-2,2- diphenylacetamide (Compound No. 79)
1HNMR (CDCl3): δ 7.30 (m, 15H), 5.90 (bs, IH), 3.7-3.6 (m, 3H), 3.13-2.6 (m, 4H), 2.5 (m, 4H), 1.6-0.8 (m, 3H); MS: 427 (M++l); IR: 3355 and 1630 cm"1.
N- \(3 -Benzyl-3-azabicyclo [3.1.01hex-6-yl)methyll -2-hydroxy-3 -methyl-2- phenylpentanamide (Compound No. 85)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.30 (m, 8H), 6.66 (bs, IH), 3.59 (s, 2H), 3.09-2.91 (m, 4H), 2.48 (m, IH), 2.34 (m, 2H), 2.0 (bs, IH), 1.48 (m, IH), 1.38 (m, IH), 1.25 (m, 2H), 0.97 (m, 3H), 0.87 (m, 2H), 0.71 (m, 2H); MS: 393 (M++l); IR: 3407 and 1654 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclopentyl-2-methoxy-2- phenylacetamide (Compound No. 86)
1HNMR (CDCl3): δ 7.46 (m, 2H), 7.27 (m, 8H), 6.92 (bs, IH), 3.57 (s, 2H), 3.20-3.08 (m, 5H), 2.93 (m, 3H), 2.34 (m, 2H), 1.88-1.66 (m, 2H), 1.50 (m, 6H), 1.2 (m, 3H); MS: 419 (M++l); IR: 3425 and 1671 cm"1.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-3-cvclohexyl-2-hvdroxy-2- phenylpropanamide (Compound No. 91) 1HNMR (CDCl3): δ 7.57 (m, 2H), 7.33 (m, 8H), 6.62 (bs, IH), 3.61 (m, 2H), 3.08-2.97 (m, 5H), 2.38 (m, 2H), 2.20 (m, IH), 1.97 (m, IH), 1.77-1.4 (m, 7H), 1.27-0.98 (m, 7H).
MS: 433 (M++l); IR (KBr): 3409 and 1644 cm"1. N-(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)-2-cvclohexyl-N-ethyl-2 -hydroxy -2- phenylacetamide (Compound No. 93)
1HNMR (CDCl3): δ 7.62-6.81 (M, 1Oh), 3.63 (S, 2h), 3.37-2.44 (M, 9h), 1.78-1.05 (M, 15H).
N-r(3-benzyl-3-azabicyclor3.1.01hex-6-yl)methvH-3,3,3-trifluoro-2-hvdroxy-2- phenylpropanamide (Compound No. 96)
1HNMR (CDCl3): δ 7.63 (m, 2H), 7.40 (m, 3H), 7.27 (m, 5H), 3.58 (s, 2H), 3.16 (m, 2H), 2.93 (m, 2H), 2.35 (m, 2H), 1.42 (m, IH), 0.85 (m, 2H); MS: 405 (M++l); IR: 3417 and 1675 cm"1.
N-r(3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2-phenylpent-4-vnamide (Compound No. 98)
1HNMR (CDCl3): δ 7.63 (m, 2H), 7.38-7.23 (m, 8H), 6.22 (bs, IH), 3.56 (s, 2H), 3.10 (m, 2H), 2.9 (m, 2H), 2.31 (m, 2H), 1.97 (s, 2H), 1.38 (m, IH), 1.22 (m, 2H); MS: 375 (M++l); IR: 3401 and 1664 cm"1.
N-r(3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-3-methyl-2- phenylbutanamide (Compound No. 101) 1HNMR (CDCl3): δ 7.62-.59 (m, 2H), 7.35-7.21 (m, 8H), 6.87 (bs, IH), 3.89-3.86 (m, 2H).
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-N-methyl-2-phenyl-2- pyridin-3-ylacetamide (Compound No. 105) 1H NMR (CDCl3): δ 8.63-8.57 (2H, bd), 7.76 (IH, bs), 7.40-7.21 (HH, bs), 3.82 (2H, bm), 3.47 (2H, bm), 3.14 (2H, bs), 3.00 (IH, bs), 2.54 (3H, bs), 1.33 (2H, s), 0.88 (IH, bs); MS: 428 (M++l). N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-N-methyl-2-phenylhex-4- enamide (Compound No. 110)
1H NMR (CDCl3): δ 7.31 (1OH, bs), 5.61 (IH, m), 5.47 (IH, bm), 3.86-2.51 (15H, m), 1.68 (4H, bs); MS: 405 (M++l).
N- [(3 -Benzyl-3 -azabicvclo [3.1.01hex-6-yl)methyll -2-hydroxy-2-phenyl-2-pyridin-3 - ylacetamide (Compound No. I ll)
1H NMR (CDCl3): δ 8.70 (IH, s), 8.51 (IH, bs), 7.80 (IH, d, 4 Hz), 7.38-7.23 (HH, m), 6.70 (IH, bs), 3.57 (2H, bs), 3.15 (2H, m), 2.95 (2H, bs), 2.36 (2H, bs), 1.31 (2H, m), 0.88 (IH, bs); MS: 414 (M++l).
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-hvdroxy-2-phenylhex-4-enamide (Compound No. 112)
1H NMR (CDCl3): δ 7.62 (2H, d, 8Hz), 7.35-7.24 (8H, m), 6.81 (IH, bs), 5.66 (IH, m), 5.30 (IH, m), 3.60 (2H, s), 3.13-3.11 (IH, m), 3.03-2.99 (4H, m), 2.37 (IH, m), 2.2 (2H, bs), 1.68 (3H, d, 8Hz), 1.30-1.25 (3H, m); MS: 391 (M++l).
N- IY3 -Benzyl-3 -azabicvclo \3.1.01hex-6-yl)methyll -N-methyl-2.2-diphenyl-2- propoxyacetamide (Compound No. 113) 1H NMR (CDCl3): δ 7.50-7.48 (8H, bs), 7.33-7.15 (7H, m), 3.82 (2H, bs), 3.42-2.05 (1OH, m), 1.61 (2H, m), 1.26 (2H, s), 1.01 (2H, t, 8Hz), 0.86 (3H, t, 8Hz).
MS: 469 (M++l).
^[(S-Benzyl-S-azabicvclorS.l.Olhex-ό-vDmethyll-N-methyl^^-diphenylpropanamide (Compound No. 119) 1H NMR (CDCl3): δ 7.35- 7.28 (m, 15H, m), 3.65 (bs, IH), 3.49 (bs, IH), 3.32 (bs, IH), 3.02-3.00 (m, 2H), 2.66 (bs, IH), 2.34-2.22 (m, 5H), 1.88 (bs, 3H), 1.03 (m, 3H); MS: 425
(M++l).
EXAMPLE Ia: Synthesis of (3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyl hydroxy(phenyl)pyridin-2-ylacetate (Compound No. 117)
To the compound 3-benzyl-6-hydroxymethyl-3-azabicyclo(3.1.0)hexane (0.197 g, 1 eqi.) was added butyl lithium (0.062 g, 0.6 ml, 1 eqi.) at -78 0C and stirred the mixture for 30 minutes at the same temperature. To the resulting reaction mixture was added a solution of ethyl phenyl (hydroxy)2-pyridylacetate (0.25 g, 1 eqi.) in tetrahydrofuran (10 ml). The mixture was allowed to warm at room temperature and subsequently stirred at room temperature for overnight. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure using 40 % ethyl acetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 60 mg.
1H NMR (CDCl3): δ 8.55 (IH, m), 7.55 (IH, m), 7.42 (2H, d, 8Hz), 7.31 (IH, d, 8Hz), 7.33-7.23 (9H, m), 4.11-4.06 (2H, m), 3.56 (2H, s), 2.90 (2H, d, 8Hz), 2.7-2.8 (IH, m), 2.30 (2H, bd), 1.28 (3H, m); MS: 415 (M++l).
EXAMPLE Ib: Synthesis of N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2- hvdroxy-2-phenyl-2-pyridin-2-ylacetamide (Compound No. 1)
Diisobutyl aluminium (0.798g, 5.612mmol) was added to a solution of 3-benzyl-3- azabicyclo [3.1.0]hex-6-yl -methyl amine (1.179g, 5.836mmol) in tetrahydrofuran (2ml) precooled to 0 0C. The reaction mixture was allowed to warm to room temperature and stirred at the same for 2 hrs. The resulting reaction mixture was added to a solution of ethyl phenyl (hydroxy)2-pyridylacetate in tetrahydrofuran (2ml) under nitrogen at room temperature. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure and residue purified by column chromatography. Yield: 120 mg. 1H NMR (CDCl3): δ 7.8 (lH,bs), 7.71(1H, m), 7.50 (2H,d = 8 Hz), 7.28 (8H, bs), 6.96 (IH, bs), 3.56 (2H, s), 3.18-3.11 (2H, m), 2.94 (2H, t), 2.33 (2H, bs), 1.46 (IH, bs), 1.28 (2H, bs); MS: 414 (M++l).
EXAMPLE 2: Synthesis of (3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyl hydroxy(phenyl)2-thienylacetate (Compound No. 3)
A solution of the compound hydroxy(phenyl)2-thienylacetic acid (0.299 g), 3-benzyl-3- azabicyclo[3.1.0]hex-6-ylmethyl methane sulfonate (0.3 g, 1.067 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (0.32 g, 2.134 mmol) in toluene (15 ml) was refluxed for 6 hours and then stirred at room temperature for overnight. The reaction mixture was concentrated and the residue thus obtained was purified by column chromatography using 15% ethyl acetate in hexane solvent mixture to furnish the title compound. Yield = 280 mg.
1H NMR (CDCl3): δ 7.52-7.49 (m, 2H), 7.32-7.25 (m, 9H), 7.13-7.12 (m, IH), 6.98-6.95 (m, IH), 4.86 (s, IH), 4.14-4.10 (m, 2H), 3.68 (s, 2H), 3.01 (m, 2H), 2.52 (m, 2H), 1.29- 1.25 (m, 3H); IR (DCM): 1727 cm"1; m.p: 81.9-82.20C.
Analogs of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)2- thienylacetate (Compound No. 3) described below, were prepared similarly.
(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyl hvdroxy(4-methylphenyl)2-thienylacetate (Compound No. 14)
1H NMR (CDCl3): δ 7.40-6.94 (m, 12H), 4.45 (s, IH), 4.13-4.09 (m, 2H), 3.57 (s, 2H), 2.93-2.91 (m, 2H), 2.32 (m, 5H), 1.66 (m, IH), 1.33-1.30 (m, 2H).
(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyl hvdroxy(di-2-thienyl)acetate (Compound
No. 15) 1H NMR (CDCl3): δ 7.29-7.18 (m, 9H), 6.96-6.93 (m, 2H), 4.14-4.12 (m, 2H), 3.57 (s, 2H), 2.94-2.91 (d, 2H), 2.38-2.31 (m, 2H), 1.68 (m, IH), 1.34 (m, 2H).
(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyl 3-hydroxy-3,3-diphenylpropanoate (Compound No. 22)
1H NMR (CDCl3): δ 7.43-7.16 (m, 15H), 5.06 (bs, IH), 3.86 (d, J=9Hz, 2H), 3.60 (m, 2H), 3.27 (s, 2H), 2.93 (m, 2H), 2.33 (m, 2H), 1.5 (m, IH), 1.20 (m, 2H); IR (KBr): 3506 and 1707 cm"1; MS: 428.4 (M++l).
(3-Benzyl-2-methyl-3-azabicvclor3.1.01hex-6-yl)methyl cyclopentyl(hvdroxy) phenylacetate (Compound No. 58)
1HNMR (CDCl3): δ 7.67 (m, 2H), 7.27 (m, 8H), 4.02-3.85 (m, 3H), 3.75 (bs, IH), 3.14 (m, IH), 2.87 (m, 2H), 2.69 (m, IH), 2.29 (m, IH), 1.61-1.22 (m, HH), 1.07 (m, 3H); IR: 3510 and 1719 cm"1; MS: 420 (M++l).
(3-Benzyl-2-methyl-3-azabicvclor3.1.01hex-6-yl)methyl hydroxy(diphenyl)acetate (Compound No. 62)
1HNMR (CDCl3): δ 7.44 (m, 4H), 7.30 (m, HH), 4.28 (bs, IH), 4.17 (m, IH), 4.0 (m, IH), 3.88 (m, IH), 3.11 (m, IH), 2.84 (m, IH), 2.65 (m, IH), 2.27 (m, IH), 1.35 (m, IH), 1.22 (m, 2H), 1.04 (m, 3H); MS: 428 (M++l); IR: 3492 and 1723 cm"1.
(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyl 2-hydroxy-2-phenylpent-4-vnoate (Compound No. 97)
1HNMR (CDCl3): δ 7.55-7.2 (m, 10H), 3.88 (m, 2H), 3.57 (s, 2H), 2.98 (m, 2H), 2.35 (m, 2H), 2.05 (m, 2H), 1.91 (m, IH), 1.28 (m, 3H); IR: 1738 cm"1.
(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyl (AE or 4Z)-2-hydroxy-2-phenylhex-4- enoate (Compound No. 115) 1H NMR (CDCl3): δ 7.62 (2H, d, 8Hz), 7.35-7.23 (8H, m), 5.60 (IH, m), 5.44 (IH, m), 4.06 (IH, m), 3.94 (IH, m), 3.69 (IH, s), 3.57 (2H, s), 2.95-2.91 (3H, m), 2.6 (IH, m), 2.32 (2H, bs), 1.64 (3H, d, 6Hz), 1.32 (3H, bs).
(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyl (2R or 25")-hvdroxy(4- methylphenvDphenylacetate (Compound No. 116)
1H NMR (CDCl3): δ 7.44-6.96 (14H, m), 6.34 (IH, bs), 3.58 (2H, bs), 3.15 (2H, bm), 2.95 (2H, m), 2.34-2.22 (5H, bs), 1.27 (3H, bs); HPLC: (96.43% pure); MS: 428 (M++l).
(3-Benzyl-3 -azabic yclo [3.1.01hex-6-yl)methyl hydroxy(phenyl)p yridin-3 -ylacetate (Compound No. 118)
1H NMR (CDCl3): δ 8.72 (IH, s), 8.54 (IH, d, 4Hz), 7.8 (IH, d, 8Hz), 7.43 (2H, bs), 7.34- 7.23 (9H, m), 4.33 (IH, bs), 4.18-4.07 (2H, m), 3.57 (2H, s), 2.91 (2H, d, 8Hz), 2.31 (2H, d, 8Hz), 1.32 (3H, m); MS: 415 (M++l).
7e/t-butyl 6-({ [(4F)-2 -hydroxy -2 -phenylhex-4-enoyl1oxylmethyl)-3- azabicyclorS.l.Olhexane-S-carboxylate (Compound No. 120)
1H NMR (CDCl3): δ 7.62-7.60 (d, 2H), 7.38-7.30 (m, 3H), 5.62 (m, IH), 5.50 (m, IH), 4.07-4.08 (m, 2H), 3.68 (s, IH), 3.54 (m, IH), 3.43 (m, IH), 3.31 (m, 2H), 2.95 (m, IH), 2.70 (m, IH), 1.68 (m, 3H), 1.4 (s, 9H).
EXAMPLE 3: Synthesis of N-(3-azabicvclor3.1.01hex-6-ylmethyl)-2-hvdroxy-2,2-bis(3- methylphenvDacetamide (Compound No. 28)
To a solution of the Compound No. 29 (0.2Ig) in methanol (25.0 ml), was added palladium on carbon (50 mg, 10%) and anhydrous ammonium formate (0.15 g) with constant stirring. The resulting reaction mixture was refluxed for half an hour followed by cooling it to room temperature. The reaction mixture was filtered through a bed of hyflo, washed with methanol, ethylacetate and water. The filtrate was concentrated under reduced pressure. The residue thus obtained was diluted with water and pH of the resulting solution was adjusted to pH~14 with IN sodium hydroxide. The solution was extracted with ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 84 mg.
1H NMR (CDCl3): δ 7.20 (m, 8H), 6.6 (bs, IH), 3.3-3.03 (m, 6H), 2.40 (s, 6H), 1.5 (m, IH), 0.92 (m, 2H); m/z: 351 (M++l).
Analogs of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2 -hydroxy -2,2-bis(3-methylphenyl) acetamide (Compound No. 28) described below, were prepared by deprotecting appropriate benzylated compound, respectively, as applicable in each case.
N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-2-hvdroxy-2-phenyl-2-(2-thienyl)acetamide (Compound No. 18) 1H NMR (CDCl3): δ 7.51-7.48 (m, 2H), 7.36-7.30 (m, 4H), 7.02-6.96 (m, 2H), 6.61 (bs, IH), 3.23-3.12 (m, 2H), 2.93-2.75 (m, 5H), 1.28 (s, 2H), 0.79 (m, IH); m.p: 70-750C .
3-Azabicvclor3.1.01hex-6-ylmethyl hvdroxyrbis(3-methylphenyl)lacetate (Compound No.
27} 1H NMR (CDCl3): δ 7.27-7.13 (m, 8H), 4.17 (d, J=7.2Hz, 2H), 2.85 (m, 4H), 2.33 (s, 6H), 1.37 (m, 2H), 0.97 (m, IH); m/z: 352.3 (M++l); m.p.: 105-1080C.
N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-2-hvdroxy-N-methyl-2.2-bis(3- methylphenvDacetamide (Compound No. 30) 1H NMR (CDCl3): δ 7.20 (m, 8H), 3.48 (m, IH), 3.14 (m, IH), 2.95 (m, 3H), 2.59 (m, 4H), 2.36 (s, 6H); m/z: 365 (M++l). N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-3-hvdroxy-3,3-diphenylpropanamide (Compound
No. 36)
1H NMR (CDCl3): δ 7.44-7.18 (m, 10H), 3.15 (s, 2H), 2.98 (m, 2H), 2.86 (m, 2H), 2.70 ( (mm,, 22HH)),, 1.15 (m, 2H), 0.65 (m, IH); IR (KBr): 3337.9 and 1640.2 cm"1; m/z: 337.2 (M++l).
N-(3-azabicyclor3.1.01hex-6-ylmethyl)-2-methoxy-N-methyl-2,2-diphenylacetamide (Compound No. 38)
1H NMR (CDCl3): δ 7.57 (m, 4H), 7.44-7.28 (m, 6H), 3.58-3.38 (m, 4H), 3.12-2.84 (m,
66HH)),, 22..22:1 (m, 2H), 1.61 (m, 2H), 1.09 (m, IH); IR: 3421 and 1639.4 cm"1; m/z: 351.2
(M++l).
N-3-azabicvclor3.1.01hex-6-yl-2-methoxy-2,2-diphenylacetamide (Compound No. 39)
1H NMR (CDCl3): δ 7.42-7.18 (m, 10H), 3.18 (m, 2H), 3.05 (m, 5H), 2.54 (5.1H), 2.08 (m, 2H), 1.28 (m, 2H); m/z: 323.2 (M++l); IR: 3409 and 1666 cm"1.
N-(3-Azabicyclor3.1.01hex-6-ylmethyl)-2-methoxy-2,2-diphenylacetamide (Compound
No. 40)
1H NMR (CDCl3): δ 7.46-7.32 (m, 10H), 3.20 (m, 2H), 3.04 (s, 3H), 2.96 (m, 2H), 2.86 (m, 2H), 1.28 (m, 2H), 0.83 (m, IH); m/z: 337.2 (M++l); IR: 3419 and 1664.6 cm"1.
N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-2-methoxy-2-(4-methylphenyl)-2- phenylacetamide (Compound No . 41 )
1H NMR (CDCl3): δ 7.38 (m, 2H), 7.24 (m, 5H), 7.09 (m, 2H), 3.10 (m, 2H), 2.90 (m, 6H), 2.28 (m, 4H), 1.23 (m, 2H), 0.80 (m, IH); IR (KBr): 3423 & 1667 cm"1. 3-Azabicvclor3.1.01hex-6-ylmethyl diphenyl(propoxy)acetate (Compound No. 42)
1H NMR (CDCl3): δ 7.46 (m, 4H), 7.30 (m, 6H), 4.02 (m, 2H), 3.20 (m, 2H), 2.82 (m, 2H), 2.28 (m, 2H), 1.60 (m, 2H), 1.40 (m, IH), 1.27 (m, 2H), 0.90 (t, J=7.2Hz, 3H).
IR: 3423 and 1739 cm"1; m/z: 366 (M++l).
N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-N-methyl-2,2-diphenyl-2-propoxyacetamide (Compound No. 43)
1H NMR (CDCl3): δ 7.52 (m, 4H), 7.32-7.14 (m, 6H), 3.66-3.27 (m, 4H), 3.00-2.8 (m, 6H), 2.40 (m, IH), 1.77 (m, 2H), 1.39 (m, IH), 1.30 (m, 2H), 1.01 (m, 3H). IR: 3383 and 1643 cm"1; m/z: 379.1 (M++l).
N-(3-Azabicyclor3.1.01hex-6-ylmethyl)-2,2-diphenyl-2-propoxyacetamide (Compound
No. 44)
1H NMR (CDCl3): δ 7.45 (m, 4H), 7.31 (m, 8H), 3.21-3.14 (m, 2H), 3.03-2.88 (m, 5H), 22..3377 ((mm,, IIHH)),, 11..6633 ((:m, 2H), 1.30 (m, 3H), 0.93 (t, J=7.5Hz, 3H); IR: 3424 and 1674 cm" m/z: 365.2 (M++l).
3-Azabicyclor3.1.01hex-6-ylmethyl hydroxyrbis(4-methylphenyl)lacetate (Compound No. 461 1H NMR (CDCl3): δ 7.31 (d, J=8.0Hz, 4H), 7.13 (d, J=8.0Hz, 4H), 4.15 (d, J=7.2Hz, 2H), 2.85 (m, 4H), 2.34 (s, 6H), 1.37 (m, 2H), 0.96 (m, IH); m/z: 352.1 (M++l).
N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-2,2-bis(4-fluorophenyl)-2-hvdroxy-N- methylacetamide (Compound No. 47) 1H NMR (CDCl3): δ 7.35 (m, 4H), 7.07 (m, 4H), 3.46 (m, 1.5H), 3.12-2.56 (m, 8.5H), 1.45 (m, 2H), 0.99 (m, IH). N-(3-Azabicvclor3.1.01hex-6-ylmethyl)-2-hvdroxy-N-methyl-2.2-bis(4- methylphenvDacetamide (Compound No. 48)
1H NMR (CDCl3): δ 7.25-7.15 (m, 8H), 3.44 (m, IH), 3.10-2.95 (m, 3H), 2.61-2.54 (m, 3H), 2.35 (s, 6H), 2.00 (m, 2H), 1.50 (m, IH), 0.9 (m, 2H); m/z: 365 (M++l).
(2-Methyl-3 -azabic vclo [3.1.01hex-6-yl)methyl cyclohexyl(hvdroxy)phenylacetate (Compound No. 64)
1HNMR (CDCl3): δ 7.65 (m, 2H), 7.33 (m, 3H), 4.15-3.96 (m, 3H), 3.29 (m, IH), 3.06- 2.92 (m, 2H), 2.4 (m, IH), 2.21 (m, 2H), 1.8-1.0 (m, 10H).
N-3-Azabicyclor3.1.01hex-6-yl-2-cvclohexyl-N-ethyl-2-hvdroxy-2-phenylacetamide (Compound No. 94)
1HNMR (CDCl3): δ 7.41-7.16 (m, 5H), 3.37-3.23 (m, IH), 3.20-3.07 (m, 2H), 2.94-2.91 (m,2H), 2.43 (m, IH), 2.24 (m, IH), 1.80-1.26 (m, 16H).
N- { 3 -Azabicvclo [3.1.Olhex-6-ylmethyl } -N-methyl-2,2-diphenylpropanamide (Compound
No. 109)
1H NMR (CDCl3): δ 7.37-7.14 (1OH, bs), 2.32 (2H, bs), 1.80 (4H, bs), 1.60 (IH, bs), 1.33 (8H, bs), 0.88 (IH, bs); MS: 335 (M++l).
EXAMPLE 4: Synthesis of 2-hvdroxy-N-r(3-methyl-3-azabicvclor3.1.01hex-6- vDmethyll -2 -phenyl -2-(2-thienyl)acetamide (Compound No. 19)
To a solution of the Compound No. 17 (0.2 g, 0.609 mmol) in acetonitrile containing formaldehyde (3 ml), was added sodium cyanoborohydride (0.192 g, 3.0487 mmol) and stirred the reaction mixture at room temperature for 3 hours. It was neutralized with acetic acid and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was diluted with water, basified to pH~14 and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated & under reduced pressure to furnish the title compound. The residue thus obtained was purified by column chromatography using 5% methanol in dichloromethane and 1% ammonium solvent mixture to furnish the title compound. Yield: 120 mg. 1H NMR (CDCl3): 7.51-7.36 (m, 2H), 7.36-7.26 (m, 4H), 7.06-6.98 (m, 2H), 6.46 (bs, IH), 3.19-3.14 (m, 2H), 2.96-2.93 (m, 2H), 2.29-2.17 (m, 6H), 1.39 (m, 3H).
Analogs of 2-hydroxy-N-[(3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-phenyl-2-(2- thienyl)acetamide (Compound No. 19) described below, were prepared by using appropriate amine in place of Compound No. 17 and appropriate aldehyde in place of formaldehyde.
(3-Methyl-3-azabicvclor3.1.01hex-6-yl)methyl hvdroxy(3-methylphenyl)phenylacetate (Compound No. 25) 1H NMR (CDCl3):δ 7.47-7.12 (m, 9H), 4.10 (d, J=6Hz, 2H), 2.98 (m, 2H), 2.31 (m, 8H), 1.59 (m, IH), 1.3 (m, 2H); MS: 352.2 (M++l); IR (KBr): 3424 and 1735 cm"1.
2-Hvdroxy-N-methyl-2.2-diphenyl-N-( r3-(2-thienylmethyl)-3-azabicvclor3.1.01hex-6- yll methyl I acetamide (Compound No. 45) 1H NMR (CDCl3): δ 7.38-7.22 (m, HH), 6.94-6.88 (m, 2H), 3.85-3.67 (m, 2H), 3.43 (m, IH), 3.14-2.00 (m, 8H), 1.00 (m, 3H); m/z: 433 (M++l).
2-Cvclopentyl-2-hvdroxy-N-r(3-methyl-3-azabicvclor3.1.01hex-6-yl)methyll-2- phenylacetamide (Compound No. 75) 1HNMR (CDCl3): δ 7.60 (m, 2H), 7.31 (m, 3H), 6.40 (bs, IH), 3.24 (bs, IH), 3.05 (m, 3 3HH)),, 22..9933 ((mm,, 22HH)), 2.24 (m, 5H), 1.70-1.55 (m, 9H), 1.24 (2H); IR: 3411 and 1658 cm" MS: 329 (M++1). 2-Cvclopentyl-2-hvdroxy-2-phenyl-N-{ r3-(2-thienylmethyl)-3-azabicvclor3.1.01hex-6- yll methyl lacetamide (Compound No. 81)
1H NMR (CDCl3): δ 7.60 (m, 2H), 7.36-7.19 (m, 4H), 6.92 (m, IH), 6.85 (m, IH), 6.42 (bs, IH), 3.77 (s, 2H), 3.18 (bs, IH), 3.07-2.95 (m, 4H), 2.36 (m, 2H), 1.9-1.75 (m, 7H), 1.30 (m, 4H), 0.89 (m, IH); IR: 3412 and 1654 cm"1; MS: 411 (M++l).
EXAMPLE 5: Synthesis of 2-cyclohexyl-2-hvdroxy-N-({3-r(6-methylpyridin-2- yl)methyll-3-azabicvclor3.1.01hex-6-yl|methyl)-2-phenylacetamide (Compound No. 50)
Step a: 2-(Bromomethyl)-6-methylpyridine To a solution of the compound (6-methylpyridine-2-yl)methanol (2 g) (commercially available) in carbon tetrachloride (40 ml), was added phosphorous bromide (2.2 g) dropwise and stirred the reaction mixture at 800C for 3 hours and then at room temperature for overnight. It was quenched with water and 10% sodium hydroxide solution. The solvent was evaporated under reduced pressure and the aqueous layer was extracted with dichloromethane. The organic layer was collected and washed with 10% sodium hydroxide solution, water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 10% ethyl acetate in hexane to furnish the title compound.
Yield = 1.7 g. Step b: 2-Cyclohexyl-2-hydroxy-iV-({3-[(6-methyl pyridin-2-yl)methyl]-3-azabicyclo [3.1.0]hex-6-yl}methyl)-2-phenyl acetamide
To a solution of the compound N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2- hydroxy-2-phenyl acetamide (disclosed in WO 04/005252) (200 mg) in dry acetonitrile (10 ml), was added 2-(bromomethyl)-6-methylpyridine (136 mg), potassium carbonate (337 mg) and potassium iodide (101 mg) and stirred the mixture 50-600C for 3 hours. The reaction mixture was stirred for overnight and quenched by addition of water and ethyl acetate. The organic layer was separated dried over anhydrous sodium sulphate, evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 2% dichloromethane in methanol to furnish the title compound. Yield = 124 mg.
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.53 (m, IH), 7.36-7.22 (m, 3H), 7.11 (m, IH), 6.99 (m, IH), 6.67 (bs, IH), 3.69 (s, 2H), 3.08-2.94 (m, 4H), 2.52 (s, 3H), 2.40 (m, 3H), 1.7-1.1 (m, 1 IH), 0.9 (m, 2H); MS: 434 (M++l).
Analogs of 2-cyclohexyl-2-hydroxy-N-({ 3-[(6-methylpyridin-2-yl)methyl]-3- azabicycloP.l.OJhex-ό-ylJmethyl^-phenylacetamide (Compound No. 50) described below were prepared by condensing appropriate amide or ester with an halo compound, respectively, as applicable in each case.
2-Cvcloheptyl-2-hvdroxy-2-phenyl-N-{ r3-(pyridin-2-ylmethyl)-3-azabicvclor3.1.01hex-6- yll methyl I acetamide (Compound No. 55)
1HNMR (CD3OD): δ 8.66 (m, IH), 8.08 (m, IH), 7.8 (m, IH), 7.64 (m, IH), 7.30 (m, 5H), 4.98 (m, 2H), 4.17 (m, IH), 3.80 (m, IH), 3.10 (m, 2H), 2.66 (m, IH), 2.33 (m, IH), 1.96- 0.8 (m, 16H); IR (KBr): 3406 and 1653 cm"1; MS: 434 (M++l).
2-Cvclopentyl-2-hvdroxy-N-({3-r(6-methylpyridin-2-yl)methyll-3-azabicvclor3.1.01hex- 6-yl|methyl)-2-phenylacetamide (Compound No. 56) 1HNMR (CDCl3): δ 7.62 (m, 2H), 7.54 (m, IH), 7.34 (m, 2H), 7.27 (m, IH), 7.12 (m, IH), 7.00 (m, IH), 6.44 (bs, IH), 3.69 (s, 2H), 3.20 (bs, IH), 3.10-2.95 (m, 5H), 2.52 (s, 3H), 2.40 (m, 2H), 1.70-1.2 (m, HH); MS: 420 (M++l).
2-Hvdroxy-N-{ r3-(3-methylbut-2-en-l-yl)-3-azabicvclor3.1.01hex-6-yllmethyl}-2,2- diphenylacetamide (Compound No. 71)
1HNMR (CDCl3): δ 7.25 (m, 10H), 6.79 (bs, IH), 5.32 (bt, IH), 3.96 (m, IH), 3.51 (m, 4H), 3.12 (m, 2H), 3.0 (m, IH), 1.69-1.44 (m, 7H), 0.76 (m, 2H); MS: 391 (M++l); IR: 3408 and 1660 cm"1. 2-Hvdroxy-N-{ r3-(4-methylpent-3-en-l-yl)-3-azabicvclor3.1.01hex-6-yllmethyl}-2,2- diphenylacetamide (Compound No. 72)
1HNMR (CDCl3): δ 7.36 (m, 10H), 6.93 (bs, IH), 4.98 (m, IH), 3.82 (m, 2H), 3.24 (m, 22HH)),, 22..99(0 (m, 3H), 2.55 (m, 2H), 1.70 (m, 10H); IR: 3406 and 1659 cm"1; MS: 405
(M++l).
2-Cvcloheptyl-2-hvdroxy-2-phenyl-N-{ r3-(pyridin-3-ylmethyl)-3-azabicvclor3.1.01hex-6- yli methyl lacetamide (Compound No. 73) 1HNMR (CD3OD): δ 8.44 (m, 2H), 7.76 (m, 2H), 7.6 (m, 2H), 7.20 (m, 3H), 5.47 (bs, IH), 3 3..7700 ((mm,, 22HH)),, 22..99C0 (m, 4H), 2.53 (m, 3H), 1.53-1.28 (m, 15H); IR: 3441 and 1644 cm" MS: 434 (M++l).
2-Cvcloheptyl-2-hvdroxy-2-phenyl-N-{ r3-(pyridin-4-ylmethyl)-3-azabicvclor3.1.01hex-6- yll methyl lacetamide (Compound No. 74)
1HNMR (CDCl3): δ 8.52 (m, 2H), 7.60 (m, 2H), 7.30 (m, 5H), 6.69 (bs, IH), 3.57 (m, 2H), 3 3..00--22..99 ((mm,, 55HH)),, 22.6 (m, IH), 2.34 (m, 3H), 1.85-1.6 (m, HH); IR: 3417 and 1650 cm" MS: 434 (M++l).
2-Cvclopentyl-2-hvdroxy-2-phenyl-N-{ r3-(2-phenylethyl)-3-azabicvclor3.1.01hex-6- yll methyl lacetamide (Compound No. 76)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.37-7.15 (m, 8H), 6.42 (bs, IH), 3.21 (bs, IH), 3.05 (m, 5H), 2.65 (m, 4H), 2.30 (m, 2H), 1.72-1.56 (m, 9H), 1.25 (m, 2H).
N-{ r3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicvclor3.1.01hex-6-yllmethyl|-2-cvclohexyl- 2-hydroxy-2-phenylacetamide (Compound No. 80)
1HNMR (CD3OD): δ 7.58 (m, 2H), 7.25 (m, 3H), 6.88 (m, 3H), 5.99 (s, 2H), 4.41 (s, 2H), 4.09 (m, 2H), 3.3-3.2 (m, 3H), 3.04 (m, 2H), 2.5 (m, IH), 1.68 (m, 6H), 1.25 (m, 7H). 2-Cvclohexyl-2-hvdroxy-2-phenyl-N-{ r3-(2-phenylethyl)-3-azabicvclor3.1.01hex-6- yll methyl lacetamide (Compound No. 82)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.29 (m, 8H), 6.88 (bs, IH), 3.41 (m, 2H), 3.14-2.92 (m, 7H), 2.69 (m, 2H), 2.41 (m, IH), 1.78-0.88 (m, 13H); MS: 433 (M++l); IR: 3409 and 1652 cm"1.
N-((3-r2-(1.3-Benzodioxol-5-yl)ethyll-3-azabicvclor3.1.01hex-6-yl}methyl)-2- cvcloheptyl-2-hvdroxy-2-phenylacetamide (Compound No. 83) 1HNMR (CDCl3): δ 7.60 (m, 2H), 7.30 (m, 4H), 6.95 (bs, IH), 6.69 (m, 2H), 5.93 (s, 2H), 3.50 (m, 2H), 3.15-2.64 (m, 9H), 1.71-1.11 (m, 14H), 0.88 (m, 2H); IR (KBr): 3407 and 1650 cm"1; MS: 491 (M++l).
2-Cvcloheρtyl-N-({3-r2-(2,3-dihvdro-l-benzofuran-5-yl)ethyll-3-azabicvclor3.1.01hex-6- yl}methyl)-2-hvdroxy-2-phenylacetamide (Compound No. 84)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.33 (m, 3H), 7.05 (m, IH), 7.01 (bs, IH), 6.91 (m, IH), 6.69 (m, IH), 4.54 (t, 2H, J=8.7Hz), 3.48 (m, 2H), 3.2-2.9 (m, 8H), 2.74-2.63 (m, 3H), 1.75-1.0 (m, 15H); MS: 489 (M++l); IR: 3413 and 1654 cm"1.
2-Cvclopentyl-N-{ r3-(cvclopropylmethyl)-3-azabicvclor3.1.01hex-6-yllmethyl|-2- hydroxy-2-phenylacetamide (Compound No. 92)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.32 (m, 3H), 6.42 (bs, IH), 3.23 (bs, IH), 3.05 (m, 4H), 2.27 (m, 4H), 1.88 (m, IH), 1.71-1.50 (m, 6H), 1.3-1.23 (m, 5H), 0.8 (m, IH), 0.45 (m, 2H), 0.06 (m, 2H); IR: 3414 and 1660 cm"1; MS: 368 (M++l).
r3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicvclor3.1.01hex-6-yllmethyl cvclohexyl(hvdroxy)phenylacetate (Compound No. 99) 1HNMR (CDCl3): δ 7.65 (m, 2H), 7.30 (m, 3H), 6.70 (m, 3H), 5.94 (s, 2H), 4.10 (m, IH), 3.93 (m, IH), 3.71 (bs, IH), 3.47 (s, 2H), 2.90 (m, 2H), 2.29 (m, 3H), 1.75 (m, IH), 1.64- 1.12 (m, 12H); IR (cm 1); 3507, 1720 cm"1; m/z: 463 (M++l).
2-Hvdroxy-2,2-diphenyl-N-{ r3-(2-phenylethyl)-3-azabicvclor3.1.01hex-6- yll methyl I acetamide (Compound No. 100)
1HNMR (CDCl3): δ 7.46-7.16 (m, 15H), 3.82-3.78 (m,2H), 3.28-3.22 (m, 6H), 3.01-2.95 (m, 2H), 1.26-1.11 (m, 3H).
N-( { 3 -\2-( 1 ,3 -benzodioxol-5-yl)ethyll -3 -azabicvclo \3.1.Olhex-6-yl } methyl)-2- cyclopentyl-2-hvdroxy-N-methyl-2-phenylacetamide (Compound No. 102)
1HNMR (CDCl3): δ 7.35-7.24 (m, 5H), 6.72-6.66 (m, 3H), 5.91 (s, 2H), 3.08-2.38 (m, 15H), 1.94-1.25 (m, HH).
2-Hvdroxy-N-methyl-N-{ r3-(4-methylpent-3-en-l-yl)-3-azabicvclor3.1.01hex-6- vHmethyl|-2,2-diphenylacetamide (Compound No. 106)
1HNMR (CDCl3): δ 7.43-7.31 (1OH, bm), 5.86 (IH, bs), 5.30 (IH, bs), 3.76-3.65 (2H, m), 3.46 (2H, d, 8Hz), 3.10 (IH, bs), 2.88 (3H, bs), 2.63 (3H, s), 2.53-2.43 (4H, m), 2.04 (IH, s), 1.70 (3H, s), 1.66 (3H, s); MS: 419 (M++l).
N-({3-r2-(l,3-Benzodioxol-5-yl)ethyll-3-azabicvclor3.1.01hex-6-yl}methyl)-2-hvdroxy-N- methyl-2,2-diphenylacetamide (Compound No. 107)
1HNMR (CDCl3): δ 7.39-7.33 (1OH, bs), 6.73-6.62 (3H, m), 5.92 (2H, s), 3.15-2.18 (13H, m), 1.11 (2H, s); MS: 485 (M++l).
N-((3-r2-(2.3-Dihvdro-l-benzofuran-5-yl)ethyll-3-azabicvclor3.1.01hex-6-yl}methyl)-2- hydroxy-N-methyl-2,2-diphenylacetamide (Compound No. 108) 1HNMR (CDCl3): δ 7.43-7.33 (bs, 10H), 7.05 (IH, s), 6.92 (IH, d, 8Hz), 6.70 (IH, d, 8Hz), 5.97 (IH, bs), 4.54 (2H, t, 8Hz), 3.46-2.44 (15H, m), 2.05 (IH, s), 1.26 (2H, m).
MS: 483 (M++l).
Scheme II
EXAMPLE 6: Synthesis of ((3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyl methoxy(diphenyl)acetate (Compound No. 31)
The title compound was synthesized following the procedure as described in Example 2, by using 3-benzyl-6-(bromomethyl)-3-azabicyclo[3.1.0]hexane in place of 3-benzyl-3- azabicyclo[3.1.0]hex-6-ylmethyl methane sulfonate and using methoxy (diphenyl acetic acid) in place of hydroxy (phenyl) 2-thienylacetic acid. Yield: 290 mg.
1H NMR (CDCl3): δ 7.46 (m, 4H), 7.28 (m, HH), 4.03 (d, J=7.5Hz, 2H), 3.54 (s, 2H), 3.17 (s, 3H), 2.84 (m, 2H), 2.27 (m, 2H), 1.30 (m, 2H), 0.88 (m, IH).
The analogs of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl methoxy(diphenyl) acetate (Compound No. 31) described below, were prepared by coupling appropriate acid with halogenated compound, respectively, as applicable in each case.
(3-benzyl-3-azabicyclor3.1.Olhex-6-vDmethyl hydroxy(phenyl)3-thienylacetate (Compound No. 4)
1H NMR (CDCl3): δ 7.48-7.14 (m, 13H), 4.31 (s, IH), 4.15-4.07 (m, 2H), 3.59 (s, 2H), 2.95-2.92 (d, 2H), 2.35-2.33 (d, 2H), 1.34 (bs, 3H); IR (DCM): 1727 cm"1.
EXAMPLE 7: Synthesis of 3-azabicyclor3.1.01hex-6-ylmethyl methoxy(diphenyl) acetate (Compound No. 35)
The title compound was prepared by following the procedure as described in Example 3, by deprotecting Compound No. 31 in place of Compound No. 29. Yield: 126 mg. 1H NMR (CDCl3): δ 7.48-7.33 (m, 10H), 4.11 (d, J=7.2Hz, 2H), 3.18 (s, 3H), 2.83 (m, 4H), 1.30 (m, 2H), 0.9 (m, IH); IR: 3423 and 1736 cm"1; MS: 338 cm"1.
EXAMPLE 8: Synthesis of 3-azabicvclor3.1.01hex-6-ylmethyl (AE or 4Z)-2-hvdroxy-2- phenylhex-4-enoate (Compound No. 114)
To a solution of the Compound No. 120 (022 g) in methanol (5 ml) was added etheral hydrochloric acid (10 ml) and stirred the mixture at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue thus obtained was diluted with water. The aqueous layer was washed with diethyl ether to remove the impurities. The aqueous layer was basified with aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 60 mg.
1HNMR (CDCl3): δ 7.62 (2H, t, 8Hz), 7.37-7.29 (3H, m), 5.62 (IH, m), 5.42 (IH, m), 4.07 (2H, d, 4Hz), 2.97-2.86 (5H, m), 2.68 (IH, m), 1.67 (3H, d, 4Hz), 1.39-1.00 (3H, m); MS:
302 (M++l).
Scheme III
EXAMPLE 9: Synthesis of tert-butγ\ (6-{ \6-(\ rcvclohexyl(hvdroxy)phenylacetyll amino}methyl)-3-azabicyclor3.1.01hex-3-yllmethyl}pyridin-2-yl)carbamate (Compound No. 65) Step a: 6-(Methoxycarbonyl)pyridine-2-carboxylic acid
To a suspension of pyridine-2,6-dicarboxylic acid (20 g) in aqueous methanol (1:1, 200 ml) at 00C, was added concentrated sulphuric acid (10 ml) dropwise under constant stirring. The mixture was warmed to room temperature and refluxed for 15 minutes. The contents of the reaction mixture were poured into saturated sodium bicarbonate solution and extracted with dichloromethane. The aqueous layer was acidified with concentrated hydrochloric acid (pH=2) and extracted with dichloromethane. The organic layer was combined and evaporated under reduced pressure to furnish the title compound. Yield =
7.2 g.
Step b: Methyl δ-fCtert-butoxycarbony^aminoJpyridine-l-ylJcarboxylate
To a solution of the compound obtained from step a above (5.9 g) in toluene (100 ml), was added triethyl amine (9 ml), hydroxybenzotriazole (20 ml) and diphenylphosphoric azide (12.5 g). The mixture was treated at 1000C for overnight and subsequently cooled to room temperature. The reaction mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 10% ethylacetate in hexane solvent mixture as eluent to furnish the title compound. Yield = 3.8 g.
Step c: Tert-butyl [6-(hydroxymethyl)pyridin-2-yl]carbamate]
The compound obtained from step b above (3.8 g) was dissolved in ethanol (75 ml) and calcium chloride (3.34 g) was added. The mixture was cooled to 00C followed by the addition of sodium cyanoborohydride (2.98 g) slowly. The reaction mixture was stirred for 2 hours at 00C. The solvent was evaporated under reduced pressure and the residue thus obtained was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, evaporated under reduced pressure to furnish the title compound. Yield = 3.4 g. Step d: {6-[(tert-butoxycarbonyl)amino]pyridin-2-yl}methyl methanesulfonate
To a solution of the compound obtained from step c above (3.4 g) in ethyl acetate (80 ml) at 00C, was added triethyl amine (7.4 ml) and methane sulphonyl chloride (3.5 ml) and stirred the mixture for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound. Yield = 3.4g.
Step e: Tert-butyl (6-{[6-Cyclohexyl(hydroxy)phenylacetyl]amino}methyl)-3- azabicyclofS.l.OJhex-S-ylJmethyllpyridin-l-y^carbamate To a solution of the compound N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2- hydroxy-2-penylacetamide (disclosed in WO 04/005252) (1.19 g) in acetonitrile (30 ml), was added the compound obtained from step d above (1.32 g) and potassium carbonate
(2 g). The reaction mixture was stirred for overnight at room temperature. The solvent was evaporated under reduced pressure and the residue thus obtained was partitioned between ethylacetate and water. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield = 1.08 g. 1H NMR (CDCl3): δ 7.76 (m, IH), 7.59 (m, 3H), 7.36-7.22 (m, 3H), 6.92 (m, IH), 6.66 (bs, IH), 3.56 (s, 2H), 3.07 (m, IH), 2.93 (m, 4H), 2.36 (m, 3H), 1.70 (m, 5H), 1.51 (s, 9H), 1.37-1.16 (m, 5H), 0.91 (m, 3H); Mass (m/z): 535 (M++l).
Analogs of tert-butyl (6-{ [6-({ [cyclohexyl(hydroxy)phenylacetyl]amino} methyl)-3-azabicyclo[3.1.0]hex-3-yl]methyl }pyridin-2-yl)carbamate
(Compound No. 65) described below were prepared by using appropriate acid in place of cyclohexyl(hydroxy)phenylacetic acid, respectively, as applicable in each case.
Tert-butγ\ (6-{ \6-(\ rhvdroxy(diphenyl)acetyllamino|methyl)-3-azabicvclor3.1.01hex-3- yllmethyl|pyridin-2-yl)carbamate (compound no. 66)
1HNMR (CDCl3): δ 7.78-7.57 (d, IH, J = 8.4Hz), 7.62-7.59 (t, IH, J = 7.8 Hz), 7.44-7.31 (m, 10H), 6.94-6.92 (d, IH, J = 7.2Hz), 6.36 (bs, IH), 3.5 (s, 2H), 3.18-3.14 (t, 2H), 2.98 (m, 2H), 2.40 (m, 2H), 2.04 (s, IH), 1.47 (s, 9H), 1.29-1.24 (m, 2H).
Tert-batγ\ (6-{ \6-({ rcvclopentyl(hvdroxy)phenylacetyllamino|methyl)-3- azabicvclor3.1.01hex-3-yllmethyl}pyridin-2-yl)carbamate (Compound No. 67) 1HNMR (CDCl3): 57.78-7.75 (d, IH, 9Hz), 7.61-7.56 (m, 3H), 7.36-7.25 (m, 3H), 6.94- 6.91 (d, IH, J = 9Hz), 3.456 (s, 2H), 3.22 (bs, IH), 3.07-2.92 (m,5H), 2.37-2.35 (m, 2H), 1.72-1.24 (m, 19H).
EXAMPLE 10: Synthesis of N-((3-r(6-aminopyridin-2-yl)methyl1-3- azabicyclor3.1.Olhex-6-yl |methyl)-2-cvclohexyl-2-hvdroxy-2-phenylacetamide (Compound No. 52)
A solution of the Compound No. 65 (140 mg) and methanolic hydrochloric acid (10 ml) was stirred for overnight at room temperature. The solvent was evaporated under reduced pressure and the residue thus obtained was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and evaporated under reduced pressure to furnish the title compound. Yield = 105 mg.
1HNMR (CDCl3): δ 7.61 (m, 2H), 7.32 (m, 5H), 7.0 (m, IH), 4.20 (m, 2H), 3.5-3.35 (m, 3H), 3.12 (m, 2H), 2.39 (m, IH), 1.96 (m, IH), 1.76-1.64 (m, 5H), 1.2 (m, 6H), 0.9 (m, 2H); MS: 435 (M++l).
Analogs of N-({3-[(6-aminopyridin-2-yl)methyl]-3-azabicyclo[3.1.0]hex-6-yl}methyl)-2- cyclohexyl-2-hydroxy-2-phenylacetamide (Compound No. 52) described below were prepared similarly.
N-({3-r(6-aminopyridin-2-yl)methyll-3-azabicvclor3.1.01hex-6-yl|methyl)-2-cvclopentyl- 2-hydroxy-2-phenylacetamide (Compound No. 51)
1HNMR (CDCl3): δ 7.60 (m, 2H), 7.30 (m, 4H), 6.63 (m, IH), 6.45 (bs, IH), 6.35 (m, IH), 4.73 (bs, 2H), 3.53 (s, 2H), 3.03 (m, 5H), 2.37 (m, 2H), 1.71-1.23 (m, HH); MS: 421
(M++l).
N-({3-r(6-aminopyridin-2-yl)methyll-3-azabicvclor3.1.01hex-6-yl|methyl)-2-hvdroxy-2,2- diphenylacetamide (Compound no. 57). 1HNMR (CDCl3): δ 7.40 (m, HH), 6.64 (m, IH), 6.36 (m, 2H), 4.39 (bs, 2H), 3.53 (s, 2H), 3.15 (m, 2H), 3.01 (m, 2H), 2.38 (m, 2H), 1.29 (m, 3H); MS: 429 (M++l).
EXAMPLE 11: Synthesis of tartarate salt of N-(3-azabicvclor3.L01hex-6-ylmethyl)-3- hydroxy-N-methyl-3,3-diphenylpropanamide (Compound No. 37)
Step a: N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-N-methyl-3,3-diphenyl propionamide
The title compound was prepared following the procedure as described in Example 3, by using compound (Compound No. 23) in place of (Compound No. 29). Yield: 249 mg.
Step b: Tartarate salt of Λ^3-azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-iV-methyl- 3,3-diphenylpropanamide
A solution of the compound obtained from step a above (249 mg) and tartaric acid (106g) in ethanol (5ml) were heated at 60-700C for 40 minutes. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was triturated with ether. The etheral layer was decanted off and the residue thus obtained was dried under reduced pressure. Yield: 90 mg.
1H NMR (CDCl3): 7.39 (m, 4H), 7.28-7.15 (m, 6H), 4.35 (s, 2H), 3.37-3.21 (m, 7H), 3.04 (m, 3H), 2.84 (m, IH), 1.55 (m, 2H), 0.9 5 (m, IH). IR (KBr): 3447.2 and 1615.3 cm"1.
The analogs of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-N-methyl-3,3- diphenylpropanamide (Compound No. 37) described below, were prepared similarly.
N-r(3-Benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclopentyl-2-hvdroxy-2-(2- thienvDacetamide (Compound No. 7) 1H NMR (CDCl3): δ 7.31-7.21 (m, 6H), 7.08-7.07 (m, IH), 6.97-6.94 (m, IH), 6.35 (bs, IH), 3.69 (s, IH), 3.57 (s, 2H), 3.10-3.06 (m, 2H), 2.94-2.82 (m, 2H), 2.79 (m, IH), 2.33- 2.31 (m, 2H), 1.63-1.25 (m, HH); IR (KBr): 1657 cm"1
Tartarate salt of N-(3-benzyl-3-azabicyclor3.1.01hex-6-yl)-2-cyclopentyl-2-hvdroxy-2-(2- thienvDacetamide (Compound No. 9)
1H NMR (CDCl3): δ 7.29-7.17 (m, 6H), 7.06-7.04 (m, IH), 6.97-6.94 (m, IH), 6.3 (bs, IH), 3.64 (bs, IH), 3.54 (s, 2H), 3.09-3.02 (m, 3H), 2.80-2.75 (m, IH), 2.37-2.35 (d, 2H), 1.63-1.28 (m, 10H); IR (DCM): 1655 cm"1.
Tartarate salt of N-(3-azabicyclor3.1.01hex-6-ylmethyl)-2-cvclopentyl-2-hvdroxy-2-(2- thienvDacetamide (Compound No. 17)
1H NMR (CDCl3): δ 7.33-7.22 (m, 6H), 7.08-7.07 (m, IH), 6.97-6.94 (m, IH), 6.51 (bs, IH), 5.09 (s, 2H), 3.62-3.4 (m, 3H), 3.22-3.12 (m, 4H), 2.87-2.82 (m, IH), 1.64-1.25 (m, 10H), 0.79 (m, IH).
Tartarate salt of N-({3-r(6-aminopyridin-2-yl)methyll-3-azabicvclor3.1.01hex-6- yl|methyl)-2-cvclopentyl-2-hydroxy-2-phenylacetamide (compound No. 53)
1HNMR (DMSOd6): δ 7.58 (m, 2H), 7.30 (m, 4H), 6.44 (m, IH), 6.33 (m, IH), 5.91 (bs, 2H), 4.19 (s, 2H), 3.5 (m, 5H dried under water in DMSO peaks), 3.0 (m, 4H), 1.52-1.23 (m, HH); HPLC: 91.41% (24.7 min).
Tartarate salt of N-(13-r(6-aminopyridin-2-yl)methyll-3-azabicvclor3.1.01hex-6- yl}methyl)-2-cvclohexyl-2-hvdroxy-2-phenylacetamide (Compound No. 54) 1HNMR (CD3OD): δ 7.64-7.53 (m, 3H), 7.35-7.21 (m, 3H), 6.82 (m, IH), 6.67 (m, IH), 4.57 (s, 2H), 4.04 (s, 2H), 3.36 (m, 4H), 3.18-3.0 (m, 5H), 2.4 (m, IH), 1.76-1.6 (m, 5H), 1.20 (m, 8H); HPLC: 95.12% (12.6 min.). Tartarate salt of N-r(3-benzyl-2-methyl-3-azabicvclor3.1.01hex-6-yl)methyll-2- cyclohexyl-2-hvdroxy-2-phenylacetamide (Compound No. 63)
1HNMR (CD3OD): δ 7.53 (m, 2H), 7.35-7.13 (m, 8H), 4.35 (s, 2H), 4.24 (m, 2H), 3.89 (m, IH), 3.51-3.41 (m, 4H), 3.10 (m, 2H), 2.34 (m, IH), 1.62-1.40 (m, 6H), 1.28-0.80 (m, 8H); HPLC: 97.07% (16.5 min).
Tartarate salt of r3-(4-methylpent-3-en-l-yl)-3-azabicyclor3.1.01hex-6-yllmethyl cvclopentyl(hydroxy)phenylacetate (Compound No. 68)
1HNMR (DMSOd6): δ 7.65 (m, 2H), 7.34 (m, 3H), 5.7 (bs, IH), 5.11 (bt, IH), 4.25 (s, 2H), 4.07-3.0 (peaks superceded by DMSO-H2O peaks), 2.6 (m, 2H), 2.19 (m, IH), 1.72- 1.26 (m, 1OH); IR (KBr): 3322 and 1722 cm"1.
Tartarate salt of r3-(l-phenylethyl)-3-azabicvclor3.1.01hex-6-yl1methyl cvclohexyl(hvdroxy)phenylacetate (Compound No. 69) 1HNMR (DMSO-de): δ 7.56 (m, 2H), 7.28 (m, 8H), 5.50 (bs, IH), 4.25 (s, 2H), 4.0-3.0 (peaks superscripted by H2O in DMSO peaks), 2.13 (m, 3H), 1.55-1.03 (m, 14H); IR (KBr): 3485 and 1723 cm"1.
Tartarate salt of N-r(3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclobutyl-2- hydroxy-2-phenylacetamide (Compound No. 70)
1HNMR (CD3 OD): δ 7.40 (m, 2H), 7.30 (m, 5H), 7.12 (m, 3H), 4.32 (s, 2H), 4.04 (s, 2H), 3.35 (m, IH), 3.20 (m, 4H), 2.98 (m, 2H), 2.04-1.6 (m, 7H), 1.20 (m, 2H); HPLC: 98.73 (12.9 min).
Tartarate salt of r3-(3-methylbut-2-en-l-yl)-3-azabicvclor3.1.01hex-6-yllmethyl cvcloρentyl(hvdroxy)phenylacetate (Compound No. 87) 1HNMR (CD3OD): δ 7.62 (m, 2H), 7.30 (m, 3H), 5.25 (m, IH), 4.40 (s, 2H), 4.03 (m, 2H), 3.70 (m, 2H), 3.35 (m, 4H), 2.98 (m, IH), 1.81-1.74 (m, 8H), 1.60 (m, 5H), 1.40 (m, 4H);
IR: 3319 and 1724 cm"
Tartarate salt of [3-(l J-benzodioxol-S-ylmethvD-S-azabicyclorS.l.Oihex-ό-ylimethyl cyclopentyl(hvdroxy)phenylacetate (Compound No. 88)
1HNMR (CD3OD): δ 7.60 (m, 2H), 7.29 (m, 2H), 7.21 (m, IH), 6.88 (m, 3H), 5.99 (s, 2H), 4.42 (s, 2H), 4.05-3.97 (m, 3H), 3.33-3.17 (m, 5H), 3.0 (m, IH), 1.72-1.26 (m, HH); IR (KBr): 3484 and 1723 cm"1.
Tartarate salt of N-r(3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclohexyl-2- hydroxy-N-methyl-2-phenylacetamide (Compound No. 89)
1HNMR (CD3OD): δ 7.43-7.21 (m, 10H), 4.43 (s, 2H), 4.21 (m, 2H), 3.4-3.1 (m, 7H), 2.88 (m, 2H), 2.26 (m, IH), 1.86-1.73 (m, 3H), 1.61 (m, 2H), 1.36-0.95 (m, 8H); IR (KBr): 3424, 1735 and 1617 cm"1; MS: 433 (M++l).
Tartarate salt of N-IY3 -benzyl-3 -azabic yclo [3.1.01hex-6-yl)methyll -2-hydroxy-N-methyl- 2,2-diphenylacetamide (Compound No. 90)
1HNMR (CD3OD): δ 7.35 (m, 5H), 7.19 (m, 10H), 4.32 (s, 2H), 4.17-4.10 (m, 2H), 3.30 (m, 3H), 3.20 (m, 4H), 2.87 (m, IH), 2.76 (m, 2H), 1.74 (m, IH), 1.3 (m, IH), 1.2 (m, IH); IR: 3424, 1735 and 1625 cm"1.
Tartarate salt of (3-benzyl-3-azabicyclor3.1.01hex-6-yl)methyl cyclopentyl(hvdroxy)2- thienylacetate (Compound No. 95) 1HNMR (CD3OD): δ 7.37 (m, 5H), 7.21 (m, IH), 7.07 (m, IH), 6.89 (m, IH), 4.38 (s, 2H), 4.02 (m, 4H), 3.15 (m, 4H), 2.81 (m, IH), 1.68-1.4 (m, HH). Tartarate salt of N-r(3-benzyl-3-azabicvclor3.1.01hex-6-yl)methyll-2-cvclopentyl-2- hydroxy-N-methyl-2-phenylacetamide (Compound No. 103)
1H NMR (CD3OD): δ 7.46-7.21 (m, 1OH), 4.49 (s, 2H), 4.29 (m, 2H), 3.5-3.0 (m, 6H), 2.83 (m, 4H), 1.83 (m, 2H), 1.52-1.28 (m, 9H); IR (KBr): 3422, 1736 and 1619 cm"1.
EXAMPLE 12: Radioligand Binding Assays:
The affinity of test compounds for M1, M2 and M3 muscarinic receptor subtypes was determined by [3H]-N-methylscopolamine binding studies using rat heart and submandibular gland respectively as described by Moriya et al., {Life Sci.,
1999, 64(25): 2351-2358) with minor modifications. In competition binding studies, specific binding of [3H] NMS was also determined using membranes from Chinese hamster ovary (CHO) cells expressing cloned human M1, M2, M3, M4 and M5 receptors. Selectivities were calculated from the Ki values obtained on these human cloned membranes.
Membrane preparation: Submandibular glands and heart were isolated and placed in ice- cold homogenizing buffer (HEPES 2OmM, 1OmM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenized in 10 volumes of homogenizing buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 500 g for 10 min. The supernatant was subsequently centrifuged at 40,000 g for 20 min. The pellets thus obtained were resuspended in assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -70 C until the time of assay.
Ligand binding assay: The compounds were dissolved and diluted in DMSO. The membrane homogenates (150-250 μg protein) were incubated in 250 μl of assay volume (HEPES 20 mM, pH 7.4) at 24-25 °c for 3 h. Non-specific binding was determined in the presence of 1 μM atropine. The incubation was terminated by vacuum filtration over GF/B fiber filters(Wallac). The filters were then 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 G Pad Prism software. The value of inhibition constant K1 was calculated from competitive binding studies by using Cheng & Prusoff equation (Biochem Pharmacol, 1973,22: 3099-3108), Ki = IC50 /(1+L/Kd), where L was the concentration of
[3H]NMS used in the particular experiment, pki is -log [Ki].
Functional Experiments using isolated rat bladder: Methodology:
Animals were euthanized by overdose of thiopentone and whole bladder was isolated and removed rapidly and placed in ice cold Tyrode buffer with the following composition (mMol/L) NaCl 137; KCl 2.7; CaCl2 1.8; MgCl2 0.1; NaHCO3 11.9; NaH2PO4 0.4; Glucose 5.55 and continuously gassed with 95 % O2 and 5 % CO2.
The bladder was cut into longitudinal strips (3 mm wide and 5-6 mm long) and mounted in 10 ml organ baths at 30 0C, 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 m 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 lμmol/L of Carbachol until a reproducible response was 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.
The contractile results were expressed as % of control E max. ED50 values were calculated by fitting a non-linear regression curve (Graph Pad Prism). pKb values are were where, dose ratio = ED50 in the presence of antagonist/ED50 in the absence of antagonist.
Compounds specifically described herein displayed Ki for rat M3 receptors of between about 1000 and about 0.1 nM, for example, between about 200 and about 0.1 nM, or for example between about 50 and about 0.1 nM, or for example between about 15 and about 0.1 nM, or for example between about 8 and about 0.1 nM, or for example between about 1 and about 0.1 nM. Compounds specifically described herein displayed Ki for rat M2 receptors of between about 1000 and about 0.15 nM, for example, between about 200 and about 0.15 nM, or for example between about 50 and about 0.15 nM, or for example between about 15 and about 0.15 nM, or for example between about 8 and about 0.15 nM, or for example between about 1 and about 0.15 nM. Based on such measurements, the compounds described herein displayed selectivity (Ki for rat M3 receptors/Ki for rat M2 receptors) of between about 0.3 and about 310, for example between about 10 and about 310, or for example between about 30 and about 310, or for example between about 60 and about 310.
Particular compounds (Nos. 51, 53, 54, 58-60, 63, 68-70, 80, 87-90, 99 and 103) were tested for pKb, and gave values from about 7.4 to about 8.6.
Particular compounds (Nos. 2-4, 6-8, 10-12, 14-19, 25, 27, 35, 95, 104-106, 108, 110-112, 114-115, and 117-118) displayed Ki for human M3 receptors of between about 113 and about 0.03 nM, for example, between about 15 and about 0.03 nM, or for example between about 7 and about 0.03 nM, or for example between about 0.5 and about 0.03 nM, or for example between about 0.15 and about 0.03 nM. Particular compounds (Nos. 105, 110-112, 114 and 115) displayed Ki for rat M2 receptors of between about 760 and about 24 nM, for example, between about 550 and about 24 nM, or for example between about 100 and about 24 nM, or for example between about 50 and about 24 nM. Based on such measurements, the compounds described herein displayed selectivity (Ki for human M3 receptors/Ki for human M2 receptors) of between about 1.8 and about 140, for example between about 7 and about 140, or for example between about 40 and about 140.

Claims

WE CLAIM 1. A compound having the structure of Formula I
Figure imgf000062_0001
Formula I and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein Ri is hydrogen or alkyl; R2 is straight or branched alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heteroaryl wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heteroaryl are optionally substituted with one or more substituents selected from alkyl, hydroxy or halogen. R3 is aryl or heteroaryl wherein the said aryl or heteroaryl are optionally substituted with one or more groups selected from alkyl, hydroxy or halogen; W = -(CHz)1; Q = -(CH2)j ; X is oxygen or -N(Rs)-; R4 is hydrogen, straight or branched alkyl, straight or branched alkenyl, aralkyl or heteroarylalkyl wherein the said aralkyl or heteroarylalkyl is further substituted with alkyl, -NH2 or alkoxycarbonylamino; R5 is hydrogen or alkyl; Rw is H or methyl; and n, i, j are integer from 0-2. 2. A compound selected from the group consisting of
N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-phenyl-2-(2-thienyl)acetamide (Compound No. 1), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-(2- thienyl)acetamide (Compound No. 2), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)2-thienylacetate (Compound No. 3), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)3-thienylacetate (Compound No. 4), N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-phenyl-2-(3-thienyl)acetamide (Compound No. 5), N- [(3-Benzyl-3-azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-2-phenyl-2-(3 - thienyl)acetamide (Compound No. 6), Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2- hydroxy-2-(2-thienyl)acetamide (Compound No. 7), N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-N-methyl-2-phenyl-2-(3 - thienyl)acetamide (Compound No. 8), Tartarate salt of N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-cyclopentyl-2-hydroxy-2-(2- thienyl)acetamide (Compound No. 9), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2,2-di-2-thienylacetamide (Compound No. 10), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenyl-2-(2- thienyl)acetamide (Compound No. 11), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2 -hydroxy -N-methyl-2- (2-thienyl)acetamide (Compound No. 12), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-(4- methylphenyl)-2-(2-thienyl)acetamide (Compound No. 13), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(4-methylphenyl)2-thienylacetate (Compound No. 14), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(di-2-thienyl)acetate (Compound No. 15), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-(4-methylphenyl)-2-(2- thienyl)acetamide (Compound No. 16), Tartarate salt of N-(3 -azabicyclo [3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-(2- thienyl)acetamide (Compound No. 17), N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2-phenyl-2-(2-thienyl)acetamide (Compound No. 18), 2-Hydroxy-N-[(3-methyl-3-azabicyclo[3.L0]hex-6-yl)methyl]-2-phenyl-2-(2- thienyl)acetamide (Compound No. 19), N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-(4-fluorophenyl)-2-hydroxy-2- phenylacetamide (Compound No. 20), N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-hydroxy-2-(4-methylphenyl)-2- phenylacetamide (Compound No. 21), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl 3-hydroxy-3,3-diphenylpropanoate (Compound No. 22), N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -3-hydroxy-N-methyl-3 ,3- diphenylpropanamide (Compound No. 23), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-3-hydroxy-3,3-diphenylpropanamide (Compound No. 24), (3 -Methyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl hydroxy (3 -methylphenyl)phenylacetate (Compound No. 25), N- [(3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)methyl] -2-hydroxy-2-(2-hydroxy-5- methylphenyl)-2 -phenylacetamide (Compound No. 26), 3-Azabicyclo[3.1.0]hex-6-ylmethyl hydroxy [bis(3-methylphenyl)]acetate (Compound No. 27), N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-bis(3-methylphenyl)acetamide (Compound No. 28), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2,2-bis(3- methylphenyl)acetamide (Compound No. 29), N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-N-methyl-2,2-bis(3-methylphenyl) acetamide (Compound No. 30), (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl methoxy(diphenyl)acetate (Compound No. 31), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-methoxy-2,2-diphenylacetamide (Compound No. 32), N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-methoxy-2,2-diphenylacetamide (Compound No. 33), N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-methoxy-N-methyl-2,2- diphenylacetamide (Compound No. 34), 3-Azabicyclo[3.1.0]hex-6-ylmethyl methoxy(diphenyl)acetate (Compound No. 35). 71 N-^-AzabicycloP.l.OJhex-ό-ylmethy^-S-hydroxy-S^-diphenylpropanamide (Compound
72 No. 36),
73 Tartarate salt of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-3-hydroxy-N-methyl-3,3-
74 diphenylpropanamide (Compound No. 37),
75 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-methoxy-N-methyl-2,2-diphenylacetamide
76 (Compound No. 38),
77 N-3-Azabicyclo[3.1.0]hex-6-yl-2-methoxy-2,2-diphenylacetamide (Compound No. 39),
78 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-methoxy-2,2-diphenylacetamide (Compound
79 No. 40),
80 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-methoxy-2-(4-methylphenyl)-2-
81 phenylacetamide (Compound No . 41 ) ,
82 3-Azabicyclo[3.1.0]hex-6-ylmethyl diphenyl(propoxy)acetate (Compound No. 42),
83 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-N-methyl-2,2-diphenyl-2-propoxyacetamide
84 (Compound No. 43),
85 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2,2-diphenyl-2-propoxyacetamide (Compound
86 No. 44),
87 2-Hydroxy-N-methyl-2,2-diphenyl-N-{ [3-(2-thienylmethyl)-3-azabicyclo[3.1.0]hex-6-
88 yl] methyl Jacetamide (Compound No. 45),
89 3-Azabicyclo[3.1.0]hex-6-ylmethyl hydroxy[bis(4-methylphenyl)]acetate (Compound No.
90 46),
91 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2,2-bis(4-fluorophenyl)-2-hydroxy-N-
92 methylacetamide (Compound No. 47),
93 N-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-N-methyl-2,2-bis(4-
94 methylphenyl)acetamide (Compound No. 48),
95 N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-N-ethyl-2-hydroxy-2,2-diphenylacetamide
96 (Compound No. 49)
97 2-Cyclohexyl-2-hydroxy-N-( { 3 -[(6-methylpyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6-
98 yl}methyl)-2 -phenylacetamide (Compound No. 50),
99 N-( { 3 - [(6-Aminopyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6-yl } methyl)-2-
100 cyclopentyl-2-hydroxy -2 -phenylacetamide (Compound No. 51),
101 N-( { 3 - [(6-Aminopyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6-yl } methyl)-2-cyclohexyl-
102 2-hydroxy-2-phenylacetamide (compound No. 52), 103 Tartarate salt of N-dS-tCo-aminopyridin^-y^methyll-S-azabicyclofS.l.OJhex-o-
104 yl}methyl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide (compound No. 53),
105 Tartarate salt of N-QS-Kό-aminopyridin^-y^methyll-S-azabicycloP.l.Olhex-ό-
106 yl}methyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (Compound No. 54),
107 2-Cycloheptyl-2-hydroxy-2-phenyl-N-{ [3-(pyridin-2-ylmethyl)-3-azabicyclo[3.1.0]hex-6-
108 yl] methyl Jacetamide (Compound No. 55)
109 2-Cyclopentyl-2-hydroxy-N-( { 3 -[(6-methylpyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-
110 6-yl}methyl)-2-phenylacetamide (Compound No. 56),
111 N-( { 3 - [(6-Aminopyridin-2-yl)methyl] -3 -azabicyclo [3.1.0]hex-6-yl } methyl)-2-hydroxy-
112 2,2-diphenylacetamide (Compound No. 57),
113 (3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclopentyl(hydroxy)
114 phenylacetate (Compound No. 58),
115 (3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclohexyl(hydroxy)
116 phenylacetate (Compound No. 59),
117 N-[(3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2-hydroxy-2-
118 phenylacetamide (Compound No. 60),
119 N-[(3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclohexyl-2-hydroxy-2-
120 phenylacetamide (Compound No. 61),
121 (3-Benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(diphenyl)acetate
122 (Compound No. 62),
123 Tartarate salt of N-[(3-benzyl-2-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-
124 cyclohexyl-2-hydroxy-2-phenylacetamide (compound No. 63),
125 (2-Methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclohexyl(hydroxy)phenylacetate
126 (Compound No. 64),
127 Tert-baty\ (6-{ [6-({ [cyclohexyl(hydroxy)phenylacetyl]amino}methyl)-3-azabicyclo
128 [3.1.0]hex-3-yl]methyl}pyridin-2-yl)carbamate (Compound No. 65),
129 Tert-buty\ (6-{ [6-({ [hydroxy(diphenyl)acetyl]amino}methyl)-3-azabicyclo[3.1.0]hex-3-
130 yl]methyl}pyridin-2-yl)carbamate (compound no. 66),
131 Tert-baty\ (6-{ [6-({ [cyclopentyl(hydroxy)phenylacetyl] amino} methyl) -3-
132 azabicyclo[3.1.0]hex-3-yl]methyl}pyridin-2-yl)carbamate (Compound No. 67),
133 Tartarate salt of [3-(4-methylpent-3-en-l-yl)-3-azabicyclo[3.1.0]hex-6-yl]methyl
134 cyclopentyl(hydroxy)phenylacetate (Compound No. 68),
135 Tartarate salt of [3-(l-phenylethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl
136 cyclohexyl(hydroxy)phenylacetate (Compound No. 69), 137 Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.L0]hex-6-yl)methyl]-2-cyclobutyl-2-
138 hydroxy-2-phenylacetamide (Compound No. 70),
139 2-Hydroxy-N-{ [3-(3-methylbut-2-en-l-yl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}-2,2-
140 diphenylacetamide (Compound No. 71),
141 2-Hydroxy-N- { [3 -(4-methylpent-3 -en- 1 -yl)-3-azabicyclo [3.1.0]hex-6-yl]methyl } -2,2-
142 diphenylacetamide (Compound No. 72),
143 2-Cycloheptyl-2-hydroxy-2-phenyl-N-{ [3-(pyridin-3-ylmethyl)-3-azabicyclo[3.1.0]hex-6-
144 yl] methyl Jacetamide (Compound No. 73),
145 2-Cycloheptyl-2-hydroxy-2-phenyl-N-{ [3-(pyridin-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-
146 yl] methyl Jacetamide (Compound No. 74),
147 2-Cyclopentyl-2-hydroxy-N-[(3-methyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-
148 phenylacetamide (Compound No. 75),
149 2-Cyclopentyl-2-hydroxy-2-phenyl-N-{ [3-(2-phenylethyl)-3-azabicyclo[3.1.0]hex-6-
150 yl] methyl Jacetamide (Compound No. 76),
151 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cycloheptyl-2 -hydroxy -2-
152 phenylacetamide (Compound No. 77),
153 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclohexyl-2-hydroxy-N-methyl-2-
154 phenylacetamide (Compound No. 78),
155 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2,2-
156 diphenylacetamide (Compound No. 79),
157 N-{ [3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}-2-cyclohexyl-
158 2-hydroxy-2-phenylacetamide (Compound No. 80),
159 2-Cyclopentyl-2-hydroxy-2-phenyl-N-{ [3-(2-thienylmethyl)-3-azabicyclo[3.1.0]hex-6-
160 yl] methyl Jacetamide (Compound No. 81),
161 2-Cyclohexyl-2-hydroxy-2-phenyl-N- { [3 -(2-phenylethyl)-3 -azabicyclo[3.1.0]hex-6-
162 yl] methyl Jacetamide (Compound No. 82),
163 N-( { 3 - [2-( 1 ,3 -Benzodioxol-5-yl)ethyl] -3 -azabicyclo [3.1.0]hex-6-yl }methyl)-2-
164 cycloheptyl-2-hydroxy -2 -phenylacetamide (Compound No. 83),
165 2-Cycloheptyl-N-({3-[2-(2,3-dihydro-l-benzofuran-5-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-
166 yl}methyl)-2 -hydroxy-2-phenylacetamide (Compound No. 84),
167 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-3-methyl-2-
168 phenylpentanamide (Compound No. 85),
169 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2-methoxy-2-
170 phenylacetamide (Compound No. 86), 171 Tartarate salt of [3-(3-methylbut-2-en-l-yl)-3-azabicyclo[3.1.0]hex-6-yl]methyl
172 cyclopentyl(hydroxy)phenylacetate (Compound No. 87),
173 [3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicyclo[3.L0]hex-6-yl]methyl cyclopentyl
174 (hydroxy )phenylacetate (Compound No. 88),
175 Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclohexyl-2-
176 hydroxy-N-methyl-2-phenylacetamide (Compound No. 89),
177 Tartarate salt of N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-
178 2,2-diphenylacetamide (Compound No. 90),
179 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-3-cyclohexyl-2-hydroxy-2-
180 phenylpropanamide (Compound No. 91),
181 2-Cyclopentyl-N- { [3 -(cyclopropylmethyl)-3 -azabicyclo [3.1.0]hex-6-yl]methyl } -2-
182 hydroxy-2-phenylacetamide (Compound No. 92),
183 N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-2-cyclohexyl-N-ethyl-2 -hydroxy -2-
184 phenylacetamide(Compound No. 93),
185 N-3-azabicyclo[3.1.0]hex-6-yl-2-cyclohexyl-N-ethyl-2-hydroxy-2-phenylacetamide
186 (Compound No. 94),
187 Tartarate salt of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl cyclopentyl(hydroxy)2-
188 thienylacetate (Compound No. 95),
189 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-3,3,3-trifluoro-2-hydroxy-2-
190 phenylpropanamide (Compound No. 96),
191 (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl 2-hydroxy-2-phenylpent-4-ynoate
192 (Compound No. 97),
193 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenylpent-4-ynamide
194 (Compound No. 98),
195 [3-(l,3-Benzodioxol-5-ylmethyl)-3-azabicyclo [3.1.0] hex-6-yl]methyl
196 cyclohexyl(hydroxy)phenylacetate (Compound No. 99),
197 2-Hydroxy-2,2-diphenyl-N-{ [3-(2-phenylethyl)-3-azabicyclo[3.1.0]hex-6-yl]
198 methyl Jacetamide (Compound No. 100),
199 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-3-methyl-2-
200 phenylbutanamide (Compound No. 101),
201 N-( { 3 -[2-( 1 ,3 -Benzodioxol-5-yl)ethyl] -3 -azabicyclo[3.1.0]hex-6-yl } methyl)-2-
202 cyclopentyl-2-hydroxy-N-methyl-2-phenylacetamide (Compound No. 102),
203 Tartarate salt of N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-cyclopentyl-2-
204 hydroxy-N-methyl-2-phenylacetamide (Compound No. 103), 205 N-IXS-Benzyl-S-azabicycloP.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-2-
206 ylacetamide (Compound No. 104),
207 N-^-Benzyl-S-azabicycloP.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenyl-2-
208 pyridin-3 -ylacetamide (Compound No. 105),
209 2-Hydroxy-N-methyl-N-{ [3-(4-methylpent-3-en-l-yl)-3-azabicyclo[3.1.0]hex-6-
210 yl]methyl}-2,2-diphenylacetamide (Compound No. 106),
211 N-( { 3 - [2-( 1 ,3 -Benzodioxol-5-yl)ethyl] -3 -azabicyclo [3.1.0]hex-6-yl }methyl)-2-hydroxy-N-
212 methyl-2,2-diphenylacetamide (Compound No. 107),
213 N-( { 3 - [2-(2,3 -Dihydro- 1 -benzofuran-5-yl)ethyl] -3 -azabicyclo[3.1.0]hex-6-yl } methyl)-2-
214 hydroxy-N-methyl-2,2-diphenylacetamide (Compound No. 108),
215 N-{3-Azabicyclo[3.1.0]hex-6-ylmethyl}-N-methyl-2,2-diphenylpropanamide (Compound
216 No. 109),
217 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenylhex-4-
218 enamide (Compound No. 110),
219 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-3-
220 ylacetamide (Compound No. I ll),
221 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenylhex-4-enamide
222 (Compound No. 112),
223 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenyl-2-
224 propoxyacetamide (Compound No. 113),
225 3-Azabicyclo[3.1.0]hex-6-ylmethyl (AE or 4Z)-2-hydroxy-2-phenylhex-4-enoate
226 (Compound No. 114),
227 (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (AE or 4Z)-2-hydroxy-2-phenylhex-4-
228 enoate (Compound No. 115),
229 (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (2R or 25')-hydroxy(4-
230 methylphenyl)phenylacetate (Compound No. 116),
231 (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-2-ylacetate
232 (Compound No. 117),
233 (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-3-ylacetate
234 (Compound No. 118),
235 N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenylpropanamide
236 (Compound No. 119),
237 7e>t-butyl 6-({ [(4£)-2-hydroxy-2-phenylhex-4-enoyl]oxy}methyl)-3-
238 azabicyclo [3.1.0]hexane-3-carboxy late (Compound No. 120).
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 together with pharmaceutically acceptable carrier, excipients or diluents.
4. A method for treatment of 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 the muscarinic receptors, comprising administering to said animal or human, a therapeutically effective amount of a compound defined in claim 1.
5. A method according to claim 4, wherein the disease of disorder is urinary incontinence, lower urinary tract symptoms (LUTS), bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes, and gastrointestinal hyperkinesis.
6. A method for treatment of 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 the muscarinic receptors, comprising administering to said animal or human a therapeutically effective amount of a pharmaceutical composition according to claim 3.
7. The method of preparing a compound of Formula VI and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein the method comprises: a. reacting a compound of Formula II
Figure imgf000070_0001
Formula Il with a compound of Formula III
Figure imgf000071_0001
Formula to give a compound of Formula IV;
Figure imgf000071_0002
Formula IV b. deprotecting a compound of Formula IV to give a compound of Formula V; and
Figure imgf000071_0003
Formula V c. N-derivatizing a compound of Formula V with a compound of Formula Rc- Rk to give a compound of Formula VI,
Figure imgf000071_0004
Formula Vl wherein
Ri is hydrogen or alkyl; M is alkyl or hydrogen;
R2 is straight or branched alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heteroaryl wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heteroaryl are optionally substituted with one or more substituents selected from alkyl, hydroxy or halogen. R3 is aryl or heteroaryl wherein the said aryl or heteroaryl are optionally substituted with one or more groups selected from alkyl, hydroxy or halogen; W = -(CHz)1; Q = -(CH2)j ; Rw is H or methyl; n is an integer from 0-2; Z is oxygen or -NR5 (wherein R5 is hydrogen or alkyl); Pi is mesyl, tosyl or H; P is benzyl or -C(=O)OCH2C6H5; and Rc is CHO or CH2hal (hal is Br, Cl or I) and Rk is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroarylalkyl, or heteroaryl.
8. The method of preparing a compound of Formula IX and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein the method comprises: a. reacting a compound of Formula II
Figure imgf000072_0001
Formula Il with a compound of Formula VII
Figure imgf000072_0002
Formula VII to give a compound of Formula VIII; and
Figure imgf000073_0001
Formula VIII b. deprotecting a compound of Formula VIII to give a compound of Formula IX,
Figure imgf000073_0002
Formula IX wherein
Fi is mesyl, tosyl, triflyl;
Ri is hydrogen or alkyl;
R2 is straight or branched alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heteroaryl wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heteroaryl are optionally substituted with one or more substituents selected from alkyl, hydroxy or halogen.
R3 is aryl or heteroaryl wherein the said aryl or heteroaryl are optionally substituted with one or more groups selected from alkyl, hydroxy or halogen;
W = -(CH2),;
Q = -(CH2)j;
Rw is H or methyl; n are integer from 0-2; and
P is benzyl or -CC=O)OCH2C6H5.
9. The method of preparing a compound of Formula XI and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein the method comprises: a. reacting a compound of Formula V
Figure imgf000074_0001
with a compound of Formula X
Figure imgf000074_0002
Formula X to give a compound of Formula XI; and
Figure imgf000074_0003
b. deprotecting a compound of Formula XI to give a compound of Formula XII,
Figure imgf000074_0004
wherein
Ri is hydrogen or alkyl;
R2 is straight or branched alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heteroaryl wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heteroaryl are optionally substituted with one or more substituents selected from alkyl, hydroxy or halogen. R3 is aryl or heteroaryl wherein the said aryl or heteroaryl are optionally substituted with one or more groups selected from alkyl, hydroxy or halogen; W = -(CHz)1; Q = -(CH2)j ; Rw is H or methyl; n are integer from 0-2; Z is oxygen or -NR5 P2 is -Omesyl or -Otosyl; and R5 is hydrogen or alkyl.
10. A compound of claim 1, wherein Ri is hydrogen R4 is benzyl.
11. A compound of claim 10, wherein R2 is phenyl cycloalkyl.
PCT/IB2006/051368 2005-05-03 2006-05-01 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives as muscarinic receptor antagonists WO2006117754A1 (en)

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