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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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 M 1 subtype is located primarily in neuronal tissues such as cerebral 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.
• WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas.
• WO 01/42212 describes carbamate derivatives.
• WO 01/90081 describes amino alkyl lactam.
• WO 02/53564 describes novel quinuclidine derivatives.
• WO 02/00652 describes carbamates derived from arylalkyl amines.
• WO 02/06241 describes 1,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives.
• azabicyclo derivatives including, for example, 6-substituted azabicyclo[3.1.0]hexanes, 2,6- and 4,6-disubstituted derivatives and 2,4,6-trisubstituted derivatives are provided as 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.
• compounds having the structure of Formula I and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or optionally substituted phenyl wherein optional substituent(s) can be selected from C 1 -C 3 alkyl, C 1-93 alkoxy or halogen; Z can represent oxygen or NR 3 wherein R 3 represents hydrogen or C 1 -C 3 alkyl.
• a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease or disorder is mediated through muscarinic receptors includes administration of at least one compound having the structure of Formula I.
• a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder associated with muscarinic receptors comprising administering to a patient in need thereof, an effective amount of a muscarinic receptor antagonist compound as described above.
• a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory system such as bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, and the like; urinary system which induce such urinary disorders as urinary incontinence, lower urinary tract symptoms (LUTS), etc.; and gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein the disease or disorder is associated with muscarinic receptors.
• a disease or disorder of the respiratory system such as bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, and the like
• urinary system which induce such urinary disorders as urinary incontinence, lower urinary tract symptoms (LUTS), etc.
• gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein the disease or disorder is associated with muscarinic receptors
• the compounds described herein exhibit significant potency in terms of their activity, as determined by in vitro receptor binding and functional assays and in vivo experiments using anaesthetized rabbits.
• the compounds that were found active in vitro were tested in vivo.
• Some of the compounds are potent muscarinic receptor antagonists with high affinity towards M 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 Formula V may be prepared, for example, by the reaction sequence as shown in Scheme I.
• the preparation comprises reacting a compound of Formula II with a compound of Formula III, wherein
• R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or optionally substituted phenyl wherein optional substituent(s) is/are selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogen;
• R 3 represents hydrogen or C 1 -C 3 alkyl
• P is any protecting group for an amino group, for example, benzyl or t-butyloxy carbonyl groups.
• the reaction between a compound of Formula II and a compound of Formula III can take place in the presence of N-methylmorpholine and 1-hydroxybenzotriazole and a condensing agent (for example, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU)), in a solvent (such as N,N-dimethylformamide, dimethylsulfoxide, toluene, xylene or chloroform, at temperatures ranging from about 0 to about 140° C.), to give a protected compound of Formula IV which on deprotection in the presence of a deprotecting agent (for example, palladium on carbon and hydrogen, ammonium formate and palladium on carbon, trifluoroacetic acid (TFA) or hydrochloric acid) in an organic solvent (for
• the compounds of Formula VIII may be prepared for example, by the reaction sequence as shown in Scheme II.
• the preparation comprises reacting a compound of Formula II with a compound of Formula VI, wherein
• R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or optionally substituted phenyl wherein optional substituent(s) is/are selected from C 1 -C 3 alkyl C 1 -C 3 alkoxy or halogen;
• R′ is any protecting group for hydroxy group, for example, p-toluene sulfonyl or methane sulfonyl and
• P is any protecting group for an amino group, for example, benzyl or t-butyloxy carbonyl groups.
• the reaction between a compound of Formula II and a compound of Formula VI can take place in the presence of a condensing agent (for example, 1,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO), in a solvent (such as benzene, toluene or xylene, at temperatures ranging from about 0 to about 140° C.), to give a protected compound of Formula VII which on deprotection in the presence of a deprotecting agent (for example, palladium on carbon and hydrogen or ammonium formate and palladium on carbon) in an organic solvent (for example, methanol or ethanol, at temperatures ranging from about 10 to about 50° C.) gives an unprotected compound of Formula VIII.
• a condensing agent for example, 1,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) or 1,4-diazabicy
• 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).
• 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). 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.
• 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.
• Step a Synthesis of methane sulfonic acid 3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl ester
• Step b Synthesis of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl) methylamine
• Step c Synthesis of N-[(1 ⁇ ,5 ⁇ ,6 ⁇ )-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-phenyl-2-hydroxy-2-(N-methyl) phenylacetamide
• Step d Synthesis of N-[(1 ⁇ ,5 ⁇ ,6 ⁇ )-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-phenyl-2-hydroxy-2-(N-methyl) phenylacetamide
• the compound exhibited a melting point of 101-103° C.
• Step a Synthesis of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl) amine
• Step b Synthesis of N-[(1 ⁇ ,5 ⁇ ,6 ⁇ )-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-isopropyl-2-hydroxy-2-phenylacetamide
• Step c Synthesis of (2R,2S)-N-[(1 ⁇ ,5 ⁇ ,6 ⁇ )-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-isopropyl-2-hydroxy-2-phenylacetamide
• the hyflo bed was washed with methanol (75.0 mL), ethyl acetate (25.0 mL) and water (25.0 mL). The filterate was concentrated under vacuum. The residue was diluted with water and pH of the resulting solution was adjusted to (pH ⁇ 14) with 1N NaOH. Extracted with ethyl acetate (2 ⁇ 50 mL) and the ethyl acetate layer was washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to give the title compound.
• Step a Synthesis of [(1 ⁇ ,5 ⁇ ,6 ⁇ )-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-cyclopentyl-2-hydroxy-2-phenylacetic acid ester
• Step b Synthesis of [(1 ⁇ ,5 ⁇ ,6 ⁇ )-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-cyclopentyl-2-hydroxy-2-phenylacetic acid ester
• the hyflo bed was washed with methanol (75.0 mL), ethtl acetate (25.0 mL) and water (25.0 mL). The filterate was concentrated under vacuum. The residue was diluted with water and pH of the resulting solution was adjusted to (pH ⁇ 14) with 1N NaOH. Extracted with ethyl acetate (2 ⁇ 50 mL) and the ethyl acetate layer was washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to give the title compound.
• Radioligand Binding Assays The affinity of test compounds for M 2 and M 3 muscarinic receptor subtypes was determined by [ 3 H]-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 as follows.
• the membrane preparation was done with the following modifications: a low spin step of 500 g for 10 minutes at 4° C. was used; the buffer was 20 mM HEPES, 10 mM EDTA, at pH 7.4; the high speed spin was done at 40,000 g and the homogenate was passed through a filter gauge before any spinning.
• the assay conditions were modified as follows: the assay volume was 250 ⁇ L; the incubation time was 3 hours; the PE concentration was 0.1%; the filtermat used was GF/B from Wallac; the scintillant used was Supermix from Wallac; the amount of scintillant was 500 ⁇ L/well; and the counter used was a 1450 microbeta PLUS, from Wallac.
• Membrane preparation Submandibular glands and heart were isolated and placed in ice cold homogenising buffer (HEPES 20 mM, 10 mM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenised in 10 volumes of homogenising buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 500 g for 10 min. The supernatant was subsequently centrifuged at 40,000 g for 20 min. The pellet thus obtained was resuspended in same volume of assay buffer (HEPES 20 mM, EDTA 5 mM, pH 7.4) and were stored at ⁇ 70° C. until the time of assay.
• HEPES 20 mM, 10 mM EDTA, pH 7.4 ice cold homogenising buffer
• Ligand binding assay The compounds were dissolved and diluted in DMSO. The membrane homogenates (150-250 ⁇ g protein) were incubated in 250 ⁇ l of assay buffer (HEPES 20 mM, pH 7.4) at 24-25° C. for 3 h. Non-specific binding was determined in the presence of 1 ⁇ M atropine. The incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac). The filters were then washed with ice cold 50 mM Tris HCl buffer (pH 7.4). The filter mats were dried and bound radioactivity retained on filters was counted. The IC 50 and K d were estimated by using the non-linear curve fitting program using G Pad Prism software.
• pK i ⁇ [log K i ].
• Ki results of the compounds observed were in the range of 0.05 nM to 136 nM for M 3 receptor and 0.06 nM to 34.6 nM for M 2 receptor.
• the bladder is cut into longitudinal strips (3 mm wide and 5-6 mm long) and mounted in 10 ml organ baths at 30° C., with one end connected to the base of the tissue holder and the other end connected to a polygraph through a force displacement transducer.
• Each tissue is maintained at a constant basal tension of 2 g and allowed to equilibrate for 1 hour during which the PSS is changed every 15 min.
• the stabilization of the tissue contractile response is assessed with 1 ⁇ mol/L of Carbachol consecutively, 2-3 times. Subsequently a cumulative concentration response curve to carbachol (10 ⁇ 9 mol/L to 3 ⁇ 10 ⁇ 5 mol/L) is obtained. After several washes, once the baseline is achieved, cumulative concentration response curve is obtained in presence of NCE (NCE added 20 min. prior to the second CRC).
• the contractile results are expressed as % of control E max.
• ED 50 values are calculated by fitting a non-linear regression curve (Graph Pad Prism).
• the bladder was exposed through a midline laparotomy and both the ureters were identified, carefully separated and ligated.
• the ureters were incised proximally to allow free flow of urine from the kidney to the exterior.
• Bladder neck was gently held and the urethra was traced and separated from the adjoining tissues.
• PE canula was introduced into the bladder and ligated.
• the bladder was drained and subsequently filled with 15 ml of warm saline (37° C.).
• the other end of the intravesical catheter was connected to the Grass model 7D polygraph through a Statham P10 EZ pressure transducer to monitor the bladder pressure. Care was taken to keep the exposed area moist and warm. A period of 30-60 min was allowed for stabilization of parameters subsequent to surgery. Salivation response was assessed by placing preweighed absorbent cotton gauze in the buccal cavity for 2 minutes after carbachol administration.
• the change in bladder pressure, salivation and agonist induced bradycardia were expressed as % change from pretreatment control.
• ID 50 values dose required to inhibit 50% of response
• the ID 50 values for bladder pressure for compounds tested ranged from about 1.89 to about 4.2 ⁇ g/kg.
• the ID 50 values for salivation for compounds tested ranged from about 3.7 to about 30.4 ⁇ g/kg.

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