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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system

Definitions

• This invention generally relates to derivatives of 3,6-disubstituted azabicyclo [3.1.0] hexanes.
• the compounds of this invention can function as muscarinic receptor antagonists, and can be used for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors.
• the invention also relates to a process for the preparation of the compounds of the present invention, pharmaceutical compositions containing the compounds of the present invention and the methods for treating the diseases mediated through muscarinic receptors.
• Muscarinic receptors as members of the G Protein Coupled Receptors are composed of a family of 5 receptor sub-types (Mi, M , 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 subtype is present mainly in the heart where it mediates chohnergically induced bradycardia
• the M subtype is located predominantly on smooth muscle and salivary glands (Nature, 1986; 323: 411; Science, 1987; 237: 527).
• 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.
• the present invention provides 3,6-disubstituted azabicyclo[3.1.0]hexanes which function as muscarinic receptor antagonists which are useful as safe treatment of various diseases of the respiratory, urinary and gastrointestinal systems, and method for the synthesis of the compounds.
• the invention also provides pharmaceutical compositions containing the compounds, and which may also contain acceptable carriers, excipients or diluents which are useful for the treatment of various diseases of respiratory, urinary and gastrointestinal systems.
• the invention also includes the enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, N-oxides and metabolites of these compounds having the same type of activity.
• the invention further includes pharmaceutical compositions comprising the compounds of the present invention, their enantiomers, diastereomers, polymorphs, pharmaceutically acceptable solvates, esters, N-oxides or metabolites, in combination with pharmaceutically acceptable carrier and optionally included excipients.
• W represents (CH 2 ) P , where p represents 0 to 1;
• X represents an oxygen, sulphur, -NR or no atom, wherein R represents hydrogen or
• Y represents CHRiCO, wherein Ri represents hydrogen, methyl or (CH 2 )q wherein q represents 0 to 4; Z represents oxygen, sulphur, NR 2 , wherein R 2 represents hydrogen or C ⁇ - 6 alkyl; Q represents (CH 2 ) n , wherein n represents 0 to 4, or CHR 3 wherein R 3 represents H,
• R 4 represents hydrogen, C 1 -C 15 saturated or unsarurated aliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may be substituted with the group independently selected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulphur atoms with an option that any 1 to 3 hydrogen atoms on an aryl or heteroaryl ring in said arylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted with lower alkyl (C1-C 4 ), lower perhalo alkyl (C ⁇ -C 4 ), cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C ⁇ -C 4 ), lower perhaloalkoxy (C ⁇ -C ), unsubstituted amino, N-lower alkylamino (C ⁇ -
• Re and R 7 are independently selected from H, COOH, CH 3 , CONH 2 , NH 2 or CH 2 NH 2 ;
• R 8 and R 9 are independently selected from a group consisting of lower alkyl (C ⁇ -C 4 ), trifluoromethyl, cyano, halogen, hydroxy, nitro, lower alkoxy (C ⁇ -C 4 ), amino or lower alkylamino.
• 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 comprising administering to a patient in need thereof, an effective amount of compounds as described above.
• 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 muscarinic receptor antagonist compounds as described above.
• a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory systems such as bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, etc., urinary system which induce such urinary disorders as urinary incontinence, lower urinary tract systems (LUTS), etc., and gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compound as described above, wherein the disease or disorder is associated with muscarinic receptors, comprising administering to a patient in need thereof, an effective amount of compounds as described above.
• a disease or disorder of the respiratory systems such as bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, etc.
• urinary system which induce such urinary disorders as urinary incontinence, lower urinary tract systems (LUTS), etc.
• gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compound as
• the compounds of the present invention exhibit significant potency in terms of their activity, which was determined by in vitro receptor binding and functional assays and in vivo experiments using anaesthetised rabbit. Compounds were tested in vitro and in vivo. Some compounds were found to function as potent muscarinic receptor antagonists with high affinity towards M receptors. Therefore, the present invention provides pharmaceutical compositions for treatment of diseases or disorders associated with muscarinic receptors. Compounds and compositions described herein can be administered orally or parenterally.
• the compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds described herein may be prepared by the following reaction sequence.
• W represents (CH 2 ) P , where p represents 0 to 1;
• X represents an oxygen, sulphur, - ⁇ R or no atom, wherein R represents hydrogen and
• R 6 and R 7 are independently selected from H, COOH, CH 3 , CONH 2 , NH 2 or CH 2 NH 2 ;
• R 8 and R 9 are independently selected from a group consisting of hydrogen, lower alkyl (C ⁇ -C ), trifluoromethyl, cyano, halogen, hydroxy, nitro, lower alkoxy (C ⁇ -C 4 ), amino or lower alkylamino; and
• P is any group which can be used to protect an amino group in the presence of a condensing agent to give a protected compound of Formula V, which on deprotection through reaction with a deprotecting agent in an organic solvent gives an unprotected compound of Formula VI which is finally N-alkylated or benzylated with a suitable alkylating or benzylating agent L-R 4 to give a compound of Formula I wherein L is any leaving group;
• R t represents hydrogen, C 1 -C 15 saturated or unsaturated aliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may be substituted with the group independently selected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulphur atoms with an option that any 1 to 3 hydrogen atoms on an aryl or heteroaryl ring in said arylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted with lower alkyl (C ⁇ -C 4 ), lower perhalo alkyl (C ⁇ -C 4 ), cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C ⁇ -C 4 ), lower perhaloalkoxy (C ⁇ -C 4 ), unsubstituted amino, N-lower alkylamino (C ⁇
• P is any protecting group for an amino group for a compound of Formula VI and is selected from benzyl and t-butyloxy carbonyl groups.
• reaction of the compound of Formula III with a compound of Formula IN to give a compound of Formula N can be carried out in presence of a condensing agent, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and 1, 8- diazabicyclo [5.4.0] undec-7ene (DBU).
• a condensing agent for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and 1, 8- diazabicyclo [5.4.0] undec-7ene (DBU).
• reaction of the compound of Formula III with a compound of Formula IN to give a compound of Formula N can be carried out in a suitable solvent for example, ⁇ , ⁇ - dimethylformamide, dimethylsulfoxide, toluene and xylene at a temperature ranging from about 0 to about 140°C.
• a suitable solvent for example, ⁇ , ⁇ - dimethylformamide, dimethylsulfoxide, toluene and xylene at a temperature ranging from about 0 to about 140°C.
• NI can be carried out with a deprotecting agent, for example, palladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid.
• a deprotecting agent for example, palladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid.
• the deprotection of the compound of Formula N to give a compound of Formula NI can be carried out in a suitable organic solvent, for example, methanol, ethanol, tetrahydrofuran and acetonitrile at temperatures ranging from about 10 to about 50°C.
• a suitable organic solvent for example, methanol, ethanol, tetrahydrofuran and acetonitrile at temperatures ranging from about 10 to about 50°C.
• the ⁇ -alkylation or benzylation of the compound of Formula NI to give a compound of Formula I can be carried out with a suitable alkylating or benzylating agent, L- R 4 wherein L is any leaving group, known in the art, for example, halogen, O-mesityl and O-tosyl group.
• the ⁇ -alkylation or benzylation of the compound of Formula NI to give a compound of Formula I can be carried out in a suitable organic solvent such as ⁇ , ⁇ - dimethylformamide, dimethylsulfoxide, tetrahydrofuran and acetonitrile, at temperatures ranging from about 25 to about 100°C. hi the above scheme, where specific bases, condensing agents, protecting groups, deprotecting agents, N-alkylating/benzylating agents, solvents, etc. are mentioned, it is to be understood that other bases, condensing agents, protecting groups, deprotecting agents, N-alkylating/benzylating agents, solvents, 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.
• a suitable organic solvent such as ⁇ , ⁇ - dimethylformamide, dimethylsulfoxide, tetrahydrofuran and acetonitrile
• Suitable salts of compounds represented by the Formula I were prepared so as to solubilize the compound in aqueous medium for biological evaluations.
• examples of such salts are pharmacologically acceptable salts such as inorganic acid salts (e.g. hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic acid salts (e.g. acetate, tartarate, citrate, fumarate, maleate, toluenesulphonate and methanesulphonate).
• inorganic acid salts e.g. hydrochloride, hydrobromide, sulphate, nitrate and phosphate
• organic acid salts e.g. acetate, tartarate, citrate, fumarate, maleate, toluenesulphonate and methanesulphonate.
• a carboxyl group When a carboxyl group is included in the Formula I as a substituent, it may be in its alkali metal salt form (e
• compositions disclosed herein can be produced and admimstered in dosage units, each unit containing a certain amount of at least one compound described herein and/or at least one physiologically acceptable salt addition 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 present invention also includes the enantiomers, diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts of these compounds as well as metabolites having the same type of activity.
• the present invention further includes pharmaceutical composition comprising the molecules of Formula I and II, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipients.
• Various solvents such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexanes, and dichloromethane were dried using various drying reagents according to procedures well known 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) spectra were recorded on a Narian XL-300 MHz instrument using teframethylsilane as an internal standard.
• 6-yl amide (3.00 mg, 1 eqv), as prepared in Example 1, was dissolved in methanol: tetrahydrofuran (80:20) (200 ml). To this reaction mixture, palladium on carbon was added and the resulting reaction mixture was stirred for 5 hours. To that mixture, acetic acid was added, followed by stirring for 4 hours. The organic compound xanthene-9- carboxylic acid-3-azabicyclo [3.1.0]-hex-6-yl amide was then filtered off and used as such without purification, which was dissolved in dimethylformamide, and potassium carbonate and potassium iodide were added. To this reaction mixture was added 4-cyano benzyl bromide and the reaction mixture was stirred overnight at room temperature.
• reaction mixture was then stirred at room temperature.
• the reaction mixture was diluted with water and then extracted the organic compound 9H-xanthene-9-carboxylic acid-(3 -benzyl)-3 -azabicyclo [3.1.0] -hex-6- yl] amide with ethyl acetate.
• the purification was done by column chromatography using silica gel.
• the reaction mixture was diluted with water and the organic compound (IR or IS) 9H-xanthene-9-carboxylic acid (3-benzyl)-3-azabicyclo[3.1.0]hex-6-yl- methyl] amide was extracted with ethyl acetate. Ethyl acetate was removed under reduced pressure and the residue dried under vacuuo. The purification was done by column chromatography using silica gel. Column was eluted with a mixture of ethyl acetate: hexane (5:95); (10:90); (15:85); (20:80); (30:70); (40-60) to yield 70 mg of the desired compound.
• Example 5 Radioligand Binding Assays The affinity of test compounds for M 2 and M 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.
• Membrane preparation Submandibular glands and heart were isolated and placed in ice cold homogenising buffer (HEPES 20mM, lOmM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenised in 10 volumes of homogenising buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 500g for lOmin.
• the supernatant was subsequently centrifuged at 40,000g for 20 min.
• the pellet thus obtained was 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 ⁇ g protein) were incubated in 250 ⁇ l of assay volume
• Ki IC50 /(1+L/Kd), where L is the concentration of [ 3 H]NMS used in the particular experiment, pki is -log [Ki].

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