3,6-DISUBSTITUTED AZABICYCLO [3.1.0] HEXANE DERIVATIVES USEFUL 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 Ma 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 J. 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, 41, 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 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 W096/33973 are other references of interest.
A report in J. Med. Chem., 44, p. 984 (2002), describes cyclohexylmethyl piperidinyl triphenylpropioamide derivatives as selective MS 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:
(Formula Removed)
Formula I
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein
RI is hydrogen or alkyl;
RI is straight or branched alkyl optionally substituted with halogen; alkenyl, alkynyl, aryl,
cycloalkyl, cycloalkylalkyl or heteroaryl wherein the said 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)i;
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;
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, the compounds of the present invention may be prepared by the process described herein, this process is 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
(Scheme Removed)
The compounds of Formula IV, V and VI can be prepared by the reaction procedure as depicted in Scheme I, thus a compound of Formula II (wherein M is alkyl or hydrogen; RI, R2, R3 and W are the same as defined earlier) is reacted with a compound of Formula III (wherein Z is oxygen or -NR5 (wherein R5 is the same as defined earlier); P\ is hal (Br, Cl or I), mesyl, tosyl or H; Q, Rw and n are the same as defined earlier and P is benzyl, -C(=:O)OtBu or -C(=O)OCH2C6H5) to give a compound of Formula IV, which undergoes deprotection to give a compound of Formula V, which undergoes N-derivatization with a compound of Formula R°-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 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 selected from tetrahydrofuran, diethyl ether, dioxane or dimethylformamide in the presence of a base selected from butyl lithium, lithium diisopropylamide, 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 -NRs and PI is H) to give a compound of Formula IV, can be carried out in an organic solvent selected from 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 deprotecting agent for example, palladium on carbon in presence of hydrogen gas or palladium on carbon with a source of hydrogen gas such as ammonium formate, cyclohexene and formic acid.
The deprotection of a compound of Formula IV (when P is -(C(=O)OCH2C6Hs) 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 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 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.
Compounds prepared following scheme I are:
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-2-ylacetamide (Compound No. 1),
N-[(3-Benzyl-3-azabicyclo[3.l.0]hex-6-yl)methyl]-hydroxy-N-methyl-2-phenyl-2-pyridin-3-ylacetamide (Compound No. 2),
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. 3),
N-({3-[2-(l,3-Benzodioxol-5-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}methyl)-2-hydroxy-N-methyl-2,2-diphenylacetamide (Compound No. 4),
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. 5),
N-{3-Azabicyclo[3.1.0]hex-6-ylmethyl}-N-methyl-2,2-diphenylpropanamide (Compound No. 6),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenylhex-4-enamide (Compound No. 7),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-3-ylacetamide (Compound No. 8),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenylhex-4-enamide (Compound No. 9),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenyl-2-propoxyacetamide (Compound No. 10),
3-Azabicyclo[3.1.0]hex-6-ylmethyl (4E&4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 11),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (4E&4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 12),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (2R or 2S)hydroxy(4-methylphenyl)phenylacetate (Compound No. 13),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-2-ylacetate (Compound No. 14),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)m ethyl hydroxy(phenyl)pyridin-3-ylacetate (Compound No. 15),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenylpropanamide (Compound No. 16),
Tert-butyl 6-({[(4E)-2-hydroxy-2-phenylhex-4-enoyl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Compound No. 17).
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
Ethyl phenyl (hydroxy)2-pyridylacetate
A solution of 2-bromo pyridine (3 g, 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 °C. 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 3-Benzyl-3-azabicyclo[3.1.0]hex-6-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-hydroxymethyl-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), J. Am. Chem. Soc. 75,2654 (1953) and EP 613232.
Scheme I, Procedure
Example 1: Synthesis of N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-
phenyl-2-pyridin-3-ylacetamide (Compound No. 8)
A solution of hydrochloride salt of hydroxy(phenyl) pyridin-3-yl acetic acid (0.25 g)) and 3-benzyl-3-azabicyclo[3.1.0]hexan-6-methyl amine (0.21 g) in chloroform (3ml) containing hydroxybenzotriazole (0.226 g) , N-methylmorpholine (0.21 ml) and l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.245 g),was stirred at room temperature for overnight. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with dichloromethane. 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 = l00mg.
1H NMR (CDC13): δ.70 (1H, s), 8.51 (1H, bs), 7.80 (1H, d, 4 Hz), 7.38-7.23 (11H, m), 6.70 (1H, bs), 3.57 (2H, bs), 3.15 (2H, m), 2.95 (2H, bs), 2.36 (2H, bs), 1.31 (2H, m), 0.88 (1H, bs). MS:414(M++1).
Analogous of N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-3-ylacetamide (Compound No. 8) described below, were prepared similarly,
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenyl-2-pyridin-3-
ylacetamide (Compound No. 2)
1H NMR (CDC13): δ 8.63-8.57 (2H, bd), 7.76 (1H, bs), 7.40-7.21 (11H, bs), 3.82 (2H, bm), 3.47
(2H, bm), 3.14 (2H, bs), 3.00 (1H, bs), 2.54 (3H, bs), 1.33 (2H, s), 0.88 (1H, bs).
MS: 428 (M++l).
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenylhex-4-enamide
(Compound No. 7)
1H NMR (CDC13): δ 7.31 (10H, bs), 5.61 (1H, m), 5.47 (1H, bm), 3.86-2.51 (15H, m), 1.68 (4H,
bs).
MS: 405 (M++l).
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenylhex-4-enamide (Compound No. 9)
1H NMR (CDC13): δ 7.62 (2H, d, 8Hz), 7.35-7.24 (8H, m), 6.81 (1H, bs), 5.66 (1H, m), 5.30 (1H, m), 3.60 (2H, s), 3.13-3.11 (1H, m), 3.03-2.99 (4H, m), 2.37 (1H, m), 2.2 (2H, bs), 1.68 (3H,d,8Hz), 1.30-1.25 (3H,m). MS: 391 (M++l).
N-[(3-Benzyl-3-azabicyclo[3.1.01hex-6-yl)methyl]-N-methyl-2.2-diphenyl-2-propoxyacetamide (Compound No. 10)
1H NMR (CDC13): δ 7.50-7.48 (8H, bs), 7.33-7.15 (7H, m), 3.82 (2H, bs), 3.42-2.05 (10H, m), 1.61 (2H, m), 1.26 (2H, s), 1.01 (2H, t, 8Hz), 0.86 (3H, t, 8Hz). MS: 469 (M++l).
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2.2-diphenylpropanamide (Compound No. 16)
1H NMR (CDC13): δ 7.35- 7.28 (m, 15H, m), 3.65 (bs, 1H), 3.49 (bs, 1H), 3.32 (bs, 1H), 3.02-3.00 (m, 2H), 2.66 (bs, 1H), 2.34-2.22 (m, 5H), 1.88 (bs, 3H), 1.03 (m, 3H) MS: 425 (M++l).
Example la: Synthesis of N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl')methyl]-2-hydroxy-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 °C. 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 (1H, bs), 3.56 (2H, s), 3.18-3.11 (2H, m), 2.94 (2H, t), 2.33 (2H, bs), 1.46 (1H, bs), 1.28 (2H, bs). MS:414(M++1).
Example 2: Synthesis of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-2-ylacetate (Compound No. 14)
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 °C 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 (CDC13): δ 8.55 (1H, m), 7.55 (1H, m), 7.42 (2H, d, 8Hz), 7.31 (1H, 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 (1H, m), 2.30 (2H, bd), 1.28 (3H,m). MS:415(M++1).
Example 3: Synthesis of (3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (4E&4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 12)
A solution of the compound hydroxy(phenyl)2-butene-2-ylacetic acid (0.2 g, 0.97 mmol), 3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl methane sulfonate (0.227 g, 0.80 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 g, 1.61 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 =1 90 mg.
1H NMR (CDC13): δ 7.62 (2H, d, 8Hz), 7.35-7.23 (8H, m), 5.60 (1H, m), 5.44 (1H, m), 4.06 (1H, m), 3.94 (1H, m), 3.69 (1H, s), 3.57 (2H, s), 2.95-2.91 (3H, m), 2.6 (1H, m), 2.32 (2H, bs), 1.64(3H,d, 6Hz), 1.32(3H,bs).
Analogues of (3-Benzyl-3-azabicyclo[3. 1 .0]hex-6-yl)methyl (4E(&4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 12) described below, were prepared similarly,
(3-Benzyl-3-azabicyclo[3. 1 .0]hex-6-yl)methyl (2R or2S)-hydroxy(4-methylphenyl)phenylacetate
(Compound No. 13)
1HNMR (CDC13): δ 7.44-6.96 (14H, m), 6.34 (1H, 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-azabicyclo[3. 1 .01hex-6-yl)methyl hydroxy(phenyl)pyridin-3-ylacetate
(Compound No. 15)
1H NMR (CDC13): δ 8.72 (1H, s), 8.54 (1H, d, 4Hz), 7.8 (1H, d, 8Hz), 7.43 (2H, bs), 7.34-7.23
(9H, m), 4.33 (1H, 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++1).
Tert-butyl 6-({[(4E)-2-hvdroxy-2-phentylhex-4-enoyl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Compound No. 17)
1H NMR (CDC13): δ 7.62-7.60 (d, 2H), 7.38-7.30 (m, 3H), 5.62 (m, 1H), 5.50 (m, 1H), 4.07-4.08 (m, 2H), 3.68 (s, 1H), 3.54 (m, 1H), 3.43 (m, 1H), 3.31 (m, 2H), 2.95 (m, 1H), 2.70 (m, 1H), 1.68 (m, 3H), 1.4 (s, 9H).
Example 4: Synthesis of N-{3-azabicyclo[3.1.0]hex-6-ylmethyl}-N-methyl-2,2-diphenylpropanamide (Compound No. 6)
To a solution of the Compound No. 16 (0.3 g, 0.7 mmol) in methanol (25.0 ml), was added palladium on carbon (0.01 g, 10%) and anhydrous ammonium formate (0.44 g, 7.0 mmol) 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 1N 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: 0.2 g. 1H NMR (CDC13): δ 7.37-7.14 (10H, 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 5: Synthesis of 2-Hydroxy-N-methyl-N-{[3-(4-methylpent-3-en-l-yl)-3-azabicycIo[3.1.0]hex-6-yl]methyl}-2,2-diphenylacetamide (Compound No. 3)
To a solution of the compound N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-N-methyl-2",2-diphenylacetamide (disclosed in W004/089900) (0.23 g, 1 eqi.) in dry acetonitrile (10 ml), was added 5-bromo-2-methyl-pent-2-ene (47.50 mg, 1.5 eqi.) (Commercially available), potassium carbonate (65.71 mg, 2.0 eqi.) and potassium iodide (39.5 mg, 1.0 eqi.) and stirred the mixture at 80°C for 5 hours. The mixture was subsequently stirred overnight at room temperature. Solvent was evaporated under reduced pressure and the residue thus obtained was partitioned between dichloromethane and water. The organic layer was separated and concentrated under reduced pressure. The residue thus obtained was purified by preparative thin layer chromatography to furnish the title compound. Yield = 37.5 mg.
1HNMR (CDC13): δ 7.43-7.31 (10H, bm), 5.86 (1H, bs), 5.30 (1H, 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), I-.70 (3H,s), 1.66(3H,s). MS: 419 (M++l).
Analogous of 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. 3) described below were prepared by condensing appropriate amide or ester with an halo compound, respectively, as applicable in each case.
N-({3-[2-(1,3-Benzodioxol-5-yl)ethyl1-3-azabicyclo[3.1.0]hex-6-yl}methyl)-2-hydroxy-N-
methyl-2.2-diphenylacetamide (Compound No. 4)
1HNMR (CDC13): δ 7.39-7.33 (10H, 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-[2-(2.3-Dihydro-l-benzofuran-5-yl)ethyl1-3-azabicyclo [3.1.0]hex-6-yl}methyl)-2-
hydroxy-N-methyl-2.2-diphenylacetamide (Compound No. 5)
'HNMR (CDC13): δ 7.43-7.33 (bs, 10H), 7.05 (1H, s), 6.92 (1H, d, 8Hz), 6.70 (1H, d, 8Hz), 5.97
(1H, bs), 4.54 (2H, t, 8Hz), 3.46-2.44 (15H, m), 2.05 (1H, s), 1.26 (2H, m).
MS:483(M++1).
Example 6: Synthesis of 3-azabicyclo[3.1.0]hex-6-ylmethyl (4E& 4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 11)
To a solution of the Compound No. 17 (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 (CDC13): δ 7.62 (2H, t, 8Hz), 7.37-7.29 (3H, m), 5.62 (1H, m), 5.42 (1H, m), 4.07 (2H, d, 4Hz), 2.97-2.86 (5H, m), 2.68 (1H, m), 1.67 (3H, d, 4Hz), 1.39-1.00 (3H, m). MS: 302 (M++l).

WE CLAIM:
1. A compound selected from the group consisting of
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-2-ylacetamide (Compound No. 1),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenyl-2-pyridin-3-ylacetamide (Compound No. 2),
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. 3),
N-({3-[2-(l,3-Benzodioxol-5-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}methyl)-2-hydroxy-N-methyl-2,2-diphenylacetamide (Compound No. 4),
N-({3-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}methyl)-2-hydroxy-Af-methyl-2,2-diphenylacetamide (Compound No. 5),
N-{3-Azabicyclo[3.1.0]hex-6-ylmethyl}-N-methyl-2,2-diphenylpropanamide (Compound No. 6),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-N-methyl-2-phenylhex-4-enamide (Compound No. 7),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenyl-2-pyridin-3-ylacetamide (Compound No. 8),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-2-hydroxy-2-phenylhex-4-enamide (Compound No. 9),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenyl-2-propoxyacetamide (Compound No. 10),
3-Azabicyclo[3.1.0]hex-6-ylmethyl (4E&4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 11),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (4E&4Z)-2-hydroxy-2-phenylhex-4-enoate (Compound No. 12),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl (2R or2S)-hydroxy(4-methylphenyl)phenylacetate (Compound No. 13),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-2-ylacetate (Compound
No. 14),
(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl hydroxy(phenyl)pyridin-3-ylacetate (Compound No. 15),
N-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-methyl-2,2-diphenylpropanamide (Compound No. 16),
Tert-butyl6-({[(4E)-2-hydroxy-2-phenylhex-4-enoyl]oxy}methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Compound No. 17).
2. A pharmaceutical composition comprising a therapeutic ally effective amount of a
compound as defined in claim 1 together with pharmaceutically acceptable carrier,
excipients or diluents.
3. 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.
4. A method according to claim 3, 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.
5. 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 2.
6. 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 reaction comprises of following steps:
a. reacting a compound of Formula II
(Formula Removed)
Formula II with a compound of Formula III
(Formula Removed)
to give a compound of Formula IV,
(Formula Removed)
b. deprotecting a compound of Formula IV to give a compound of Formula V,
(Formula Removed)
c. N-derivatizing a compound of Formula V with a compound of Formula R°-Rk to give a
compound of Formula VI
(Formula Removed)
wherein
RI is hydrogen or alkyl;
M is alkyl or hydrogen;
R2 is straight or branched alkyl optionally substituted with halogen; alkenyl, alkynyl, aryl,
cycloalkyl, cycloalkylalkyl or heteroaryl wherein the said 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)i;
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
Rc is CHO or CH2hal (hal is Br, Cl or I) and Rk is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroarylalkyl, or heteroaryl.