Title of Invention

"AZABICYCLO DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS"

Abstract 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 6-substituted azabicyclo[3.1.0] hexanes as well as use of such compounds and methods of treating diseases mediated through muscarinic receptors.
Full Text 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 6-substituted azabicyclo[3.1.0] hexanes as well as use of 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 neuro transmission. The regional distribution of these receptor sub-types in the brain and other organs has been documented. For example, the M1 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 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; W096/33973 and WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives.
A report in J. 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, 6-substituted azabicyclo[3.1.0]hexanes 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.
In another aspect, use of such compounds are provided 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 Rempved)
wherein
Ar represents an aryl which may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C1-C4), lower perhalo alkyl (C1-C4), cyano, hydroxy, nitro, lower alkoxy (C1-C4), lower perhalo alkoxy (C1-C4), unsubstituted amino, N-lower alkyl (C1-C4) or -aryl amino, amino carbonyl, or N-lower alkyl (C1-C4) or -aryl amino carbonyl;
R1 represents a hydroxy;
R2 represents C3-C7 cycloalkyl ring, an aryl wherein the aryl, or a cycloalkyl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C1-C4), hydroxy, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C1-C4), unsubstituted amino, N-lower alkyl (C1-C4) or -aryl amino, amino carbonyl, or N-lower alkyl (C1-C4) or -aryl amino carbonyl;
W represents (CH2)P, wherein p represents 0;
X represents no atom;
Y represents (CH2)q q represents 0;
Z represents oxygen or NR10, wherein R10represents hydrogen, or C1-6 alkyl;
Q represents (CH2)n(wherein n represents 0 to 4); and
R6 and R7 are independently selected from H.
In accordance with a second aspect, there are provided compounds having the structure of Formula II (Formula I wherein W is (CH2)p where p = 0, X is no atom and Y is (CH2)q where q=0, R6 = H, R7 = H, R2 = R1is hydroxy, Ar is phenyl), wherein Z and Q are the same as defined for Formula I, s represents 1 or 2.
(Formula Rempved)
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 of the respiratory, urinary and
gastrointestinal systems, 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 another aspect, there is provided the use of the compounds in the preparation of medicaments for treatment or prophylaxis of an animal or a human suffereing 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 muscarinic receptor antagonist compounds as described above.
In accordance with yet another aspect of the present invention, there is provided the use of the compounds in the preparation of medicament 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, etc.; urinary system which induce such urinary disorder as urinary incontinence, as lower urinary tract symptoms (LUTS), etc.; and gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis, wherein the disease or disorder is associated with muscarinic recptors.
In accordance with another 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 are 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.
Scheme I

(Scheme Removed )
The compounds of Formula I may be prepared, for example, by the reaction sequence as shown in Scheme I. The preparation comprises reacting a compound of Formula VII with a compound of Formula VI, wherein Ar, R1 ,R2 ,W, X , Y, Z ,Q, R6 and R7 are the same as defined earlier 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 VII and a compound of Formula VI can take place in the presence of a condensing agent (for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) or 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU)), in a solvent (such as N,N-dimethylformamide, dimethylsulfoxide, toluene, or xylene, at temperatures ranging from about 0 to about 140°C), to give a protected compound of Formula VIII which on deprotection in the presence of a deprotecting agent (for example, palladium on carbon, trifluoroacetic acid (TFA) or hydrochloric acid) in an organic solvent (for example, methanol, ethanol, tetrahydrofuran or acetonitrile, at temperatures ranging from about 10 to about 50°C) gives an unprotected compound of Formula I.
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.
Particular compounds are shown here:
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound 1);
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide hydrochloride salt (Compound 2);
(2R)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide (Compound 3);
(2R)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide hydrochloride salt (Compound 4);
(2S)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide (Compound 5);
(2S)-(1α5α6α-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide hydrochloride salt (Compound 6);
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-methoxy-2-cyclopentyl-2-phenyl acetamide (Compound 7);
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cycloheptyl-2-phenyl acetamide (Compound 8);
(2R, 2S) (1α,5a,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclobutyl-2-phenyl acetamide (Compound 9);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclobutyl-2-phenyl acetamide tartarate salt (Compound 10);
(2R)(1α,5α,6α)-N- [3 -azabicyclo [3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-(3,3 -difluorocyclopentyl)-2-phenyl acetamide (Compound 11);
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3-fluorocyclopentyl)-2-phenyl acetamide (Compound 12);
(2R,2S)( 1 a,5a,6a)-N- [3 -azabicyclo [3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-(3,3 -difluorocyclopentyl)-2-phenyl acetamide (Compound 13);
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluorocyclopentyl)-2-phenyl acetamide tartarate salt (Compound 14);
(2R,2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2,2-diphenyl acetate (Compound 15);
(2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2,2-diphenyI acetamide (Compound 16);
(2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound 17) and
(2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hex-6-yl methyl)-2-cyclopentyl-2-hydroxy-N-methyl-2-phenyl acetamide (Compound 18).
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 Formulae I and II 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.
Compounds described herein can be prepared from the appropriate acetic acid, in analogy to specific examples provided below. The preparation of such acetic acids is known to those of ordinary skill in the art, and will be recognized by reference to the cited specific examples given below. Other compounds within the scope of the invention, such as those having P6 and/or R7 as methyl, carboxylic acid, amide, amino or methylamino will be readily prepared in analogy to the specific procedures given in the specific examples below, using appropriate azabicylo[3.1.0]hexanes which are synthesized using known methods. Other compounds within the scope of the invention, such as those having Z as oxygen, sulfur or secondary or tertiary amino can be made in analogy to the specific procedures given in the specific examples below, using appropriate starting materials which are made by procedures known to those of ordinary skill in the art.
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.
EXAMPLES
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.
Example 1: Preparation of (2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 1)
Step a: Synthesis of (2R,2S) (1α,5α,6α)-N-[3-benzyl 3-azabicyclo[3.1.0] hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide
To a solution of (1α,5α,6α)-6-aminomethyl-3-benzyl-3-azabicylo[3.1.0]hexane
(prepared as described in EP 0413455 A2) (29.9 mmol, 6.05 gm) in dimethyl formamide (100
ml) was added 2-(R,S)-hydroxy-2-cyclopentyl-2-phenyl acetic acid (prepared following J. Amer
Chem. Soc, 1953; 75:2654) (27.2 mmol, 6.0 gm) and cooled to 0°C. The reaction mixture was
treated with hydroxy benzotriazole (29.9 mmol, 4.04 gm) followed by N-methyl morpholine
(54.4 mmol, 5.2 gm) was stirred at 0°C for 0.5 hours. EDC (l-[3-(dimethylamino)propyl]-3-
ethyl carbodiimide hydrochloride (29.9mmol, 5.7 gms) was added and the reaction mixture was
stirred at 0° C for 1 hour and further at room temperature (RT) overnight. The reaction mixture
was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic
layers were washed with water and dried over sodium sulphate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica gel 100-200 mesh) eluting
compound in 93-95% purity. To obtain higher purity (about 99%) of the compound, it was
triturated with toluene and filtered.
Step b: Preparation of (2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyI-2-phenyl acetamide
To a solution of (2R,2S) (1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-aminomethyl-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide from Example 1, step a (1.0 g, 2.48 mmol) in methanol (25.0 ml), 5% Pd-C (0.2 g), (50% wet) was added under N2. Then, anhydrous ammonium formate (0.8 g, 12.38 mmol) was added under stirring and the reaction mixture was refluxed for half an hour under the N2 atmosphere. The mixture was cooled to room temperature and the reaction mixture was filtered through a bed of hyflo. The hyflo bed was washed with methanol (75.0 ml), ethyl acetate (25. 0ml) and water (25.0 ml). The filtrate was concentrated under vaccum. The residue was diluted with water and pH of the resulting solution was adjusted to pH~14 with 1N NaOH. The solution was extracted with ethyl acetate (2x50 ml) and the ethyl acetate layer was washed with water and brine solution. The layer was dried over anhydrous Na2SO4 and concentrated to give the title compound as solid in 96.2% (0.75g, 2.39 mmol) yield with >98 % purity by HPLC.
The compound exhibited a melting point of 149-151°C, and had infrared absorbance (KBr) at 3410, 2951.5, 2868.3, and 1652.5 cm'1.
1HNMR (CDC13) spectral data were as follows: 5 7.59-7.62 (m, 2H), 7.23-7.36 (m, 3H), 6.56 (brs, 1H), 3.03-3.15 (m, 3H), 2.78-2.90 (m, 4H, including OH), 1.51-1.71 (m, 8H), 1.19-1.27 (m, 4H), 0.70-0.72 (m, 1H). The mass spectrum showed peaks at m/e of 315 (MH+), 297 (M-OH).
Example 2: Preparation of (2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. Hydrochloride salt (Compound No.2)
To a solution of (2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-
2-hydroxy-2-cyclopentyl-2-phenyl acetamide (prepared in Example 1) (0.2g, 0.637 mmole) in
dichloromethane (4.0 ml), ethanolic HCL (1.45 N, 0.5 ml, 0.725 mmol) was added at room
temperature and stirred for 10 minutes. At the same temperature diethyl ether (100 ml) was
added to the reaction mixture, stirred for 5 minutes and concentrated under vacuum without
heating. The residue was triturated with ether to get solid material. The ether layer was
decanted and the solid was dried under vacuum to get the title compound as a hygroscopic solid
in 94% (0.2 lg, 0.6 mmole) yield with >98% purity by HPLC.
Example 3: Preparation of (2R)-(1α,5α,6α)-N-[3-azabicyclo[3.1.01hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.3)
Step a: Synthesis of (2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide
This compound was synthesised following the procedure of Example 1, Step a, using
(2R)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid (synthesised as in Grover et. al., J. Org.
Cherry, 2000; 65:6283-6287), instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step b: Synthesis of (2R)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide
This compound was synthesised following the procedure of Example 1, Step b, using
(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6(aminomethyl)-yl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide instead of (2R,2S) (la,5oc,6a)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. The
enantiomeric excess (ee) was determined by HPLC (Chinacel OD, mobile phase 90%
hexane/10% EtOH/0.1% TFA) by observing the (S) and (R) isomers. The (S) isomer eluted at
approximately 11.11 min. The (R) isomer eluted at approximately 11.81 min. The optical purity
was > 99%.
The compound exhibited a melting point of 150.2°C. Infrared spectral data showed ( DCM):
1653.8 cm-1.
1HNMR spectral data showed (CDC13):8 7.61 (d, J=9Hz, 2H), 7.30-7.38 (m, 2H), 6.70 (s,lH),
3.61-3.68 (m, 2H), 3.08-3.28 (m, 5H), 1.49-1.68 (m, 10H), 1.11-1.26 (m, 2H), 0.75-0.85 (m,
1H).
Example 4: Preparation of (2R)-(1α.5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. hydrochloride salt (Compound No.4)
The hydrochloride salt was synthesised following the same procedure as in Example 2,
using (2R)-(1α, 5α, 6α)-N-[3-azabicylo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide instead of (2R,2S) (1α, 5α, 6α)-N-3-azabicyclo[3.1.0]hexyl-6-
(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide.
Example 5: Preparation of (2S)-(1α,5α,6α)-N-[3-azabicvclo[3.1.01hexvl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.5)
Step a: Synthesis of (2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide
This compound was synthesized following the procedure of Example 1, Step a, using
(2S)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid (synthesised as in Grover et. al., J. Org.
Chem., 2000; 65:6283-6287), instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step b: Synthesis of (2S)-(1α,5α,6α)-N-[3-azabicycIo[3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-cyclopentyl-2-phenyl acetamide
This compound was synthesized following the procedure of Example 1, Step b, using
(2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6(aminomethyl)-yl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide instead of (2R,2S) (1α,5α,6α)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. The
ee was determined by HPLC (Chinacel OD, mobile phase 90% hexane/10% EtOH/0.1% TFA)
by observing the (S) and (R) isomers. The (S) isomer eluted at approximately 11.11 min. The
(R) isomer eluted at approximately 11.81 min. The optical purity was > 99%.
The compound exhibited a melting point of 62.6-63.3 °C. Infrared spectral data showed (KBr): 1653.7 cm-1.
1HNMR spectral data showed (CDC13):δ 7.59-7.62 (m, 2H), 7.29-7.37 (m, 3H), 3.58-3.65 (m, 2H), 3.02-3.24 (m, 4H), 1.11-1.34 (m, 11H), 0.75-0.95 (m, 1H).
Example 6: Preparation of (2S)-(1α,5α,6α')-N-[3-azabicyclo[3.1.0]hexyl-6-aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. hydrochloride salt (Compound No.6)
The hydrochloride salt was synthesized in 90 % yield following the procedure of Example 2, using (2S)-(1α, 5α, 6α)-N-[3-azabicylo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide instead of (2R,2S) (1α, 5α, 6α)-N-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide.
Example 7: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-methoxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 7)
Step a: Preparation of (2R, 2S) 2-methoxy-2-cyclopentyl-2-phenyl acetic acid ethyl ester
To a cold solution of (2R, 2S) 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ethyl ester
(synthesized as per J. Am. Chem. Soc, 1953; 75:2654) (4.5 mmol) in dimethyl formamide was
added sodium hydride (9.08 mmol) in portions at 0°C and stirred at room temperature for 1 hr.
Reaction mixture was cooled to 0°C and iodomethane (18.0 mmol) was added. Reaction
mixture was then stirred at room temperature for 2 hrs. TLC showed absence of starting
material. Water was added to reaction mixture extracted with ethylacetate. The organic layer
dried over anhydrous sodium sulfate and concentrated. Crude compound was purified by
column chromatography & desired product eluted with 2% EtOAc/Hexane.
1H NMR (CDCl3)spectral data were as follows:5 7.47-7.36 (5H, m), 4.31 (2H, q), 3.26 (3H, s), 2.43 (1H, m), 1.66-1.46 (11H, m)
Step b: Synthesis of (2R, 2S) 2-methoxy-2-cyclopentyl-2-phenyI acetic acid
To a solution of (2R, 2S) 2-methoxy-2-cyclopentyl-2-phenyl acetic acid ethyl ester (1.8
mmol) in methanol, potassium hydroxide (KOH) (2.2 mmol) was added and the reaction mixture
refluxed for 7 hrs. TLC showed presence of starting material then 3 mole equivalent KOH was
added and reaction mixture refluxed for 3 hrs. TLC showed absence of starting materials.
Reaction mixture was concentrated, residue was taken in water and neutralized with
concentrated hydrochloric acid & extracted with ethylacetate. Organic layer was washed with
water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to
obtain the desired compound.
1H NMR (CDCl3)spectral data were as follows:5 7.48-7.35 (5H, m), 3.20 (3H, s), 2.94-2.86 (lH,m), 1.86-1.50 (8H,m)
Step c: Preparation of (2R, 2S) (la, 5a, 6a)-N-[3-benzyl-3-azabicyclo[3.1.0] hexyl-6-(aminomethyl)-yl]-2-methoxy-2-cyclopentyl-2-phenyl acetamide
This was prepared following the procedure of Example 1, step 'a' by using 2-methoxy-2-
cyclopentyl-2-phenyl acetic acid instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step d: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-y1] -2-methoxy-2-cyclopenty1-2-pheny1 acetamide
This was prepared following the procedure of Example 1, step b by using (2R, 2S) (1α,
5α, 6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-methoxy-2-cyclopentyl-2-phenyl
acetamide instead of (2R, 2S) (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-
(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide
1H NMR (CDCl3)spectral data showed:5 7.45-7.30 (5H, m), 7.03 (1H, m), 3.25-3.02 (9H, m), 2.00-0.86 (12H,m).
Example 8: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-vl]-2-hydroxy-2-cycloheptyl-2-phenyl acetamide (Compound 8)
Step a: Synthesis of (2R, 2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cycloheptyl-2-phenyl acetamide
This compound was synthesized following the procedure of Example 1, step a, using
(2R, 2S)-2-hydroxy-2-cycloheptyl-2-phenyl acetic acid (synthesized as in Grover et. al, J. Org.
Chem, 2000; 65:6283-6287), instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step b: Synthesis of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yI]-2-hydroxy-2-cycloheptyl-2-phenyl acetamide
This compound was synthesized following the procedure of Example 1, step b, using
(2R, 2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-
cycloheptyl-2-phenyl acetamide instead of (2R, 2S) (1α, 5α, 6α)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide in
90% yield.
1H NMR spectral data showed (CDC13):δ 7.59-7.61 (m, 2H), 7.13-7.36 (m, 3H), 6.76 (brs, 1H),
3.00-3.20 (m, 2H), 2.80-2.92 (m, 2H), 2.50-2.80 (m, 1H), 2.40 (brs, 2H), 1.28-1.73 (m, 12H),
1.00-1.20 (m, 2H), 0.80-0.90 (m, 1H).
Infrared absorbence (DCM) at 1655.7 cm-1
The mass spectrum showed peaks at m/e of: 343 (MH+)
Example 9: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(ammomethyl)-yl]-2-hydroxy-2-cyclobutyl-2-phenyl acetamide (Compound 9)
Step a: synthesis of (2R, 2S) (1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-cyclobutyl-2-pheny 1 acetamide
This compound was synthesized following the procedure of Example 1, step a, using (2R, 2S) 2-hydroxy-2-cyclobutyl-2-phenyl acetic acid (synthesized as per reported procedure of Saul B. Kadin and Joseph G.Cannon., J. Org. Chem., 1962; 27:240-245), instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step b: Synthesis of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-y 1] -2-hydroxy-2-cyclobutyl-2-phenyl acetamide
This compound was synthesized following the procedure of Example 1, step b, using
(2R, 2S) (la, 5a, 6a)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-
cyclobutyl-2-phenyl acetamide instead of (2R, 2S) (1α, 5α, 6α)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide to
give the title compound with 90.6% purity by HPLC.
1HNMR (CDC13) spectral data were as follows: 5 7.50 (2H, m), 7.30 (3H, m), 6.60 (1H, m), 3.60-3.00 (9H, m), 2.04 (1H, m), 1.96-1.74 (6H, m), 1.45 (1H, m), 1.00 (1H, m).
Example 10: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclor3.1.0]hexyl-6-
(aminomethyl)-yl]-2-hydroxy-2-cyclobutyl-2-phenyl acetamide tartarate salt (Compound 10)
To a solution of compound No. 9 in ethanol, solid tartaric acid was added and the
solution was stirred for 1 hour at room temperature and the solvent was evaporated. Ether was
added to it to precipitate the salt. It was washed with ether (4 times) by decanting supernatant
liquid to give the salt as powder with 95.66% purity by HPLC.
1H NMR (CDC13) spectral data were as follows: 8 7.45 (2H, m), 7.21 (3H, m), 4.36 (2H, s), 3.42 (2H, m), 3.20 (3H, m), 3.05 (2H, m), 1.97 (1H, m), 1.90-1.60 (7H, m), 1.10 (1H, m).
Example 11: Preparation of (2R) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluoro cyclopentyl)-2-phenyl acetamide (Compound No. 11)
Step a: Preparation of (2R,5R)-2-tert-butyl-5-phenyl-l,3-dioxalan-4-one
The compound was synthesized following the procedure described in J. Org. Chem., 2000;
65:6283-6287.
Step b: Preparation of (2R,5R)-2-tert-butyl-5-[(lRorlS)-3-oxocyclopentyl]-5-phenyl-1,3-dioxalan-4-one
To a suspension of compound of step a (1.36mmol) in tetrahydrofuran (THF) (12ml) was
added lithium diisopropyl amide (LDA) in THF (1.5 mmol) drop wise at -78°C under nitrogen
atmosphere. The reaction mixture was stirred at the same temperature for 2 hours. A solution of
2-cyclopenten-l-one (1.52mmol) in THF (2ml) was added to the reaction mixture dropwise and
stirred for additional 3hours. The reaction mixture was quenched with saturated aq.ammonium
chloride solution and extracted with ethyl acetate. The organic layer was dried and the residue
obtained after removing the solvents in vacuo was purified by column chromatography (100-
200mesh silica gel). The product was eluted with 10% EtOAc-hexane mixture.
1HNMR(CDCl3):δ-values: 7.70-7.26 (m,5Ar-H), 5.43-5.37 (d,lH), 2.91-2.88 (m,lH), 2.37-1.77 (m,6H), 0.92 (s, 9H) IR(DCM): 1791 and 1746 cm-1
Step c: Preparation of (2R, 5R)-2-tert-butyl-5-[(lRorlS)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one
To a solution of compound of step-b (1mmol) in chloroform (15ml) was added
diethylamino sulphurtrifluoride (DAST), (3.3 mmol) at 0°C under nitrogen atmosphere. The
reaction mixture was stirred at the same temperature for 30 minutes and then at room
temperature for 3 days. After being cooled to 0°C, the reaction mixture (RM) was quenched
carefully by adding water. The organic layer was separated and the aqueous layer extracted with
chloroform. The combined organic layers were dried and the residue obtained after removing the
solvent was purified by column chromatography (100-200 mesh size silica gel) eluting the
compound with 5% EtOAc-hexane mixture.
1HNMR(CDCl3):δ-values : 7.73-7.35 (m,5Ar-H), 5.49 (s,lH), 2.86-2.82 (m,lH), 2.27-1.80 (m,6H), 0.98 (s,H) IR(DCM): 1793 cm-1
Step d: Preparation of (2R)- [(lSorlR)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylaceticacid
The solution of compound of step-c (1mmol) in MeOH (10ml ) was stirred with 3N
aqueous sodium hydroxide solution for overnight at room temperature. The reaction mixture was
concentrated under reduced pressure. The residue was diluted with water and extracted with
dichloromethane. The aqueous layer was acidified with cone.hydrochloric acid and extracted
with EtOAc. The organic layer was dried and concentrated under reduced pressure to give the
product.
m.pt. :123°C
1HNMR(CDCl3):δ-values : 7.69-7.37(m,5Ar-H), 3.29-3.20(m,1H), 2.39-1.68 (m,6H)
Step e: Preparation of (1α,5α ,6α)-6-aminomethyl-3-benzyl-3-azabicyclo [3.1.0] hexane.
The compound was synthesised as per the procedure of EP 0413455A2.
Step f: Preparation of (2R)- (1α,5α ,6α)-N-[3-benzyl-3-azabicyclo [3.1.0] hexy 1-6-(aminomethyl)-yl]-2-[(lRor lS)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylacetamide.
It was prepared following the procedure of Example 1, step a, using the acid synthesized
in step d instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step g: Synthesis of (2R) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-(3,3-difluorocyclopentyl)-2-pheny1 acetamide
It was prepared by following the procedure of Example 1, step b by using (2R) (1α, 5α,
6a)-N- [3 -benzyl-3 -azabicyclo [3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-(3,3 -
difluorocyclopentyl)-2-phenyl acetamide instead of (2R, 2S) (1α, 5α, 6α)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. The
optical purity is 87.27% (HPLC).
1H NMR (CDC13) spectral data showed: 5 7.59-7.55 (2H, m), 7.35-7.31 (3H, m), 7.03 (1H, m), 3.18-3.11 (7H,m), 1.87-1.62 (9H, m).
Example 12: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3-fluorocyclopentyl)-2-phenyl acetamide (Compound 12)
Step-a: Preparation of (2R,2S)-2-tert-butyl-5-[(lR or 1S, 3R or 3S)-3-hydroxy cyclopentyl]-5-phenyl-l,3-dioxalan-4-one.
To a solution of (2R, 2S, 5R)-2-tert-butyl-5-[(lR or lS]-3-oxocyclopentyl]-5-phenyl-l,3-
dioxalan-4-one (1 mmol) in methanol (10 ml) cooled to 0°C, sodium borohydride (2 mmol) was
added in small lots with stirring. The RM was stirred at 0°C for 1 hr. It was concentrated under
reduced pressure and the residue diluted with water and extracted with EtOAc. The organic layer
was dried and the residue obtained after the removal of solvents was purified by column
chromatography (100-200 mesh silica gel) eluting the compound with 20% EtOAc-hexane
mixture.
1HNMR(CDCl3):δ-values : 7.68-7.29 (m, 5H, ArH), 5.45 (d,lH), 4.30 (m, 1H), 3.25 (m, 1H), 2.65-2.63 (m, 1H), 1.80-1.63 (m, 6H), 0.92 (s, 9H) IR(DCM): 1789 cm-1, 3386 cm-1
Step-b: Preparation of (2R, 2S)-2-tert-butyl-5-[lR or 1S, 3R or 3S]-3-fluorocycIopentyl]-5-phenyl-l,3-dioxolan-4-one.
The solution of compound of step-a (1 mmol) in chloroform (10 ml) was cooled to 0°C
and diethylamino sulphur trifluoride (DAST) (1.5 mmol) was added dropwise under nitrogen
atmosphere. The RM was stirred at 0°C for 30 minutes and then at room temperature for 3 days.
The RM was cooled and carefully quenched with aqueous ammonium chloride solution. The
organic layer was separated and aqueous layer extracted with EtOAc. The combined organic
layer was dried and residue obtained after removing the solvents was purified by column
chromatography (100-200 mesh, silica gel) eluting the compound with 5% EtOAc-hexane
mixture.
1HNMR(CDCl3):δ-values : 7.68-7.28 (m, 5H, Ar-H) , 5.46 (d,lH), 5.39 (m, 1H), 2.90 (m, 1H), 1.98-1.25 (m,6H), 0.93 (s,9H)
Step-c: Preparation of (2R, 2S)-[(1R or 1S, 3R or 3S]-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.
The compound was synthesised following the procedure of Example 11, step-d using
(2R, 2S, 5R)-2-tert-butyl-5-[(1R or 1S, 3R or 3S)-3-fluorocyclopentyl]-5-phenyl-l,3-dioxolan-4-
one instead of (2R, 5R)-2-tert-butyl-5-[(lR or 1S)-3,3-difluorocyclo pentyl]-5-phenyl-l,3-
dioxolan-4-one.
1HNMR(CDC13):δ 7.66-7.27 (m, 5Ar-H), 5.30-5.00 (m, H), 3.32-3.16 (m, 1H), 2.05-1.26 (m,
6H).
IR(DCM): 1710 cm-1
Step-d: Preparation of (2R, 2S)-(1α,5α ,6α)-N-[3-benzyl-3-aza bicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[lR or 1S, 3R or 3S]-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide.
This compound was synthesized following the procedure of Example 1, step a, using the
acid synthesized in the above step-c, instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step-e: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3-fluorocyclopentyl)-2-phenyla cetamide
This compound was synthesized following the procedure of Example 1, step b, using (2R, 2S)-(1α,5α ,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[1R or 1S, 3R or 3S]-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide instead of (2R, 2S) (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide. The optical purity was 87.27% (HPLC).
1H NMR spectral data showed (CDC13):δ 7.56 (2H, m), 7.35 (3H, m), 6.08 (1H, m), 5.30-5.03
(1H, m), 3.27 (1H, m), 3.11 (2H, m), 2.91 (4H, m), 2.04-1.48 (9H, m), 0.71 (1H, m).
Example 13: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-
(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluoro cyclopentyl)-2-phenyl acetamide (Compound 13)
This compound was prepared following the procedure of Example 11, by using (2R, 2S)
[(1α, 5α, 6α)-N- [3 -benzyl-3 -azabicyclo [3.1.0]hexyl-6-(aminomethyl)-yl] -2-hydroxy-2-(3,3 -
difluorocyclo-pentyl)-2-phenyl acetamide]instead of (2R) [(1α, 5α, 6α)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluorocyclo-pentyl)-2-phenyl
acetamide] in step g, Example 11.
The optical purity is 83.778% (HPLC).
1H NMR spectral data showed (CDC13) δ : 7.57-7.30 (5H, m), 6.49-6.44 (1H, m), 3.33 (1H, m),
3.10 (2H, m), 6.49-6.44 (1H, m), 3.33 (1H, m), 3.10 (2H, m), 2.87 (3H, m), 2.23-1.80 (8H, m),
1.79-1.20 (2H,m)
IR(KBr) :3410,1654 cm-1
Example 14: Preparation of (2R, 2S) (1α.5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-
yl]-2-hydroxy-2-(3.,3-difluorocyclopentyl)-2-phenyl acetamide tartarate salt (Compound 14)
To a solution of compound No. 13 in ethanol was added tartaric acid & heated the reaction
mixture at 60°C for 1 hour. The reaction mixture was then concentrated under reduced pressure,
added diethyl ether and the organic layer was removed to get light brown solid as the desired
compound. The optical purity was found to be 98.14% (HPLC)
1H NMR spectral data showed (CD3OD):δ 7.50 (2H, m), 7.20 (3 H, m), 4.40 (2H, s), 3.60-3.00 (6H, m), 2.10-1.60 (8H, m), 1.19 (1H, m), 0.90 (1H, m). IR(KBr) :3407,1653 cm-1
Example 15: Preparation of (2R, 2S) (1α.5α.6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2,2-diphenyl acetate (Compound 15)
Step a: Synthesis of (2R, 2S) (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl] -2-hydroxy-2,2-diphenyl acetate.
Step (i): Preparation of (la, 5a, 6a)-3-benzyl-6-hydroxymethyl-3-aza bicyclo[3.1.0]hexane.
Synthesized as per reported procedure of EP 0 413 455 A2.
Step (ii): Preparation of (1α, 5α, 6α)-3-benzyl-6-(methanesulfonyloxy)methyl-3-azabicyclo[3.1.0]hexane:
A solution of the title compound of preparation of step (i) (0.203 g; 1 mmol) and triethyl
amine (0.21 gms, 2 mmol) in ethyl acetate (25 ml) was cooled to -10°C and treated with
methanesulfonyl chloride (0.17 gms, 1.5 mmol). After stirring for one hour at- 10°C, the
reaction was poured into a saturated aqueous sodium bicarbonate solution. The organic layer
was dried over sodium sulphate. Filtration and removal of solvent in vacuo provided the title
compound as a yellow oil, which was used as such in the following step without further
purification.
1H NMR (CDCl3):δ-values: 7.45 (m, 5H, arom.), 4.29 (s, 2H), 3.81 (m, 2H), 3.13 (m, 4H), 2.84 (s,3H), 1.38 (m,3H)
Step (iii): Preparation of (1α, 5α, 6α)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2,2-diphenyl acetate
To a solution of 2-hydroxy-2,2-diphenyl acetic acid (synthesized as per reported
procedures in Vogel's textbook of "Practical Organic Chemistry," page 1046 (5th Ed); J. Am.
Chem. Soc, 1953; 75:2654 and EP 613232) (1 mmol, 0.228 gms) in xylene was added, (1α, 5α,
6α)-3-benzyl-6-(methanesulfonyloxyl) methyl-3-azabicyclo[3.1.0]hexane (0.28 gms, 1 mmol)
followed by DBU (l,8-diazabicyclo[5,4,0] undec-7-ene), (2 mmol, 0.305 gms) and the reaction
mixture refluxed for 6 hrs. The RM was then washed with water, brine and dried over sodium
sulphate. The solvents were evaporated and the crude compound thus obtained was purified by
column chromatography (silicagel, 100-200 mesh) eluting the compound with 20-80,
ethylacetate hexane.
1H NMR (CDC13):δ - values: 7.46-7.22 (m, 15H, arom), 4.24 (s, 1H), 4.11-4.09 (d, 2H), 3.56 (s, 2H), 2.91-2.89 (d, 2H), 2.31-2.29 (d, 2H), 1.67-1.62 (m, 1H), 1.3 (s, 2H) IR(DCM): 1724 cm-1
Step b: Synthesis of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2,2-diphenyl acetate
It was debenzylated by following the procedure of Example 1, step b to give the title
compound in 60% yield.
IR(KBr): 1731.6 cm-1
1H NMR (CDC13) spectral data showed: 5 7.33-7.47 (m, 10H), 4.17 (d, 2H, J=6Hz), 2.72-2.92
(m, 4H), 0.94-0.99 (m, 2H), 0.88 (t, 1H),
The mass spectrum showed peaks at m/e of 324 (M+1)
Example 16: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2,2-diphenyl acetamide (Compound 16)
Step a: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyI-6-(aminomethyl)-yl]-2-hydroxy-2,2-diphenyl acetamide.
It was prepared following the procedure of Example 1, step a by using 2-hydroxy-2,2-
diphenyl acetic acid (synthesized as per reported procedures in Vogel's textbook of "Practical Organic Chemistry," page 1046 (5th Ed), J. Am. Chem. Soc, 1953; 75:2654 and EP 613232) instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step b: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluorocyclopentyl)-2-phenyl acetamide
This compound was prepared following the procedure of Example 1, step b, using
(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2,2-
diphenylacetamide instead of (2R, 2S) (1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-
(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide to give the title compound in
70% yield.
IR(KBr): 1658.0 cm-1
1H NMR (CDCl3) spectral data showed:5 7.34-7.44 (m, 10H), 6.53 (s, 1H), 3.17-3.26 (m, 2H),
2.87-3.01 (m, 4H), 1.38 (s, 2H), 0.88 (t, 1H).
The mass spectra showed peaks at m/e 323 (M+1), 305 (M-OH).
Example 17: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound No. 17)
Step a: Synthesis of (1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide
It was prepared following the procedure of Example 1, step a by using 2-hydroxy-2-
cyclohexyl-2-phenyl acetic acid (synthesized as per the procedure described in J. Amer. Chem.
Soc, 1953; 75:2654) instead of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid.
Step b: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-y 1] -2-cyclohexyl-2-phenyl acetamide
This compound was prepared following the procedure of Example 1, step b using (2R, 2S)
(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-
cyclohexyl-2-phenyl acetamide instead of (2R, 2S) (1α,5α,6α)-N-[3-benzyl-3-
azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide to
give the title compound in 80% yield.
IR(KBr): 1654.7 cm-1
1H NMR (CDCl3) spectral data showed:8 7.59-7.62 (m, 2H), 7.29-7.37 (m, 3H), 6.71 (s, 1H),
3.03-3.14 (m, 2H), 2.80-2.92 (m, 4H), 2.42 (m, 1H), 1.13-1.35 (m, 12H), 0.88 (m, 1H)
The mass spectra recorded peaks of 329 (M+l), 311 (M-OH).
Example 18: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hex-6-yl methyl)-2-cyclopentyl-2-hydroxy-N-methyl-2-phenyl acetamide (Compound 18)
Step a: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-tert-butyloxycarbonyl-3-azabicyclo [3.1.0] -hexyl-6-yl methyl] -2-hydroxy-2-cyclopenty1-2-pheny1 acetamide
To a solution of (1α,5α,6α)-3N-benzyl-6-amino-3-azabicyclo[3.1.0] hexane (synthesized as
per reported procedure of Braish T.F. et. al., Synlett, 1996; 1100) (2.5 g, 7.96 mole) in (50.0
mmol) at 0°C, triethylamine (3.9 ml, 28 mmol) and Boc-anhydride (5.2 g, 23.9 mmol) were
added. The reaction mixture was stirred at 0°C for 30 minute and at room temperature for 12
hrs. Diluted with dichloromethane (50 ml) and washed with water and brine solution. Dried
over anhydrous sodium sulfate and concentrated. The residue was purified by column
chromatography using 25% ethyl acetate in hexane to give the title compound as solid in 86% (2.85 g, 6.9 mmol) yield. The compound exhibited a melting point of 179.5-182.9°C.
Step b: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-tert-butyloxycarbonyl-3-azabicyclo [3.1.0] hexyl-6-ylmethyl)-2-(3-silyltrimethyloxy)-2-cyclopentyl-2-phenyl acetamide
To a solution of Boc-derivative (2.0 g, 4.8 mmol) in dimethylformamide (10.0 ml),
imidazole (1.2 g, 16.9 mmol) and trimethylsilyl chloride (1.54 ml, 12.0 mmol) were added and
the reaction mixture was stirred at RT for 12 hrs. Diluted with water (50.0 ml) and extracted
with ethyl acetate. The ethyl acetate layer was washed with water and brine solution. Dried and
concentrated. The residue was purified by column chromatography using 15% ethyl acetate in
hexane to give the title compound in 85% (2.0 g, 4.1 mmol) yield.
Step c: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-tert-butyloxycarbonyl-3-azabicyclo [3.1.0] hex-6-yl methyl)-2-cyclopentyl-2-hydroxy-N-methy1-2-phenyl acetamide
To a solution of trimethylsilyl derivative (2.0 g, 4.1 mmol) and n-tetrabutyl ammonium
iodide (0.11 gm, 0.3 mmol) in dry tetrahydrofuran (THF) (20.9 ml) at 0°C, sodium hydride (0.6
g, 12.3 mmol) was added in portion and the resulting solution was stirred at 0°C for 15 minutes
and allowed to cool to room temperature and stirred for 1 hours at RT. Again cooled to 0°C and
methyl iodide (2.3 ml, 36.8 mmol) in dry THF (2.0 ml) was added dropwise. Stirred for 12 hrs
at RT. Saturated aqueous NaHCO3 solution (10.0 ml) was added organic layer was separated
and dried over anhydrous sodium sulfate Concentrated and the residue was purified by
column chromatograph using 15% ethyl acetate in hexane to give the title compound as
semisolid in 61% (1.25 g, 2.49 mmol) yield.
Step d: Preparation of (2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cycIopentyI-2-hydroxy-N-methyl-2-phenyl acetamide
To a solution of the compound (0.2 g, 0.4 mmol) from the above step in ethanol (5.0
ml), conc.HCl was added dropwise till the pH of the reaction mixture was 2. The reaction
mixture was stirred at RT for 24 hrs. Neutralized with saturated aqueous sodium bicarbonate
solution. Concentrated under vacuum and the residue was taken in dichloromethane (10.0 ml)
and washed with water and brine solution. The organic layer was dried over anhydrous sodium
sulfate and concentrated to give the title compound as solid in 54% (0.07 g, 0.21 mmol) yield.
m.p.: 91.5°C
1H NMR (CDC13) spectral data showed:5 7.29-7.42 m, 5H), 5.39 (m, 1H), 2.81-3.52 (m, 10H),
1.11-1.82 (m, 12H)
IR(DCM): 1621.9 cm-1
The mass spectrum showed peak of 329 (MH+).
Biological Activity
Radioligand Binding Assays: The affinity of test compounds for M2 and M3 muscarinic receptor subtypes was determined by [ 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 500g 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 40,000g and the homogenate was passed through a filter gauge before any spinning. The assay conditions were modified as follows: the assay volume was 250 µL; 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 µL/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 20mM, 10mM 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 10min. The supernatant was subsequently centrifuged at 40,000g for 20 min. The pellet thus obtained was resuspended in same volume of 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 buffer (HEPES
20 mM, pH 7.4) at 24-25°C for 3h. Non-specific binding was determined in the presence of 1 uM atropine. The incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac). The filters were then washed with ice cold 50mM Tris HC1 buffer (pH 7.4). The filter mats were dried and bound radioactivity retained on filters was counted. The IC50 and Kd were
estimated by using the non-linear curve fitting program using G Pad Prism software. The value
of inhibition constant Kj was calculated from competitive binding studies by using Cheng &
Prusoff equation (Biochem Pharmacol, 1973; 22:3099-3108), Ki = IC50 /(1+L/Kd), where L is
the concentration of [ H]NMS used in the particular experiment. pKj = -[log Kj]
Functional Experiments using isolated rat bladder:
Methodology: Animals were euthanized by overdose of urethane and whole bladder
was isolated and removed rapidly and placed in ice cold Tyrode buffer with the following
composition (mMol/L) NaCl 137; KC1 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 (3mm wide and 5-6 mm long) and mounted in 10 ml organ baths at 30° C, with one end connected to the base of the tissue holder and the other end connected to a polygraph through a force displacement transducer. Each tissue was maintained at a constant basal tension of 2 g and allowed to equilibrate for 1 hour during which the PSS was changed every 15 min. At the end of equilibration period the stabilization of the tissue contractile response was assessed with 1µmol/L of Carbachol consecutively for 2-3 times. Subsequently a cumulative concentration response curve to carbachol (10-9 mol/L to 3 X 10-5 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 CRC).
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 were calculated by the formula pKB = - log [ (molar concentration of antagonist/ (dose ratio-1))] where, dose ratio = ED50 in the presence of antagonist/ED50 in the absence of antagonist.
In vivo experiments using anesthetized rabbit: The effect of test substances was studied on carbachol evoked changes on bladder pressure, heart rate and salivation. Male rabbits weighing 1.2-3 kg were anaesthetized with urethane (1.5g/kg), and administered as a slow intravenous infusion through the marginal ear vein. The tracheae were cannulated to maintain airway patency. Blood pressure was recorded from the femoral artery by means of a Statham P10 EZ pressure transducer connected to a Grass model 7D polygraph. The heart rate was monitored by a tachograph triggered by the pulse wave of blood pressure. The other femoral artery was cannulated for the administration of carbachol. Test compound and saline were infused intravenously via the femoral vein.
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 15ml 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 effect of the compound on carbachol (1.5µg/kg, intrarterial) induced changes on blood pressure, heart rate and bladder pressure were observed. At least two stable responses
were obtained. These responses were considered as 100%. Subsequently, effect of increasing dose of test compound or vehicle (i.v,12 to 15 min before carbachol challenge) was studied.
The change in bladder pressure, salivation and agonist induced bradycardia were expressed as % change from pretreatment control. ID50 values (dose required to inhibit 50% of response) were calculated from non-linear curve fitting for sigmoidal dose response curve using Graph Pad Prism software and values were expressed as µg/kg . The results of the in-vitro and in-vivo tests are listed in Table I and Table II.
Table I
(Table Removed)









WE CLAIM:
1. Azabicyclo[3.1.0]hexane compounds as muscarinic receptor antagonists, having the structure of Formula I:
(Formula Rempved)
wherein Ar represents an aryl which may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C1-C4), lower perhalo alkyl (C1-C4), cyano, hydroxy, nitro, lower alkoxy (C1-C4), lower perhalo alkoxy (C1-C4), unsubstituted amino, N-lower alkyl (C1-C4) or -aryl amino, amino carbonyl, or N-lower alkyl (C1-C4) or -aryl amino carbonyl;
R1 represents a hydroxy;
R2 represents C3-C7 cycloalkyl ring, an aryl wherein the aryl, or a cycloalkyl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C1-C4), hydroxy, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C1-C4), unsubstituted amino, N-lower alkyl (C1-C4) or -aryl amino, amino carbonyl, or N-lower alkyl (C1-C4) or -aryl amino carbonyl;
W represents (CH2)P, wherein p represents 0;
X represents no atom;
Y represents (CH2)q q represents 0;
Z represents oxygen or NR10, wherein R10 represents hydrogen, or C1-6 alkyl;
Q represents (CH2)n (wherein n represents 0 to 4); and
R6 and R7 are independently selected from H.
2. The compounds as claimed in claim 1 having the structure of Formula II wherein s represents 1 to 2.
(Formula Rempved)
3. A compound as claimed in claim 1 selected form the group consisting of:
(2R,2S) (lα,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound 1);
(2R,2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide hydrochloride salt (Compound 2);
(2R)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide (Compound 3);
(2R)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide hydrochloride salt (Compound 4);
(2S)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide (Compound 5);
(2S)-(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl 2-phenyl acetamide hydrochloride salt (Compound 6);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-methoxy-2-cyclopentyl-2-phenyl acetamide (Compound 7);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cycloheptyl-2-phenyl acetamide (Compound 8);
(2R, 2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclobutyl-2-phenyl acetamide (Compound 9);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclobutyl-2-phenyl acetamide tartarate salt (Compound 10);
(2R) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluorocyclopentyl)-2-phenyl acetamide (Compound 11);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3-fluorocyclopentyl)-2-phenyl acetamide (Compound 12);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluorocyclopentyl)-2-phenyl acetamide (Compound 13);
(2R, 2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-(3,3-difluorocyclopentyl)-2-phenyl acetamide tartarate salt (Compound 14);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2,2-diphenyl acetate (Compound 15);
(2R, 2S)(1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2,2-diphenyl acetamide (Compound 16);
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound 17) and
(2R, 2S) (1α,5α,6α)-N-[3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-N-methyl-2-phenyl acetamide (Compound 18).
4. A compound as claimed in claim lor 2, as and when used in the preparation of medicaments 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 receptor.
5. A compound as claimed in claim 4 wherein the said disease or disorder is urinary incontinence, lower urinary tract symptoms (LUTS), bronchial athma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, irritable bowel-syndrome, obesity, diabetes and gastrointestinal hyperkinesis.
6. A method of preparing a compound of Formula I as claimed in claim 1,
(Formula Rempved)
wherein Ar ,R1, R2 ,W, X, Y , Z , Q and R6 and R7 are the same as defined in claim 1
said method comprising:
(a) reacting a compound of Formula VII with a compound of Formula VI
(Formula Rempved)
to give a protected compound of Formula VIII wherein Ar, R1, R2, W, X, Y, Z, and Q are as defined, and P is a protecting group for an amino group
(Formula Rempved)
(b) deprotecting the compound of Formula VIII in the presence of a deprotecting agent to give compound of Formula I wherein Ar, R1, R2, W , X, Y, Z, and Q are as defined.
(Formula Rempved)

Documents:

405-delnp-2005-Abstract (19-11-2009).pdf

405-DELNP-2005-Abstract-(03-09-2009).pdf

405-DELNP-2005-Abstract-(28-02-2011).pdf

405-DELNP-2005-Abstract.pdf

405-delnp-2005-Claims (19-11-2009).pdf

405-DELNP-2005-Claims-(03-09-2009).pdf

405-DELNP-2005-Claims-(28-02-2011).pdf

405-DELNP-2005-Claims.pdf

405-delnp-2005-Correspondence-Others (19-11-2009).pdf

405-DELNP-2005-Correspondence-Others-(03-09-2009).pdf

405-DELNP-2005-Correspondence-Others-(09-03-2011).pdf

405-DELNP-2005-Correspondence-Others-(12-11-2009).pdf

405-DELNP-2005-Correspondence-Others-(28-02-2011).pdf

405-DELNP-2005-Correspondence-Others.pdf

405-DELNP-2005-Description (Complete)-(03-09-2009).pdf

405-DELNP-2005-Description (Complete)-(28-02-2011).pdf

405-DELNP-2005-Description (Complete).pdf

405-DELNP-2005-Form-1-(03-09-2009).pdf

405-DELNP-2005-Form-1-(12-11-2009).pdf

405-DELNP-2005-Form-1.pdf

405-DELNP-2005-Form-18.pdf

405-DELNP-2005-Form-2-(03-09-2009).pdf

405-DELNP-2005-Form-2.pdf

405-DELNP-2005-Form-3-(12-11-2009).pdf

405-DELNP-2005-Form-3-(28-02-2011).pdf

405-DELNP-2005-Form-5-(12-11-2009).pdf

405-DELNP-2005-Form-5-(28-02-2011).pdf

405-DELNP-2005-GPA-(09-03-2011).pdf

405-DELNP-2005-Petition 137-(12-11-2009).pdf


Patent Number 247532
Indian Patent Application Number 405/DELNP/2005
PG Journal Number 16/2011
Publication Date 22-Apr-2011
Grant Date 18-Apr-2011
Date of Filing 02-Feb-2005
Name of Patentee RANBAXY LABORATORIES LIMITED
Applicant Address CORPORATE OFFICE AT 19, NEHRU PLACE, NEW DELHI -110019, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 MOHAMMAD SALMAN PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
2 ANITA MEHTA PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
3 PAKALA KUMARA SAVITHRU SARMA PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
4 SHANKAR JAYRAM SHETTY PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
5 SANKARANARAYANAN DHARMARAJAN PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
6 NARESH KUMAR PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
7 ARUNDUTT VISWANATHAM SILAMKOTI PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
8 ANITA CHUGH PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARYANA), INDIA.
PCT International Classification Number C07D 209/52
PCT International Application Number PCT/IB2003/001367
PCT International Filing date 2003-04-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PCT/IB2003/001367 2003-04-11 PCT