Source: http://www.google.com/patents/US5948792?dq=7222078
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Patent US5948792 - Fluorine-containing 1,4-disubstituted piperidine derivatives - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsNovel fluorine-containing 1,4-disubstituted piperidine derivatives, represented by general formula I! ##STR1## such as, for example, (2R)-N- 1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide or pharmaceutically acceptable salt thereof, are potent...http://www.google.com/patents/US5948792?utm_source=gb-gplus-sharePatent US5948792 - Fluorine-containing 1,4-disubstituted piperidine derivativesAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS5948792 APublication typeGrantApplication numberUS 08/903,768Publication dateSep 7, 1999Filing dateJul 31, 1997Priority dateAug 1, 1996Fee statusPaidAlso published asCA2261680A1, CA2261680C, CN1226888A, DE69718026D1, DE69718026T2, EP0930298A1, EP0930298A4, EP0930298B1, US6040449, WO1998005641A1Publication number08903768, 903768, US 5948792 A, US 5948792A, US-A-5948792, US5948792 A, US5948792AInventorsYoshimi Tsuchiya, Takashi Nomoto, Hirokazu Ohsawa, Kumiko Kawakami, Kenji Ohwaki, Masaru NishikibeOriginal AssigneeBanyu Pharmaceutical Co., Ltd.Export CitationBiBTeX, EndNote, RefManPatent Citations (9), Non-Patent Citations (10), Referenced by (49), Classifications (27), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetFluorine-containing 1,4-disubstituted piperidine derivatives
US 5948792 AAbstract
Novel fluorine-containing 1,4-disubstituted piperidine derivatives, represented by general formula I! ##STR1## such as, for example, (2R)-N- 1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide or pharmaceutically acceptable salt thereof, are potent and selective antagonists for muscarinic M3 receptors with little side effects. The compounds of formula I! exhibit excellent oral activity, duration of activity and pharmacolkinetics. They are useful for treatment and prophylaxis of respiratory diseases, such as chronic obstructive pulmonary diseases; urinary diseases, such as urinary incontinence; and digestive diseases, such as irritable bowel syndrome, and motion sickness.
1. A flourine-containing 1,4-disubstituted piperidine compound selected from formula I! ##STR52## and its pharmaceutically acceptable salt thereof, wherein:Ar represents an aryl group or a heteroaryl group having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogen atoms on the ring of said aryl or heteroaryl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino); R1 represents C3 -C6 cycloalkyl substituted with 1 to 4 fluorine atom(s); R2 represents C5 -C15 saturated or unsaturated aliphatic hydrocarbon groups whose any 1 to 6 hydrogen atoms may be substituted with fluorine atom(s), aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulfur (optionally any 1 to 3 hydrogen atoms on the ring in said aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl group may be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino); and X stands for O or NH,provided that at least either one of R1 and R2 contains one or more fluorine atoms. 2. The compound or its their pharmaceutically acceptable salt according to claim 1, in which Ar is phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino and alkylamino.
This invention relates to novel fluorine-containing 1,4-disubstituted piperidine derivatives, processes for preparing them, pharmaceutics containing them and their use as medicines, especially in the treatment or prophylaxis of various diseases of the respiratory, urinary and digestive systems.
Antagonism to muscarinic receptors are known to cause bronchodilation, gastrointestinal hypanakinetics, gastric hyposecretion, dry mouth, mydriasis, suppression of bladder contraction, hypohidrosis, tachycardia and the like "Basic and Clinical Pharmacology", 4th ed., APPLETON & RANGE, pp. 83-92 (1989); Drug News & Perspective, 5(6), pp. 345-352 (1992)!.
According to the present invention, there are provided novel fluorine-containing 1,4-disubstituted piperidine derivatives of the general formula I! ##STR2## and pharmaceutically acceptable salts thereof, wherein:
The reaction temperature may usually range from -70° C. to the boiling point of the solvent used for the reaction and preferably from -20° C. to 100° C. Under these conditions, the reaction can usually be completed in a period of time ranging from 5 minutes to 7 days and preferably from 10 minutes to 24 hours.
The reaction temperature may usually range from -70° C. to the boiling point of the solvent used for the reaction and preferably from -20° C. to 100° C.
Removal of protective groups from hydroxyl and oxo groups which are protected in the form of ketals in the compounds of formula IX! can normally be effected in aqueous solvent, using an inorganic acid, an organic acid, a weakly acidic salt or the like. Suitable inorganic acids include, for example, hydrochloric acid and sulfuric acid; suitable organic acids include, for example, p-toluenesulfonic acid, benzenesulfonic acid, camphor-sulfonic acid and acetic acid; and suitable weakly acidic salts include, for example, ammonium chloride and pyridinium p-toluenesulfonate. Preferred aqueous solvents include aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, aqueous dioxane and the like. The reaction may usually be carried out in the presence of a catalytic amount to 5 equivalents, preferably a catalytic amount to 1 equivalent, of such an acid or salt at a temperature ranging from 0° C. to 100° C. and preferably from room temperature to 80° C.
Conversion of the hydroxyl or oxo group(s) to fluorine atom(s) can normally be effected by causing the compound to react in an inert solvent which is not detrimental to the reaction, e.g., methylene chloride, chloroform, tetrahydrofuran, methanol, acetonitrile, dimethylsulfoxide or pyridine, or in the absence of a solvent, using one equivalent to an excessive amount, preferably 1-2 equivalents, of a fluorinating agent such as sulfurtetrafluoride, diethylaminosulfurtrifluoride, cesium fluorosulfate, tetrabutylammonium fluoride, tris(dimethylamino)sulfonium-difluorotrimethylsilicate, hydrogen fluoride or tosyl fluoride, preferably at temperatures ranging -80° C.-180° C. for 10 minutes to 72 hours.
Solvolysis with an acid can normally be carried out by treating the compound with an acid such as formic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid, in an inert solvent such as methylene chloride, anisole, tetrahydrofuran, dioxane, methanol or ethanol or a mixture of such a solvent and water, or in the absence of solvent, preferably at a temperature in the range from about 0° to about 100° C., for a period of time ranging from 10 minutes to 24 hours.
Solvolysis with a base can normally be carried out by treating the compound with an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate, e.g., sodium carbonate or potassium carbonate, in an inert solvent which exerts no adverse effect on the reaction, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane or a mixture of such a solvent and water, preferably at a temperature in the range of from about -20 to about 80° C., for a period of time ranging from 10 minutes to 24 hours.
Catalytic reduction can normally be carried out in the presence of a catalyst such as palladium-on-carbon, palladium hydroxide, Raney nickel or platinum oxide, in an inert solvent, e.g., methanol, ethanol, water or acetic acid or a mixture of such solvents, preferably under a pressure of hydrogen of about 1 to about 20 kg/cm2, preferably at a temperature in the range of from about 0 to about 40° C., for a period of time ranging from 10 minutes to 24 hours.
The reaction temperature may usually range from about 0° C. to the boiling point of the solvent, and the reaction time may usually range from 10 minutes to 48 hours. If desired, however, reaction conditions beyond these limits may be used.
The reaction temperature may usually range from about -30° C. to about 200° C. and preferably from about 0° C. to about 100° C. The reaction time may usually range from 10 minutes to 7 days and preferably from 10 minutes to 24 hours.
These tests were performed according to a modification of the method of Hargreaves et al. (Br. J. Pharmacol. 107: 494-501, 1992). Membranes from CHO cells expressing cloned human m1-m5 (Receptor Biology, Inc.) were incubated with 0.2 nM 3 H!-N-methylscopolamine and each a compound of the present invention to be tested in 0.5 ml of 50 mM Tris-HCl-10 mM MgCl2 -1 mM EDTA (pH 7.4) for 2 hours at 25° C. Free and membrane-bound 3 H!-N-methylscopolamine were separated by filtration over glass filters (UniFilter-GF/C; Packard Instruments Co., Inc.) using cell harvester (Filtermate™ 196; Packard Instruments Co., Inc.). Then the filter was washed four times with 1 ml of ice-cold Tris-HCl (pH 7.4) and dried at 50° C. After adding a scintillator (Microscinti 0; Packard Instruments Co., Inc.), the radioactivity was counted by a liquid scintillation counter (TopCount™; Packard Instruments Co., Inc.). Non-specific binding was measured in the presence of 1 μM N-methylscopolamine. According to the method of Cheng and Prussoff (Biochem. Pharmacol. 22: 3099-3108, 1973), the binding affinity (Ki value) of the test compound (i.e., a compound of the present invention) for muscarinic receptors was calculated from the concentration of the test compound which achieved 50% inhibition of binding of 3 H!-N-methylscopolamine (IC50 value).
These tests were performed according to a conventional method. A male SD strain rat (weighing 300-500 g) was killed by exsanguination, and the right atrium was isolated. This preparation was isometrically suspended in organ bath filled with 20 ml of Krebs-Henseleit solution (gassed with 95% O2 -5% CO2 and kept at 32° C.) with an initial tension of 0.5 g. The heart rate was recorded with a heart rate counter. After the preparation was equilibrated for 30 minutes, carbachol (10-9 to 10-6 M) was cumulatively administered in three-fold increasing doses. Thus, a decrease in heart rate was measured to obtain a dose-response curve for the control experiment. After the preparation was washed with fresh solution to restore the heart rate, a test compound was administered thereto. Ten minutes later, carbachol was cumulatively administered again. Responses to carbachol were expressed as percentages based on the heart rate before administration of carbachol as 100%. The antagonistic potency (KB value) of the test compound was determined from the degree of shift of the dose-response curve obtained by treatment with individual test compound of the present invention.
These tests were performed according to a conventional method. A male SD strain rat (weighing 300-500 g) was killed by exsanguination, and the trachea was isolated. Annular segments (2 mm wide) were cut out from the trachea and cut transversely at the anterior cartilage part to make open ring preparation. A preparation was suspended in a Magnus tube filled with 5 ml of Krebs-Henseleit solution (gassed with 95% O2 -5% CO2 and kept at 32° C.) with an initial tension of 1.0 g and a resting tension of 0.6 g. The tension of the preparation was recorded isometrically. After being equilibrated for an hour, the preparation was made to contract twice by treatment with 10-4 M carbachol, and the second contraction induced by carbachol was used as the reference contraction. After the preparation was washed with fresh solution to be restored to the base line, a test compound was administered thereto (or no treatment was given). Ten minutes later, carbachol (10-8 to 10-3 M) was cumulatively administered in three-fold increasing doses to obtain a dose-response curve. The dose-response curve was plotted by expressing responses as percentages based on the reference contraction of the preparation as 100%. The antagonistic potency (KB value) of the test compound was determined from the degree of shift of the dose-response curve obtained by treatment with the test compound.
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR10## Step 1. Synthesis of 1-(4-methyl-3-pentenyl)-4-piperidone
To a solution of 75 mg of (2R)- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetic acid in 3 ml of N,N-dimethylformamide, 55 mg of 1,1'-carbonyidiimidazole was added at room temperature, followed by stirring for 2 hours at the same temperature. Then 60 mg of 4-amino-1-(4-methyl-3-pentenyl)piperidine and 5 mg of 4-dimethylaminopyridine were added sequentially, followed by stirring overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified by preparative thin layer chromatography Kieselgel™ 60F254, Art 5744 (manufactured by E. Merck); chloroform/methanol=10/1!, to provide 23 mg of the title compound as an oil.
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1S)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR11##
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1S,3S)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetamide and (2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1S,3R)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR12##
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1S, 3S)-3-fluorocyclopentyl!-2-hydroxyl-2-phenylacetamide
1 H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.31-2.33 (15H, m), 2.44-2.49 (1H, m), 2.69-2.81 (2H, m), 3.19-3.30 (1H, m), 3.62-3.74 (1H, m), 3.90 (1H, brs), 5.03-5.28 (2H, m), 5.87-5.91 (1H, m), 7.25-7.40 (3H, m), 7.53-7.57 (2H, m)
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1S,3R)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetamide
1 H-NMR (CDCl3, δ ppm): 1.61 (3H, s), 1.68 (3H, s), 1.37-2.26 (14H, m), 2.32-2.37 (2H, m), 2.75-2.90 (2H, m), 3.43-3.56 (1H, m), 3.62-3.76 (1H, m), 5.04-5.13 (2H, m), 6.91-6.95 (1H, m), 7.23-7.35 (3H, m), 7.67-7.71 (2H, m)
(2R)-N- -1(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1R,3S)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetamide and (2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1R,3R)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR13##
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1R,3S)-3-fluorocyclopentyl!-2-hydroxy-2phenylacetamide
1 H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.70 (3H, s), 1.38-2.17 (14H, m), 2.27-2.32 (2H, m), 2.70-2.81 (2H, m), 3.19-3.32 (1H, m), 3.63-3.74 (1H, m), 3.93 (1H, brs), 5.00-5.21 (2H, m), 5.96-6.02 (1H, m), 7.26-7.38 (3H, m), 7.55-7.58 (2H, m)
(2R)-N- 1-(4-methyl-3-pentenyl)piperidin-4-yl!-2- (1R,3R)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetamide
1 H-NMR (CDCl3, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.38-2.32 (6H, m), 2.74-2.88 (2H, m), 3.41-3.52 (1H, m), 3.63-3.74 (1H, m), 5.02-5.21 (2H, m), 6.90 (1H, d, J=8.2 Hz), 7.23-7.35 (3H, m), 7.66-7.69 (2H, m)
N- 1 (3Z)-4-trifluoromethyl-3-pentenyl!piperidin-4-yl!-2-cyclopentyl-2-hydroxy-2-phenylacetamide
Structural formula ##STR14## Step 1. Synthesis of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide
To a solution of 2.94 g of (3-t-butyidiphenylsilyl oxypropyl)triphenylphosphoniumbromide in 40 ml of tetrahydrofuran, 2.5 ml of 1.7 M hexane solution of n-butyllithium was added dropwise at -78° C. The temperature was raised to -20° C. After stirring for an hour at said temperature, reaction mixture was cooled to -78° C. into which 0.5 ml of trifluoroacetone was added dropwise, followed by stirring overnight while raising the temperature to room temperature. The reaction liquid was diluted with hexane, washed with 10% hydrochloric acid, water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to provide 1.44 g of the title compound.
To a solution of 77 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-phenylacetamide in 3 ml of N,N-dimethylformamide, 74 mg of (3Z)-4-trifluoromethyl-3-pentenyl p-toluenesulfonate, 102 mg of potassium carbonate and 43 mg of potassium iodide were added by the order stated, followed by 3 hours' heating under reflux. The reaction liquid was diluted with diethyl ether, washed with water and saturated saline solution by the order stated, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck) chloroform/methanol=9/1) to provide 27 mg of the title compound as an oily substance.
N- 1- (3Z)-4-fluoromethyl-3-pentenyl!piperidin-4-yl!-2-cyclopentyl-2-hydroxy-2-phenylacetamide
Structural formula ##STR15##
N- 1- (3E)-4-fluoromethyl-3-pentenyl!piperidin-4-yl!-2-cyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR16## Step 1. Synthesis of (2E)-5-bromo-2-methyl-2-pentenol
To a solution of 59 mg of tetrabutylammonium-fluoride trihydrate in 3 ml of tetrahydrofuran, 200 mg of molecular sieves 4A, 31 mg of N- 1- (3E)-4-t-butyidimethylsilyloxymethyl-3-pentenyl!piperidin-4-yl!-2-cyclopentyl-2-hydroxy-2-phenylacetamide and 22 mg of p-toluenesulfonylfluoride were added sequentially, followed by overnight heating under reflux at 80° C. After removal of the insoluble material by filtration, the solvent was distilled off under reduced pressure. The remaining residue was purified by preparative thin layer chromatography Kieselgel™ 60F254, Art 5744 (Merck); chloroform/methanol=20/1!, to provide 11 mg of the title compound as an oily substance.
(2R)-N-(1-cycloheptylmethylpiperidin-4-yl)-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR17##
(2R)-N- 1- (3E)-4-fluoromethyl-3-pentenyl!-piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR18##
(2R)-N- 1-(6-methylpyridin-2-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR19## Step 1. Synthesis of (2R)-N-(piperidin-4-yl)-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
To a solution of 17 mg of (2R)-N-(piperidin-4-yl)-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide in 2 ml of tetrahydrofuran, 3 μl of acetic acid, 12 mg of 6-methylpyridine-2-carbaldehyde and 21 mg of sodium triacetoxyborohydride were added sequentially at room temperature, and stirred overnight at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck) chloroform/methanol=10/1) to provide 9 mg of the title compound as a solid substance.
(2R)-N- 1-(3-thienylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
(2R)-N- 1-(3-furylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR21##
(2R)-N- 1-(2-furylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR22##
(2R)-N- 1-(2-pyridylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR23##
(2R)-N- 1-(3-methoxybenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2hydroxy-2-phenylacetamide
Structural formula ##STR24##
To a solution of 71 mg of (2R)-N-(piperidin-4-yl)-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide in 2 ml of N,N-dimethylformamide, 74 mg of 3-methoxybenzyl chloride and 80 mg of potassium carbonate were added at room temperature, followed by stirring for about 12 hours. The reaction mixture was diluted with diethyl ether, washed with water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography (Kieselgel™ 60F,254, Art 5744 (Merck) chloroform/methanol=9/1) to provide 75 mg of the title compound as a white solid.
(2R)-N-(1-benzylpiperidin-4-yl)-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR25##
(2R)-N- 1-(3-fluorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR26##
(2R)-N- 1-(3-chlorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR27##
(2R)-N- 1-(2-thienylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR28##
(2R)-N- 1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide dihydrochloride
Structural formula ##STR29##
To a solution of 1.8 g of ethyl 6-hydroxymethylpyridine-2-carboxylate in 55 ml of N,N-dimethylformamide, 1.4 g of imidazole and 3.9 g of tert-butyldiphenylsilane chloride were added under cooling with ice, sequentially, followed by stirring for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was dissolved in 60 ml of methanol. To the solution 7.5 ml of 4N aqueous sodium hydroxide solution was added, stirred for 20 hours at room temperature and for further 2 hours at 60° C. Distilling the methanol off under reduced pressure, the residue was made acidic with 1N hydrochloric acid. The system was extracted with chloroform, washed with water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to provide 895 mg of the title compound as a white solid.
To a solution of 890 mg of the 6-tert-butyidiphenylsilyloxymethylpyridine-2-carboxylic acid as obtained in above step 1 in 30 ml of toluene, 0.63 ml of triethylamine, 3.2 ml of tert-butanol and 887 mg of diphenylphosphorylazide were added sequentially at room temperature, followed by heating for 16 hours at 100° C. under stirring. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution, water and then brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to provide 863 mg of the title compound as an oily substance.
163 mg of the 4-tert-butyloxycarbonyl-amino-1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidine as obtained in above step 3 was dissloved in 5 ml of 10% HCl-methanol solution, followed by stirring for 13 hours at 40° C. Distilling the methanol off under reduced pressure, the remaining residue was suspended in 15 ml of chloroform, to which 0.16 ml of triethylamine, 86 mg of (2R)-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetic acid, 114 mg of hydroxybenzotriazole and 75 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added under cooling with ice sequentially, followed by stirring for 1.5 hours at room temperature. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate solution and then brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=50/1 to 20/1) to obtain 101 mg of the title compound as a white solid.
To a solution of 2 g of 6-methyl-2-aminopyridine in 30 ml of chloroform, 5 g of di-tert-butyloxydicarbonate was added at room temperature. Then the mixture was heated to 70° C., to which 2.5 g of 4-dimethylaminopyridine was added, followed by stirring for 2 hours at the same temperature. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=20/1) to provide 4.1 g of the title compound as a white solid.
(2R)-N- 1-(6-amino-4-methoxypyridin-2-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide dihydrochloride
Structural formula ##STR30##
(2R)-N- 1-(3-amino-5-methylbenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide dihydrochloride
Structural formula ##STR31## Step 1. Synthesis of N-(tert-butyloxycarbonyl)-3,5-dimethylaniline
To a solution of 1.2 g of 3,5-dimethylaniline in a liquid mixture of 20 ml of dioxane, 10 ml of 10% aqueous sodium hydroxide solution and 2.7 g of di-tert-butyl-dicarbonate were added, followed by heating for 1.5 hours at 100° C. with stirring. The reaction mixture as diluted with diethyl ether, washed with water and then brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to provide 1.8 g of the title compound as an oil.
To a solution of 1.8 g of the N-(tert-butyloxycarbonyl)-3,5-dimethylaniline as obtained in above step 1 in 20 ml of carbon tetrachloride, 1.5 g of N-bromosuccinimide and 53 mg of 2,2'-azobis(isobutyronitrile) were added, followed by heating for 3 hours at 100° C. under stirring. The reaction mixture was diluted with hexane, filtered and the solvent was distilled off under reduced pressure to provide 2.8 g of the title compound as an oil.
(2R)-N- 1-(3-aminobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR32## Step 1. Synthesis of (2R)-N- 1(3-nitrobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
6. 5 mg of the (2R)-N- 1-(3-nitrobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide as obtained in above step 1 was heated to 60° C. together with 2 mg of iron powder in aqueous ethanol. After adding thereto 1 drop of conc. hydrochloric acid, the heating was continued at 100° C. for about 1 hour under stirring. The reaction mixture was made basic with 4N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to provide 4.8 mg of the title compound as a white solid.
(2R)-N- 1-(2-aminobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide dihydrochloride
Structural formula ##STR33##
(2R)-N- 1-(4-aminobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR34##
(2R)-N- 1-(4-amino-3-methoxybenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR35##
(2R)-N- 1-(3,5-diaminobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR36##
(2R)-N- 1-(5-methylfuran-2-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR37## Step 1. Synthesis of 4-(tert-butyloxycarbonylamino)-1-(5-methyl-2-furylmethyl)piperidine
(2R)-N- 1-(3-methylbenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR38## Step 1. Synthesis of 4-(tert-butyloxycarbonylamino)-1-(3-methylbenzyl)piperidine
(2R)-N- 1-(4-methoxybenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR39##
(2R)-N- 1-(3-amino-5-methoxybenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide dihydrochloride
Structural formula ##STR40## Step 1. Synthesis of methyl 3-tert-butoxycarbonylamino-5-methoxybenzoate
To a solution of 1.28 mg of the methyl 3-tert-butoxycarbonylamino-5-methoxybenzoate as obtained in above step 1 in 8 ml of toluene, 12.1 ml of 1.0 M solution of diisobutylaluminum hydride in tetrahydrofuran was added at -78° C., followed by stirring for an hour at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with water and then brine and dried over anhydrous magnesium sulfate. After distilling the solvent off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=7/3) to provide 262 mg of the title compound as an oil.
(2R)-N- 1-(4-amino-3-fluorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR41##
(2R)-N- 1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR42## Step 1. Synthesis of 6-chloromethyl-4-methyl-2-acetylaminopyridine
To a solution of 16.5 mg of the (2R)-N- 1-(6-acetylamino-4-methylpyridin-2-yl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide as obtained in above step 2 in 1 ml of methanol, 0.5 ml of 3M aqueous sodium hydroxide solution was added, and stirred for 1.5 hours at 60° C. The reaction liquid was diluted with diethyl ether, washed with water and brine by the order stated and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified by preparative thin-layer chromatography Kieselgel™60F254, Art 5744 (Merck); developing solvent: chloroform/methanol=10/1) to provide 14 mg of the title compound as an oily substance.
(2R)-N- 1-(3-amino-4-fluorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide dihydrochloride
Structural formula ##STR43##
(2R)-N- 1-(5-amino-2-fluorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR44##
(2R)-N- 1-(2-amino-4-chloropyridin-6-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR45##
(2R)-N- 1-(3-amino-5-chlorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR46## Step 1. Synthesis of 3-chloro-5-nitrobenzyl methanesulfonate
(2R)-N- 1-(4-amino-3,5-difluorobenzyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR47##
(2R)-N- 1-(benzimidazol-5-ylmethyl)piperidin-4-yl!-2- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetamide
Structural formula ##STR48##
(2R)-N- 1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl!-2-(3,3-difluorocyclobutyl)-2-hydroxy-2-phenylacetamide
Structural formula ##STR49##
(2R)-N- 1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl!-2-(4,4-difluorocyclohexyl)-2-hydroxy-2-phenylacetamide
Structural formula ##STR50##
(2R)-N- 1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl!-2- (1R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetamide
Structural formula ##STR51##
(2R)- (1R)-3-oxocyclopentyl!-2-hydroxy-2-phenylacetic acid
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5- (1R)-3-oxocyclopentyl!-5-phenyl-1,3-dioxolan-4-one and (2R,5R)-2-(t-butyl)-5- (1S)-3-oxocyclopentyl!-5-phenyl-1,3-dioxolan-4-one
To a mixture of 510 mg of (2R,5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one which had been synthesized by the method of D. Seebach, et al. Tetrahedron. Vol. 40, pp. 1313-1324 (1984)! in 20 ml of tetrahydrofuran and 1 ml of hexamethylphosphoric triamide, 1.7 ml of 1.5M lithium diisopropylamide solution in hexane was added dropwise at -78° C., followed by stirring for 30 minutes. Then a solution of 285 mg of cyclopentenone in 1.5 ml of tetrahydrofuran was added, and the reaction mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, resulting residue was purified by medium pressure silica gel column chromatography (developing solvent: hexane/ethyl acetate=15/1-10/1). Thus 150 mg and 254 mg, respectively, of the title compounds were obtained as oil. Configuration of each of the compounds was determined from NOE of NMR.
(2R)- (1S)-3-oxocycolpentyl!-2-hydroxy-2-phenylacetic acid
The title compound was prepared by a method similar to the step 2 of Referential Example 1, using (2R,5R)-2-(t-butyl)-5- (1S)-3-oxocyclopentyl!-5-phenyl-1,3-dioxolan-4-one.
(2R)- (1R)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetic acid
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5- (1R)-3,3-difluorocyclopentyl!-5-phenyl-1,3-dioxolan-4-one
(2R)- (1S)-3,3-difluorocyclopentyl!-2-hydroxy-2-phenylacetic acid
The title compound was prepared by a method similar to Referential Example 3, using (2R,5R)-2-(t-butyl)-5- (1S)-3-oxocyclopentyl!-5-phenyl-1,3-dioxolan-4-one.
(2R)- (1S)-3-hydroxycyclopentyl!-2-hydroxy-2-phenylacetic acid
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5- (1S)-3-hydroxycyclopentyl!-5-phenyl-1,3-dioxolan-4-one
(2R)- (1R)-3-hydroxycyclopentyl!-2-hydroxy-2-phenylacetic acid
The title compound was prepared by a method similar to Referential Example 5, using (2R,5R)-2-(t-butyl)-5- (1R)-3-oxocyclopentyl!-5-phenyl-1,3-dioxolan-4-one.
(2R)- (1S)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetic acid
The title compound was prepared by a method similar to Referential Example 3, using (2R)- (1S)-3-hydroxycyclopentyl!-2-hydroxy-2-phenylacetic acid.
(2R)- (1R)-3-fluorocyclopentyl!-2-hydroxy-2-phenylacetic acid
The title compound was prepared by a method similar to Referential Example 3, using (2R)- (1R)-3-hydroxycyclopentyl!-2-hydroxy-2-phenylacetic acid.
To a solution of 23.5 g of ethyl phenylglyoxylate in 200 ml of tetrahydrofuran, 70 ml of 2.0 M cyclopentylmagnesium chloride solution in diethyl ether was added dropwise under cooling with ice, followed by stirring for 30 minutes at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off-under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=30/1-20/1) to provide 11 g of ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate, which was dissolved in 40 ml of methanol. To the solution 20 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by stirring for 2 hours at the same temperature and further for 1 hour at 50° C. Distilling the methanol off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was washed with 1:1 mixture of diethyl ether and hexane. Thus, 8.7 g of the title compound was obtained.
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5- (1S,2R,5R,6S,7R)-3-oxotricyclo 5.2.1.02.6 !dec-8-en-5-yl!-5-phenyl-1,3-dioxolan-4-one
To a solution of 32 g of (2R,5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one in 1.1 l of tetrahydrofuran, 105 ml of 1.5 M lithium diisopropylamide solution in hexane was added dropwise at -78° C., followed by stirring for 30 minutes, addition of 23.4 g of (1S,2R,6S,7R)-tricyclo 5.2.1.02.6 !dec-4,8-dien-3-one as dissolved in 300 ml of tetrahydrofuran, and further stirring for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was recrystallized from hexane-ethyl acetate. Thus 36.9 g of the title compound was obtained as a white solid.
A solution of 25.6 g of the (2R,5R)-2-(t-butyl)-5- (1S,2R,5R,6S,7R)-3-oxo-8-tricyclo 5.2.1.02.6 !-dec-8-en-5-yl!-5-phenyl-1,3-dioxolan-4-one as obtained in above step 1 in 350 ml of 1,2-dichlorobenzene was heated at 175° C. for 7 hours with stirring, under nitrogen atmosphere. Thus precipitated solid was recovered by filtration and washed with hexane to provide 14 g of the title compound as a white solid.
(2R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetic acid
The title compound was prepared by a method similar to the step 1 of Referential Example 1 and Referential Example 3, using (R)-4-fluoromandelic acid.
(2R)-(3,3-difluorocyclobutyl)-2-hydroxy-2-phenylacetic acid
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5-(3-benzyloxy-1-hydroxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one
To a solution of 2.82 g of the (2R,5R)-2-(t-butyl)-5-(3-benzyloxy-1-hydroxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one as obtained in above step 1 in 80 ml of chloroform, 2.6 g of 4-dimethylaminopyridine was added under cooling with ice, followed by stirring for an hour at the same temperature. To the reaction mixture, 1 ml of methyl chloroglyoxylate was added, followed by stirring for an hour. The reaction mixture was diluted with chloroform, washed with water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was mixed with hexane/ethyl acetate=1/1 liquid mixture and filtered through a silica gel column. Distilling the solvent off under reduced pressure, the residue was dissolved in 80 ml of toluene, and to the solution 56 mg of 2,2'-azobis(isobutyronitrile) and 2.3 ml of tri-n-butyltin hydride were added, followed by heating for 4 hours at 110° C. with stirring. Distilling the solvent off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1) to provide 1.82 g of the title compound as an oily substance.
To a solution of 1.82 g of the (2R,5R)-2-(t-butyl)-5-(3-benzyloxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one as obtained in above step 2 in 40 ml of ethanol, 430 mg of palladium hydroxide-carbon was added, followed by stirring for 6 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite. Distilling the solvent off under reduced pressure, the residue was dissolved in 5 ml of dichloromethane, and the resulting solution was added dropwise at -78° C. to a reaction mixture formed by adding 0.63 ml of oxalyl chloride to 1.1 ml of dimethylsulfoxide in 50 ml of dichloromethane at -78° C. and stirring for 5 minutes. After stirring for 15 minutes at the same temperature, 0.5 ml of triethylamine was added to the reaction mixture and stirred for 30 minutes while raising the temperature to room temperature. The reaction liquid was diluted with chloroform, washed with water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=8/1) to provide 1.36 g of the title compound as an oily substance.
(2R)-(4,4-difluorocyclohexyl)-2-hydroxy-2-phenylacetic acid
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5-(1,4-dioxaspiro 4.5!-dec-8-yl)-5-phenyl-1,3-dioxolan-4-one
To a solution of 83 mg of the (2R,5R)-2-(t-butyl)-5-(1,4-dixoaspiro 4.5!dec-8-yl)-5-phenyl-1,3-dioxolan-4-one in a mixture of 4 ml of acetone and 0.4 ml of water, 52 mg of p-toluenesulfonic acid was added at room temperature, followed by stirring for 13 hours at 50° C. Distilling the acetone off under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 70 mg of the title compound was obtained as an oil.
Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5- (1R)-3-hydroxyiminocyclopentyl!-5-phenyl-1,3-dioxolan-4-one
To a mixture of 20 mg of nitrosonium tetrafluoro borate and 0.5 ml of 70% hydrogen fluoride-pyridine, a solution of 34 mg of (2R,5R)-2-(t-butyl)-5- (1R)-3-hydroxyiminocyclopentyl!-5-phenyl-1,3-dioxolan-4-one in 0.5 ml of dichloromethane was added under ice-cooling. The mixture was stirred for 10 minutes at 0° C. and 5 hours at room temperature. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 35 mg of the title compound.
Industrially Utilizability
The fluorine-containing 1,4-disubstituted piperidine derivatives of the present invention have not only potent selective antagonistic activity for muscarinic M3 receptors but also little side effect. Furthermore they exhibit excellent oral activity, duration of action and pharmacokinetics. Hence, they are very useful in the treatment or prophylaxis of diseases such respiratory diseases as chronic obstructive pulmonary diseases, chronic bronchitis, asthma and rhinitis: digestive diseases such as irritable bowel syndrome, convulsive colitis, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system: urinary disorders like urinary incontinence and frequency in neurogenic pollakiurea, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis: and motion sickness.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS5750540 *Apr 25, 1996May 12, 1998Banyu Pharmaceutical Co., Ltd.1,4-di-substituted piperidine derivativesEP0309424A2 *Sep 19, 1988Mar 29, 1989ISTITUTO DE ANGELI S.p.A.New amidino derivativesEP0733621A1 *Dec 1, 1994Sep 25, 1996Kyorin Pharmaceutical Co., Ltd.Novel imidazole derivative and process for producing the sameEP0751127A1 *Jun 24, 1996Jan 2, 1997Ss Pharmaceutical Co., Ltd.4-(.Alpha.-hydroxy-.alpha-aryl-alkylcarbonylamino)-piperidines for the treatment and prophylaxis of disorders of the urinary tractJPH07258250A * Title not availableJPS5283763A * Title not availableJPS5679688A * Title not availableWO1990005133A1 *Oct 26, 1989May 17, 1990Pfizer LimitedMuscarinic receptor antagonistsWO1997013766A1 *Oct 7, 1996Apr 17, 1997Banyu Pharmaceutical Co., Ltd.Substituted heteroaromatic derivatives* Cited by examinerNon-Patent CitationsReference1Chem. Pharm. Bull. vol. 32, No. 3, (1984), Sugai, Saburo et al, "Studies on Spasmolytics. III. Synthesis . . . Salts", p. 1126-1134.2 *Chem. Pharm. Bull. vol. 32, No. 3, (1984), Sugai, Saburo et al, Studies on Spasmolytics. III. Synthesis . . . Salts , p. 1126 1134.3Chem. Pharm. Bull. vol. 33, No. 2, (1985), Yoshida, Seiichiro et al., "Structure-Activity Relationship . . . piperidine Derivatives", p. 818-822.4 *Chem. Pharm. Bull. vol. 33, No. 2, (1985), Yoshida, Seiichiro et al., Structure Activity Relationship . . . piperidine Derivatives , p. 818 822.5Chem. Pharm. Bull., vol. 32, No. 3, (1984), Sugai, Saburo et al., "Studies on Spasmolytics. II. Synthesis . . . Compounds", p. 977-985.6 *Chem. Pharm. Bull., vol. 32, No. 3, (1984), Sugai, Saburo et al., Studies on Spasmolytics. II. Synthesis . . . Compounds , p. 977 985.7Chem. Pharm. Bull., vol. 32, No. 3, (1984), Sugai, Saburo, et al., "Studies on Spasmolytics I. Synthesis and Spasmolytic . . . piperidines", p. 967-976.8 *Chem. Pharm. Bull., vol. 32, No. 3, (1984), Sugai, Saburo, et al., Studies on Spasmolytics I. Synthesis and Spasmolytic . . . piperidines , p. 967 976.9Japanese language publication "Seitai no Kagaku" (biochemistry), vol. 42(5), p. 380-385, 1991 and partial English translation.10 *Japanese language publication Seitai no Kagaku (biochemistry), vol. 42(5), p. 380 385, 1991 and partial English translation.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS6180823 *Nov 6, 1998Jan 30, 2001Sepracor Inc.Stereoselective process for alkyl phenylglycolic acidsUS6376684Nov 13, 2000Apr 23, 2002Sepracor Inc.Stereoselective process for alkyl phenylglycolic acidsUS6403584 *Jun 15, 2001Jun 11, 2002Merck & Co., Inc.Substituted nipecotyl derivatives as inhibitors of cell adhesionUS6469172Mar 5, 2001Oct 22, 2002Merck & Co., Inc.Process for the preparation of chemical compoundsUS6479672Apr 7, 2000Nov 12, 2002Merck & Co., Inc.Diastereoselective preparation of Michael adductsUS6583103Aug 9, 2002Jun 24, 2003S.C. Johnson & Son, Inc.Two part cleaning formula resulting in an effervescent liquidUS6867220 *Dec 14, 2000Mar 15, 2005Sanofi-SynthelaboPhenoxypropanolamines, method for producing them and pharmaceutical compositions containing themUS6878730 *Oct 17, 2003Apr 12, 2005Pharmacia & UpjohnQuaternary ammonium compoundsUS7232835Dec 10, 2002Jun 19, 2007Ranbaxy Laboratories Limited3,6-Disubstituted azabicyclo derivatives as muscarinic receptor antagonistsUS7265147Jul 31, 2002Sep 4, 2007Ranbaxy Laboratories Limited3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonistsUS7288562Aug 23, 2002Oct 30, 2007Ranbaxy Laboratories LimitedFluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonistsUS7399779Jul 8, 2002Jul 15, 2008Ranbaxy Laboratories Limited3,6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonistsUS7410993Aug 9, 2002Aug 12, 2008Ranbaxy Laboratories Limited3,6-disubstituted azabicyclo [3.1.0] hexane deriviatives useful as muscarinic receptor antagonistsUS7446123 *Jan 7, 2004Nov 4, 2008Ranbaxy Laboratories LimitedAzabicyclo derivatives as muscarinic receptor antagonistsUS7465751Dec 23, 2002Dec 16, 2008Ranbaxy Laboratories Limited1-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonistsUS7488748Jan 23, 2003Feb 10, 2009Ranbaxy Laboratories Limited3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsUS7501443Dec 23, 2002Mar 10, 2009Ranbaxy Laboratories LimitedFlavaxate derivatives as muscarinic receptor antagonistsUS7517905Apr 9, 2003Apr 14, 2009Ranbaxy Laboratories LimitedSubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsUS7544708Apr 11, 2003Jun 9, 2009Ranbaxy Laboratories LimitedAzabicyclo derivatives as muscarinic receptor antagonistsUS7560479Apr 10, 2003Jul 14, 2009Ranbaxy Laboratories Limited3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsUS7592359Apr 10, 2003Sep 22, 2009Ranbaxy Laboratories LimitedSubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsUS7994188Aug 20, 2003Aug 9, 2011Boehringer Ingelheim Pharma Gmbh & Co. KgCompounds for treating inflammatory diseasesUS20030040530 *Dec 14, 2000Feb 27, 2003Roberto CecchiPhenoxypropanolamines, method for producing them and pharmaceutical compositions containning themUS20040039011 *Aug 20, 2003Feb 26, 2004Boehringer Ingelheim Pharma KgCompounds for treating inflammatory diseasesUS20040132774 *Oct 17, 2003Jul 8, 2004Heath Timothy GordonQuaternary ammonium compoundsUS20040220224 *Apr 13, 2004Nov 4, 2004Pfizer IncMethod of treating irritable bowel syndromeUS20060004083 *Aug 23, 2002Jan 5, 2006Anita MehtaFluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonistsUS20060122253 *Jul 31, 2002Jun 8, 2006Anita Mehta3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonistsUS20060128781 *Dec 23, 2002Jun 15, 2006Anita MehtaFlavaxate derivatives as muscarinic receptor antagonistsUS20060142371 *Aug 9, 2002Jun 29, 2006Anita Mehta3,6-Disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptorUS20060194862 *Dec 23, 2002Aug 31, 2006Anita Mehta1-Substituted-3-pyrrolidine derivatives as muscarinic receptor antagonistsUS20060217432 *Dec 10, 2002Sep 28, 2006Anita Mehta3,6-Disubstituted azabicyclo [3.1.0] hexane derivatives as muscarinic receptor antagonistsUS20060281805 *Apr 9, 2003Dec 14, 2006Anita MehtaSubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsUS20060287380 *Jan 7, 2004Dec 21, 2006Mohammad SalmanAzabicyclo Derivatives as Muscarinic Receptor AntagonistsUS20070021487 *Jan 6, 2004Jan 25, 2007Mohammad SalmanAzabicyclo derivatives as muscarinic receptor antagonistsUS20070208060 *Jan 18, 2007Sep 6, 2007Boehringer Ingelheim Pharma KgCompounds for treating inflammatory diseasesUS20070287732 *Apr 10, 2003Dec 13, 2007Ranbaxy Laboratories LimitedSubstituted Azabicyclo Hexane Derivatives as Muscarinic Receptor AntagonistsUS20080262075 *Aug 18, 2005Oct 23, 2008Ranbaxy Laboratories LimitedPyrrolidine Derivatives as Muscarinic Receptor AntagonistsUS20080280883 *Sep 23, 2005Nov 13, 2008Mohammad SalmanMuscarinic Receptor AntagonistsUS20080319002 *Jun 16, 2004Dec 25, 2008Ranbaxy Laboratories LimitedXanthine Derivatives a Useful as Muscarinic Receptor AntagonistsUS20080319043 *May 1, 2006Dec 25, 2008Mohammad Salman3,6-Disubstituted Azabicyclo (3.1.0) Hexane Derivatives as Muscarinic Receptor AntagonistsUS20090010923 *Apr 24, 2008Jan 8, 2009University Of Maryland, BaltimoreTreatment of cancer with anti-muscarinic receptor agentsUS20090105221 *Sep 28, 2005Apr 23, 2009Ranbaxy Laboratories LimitedMuscarinic receptor antagonistsUS20100016400 *Nov 18, 2005Jan 21, 2010Naresh KumarAzabicyclic muscarinic receptor antagonistsUS20100035954 *Dec 15, 2004Feb 11, 2010Mohammad SalmanAcid addition salts of muscarinic receptor antagonistsWO2000061572A1 *Apr 4, 2000Oct 19, 2000Merck & Co., Inc.Diastereoselective preparation of michael adductsWO2004067510A1 *Jan 28, 2003Aug 12, 2004Ranbaxy Laboratories Limited3,6-disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsWO2004089899A1 *Apr 10, 2003Oct 21, 2004Ranbaxy Laboratories LimitedSubstituted azabicyclo hexane derivatives as muscarinic receptor antagonistsWO2007045979A1Oct 19, 2006Apr 26, 2007Ranbaxy Laboratories LimitedPharmaceutical compositions of muscarinic receptor antagonists* Cited by examinerClassifications U.S. Classification514/317, 546/209, 546/210, 546/208, 546/224, 514/256, 546/214, 546/222, 544/233, 546/194, 514/326, 546/213, 514/318, 544/242International ClassificationC07D401/06, C07D405/06, C07D409/06, C07D211/58, C07D211/46Cooperative ClassificationC07D405/06, C07D401/06, C07D409/06, C07D211/58European ClassificationC07D211/58, C07D405/06, C07D409/06, C07D401/06Legal EventsDateCodeEventDescriptionJul 31, 1997ASAssignmentOwner name: BANYU PHARMACEUTICAL CO., LTD., JAPANFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TSUCHIYA, YOSHIMI;KAWAKAMI, KUMIKO;NOMOTO, TAKASHI;AND OTHERS;REEL/FRAME:008727/0205Effective date: 19970725Jun 20, 2000CCCertificate of correctionMar 6, 2003FPAYFee paymentYear of fee payment: 4Feb 20, 2007FPAYFee paymentYear of fee payment: 8Feb 18, 2011FPAYFee paymentYear of fee payment: 12Mar 9, 2011ASAssignmentOwner name: MSD K.K., JAPANFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BANYU PHARMACEUTICAL CO., LTD.;REEL/FRAME:025920/0079Effective date: 20110224RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services