US 6,319,920 B1Granted

2-arylethyl-(piperidin-4-ylmethyl)amine derivatives

AssigneeSyntex (U.S.A.) Inc.

InventorsJoan Marie Caroon, Robin Douglas Clark, Michael Patrick Dillon, Ralph New Harris, III, Sharathchandra Surendra Hegde, Clara Jeou Jen Lin, Hans Maag, David Bruce Repke

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Abstract

This invention relates to muscarinic receptor antagonist compounds selected from the group of compounds represented by Formula I: wherein the substituents are as defined in the specification; and their pharmaceutically acceptable salts, individual isomers or a racemic or non-racemic mixture; pharmaceutical compositions containing them; and methods for their use as therapeutic agents.

Claims35

Dependent claims

A compound selected from the group of compounds represented by Formula I:

wherein:
R1 is independently in each occurrence:
hydrogen, alkyl, alkyloxy, halogen, haloalkyl, or amino;
R2 is independently in each occurrence:
(1) alkyl,
(2) alkyloxy,
(3) halogen,
(4) haloalkyl,
(5) nitro,
(6) heterocyclyl, unsubstituted or heterocyclyl optionally substituted with oxo,
(7) —O(CH2)pX wherein p is 0-6 and X is independently selected from haloalkyl or aryl,
(8) —NR7R8,
(9) —NR6COR9,
(10) —NR6CONR7R8,
(11) —NR6CSR9,
(12) —NR6CSNR7R8,
(13) —NR6SO2R9,
(14) —NR6SO2NR7R8,
(15) —SR9,
(16) —SOR9,
(17) —SO2R9,
(18) —SO2NR7R8;
or
R1 and R2 taken together with the ring to which they are attached form a 5- or 6-membered monocyclic saturated or unsaturated ring optionally containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R3 and R4 are independently in each occurrence:
lower alkyl, alkenyl, or cycloalkyl;
R5 is independently in each occurrence:
(1) hydrogen,
(2) —COR9,
(3) —COOR7,
(4) —CONR7R8,
(5) —CO(CH2)nCOR9,
(6) —CO(CH2)nSO2R9,
(7) —CO(CH2)nCONR7R8,
(8) —CO(CH2)nSO2NR7R8,
(9) —CO(CH2)nNR6COR9,
(10) —CO(CH2)nNR6SO2R9,
(11) —CO(CH2)nNR6CONR7R8,
(12) —CO(CH2)nNR6SO2NR7R8,
(13) —CSR9,
(14) —CSNR7R8,
(15) —SO2R9,
(16) —SO2NR7R8,
(17) —SO2(CH2)nNR6SO2R9, or
(18) —SO2NR6(CH2)nCOOR7;
wherein
n is 1-6;
R6 and R7 are independently in each occurrence:
hydrogen or lower alkyl;
R8 is independently in each occurrence:
hydrogen, lower alkyl, cycloalkyl, aryl, or heteroaryl;
R9 is independently in each occurrence:
(1) alkyl,
(2) cycloalkyl,
(3) arylalkyl,
(4) aryl, unsubstituted or mono-, di-, or tri-substituted aryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, hydroxyalkyl, haloalkyl, cyano, nitro, —CONR7R8, —COR7, —COOR7, —NR7R8, —NCOR9, —SO2R9, —SO2NR7R8, or —O(CH2)pX wherein p is 0-6 and X is haloalkyl or aryl,
(5) heterocyclyl, unsubstituted or mono- or di-substituted heterocyclyl, the substitutents independently selected from lower alkyl, hydroxy, hydroxyalkyl, oxo, —COR7, or —COOR7, or
(6) heteroaryl, unsubstituted or mono-, di-, or tri-substituted heteroaryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, hydroxyalkyl, haloalkyl, cyano, nitro, —CONR7R8, —COR7, —COOR7, —NR7R8, —NCOR9, —SO2R9, —SO2NR7R8, or —O(CH2)pX wherein p is 0-6 and X is haloalkyl or aryl;
as an individual isomer or as a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt thereof.

56 more elements

A compound of Formula I selected from:

N-[2-(2,3,-Dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine;
N-[2-(2,3-Dihydrobenzofuran-5-yl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine;
N-[2-(2,3-Dihydrobenzofuran-6-yl)-1-methylethyl]-N-propyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(2,3-Dihydrobenzofuran-6-yl)-1-methylethyl]-N-cyclopropylmethyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl)amine;
N-[2-(2,3-Dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(2,3-Dihydrobenzofuran-5-yl)-1-methylethyl]-N-propyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
(S)-N-{3-[4-({[2-(2,3-Dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidin-1-yl]-3-oxopropyl}-methanesulfonamide;
N-[2-(Indan-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine;
N-[2-(Indan-5-yl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine;
N-[2-(3,3-Dimethyl-2,3-dihydrobenzofuran-6-yl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3,3-Dimethyl-2,3,-dihydrobenzofuran-6-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine;
N-[2-(4-Methoxyphenyl)-1-methylethyl]-N-ethyl-[1-(dimethylaminocarbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3-Trifluoromethylphenyl)-1-methylethyl]-N-ethyl-[1-(dimethylaminocarbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3-Trifluoromethylphenyl)-1-methylethyl]-N-ethyl-[1-(piperidine-1-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(4-Trifluoromethylphenyl)-1-methylethyl]-N-ethyl-[1-(piperidine-1-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(4-Trifluoromethylphenyl)-1-methylethyl]-N-ethyl-[1-(dimethylaminocarbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3-Trifluoromethylphenyl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3-Trifluoromethylphenyl)-1-methylethyl]-N-ethyl-[1-(1,2,3,4-tetrahydro[1,5]naphthyridine-1-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3-Chlorophenyl)-1-methylethyl]-N-ethyl-[1-(piperidine-1-carbonyl)piperidin-4-ylmethyl]amine;
N-[2-(3-Trifluoromethylphenyl)-1-methylethyl]-N-propyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
N-{2-[3-(4-Methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-N-propyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine;
or
N-{2-[3-(4-Methylphenylcarbonylamino)-phenyl]-1-methylethyl}-N-propyl-[1-(morpholine-4-carbonyl)piperidin-4-ylmethyl]amine.

21 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/241,816Filed 1 Feb 1999 · us provisional application
Priority: 27 Feb 1998
Granted: 20 Nov 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/06
Drugs for disorders of the alimentary tract or the digestive system: anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics

Family

Application60/076,113Us provisional application · filed 27 Feb 1998
Application60/109,097Us provisional application · filed 19 Nov 1998
US 6,319,920 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound selected from the group of compounds represented by Formula I:

wherein:
R1 is independently in each occurrence:
hydrogen, alkyl, alkyloxy, halogen, haloalkyl, or amino;
R2 is independently in each occurrence:
(1) alkyl,
(2) alkyloxy,
(3) halogen,
(4) haloalkyl,
(5) nitro,
(6) heterocyclyl, unsubstituted or heterocyclyl optionally substituted with oxo,
(7) —O(CH2)pX wherein p is 0-6 and X is independently selected from haloalkyl or aryl,
(8) —NR7R8,
(9) —NR6COR9,
(10) —NR6CONR7R8,
(11) —NR6CSR9,
(12) —NR6CSNR7R8,
(13) —NR6SO2R9,
(14) —NR6SO2NR7R8,
(15) —SR9,
(16) —SOR9,
(17) —SO2R9,
(18) —SO2NR7R8;
or
R1 and R2 taken together with the ring to which they are attached form a 5- or 6-membered monocyclic saturated or unsaturated ring optionally containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R3 and R4 are independently in each occurrence:
lower alkyl, alkenyl, or cycloalkyl;
R5 is independently in each occurrence:
(1) hydrogen,
(2) —COR9,
(3) —COOR7,
(4) —CONR7R8,
(5) —CO(CH2)nCOR9,
(6) —CO(CH2)nSO2R9,
(7) —CO(CH2)nCONR7R8,
(8) —CO(CH2)nSO2NR7R8,
(9) —CO(CH2)nNR6COR9,
(10) —CO(CH2)nNR6SO2R9,
(11) —CO(CH2)nNR6CONR7R8,
(12) —CO(CH2)nNR6SO2NR7R8,
(13) —CSR9,
(14) —CSNR7R8,
(15) —SO2R9,
(16) —SO2NR7R8,
(17) —SO2(CH2)nNR6SO2R9, or
(18) —SO2NR6(CH2)nCOOR7;
wherein
n is 1-6;
R6 and R7 are independently in each occurrence:
hydrogen or lower alkyl;
R8 is independently in each occurrence:
hydrogen, lower alkyl, cycloalkyl, aryl, or heteroaryl;
R9 is independently in each occurrence:
(1) alkyl,
(2) cycloalkyl,
(3) arylalkyl,
(4) aryl, unsubstituted or mono-, di-, or tri-substituted aryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, hydroxyalkyl, haloalkyl, cyano, nitro, —CONR7R8, —COR7, —COOR7, —NR7R8, —NCOR9, —SO2R9, —SO2NR7R8, or —O(CH2)pX wherein p is 0-6 and X is haloalkyl or aryl,
(5) heterocyclyl, unsubstituted or mono- or di-substituted heterocyclyl, the substitutents independently selected from lower alkyl, hydroxy, hydroxyalkyl, oxo, —COR7, or —COOR7, or
(6) heteroaryl, unsubstituted or mono-, di-, or tri-substituted heteroaryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, hydroxyalkyl, haloalkyl, cyano, nitro, —CONR7R8, —COR7, —COOR7, —NR7R8, —NCOR9, —SO2R9, —SO2NR7R8, or —O(CH2)pX wherein p is 0-6 and X is haloalkyl or aryl;
as an individual isomer or as a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt thereof.

56 more elements

Facts

Application

09/241,816Filed 1 Feb 1999 · us provisional application

Priority

27 Feb 1998

Granted

20 Nov 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/06
Drugs for disorders of the alimentary tract or the digestive system: anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics