US 9,868,717 B2Granted

Tricyclic sulphonamide compounds and methods of making and using same

AssigneeZafgen, Inc.

InventorsThomas D. Pallin, Susan M. Cramp, Hazel J. Dyke, Robert Zahler

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Abstract

The invention provides tricyclic compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making various tricyclic compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

Claims5

Dependent claims

A compound selected from the group consisting of:

(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof;
(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof;
(1aR,7bS)-5-[2-((R)-1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1 aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1 aR,7bS)-5{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1 aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino-methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1);
(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid formic acid (1:1) and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

27 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/440,745Filed 5 Nov 2013 · us provisional application
Priority: 5 Nov 2012
Published: US 2016/0083362 A124 Mar 2016
Granted: 16 Jan 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 311/94
Ortho- or peri-condensed with carbocyclic rings or ring systems: condensed with rings other than six-membered or with ring systems containing such…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

Application61/722,449Us provisional application · filed 5 Nov 2012
US 2016/0083362 A1Pre-grant publication · published 24 Mar 2016
US 9,868,717 B2This patent

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

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Abstract

A compound selected from the group consisting of:

(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof;
(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, or enantiomers thereof;
(1aR,7bS)-5-[2-((R)-1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1 aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1 aR,7bS)-5{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;
(1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;
(1 aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino-methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid-formic acid (1:1);
(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid formic acid (1:1) and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

27 more elements

Facts

Application

14/440,745Filed 5 Nov 2013 · us provisional application

Priority

5 Nov 2012

Published

US 2016/0083362 A124 Mar 2016

Granted

16 Jan 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 311/94
Ortho- or peri-condensed with carbocyclic rings or ring systems: condensed with rings other than six-membered or with ring systems containing such…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00