Coferons and methods of making and using them

Patent metadata

Field	Value
Publication number	US-9771345-B2
Application number	US-201013500857-A
Country	US
Kind code	B2
Filing date	Oct 7, 2010
Priority date	Oct 7, 2009
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.

First claim

What is claimed is:

1. A therapeutic dimer comprising:
covalently or non-covalently linked monomers, each monomer comprising either a boronic acid linker element or a binding partner linker element,
wherein the monomer comprising the boronic acid linker element is selected from the group consisting of:
[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-4-yl]boronic acid; (2-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}-1H-indol-4-yl)boronic acid; (5-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}naphthalen-2-yl)boronic acid; [5-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)naphthalen-2-yl]boronic acid; [2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-5-yl]boronic acid; [5-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-2-yl]boronic acid; [2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-6-yl]boronic acid; [8-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)naphthalen-2-yl]boronic acid; (2-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}-1H-indol-6-yl)boronic acid; (2-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}-1H-indol-5-yl)boronic acid; (2-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}-1H-indol-5-yl)boronic acid; (5-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}-1H-indol-3-yl)boronic acid; [4-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1-benzofuran-2-yl]boronic acid; (3-{[5-(aminomethyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]carbonyl}-1H-indol-6-yl)boronic acid; and
wherein the monomer comprising the binding partner linker element is selected from the group consisting of:
4-(2-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-oxoethyl)-2-hydroxybenzamide; 4-[(1E)-3-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-hydroxybenzamide; 5-[(1E)-3-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-hydroxybenzamide; 8-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1,3-dihydroxynaphthalene-2-carboxamide; 3-[(1E)-3-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2,6-dihydroxybenzamide; (2R)-2-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-2-hydroxy-2-phenylacetic acid; (2R)-2-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-2-cyclopentyl-2-hydroxyacetic acid; (2R)-2-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-2-cyclopropyl-2-hydroxyacetic acid; 4-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-7,8-dihydroxy-2H-chromen-2-one; 3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-6,7-dihydroxy-2H-chromen-2-one; 4-(2-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-oxoethyl)-6,7-dihydroxy-2H-chromen-2-one; 3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-7,8-dihydroxy-2H-chromen-2-one; 3-(2-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-oxoethyl)-6,7-dihydroxy-4-methyl-2H-chromen-2-one; 3-(2-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-oxoethyl)-7,8-dihydroxy-4-methyl-2H-chromen-2-one; 4-(2-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-oxoethyl)-7, 8-dihydroxy-2H-chromen-2-one; (1S,2S,3R,5S)-2-{2-[4-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]ethyl}-6,6-dimethylbicyclo[3.1.1]heptane-2,3-diol; (1R,2R,4S,5R,6S)—N-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-5,6-dihydroxybicyclo[2.2.2]octane-2-carboxamide; (1R,2R,3R,4R,5S)-4-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (1R,2R,4S,5S,6R)—N-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-5,6-dihydroxybicyclo[2.2.2]octane-2-carboxamide; (1S,2R,3R,4R,5R)-4-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (1R,2R,4S,5R,6S)—N-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-5,6-dihydroxybicyclo[2.2.1]heptane-2-carboxamide; (1S,2R,3S,4S,5R)-5-[4-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-5-methylbicyclo[2.2.1]heptane-2,3-diol; (1S,2R,4R,5S,6R)—N-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-5,6-dihydroxybicyclo[2.2.2]octane-2-carboxamide; (1R,2R,3S,4R,5S)-5-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]bicyclo[2.2.2]octane-2,3-diol; (1R,2S,3R,4R,5S)-5-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-5-methylbicyclo[2.2.1]heptane-2,3-diol; (2R)-3-{[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]carbamoyl}-2-hydroxy-2-phenylpropanoic acid; (2S)-3-{[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]carbamoyl}-2-hydroxy-2-phenylpropanoic acid; (2R)-2-[4-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-]H-indol-2-yl]-2-hydroxypropanoic acid; (2S)-3-{[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]carbamoyl}-2-hydroxy-2-methylpropanoic acid; (2S)-3-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2-hydroxy-2-phenylpropanoic acid; (2R)-3-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2-hydroxy-2-phenylpropanoic acid; (2S)-3-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2-hydroxy-2-methylpropanoic acid; (2R)-3-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2-hydroxy-2-methylpropanoic acid; (2S)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-4-yl]-2-hydroxypropanoic acid; (2R)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-]H-indol-4-yl]-2-hydroxy-2-phenylacetic acid; (2R)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-4-yl]-2-hydroxypropanoic acid; (2R)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-6-yl]-2-hydroxypropanoic acid; 2-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]ethan-1-one; (2R)-3-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]propane-1,2-diol; 2-[(1E)-3-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-6-hydroxybenzamide; 8-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-3-hydroxynaphthalene-2-carboxamide; (1R,2S,3R,4R,5S)-5-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]bicyclo[2.2.2]octane-2,3-diol; (1R,2S,4S,5S,6R)—N-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-5,6-dihydroxybicyclo[2.2.2]octane-2-carboxamide; (2S)-3-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenoxy]-2-cyclopentyl-2-hydroxypropanoic acid; (2S)-3-{[4-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]carbamoyl}-2-hydroxy-2-phenylpropanoic acid; (2R)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-]H-indol-6-yl]-2-hydroxy-2-phenylacetic acid; (2R)—S-[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-3,3,3-trifluoro-2-hydroxypropane-1-sulfonamido; 1-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-(3,4-dihydroxyphenyl)ethan-1-one; (2R)-2-[3-(2-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-2-oxoethyl)phenyl]-2-hydroxy-2-phenylacetic acid; (2S)-2-[5-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)naphthalen-2-yl]-2-hydroxypropanoic acid; (2S)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-]H-indol-6-yl]-2-hydroxypropanoic acid; (2S)-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-6-yl]-2-hydroxy-2-phenylacetic acid; (4-(3-(aminomethyl)phenyl)piperidin-1-yl)(3-(2-hydroxy-2-(1-hydroxycyclobutyl)ethoxy)phenyl)methanone; (E)-1-(4-(3-(aminomethyl)phenyl)piperidin-1-yl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one; (4-(3-(aminomethyl)phenyl)piperidin-1-yl)(6,7-dihydroxynaphthalen-1-yl)methanone; and 4-(aminomethyl)-N-(4-(2-((3R,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethoxy)benzyl)benzamide.

2. The therapeutic dimer of claim 1 , wherein the therapeutic dimer is selected from the group consisting of:
7-[(1E)-3-{4-[3-(aminomethyl)phenyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-[2-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)-1H-indol-4-yl]-3,4-dihydro-2H-1,3,2-benzoxazaborinin-4-one; 2-(2-{[5-(aminomethyl)-2H-s

Assignees

• Barany Francis
• Pingle Maneesh
• Giardina Sarah Filippa
• Bergstrom Donald
• Arnold Lee Daniel
• Univ Cornell
• Purdue Research Foundation
• Blinkbio Inc

Inventors

• Barany Francis
• Pingle Maneesh
• Giardina Sarah Filippa
• Bergstrom Donald
• Arnold Lee Daniel

Classifications

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D207/24

  Oxygen or sulfur atoms · CPC title

• C07D319/14 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title