US 7,094,791 B2Granted

Derivatives of 3-hydroxy-pyrrole-2,4-dicarboxylic acid and uses thereof

AssigneeAvalon Pharmaceuticals, Inc.

InventorsWieslaw M. Cholody, Valentina Petukhova, Sean O'Brien, Norman Ohler, Stanislaw Pikul

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Abstract

Chemical agents of the general formula (I) and (II), such as derivatives of 3-hydroxy-pyrrole containing hydroxamic acid, and including salts thereof, that modulate levels of gene expression in cellular systems, including cancer cells, are disclosed, along with methods for preparing such agents, as well as pharmaceutical compositions containing such agents as active ingredients and methods of using these as therapeutic agents.

Claims22

Dependent claims

A compound having the structure of Formula (I) or Formula (II)

wherein:
R1 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heteroarylalkyl, and substituted and unsubstituted cycloalkyl;
R2 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heteroarylalkyl, and substituted and unsubstituted cycloalkyl;
R3 is selected from a substituted and unsubstituted alkyl or a substituted and unsubstituted heteroalkyl;
R4 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heteroarylalkyl, and substituted and unsubstituted cycloalkyl;
R3 and R4 can be connected together to form a pyridine or piperidine ring;
R5 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted pyridine, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted piperidine;
X and Y are independently selected from substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted pyridine, substituted and unsubstituted cycloalkyl, substituted and unsubstituted piperidine, CO2, CO and SO2,
wherein a, b and c are each independently 0 or 1, and
including pharmaceutically acceptable salts thereof.

7 more elements

A compound, including pharmaceutically acceptable salts thereof, having the structure of:

3-Benzyloxy-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(1-benzyl-piperidin-4-yl)-amide]4-hydroxyamide,
3-Benzyloxy-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-dimethylamino-benzylamide) 4-hydroxyamide,
3-Benzyloxy-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(3-dimethylamino-2,2-dimethyl-propyl)-amide]4-hydroxyamide,
3-(4-Methoxy-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-dimethylaminobenzylamide)4-hydroxyamide,
3-(4-Methoxy-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(1-benzyl-piperidin-4-yl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-dimethylamino-benzylamide)4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-{[3-(2-methyl-piperidin-1-yl)-propyl]-amide},
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(3-dimethylamino-propyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(3-dimethylamino-2,2-dimethyl-propyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(3-piperidin-1-yl-propyl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(3-diethylamino-propyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(3-dibutylamino-propyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-amino-benzylamide)4-hydoxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(2-diethylamino-ethyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(1-benzyl-piperidin-4-yl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide},
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-aminomethyl-benzylamide)4-hydroxyamide,
6-{[3-(3,4-Dichloro-benzyloxy)4-hydroxycarbamoyl-1-methyl-1H-pyrrole-2-carbonyl]-amino}-hexanoic acid methyl ester,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(3,4-dihydroxy-benzylamide)4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)4-hydroxycarbamoyl-1-methyl-1H-pyrrole-2-carboxylic acid 1-benzyl-piperidin-4-yl ester,
5-([1,4′]Bipiperidinyl-1′-carbonyl)-4-(3,4-dichloro-benzyloxy)-1-methyl-1H-pyrrole-3-carboxylic acid hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(1-naphthalen-1-yl-ethyl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(benzo[1,3]dioxol-5-ylmethyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-{[(4-methyl-pyridin-2-yl)-phenyl-methyl]-amide},
5-(N′-Benzyl-hydrazinocarbonyl)-4-(3,4-dichloro-benzyloxy)-1-methyl-1H-pyrrole-3-carboxylic acid hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-{[2-(1-benzyl-piperidin-4-ylamino)-phenyl]-amide}4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-{[4-(4-methyl-piperidin-1-yl)-phenyl]-amide},
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-piperidin-4-ylamide,
5-(4-Amino-piperidine-1-carbonyl)-4-(3,4-dichloro-benzyloxy)-1-methyl-1H-pyrrole-3-carboxylic acid hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-{[1-(4-dimethylamino-butyryl)-piperidin-4-yl]-amide}4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-{[1-(4-cyano-benzyl)-piperidin-4-yl]-amide}4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 4-[(1,2,2,6,6-pentamethyl-piperidin-4-yl)-amide],
4-{[3-(3,4-Dichloro-benzyloxy)4-hydroxycarbamoyl-1-methyl-1H-pyrrole-2-carbonyl]-amino}-piperidine-1-carboxylic acid ethyl ester,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-indan-1-ylamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(9H-fluoren-9-yl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4- hydroxyamide 2-piperidin-1-ylamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(2-hydroxy-indan-1-yl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(1-benzyl-pyrrolidin-3-yl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(2-hydroxy-indan-1-yl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-[(2-carbamoyl-cyclohexyl)-amide]4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-benzylamide 4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-(2-methoxy-benzylamide),
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-(3-methoxy-benzylamide),
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(2,4-dimethoxy-benzylamide)4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(3,4-dimethoxy-benzylamide)4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 4-(2,4,6-trimethoxy-benzylamide),
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-{[2-(4-hydroxy-phenyl)-ethyl]-amide},
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(pyridin-3-ylmethyl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(pyridin-4-ylmethyl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-[(pyridin-2-ylmethyl)-amide],
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-(4-pentyl-benzylamide),
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethyl]-amide}4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-{[2-(2,6-dichloro-benzylsulfanyl)-ethyl]-amide}4-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-{[3-(3-acetylamino-phenoxy)-propyl]-amide}4-hydroxyamide,
4-({[3-(3,4-Dichloro-benzyloxy)-4-hydroxycarbamoyl-1-methyl-1H-pyrrole-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-hydroxyamide 2-(4-methyl-benzylamide),
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-(2-chloro-6-phenoxy-benzylamide)4-hydroxyamide,
3-(2,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-dimethylamino-benzylamide)4-hydroxyamide,
3-(2,6-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-(4-dimethylamino-benzylamide)4-hydroxyamide,
1-Benzyl-3-(3,4-dichloro-benzyloxy)-1H-pyrrole-2,4-dicarboxylic acid 2-[(1-benzyl-piperidin-4-yl)-amide]4-hydroxyamide,
1-Benzyl-3-(3,4-dichloro-benzyloxy)-1H-pyrrole-2,4-dicarboxylic acid 2-[(1-benzyl-piperidin-3-yl)-amide]4-hydroxyamide,
1-Benzyl-3-(3,4-dichloro-benzyloxy)-1H-pyrrole-2,4-dicarboxylic acid 2-{[2-(1-benzyl-piperidin-4-ylamino)-phenyl]-amide}4-hydroxyamide,
3-Benzyloxy-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide,
3-(4-Methoxy-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-(4-dimethylamino-benzylamide)2-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide,
3-(3,4-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-3-yl)-amide]2-hydroxyamide,
3-(2,6-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide,
3-(2,6-Dichloro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-3-yl)-amide]2-hydroxyamide,
3-(4-Cyano-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-3-yl)-amide]2-hydroxyamide,
3-(4-Cyano-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide,
1-Methyl-3-(pyridin-4-ylmethoxy)-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide,
1-Methyl-3-(pyridin-4-ylmethoxy)-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-3-yl)-amide]2-hydroxyamide, or,
3-(3,4-Difluoro-benzyloxy)-1-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-[(1-benzyl-piperidin-4-yl)-amide]2-hydroxyamide.

72 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/631,887Filed 31 Jul 2003
Published: US 2005/0026991 A13 Feb 2005
Granted: 22 Aug 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 207/36
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 453/02
Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids: containing not further condensed…

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US 2005/0026991 A1Pre-grant publication · published 3 Feb 2005
US 7,094,791 B2This patent

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

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Abstract

A compound having the structure of Formula (I) or Formula (II)

wherein:
R1 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heteroarylalkyl, and substituted and unsubstituted cycloalkyl;
R2 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heteroarylalkyl, and substituted and unsubstituted cycloalkyl;
R3 is selected from a substituted and unsubstituted alkyl or a substituted and unsubstituted heteroalkyl;
R4 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heteroarylalkyl, and substituted and unsubstituted cycloalkyl;
R3 and R4 can be connected together to form a pyridine or piperidine ring;
R5 is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted pyridine, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted piperidine;
X and Y are independently selected from substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted pyridine, substituted and unsubstituted cycloalkyl, substituted and unsubstituted piperidine, CO2, CO and SO2,
wherein a, b and c are each independently 0 or 1, and
including pharmaceutically acceptable salts thereof.

7 more elements

Facts

Application

10/631,887Filed 31 Jul 2003

Published

US 2005/0026991 A13 Feb 2005

Granted

22 Aug 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 207/36
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 453/02
Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids: containing not further condensed…