US 9,000,009 B2Granted

Small molecule activators of mitochondrial function

AssigneeThe Trustees of the University of Pennsylvania

InventorsRobert B. Wilson, Maria Grazia Cotticelli, Phillip A. Benedetti, Amos Smith, Jason E. Melvin, Donna M Huryn

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Abstract

Methods for improving mitochondrial function, decreasing iron accumulation, and/or decreasing oxidative stress by exposing cells or treating a subject to compounds or compositions of the general formula (I) are described that are beneficial in treating, for example, diseases and conditions such as Friedreich's ataxia, normal aging, and various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Furthermore, such compounds are useful as probes for identifying defects in mitochondrial metabolism, mitochondrial iron accumulation, cellular stress among other mitochondrial diseases and helping to identify compounds active in overcoming such defects.

Claims15

Dependent claims

A method for increasing cellular frataxin gene activity in a yeast or mammalian cell comprising contacting said yeast or mammalian cell with an effective amount of a compound having the structure of formula (I):

wherein A is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R1 is hydrogen, hydroxy, halogen, cyano, alkyloxy, nitro, NH2, NHCOR4, NHSO2R4, CONHR4, COOR4, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R2 is hydroxy or —OR, wherein R is —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —SO2NR4R6, —SO2R7, —COR7, —COOR7 or —CONR4R6, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl or alkynyl group is optionally substituted with a —C1-C3-alkyl;
R3 is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
and
R4 and R6 are each independently hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —COR7, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with an oxygen, a —C1-C3-alkyl, or a —C5-C7-aryl;
and
R7 is hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with a halogen, a —C1-C3-alkyl, a —C5-C7-aryl, or —NR4R6 or —OR4;
or an isomer, stereoisomer, racemate, prodrug, active metabolite, metal chelate, or a pharmaceutically-acceptable derivative or salt form of any of the foregoing.

6 more elements

A method for decreasing mitochondrial iron accumulation or for decreasing cellular iron import in a subject, comprising administering to the subject an effective amount of a compound having the structure of formula (I):

wherein A is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R1 is hydrogen, hydroxy, halogen, cyano, alkyloxy, nitro, NH2, NHCOR4, NHSO2R4, CONHR4, COOR4, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R2 is hydroxy or —OR, wherein R is —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —SO2NR4R6, —SO2R7, —COR7, —COOR7 or —CONR4R6, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl or alkynyl group is optionally substituted with a —C1-C3-alkyl;
R3 is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
and
R4 and R6 are each independently hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —COR7, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with an oxygen, a —C1-C3-alkyl, or a —C5-C7-aryl;
and
R7 is hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with a halogen, a —C1-C3-alkyl, a —C5-C7-aryl, or —NR4R6 or —OR4;
or an isomer, stereoisomer, racemate, prodrug, active metabolite, metal chelate, or a pharmaceutically-acceptable derivative or salt form of any of the foregoing,
wherein administering said compound increases frataxin gene activity in said subject.

7 more elements

A method for improving mitochondrial or cellular respiratory activity or function in a subject comprising administering to the subject an effective amount of a compound having the structure of formula (I):

wherein A is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R1 is hydrogen, hydroxy, halogen, cyano, alkyloxy, nitro, NH2, NHCOR4, NHSO2R4, CONHR4, COOR4, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R2 is hydroxy or —OR, wherein R is —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —SO2NR4R6, —SO2R7, —COR7, —COOR7 or —CONR4R6, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl or alkynyl group is optionally substituted with a —C1-C3-alkyl;
R3 is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
and
R4 and R6 are each independently hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —COR7, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with an oxygen, a —C1-C3-alkyl, or a —C5-C7-aryl;
and
R7 is hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with a halogen, a —C1-C3-alkyl, a —C5-C7-aryl, or —NR4R6 or —OR4;
or an isomer, stereoisomer, racemate, prodrug, active metabolite, metal chelate, or a pharmaceutically-acceptable derivative or salt form of any of the foregoing,
wherein administering said compound increases frataxin gene activity in said subject.

7 more elements

A method for treating a subject suffering from Friedreich's ataxia or reducing the symptoms thereof comprising administering to the subject an effective amount of a compound having the structure of formula (I):

wherein A is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R1 is hydrogen, hydroxy, halogen, cyano, alkyloxy, nitro, NH2, NHCOR4, NHSO2R4, CONHR4, COOR4, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R2 is hydroxy or —OR, wherein R is —C1-C6-alkyl, —C2-C6-alkynyl, —SO2NR4R6, —SO2R7, —COR7, —COOR7 or —CONR4R6, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl or alkynyl group is optionally substituted with a —C1-C3-alkyl;
R3 is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
and
R4 and R6 are each independently hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —COR7, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with an oxygen, a —C1-C3-alkyl, or a —C5-C7-aryl;
and
R7 is hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with a halogen, a —C1-C3-alkyl, a —C5-C7-aryl, or —NR4R6 or —OR4;
or an isomer, stereoisomer, racemate, prodrug, active metabolite, metal chelate, or a pharmaceutically-acceptable derivative or salt form of any of the foregoing,
wherein administering said compound increases frataxin gene activity in said subject.

7 more elements

A method for treating a subject having neurodegeneration with brain iron accumulation (NBIA), Friedreich's ataxia, Parkinson's disease, Alzheimer's disease, a mitochondrial encephalopathy, hemochromatosis, aceruloplasminemia, thalassemia, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, diabetes, or age-related macular degeneration, comprising administering to the subject an effective amount of a compound of having the structure of formula (I):

wherein A is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R1 is hydrogen, hydroxy, halogen, cyano, alkyloxy, nitro, NH2, NHCOR4, NHSO2R4, CONHR4, COOR4, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
R2 is hydroxy or —OR, wherein R is —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —SO2NR4R6, —SO2R7, —COR7, —COOR7 or —CONR4R6, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl or alkynyl group is optionally substituted with a —C1-C3-alkyl;
R3 is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic;
and
R4 and R6 are each independently hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —COR7, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with an oxygen, a —C1-C3-alkyl, or a —C5-C7-aryl;
and
R7 is hydrogen, —C1-C6-alkyl, —C2-C6-alkenyl, —C2-C6-alkynyl, —C5-C7-aryl, or —C5-C10-arylalkyl, wherein (a) one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, aryl or arylalkyl group is each independently optionally replaced with a nitrogen, sulfur or oxygen atom, and (b) the alkyl, alkenyl, alkynyl, aryl or arylalkyl is optionally substituted with a halogen, a —C1-C3-alkyl, a —C5-C7-aryl, or —NR4R6 or —OR4;
or an isomer, stereoisomer, racemate, prodrug, active metabolite, metal chelate, or a pharmaceutically-acceptable derivative or salt form of any of the foregoing,
wherein administering said compound increases frataxin gene activity in said subject.

7 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/139,162Filed 10 Dec 2009 · us provisional application
Priority: 10 Dec 2008
Published: US 2012/0041023 A116 Feb 2012
Granted: 7 Apr 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 409/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 31/47
Having six-membered rings with one nitrogen as the only ring hetero atom: quinolines; Isoquinolines
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs