# US 10,766,886 B2 · Retinoic acid receptor antagonists as chaperone-mediated autophagy modulators and uses thereof

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- Number: US 10,766,886 B2
- Document ID: US10766886B2
- Status: Granted
- Kind: B2
- Application number: 16/210,895
- Filed: 2018-12-05
- Published: 2019-07-25
- Granted: 2020-09-08
- Earliest claimed: 2013-12-12
- Assignees: Albert Einstein College of Medicine
- Applicants: Albert Einstein College of Medicine
- Inventors: Ana Maria Cuervo; Evripidis Gavathiotis; Qisheng Xin; Bhaskar C. Das
- Web page: https://patentgrep.com/patent/US10766886B2

## CPC

- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07C 279/22: Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
- C07D 265/36: condensed with one six-membered ring
- C07B 2200/11: Compounds covalently bound to a solid support
- C07C 2601/16: the ring being unsaturated
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2800/7009: Oxidative stress
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Compounds, compositions and methods are provided for selectively activating chaperone-mediated autophagy (CMA), protecting cells from oxidative stress, proteotoxicity and lipotoxicity, and/or antagonizing activity of retinoic acid receptor alpha (RARα) in subjects in need thereof.

## Claims

### Claim 1

A compound of formula (II), wherein formula (II) is
wherein
R1, R2, R3, R4, R5, R6, R8 and R9 of formula (II) are independently H, hydroxyl, halogen, SH, NO2, CF3, COOH, COOR10, CHO, CN, NH2, NHR10, NHCONH2, NHCONHR10, NHCOR10, NHSO2R10, OCR10, COR10, CH2R10, CON(R10,R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO2R10, COOR10, CH2N(R10,R11), N(R10,R11), or optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO2, COOH, COOR10, R10, CHO, CN, NH2, NHR10, NHCONH2, NHCONHR10, NHCOR10, NHSO2R10, HOCR10, COR10, CH2R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO2R10, COOR10, CH2N(R10, R11), N(R10, R11);
R7 of formula (II) is H, hydroxyl, halogen, CF3, CN, OCF3, COOH, COOCH3, COOR10, COO(CH2)2Si(CH3)3, COOR10Si(CH3)3, NHCOCH3, C═C—CH2OH, C═C—R10-OH or optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaroaralkyl, cyclic or heterocyclic; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO2, CH3, R10, COOH, COOR10, CHO, CN, NH2, NHR10, NHCONH2, NHCONHR10, NHCOR10, NHSO2R10, HOCR10, COR10, CH2R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO2R10, COOR10, CH2N(R10, R11), N(R10, R11);
R10 and R11 are independently H or C1-C6 alkyl; and
X is N; and Y is N;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein
R7 is optionally substituted aryl or heteroaryl and the optionally substituted aryl or heteroaryl is

### Claim 3

A compound of formula (II), wherein formula (II) is
or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R4, R5, R6, R8 and R9 of formula (II) are independently H, hydroxyl, halogen, SH, NO2, CF3, COOH, COOR10, CHO, CN, NH2, NHR10, NHCONH2, NHCONHR10, NHCOR10, NHSO2R10, OCR10, COR10, CH2R10, CON(R10,R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO2R10, COOR10, CH2N(R10,R11), N(R10,R11), or optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO2, COOH, COOR10, R10, CHO, CN, NH2, NHR10, NHCONH2, NHCONHR10, NHCOR10, NHSO2R10, HOCR10, COR10, CH2R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO2R10, COOR10, CH2N(R10, R11), N(R10, R11);
R7 of formula (II) is H, hydroxyl, halogen, CF3, CN, OCF3, COOH, COOCH3, COOR10, COO(CH2)2Si(CH3)3, COOR10Si(CH3)3, NHCOCH3, C═C—CH2OH, C═C—R10-OH or optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaroaralkyl, cyclic or heterocyclic; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO2, CH3, R10, COOH, COOR10, CHO, CN, NH2, NHR10, NHCONH2, NHCONHR10, NHCOR10, NHSO2R10, HOCR10, COR10, CH2R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO2R10, COOR10, CH2N(R10, R11), N(R10, R11); and
R10 and R11 are independently H or C1-C6 alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein any one or more alkyl is C1-C3 alkyl independently of any other alkyl.

### Claim 5

A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
R1 is Cl,
R2, R3, R4, R5, R6, R8, and R9 are H, and
R7 is NHCOCH3.

### Claim 6

A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
R1 is Cl,
R2, R3, R4, R5, R6, R8, and R9 are H, and
R7 is phenyl.

### Claim 7 (depends on 5)

A method of selectivity activating chaperone-mediated autophagy (CMA) in a subject in need thereof, comprising administering to the subject a compound or salt of claim 5, in an amount effective to activate CMA,
wherein the subject has Parkinson's Disease, Huntington's Disease, frontotemporal dementia, retinal degeneration, multiple sclerosis, diabetes, a lysosomal storage disorder, a retinal disease, a cardiovascular disease, myocardial infarction, cardiac hypertrophy, or a cardiomyopathy.

### Claim 8 (depends on 7)

The method of claim 7, wherein the subject has reduced CMA compared to a normal subject prior to administering the compound.

### Claim 9 (depends on 5)

A method of protecting cells from oxidative stress, proteotoxicity, and/or lipotoxicity in a subject in need thereof, comprising administering to the subject a compound or salt claim 5, in an amount effective to protect cells from oxidative stress, proteotoxicity, and/or lipotoxicity,
wherein the subject has Parkinson's Disease, Huntington's Disease, frontotemporal dementia, retinal degeneration, multiple sclerosis, diabetes, a lysosomal storage disorder, a retinal disease, a cardiovascular disease, myocardial infarction, cardiac hypertrophy, or a cardiomyopathy.

### Claim 10 (depends on 9)

The method of claim 9, wherein the cells being protected comprise cardiac cells, liver cells neurons, myocytes, fibroblasts, and/or immune cells.

### Claim 11 (depends on 5)

A method of antagonizing activity of retinoic acid receptor alpha (RARα) in need thereof comprising administering to the subject a compound or salt of claim 5, in an amount effective to act as an RARα antagonist,
wherein the subject has Parkinson's Disease, Huntington's Disease, frontotemporal dementia, retinal degeneration, multiple sclerosis, diabetes, a lysosomal storage disorder, a retinal disease, a cardiovascular disease, myocardial infarction, cardiac hypertrophy, or a cardiomyopathy.