US 2021/0069082 A1Published application

Spiroketals and uses thereof

AssigneeMemorial Sloan Kettering Cancer Center

InventorsDerek Shieh Tan, Alyssa Verano

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Abstract

The invention relates to novel spiroketal antioxidants, including compounds of Formula (I) and (II). The compounds have antioxidant properties and are useful for the treatment and/or prevention of diseases and conditions associated with oxidative stress in the body (e.g., metabolic conditions, neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, renal diseases). The invention provides pharmaceutical compositions comprising the compounds, and kits comprising the same. Additionally, the invention provides uses of the compounds described herein (e.g., for inhibiting the concentration or production of reactive oxygen species (ROS), inhibiting the concentration or production of reactive nitrogen species (RNS), reducing oxidative stress, inhibiting NADPH oxidase activity, and for slowing or reducing the effects of aging).

Claims38

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is optionally substituted alkyl, —OR1a, —N(R1b)2, or —SR1c;
R2 is hydrogen, halogen, optionally substituted alkyl, —OR2a, —N(R2b)2, or —SR2c;
R3 is hydrogen, halogen, optionally substituted alkyl, —ORO, —N(RN)2, or —SRS;
each instance of R4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —ORO, —N(RN)2′;
or —SRS;
each instance of R5 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —ORO, —N(RN)2, or —SRS;
each instance of R1a, R2a, and RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
each instance of R1b, R2b, and RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group;
each instance of R1b, R2b, and RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acryl, or a nitrogen protecting group;
or optionally two R1b, R2b, or RN on the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of R1c, R2c, and RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group;
s is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
provided that the sum of s and p is 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
and
m is 0, 1, 2, 3, or 4.

15 more elements

A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is halogen, optionally substituted alkyl, —OR1a, —N(R1b)2, or —SR1c;
R2 is hydrogen, halogen, optionally substituted alkyl, —OR2a, —N(R2b)2, or —SR2c;
R3 is hydrogen, halogen, optionally substituted alkyl, —ORO, —N(RN)2, or —SRS;
R6 is hydrogen, halogen, optionally substituted alkyl, —ORO, —N(RN)2, or —SRS;
each instance of R4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —ORO, —N(RN)2′, or —SRS;
each instance of R5 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —ORO, —N(RN)2, or —SRS;
each instance of R1a, R2a, and RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
each instance of R1b, R2b, and RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group;
or optionally two R1b, R2b, or RN on the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of R1c, R2c, and RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group;
s is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
provided that the sum of s and p is 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
and
m is 0, 1, 2, 3, or 4.

14 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/496,242Filed 23 Mar 2018
Priority: 23 Mar 2017
Published: 11 Mar 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

A61K 8/498
With oxygen as the only hetero atom: having 6-membered rings or their condensed derivatives, e.g. coumarin
A61P 39/06
General protective or antinoxious agents: free radical scavengers or antioxidants
A61Q 19/00
Preparations for care of the skin
C07D 493/10
In which the condensed system contains two hetero rings: spiro-condensed systems

Family

Application62/475,782Us provisional application · filed 23 Mar 2017
US 2021/0069082 A1This patent

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

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