US 2024/0366529 A1Published application

Substituted alkylphenols as hcn1 antagonists

AssigneeCornell University

InventorsGareth R. Tibbs, Peter A. Goldstein, Anthony A. Sauve, Rajendra Uprety, James David Warren, JR., Rebecca L. Joyce, Dipti N. Barman

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Abstract

Provided herein are compounds (e.g., compounds of Formula (I) and Formula (II), that modulate HCN channels, intermembrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells. Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating HCN-related disorders (e.g., pain) with the compounds in a subject, by administering the compounds and/or compositions described herein.

Claims23

Dependent claims

A method of treating pain in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R1 is unsubstituted alkyl;
R2 is unsubstituted alkyl;
X is halogen, —OP, —N(RA)2, —NRAN(RA)2, —SP, or —NCO;
P is hydrogen, an oxygen protecting group, a sulfur protecting group, or substituted or unsubstituted heterocyclyl;
L1 is —(C═O)—, —CH2—, —CH═CH—, —C≡C—, —O—, —S—, or —NRA—;
L2 is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, or substituted or unsubstituted heteroalkynylene, wherein L2 comprises a chain of at least 8 continuous non-hydrogen atoms from its point of attachment to L1 to its point of attachment to T;
T is substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, —ORC, —N(RA)2, —SRA, —CO2H, halogen, —OS(O2)RB, —O(C═O)RC, —(C═O)ORC, —O(C═O)ORC, —(C═O)N(RA)2, —O(C═O)N(RA)2, —NRA(C═O)N(RA)2, —CN, —CHO, —N3, —N═C═S,
Q is S or O;
each RA is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted heterocyclyl, a nitrogen protecting group, or a sulfur protecting group;
RB is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
RC is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
RD is halogen or —OS(O2)RB;
RE is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
and
RF is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

13 more elements

A method of modulating HCN channel gating, the method comprising contacting an HCN channel with an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R1 is unsubstituted alkyl;
R2 is unsubstituted alkyl;
X is halogen, —OP, —N(RA)2, —NRAN(RA)2, —SP, or —NCO;
P is hydrogen, an oxygen protecting group, a sulfur protecting group, or substituted or unsubstituted heterocyclyl;
L1 is —(C═O)—, —CH2—, —CH═CH—, —C≡C—, —O—, —S—, or —NRA—;
L2 is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, or substituted or unsubstituted heteroalkynylene, wherein L2 comprises a chain of at least 8 continuous non-hydrogen atoms from its point of attachment to L1 to its point of attachment to T;
T is substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, —ORC, —N(RA)2, —SRA, —CO2H, halogen, —OS(O2)RB, —O(C═O)RC, —(C═O)ORC, —O(C═O)ORC, —(C═O)N(RA)2, —O(C═O)N(RA)2, —NRA(C═O)N(RA)2, —CN, —CHO, —N3, —N═C═S,
Q is S or O;
each RA is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted heterocyclyl, a nitrogen protecting group, or a sulfur protecting group;
RB is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
RC is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
RD is halogen or —OS(O2)RB;
RE is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
and
RF is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

13 more elements

A method of inhibiting an HCN1 channel without enhancing a gamma-aminobutyric acid-A (GABA-A) receptor, the method comprising contacting an HCN1 channel with an effective amount a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R1 is unsubstituted alkyl;
R2 is unsubstituted alkyl;
X is halogen, —OP, —N(RA)2, —NRAN(RA)2, —SP, or —NCO;
P is hydrogen, an oxygen protecting group, a sulfur protecting group, or substituted or unsubstituted heterocyclyl;
L1 is —(C═O)—, —CH2—, —CH═CH—, —C≡C—, —O—, —S—, or —NRA—;
L2 is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, or substituted or unsubstituted heteroalkynylene, wherein L2 comprises a chain of at least 8 continuous non-hydrogen atoms from its point of attachment to L1 to its point of attachment to T;
T is substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, —ORC, —N(RA)2, —SRA, —CO2H, halogen, —OS(O2)RB, —O(C═O)RC, —(C═O)ORC, —O(C═O)ORC, —(C═O)N(RA)2, —O(C═O)N(RA)2, —NRA(C═O)N(RA)2, —CN, —CHO, —N3, —N═C═S,
Q is S or O;
each RA is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted heterocyclyl, a nitrogen protecting group, or a sulfur protecting group;
RB is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
RC is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
RD is halogen or —OS(O2)RB;
RE is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
and
RF is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

13 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/307,174Filed 26 Apr 2023
Priority: 27 Jun 2018
Published: 7 Nov 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

A61K 31/05
Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates: phenols
C07D 207/46
Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom: with…
A61K 31/11
Medicinal preparations containing organic active ingredients: aldehydes
A61K 31/20
Carboxylic acids, e.g. valproic acid: having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids

Family

Application62/690,778Us provisional application · filed 27 Jun 2018
Application62/803,109Us provisional application · filed 8 Feb 2019
Application17/254,787Division · filed 21 Dec 2020
Application18/307,174Division
US 11,684,590 B2Related patent
US 12,274,679 B2Related patent
US 2021/0267909 A1Published application
US 2024/0366529 A1This patent

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

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