L-pag derivatives for treatment of sleep disordered breathing (sdb)

Patent metadata

Field	Value
Publication number	US-2025241896-A1
Application number	US-202519084506-A
Country	US
Kind code	A1
Filing date	Mar 19, 2025
Priority date	Dec 20, 2016
Publication date	Jul 31, 2025
Grant date	—

Abstract

Described herein are novel γ- and δ-propargyl carboxylic acids and esters. The novel compositions are antagonists of CSE and may be used to modulate of the activity of the carotid body, therefore providing therapeutic benefits for sleep-related breathing disorders and related conditions.

First claim

The invention claimed is:

1 . A method of treating, preventing, or reducing a sleep-related breathing disorder in an individual in need thereof comprising administering a therapeutically effective amount of a cystathionine-γ-lyase (CSE) antagonist, wherein the CSE antagonist is a compound of the formula

wherein:
R 1 and R 3 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycle;
R 2 is hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycle; and
X is a hydrogen, a halide, CN, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycle;

or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.

2 . The method of claim 1 , wherein the CSE antagonist reduces CSE-catalyzed synthesis of hydrogen sulfide (H 2 S).

3 . The method of claim 2 , wherein reduced synthesis of H 2 S results in attenuation of carotid body activity.

4 . The method of any of claims 1 to 3 , wherein the CSE antagonist reduces chemosensitivity of the carotid body.

5 . The method of claim 4 , wherein reduced carotid body chemosensitivity is reduction of arterial blood oxygen sensitivity.

6 . The method of claim 4 , wherein reduced carotid body reduction chemosensitivity is reduction of arterial blood carbon dioxide sensitivity.

7 . The method of either of claim 5 or 6 , wherein the reduced carotid body chemosensitivity reduces loop gain of the ventilator drive control system, blunts hypoventilation, lowers blood pressure, and/or dampens carotid sinus nerve activity.

8 . The method of either of claims 1 to 7 , wherein the CSE antagonist bolsters the carotid body's response to hypoxia.

9 . The method of claim 1 , wherein the individual is suffering from or suspected to be suffering from a sleep-related breathing disorder selected from central sleep apnea (CSA), Cheyne-Stokes breathing-central sleep apnea (CSB-CSA), obesity hypoventilation syndrome (OHS), congenital central hypoventilation syndrome (CCHS), obstructive sleep apnea (OSA), idiopathic central sleep apnea (ICSA), narcotic-induced CSA, high altitude periodic breathing, chronic mountain sickness, impaired respiratory motor control associated with stroke, upper airway resistance syndrome (UARS), or impaired respiratory motor control associated with a neurologic disorder.

10 . The method of any one of claims 1-9 , further comprising administering a second therapeutic selected from carbonic anhydrase inhibitors, cholinesterase inhibitors, adenosine inhibitors, progestational agents, opioid antagonists, central nervous system stimulants, selective serotonin reuptake inhibitors (SSRis), antidepressants, antihypertensives, calcium channel antagonists, ACE inhibitors, respiratory stimulants, alpha-2 adrenergic agonists, gamma aminobutyric acid agonists, and glutamate antagonists.

11 . The method of any one of claims 1-10 , further comprising administering an additional therapeutic selected from acetazolamide, theophylline, progesterone, donepezil, naloxone, nicotine, paroxetine, protriptyline, metoprolol, cilazapril, propranolol, atenolol, hydrochlorothiazide, isradipine, spirapril, doxapram, clonidine, baclofen, and sabeluzole.

12 . The method of any one of claims 1-11 , wherein the CSE antagonist is administered orally, subcutaneously, topically, intramuscularly, or intravenously.

13 . The method of any of claims 1-12 , wherein the CSE antagonist is at least one of:

14 . A method of treating, preventing, or reducing a sleep-related breathing disorder in an individual in need thereof comprising administering a therapeutically effective amount of a cystathionine-γ-lyase (CSE) antagonist, wherein the CSE antagonist is a compound of the formula

wherein:
R 1 and R 3 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycle;
R 2 is hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycle;
X is a hydrogen, a halide, CN, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycle; and
Y is a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or an electron-donating group;

or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.

15 . The method of claim 14 , wherein the CSE antagonist reduces CSE-catalyzed synthesis of hydrogen sulfide (H 2 S).

16 . The method of claim 15 , wherein reduced synthesis of H 2 S results in attenuation of carotid body activity.

17 . The method of any of claims 14 to 16 , wherein the CSE antagonist reduces chemosensitivity of the carotid body.

18 . The method of claim 17 , wherein reduced carotid body chemosensitivity is reduction of arterial blood oxygen sensitivity.

19 . The method of claim 17 , wherein reduced carotid body reduction chemosensitivity is reduction of arterial blood carbon dioxide sensitivity.

20 . The method of either of claim 18 or 19 , wherein the reduced carotid body chemosensitivity reduces loop gain of the ventilator drive control system, blunts hypoventilation, lowers blood pressure, and/or dampens carotid sinus nerve activity.

21 . The method of either of claims 14 to 20 , wherein the CSE antagonist bolsters the carotid body's response to hypoxia.

22 . The method of claim 14 , wherein the individual is suffering from or suspected to be suffering from a sleep-related breathing disorder selected from central sleep apnea (CSA), Cheyne-Stokes breathing-central sleep apnea (CSB-CSA), obesity hypoventilation syndrome (OHS), congenital central hypoventilation syndrome (CCHS), obstructive sleep apnea (OSA), idiopathic central sleep apnea (ICSA), narcotic-induced CSA, high altitude periodic breathing, chronic mountain sickness, impaired respiratory motor control associated with stroke, upper airway resistance syndrome (UARS), or impaired respiratory motor control associated with a neurologic disorder.

23 . The method of any one of claims 14-22 , further comprising administering a second therapeutic selected from carbonic anhydrase inhibitors, cholinesterase inhibitors, adenosine inhibitors, progestational agents, opioid antagonists, central

Assignees

• Univ Chicago
• Iit Res Inst

Inventors

• Kates Michael J
• Prabhakar Nanduri B
• Mccormick David L
• Muzzio Miguel

Classifications

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D277/30

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C255/07

  Mononitriles · CPC title

• C07C229/30

  the carbon skeleton being acyclic and unsaturated · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title