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US-20260125388-A1 - GABA(A) RECEPTOR MODULATORS AND METHODS TO CONTROL SMOOTH MUSCLE CONTRACTION AND INFLAMMATION

US20260125388A1US 20260125388 A1US20260125388 A1US 20260125388A1US-20260125388-A1

Abstract

Substituted [benzo[f]imidazo[1,5-a][1,4]diazepine]-3-carboxylic acid compounds are GABA(A) receptor modulators and have utility to treat inflammation and/or inhibit smooth muscle contraction.

Inventors

  • Alexander E. Arnold
  • Michelle J. Meyer
  • Daniel A. Webb
  • Douglas C. Stafford
  • Charles W. Emala

Assignees

  • UWM RESEARCH FOUNDATION, INC.
  • THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

Dates

Publication Date
20260507
Application Date
20231004

Claims (20)

  1. 1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is H, halogen, CF 3 , —OC 1-4 alkyl, —C≡CH, or cyclopropyl; and R 2a and R 2b are independently C 1-4 alkyl, CF 3 , or CCl 3 ; or R 2 and R 2b together with the carbon to which each attaches form a 3- to 6-membered saturated carbocyclic ring, the carbocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of methyl and fluoro.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently C 1-4 alkyl, CF 3 , or CCl 3 .
  3. 3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently C 1-4 alkyl.
  4. 4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are methyl.
  5. 5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together with the carbon to which each attaches form the optionally substituted 3- to 6-membered saturated carbocyclic ring.
  6. 6 . The compound of claim 1 or 5 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together with the carbon to which each attaches form a cyclopropyl.
  7. 7 . The compound of claim 1 or 5 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together with the carbon to which each attaches form a cyclobutyl.
  8. 8 . The compound of claim 1 or 5 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together with the carbon to which each attaches form a cyclopentyl.
  9. 9 . The compound of claim 1 or 5 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together with the carbon to which each attaches form a cyclohexyl.
  10. 10 . The compound of any of claims 1-9 , or a pharmaceutically acceptable salt thereof, wherein R b is H.
  11. 11 . The compound of any of claims 1-9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is Br.
  12. 12 . The compound of any of claims 1-9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C≡CH.
  13. 13 . The compound of any of claims 1-9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  15. 15 . A pharmaceutical composition comprising a compound of any of claims 1-14 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  16. 16 . A method of reducing inflammation in a subject suffering an inflammatory disease or disorder comprising administering to the subject, an amount of a compound of formula (II), or a pharmaceutically acceptable salt or composition thereof, that is effective to reduce inflammation in the subject, wherein X is C—R x or N; R x is halogen; R 1 is H, halogen, CF 3 , —OC 1-4 alkyl, —C≡CH, or cyclopropyl; and R 2a and R 2b are independently H, C 1-4 alkyl, CF 3 , or CCl 3 ; or R 2 and R 2b together with the carbon to which each attaches form a 3- to 6-membered saturated carbocyclic ring, the carbocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of methyl and fluoro.
  17. 17 . The method of claim 16 , wherein the inflammatory disease or disorder is an acute inflammatory disease or disorder.
  18. 18 . The method of claim 16 , wherein the inflammatory disease or disorder is a chronic inflammatory disease or disorder.
  19. 19 . The method of claim 16 , wherein the inflammatory disease or disorder is a respiratory disease or condition.
  20. 20 . The method of claim 19 , wherein the respiratory disease or condition is asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, inflammatory diseases of the upper respiratory tract such as allergic rhinitis and allergic sinusitis, acute lung injury, acute respiratory distress syndrome (ARDS), lung infection, interstitial lung disease, or constrictive bronchiolitis.

Description

RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/413,044, filed Oct. 4, 2022, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD The present disclosure relates to compounds, compositions, and methods for treating or preventing inflammatory disorders and disorders associated with smooth muscle contraction. BACKGROUND Chronic inflammatory diseases are the most significant cause of death in the world and The World Health Organization (WHO) ranks chronic diseases as the greatest threat to human health. Inflammation can be acute, resulting from tissue damage due to trauma, microbial invasion, or noxious compounds. It starts rapidly, can become severe in a short time and symptoms may last for a few days for example cellulitis or acute pneumonia. Inflammation can be chronic with symptoms lasting for prolonged periods of weeks, years, or lifelong. Generally, the extent and effects of chronic inflammation vary with the inducing agent and the ability of the body to repair and overcome the damage. Inflammation involves a complex network of many mediators, a variety of cells, and can be manifested in multiple anatomical sites. Treatment of the chronic inflammation includes steroidal and non-steroidal anti-inflammatory agents, and biologic therapeutics. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, central nervous system, and renal abnormalities, among others. Inflammation can also contribute to other disease conditions such as abnormal smooth muscle contraction, such as airway hyperresponsiveness associated with lung inflammation, or itch associated with atopic dermatitis. SUMMARY In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, whereinR1 is H, halogen, CF3, —OC1-4alkyl, —C≡CH, or cyclopropyl; and R2a and R2b are independently C1-4alkyl, CF3, or CCl3; or R2a and R2b together with the carbon to which each attaches form a 3- to 6-membered saturated carbocyclic ring, the carbocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of methyl and fluoro. In another aspect, the present invention provides a pharmaceutical composition including a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the composition may be an oral, topical, injectable, or aerosol formulation. In another aspect, the invention provides compounds of formula (II) and pharmaceutically acceptable salts thereof, for use in the therapeutic methods disclosed herein, whereinX is C—Rx or N;Rx is halogen;R1 is H, halogen, CF3, —OC1-4alkyl, —C≡CH, or cyclopropyl; andR2a and R2b are independently H, C1-4alkyl, CF3, or CCl3; or R2a and R2b together with the carbon to which each attaches form a 3- to 6-membered saturated carbocyclic ring, the carbocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of methyl and fluoro. In another aspect, the invention provides a method of reducing airway constriction comprising administering an effective amount of a compound or composition of formula (I) or (II), or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, compounds of formula (I) or (II) have reduced benzodiazepine-type CNS effects in a subject compared to diazepam at therapeutic doses. In another aspect, the invention provides a method of reducing inflammation comprising administering an effective amount of a compound or composition of formula (I) or (II), or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, compounds of formula (I) or (II) have reduced benzodiazepine-type CNS effects in a subject compared to diazepam at therapeutic doses. In another aspect, the invention provides a method of reducing itch, comprising administering an effective amount of a compound or composition of formula (I) or (II), or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, compounds of formula (I) or (II) have reduced benzodiazepine-type CNS effects in a subject compared to diazepam at therapeutic doses. In another aspect, the invention provides a method of reducing development of disease in a subject having risk factors associated with inflammation comprising administering an effective amount of a compound or composition of formula (I) or (II), or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, compounds of formula (I) or (II) have reduced benzodiazepine-type CNS effects in a subject compared to diazepam at therapeutic doses. In another aspect, the invention provides a method of treating inflammation comprising administering an effective amount of a compound or composition of formula (I) or (II), or a pharmace