2-Oxooxazolidine-5-carboxamides as Na_v1.8 Inhibitors for Treating Pain Disorders, Cough Disorders, and Acute and Chronic Itch Disorders

Important Compound Classes

Title

2-Oxo-Oxazolidine-5-Carboxamides as Na_v1.8 Inhibitors

Patent Publication Number

WO 2021/257418 A1

URL: https://patents.google.com/patent/WO2021257418A1/en

Publication Date

December 23, 2021

Priority Application

US 63/040,463

Priority Date

June 17, 2020

Inventors

Arasappan, A.; Bell, I. M.; Bungard, C. J.; Burgey, C. S.; Cox, J. M.; Guiadeen, D. G.; Kelly, M. J., III; Layton, M. E.; Liu, H.; Liu, J.; Olsen, J. T.; Perkins, J. J.; Schubert, J. W.; Shah, A. A.; Vanheyst, M. D.; Wu, Z.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Pain disorders, cough disorders, acute itch disorders and chronic itch disorders

Biological Target

Na_v1.8

Summary

Voltage-gated sodium channels (VGSCs) mediate the selective influx of sodium ions in excitable cells and play a central role in initiating and propagating action potentials. VGSCs are ubiquitous in the central and peripheral nervous system. VGSCs are multimeric complexes characterized by one α-subunit, which forms an ion-conducting aqueous pore, and at least one β-subunit that modifies the kinetics and voltage-dependence of the channel gating. Nine different α-subunits have been identified and characterized in mammalian voltage-gated sodium channels, including Na_v1.8. Expression of sodium channels can be tissue specific. Na_v1.8 voltage-gated sodium ion channels are expressed primarily in sensory neurons, which are responsible for conveying information via the spinal cord.

Na_v1.8 voltage-gated sodium ion channels are believed to play a role in various maladies, including neuropathic pain, chronic itch, and inflammatory pain perception. It is believed that inhibitors of Na_v1.8 voltage-gated sodium ion channel activity may be useful to treat diseases involving Na_v1.8 receptors and/or stemming specifically from dysfunction of Na_v1.8 voltage-gated sodium ion channels, including but not limited to migraine, neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, and postoperative pain.

The present application describes a series of novel 2-oxooxazolidine-5-carboxamides as Na_v1.8 inhibitors for the treatment of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

A and B = aryl and heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from R_a;

R₁ = H, C_1–6alkyl, C_3–6alkenyl, C_3–6alkynyl, C_3–10cycloalkyl, C_2–10cycloheteroalkyl, C_1–6alkyl–O–C_1–6alkyl, (CH₂)_sC(O)R_j, (CH₂)_sC(O)R_eR_j, (CH₂)_nNR_eC(O)R_j, (CH₂)_nNR_eC(O)OR_j, (CH₂)_nNR_eC(O)NR_eR_j, (CH₂)_nNR_eS(O)_mR_j, (CH₂)_nNR_eS(O)_mN(R_e)₂, (CH₂)_nNR_eS(O)_mNR_eR_j, (CH₂)_nNR_eR_j, wherein CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R_c;

R₂ = H, C_1–6alkyl, C_3–6alkenyl, C_3–6alkynyl, C_3–10cycloalkyl, C_2–10cycloheteroalkyl, C_1–6alkyl–O–C_1–6alkyl, (CH₂)_sC(O)R_j, (CH₂)_sC(O)R_eR_j, (CH₂)_nNR_eC(O)R_j, (CH₂)_nNR_eC(O)OR_j, (CH₂)_nNR_eC(O)NR_eR_j, (CH₂)_nNR_eS(O)_mR_j, (CH₂)_nNR_eS(O)_mN(R_e)₂, (CH₂)_nNR_eS(O)_mNR_eR_j, (CH₂)_nNR_eR_j, wherein CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R_f;

R₃ = H, C_1–6alkyl, C_3–6alkenyl, C_3–6alkynyl, C_3–10cycloalkyl, C_2–10cycloheteroalkyl, C_1–6alkyl–O–C_1–6alkyl, (CH₂)_sC(O)R_j, (CH₂)_sC(O)R_eR_j, (CH₂)_nNR_eC(O)R_j, (CH₂)_nNR_eC(O)OR_j, (CH₂)_nNR_eC(O)NR_eR_j, (CH₂)_nNR_eS(O)_mR_j, (CH₂)_nNR_eS(O)_mN(R_e)₂, (CH₂)_nNR_eS(O)_mNR_eR_j, (CH₂)_nNR_eR_j, wherein CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R_g;

R₄ = H and C_1–6alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen;

R₅ = H and C_1–6alkyl; and

R₆ = H, C_1–6alkyl, C_2–6alkenyl, C_2–6alkynyl, wherein alkyl, alkenyl, alkynyl is unsubstituted or substituted with one to five substituents selected from halogen.

Key Structures

Biological Assay

The Na_v1.8 Qube assay on human Na_v1.8 channels in human embryo kidney (HEK) 293 cells was performed. The compounds described in this application were tested for their ability to inhibit Na_v1.8. The Na_v1.8 IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for Na_v1.8 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 29

Compound claims: 20

Pharmaceutical composition claims: 1

Method of treatment claims: 4

Use of compound claims: 4

Recent Review Articles

• 1.Obeng S.; Hiranita T.; Leon F.; McMahon L. R.; McCurdy C. R.. J. Med. Chem. 2021, 64, 6523.
• 2.Xue Y.; Chidiac C.; Herault Y.; Gaveriaux-Ruff C.. Neurosci. Lett. 2021, 753, 135844.
• 3.Ye D.; Fairchild T. J.; Vo L.; Drummond P. D.. Diabet. Med. 2022, 39, e14729.
• 4.Ghosh K.; Pan H.. ACS Chem. Neurosci. 2022, 13, 432.
• 5.Chen L.; He Y.; Wang X.; Ge J.; Li H.. Clin. Transl. Med. 2021, 11, e530.
• 6.Cheng X.; Choi J.; Waxman S. G.; Dib-Hajj S. D.. Neurosci. Lett. 2021, 741, 135446.

The author declares no competing financial interest.