Compound useful as toll-like receptor 7 activation inhibitor

Patent metadata

Field	Value
Publication number	US-12410157-B2
Application number	US-202118008871-A
Country	US
Kind code	B2
Filing date	Jun 7, 2021
Priority date	Jun 8, 2020
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

CB-7 exhibits a weak TLR7 inhibiting effect in normal mice. The present invention provides a novel compound with a stronger TLR7 inhibiting effect than CB-7, a pharmaceutically acceptable salt of said compound, or a prodrug of said compound or salt. The present invention also provides a drug for the prevention or treatment of diseases associated with the activation of TLR7, said drug including the aforementioned TLR7 activation inhibitor.

First claim

The invention claimed is:

1. A chemical compound represented by the following formula

a pharmacologically acceptable salt thereof, or a prodrug thereof,
wherein in formulae (I) and (II),
R 1 is:
C 3-5 alkoxy group containing at least two oxygen atoms;
C 2-4 alkoxy group containing at least one hydroxyl group; and
the following formula

wherein R 2 and R 3 are each independently C 1-3 alkyl group; or

wherein C ring is a 3- to 7-membered nitrogen-containing heterocyclic ring,
R 4 is a group represented by a combination of —NH—, —O—, —CF 2 —, —CHF—, —C 2 H 2 F 2 — or —CHF—X—CHF—, and
X is C 1-4 alkyl group.

2. The chemical compound according to claim 1 , the pharmacologically acceptable salt thereof, or the prodrug thereof, wherein R 1 is:

3. The compound according to claim 1 , the pharmacologically acceptable salt thereof, or the prodrug thereof, wherein the chemical compound is represented by any of the following formulae:

4. The chemical compound according to claim 1 , the pharmacologically acceptable salt, or the prodrug thereof, wherein the pharmacologically acceptable salt is a hydrochloride salt or a formate salt.

5. A toll-like receptor 7 (TLR7) activation inhibitor comprising a chemical compound according to claim 1 , a pharmacologically acceptable salt thereof, or a prodrug thereof.

6. The TLR7 activation inhibitor according to claim 5 , comprising an inhibitory effect on production of NF-κB, IL-6, TNF-α or IFN-α due to activation of TLR7.

7. A method for treatment of a disease involving TLR7 activation in a subject, the method comprising administering an TLR7 activation inhibitor according to claim 5 to the subject, wherein the disease involving the TLR7 activation is an autoimmune disease, an autoinflammatory syndrome, autoimmune pancreatitis, atherosclerosis, sepsis, neurodegenerative disease, graft rejection, graft-versus-host disease, periodontal disease, viral immunodeficiency, IgA nephropathy, primary nephrotic syndrome, primary membranous proliferative glomerulonephritis, purpura nephritis, Langerhans cell histiocytosis, hemophagocytic lymphohistiocytosis, Rosai-Dorfman disease, obesity, type 2 diabetes mellitus or ulcerative colitis.

8. The method according to claim 7 , wherein the disease involving the TLR7 activation is the autoimmune disease.

9. The method according to claim 7 , wherein the autoimmune diseases is systemic lupus erythematosus, Sjogren syndrome, scleroderma, polymyositis/dermatomyositis, mixed connective tissue disease, duplication syndrome, antiphospholipid antibody syndrome, Behcet's disease, adult Still's disease, rheumatic fever, malignant rheumatoid arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, HLA-B27 related rheumatic diseases, IgG4-related syndrome, ANCA-related vasculitis, vasculitis syndrome, multiple sclerosis, psoriasis vulgaris, inflammatory bowel disease, autoimmune thyroid disease, autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura, primary biliary cirrhosis, primary biliary cholangitis, myasthenia gravis, Goodpasture's syndrome, Guillain-Barre syndrome, chronic atrophic gastritis, rapidly progressive glomerulonephritis, anti-glomerular basement membrane nephritis, Addison's disease, type I diabetes mellitus, vitiligo vulgaris, pemphigus vulgaris, pemphigoid, autoimmune neutropenia, autoimmune hepatitis, or autoimmune pancreatitis.

10. The method according to claim 9 , wherein the autoimmune disease is the systemic lupus erythematosus.

Assignees

• Univ Toyama Prefectural
• Teika Pharmaceutical Co Ltd
• Aist

Inventors

• Nagai Yoshinori
• Okamoto Naoki
• Fujishita Shigeto
• Hirokawa Takatsugu

Classifications

• C07D307/94

  spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D295/096

  with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D211/38

  Halogen atoms or nitro radicals · CPC title

• C07D205/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title