CN-114025758-B - P2X7R antagonists

Abstract

A compound having formula I: R1 is hydrogen, hydroxy, halogen, nitro, amino, alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkylamino, heterocyclyl, aryl, heteroaryl, -NR 7 R 8 、-CO-R 10 , or-NH-CO-R 10 , L is a bond, a heterocyclic divalent group, a heteroaromatic divalent group, or an aromatic divalent group, M is a bond, alkyl, aryl, heterocyclic divalent group, heteroaromatic divalent group, or aromatic divalent group, X is a bond, -O-, -S-, -SO 2 -、-CO-、-NR 9 -、-(CH 2 ) M-or a heterocyclic divalent group, M is 1,2,3,4,5, or 6, Y is a bond, -NH-, heterocyclic divalent group, heteroaromatic divalent group, divalent benzyl, or aromatic divalent group, and Z is hydrogen, halogen, alkyl, aryl, heterocyclyl, heteroaryl, -NR 7 R 8 、-CO-R 10 , or-NH-CO-R 10 ;R 7 、R 8 , and R 9 are independently hydrogen, hydroxy, halogen, nitro, amino, alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkylamino, heterocyclyl, or heteroaryl, and R 10 is-O-tert-butyl, -CH 2 CH 2 is hydrogen, hydroxy, nitro, cycloalkyl, alkylamino, cycloalkyl, heterocyclyl, or heteroaryl.

Inventors

• QIAN LIGANG
• ZHANG CHUNBO

Assignees

• 钱立刚
• 张春波

Dates

Publication Date

20260508

Application Date

20200629

Priority Date

20190701

Claims (1)

1. 1. A compound of the structure or selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , 。

Description

P2X7R antagonists The present application claims priority from U.S. provisional application No. 62/869,040 filed on 7/1/2019, which provisional application is incorporated by reference for all purposes as if fully set forth herein. Technical Field The present invention relates to medicinal chemistry, in particular, purinergic receptor P2X7 (P2X 7R) antagonists and their use in medicine and diagnostics. Background P2X7R is a member of the ligand-gated ion channel and is expressed in a variety of cell types. It plays a key role in development and normal physiological activity. In contrast to other P2X receptors, P2X7R exhibits the most prominent effect in various pathological states, as it is a key factor in inflammation and immune processes. Its expression in peripheral macrophages and monocytes and in particular its expression in glial cells of the nervous system (microglial cells, astrocytes, oligodendrocytes and Schwann (Schwann) cells) makes them therapeutic targets for neurodegenerative diseases and other neuropathological states. P2X7R is also expressed in antigen presenting cells, keratinocytes, salivary acinar cells, hepatocytes, erythrocytes, erythroleukemia cells, monocytes, fibroblasts, bone marrow cells, neurons, and mesangial cells. In the brain, the P2X7R high expression regions are found in the olfactory anterior nucleus, cerebral cortex, pyriform cortex, lateral nucleus pulposus, hippocampal pyramidal cell layers (CA 1, CA3 and CA 4), pontic nucleus, lateral wedge bundle nucleus and vestibular medial nucleus. P2X7R mRNA hybridization signals were also observed in motor neurons of the trigeminal motor nucleus, the facial nerve nucleus, the sublingual nucleus, and the anterior horn of the spinal cord. Studies have shown that P2X7R acts as a scavenger receptor, promoting phagocytosis by binding apoptotic cadavers and foreign debris directly to their extracellular domains in the absence of extracellular Adenosine Triphosphate (ATP). P2X7R differs from other P2X receptors in that high concentrations of ATP are required to activate it, consistent with P2X7R being involved in various pathological states. After activation by an agonist, the ion channel formed by P2X7R is initially permeable to only small ions, but slowly moves to a state permeable to both small and large molecules in the continued presence of the agonist. The prolonged macroporous opening of the P2X7R channel results in the release of pro-inflammatory cytokines such as IL-1 beta, IL-6, IL-18, chemokine CCL2 and/or tumor necrosis factor tnfα, which promotes inflammation and may regulate additional events leading to cell degeneration or even death. Inhibition of P2X7R may provide a novel view of anti-inflammatory therapy. Accumulated data has shown that P2X7R is a key factor in inflammation. Inhibition of P2X7R activity with agents or P2X7R deficiency by gene deletion, gene mutation or gene silencing may ameliorate various pathological conditions mediated by P2X 7R. The compounds of the invention or pharmaceutically acceptable salts thereof for the treatment of humans and lower animals are useful for the established symptomatology and for the prophylactic treatment of P2X7R mediated pathologies, including but not limited to platelet dysfunction diseases, hyperplasia (condition), bone diseases, cancer, cardiovascular diseases, depression, diabetes, fever, gastrointestinal dysfunction, inflammation and inflammatory conditions, immune diseases, impotence or erectile dysfunction, renal dysfunction, liver dysfunction, neurodegenerative diseases and other neuropathological conditions, as well as pain and pain associated disorders. Examples of P2X7R involvement are shown are neuropathological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, huntington's disease, parkinson's disease, spinal cord injury, cerebral ischemia, head trauma, meningitis, sleep disorders, affective and anxiety disorders, epilepsy, HIV-induced neuroinflammation and CNS injury, chronic neuropathic and inflammatory pain, and peripheral inflammatory disorders and autoimmune diseases including age-related macular degeneration, airway hyperreactivity, allergic dermatitis, asthma, atherosclerosis, bronchitis, burns, chronic obstructive pulmonary disease, crohn's disease, diabetes, fatty liver disease, fibrosis, glomerulonephritis, growth and metastasis of malignant cells, irritable bowel syndrome, ischemic heart disease, liver fibrosis, emphysema, muscular dystrophy, myeloblastic leukemia, osteoporosis, osteoarthritis, psoriasis, rheumatoid arthritis, hemorrhagic fever, sjogren's injury, and skin injury. Because of the importance of P2X7R in human health, the invention of new P2X7R antagonists represents an attractive route to develop new therapeutic agents. Although P2X7R antagonists are described in various patent applications, there is a need for new P2X7R antagonists that are effective and deliverable into different target organs whose pathology is m