KR-102962516-B1 - Triazine derivatives for the treatment of neurotrophin-related diseases

Abstract

A compound of the following chemical formula I is provided; In the above formula, R1 and R2 are as defined in this specification, and this compound is useful for treating diseases characterized by impaired signaling of neurotrophins and/or other trophic factors, such as Alzheimer's disease.

Inventors

• 노르드발, 군나르
• 포셀, 폰투스

Assignees

• 알제큐어 파마 에이비

Dates

Publication Date

20260508

Application Date

20200828

Priority Date

20190829

Claims (20)

1. As a compound of the following chemical formula I or a pharmaceutically acceptable salt thereof, In the above formula, R 1 is or Represents, represents the attachment point to the nitrogen atom; R3 represents hydrogen, methyl, or methoxymethyl; R 4 represents hydrogen, methoxy, or methoxymethyl; R2 represents methyl, ethyl, methoxymethyl, methylsulfanyl, or -AR5 ; A represents a C 1-2 alkylene, -C 1-2 alkyleneO-, or -OC 1-2 alkylene-, and these three groups are optionally substituted by one or more groups selected from halo, C 1-2 alkyl, and =O; R5 represents an oxetanyl or a 4 to 7-membered nitrogen-containing heterocyclyl group, each of which is optionally substituted by one or more groups selected from halos, C1-2 alkyls, and =O; However, the compound of chemical formula I is or A compound or a pharmaceutically acceptable salt thereof that does not represent
2. In paragraph 1, R 1 is Represents, , R3 and R4 are compounds as defined in paragraph 1.
3. A compound according to claim 1 or 2, wherein at least one of R3 and R4 represents hydrogen.
4. A compound according to claim 1 or 2, wherein R3 represents methyl or methoxymethyl and R4 represents hydrogen.
5. A compound according to claim 1 or 2, wherein R3 represents hydrogen and R4 represents methoxy.
6. A compound according to paragraph 1 or 2, wherein R3 and R4 each represent hydrogen.
7. A compound according to claim 1 or 2, wherein R2 represents methyl, ethyl, or methoxymethyl.
8. In paragraph 7, R2 represents a compound, wherein R2 is ethyl or methoxymethyl.
9. In paragraph 1 or 2, R2 represents -AR5 , and A and R5 are compounds as defined in paragraph 1.
10. A compound according to claim 9, wherein R5 represents a 4 to 7-membered nitrogen-containing heterocyclyl group, the heterocyclyl group being optionally substituted by one or more groups selected from halo, C1-2 alkyl, and =O.
11. A compound according to claim 1 or 2, wherein A represents -CH₂- or -OCH₂C (O)-.
12. A compound according to claim 1 or 2, wherein R5 represents a 4 to 6-membered nitrogen-containing heterocyclyl group, and the heterocyclyl group is optionally substituted by one or more groups selected from halo, C1-2 alkyl, and =O.
13. In Paragraph 12, R 5 is Representing a nitrogen-containing heterocyclyl group of 4 to 6 selected from, represents the attachment point for A, A compound in which each of these heterocyclyl groups is selectively substituted by an =O group.
14. In paragraph 1, the compound is A compound selected from the group consisting of or pharmaceutically acceptable salts thereof.
15. A pharmaceutical composition comprising a compound defined in claim 1 or 14—including a pharmaceutically acceptable salt thereof—in combination with one or more pharmaceutically acceptable excipients for use in the treatment and/or prevention of a disease or disorder characterized by impaired signaling of neurotrophins and/or other trophic factors, wherein the disease or disorder characterized by impaired signaling of neurotrophins and/or other trophic factors is Alzheimer's disease, Lewy body dementia, frontotemporal dementia, cognitive impairment, mild cognitive impairment, other dementia disorders, Parkinson's disease, other Parkinson's disease disorders and/or other tauopathy, Huntington's disease, brain injury, stroke, motor neuron disease, multiple sclerosis, spinal cord injury, hypoxia, ischemia, hypoxic-ischemic injury, coronary artery disease, obesity, diabetes, metabolic syndrome, diabetic neuropathy, Charcot-Marie-Tooth disease, and A pharmaceutical composition selected from variants of this, nerve damage, genetic, acquired, or traumatic hearing loss, blindness, posterior eye disease, anterior eye disease, dry eye syndrome, neurotrophic keratitis, glaucoma, ocular hypertension, retinitis pigmentosa, post-traumatic stress disorder, WAGR syndrome, Prader-Willi syndrome, olfactory decline, olfactory dysfunction, fragile X syndrome, central respiratory depression syndrome, obsessive-compulsive disorder, anxiety, generalized anxiety disorder, schizophrenia, depression, eating disorders, bipolar disorder, chronic fatigue syndrome, neuromyelitis optica, Rett syndrome, epilepsy, Friedreich's ataxia, obstructive sleep apnea-hypopnea syndrome, pain, and constipation.
16. A compound as defined in paragraph 1 or 14 or a pharmaceutically acceptable salt thereof for use in medicine.
17. A compound as defined in claim 1 or 14—including pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of a disease or disorder characterized by impaired signaling of neurotrophins and/or other trophic factors, wherein the disease or disorder characterized by impaired signaling of neurotrophins and/or other trophic factors is Alzheimer's disease, Lewy body dementia, frontotemporal dementia, cognitive impairment, mild cognitive impairment, other dementia disorders, Parkinson's disease, other Parkinson's disease disorders and/or other tauopathy, Huntington's disease, brain injury, stroke, motor neuron disease, multiple sclerosis, spinal cord injury, hypoxia, ischemia, hypoxic-ischemic injury, coronary artery disease, obesity, diabetes, metabolic syndrome, diabetic neuropathy, Charcot-Marie-Tooth disease and variants thereof, neurological injury, genetic, acquired, or traumatic hearing loss, A compound selected from blindness, posterior eye disease, anterior eye disease, dry eye syndrome, neurotrophic keratitis, glaucoma, ocular hypertension, retinitis pigmentosa, post-traumatic stress disorder, WAGR syndrome, Prader-Willi syndrome, olfactory decline, olfactory dysfunction, fragile X syndrome, central respiratory depression syndrome, obsessive-compulsive disorder, anxiety, generalized anxiety disorder, schizophrenia, depression, eating disorders, bipolar disorder, chronic fatigue syndrome, neuromyelitis optica, Rett syndrome, epilepsy, Friedreich's ataxia, obstructive sleep apnea-hypopnea syndrome, pain, and constipation.
18. A compound for use according to claim 17, wherein the disease characterized by impaired signaling of neurotrophin and/or other trophic factors is selected from the group consisting of Alzheimer's disease, Parkinson's disease, other Parkinson's disease, other tauopathy, Lewy body dementia, motor neuron disease, Pick's disease, obesity, metabolic syndrome, diabetes mellitus, diabetic neuropathy, glaucoma, dry eye syndrome, neurotrophic keratitis, genetic, acquired or traumatic hearing loss, and Rett syndrome.
19. A compound for use in claim 18, wherein the disease characterized by impaired signaling of neurotrophin and/or other trophic factors is selected from the group consisting of Alzheimer's disease, Parkinson's disease, cognitive impairment, depression, diabetic neuropathy, glaucoma, dry eye syndrome, genetic, acquired or traumatic hearing loss, and Rett syndrome.
20. In paragraph 19, a compound for use in a disease characterized by impaired signaling of neurotrophin and/or other trophic factors, which is Alzheimer's disease.

Description

Triazine derivatives for the treatment of neurotrophin-related diseases The present invention relates to novel pharmaceutically active compounds, pharmaceutical compositions comprising said compounds, as well as pharmaceutical uses thereof. In particular, the present invention relates to the use of said compounds and compositions in methods for treating and/or preventing diseases characterized by impaired signaling of neurotrophins and/or other trophic factors. Any enumeration or discussion of documents explicitly disclosed in this specification shall not be construed as meaning that such documents are part of the latest technology or are recognized as common general knowledge. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 all belong to the neurotrophin protein family. These hormones act through a class of receptor tyrosine kinases called tropomyosin-receptor kinases (Trk). Ligands binding to Trk initiate receptor dimerization and autophosphorylation of the kinase domain, thereby activating the kinase activity of the receptor. This results in additional receptor phosphorylation at Tyr490, Tyr751, and Tyr785 of TrkA (or their equivalent residues on other Trk receptors). This phosphorylation leads to adapter binding sites that bind the receptor to SHC adapter protein 1 (SHC-1), phosphoinositide 3-kinase (PI3K), and phospholipase Cγ1 (PLCγ1). The binding of adapter proteins to the receptor initiates several different cellular events leading, for example, to neurite overgrowth and axonal elongation. These receptors and their signaling pathways play a pivotal role in numerous major processes in the brain, such as hippocampal neurogenesis, synaptic plasticity, and long-term potentiation—proposed mechanisms underlying memory formation at the synaptic level. NGF/TrkA and BDNF/TrkB-stimulated signaling are also essential for neuronal survival and morphogenesis. In addition to the activation of Trk receptors by classical ligand binding, there exist ligand-independent events capable of regulating neurotrophin signaling. The balance between the activity of receptor tyrosine kinases and the activity of tyrosine phosphatases complexly regulates the levels of phosphorylated receptors. Thus, protein tyrosine phosphatases, such as PTP-1B or other phosphatases, can increase neurotrophin signaling and regulate the temporal and spatial activity of receptor tyrosine kinases as well as Trk-receptors. In addition, adenosine and adenosine agonists can mediate the phosphorylation of Trk receptors through a mechanism requiring adenosine 2A (A2A) receptors. This phosphorylation of Trk receptors is independent of ligand binding, which suggests that the regulation of Trk receptor signaling can be achieved through several different mechanisms. Synaptic loss and a decrease in hippocampal volume are pathological features of Alzheimer's disease in the brain, and numerous studies suggest that synaptic loss is the most significant neuroanatomical indicator of cognitive decline in this disease. Basal forebrain cholinergic neurons (BFCNs) are a subgroup of neurons that appear to be particularly vulnerable to the pathology of AD. Dysfunctional atrophy of these neurons eventually leads to severe loss of cortical and hippocampal neural distribution, which may be the origin of the malfunction of the cholinergic system in AD (Bartus RT Exp Neurol 2000;163:495-529). Severe cortical cholinergic deficits in the disease also involve a loss of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity. The basal forebrain cholinergic system is dependent on NGF, and cholinergic basal forebrain neurons are the major cell population expressing the receptor for NGF, namely TrkA. Although the role of NGF in cholinergic neuronal survival and function is well established, studies have also revealed that neuroprotective/neurorestorative effects mediated by this system, for example, axotomized cholinergic release in animals, can be prevented by TrkA activation (Lucidi-Phillipi CA, Neuron., 1996, 16(3):653-663). The first morphological change in the brains of AD patients is a reduction in hippocampal volume. BDNF/TrkB-stimulated signaling has already been established to be essential for the survival and morphogenesis of hippocampal neurons, particularly. Furthermore, it is widely accepted that BDNF plays a decisive role in neuronal plasticity and long-term potentiation (LTP). Indeed, increasing experimental evidence suggests that increased BDNF signaling may potentially improve cognition in AD. Transplanting stem cells into the brains of triple-transgenic mouse models of AD that express amyloid and tau pathology—that is, the major neuropathological features of AD—improves cognition (Blurton-Jones M, PNAS, 2009. 106(32): p. 13594-13599). These effects are mediated by BDNF, as gain-of-function studies have shown that recombinant BDNF mimics the beneficial effects of neural stem cell (