Search

CN-122003399-A - 4-Amino-2, 6-bis (benzylidene) cyclohexanone and use thereof

CN122003399ACN 122003399 ACN122003399 ACN 122003399ACN-122003399-A

Abstract

The present invention relates to 4-amino-2, 6-bis (benzylidene) cyclohexanone of the general formula I, and pharmaceutically acceptable salts, addition salts and solvates thereof, Wherein R 1 、R 2 、R 3 and R 4 are independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a C1-C3 alkoxy group, a trifluoromethoxy group, and a difluoromethoxy group, R 5 and R 6 are independently selected from the group consisting of a C1-C3 alkyl group and a hydrogen atom, or R 5 is a hydrogen atom and R 6 is an acyl or thioacyl group of formula II, or a sulfonic acid group of formula III, wherein X is O or S; R 7 is selected from the group consisting of R 8 and NH-R 8 , wherein R 8 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, ternary to octaheterocycloalkyl, (CH 2 CH 2 O) n - (C1-C3 alkyl), CH 2 O(CH 2 CH 2 O) n - (C1-C3 alkyl), C6-C12 aryl, five-to nine-membered heteroaryl, (C6-C12) aryl- (C1-C3) alkyl-, five-to seven-membered heteroaryl-O- (C1-C3) alkyl-, (C1-C3 alkyl) O-C (O) - (C1-C3) alkyl-, wherein n is 1,2, 3,4 or 5, wherein substituent R 8 is optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, OH, halogen, = O, NH 2 、NH 2 C (=o) - (C1-C3 alkoxy), NHR 9 wherein R 9 is selected from C1-C3 alkyl and NR 10 2 wherein R 10 is independently selected from C1-C3 alkyl or two R 10 groups together are formed from C2-C5 alkylene with the proviso that at least one of the substituents R 1 and R 2 is not a hydrogen atom and at least one of the substituents R 3 and R 4 is not a hydrogen atom. The compounds are suitable for the treatment of proteinopathies, viral diseases, and diseases directly associated with elevated levels of iron death, such as stroke, rhabdomyolysis, nonalcoholic steatohepatitis, acute pancreatitis, and psoriasis.

Inventors

  • MACHARA ALES
  • K. Grants Saskova
  • L. Svobodova
  • Z. Smahlova
  • J. Cedric Lasker
  • M. Adamek
  • P Maier

Assignees

  • 捷克有机化学和生物化学研究院
  • 查理大学

Dates

Publication Date
20260508
Application Date
20240712
Priority Date
20230721

Claims (11)

  1. 1. 4-Amino-2, 6-bis (benzylidene) cyclohexanone of formula I, and pharmaceutically acceptable salts, addition salts and solvates thereof, Wherein, the R 1 、R 2 、R 3 and R 4 are independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a C1-C3 alkoxy group, a trifluoromethoxy group, and a difluoromethoxy group; R 5 and R 6 are independently selected from the group consisting of C1-C3 alkyl and hydrogen, or R 5 is hydrogen and R 6 is acyl or thioacyl of formula II, or sulfonic acid of formula III, Wherein, the X is O or S; R 7 is selected from the group consisting of R 8 and NH-R 8 , wherein R 8 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, ternary to octaheterocycloalkyl, (CH 2 CH 2 O) n - (C1-C3 alkyl), CH 2 O(CH 2 CH 2 O) n - (C1-C3 alkyl), C6-C12 aryl, five-to nine-membered heteroaryl, (C6-C12) aryl- (C1-C3) alkyl-, five-to seven-membered heteroaryl-O- (C1-C3) alkyl-, (C1-C3 alkyl) O-C (O) - (C1-C3) alkyl-, Wherein n is 1,2,3, 4 or 5, Wherein the substituent R 8 is optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, OH, halogen, = O, NH 2 、NH 2 C (=o) - (C1-C3 alkoxy), NHR 9 , wherein R 9 is selected from C1-C3 alkyl and NR 10 2 , wherein R 10 is independently selected from C1-C3 alkyl, or two R 10 are formed together from C2-C5 alkylene; Provided that at least one of the substituents R 1 and R 2 is not a hydrogen atom and at least one of the substituents R 3 and R 4 is not a hydrogen atom.
  2. 2. 4-Amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to claim 1, wherein R 1 、R 2 、R 3 and R 4 are independently selected from the group comprising methoxy and ethoxy.
  3. 3. 4-Amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to claim 1 or 2, wherein R 5 is a hydrogen atom, R 6 is a group of formula II, and R 7 is selected from the group comprising methyl, ethyl, propyl, cyclopropyl, azepanyl, morpholinyl, piperazinyl, phenyl, naphthyl, pyridinyl, imidazolyl, pyrrolidinyl, quinuclidinyl, thiazolyl, oxazolyl, aminomethyl, aminoethyl, aminopropyl, N-dimethylaminopropyl, N-dimethylaminoethyl, N-dimethylaminomethyl, aminophenyl, diaminophenyl, N-dimethylaminophenyl, N-diethylaminomethyl, N-methylimidazolyl, (fluoro) pyrrolidinyl, (methoxymethyl) pyrrolidinyl, isopropylamino, N-methylpiperazinyl, aminocarbonylmethoxyphenyl, hydroxypyridinyl, methylpyridinyl, 6-hydroxy-4-methylpyridin-3-yl, (morpholin-4-yl) ethyl, difluoropyridinyl, (ethoxymethyl) pyrazolo [1,5 ] piperidyl.
  4. 4. 4-Amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to claim 1 or 2, wherein R 5 is a hydrogen atom, R 6 is a sulphonic acid group of formula III and R 7 is selected from the group comprising methyl, ethyl, propyl, cyclopropyl, azepanyl, morpholinyl, piperazinyl, phenyl, pyridinyl, imidazolyl, pyrrolidinyl, aminopropyl, aminoethyl, aminophenyl, diaminophenyl, N-methylimidazolyl, (fluoro) pyrrolidinyl, (methoxymethyl) pyrrolidinyl, isopropylamino, N-methylpiperazinyl, aminocarbonylmethoxyphenyl, hydroxypyridinyl, picolyl, 6-hydroxy-4-methylpyridin-3-yl, (morpholin-4-yl) ethyl.
  5. 5. Use of 4-amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to any one of claims 1 to 4 as a medicament.
  6. 6. Use of 4-amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to any one of claims 1 to 4 for the treatment of proteinopathies and viral diseases.
  7. 7. Use of 4-amino-2, 6-bis (benzylidene) cyclohexanone of general formula I according to any one of claims 1 to 4 for the treatment of neurodegenerative diseases selected from polyglutamine disease, tauopathies, synucleinopathies, amyotrophic lateral sclerosis, amyloidosis and cystic fibrosis.
  8. 8. Use of 4-amino-2, 6-bis (benzylidene) cyclohexanone of general formula I according to any one of claims 1 to 4 for the prevention of familial forms of neurodegenerative diseases selected from polyglutamine disease, tauopathies, synucleinopathies, amyotrophic lateral sclerosis, familial amyloidosis and cystic fibrosis.
  9. 9. Use of 4-amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to any one of claims 1 to 4 for the treatment of diabetes or of viral diseases caused by HBV virus.
  10. 10. Use of 4-amino-2, 6-bis (benzylidene) cyclohexanone of formula I according to any one of claims 1 to 4 for the treatment of stroke, rhabdomyolysis, non-alcoholic steatohepatitis, acute pancreatitis and psoriasis.
  11. 11. A pharmaceutical formulation, characterized in that it comprises at least one 4-amino-2, 6-bis (benzylidene) cyclohexanone of general formula I according to any one of claims 1 to 4, and at least one pharmaceutically acceptable excipient.

Description

4-Amino-2, 6-bis (benzylidene) cyclohexanone and use thereof Technical Field The present invention relates to novel compounds derived from 4-amino-2, 6-bis (benzylidene) cyclohexanone, and the use of these compounds to reduce the proteolytic stress in cells and tissues and to inhibit iron death in cells and tissues. Background Intracellular protein degradation is a tightly regulated process that is critical to maintaining cellular homeostasis. More than 90% of cytoplasmic proteins are degraded by the so-called ubiquitin-proteinase system (UPS), which removes proteins that are defective in synthesis or misfolded and regulates the amount of protein in the cell, which is directly related to the regulation of protein activity. The core of the UPS system is the 26S proteasome, which degrades proteins covalently labeled with a polyubiquitin chain (Lys 48) into a mixture of peptides. The 26S proteasome consists of a 20S catalytic subunit with three catalytic sites (with chymotrypsin-like, trypsin-like or caspase-like activity) and one or two regulatory subunits (called 19S). The aging process and the progression of neurodegenerative diseases are closely related to the accumulation of misfolded or damaged proteins that may be toxic to cells or even directly induce apoptosis. Both aging and neurodegenerative diseases occur with reduced UPS activity, which is often accompanied by the formation of intracellular protein aggregates. For these reasons, modulating or enhancing UPS activity is considered a very promising approach to delay the onset of or treat diseases associated with accumulation of toxic protein forms (e.g., amyotrophic Lateral Sclerosis (ALS), parkinson's disease, alzheimer's disease, kennedy's disease, huntington's disease, etc.) (Kleiger et al: TRENDS IN CELL biology,2014,24,6,352-359; ciechanover et al: experimental & molecular medicine,2015,47,3, e147-e147; calamini et al: nature chemical biology,2012,8.2,185-196). For example, the activity of a UPS may be enhanced by stimulating its catalytic activity with a low molecular weight compound. Unfortunately, the effect of compounds having such activity on intracellular levels is currently known to be only very limited (Trader et al: biochimica et Biophysica Acta (BBA) -General Subjects,2017,1861.4,892-899; leestemaker et al: CELL CHEMICAL biology,2017,24.6,725-736). The most promising way to increase UPS capacity is to increase synthesis of the proteasome itself, ideally with simultaneous activation of Heat Shock Protein (HSP) synthesis. Both can be achieved by activating the stress transcription factors NRF1 (NFE 2L 1) and NRF2 (NFE 2L 2) from the so-called Cap-n-Cold (CNC) family of transcription factors (Huryn et al J Med Chem,2019,63.5,1892-1907; bott et al Human molecular genetics,2016,25.10,1979-1989). Recently, activation of the transcription factor NRF1 seems more suitable, which is responsible for triggering the coordinated expression of all genes of the proteasome subunit to cope with the proteolytic stress. An important finding is that the activated NRF1 pathway prevents the formation of toxic protein aggregates compared to gene knockdown. Thus, low molecular weight compounds that selectively activate the signal pathway without interacting with the UPS and without causing oxidative stress are considered the most promising methods for the future treatment of proteinopathies, including neurodegenerative diseases, whose progression is related to the formation of protein aggregates and to the proteolytic toxic stress (Njomen et al: J Med Chem,2019,62.14,6469-6481). When proteasome activity is inhibited, the transcription factor NRF1 preferentially induces synthesis of all proteasome subunits (Kleiger et al: TRENDS IN CELL biology,2014,24,6,352-359; koizumi et al: proceedings of the Japan academy, series B,2018, 325-336). NRF1 also increases expression of the transcription factor HSF1, HSF1 being responsible for inducing expression of heat shock proteins, which ensures a cellular response to exposure to stress conditions. Heat shock proteins help misfolded or stress damaged proteins to achieve the correct conformation, which is currently considered one of the important defense mechanisms against the formation of aggregates or toxic protein forms, both at the cell culture level and in a mouse model (Bose et al: AGEING RESEARCH REVIEWS,2017,35,155-175). It has recently been found that NRF 1-controlled transcriptional pathways protect cells and tissues from iron death. Iron death is a newly discovered regulated cell death type that is morphologically, biochemically, and genetically different from other currently described cell death types. Iron death is primarily characterized by iron dependence, which is characterized by accumulation of peroxidized lipids and reactive oxygen species derived from iron metabolism. In degenerative and ischemic diseases, iron death is involved in the development and pathogenesis of these diseases, and inhibition of iron