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WO-2026093525-A1 - COUMARIN DERIVATIVES FOR USE IN THE TREATMENT OF A SYNUCLEINOPATHY

WO2026093525A1WO 2026093525 A1WO2026093525 A1WO 2026093525A1WO-2026093525-A1

Abstract

The present invention relates to coumarin derivatives for use in the treatment of a synucleinopathy

Inventors

  • El Amri, Chahrazade
  • SOUALMIA, Feryel

Assignees

  • SORBONNE UNIVERSITE
  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
  • INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
  • MUSEUM NATIONAL D HISTOIRE NATURELLE

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241031

Claims (10)

  1. 1. Compound for use in the treatment of a disease being a synucleinopathy, said compound having the following formula (I): in which: Ri represents: H, a linear or branched alkyl group of 1 to 6 carbon atoms, a phenyl group possibly substituted by a group R' in particular chosen from OR”, with R” represents a linear or branched alkyl of 1 to 6 carbon atoms, in particular Me, or a group of the following formula (A): in which: X is chosen from -C(=O)-O-, -C(=O)-S-, -OC(=O)-, and -SC(=O)-, Ra represents a heterocycle chosen from: These heterocycles may optionally be substituted by at least one group chosen from linear or branched alkyl groups of 1 to 6 carbon atoms, in particular Me, and halogens, in particular Cl or Br, in which: Xi, X2 and X3 independently represent CH or N, one representing N, the other two CH, X4 and X5 independently represent CH or N, one representing N, the other CH. R 2 represents: H, a linear or branched alkyl group of 1 to 6 carbon atoms, or a group of the following formula (B): (B), in which: Y is chosen from -OC(=O)-, -CH 2 -C(=O)-, -SC(=O)-, -C(=O)-O-, -C(=O)-S-, -OH- (Rb being absent), -NH-, -CONH-, -C(=O)-NRb'-, Rb represents a linear or branched alkyl group of 1 to 6 carbon atoms, in particular Me, Or Rb forms with Ri, particularly when Y represents -OC(=O)-, a bicycle with the following formula: , which is possibly substituted, being in particular , with Rd representing a linear or branched alkyl of 1 to 6 carbon atoms, in particular Me, Rb' represents a linear or branched alkyl group of 1 to 6 carbon atoms, in particular Me, Ri representing H, a linear or branched alkyl group of 1 to 6 carbon atoms, or a phenyl group possibly substituted by a group R' in particular chosen from OR”, where R” represents a linear or branched alkyl group of 1 to 6 carbon atoms, in particular Me, and R 2 being of formula (B), or R 2 representing H or a linear or branched alkyl group of 1 to 6 carbon atoms, and Ri being of formula (A), R3, R4, Rs and RÔ represent, independently of each other, H, OH, ORc or OC(=O)Rc, Rc representing a linear or branched alkyl of 1 to 6 carbon atoms, in particular Me, or R4 and R5 together form a possibly substituted heterocycle, for example a heterocycle of the following formula: , pp damment a linear or branched alkyl of 1 to 6 carbon atoms, in particular Me.
  2. 2. Compound for its use according to claim 1, said compound having the following formula (Ii): (II).
  3. 3. Compound for its use according to claim 1, said compound having the following formula (III): in which R2 represents: H, or a linear or branched alkyl group of 1 to 6 carbon atoms, said compound having in particular the following formula (II2): (II2), said compound being more particularly of the following formula (II3): 4. Compound for use according to any one of the preceding claims, said compound having the formula
  4. (II4) following: (I -
  5. 5. Compound for use according to any one of the preceding claims, wherein Ra has the following formula: in which Xi, X2 and X3 independently represent CH or N, one representing N, the other two CH.
  6. 6. Compound for its use according to claim 1, said compound having the following formula (IIIi): (nii), in which Ri represents H, a phenyl group possibly substituted by a group R' in particular chosen from OR”, with R” represents a linear or branched alkyl of 1 to 6 carbon atoms, in particular Me, or a linear or branched alkyl group of 1 to 6 carbon atoms 5. The said compound being in particular of the following formula (III2): (IH2), said compound being more particularly of the following formula (III3): (III3).
  7. 7. Compound for its use according to claim 6, wherein Rb is Me.
  8. 8. Compound for its use according to any one of claims 6 to 7, wherein Ri is Me, Et, nPr or nBu.
  9. 9. Compound for use according to any one of the preceding claims, which is selected from:
  10. 10. Compound for use according to any one of the preceding claims, wherein the synucleinopathy is an alpha-synucleinopathy of the group comprising Parkinson's disease, Lewy body dementia, multiple system atrophy, amyotrophic lateral sclerosis, pure autonomic insufficiency (and REM sleep behavior disorder).

Description

DESCRIPTION TITLE OF THE INVENTION: COMPOUNDS FOR TREATING SYNUCLEOPATHY The present invention relates to compounds for use in the treatment of synucleinopathy. Synucleinopathies are a group of neurodegenerative proteinopathies characterized by pathological lesions composed of alpha-synuclein (or a-syn) aggregates. These lesions can be located in various parts of the brain and affect neurons or glial cells. The main synucleinopathies are Parkinson's disease, Lewy body dementia, and multiple system atrophy. Although environmental factors have been identified through epidemiological studies, the causes of these diseases remain poorly understood. Despite significant research efforts, these diseases remain incurable. Parkinson's disease is one of the few degenerative disorders of the central nervous system that can be treated with medication. These treatments are purely symptomatic, meaning they can alleviate or even eliminate the manifestations of the disease, but they do not affect its progression. In the long term, however, these treatments become less and less effective and can lead to motor complications. For over a decade now, the involvement of serine proteases in the functioning of the central nervous system (CNS) has been continually highlighted. Among serine proteases, tissue kallikreins form a family of proteases present in at least six mammalian orders. They are involved in functions as diverse as the regulation of synaptic plasticity, neuronal survival, memory acquisition, and vascular function. Among the tissue kallikreins, KLK6 (kallikrein-6 or hK6) is the most abundant in the adult CNS. It is produced by neurons and oligodendrocytes and has tryptic proteolytic activity. KLK6 thus plays a central role in the brain and spinal cord. Various studies converge on the hypothesis that KLK6 is involved in numerous neurodegenerative diseases, including synucleinopathies. The involvement of KLK6 in α-syn degradation was reported as early as 2003. These initial observations demonstrated the in vivo colocalization of KLK6 with α-syn within Lewy bodies found in Parkinson's disease. It has also been shown that in vitro, KLK6 prevents α-syn polymerization by reducing the amount of monomers available for polymerization and by generating α-syn fragments that, in turn, inhibit polymerization. Finally, peripheral administration of a lentivirus expressing KLK6 in murine models of synucleinopathies led to the accumulation of this protease in the brain, associated with a decrease in α-syn deposition in oligodendrocytes and astrocytes, as well as an improvement in parkinsonian behavior. Thus, these studies suggest that strong KLK6 activity, including under unfavorable pH conditions, could limit or stop the spread of a-syn in the brain and consequently prevent and/or treat alpha-synucleinopathies. Biochemical studies on KLK6 had reported that certain high molecular weight polymers belonging to the glycosaminoglycan and heparin families could act as KLK6 activators. However, these compounds exhibit low activating efficacy and are unlikely to cross the blood-brain barrier. The identification of small molecules capable of activating KLK6 and likely to distribute in the CNS is therefore a real challenge in the context of the treatment of synucleinopathies. In a particularly unique development, the inventors discovered that the compounds according to the invention are effective and highly selective activators of KLK6. These compounds also have the advantage of not being cytotoxic, particularly neurotoxic, for example, to primary murine neurons. They are therefore of significant therapeutic interest in the context of synucleinopathies. Furthermore, these compounds are small molecules that are easy to synthesize, making their production quick and economical. Thus, the present invention relates to a compound for use in the treatment of a disease linked to a deficiency in the expression and/or activity of KLK6, said compound having the following formula (I): (I), in which: Ri represents: H, a linear or branched alkyl group of 1 to 6 carbon atoms, a phenyl group possibly substituted by a group R' in particular chosen from OR”, with R” represents a linear or branched alkyl of 1 to 6 carbon atoms, in particular Me, or a group of the following formula (A): in which: X is chosen from -C(=O)-O-, -C(=O)-S-, -OC(=O)-, and -SC(=O)-, Ra represents a heterocycle chosen from: , these heterocycles may optionally be substituted by at least one group chosen from linear or branched alkyl groups of 1 to 6 carbon atoms, in particular Me, and halogens, in particular Cl or in which: Xi, X2 and X3 independently represent CH or N, one representing N, the other two CH. X4 and X5 independently represent CH or N, one representing N, the other CH. R2 represents: H, a linear or branched alkyl group of 1 to 6 carbon atoms, or a group of the following formula (B): (B), in which: Y is chosen from -OC(=O)-, -CH 2 -C(=O)-, -SC(=O)-, -C(=O)-O-, -C(=O)-S-, -O