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US-20260125357-A1 - LACTATE ENHANCING COMPOUNDS AND USES THEREOF

US20260125357A1US 20260125357 A1US20260125357 A1US 20260125357A1US-20260125357-A1

Abstract

The present invention relates to new agents useful for stimulating uptake of glucose and release of lactate by astrocytes. The invention further relates to methods of preparation, formulations and therapeutic uses of those agents, notably for the prevention and/or treatment of neurological disorders with brain energy hypometabolism, in particular neurodegenerative, neurometabolic and psychiatric disorders or improving cognitive and memory functions.

Inventors

  • Charles FINSTERWALD
  • Sylvain Lengacher
  • Pierre Magistretti
  • Timothy RITCHIE
  • Hans Maag
  • Guillaume DUVEY

Assignees

  • GLIAPHARM SA

Dates

Publication Date
20260507
Application Date
20231002
Priority Date
20221003

Claims (20)

  1. 1 - 24 . (canceled)
  2. 25 . A compound of Formula (I), wherein Y is selected from NH and CH 2 ; R1 is selected from H, halogen and C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NR 13 R 14 ; R2 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or C 2 -C 6 alkenyl, or a group OR 12 , NR 13 R 14 or a cyano group or an optionally substituted heterocycle; R3 is selected from H, halogen, C 1 -C 6 alky, optionally substituted with a group selected from halogen, OR 12 and NR 13 R 14− or C 2 -C 6 alkenyl, or a group OR 12 , or NHR 13 , or an optionally substituted heterocycle or a cyano group; R4 is selected from H, halogen C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or an optionally substituted heterocycle and a cyano group; R5 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or a group OR 12 , or NR 13 R 14 ; R6 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or a group OR 12 , or NHR 13 ; R7 and R8 are independently selected from H and halogen; R9 is selected from SO—C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl, SO 2 -C 3 -C 6 cycloalkyl, or an optionally substituted heterocycle selected from optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrrolinone, and optionally substituted oxetane; R10 and R11 are independently selected from H and halogen; R12, R13, and R14 are independently selected from H, C(O)—C 1 -C 6 alkyl and optionally substituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; any pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, tautomers, optically active forms, enantiomeric mixtures thereof, and mixtures thereof, with the provision that said compound is not a compound selected from the following list: N-[4-[5-Ethyl-3-(1-methylethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-63-4; N-[4-[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-99-5; N-[4-[5-Ethyl-3-(3-pyridinyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-04-5; N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-94-0; N-[4-[3-(Tetrahydro-2-furanyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-82-7; N-[4-[3-(3-Pyridinyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-03-4; 3-Methyl-N-[4-(4-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-93-7; 1-[[4-(4-Pyridinyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN:1368269-53-7; 8-Methyl-N′-[4-(4-pyridinyl)phenyl]-1,5-isoquinolinediamine, RN:1369288-67-4; 5-Nitro-N-[4-(4-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-43-7; N-[4-(4-Pyridinyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and 4-Bromo-N′-[4-(4-pyridinyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1.
  3. 26 . The compound according to claim 25 , wherein Y is CH 2 .
  4. 27 . The compound according to claim 25 , wherein Y is NH.
  5. 28 . The compound according to claim 25 , wherein R1, R5, R4 and R6 are H.
  6. 29 . The compound according to claim 25 , wherein R2 is OR 12 .
  7. 30 . The compound according to claim 25 , wherein R3 is OR 12 .
  8. 31 . The compound according to claim 25 , wherein R3 is NHR 13 .
  9. 32 . The compound according to claim 25 , wherein R3 is halogen.
  10. 33 . The compound according to claim 25 , wherein R3 is H.
  11. 34 . The compound according to claim 25 , wherein R3 is optionally substituted C 1 -C 6 alkyl.
  12. 35 . The compound according to claim 25 , wherein R10 and R11 are H.
  13. 36 . The compound according to claim 25 , wherein R10 is halogen.
  14. 37 . The compound according to claim 25 , wherein R11 is halogen.
  15. 38 . The compound according to claim 25 , wherein R7, R8, R10 and R11 are H.
  16. 39 . The compound according to claim 25 , wherein R9 is selected from SO 2 -C 1 -C 6 alkyl.
  17. 40 . The compound according to claim 25 , wherein R9 is SO 2 -C 3 -C 6 cycloalkyl.
  18. 41 . A pharmaceutical composition comprising a compound of Formula (I), wherein Y is selected from NH and CH 2 ; R1 is selected from H, halogen and C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NR 13 R 14 ; R2 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or C 2 -C 6 alkenyl, or a group OR 12 , NR 13 R 14 or a cyano group or an optionally substituted heterocycle; R3 is selected from H, halogen, C 1 -C 6 alky, optionally substituted with a group selected from halogen, OR 12 and NR 13 R 14− or C 2 -C 6 alkenyl, or a group OR 12 , or NHR 13 , or an optionally substituted heterocycle or a cyano group; R4 is selected from H, halogen C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or an optionally substituted heterocycle and a cyano group; R5 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or a group OR 12 , or NR 13 R 14 ; R6 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or a group OR 12 , or NHR 13 ; R7 and R8 are independently selected from H and halogen; R9 is selected from SO—C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl, SO 2 —C 3 -C 6 cycloalkyl, or an optionally substituted heterocycle selected from optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrrolinone, and optionally substituted oxetane; R10 and R11 are independently selected from H and halogen; R12, R13, and R14 are independently selected from H, C(O)— C 1 -C 6 alkyl and optionally substituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and a pharmaceutically acceptable carrier, diluent or excipient thereof, with the proviso that the compound is not a compound selected from the following list: 3-Methyl-N-[4-(4-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-93-7; 1-[[4-(4-Pyridinyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN:1368269-53-7; 8-Methyl-N 1 -[4-(4-pyridinyl)phenyl]-1,5-isoquinolinediamine, RN:1369288-67-4; 5-Nitro-N-[4-(4-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-43-7; N-[4-(4-Pyridinyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and 4-Bromo-N 1 -[4-(4-pyridinyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1.
  19. 42 . A method of increasing intracerebral glucose and/or lactate levels in a subject, enhancing cognitive and memory functions in a subject, preventing or treating a disorder or a disease associated with an abnormally low energy metabolism or in the central nervous system and/or a neurological disorder or for the treatment or stabilizing a neurological disorder with brain hypometabolism or associated symptoms in a subject, said method comprising administering in a subject in need thereof a therapeutically effective amount of a compound of Formula (I), wherein Y is selected from NH and CH 2 ; R1 is selected from H, halogen and C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NR 13 R 14 ; R2 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or C 2 -C 6 alkenyl, or a group OR 12 , NR 13 R 14 or a cyano group or an optionally substituted heterocycle; R3 is selected from H, halogen, C 1 -C 6 alky, optionally substituted with a group selected from halogen, OR 12 and NR 13 R 14− or C 2 -C 6 alkenyl, or a group OR 12 , or NHR 13 , or an optionally substituted heterocycle or a cyano group; R4 is selected from H, halogen C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or an optionally substituted heterocycle and a cyano group; R5 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or a group OR 12 , or NR 13 R 14 ; R6 is selected from H, halogen, C 1 -C 6 alkyl, optionally substituted with a group selected from halogen, OR 12 and NHR 13 , or a group OR 12 , or NHR 13 ; R7 and R8 are independently selected from H and halogen; R9 is selected from SO—C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl, SO 2 —C 3 -C 6 cycloalkyl, or an optionally substituted heterocycle selected from optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrrolinone, and optionally substituted oxetane; R10 and R11 are independently selected from H and halogen; R12, R13, and R14 are independently selected from H, C(O)— C 1 -C 6 alkyl and optionally substituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; a tautomer, a geometrical isomer, an optically active form, an enantiomeric mixture, a pharmaceutically acceptable salt, a pharmaceutically active derivative thereof or a mixture thereof.
  20. 43 . The method according to claim 42 , said method increasing the intracerebral glucose and/or lactate levels in a subject and said method comprising administering to a subject in need thereof an effective amount of said compound or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, tautomers, optically active forms, enantiomeric mixtures thereof and pharmaceutically active derivative and mixtures thereof to induce increased intracerebral glucose and/or lactate levels.

Description

FIELD OF THE INVENTION The present invention relates generally to the field of lactate enhancing agents and in particular the use of lactate enhancing agents for the treatment of neurological disorders, comprising neurodegenerative and psychiatric diseases. BACKGROUND OF THE INVENTION Neurological disorders represent some of the pathologies with the highest unmet needs. They are expected to become the first cause of death by 2050. These pathologies are complex and difficult to treat. Finding treatments has been a challenge for the pharmaceutical industry for the past decades, but limited progress has been made in the field. Most of the therapeutic strategies so far have aimed at targeting neurons directly, using a ‘neuro-centric’ approach, largely letting aside the important role of other cell types of the nervous system, including astrocytes. Astrocytes outnumber neurons in the brain and together with oligodendrocytes and microglia form a category of cells called glial cells that support neuronal activity and survival. In the past decade, considerable attention has been focused on understanding the role of astrocytes in physiological processes, as well as their implication in the development of neurological diseases including neurodegenerative disorders, age-related cognitive impairments and psychiatric diseases. While glial cells were though for a long time to only be important for nervous tissue structural support—a sort of brain ‘glue’—, their much more important role for the control of fundamental processes has now been largely acknowledged. In particular, astrocytes play a fundamental role by providing energy to neurons, which is required for their function—transmit electrical information—and survival. Hence, astrocytes were found to be key for numerous brain physiological processes that include neuronal protection, neuronal function, synaptic plasticity, and memory consolidation (Magistretti et al., 2018, Nat. Rev. Neurosci., 19(4):235-249). Although neurological disorders have historically been considered as pathologies that exclusively result from neuronal dysfunction and death, it has become clear that other cell types, such as astrocytes, contribute to these pathologies. A large body of evidence has linked astrocytes activity to mild cognitive impairments (MCI), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), depression and others. For instance, in AD patients, activated astrocytes are preferentially located in the vicinity of amyloid plaques, where they exhibit abnormal morphology and mitochondrial function. In the early stage of the disease, activated astrocytes have neuroprotective action by internalizing and degrading amyloid plaques, while upon progression of the disease, deposit of amyloid plaques leads to astrocytic death that in turn results in further amyloid accumulation (Nagele et al. 2004, Neurobiol. Aging, 25(5):663-74). There are clear indications that age-related changes of astrocytes have a role in the development of age-related neurodegenerative disorders, such as MCI and AD (Cai et al., 2017, J. Neurol. 264(10):2068-74). Astrocytosis is a typical morphological feature of the AD brain and represents either proliferation of astrocytes, in an effort to support dying neurons, or a reaction to degrade the increasing amounts of toxic β-amyloid peptides. Of particular interest, exposure of astrocytes to β Amyloid in vitro alters their metabolic activity thus resulting in reduction of the neuronal protection against oxidative stresses (Allaman et al., 2010, J. Neurosci 30(9):3326-38). Deregulation of brain energy metabolism is an important contributor to the development of several neurological disorders and age-associated cognitive decline. These disorders have been linked to decreased mitochondrial activity, increased oxidative stress and diminished cerebral glucose metabolism. For instance, glucose hypometabolism in the brain appears early in the genesis of AD and in fact represents a common phenomenon with other neurodegenerative diseases (Yin et al, 2016, Free Radic. Biol. Med., 100:108-22; Fu et al. 2014, Biogerontology, 15(6):579-86; Demetrius et al, 2013, Biogerontology, 14(6):641-9; Demetrius et al., 2014, front Physiol 5:522; Tomi et al., 2013, Brain Res., 1495:61-75; Ferreira et al., 2010, Curr Drug Targets, 11(10):1193-2016). Mitochondrial dysfunction, which is associated with age-related neurodegeneration, is particularly prevalent in AD (Beal, 2005, Neurobiol Aging, 26(5):585-6; Yao et al., 2011, Curr Pharm Des 17(31):3474-9). Studies on patients with AD and mouse models have highlighted the down regulation of several cerebral genes involved in energy regulation (Liang et al., 2008, Proc. Natl. Acad. Sci. USA, March 18; 105(11):4441-6). As a result, significant correlation between diminished cerebral glucose metabolism and cognitive performance has been shown in AD patients (Thomas et al., 2015, J. Nutr. Health Aging, 19(1):58-63; Woo et al, 2010, Int. J. Ger