RU2022101643A - ALCOHOL DERIVATIVES AS COMPOUNDS THAT INDUCE THE OPENING OF Kv7 POTASSIUM CHANNELS - Google Patents

Claims (87)

1. Compound of formula I formula I, where R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, CF ₃ , CH ₂ CF ₃ , CF ₂ CHF ₂ , C ₃ -C ₈ cycloalkyl, where said C ₃ -C ₈ cycloalkyl may be substituted with 1 or 2 substituents selected from the group consisting of C ₁ -C ₃ alkyl, F, CHF ₂ and CF ₃ ; R ² represents H, C ₁ -C ₆ alkyl or CF ₃ ; or R ¹ and R ² combine to form a C ₃ -C ₅ cycloalkyl, optionally substituted with 1 or 2 F, CHF ₂ or CF ₃ ; R ³ represents C ₁ -C ₃ alkyl or CH ₂ O -C _1-3 alkyl, wherein said C ₁ -C ₃ alkyl or CH ₂ O -C ₁ -C ₃ represents alkyl substituted with C≡N, 3 from F or C ₃ -C ₅ cycloalkyl; R ⁴ is selected from the group consisting of OCF ₃ or OCHF ₂ , or a pharmaceutically acceptable salt of any of these compounds. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ represents OCF ₃ or OCHF ₂ . 3. A compound according to any of the previous paragraphs or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from the group consisting of CH ₂ -O-CF ₃ , CH ₂ -O-cyclopropyl, CH ₂ -ON. 4. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₄ cycloalkyl, optionally substituted with 1 or 2 of C ₁ -C ₃ alkyl, F, CHF ₂ or CF ₃ . 5. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are combined to form cyclobutyl, optionally substituted with 1 or 2 F, and R 4 is OCF ₃ or OCHF ₂ . 6. The compound according to claim 1, where the compound is selected from the group consisting of (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-l-hydroxycyclobutyl)acetamide; (R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-l-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide or (S)-N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide or a pharmaceutically acceptable salt of any of these compounds. 7. A connection selected from the group consisting of (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(33-Difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(33-Difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-Difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-l-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (S)-N-(R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-2-(3,3-Difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3,3-Difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide; (S)-2-(3,3-Difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide; (S)-N-(3,3-Difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-Difluoro-1-hydroxycyclobutyl)acetamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)-N-((R-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylciutobutyl)-3-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide; (S)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide or a pharmaceutically acceptable salt of any of these compounds. 8. Pharmaceutical composition containing a compound according to any one of paragraphs. 1-7 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 9. A method of treating a patient in need thereof suffering from epilepsy, bipolar disorder, migraine or schizophrenia, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims. 1-7 or a pharmaceutically acceptable salt thereof. 10. A method of treating a patient in need suffering from psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims. 1-7 or a pharmaceutically acceptable salt thereof. 11. Application of the connection according to paragraphs. 1-7 or its pharmaceutically acceptable salt in therapy. 12. Application of the connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. 13. Application of the connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease. 14. Connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. 15. Connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, multiple sclerosis, multiple sclerosis, Alzheimer's disease. 16. The compound or its pharmaceutically acceptable salt according to claims. 1-7 or a pharmaceutical composition according to claim 8 for use in the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures. 17. The compound or its pharmaceutically acceptable salt according to claims. 1-7 or a pharmaceutical composition according to claim 16 for use in the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ- associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of early childhood, epilepsy with continuous spike-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet and early myoclonic encephalopathy, Ohtahara syndrome) or seizures associated with stressors, hormonal changes, drug use, alcohol use, infection, traumatic brain injury, stroke, forms of brain cancer, autism spectrum disorders or metabolic disorders ( such as hyponatremia). 18. The compound or its pharmaceutically acceptable salt according to claims. 1-7 or a pharmaceutical composition according to claim 16 for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders, such as Alzheimer's disease, Lewy body disease, juvenile form of Huntington's disease, frontotemporal lobar degeneration. 19. A method of treating a patient in need thereof suffering from epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims. 1-7 or a pharmaceutically acceptable salt thereof. 20. A method of treating a patient in need suffering from focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, neonatal seizures, KCNQ-associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of early childhood, epilepsy with continuous spike-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome) or seizures associated with stressors, hormonal changes, drug use, alcohol use, infection, traumatic brain injury, stroke, forms of brain cancer, autism spectrum disorders or metabolic disorders (such as hyponatremia), or intended for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders, such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims . 1-7 or a pharmaceutically acceptable salt thereof. 21. Application of the connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures. 22. Application of the connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the treatment, for use in the treatment of focal epilepsy with simple partial seizures, focal epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ -associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of early childhood, epilepsy with continuous spike-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome) or seizures associated with stressors, hormonal changes, drug use, alcohol use, infection or metabolic disorders (such as hyponatremia), or for use in the treatment of epileptic symptoms that are a component neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration. 23. Connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures. 24. Connection according to paragraphs. 1-7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ- associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of early childhood, epilepsy with continuous spike-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet and early myoclonic encephalopathy, Ohtahara syndrome) or for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration.