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US-12624011-B2 - Oxadiazole derivative

US12624011B2US 12624011 B2US12624011 B2US 12624011B2US-12624011-B2

Abstract

The present invention relates to a compound of formula (1) wherein Q 1 is halogen atom, Q 2 is hydrogen atom, etc., X, Y, and Z are nitrogen atom or oxygen atom, and R 1 has a given structure, or a pharmaceutically acceptable salt thereof, and a medicament comprising the compound for treating and/or preventing a disease such as epilepsy.

Inventors

  • Yoshiaki Isobe
  • Tomoyuki Tanaka
  • Hirotaka MIYACHI

Assignees

  • Sumitomo Pharma Co., Ltd.

Dates

Publication Date
20260512
Application Date
20210316
Priority Date
20200317

Claims (16)

  1. 1 . A compound of formula (1): or a pharmaceutically acceptable salt thereof, wherein Q 1 is halogen, Q 2 is hydrogen, fluorine, cyano, C 1-3 alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 3-6 cycloalkyl, and C 1-3 alkoxy, or C 1-3 alkoxy which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 3-6 cycloalkyl, and C 1-3 alkoxy, X, Y, and Z are the same or different and are nitrogen atom or oxygen atom, provided that the ring containing X, Y, and Z is a heteroaryl wherein any two of X, Y, and Z are nitrogen atom and the other is oxygen atom, R 1 is any one of the following formulae (2) to (4): R 2 and R 3 are the same or different and are C 1-6 alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 3-6 cycloalkyl, and C 1-3 alkoxy or C 3-6 cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy, R 4 and R 5 are the same or different and are hydrogen, halogen, hydroxy, C 1-6 alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 3-6 cycloalkyl, and C 1-3 alkoxy, or C 3-6 cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy; or when R 4 and R 5 are attached to the same carbon atom or to two adjacent carbon atoms respectively, R 4 and R 5 may be taken together with the carbon atom(s) to which they are attached to form C 3-6 cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy, or C 4-6 saturated hetero ring containing one or two heteroatoms selected independently from nitrogen atom and oxygen atom, said saturated hetero ring may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy, and n is 0 or 1.
  2. 2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same or different and are C 1-3 alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine, hydroxy, and C 1-3 alkoxy.
  3. 3 . The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same or different and are C 1-3 alkyl which may be substituted with fluorine.
  4. 4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are the same or different and are hydrogen, fluorine, hydroxy, C 1-3 alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine, hydroxy, and C 1-3 alkoxy, or C 3-6 cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy; or when R 4 and R 5 are attached to the same carbon atom or to two adjacent carbon atoms respectively, R 4 and R 5 may be taken together with the carbon atom(s) to which they are attached to form C 3-6 cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy, or C 4-6 saturated hetero ring containing one or two heteroatoms selected independently from nitrogen atom and oxygen atom, said saturated hetero ring may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine, hydroxy, C 1-3 alkyl, and C 1-3 alkoxy.
  5. 5 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are the same or different and are hydrogen, fluorine, hydroxy, C 1-3 alkyl which may be substituted with fluorine, or C 3-6 cycloalkyl which may be substituted with fluorine; or when R 4 and R 5 are attached to the same carbon atom or to two adjacent carbon atoms respectively, R 4 and R 5 may be taken together with the carbon atom(s) to which they are attached to form C 3-6 cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of fluorine and C 1-3 alkyl.
  6. 6 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 1 is fluorine, chlorine, or bromine, and Q 2 is hydrogen, fluorine, cyano, C 1-3 alkyl which may be substituted with fluorine, or C 1-3 alkoxy which may be substituted with fluorine.
  7. 7 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring containing X, Y, and Z is the following (5a), (5b), or (5c).
  8. 8 . The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the ring containing X, Y, and Z is the following (5a) or (5b).
  9. 9 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is the following (4).
  10. 10 . A compound which is selected from the following compounds, or a pharmaceutically acceptable salt thereof: 2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide, 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide, 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-fluorocyclobutane-1-carboxamide, 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3,3-difluorocyclobutane-1-carboxamide, 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide, 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxamide, 4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]tetrahydro-2H-pyran-4-carboxamide, 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-ethylbutanamide, 2-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide, 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide, 2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide, 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropanamide, 2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropanamide, 2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide, 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide, 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide, 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide, 2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide, 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide, 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide, 2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide, 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, 5-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, 5-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1,5-dimethylpyrrolidin-2-one, 5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, 5-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, and (R)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one.
  11. 11 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide, 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide, 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, 5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, and (R)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one.
  12. 12 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  13. 13 . A method for treating a disease selected from the group consisting of epilepsy, depressive syndrome, anxiety disorders, and bipolar disorder, comprising: administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  14. 14 . A pharmaceutical combination, comprising: the compound of claim 1 or a pharmaceutically acceptable salt thereof; and at least one drug selected from the group consisting of an antiepileptic drug, an antidepressant drug, and an antipsychotic drug.
  15. 15 . A method for treating a disease selected from the group consisting of epilepsy, depressive syndrome, anxiety disorders, and bipolar disorder, comprising: administering the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one drug selected from the group consisting of an antiepileptic drug, an antidepressant drug, and an antipsychotic drug.
  16. 16 . The method of claim 13 , wherein the disease is selected from Dravet syndrome, Lennox-Gastaut syndrome, epileptic seizure, tonic seizure, clonic seizure, absence seizure, myoclonic seizure, generalized seizure, atonic seizure, focal seizure, status epilepticus, Angelman syndrome, West syndrome, tuberous sclerosis, depression/major depressive disorder, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, depressive symptom associated with bipolar disorder depressive state associated with bipolar disorder, and an anxiety symptom associated with bipolar disorder.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/JP2021/010628, filed on Mar. 16, 2021, which is based on and claims the benefits of priority to Japanese Application No. 2020-046138, filed on Mar. 17, 2020. The entire contents of these applications are incorporated herein by reference. TECHNICAL FIELD The present invention relates to an oxadiazole derivative or a pharmaceutically acceptable salt thereof which is useful as a medicament, and a pharmaceutical composition or a medicament for treating and/or preventing epilepsy and/or depressive syndrome, etc., comprising the derivative as an active ingredient. BACKGROUND ART Epilepsy is a chronic disease caused by the hyperexcitability of cerebral neuron, whose symptom is that unusual somatic symptom, or the change of motion, consciousness, or sensation suddenly comes up repeatedly. The epileptic seizure type is classified by the International League Against Epilepsy (ILAE) into generalized seizure, focal seizure, and an unknown seizure, wherein generalized seizure is further classified into tonic seizure, clonic seizure, absence seizure, myoclonic seizure, atonic seizure, etc. (Non-patent Literature 1). The etiologies for epilepsy are roughly categorized into genetic, structural/metabolic, and unknown. In addition, epilepsy is classified into various disease types and syndromes based on the characters such as electroencephalogram/clinical symptom, age of onset, and disease pathogenesis. It includes, for example, West syndrome and Dravet syndrome which occur during infancy, Lennox-Gastaut syndrome and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) which occur during childhood, mesial temporal lobe epilepsy associated with hippocampal sclerosis which is a definitely identified symptom, Rasmussen's syndrome, and many others (Non-patent Literature 2). Since the 1990s, international collaborative researches of, especially, molecular pathology of epilepsy have been developed, and many of causative genes have been identified until now. These genes include ion channel such as Na, K, Ca, Cl, GABA-A, and ACh, and it is guessed that epilepsy is caused by ion homeostasis abnormality which is one of the causes. Epilepsy is a severe disease which can affect prognosis, and it is known that about 1% of the world's population suffer from epilepsy. The treatment of these epileptic seizures has been carried out mainly by drug therapy. Despite the fact that various antiepileptic drugs have been prescribed for many years, one of three examples in the treatment of epilepsy is refractory and resistant to multidrug therapy with existing drugs. In addition, existing drugs for epilepsy have dose-related side effects to nervous system such as excessive sleepiness, wobble, cognitive impairment, and psychiatric symptom; severe idiosyncratic side effects such as Stevens-Johnson syndrome though in rare cases; teratogenic risks; and drug-interaction risks such as loss of drug-efficacy and increase of side effects. Furthermore, patients suffering from epilepsy have high complication risk with psychiatric symptom such as depression, anxiety, and cognitive impairment (Non-patent Literature 3). However, existing drugs for epilepsy have no therapeutic effect to such complicated psychiatric symptoms. Thus, it has been strongly desired to develop a new antiepileptic drug having multiple properties, for example, a high efficacy for refractory epilepsy, a superior profile on pharmacokinetics and safety, and an efficacy for both epilepsy and complicated psychiatric symptoms. Epilepsy causes seizure by hyperexcitability of brain neuron, which is caused when excitatory neuron strongly acts, or inhibitory neuron weakens, i.e., the cause is thought to be abnormality of the balance between excitation (E) and inhibition (I) (E/I balance). Besides epilepsy, some diseases that are caused by abnormality of E/I balance are known. Drugs that enhance the GABAergic system by activation of inhibitory neurons exhibit some therapeutic effects for anxiety disorder, obsessive-compulsive disorder, and REM sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies. And, it is known that the abnormality of E/I balance is also related to neuropathic pain, developmental disorder, autism, bipolar disorder, schizophrenia, Alzheimer's disease and the other dementia, amyotrophic lateral sclerosis, Parkinson's disease, etc. In fact, some of antiepileptic drugs which can improve the abnormality of E/I balance have been broadly used in the treatment of these diseases. However, these drugs have limitations of the efficaciousness for these diseases other than epilepsy, and also have problems of side effects and pharmacokinetics. Thus, if a new antiepileptic drug having new profiles of efficacies and side effect is developed, the drug may have a possibility of applying to many psychiatr