JP-2022513933-A5 -

Dates

Publication Date

20221223

Application Date

20191217

Description

These results suggest that increased deuteration of imidazoles increases the metabolic stability of these compounds in hepatocytes (comparing Example 1 to Example 2), while deuteration on the methoxy group or deuteration of the carbon adjacent to the carbonyl group provides an unknown effect. This application also includes the following aspects. [Aspect 1] Formula I: Free or salt form (e.g., pharmaceutically acceptable salt form), e.g., isolated or purified free or salt form: Equation I [In the formula, X is selected from H, -(C=O)-R a , -CH 2 -(C=O)-OR a and -CH 2 -(C=O)-N(R a )(R b ); R1 is selected from CH3 , CDH2 , CD2H , and CD3 ; Each of R2 through R9 is independently selected from H and D ; Ra and Rb are independently selected from H, C1-20 alkyl (e.g., methyl), and C1-4 alkyl-aryl (e.g. , benzyl); However, if R1 is CH3 and R2 through R9 are all H, then X is selected from -(C=O)-R a , -CH2 - (C=O)-OR a , and -CH2 - (C=O)-N(R a )(R b ). The compound shown by [this symbol]. [Aspect 2] The compound according to embodiment 1, wherein X is H. [Appearance 3] The compound according to embodiment 1, wherein X is selected from -(C=O)-Ra , -CH2- ( C=O)-ORa , and -CH2- ( C=O)-N(Ra ) (Rb ) . [Aspect 4] The compound according to embodiment 1, wherein X is -(C=O)-R a . [Aspect 5] The compound according to embodiment 1, wherein X is -CH2- ( C=O)-OR a . [Pattern 6] The compound according to embodiment 1, wherein X is CH2- ( C=O)-N(Ra ) ( Rb ). [Appearance 7] The compound according to embodiment 1, wherein X is CH2- (C=O)-N(R a )(R b ) and R b is H. [Patent 8] A compound according to any one of embodiments 1 to 7, wherein R1 is CH3 . [Aspect 9] A compound according to any one of embodiments 1 to 7, wherein R 1 is CD 3 . [Aspect 10] A compound according to any one of embodiments 1 to 7, wherein one, two, three, or four of R2 to R9 are D. [Personalization 11] The compound according to any one of embodiments 1 to 7, wherein R2 and R3 are D. [Aspect 12] A compound according to any one of embodiments 1 to 7, wherein R 5 to R 6 is D. [Aspect 13] The compound according to any one of embodiments 1 to 7, wherein one, two, or three of R 7 to R 9 are D. [Aspect 14] The compound, A compound according to any one of embodiments 1 to 13, selected from the group consisting of the following. [Phenomenon 15] A compound according to any one of embodiments 1 to 14, in salt form, for example, a pharmaceutically acceptable salt form. [Personal 16] The compound according to any one of embodiments 1 to 15, wherein deuterium is incorporated in greater than 50% (i.e., greater than 50 atomic percent of D) at one or more designated positions of the structure, for example, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. [Personal 17] A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 16 in free or pharmaceutically acceptable salt form, mixed with a pharmaceutically acceptable diluent or carrier. [Pattern 18] The pharmaceutical composition according to embodiment 17, which is in an oral administration form (e.g., a tablet or capsule). [Aspect 19] For example, the pharmaceutical composition according to embodiment 17, formulated for long-acting injection for intramuscular or subcutaneous injection. [Aspect 20] A method for treating or preventing central nervous system disorders suitable for improvement with a GABA A receptor modulator (e.g., a positive allosteric modulator of a GABA A receptor), comprising administering to a patient in need a compound according to any of embodiments 1 to 16, or a pharmaceutical composition according to any of embodiments 17 to 19, in free or pharmaceutically acceptable salt form. [Aspect 21] Disorders include sleep disorders (e.g., insomnia), circadian rhythm disorders, phase shift disorders (e.g., jet lag), anxiety (including generalized anxiety, social anxiety, and panic disorder), post-traumatic stress disorder, depression (e.g., treatment-resistant depression, major depressive disorder, bipolar depression, postpartum depression, seasonal affective disorder, dysthymia, treatment-resistant depression, suicidal ideation or suicidal behavior, and premenstrual dysphoric disorder), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder), schizophrenia, schizoaffective disorder, attention deficit (e.g., Attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), convulsive disorders (e.g., seizure disorders, epilepsy or status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus, and non-convulsive status epilepticus, e.g., generalized status epilepticus and complex partial status epilepticus), aggression disorders (e.g., acute or chronic aggression), agitation disorders (e.g., acute or chronic agitation), memory and/or cognitive im