Cyclic amine derivatives having serotonin receptor binding activity

Inventors

Nakahara, Kenji

Assignees

Shionogi and Co Ltd

Abstract

Provided are a compound having serotonin 5-HT2A receptor antagonism and/or inverse agonism, a pharmaceutically acceptable salt thereof, and a composition for serotonin 5-HT2A receptor antagonism and/or inverse agonism comprising them.A compound represented by Formula (I):wherein R1 is substituted or unsubstituted aromatic heterocyclyl or the like; R2 is each independently a hydrogen atom or the like; R3 is each independently a hydrogen atom or the like; n is 1 or the like; a combination of (L1, L2) is (NH, N) or the like; R4 is a group represented by Formula:wherein p and q are each independently 2 or the like; Ra is substituted or unsubstituted alkyl or the like; Xb is each independently CRbRb′; Rb is each independently a hydrogen atom or the like; Rb′ is each independently a hydrogen atom or the like; Xc is each independently CRcRc′; Rc is each independently a hydrogen atom or the like; Rc′ is each independently a hydrogen atom or the like; Xd is CRd or the like; and Rd is a hydrogen atom or the like; R5 and R6 are each independently a hydrogen atom or the like; and R7 is a group represented by Formula:wherein A is CR11 or the like; R9 is substituted or unsubstituted alkyloxy or the like; R10 is a hydrogen atom or the like; and R11 is each independently a hydrogen atom or the like; or a pharmaceutically acceptable salt thereof.

Core Innovation

The invention relates to compounds represented by Formula (I), wherein R1 is a substituted or unsubstituted 5-membered aromatic heterocyclyl or substituted or unsubstituted 6-membered aromatic heterocyclyl, and R2 and R3 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. The scaffold includes a combination of (L1, L2) as (NH, N) or (CH2, N), with R4 defined by a further Formula having p and q each equal to 2, p' and q' each independently 1 or 2, and variable groups including Xb, Xc, Xd and multiple substituent options with ring-closure and bridge formation rules.

R5 and R6 are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or may be taken together to form a substituted or unsubstituted non-aromatic carbocycle. R7 is defined by another Formula in which A is CR11 or N, and R9 and R10 are selected from substituted or unsubstituted alkyloxy, amino, aromatic carbocyclyloxy, alkyl, non-aromatic carbocyclyl, or cyano, with optional formation of a non-aromatic carbocycle or heterocycle. The disclosure also provides exclusions of certain compounds and allows pharmaceutically acceptable salts, and some items further describe all isomers, isotopically labeled forms, solvates, hydrates, co-crystals, crystal polymorphs, and prodrugs.

The compounds are stated to act as serotonin 5-HT2A receptor antagonists and/or inverse agonists. The disclosure further states use for treating serotonin 5-HT2A-related diseases, including serotonin-related diseases and, in particular, Parkinson's disease-related hallucinations and delusions and dementia-related hallucinations and delusions. One item also references neurodegenerative disorders such as Alzheimer's disease/dementia and Parkinson's disease, along with a behavioral assay involving rat MK801-induced hyperactivity.

Claims Coverage

The consolidated claim coverage includes one independent claim to a Formula (I) compound family and directly referenced dependent scope that narrows substituent choices and extends to salts and related use. The inventive coverage centers on 4 core inventive features: the Formula (I) scaffold with defined R1 and R2/R3 options, the structured R4 group with ring-closure/bridge rules, the R5/R6 and R7 definitions, and exclusions with pharmaceutically acceptable salt coverage.

Overall, the claim coverage is directed to a Formula (I) compound family with detailed R1-R7 structural definitions, optional ring closure and bridge formation in the R4 framework, and additional narrowing through exclusions while retaining pharmaceutically acceptable salt coverage.

Stated Advantages

Documented Applications