Heteroaromatic derivatives having serotonin receptor binding activity
Inventors
Nakahara, Kenji • FUCHINO, Kouki • NAGATANI, Kotaro
Assignees
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Publication Number
US-12527775-B2
Publication Date
2026-01-20
Expiration Date
Abstract
Provided are compounds having a serotonin 5-HT2A receptor inverse agonism, pharmaceutically acceptable salts thereof, and a composition comprising them,A composition comprising the compounds of Formula (I):or pharmaceutically acceptable salts thereof,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 2; R4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl or the like; L is —NR8— or the like; R8 is a hydrogen atom or the like; R5 is each independently a hydrogen atom or the like; R6 is each independently a hydrogen atom or the like; p is 1 or 2; and R7 is a group represented by Formula:wherein R9 is substituted or unsubstituted alkyloxy or the like; R10 is a hydrogen atom or the like; R11 is halogen or the like; and m is 0 or 1.
Core Innovation
The invention relates to compounds represented by Formula (II) and related formulae, together with pharmaceutically acceptable salts and pharmaceutical compositions. The compounds include substituted or unsubstituted pyridyl, pyrrolyl, or pyrazolyl at R1, with R2 and R3 as hydrogen atoms, n being 1, and R4 defined by a further formula with R21, R22, and R23 options, including an alternative where R22 and R23 are taken together with the carbon atom to form a substituted or unsubstituted non-aromatic carbocycle.
The compound further specifies R5, R6, and R8 as hydrogen atoms, and R7 as a group represented by a further formula in which R9 is substituted or unsubstituted alkyloxy. The scope includes at least one excluded compound structure. The provided structure set is described as a common scaffold featuring a carbonyl-linked diamine motif and a substituted aryl-ether side chain with phenoxy/alkoxy substituents.
The compounds are described as serotonin 5-HT2A receptor inverse agonists, with pharmacological activity linked to serotonin 5-HT2A related diseases. The disclosure includes treatment and/or prevention of serotonin-5-HT2A related diseases, including neuropsychiatric symptoms associated with neurodegenerative disorders. The partial content specifically references Parkinson’s disease and dementia, and symptoms such as hallucinations and delusions.
Claims Coverage
The consolidated claim coverage centers on one independent Formula (II) compound claim with defined substituent scope and an explicit exclusion, plus dependent refinements. Across the provided claim text, the inventive features focus on the Formula (II) scaffold, heteroaryl selection at R1, fixed hydrogen assignments at R2, R3, R5, R6, and R8, ring-based options for R4 including a non-aromatic carbocycle alternative, and an alkyloxy-based definition for R7 via R9.
Formula (II) compound with defined heteroaryl and substituent constraints
A compound represented by Formula (II) wherein R1 is substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted pyrazolyl; R2 and R3 are hydrogen atoms; n is 1; R4 is defined by a formula with R21, R22, and R23 options, including an alternative where R22 and R23 together with the carbon atom form a substituted or unsubstituted non-aromatic carbocycle; R5, R6, and R8 are hydrogen atoms; and R7 is a group represented by a formula wherein R9 is substituted or unsubstituted alkyloxy, with at least one specified compound excluded and pharmaceutically acceptable salts included.
Refined R1 heteroaryl substitution patterns
R1 includes substituted or unsubstituted pyridyl, pyrrolyl, or pyrazolyl, including halogen-/haloalkyl-substituted patterns in the provided dependent claim wording, with pharmaceutically acceptable salts.
Defined R4 ring options via R21/R22/R23
R4 is defined by a ring formula where R21 is a hydrogen atom or substituted or unsubstituted alkyl; R22 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; and R23 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; or R22 and R23 are taken together with the carbon atom to which they are bonded to form a substituted or unsubstituted non-aromatic carbocycle.
R7 defined by alkyloxy group with halogen substitution options via R9
R7 is a group represented by a specified chemical structure in which R9 is an alkyloxy group that is halogen-substituted or unsubstituted.
Pharmaceutical composition characterized as a serotonin 5-HT2A receptor inverse agonist
A pharmaceutical composition characterized as a serotonin 5-HT2A receptor inverse agonist.
Overall, the claim set is centered on a Formula (II) compound scaffold with constrained heteroaryl selection at R1, fixed hydrogen positions, defined R4 options including a non-aromatic carbocycle alternative, and R7 defined through an alkyloxy group via R9, while excluding at least one specified compound and including pharmaceutically acceptable salts. Dependent refinements further narrow R1, R4, and R7, and include a pharmaceutical composition characterized as a serotonin 5-HT2A receptor inverse agonist.
Stated Advantages
Weak CYP inhibition.
High bioavailability and clearance.
Metabolic stability.
Non-mutagenicity.
Low cardiovascular risk.
High solubility.
Strong 5-HT2A and 5-HT2C binding.
Good brain distribution ability.
Low P-gp substrate property.
Documented Applications
Treatment and/or prevention of serotonin-5-HT2A related diseases, including neuropsychiatric symptoms in Parkinson’s disease and dementia, with hallucinations and delusions referenced.
Treating serotonin 5-HT2A-associated disorders, including schizophrenia and dementia hallucinations/delusions.
Treating Parkinson’s disease-related hallucinations/delusions/irritability.
Treating depression-related hallucinations/delusions.
Treating autism.
Treating dependence.
Treating dyskinesia.
Treating sleep disorder.
Treating sexual dysfunction.
Treating or preventing serotonin 5-HT2A receptor-related disease.
Use as serotonin 5-HT2A inverse agonists for treating associated diseases, with biological testing including serotonin 5-HT2A receptor binding inhibition, serotonin 5-HT2C receptor binding inhibition, hERG (IKr) functional assessment, and ADME-related assays including oral absorption, clearance, metabolism stability in human hepatic microsomes, and P-gp substrate testing.
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