Therapeutic thiophene-, furan-, and pyridine-fused azolopyrimidin-5-(6H)-ones
Inventors
Branstetter, Bryan • Breitenbucher, James • Dyck, Brian • Gomez, Laurent • Hudson, Andrew Richard • Marrone, Tami Jo • Peters, Marco • VICKERS, Troy • Weinhouse, Michael I.
Assignees
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Publication Number
US-9175010-B2
Publication Date
2015-11-03
Expiration Date
Abstract
Described herein are compounds of Formula I and Formula II, methods of their synthesis, compositions comprising the compounds, and use of the compounds and compositions in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.
Core Innovation
The document describes compounds of Formula II, or pharmaceutically acceptable salts thereof, defined by structural variables including X and Y, where X and Y are independently nitrogen or carbon and at least one is nitrogen, and M is 0-4. The substituent architecture includes R1, R2, R3, and R4, with broad selections and alternative ring-forming constraints in which R1 and R2 are on adjacent carbons and form a 5-6 member saturated or unsaturated monocyclic ring system comprising one or more oxygen or nitrogen atoms, optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.
The document further defines R5, R6, R7, and R8, with options including hydrogen, fluoro, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, sulfonyl, and amide/carbonyl-containing groups, together with optional ring formation involving azetidine, pyrrolidine, piperidine, homopiperidine, morpholine, morpholinone, homomorpholine, homomorpholinone, piperazine, piperazinone, homopiperazine, and homopiperazinone, and additional monocyclic ring structures containing up to two heteroatoms selected from nitrogen, oxygen, and sulfur. The disclosure includes examples characterized by 1H NMR and LC-MS, together with structural drawings and preparative examples.
The therapeutic rationale centers on PDE1/PDE1B inhibition, including cognitive impairment and CNS-related disorders, with downstream cAMP/CREB-related rationale and concepts of dopamine signaling and neuronal plasticity. The document also states that PDE1B inhibition promotes neurite outgrowth in PC12 NS1 cells and reports improved memory in object recognition/fear conditioning, alongside assay characterization for PDE1B inhibition and PDE selectivity across PDE isoforms.
Claims Coverage
The consolidated claim coverage is anchored on Formula II compounds (or pharmaceutically acceptable salts) defined by X and Y constraints, M = 0-4, and extensive substituent and ring-forming options for R1-R8. Across the independent claims, the inventive features include the scaffold definition itself, adjacency-based ring formation for R1/R2, oxygen-containing ring formation for R3/R4, optional ring formation for R5-R8, and a separate selection claim limited to specific example compounds.
Formula II compound definition with X and Y heteroatom constraints
A compound of Formula II (or a pharmaceutically acceptable salt thereof) wherein X and Y are independently nitrogen or carbon, but at least one is nitrogen, and M is 0-4.
R1 and R2 substituent selection with adjacent ring-forming option
Each occurrence of R1 and R2 is independently selected from broad substituent classes, or R1 and R2 are on adjacent carbons and together form a 5-6 member saturated or unsaturated monocyclic ring system comprising one or more oxygen or nitrogen atoms, optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.
R3 and R4 substituent selection with oxygen-containing ring option
R3 and R4 are independently selected from defined substituent classes, or R3 and R4 taken together with the carbons to which they are attached form a 5-6 member monocyclic ring system comprising one or more oxygen atoms.
R5-R8 substituent selection with optional ring formation
R5, R6, R7, and R8 are independently selected from defined groups, or optionally R5 and R6 and the nitrogen to which they are attached form a ring taken from azetidine, pyrrolidine, piperidine, homopiperidine, morpholine, morpholinone, homomorpholine, homomorpholinone, piperazine, piperazinone, homopiperazine and homopiperazinone with the ring optionally substituted with up to three independent occurrences of R1; and any two of R5, R6, R7, and R8 taken together with the atoms to which they are attached form a 3-7 member monocyclic ring containing up to two heteroatoms selected from nitrogen, oxygen, and sulfur.
Selection of specific example compounds
A compound selected from the group consisting of Examples 220, 222, 223, 225, 229, 247, 248, 266, 267, 268, 270, 272, 277, 290, 294 and 295, or a pharmaceutically acceptable salt thereof.
Overall, the claims define a Formula II scaffold by heteroatom assignment, a bounded M value, and broad but structured substituent frameworks across R1-R8, including multiple ring-forming alternatives. A separate independent claim restricts coverage to specifically listed Example compounds and their pharmaceutically acceptable salts.
Stated Advantages
Enhances Ca2+ and cAMP/cGMP signaling.
Supports CREB-dependent neuronal plasticity related to memory formation.
Enhances long-term memory as reported for contextual and trace fear outcomes.
Promotes neurite outgrowth in PC12 NS1 cells.
Improves memory in object recognition/fear conditioning.
Inhibition of PDE1, including PDE1B.
Use for cognitive/neurological, cardiovascular, and renal related therapeutic applications.
Documented Applications
Measurement of PDE1B inhibition using an IMAP TR-FRET enzymatic assay, with pIC50 results provided.
Assessment of PDE selectivity across PDE isoforms.
Therapeutic indications centered on PDE1/PDE1B inhibition, including cognitive impairment and CNS disorders.
Augmentation of cognitive training (ACT) by enhancing CREB pathway function.
Therapeutic indications across multiple CNS and psychiatric disorders, including Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, ADHD, Mild cognitive impairment, substance abuse, and pain.
Cognitive/neurological related therapeutic use.
Cardiovascular related therapeutic use.
Renal related therapeutic use.
Example-specific substituted heterocyclic derivatives are documented with characterization data, including molecular formulas, 1H NMR shifts, and LC-MS entries.
Preparative examples document synthesis of specific substituted targets from bromo-substituted cores, with reported isolated yields and analytical characterization tables.
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