Deuterium-enriched isoindolinonyl-azepanediones and related compounds and methods of treating medical disorders using same
Inventors
DeWitt, Sheila • Jacques, Vincent
Assignees
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Publication Number
US-11773080-B2
Publication Date
2023-10-03
Expiration Date
Abstract
The invention provides deuterium-enriched isoindolinonyl-azepanediones, deuterium-enriched oxoquinazolin-3(4H)-yl-azepanediones, related compounds, pharmaceutical compositions, and methods of using such compounds and pharmaceutical compositions to treat cancer, angiogenesis disorders, immune disorders, and other medical disorders.
Core Innovation
The invention relates to deuterium-enriched compounds of Formula II, including pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and deuterium-enriched isoindolinonyl-azepanediones and oxoquinazolin-3(4H)-yl-azepanediones having a variable deuteration site denoted as Z. Z is H or D, with deuterium abundance in Z of at least 30% when Z is D, and the structures include additional positions where H/D substitution is defined with variable substituents, supporting stereochemical forms including racemic and enantioenriched compounds.
The compounds further define multiple substituents selected from H and D, including R5, R6, R7, R9, R10, R11, and R12, with optional replacement of any hydrogen atom in any substituent by D. The disclosure also provides extensive substituent selection for R13 and for R1-R4 and additional group definitions, including optional formation of a 5-6 membered carbocyclic or heterocyclic ring from two of R1-R4.
The specification includes stereochemical purity constraints at the carbon atom bearing variable Z, including at least 75% enantiomeric excess in dependent embodiments, and refers to specific Formula II sub-embodiments such as Formula II-B, II-C, II-H, and II-J. The document also states that the deuterium-enriched compounds may be listed in tables, including Table 1, Table 6, and Table 7, with deuterium labeling and halogen-substituted aryl variants.
Claims Coverage
The claim set centers on Formula II compounds with a minimum deuterium abundance requirement at Z and multiple H/D-selectable substituents. Dependent claims further refine the formula-specific embodiments, add stereochemical purity requirements, and specify particular choices for R13.
Deuterium-enriched formula II with variable Z
A compound of Formula II, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is H or D and the abundance of deuterium in Z is at least 30% when Z is D.
H/D-selectable substituents including R5, R6, R7, R9-R12
R5, R6, R7, R9, R10, R11, and R12 are each independently selected from H and D, with a hydrogen atom present in any substituent optionally replaced by D.
Extensive substituent framework for R13 and R1-R4
R13 is selected from H, D, halo, —(CH2)nOH, phenyl, —O(C1-C6)alkyl, and (C1-C6)alkyl optionally substituted with one or more halo, while R1, R2, R3, and R4 are selected from defined H/D/halo/hydroxyl/amine/alkyl/alkoxy and related group options, or two of R1-R4 are taken together to form a 5-6 membered carbocyclic or heterocyclic ring optionally substituted with halo, substituted (C1-C6)alkyl, or substituted (C1-C6)alkoxy.
Additional substituted framework with aryl and heteroaryl options
Ra, Rb, Rc, and related substituent definitions include H, D, substituted alkyl, alkoxy, aryl, heteroaryl, acyl, and halo-containing options, with optional halogen, —SCF3, alkyl, and alkoxy substitution in aryl and heteroaryl groups.
Stereochemical purity at the carbon bearing Z
Dependent embodiments require stereochemical purity of at least 75% enantiomeric excess at the carbon atom bearing variable Z, while retaining the deuterium-abundance and H/D substituent constraints.
Specific Formula II sub-embodiments and R13 selection
Dependent claims limit the compound to specific Formula II sub-embodiments such as Formula II-B, II-C, II-H, or II-J, and in selected embodiments specify R13 as CH3 or CD3.
The claims cover Formula II compounds with a minimum deuterium abundance at variable Z, extensive H/D-selectable substituent definitions, and broad substituent selection across R13 and R1-R4. Dependent claims further add at least 75% enantiomeric excess at the Z-bearing carbon and restrict selected embodiments to specific Formula II forms and R13 methyl or deuteromethyl options.
Stated Advantages
Improved properties are attributed to reduced enantiomer interconversion.
Pharmaceutical composition concepts using pharmaceutically acceptable carrier material and therapeutically effective amount ranges are described.
Documented Applications
Methods of treating cancer via administration of the deuterium-enriched compounds.
Methods of treating angiogenesis disorders via administration of the deuterium-enriched compounds.
Methods of treating immune disorders via administration of the deuterium-enriched compounds.
Methods of treating inflammatory-related conditions via administration of the deuterium-enriched compounds.
Therapeutic use of deuterium-enriched compounds, including deuterium-enriched isoindolinonyl-azepanediones and oxoquinazolin-3(4H)-yl-azepanediones.
Therapeutic use for cancer.
Therapeutic use for immune and inflammatory disorders, including cytokine-related disorders.
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