Apaf-1 inhibitor compounds
Inventors
Messeguer Peypoch, Ángel • Moure Fernández, Alejandra • GONZÁLEZ PINACHO, DANIEL • Masip Masip, Isabel • Pérez Payá, Enrique • García Villar, Natividad • Monlleó Mas, Ester • Catena Ruiz, Juanlo
Assignees
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Publication Number
US-9040701-B2
Publication Date
2015-05-26
Expiration Date
Abstract
Derivatives of 2,5-piperazinedione of formula (I) are apoptotic peptidase activating factor 1 (Apaf-1) inhibitors, therefore they are useful as active pharmaceutical ingredients for the prophylaxis and/or treatment of a pathological and/or physiological condition associated with an increase of apoptosis.
Core Innovation
The invention relates to a compound of formula (I), or pharmaceutically acceptable salts thereof, defined by substituents R1, R2, R3, and R4 together with integer parameters n and m. The definitions specify allowed alkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl groups and optional substitution patterns using a listed set of substituents.
Within the formula (I) framework, R5 and R6 are independently selected from hydrogen, C1-5 alkyl, and (CH2)0-3-aryl, and R7 is selected from hydrogen, C1-5 alkyl, (CH2)1-3-aryl, and (CH2)1-3-heteroaryl. The disclosure further states that when m is greater than 1 the R7 substituents can be equal to or different from one another.
The record includes a conditional exclusion relationship for a particular parameter context: when R2 is 2-(4-fluorophenyl)ethyl, R4 is CH2-CO-NH2 and n is 1, specific R3 alternatives are excluded depending on whether R1 is 2-(4-fluorophenyl)ethyl or 2-(2,4-dichlorophenyl)ethyl. The disclosure also describes multiple specific compounds within the same compound class, including examples with varied N-substituents, aryl and heteroaryl groups, and related structural variations.
Claims Coverage
The claims define a broad formula-(I) genus with structured substituent sets, optional substitution rules, integer parameters n and m, and a conditional exclusion relationship. Dependent claims further narrow the genus by fixing n or m, restricting R5 or R7, and selecting specific depicted members.
Formula (I) compounds with defined substituents
A compound of formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, and R4 are selected from specified alkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl patterns, with optional substitution by listed substituents.
Integer parameter constraints for n and m
n is selected from 1 and 2 and m is selected from 1, 2 and 3, including the rule that when m is greater than 1 the R7 substituents can be equal to or different from one another.
Defined restrictions for R5, R6, and R7
R5 and R6 are independently selected from hydrogen, C1-5 alkyl, and (CH2)0-3-aryl; R7 is selected from hydrogen, C1-5 alkyl, (CH2)1-3-aryl, and (CH2)1-3-heteroaryl.
Optional substitution rules for selected groups
C1-5 alkyl, C2-5 alkenyl, cycloalkyl and heterocycle groups can be optionally substituted with one or several substituents selected independently from the listed set, and aryl and heteroaryl groups can be optionally substituted with one or several substituents selected independently from the listed set.
Conditional exclusion of R3 for a specified R2/R4/n context
When R2 is 2-(4-fluorophenyl)ethyl, R4 is CH2-CO-NH2 and n is 1, the claim imposes explicit exclusions on R3 depending on whether R1 is 2-(4-fluorophenyl)ethyl or 2-(2,4-dichlorophenyl)ethyl.
Selection of specific depicted alternative members
A dependent claim selects a specific member from a defined group of alternative compounds shown in the claim images.
Overall, the claims define a broad formula-(I) genus with structured substituent sets, optional substitution rules, integer parameters n and m, and a conditional exclusion relationship. Dependent claims further narrow the genus by fixing n or m, restricting R5 or R7, and selecting specific depicted members.
Stated Advantages
Apaf-1 inhibition is demonstrated in an in vitro assay context for apoptosome formation inhibition.
Apoptosis-related tissue and cell preservation, including organ transplant or conservation.
Prevention of cytotoxicity.
Prophylaxis or treatment of conditions associated with increased apoptosis, including hypoxia-induced pathologies such as heart attack and cerebral infarction.
Therapeutic use for ocular injuries.
Therapeutic use for neurodegenerative diseases including Alzheimer’s, Huntington’s, and Parkinson’s.
Therapeutic use for diabetes-related cytotoxicity.
Therapeutic use for osteoarthritis/arthritis/inflammation.
Therapeutic use for immunodeficiencies including AIDS-associated CD4+ T lymphocyte depletion.
Documented Applications
In vitro Apaf-1 inhibition measurement in an apoptosome formation inhibition assay context.
Prophylaxis or treatment of conditions associated with increased apoptosis via Apaf-1 inhibition, including apoptosis-related tissue or cell preservation.
Prophylaxis or treatment of hypoxia-induced pathologies, including heart attack and cerebral infarction.
Prophylaxis or treatment of ocular injuries.
Prophylaxis or treatment of neurodegenerative diseases, including Alzheimer’s, Huntington’s, and Parkinson’s.
Prophylaxis or treatment of diabetes-related cytotoxicity.
Prophylaxis or treatment of osteoarthritis/arthritis/inflammation.
Prophylaxis or treatment of immunodeficiencies, including AIDS-associated CD4+ T lymphocyte depletion.
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