# US 9,040,701 B2 · Apaf-1 inhibitor compounds

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- Number: US 9,040,701 B2
- Document ID: US9040701B2
- Status: Granted
- Kind: B2
- Application number: 13/387,240
- Filed: 2010-07-29
- Published: 2012-05-17
- Granted: 2015-05-26
- Earliest claimed: 2009-07-30
- Assignees: Laboratorios Salvat, S.A.
- Applicants: Ángel Messeguer Peypoch; Alejandra Moure Fernández; Daniel González Pinacho; Isabel Masip Masip; Enrique Pérez Payá; Natividad García Villar; Ester Monlleó Mas; Juanlo Catena Ruiz
- Inventors: Ángel Messeguer Peypoch; Alejandra Moure Fernández; Daniel González Pinacho; Isabel Masip Masip; Enrique Pérez Payá; Natividad García Villar; Ester Monlleó Mas; Juanlo Catena Ruiz
- Web page: https://patentgrep.com/patent/US9040701B2

## CPC

- C07D 241/08: with oxygen atoms directly attached to ring carbon atoms
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of formula (I)
or pharmaceutically acceptable salts thereof, wherein:
R1 is —(CH2)0-3-aryl,
R2 is selected from —C1-5 alkyl, —C2-5 alkenyl, —(CH2)0-3-cycloalkyl, —(CH2)1-3-heterocycle, —(CH2)0-3-aryl, —(CH2)0-3-heteroaryl, —(CH2)1-2—CH(aryl)2, —(CH2)1-2—CH(aryl)(heteroaryl) and —(CH2)1-2—CH(heteroaryl)2,
R3 is selected from —H, —C1-5 alkyl, —C2-5 alkenyl, —(CH2)0-3-cycloalkyl, —(CH2)1-3-heterocycle, —(CH2)1-3-aryl, —(CH2)1-3-heteroaryl, —(CH2)1-3—CONR5R6, —(CH2)1-2—CH(aryl)2, —(CH2)1-2—CH(aryl)(heteroaryl) and —(CH2)1-2—CH(heteroaryl)2,
R4 is selected from —H, —C1-5 alkyl, —(CHR7)1-3—CO—NR5R6, —(CHR7)1-3—CO—OR5, —(CH2)1-3—NR5R6, —(CH2)1-3—CO[NCHR7CO]mNH2 and —(CH2)1-3—CO[NCHR7CO]mOR5,
n is an integer selected from 1 and 2;
m is an integer selected from 1, 2 and 3;
R5 and R6 are independently selected from —H, —C1-5 alkyl and —(CH2)0-3-aryl,
R7 is selected from —H, —C1-5 alkyl, —(CH2)1-3-aryl and —(CH2)1-3-heteroaryl, such that when m is greater than 1 the R7 substituents can be equal to or different from one another,
wherein the C1-5 alkyl, C2-5 alkenyl, cycloalkyl and heterocycle groups can be optionally substituted with one or several substituents selected independently from halogen, OH, OR5, OCF3, SH, SR5, NH2, NR5R6, NHCOR5; COOH, COOR5, OCOR5, aryl and heteroaryl,
wherein the aryl and heteroaryl groups can be optionally substituted with one or several substituents selected independently from halogen, CF3, OH, ORS, OCF3, SH, SR5, NH2, NHCOR5; NO2, CN, COR5, COOR5, OCOR5, CONR5R6, —(CH2)0-3NR5R6, SO2NH2, NHSO2CH3, C1-5 alkyl, aryl and heteroaryl,
wherein the heterocycle and heteroaryl groups can be optionally substituted on a secondary nitrogen atom with C1-5 alkyl, cycloalkyl or —(CH2)0-3-aryl,
on the condition that when R2 is 2-(4-fluorophenyl)ethyl, R4 is —CH2—CO—NH2 and n is 1, then:
if R1 is 2-(4-fluorophenyl)ethyl, R3 is not 2-(4-methoxyphenyl)ethyl, 2-(2-pyridyl)ethyl or 2-(2,4-dichlorophenyl)ethyl, and
if R1 is 2-(2,4-dichlorophenyl)ethyl, R3 is not 2-(4-methoxyphenyl)ethyl or 2-(2-pyridyl)ethyl.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R2 is —C1-5 alkyl, —(CH2)0-3-aryl, —(CH2)0-3-heteroaryl or —(CH2)1-2—CH(aryl)2.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R3 is —H, —C1-5 alkyl, —(CH2)1-3-heterocycle, —(CH2)1-3-aryl or —(CH2)1-3-heteroaryl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R4 is —H, —(CHR7)1-3—CO—NR5R6, —(CHR7)1-3—CO—OR5 or —(CH2)1-3—CO[NCHR7CO]mNH2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein n is 1.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein m is 1.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R5 is —H or —C1-5 alkyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R6 is —H.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R7 is —H, —C1-5 alkyl, —(CH2)1-3-aryl or —(CH2)1-3-heteroaryl.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R2 is —C1-5 alkyl, —(CH2)0-3-aryl, —(CH2)0-3-heteroaryl or —(CH2)1-2—CH(aryl)2; R3 is —H, —C1-5 alkyl, —(CH2)1-3-heterocycle, —(CH2)1-3-aryl or —(CH2)1-3-heteroaryl; R4 is —H, —(CHR7)1-3—CO—NR5R6, —(CHR7)1-3—CO—OR5 or —(CH2)1-3—CO[NCHR7CO]mNH2; and n is 1.

### Claim 11 (depends on 1)

The compound according to claim 1 which is

### Claim 12 (depends on 1)

The compound according to claim 1 which is

### Claim 13 (depends on 1)

The compound according to claim 1 which is selected from the group consisting of: