Heterocyclic compounds having cholesterol 24-hydroxylase activity

Patent metadata

Field	Value
Publication number	US-10112956-B2
Application number	US-201715467548-A
Country	US
Kind code	B2
Filing date	Mar 23, 2017
Priority date	Dec 11, 2012
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

An object of the present invention is to provide a compound having a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of epilepsy, neurodegenerative disease and the like. The present invention relates to a compound represented by the formula:

wherein each symbol is as defined in the specification, or a salt thereof.

First claim

The invention claimed is:

1. A compound represented by the formula (1):

wherein
X 1 is a carbon atom or a nitrogen atom;
Ring A is

each of which is optionally further substituted and optionally bridged;
R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted hydroxy group, an optionally substituted amimo group, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, or R 1 is optionally bonded to the atom on Ring A to form, together with Ring A, a spiro ring or a fused ring, each of which is substituted by an oxo group and optionally further substituted;
R 2 is an optionally substituted C 6-14 aryl group, or an optionally substituted aromatic heterocyclic group; and
R 3 is a hydrogen atom or a substituent when X 1 is a carbon atom, or absent when X 1 is a nitrogen atom,

wherein tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate is excluded, or a salt thereof.

2. The compound or salt of claim 1 , wherein R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, an optionally substituted C 3-8 cloalkyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted non-aromatic heterocyclic group.

3. The compound or salt of claim 1 , wherein
R 1
(1)a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(a) a cyano group,
(b) a C 6-14 aryl group optionally substituted by 1 to 3 alkoxy groups,
(C) a C 6-14 aryloxy group,
(d) a C 3-8 cycloalkyl group,
(e) a pyrazolyl group,
(f) an indazolyl group, and
(g) a dihydropyridyl group optionally substituted by 1 to 3 oxo groups,

(2) a C 1-6 alkoxy group optionally substituted by 1 to 3 aryl groups,
(3) an amino group optionally mono- or di-substituted by substituent(s) selected from the group consisting of:
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(i) a halogen atom,
(ii) a cyano group,
(iii) a C 3-8 cycloalkyl group,
(iv) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group,
(v) a pyridyl group, and
(vi) an oxetanyl group optionally substituted by 1 to 3 C 1-6 alkyl groups,

(b) a C 3-8 cycloalkyl group optionally substituted by 1 to 3 halogen atoms,
(c) a C 6-14 aryl group, and
(d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuryl group and a pyrrolidinyl group, each of which is optionally substituted by 1 to 3 C 6-14 alkyl groups,

(4)a C 3-8 cycloalkyl group optionally substituted by 1 to 3 C 6-14 aryl groups,
(5) a C 6-14 aryl group, or
(6) a 3- to 8-membered monocyclic non-aromatic heterocyclic group or a 3,7-dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is optionally substituted by 1 to 5 substituents selected from the group consisting of:
(a) a halogen atom,
(b) a cyano group,
(c) a hydroxy group,
(d) an oxo group,
(e) a carbamoyl group optionally mono- or di-substituted by C 1-6 alkyl group(s),
(f) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(i) a hydroxy group, and

(ii) a C 1-6 alkoxy group,
(g) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(h) a C 1-6 alkoxy-carbonyl group, and
(i) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, or

R 1 is bonded to the atom on Ring A to, form, together with Ring A, a 2,8-diazaspiro[4.5]decane ring substituted by, oxo and optionally further substituted, by 1 to 3 C 1-6 alkyl groups:
R 2 is
(1) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(a) a halogen atom, and
(b) a C 1-16 alkyl group optionally substituted by 1 to 3 halogen atoms, or

(2) a 5- or 6-membered monocyclic aromatic heterocyclic group or a 8- to 12-membered fused aromatic heterocyclic group, each of which is optionally substituted by 1 to 3 substituents selected from the group consisting of:
(a) a halogen atom,
(b) a cyano group,
(c) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and
(d) a C 3-8 cycloalkyl group;

X 1 is a carbon atom or a nitrogen atom;
R 3 is
(1) a hydrogen atom, or
(2) a halogen atom; and
Ring A is
(1)

each of which is optionally further substituted by 1 to 3 substituents selected from the group consisting of:
(a) a halogen atom,
(b) a C 1-6 alkyl group, and
(c) oxo group, or

(2) a 8-azabicyclo[3.2.1]octane ring, a 2,5- diazabicyclo[2.2.1]heptane ring or a 3-azabicyclo[3.1.0]hexane ring.

4. The compound or salt of claim 3 , wherein R 1 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(a) a cyano group,
(b) a C 6-14 aryl group optionally substituted by 1 to 3 C 1-6 alkoxy groups,
(c) a C 6-14 aryloxy group,
(d) a C 3-8 cycloalkyl group,
(e) a pyrazolyl group,
(f) an indazolyl group, and
(g) a dihydropyridyl group optionally substituted by 1 to 3 oxo groups,

(2) a C 1-3 alkoxy group optionally substituted by 1 to 3 C 6-14 aryl groups,
(3) an amino group optionally mono- or di-substituted by substituent(s) selected from the group consisting of:
(a) a C 1-6 alkyl, group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(i) a halogen atom,
(ii) a cyano group,
(iii) a C 3-8 cycloalkyl group,
(iv) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group,
(v) a pyridyl group, and
(vi) an oxetanyl group optionally substituted by 1 to 3 C 1-6 alkyl groups,

(b) a C 3-8 cycloalkyl group optionally substituted by 1 to 3 halogen atoms,
(c) a C 6-14 aryl group, and
(d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuryl group and a pyrrolidiny group, each of which is optionally substituted by 1 to 3 C 1-6 alkyl groups,

(4) C 3-8 cycloalkyl group optionally substituted by 1 to 3 C 6-14 aryl groups,
(5) a C 6-14 aryl group, or
(6) a 3- to 8-membered monocyclic non-aromatic heterocyclic group or a 3,7-dioxa-9-azabicyclo [3.3.1]nonyl group, each of which is optionally substituted by 1 to 5 substituents selected from the group consisting of:
(a) a halogen atom,
(h) a cyano group,
(c) a hydroxy group,
(d) an oxo group,
(e) a carbamoyl group optionally mono- or di-substituted by C 1-6 alkyl group(s),
(f) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(i) a hydroxy group, and
(ii) a C 1-6 alkoxy group,

(g) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(h) a C 1-6 alkoxy-carbonyl group, and
(i) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, or

R 1 is bonded to the atom or Ring A to form, together with Ring A, a 2,8-diazaspiro[4,5]decane ring substituted by oxo and optionally further substituted by 1 to 3 C 1-6 alkyl groups.

5. The compound or salt of claim 1 , wherein
R 1
(1) an amino group optionally mono- or di-substituted by substituent(s) selected from the group consisting of:
(a) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of;
(i) a halogen atom, and
(ii)

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Koike Tatsuki
• Kajita Yuichi
• Yoshikawa Masato
• Ikeda Shuhei
• Kimura Eiji
• Hasui Tomoaki
• Nishi Toshiya
• Fukuda Hiromi

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  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 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title