Fused heterocyclic derivatives as S1P modulators

Patent metadata

Field	Value
Publication number	US-9670220-B2
Application number	US-201514743234-A
Country	US
Kind code	B2
Filing date	Jun 18, 2015
Priority date	Jul 9, 2010
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The present invention relates to a fused heterocyclic derivative of the formula (I) The variables R1-R4, z, A, Q, X and Y are as defined in the claims. The following heterocycles are exemplified sub-structures of formula (I): The compounds of formula (I) are modulators of the S1P receptor (Sphingosine-1-phosphate receptor), More specifically, they are agonists of S1P5. The compounds have therapeutic use in treatment of cognitive disorders, age-relate cognitive decline and dementia.

First claim

The invention claimed is:

1. A method of treating or alleviating a disorder mediated by the S1P signaling pathway selected from the group consisting of dementia, Niemann Pick disease, cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis and pain, the method comprising administering to a patient in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an N-oxide thereof:

wherein
R1 is selected from the group consisting of:
a cyano group,
a group selected from the group consisting of a (2-4C)alkenyl group, a (2-4C)alkynyl group, and a (1-4C)alkyl group, wherein each group is optionally substituted with a substituent independently selected from the group consisting of CN and at least one fluoro atom,
a group selected from the group consisting of a (3-6C)cycloalkyl group, a (4-6C)cycloalkenyl group, and a (8-10C)bicyclic group, wherein each group is optionally substituted with a substituent selected from the group consisting of a halogen atom and a (1-4C)alkyl group optionally substituted with at least one fluoro atom,
a group selected from the group consisting of a phenyl group, a biphenyl group, a naphthyl group, wherein each group is optionally substituted with at least one substituent independently selected from the group consisting of halogen, cyano, (1-4C)alkyl optionally substituted with at least one halogen atom, (1-4C)alkoxy optionally substituted with at least one halogen atom, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with a phenyl group wherein the phenyl group is optionally substituted with a substituent selected from the group consisting of (1-4C)alkyl and a halogen atom, and
a phenyl group substituted with a group selected from the group consisting of a phenoxy group, a benzyl group, a benzyloxy group, a phenylethyl group, and a monocyclic heterocycle group, wherein each group is optionally substituted with (1-4C)alkyl,

Z is a —W—(C n -alkylene)-T- group wherein
W is attached to R1 and selected from the group consisting of a bond, —O—, —CO—, —S—, —SO—, —SO 2 —, —NH—, —CH═CH—, —C(CF 3 )═CH—, —C≡C—, —CH 2 —O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO— and a trans-cyclopropylene;
n is an integer from 0 to 10; and
T is attached to the phenylene/pyridyl moiety and selected from the group consisting of a bond, —O—, —S—, —SO—, —SO 2 —, —NH—, —CO—, —C═C—, —C≡C—, and a trans-cyclopropylene;

R2 is selected from the group consisting of H and at least one substituent independently selected from the group consisting of cyano, halogen, (1-4C)alkyl optionally substituted with at least one halogen atom, and (1-4C)alkoxy optionally substituted with at least one halogen atom;
ring structure A optionally contains a nitrogen atom;
X is selected from the group consisting of C and N;
wherein if X is C, R3 is selected from the group consisting of H and (1-4C)alkyl, and if X is N, R3 is not present;

Y is selected from the group consisting of NH, O and S;
Structure Q is selected from the group consisting of a 5-, 6- and 7-membered cyclic amine;
and
R4 is selected from the group consisting of
a (1-4C)alkylene-R5 group wherein at least one carbon atom in the alkylene group may independently be substituted with a substituent selected from the group consisting of at least one halogen atom and a (CH 2 ) 2 to form a cyclopropyl moiety, and
a group selected from the group consisting of (3-6C)cycloalkylene-R5, —CH 2 -(3-6C)cycloalkylene-R5, (3-6C)cycloalkylene-CH 2 —R5 and —CO—CH 2 —R5, wherein R5 is selected from the group consisting of —OH, —PO 3 H2, —OPO 3 H2, —COOH, —COO(1-4C)alkyl, and tetrazol-5-yl.

2. A method of treating or alleviating a disorder mediated by the S1P signaling pathway selected from the group consisting of dementia, Niemann Pick disease, cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis and pain, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an N-oxide thereof, and at least one pharmaceutically auxiliary:

wherein
R1 is selected from the group consisting of:
a cyano group,
a group selected from the group consisting of a (2-4C)alkenyl group, a (2-4C)alkynyl group, and a (1-4C)alkyl group, wherein each group is optionally substituted with a substituent independently selected from the group consisting of CN and at least one fluoro atom,
a group selected from the group consisting of a (3-6C)cycloalkyl group, a (4-6C)cycloalkenyl group, and a (8-10C)bicyclic group, wherein each group is optionally substituted with a substituent selected from the group consisting of a halogen atom and a (1-4C)alkyl group optionally substituted with at least one fluoro atom,
a group selected from the group consisting of a phenyl group, a biphenyl group, a naphthyl group, wherein each group is optionally substituted with at least one substituent independently selected from the group consisting of halogen, cyano, (1-4C)alkyl optionally substituted with at least one halogen atom, (1-4C)alkoxy optionally substituted with at least one halogen atom, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with a phenyl group wherein the phenyl group is optionally substituted with a substituent selected from the group consisting of (1-4C)alkyl and a halogen atom, and
a phenyl group substituted with a group selected from the group consisting of a phenoxy group, a benzyl group, a benzyloxy group, a phenylethyl group, and a monocyclic heterocycle group, wherein each group is optionally substituted with (1-4C)alkyl,

Z is a —W—(C n -alkylene)-T- group wherein
W is attached to R1 and selected from the group consisting of a bond, —O—, —CO—, —S—, —SO—, —SO 2 —, —NH—, —CH═CH—, —C(CF 3 )═CH—, —C≡C—, —CH 2 —O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO— and a trans-cyclopropylene;
n is an integer from 0 to 10; and
T is attached to the phenylene/pyridyl moiety and selected from the group consisting of a bond, —O—, —S—, —SO—, —SO 2 —, —NH—, —CO—, —C═C—, —C≡C—, and a trans-cyclopropylene;

R2 is selected from the group consisting of H and at least one substituent independently selected from the group consisting of cyano, halogen, (1-4C)alkyl optionally substituted with at least one halogen atom, and (1-4C)alkoxy optionally substituted with at least one halogen atom;
ring structure A optionally contains a nitrogen atom;
X is selected from the group consisting of C and N;
wherein if X is C, R3 is selected from the group consisting of H and (1-4C)alkyl, and if X is N, R3 is not present;

Y is selected from the group consisting of NH, O and S;
Structure Q is selected from the group consisting of a 5-, 6- and 7-membered cyclic amine;
and
R4 is selected from the group consisting of
a (1-4C)alkylene-R5 group wherein at least one carbon atom in the alkylene group may independently be substituted with a substituent selected from the group consisting of at least one halogen atom and a (CH 2 ) 2 to form a cyclopropyl moiety, and
a group selected from the group consisting of (3-6C)cycloalkylene-R5, —CH 2 -(3-6C)cycloalkylene-R5, (3-6C)cycloalkylenc-CH 2 —R5 and —CO—CH 2 —R5, wherein R5 is selected from the group consisting of —OH, —PO 3 H2, —OPO 3 H2, —COOH, —COO(1-4C)alkyl, and tetrazol-5-yl.

3. The method of claim 1 , wherein
R1 is selected from the gro

Assignees

• Abbvie Bv
• Abbvie Inc
• Abbivie Inc

Inventors

• Smid Pieter
• Iwema Bakker Wouter I
• Coolen Hein K A C
• Sliedregt Leonardus A J M
• Van Dongen Maria J P
• Den Hartog Jacobus A J
• Hobson Adrian

Classifications

• A61P25/24

  Antidepressants · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · 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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title