Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy

Patent metadata

Field	Value
Publication number	US-9586945-B2
Application number	US-201414517034-A
Country	US
Kind code	B2
Filing date	Oct 17, 2014
Priority date	Oct 17, 2013
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

The present invention relates to aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives of the formula (I)

or a physiologically tolerated salt thereof.

The invention relates to pharmaceutical compositions comprising such aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, and the use of such aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives for therapeutic purposes. The aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives are GlyT1 inhibitors.

First claim

We claim:

1. A compound of the formula (I)

wherein
A is selected from the group consisting of:

and a benzene ring;
R 1 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 6 -alkyl, tri-(C 1 -C 4 -alkyl)-silyl-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted M 3 -M 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, M 3 -M 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, M 3 -M 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, M 3 -M 12 -heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted M 3 -M 12 -heterocyclyl;
W is —NR 7 — or a bond;
A 1 is optionally substituted C 1 -C 4 -alkylene or a bond;
Q is —S(O) 2 — or —C(O)—;
Y is —NR 8 — or a bond;
n1 is 0, 1, 2, or 3;
n2 is 0, 1, 2, or 3;
X 1 is >N— or >CH—;
R 6 is hydrogen, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, —CN, OH C 1 -C 6 -alkoxy or halogenated C 1 -C 6 -alkoxy, or two radicals R 6 together with the carbon atom to which they are attached form a carbonyl group;
R 2 is hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, —CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -alkenylamino, nitro or optionally substituted M 3 -M 12 -heterocyclyl, or two radicals R 2 together with the ring atoms of A to which they are bound form a 5- or 6 membered ring;
A 2 is —O—;
R 3 is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;
Y 1 is a bond or optionally substituted C 1 -C 4 -alkylene;
R 4a is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, —CH 2 CN, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 6 -C 12 -arylsulfonyl, amino, —NO or optionally substituted M 3 -M 12 -heterocyclyl; or
R 4b is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, —CH 2 CN, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 6 -C 12 -arylsulfonyl, amino, —NO or M 3 -M 12 -heterocyclyl; or
R 4a , R 4b
together are optionally substituted C 2 -C 6 -alkylene, wherein one —CH 2 — of C 2 -C 6 -alkylene may be replaced by an oxygen atom or —NR 10 ;

X 2 is —O—, —NR 11a —, —S—, >CR 12a R 12b or a bond;
X 3 is —O—, —NR 11b —, —S—, >CR 13a R 13b or a bond;
R 5 is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl or optionally substituted M 3 -M 12 -heterocyclyl;
R 7 is hydrogen or C 1 -C 6 -alkyl;
R 8 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl, amino-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl or M 3 -M 12 -heterocyclyl; or
R 8 , R 1
together are C 1 -C 4 -alkylene;

R 10 is hydrogen or C 1 -C 6 -alkyl;
R 11a is hydrogen or C 1 -C 6 -alkyl;
R 11b is hydrogen or C 1 -C 6 -alkyl;
R 12a is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, M 3 -M 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;
R 12b is hydrogen or C 1 -C 6 -alkyl, or
R 12a , R 12b
together with the carbon atom to which they are attached form a carbonyl or are optionally substituted C 2 -C 4 -alkylene, wherein one —CH 2 — of C 2 -C 4 -alkylene may be replaced by an oxygen atom or —NR 14 —;

R 13a is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, M 3 -M 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;
R 13b is hydrogen or C 1 -C 6 -alkyl, or
R 13a , R 13b
together with the carbon atom to which they are attached form a carbonyl or are optionally substituted C 2 -C 4 -alkylene, wherein one —CH 2 — of C 2 -C 4 -alkylene may be replaced by an oxygen atom or —NR 15 —;

R 14 is hydrogen or C 1 -C 6 -alkyl; and
R 15 is hydrogen or C 1 -C 6 -alkyl,
or a physiologically tolerated salt thereof wherein at least one of n1 and n2 is 1, 2 or 3.

2. The compound of claim 1 , wherein A is a benzene ring or a ring selected from the group consisting of:

3. The compound of claim 1 , wherein R 1 is C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, or C 3 -C 12 -cycloalkyl.

4. The compound of claim 1 , wherein W is a bond and A 1 is a bond.

5. The compound of claim 1 , wherein Q is —S(O) 2 —.

6. The compound of claim 1 , wherein the sum of n1+n2 is 2, 3, or 4.

7.

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Amberg Wilhelm
• Pohlki Frauke
• Lange Udo
• Wang Ying
• Brewer Jason
• Vasudevan Anil
• Lao Yanbin
• Hutchins Charles
• Zhao Hongyu
• Li Huan-Qiu

Classifications

• A61P43/00

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

• A61P25/22

  Anxiolytics · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P25/04

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

• A61P25/18

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