Quinoline compounds suitable for treating disorders that respond to the modulation of the serotonin 5-HT6 receptor

Patent metadata

Field	Value
Publication number	US-10160744-B2
Application number	US-201715458534-A
Country	US
Kind code	B2
Filing date	Mar 14, 2017
Priority date	Mar 14, 2016
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

The present invention relates to quinoline compounds of formula I

wherein the variables are defined as in the claims and the description. The invention further relates to a pharmaceutical composition containing such compounds, to their use as modulators of the 5-HT 6 receptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of the 5-HT 6 receptor, and to methods for preventing or treating conditions and disorders which respond to the modulation of the 5-HT 6 receptor.

First claim

We claim:

1. A compound of formula (I)

wherein
R 1 is selected from the group consisting of a ring R a and halogen;
R 2 is a phenyl ring, which may carry one ring R a and/or one or two substituents R 5 ;
with the proviso that R 1 is R a if the ring R 2 is not substituted by R a ;

each R 4 is independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl;
each R 5 is independently selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, aminocarbonyl; and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, S(O) and S(O) 2 as ring members, where the heterocyclic ring may carry one or more substituents R 7 ;
each R 7 is independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl;
R 8 and R 9 , independently of each other and independently of each occurrence, are hydrogen;

L is S(O) 2
R a is an N-bound saturated 4-, 5-, or 6-membered heteromonocyclic ring containing one nitrogen atom as ring member, where the heteromonocyclic ring carries 1 or 2 substituents R b and optionally 1 further substituent R 4 ; and
R b is an oxygen-containing radical independently selected from the group consisting of hydroxyl, C 1 -C 4 -alkoxy, —C(O)OH, —CH 2 —C(O)OH and —C(O)N(R 8 )R 9 ;
or an N-oxide, tautomer, or stereoisomer thereof; or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1 , where R 1 is R a .

3. The compound as claimed in claim 1 , where R 1 is halogen; and the phenyl ring R 2 carries one substituent R a and optionally also one or two substituents R 5 .

4. The compound as claimed in claim 1 , where the oxygen-containing radical R b is selected from the group consisting of hydroxyl (—OH), carboxyl (—C(O)OH), —CH 2 —C(O)OH and —C(O)NH 2 .

5. The compound as claimed claim 4 , where the oxygen-containing radical R b is selected from the group consisting of —OH, —C(O)OH and —C(O)NH 2 .

6. The compound as claimed in claim 1 , where
R 1 is R a , where R a is an N-bound saturated heterocyclic ring selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl, where the ring carries one or two substituents R b ; and carries optionally one or two substituents R 4 ; and
R 2 is phenyl which may be substituted by 1 or 2 substituents selected from the group consisting of halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, COOH, CONH 2 and an N-bound saturated heterocyclic ring selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl and piperazin-1-yl, where the heterocyclic ring carries one or two substituents selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, OH and COOH.

7. A compound selected from the group consisting of
1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-4-ol;
1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-pyrrolidin-3-ol;
1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-4-carboxylic acid;
(S)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol;
(R)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol;
1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylic acid;
4-Methyl-1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol;
1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidin-3-ol;
1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-4-ol;
1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]azetidin-3-ol;
(3S)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylic acid;
(3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylic acid;
1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol;
1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol;
1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-[[8-(4-Hydroxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidin-4-ol;
1-[3-[[8-(4-Carboxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidine-4-carboxylic acid;
1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-4-ol;
(3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidin-3-ol;
(3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol;
1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol;
(3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol;
(3R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-01;
1-[3-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol;
1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol;
(3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol,
(3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol;
1-[3-(2-Hydroxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol;
1-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol;
(3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidin-3-ol;
1-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
(3 S,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;
(3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol;
(3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol;
1-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol;
(3R,5S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,5-diol;
1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-4-carboxylic acid;
1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]azetidin-3-ol;
1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol;
1-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]azetidin-3-ol;
(3 S,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol;
(3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;
(3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]-3-fluoro-piperidin-4-ol;
1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidine-3-carboxylic acid;
(3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;
1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylic acid amide;
1-[3-(3-Cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-(3-Carbamoylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-(3-Carboxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-(m-Tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-[3-(Trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-(3-Pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-[3-(3-Methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-(3-Piperazin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
1-[3-[3-(4-Methylpiperazin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;
2-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]acetic acid; and
2-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-3-piperidyl]acetic acid;

or an N-oxide, tautomer, stereoisomer, or stereoisomeric mixture thereof; or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound as claimed in claim 1 or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier and

Assignees

• Abbvie Deutschland

Inventors

• Geneste Hervé
• Haupt Andreas
• Pohlki Frauke
• Relo Ana Lucia
• Unger Liliane
• Wicke Karsten

Classifications

• A61P25/30

  for treating abuse or dependence · 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

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title