Quinoline compounds suitable for treating disorders that respond to modulation of the serotonin-5-HT 6 receptor

• US 8,440,694 B2
• Filed: 09/13/2012
• Issued: 05/14/2013
• Est. Priority Date: 08/07/2007
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Inventors: Turner, Sean Colm, Braje, Wilfried, Haupt, Andreas, Lange, Udo, Drescher, Karla, Wicke, Karsten, Unger, Liliane, Mezler, Mario, Mayrer, Matthias, Wernet, Wolfgang
• Primary Examiner(s): Andres, Janet
• Assistant Examiner(s): Rozof, Timothy R.
• Application Number:
  US13/613,344
• Publication Number:
  US 20130005703A1
• Time in Patent Office: 243 Days
• Field of Search: None
• US Class Current: 514/312
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: 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
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention relates to novel quinoline compounds of the formula (I) and to the salts thereof. The compounds possess valuable therapeutic properties and are particularly suitable, for treating diseases that respond to modulation of the serotonin 5-HT₆ receptor. In formula (I) R is a moiety of the formula (R) wherein * indicates the binding site to the quinolinyl radical and wherein A, B, X′, Y, Q, R¹, R², R³, R⁴, R⁵, m, n, p, q, R^a, R^b, X and Ar are as defined in claim 1.

Claims

1. A method for treating a cognitive dysfunction associated with Alzheimer'"'"'s disease, a cognitive dysfunction associated with schizophrenia, or obesity, said method comprising administering an effective amount of the compound of formula (I) or a physiologically tolerated acid addition salt or a N-oxide thereof to a subject in need thereof

2. The method of claim 1, wherein R¹ is hydrogen.

3. The method of claim 1, wherein X is located in the 3-position of the quinolinyl moiety.

4. The method of claim 1, wherein X is located in the 4-position of the quinolinyl moiety.

5. The method of claim 1, wherein R^x is selected from the group consisting of halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl and a group NR^x1R^x2.

6. The method of claim 1, wherein m is 0.

7. The method of claim 1, wherein n is 0.

8. The method of claim 1, where the compound of formula (I) is a compound of the formula (Ia.a)

9. The method of claim 8 where R in formula (Ia.a) is a radical of the formula R-16b,

10. The method of claim 1, where the compound of formula (I) is a compound of the formula (Ia.a)

11. The method of claim 1, where the compound of formula (I) or a physiologically tolerated acid addition salt or a N-oxide thereof is administered as a pharmaceutical composition comprising the compound of formula (I) or a physiologically tolerated acid addition salt or a N-oxide thereof together with at least one physiologically acceptable carrier or auxiliary substance.

12. The method of claim 1, wherein R^x is selected from the group consisting of halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-haloalkoxy, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl and a group NR^x1R^x2.

13. The method of claim 1, wherein the compound of formula (I), or a physiologically tolerated acid addition salt or a N-oxide thereof, is selected from the group consisting of:

8-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(phenylsulfonyl)quinoline;

Benzyl 6-(3-(phenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate;

tert-butyl 2-(3-(phenylsulfonyl)quinolin-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;

3-(Phenylsulfonyl)-8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)quinoline;

(1R,5S)-tert-butyl 3-(3-(phenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate;

8-((1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-3-(phenylsulfonyl)quinoline;

(3aS,6aS)-ethyl 1-(3-(phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate;

tert-butyl 5-(3-(4-fluorophenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;

tert-butyl 5-(3-(phenylsulfonyl)quinolin-8-yl)octahydro-1,5-naphthyridine-1(2H)-carboxylate;

1-(3-(phenylsulfonyl)quinolin-8-yl)decahydro-1,5-naphthyridine;

tert-butyl 2-(3-(4-fluorophenylsulfonyl)quinolin-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;

8-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-3-(phenylsulfonyl)quinoline;

3-(4-fluorophenylsulfonyl)-8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)quinoline;

3-(4-fluorophenylsulfonyl)-8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoline;

tert-butyl 5-(3-(3-(trifluoromethoxy)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(3-(trifluoromethoxy)phenylsulfonyl)quinoline;

tert-butyl 5-(3-(3-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline;

tert-butyl 2-(3-(3-(trifluoromethoxy)phenylsulfonyl)quinolin-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;

8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-(trifluoromethoxy)phenylsulfonyl)quinoline;

tert-butyl 5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;

8-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline;

(3aR,6aS)-tert-butyl 5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

8-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline;

(3aS,6aS)-ethyl-1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate;

3-(3-Fluoro-benzenesulfonyl)-8-(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1-yl-quinoline;

(1S,5R)-tert-butyl 3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate;

8-(1R,5R)-3,6-Diaza-bicyclo[3.2.0]hept-3-yl-3-(3-fluoro-benzenesulfonyl)-quinoline;

3-(3-Fluoro-benzenesulfonyl)-8-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-quinoline;

3-(3-Fluoro-benzenesulfonyl)-8-(3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-quinoline;

3-(3-fluorophenylsulfonyl)-8-(tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)quinoline;

8-((1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-3-(3-fluorophenylsulfonyl)quinoline;

5-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)octahydro-1H-pyrrolo[3,4-c]pyridin-2-ium chloride;

8-(5-benzyl-1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-fluorophenylsulfonyl)quinoline;

3-(3-Fluoro-benzenesulfonyl)-8-(octahydro-pyrrolo[3,4-c]pyridin-2-yl)-quinoline;

8-((3aS,6aS)-1-benzyl hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(3-fluorophenylsulfonyl)quinoline;

3-(3-Fluoro-benzenesulfonyl)-8-((3aR,6aS)-5-methyl-hexahydropyrrolo[3,4-c]pyrrol-2-yl)-quinoline;

3-(4-fluorophenylsulfonyl)-8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoline;

3-(4-fluorophenylsulfonyl)-8-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)quinoline;

8-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)-quinoline;

8-(5-methyl-1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(phenylsulfonyl)quinoline;

2-(3-(phenylsulfonyl)quinolin-8-yl)dodecahydro-1H-pyrido[4,3-b]indole;

8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)quinoline; and

8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinolone.