Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists

• US 6,048,900 A
• Filed: 02/13/1998
• Issued: 04/11/2000
• Est. Priority Date: 02/13/1998
• Status: Expired due to Fees

• Current Assignee: Bayer Pharmaceuticals Corporation (Bayer AG)
• Original Assignee: Bayer Corporation (Bayer AG)
• Inventors: Ladouceur, Gaetan H., Connell, Richard D., Lease, Timothy G., Osterhout, Martin H.
• Primary Examiner(s): Jones, Dwayne C.
• Application Number:
  US09/023,498
• Time in Patent Office: 788 Days
• Field of Search: 514/663, 514/665, 514/670
• US Class Current: 514/663
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients

Abstract

Amide derivatives and methods of administering the compositions to mammals to treat disorders such as obesity that are mediated by NPY and especially those mediated by NPY via the Y5 receptor.

Claims

1. A method for treating mammalian disorders mediated by the NPY Y5 receptor comprising administering to the mammal a therapeutically effective amount of at least one compound having the formula:

##STR11## or pharmaceutically acceptable salts thereof wherein R₁ -R₅ are each individually selected from the group of substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, and cyano.

2. The method according to claim 1 wherein R¹ is cyclohexyl;

benzoyl;

phenyl;

phenyl substituted at least once with a lower alkyl that is in turn substituted at least once with a substituent selected from cycloalkyl, alkoxy, furan, oxo, phenyl, diisopropylamine, alkoxy, or mixtures thereof, lower alkyl, alkyl substituted at least once by oxo, phenyl, or by mixtures thereof, phenyl substituted alkene, carboxamide, carboalkoxy, methyl substituted carbophenoxy, phenyldiazo, halogen, nitro, trifluoroalkyl, amino, phenyl substituted amino, lower alkyl substituted amino, aminoacyl, sulfonylphenyl, hydroxy, alkoxy, fluoro substituted phenyl, oxazole, phenoxy, thioalkoxy, and mixtures thereof;

hydroxy or alkoxy substituted naphthyl;

1H-indazole;

fluorene;

fluorene; and

phenyl.

3. The method according to claim 1 wherein R² is selected from the group hydrogen and lower alkyl.

4. The method according to claim 1 wherein R³ and R⁴ are each individually selected from the group hydrogen, lower alkyl, and phenyl.

5. The method according to claim 1 wherein R³ and R⁴ are each individually selected from hydrogen or methyl.

6. The method according to claim 1 wherein R⁵ is pyrrolidine;

pyrrolidine substituted at least once by amino, acylamino, trifluoroacylamino, hydroxyl, carboxyl, carbobenzyloxyamino, carbomethoxyamino, carbotertbutoxyamino, alkyl substituted carbotertbutoxyamino, pyridine, lower alkyl, alkene, carboxamide, hydroxymethyl, aminoalkyl, pyrolidinemethyl, alkoxy methyl, carboxylmethyl, hydroxymethyl substituted at least once by phenyl and mixtures thereof, morpholine;

piperazine substituted at least once with benzyl, phenyl, halogen substituted phenyl, and mixtures thereof, unsubstituted piperidine;

substituted piperidine;

piperidine substituted at least once by 2-oxo-2,3-dihydrobenzimidaz-1-ol, unsubstituted lower alkyl, lower alkyl substituted at least once by aminoethylamino, iodide, ═

O, piperidine, hydroxymethyl substituted piperdine, acylamino, hydroxyl, phenyl, and mixtures thereof, cyano, halogen, cyanomethylphenyl, piperidine, pyrolidine, carboxyl, phenyl, phenyl substituted at least once by trifluoromethyl, lower alkyl, halogen, and mixtures thereof, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5dec-8-yl], hydroxyl, alkoxy, carboxyl amide having the formula CONR⁸ R⁹ wherein R⁸ and R⁹ are each individually hydrogen or lower alkyl, or R⁸ and R⁹ are united with a nitrogen atom to form a piperidine substituent, amino alkyl having the formula NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are each individually selected from lower alkyl, cycloalkyl and phenyl, a ketone having the formula--COR¹² where R¹² is phenyl substituted by halogen or alkoxy or mixtures thereof;

3,6-dihydro-2H-pyridin-1-yl;

halogen substituted phenyl substituted 3,6-dihydro-2H-pyridin-1-yl;

1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octyl-6-yl;

2-aza-bicyclo[2.2.1]hept-6-yl;

an amine having the formula NR⁶ R⁷ where R⁶ and R⁷ are the each individually selected from hydrogen, unsubstituted and substituted alkyl having from 1 to 10 carbon atoms, cycloalkyl, alkene, carboxy substituted alkene, lower alkyl substituted at least once by cyano, alkyne, cycloalkyl, hydroxyl, 2-hydroxyethoxy, pyridine, piperidine, pyrrolidine, piperazine, morpholine, methylpiperazine, 1-Methylpyrrol, phenyl, phenyl substituted at least once by alkoxy, halogen, carboxyl, phenoxy, hydroxy, nitro, iodine, and mixtures thereof, imidazole, 5-nitropyridylamino, furan, benzo[1,3]dioxol-5-yl, indole, alkoxy substituted indole, diethylamino, alkoxy, carboxy, trifluoromethyl, lower alkyl, hydroxymethyl, and mixtures thereof, benzyl, phenyl, benzo[1,2,5]thiadiazol, pyridine, 1,2,4-triazole, and 3-oxo-cyclohex-1-en.

7. The method according to claim 1 wherein the pharmaceutical result is the treatment of mammals with disorders selected from obesity and eating disorders.

8. The method according to claim 7 wherein the mammal is a human and the eating disorder is selected from the group consisting of bulimia and obesity.

9. The method according to claim 1 wherein the pharmaceutical result is the treatment of obesity related disorders.

10. The method according to claim 1 wherein the mammal is a human.

11. The method according to claim 1 wherein the therapeutically effective amount ranges from about 0.001 to about 100 mg/kg weight of the mammal.

12. The method according to claim 1 wherein the composition is administered orally in the form of a solution.

13. The method according to claim 1 wherein the composition is administered orally in the form of a tablet.