US2005038100A1PendingUtilityA1
Substituted urea neuropeptide Y Y5 receptor antagonists
Priority: Sep 14, 2000Filed: Sep 1, 2004Published: Feb 17, 2005
Est. expirySep 14, 2020(expired)· nominal 20-yr term from priority
C07D 409/12C07C 275/30C07D 409/14C07D 417/04C07C 2601/14C07D 401/06C07D 401/04C07D 211/58C07C 311/07C07D 211/96
50
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Claims
Abstract
A novel class of compounds such as antagonists of the neuropeptide Y Y5 receptor, methods of making such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the neuropeptide Y Y5 receptor are disclosed.
Claims
exact text as granted — not AI-modified1 . A compound having the structural formula I:
R 1 is hydrogen or (C 1 -C 6 )alkyl;
R 2 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 9 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl;
where Z is OR 10 or —N(R 9 )(R 10 );
j is 0, 1 or 2;
k is 1 or 2;
l is 0, 1 or 2;
m is 0, 1 or 2;
p is 1, 2 or 3;
r is 1, 2 or 3;
and s is 0, 1, 2, 3, 4, 5 or 6;
R 4 is a subsituent independently selected from hydrogen, —OH, halogen, haloalkyl, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, —CN, (C 1 -C 6 )alkylO—, (C 3 -C 7 )cycloalkylO—, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylO—, (C 1 -C 6 )alkylS—, (C 3 -C 7 )cycloalkylS—, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylS—, —NR 9 R 10 , —NO 2 , —CONR 9 R 10 and —NR 2 COR 10 ;
R 5 is a substituent independently selected from hydrogen, halogen, —OH, haloalkyl, haloalkoxy, —CN, —NO 2 , (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylO—, (C 3 -C 7 )cycloalkylO—, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylO—, —CONH 2 and
—CONR 9 R 10 ;
R 6 is (C 1 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )haloalkylSO 2 —, hydroxy(C 2 -C 6 )alkyl)SO 2, —, (amino(C 2 -C 6 )alkyl)SO 2 —, alkoxy(C 2 -C 6 )alkyl)SO 2 —, alkylamino(C 2 -C 6 )alkyl)SO 2 —, dialkylamino(C 2 -C 6 )alkyl)SO 2 —, arylSO 2 —, heteroarylSO 2 —, aryl(C 2 -C 6 -alkylSO 2 —, R 9 R 10 NSO 2 —, (C 1 -C 6 )alkylC(O)—, (C 3 -C 7 )cycloalkylC(O)—, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkylC(O)—, arylC(O)—, heteroarylC(O)—, R 9 R 10 NC(O)—, —(S)CNR 9 R 10 , aryl, heteroaryl, —(CH 2 ) n C(O)NR 9 R 10 , alkylS(NCN═)C—, R 9 R 1 ON(NCN═)C—, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, or R 9 OC(O)—;
R 7 =hydrogen or alkyl;
R 8 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkylSO 2 —, (C 1 -C 6 )haloalkylSO 2 — or arylSO 2 —;
R 9 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl, acyl or heteroaryl; and,
R 10 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, aryl or heteroaryl;
or R 9 and R 10 taken together with the nitrogen atom form a 4-7 membered ring containing 1 or 2 heteroatoms selected from N, O or S with proviso that two O or S atoms are not adjacent to one another;
n=1 to 6;
or a pharmaceutically acceptable salt and/or hydrate thereof.
2 . A compound of claim 1 wherein
3 . A compound of claim 2 wherein R 5 is a substituent independently selected from hydrogen, halogen, haloalkyl, alkoxy and haloalkoxy and the sum of j and k is 1, 2 or 3.
4 . A compound of claim 2 wherein R 6 is (C 1 -C 6 )alkyl SO 2 —, hydroxy(C 2 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, R 9 R 10 NSO 2 — or NH 2 SO 2 —.
5 . A compound of claim 1 selected from
or a pharmaceutically acceptable salt and/or hydrate thereof.
6 . A compound of claim 1 , wherein th e compound is
or a pharmaceutically acceptable salt and/or hydrate thereof.
7 . A compound of claim 2 wherein R 6 is heterorarylC(O)—, (C 1 -C 6 )alkylC(O)— or (C 3 -C 7 )cycloalkyl C(O)—.
8 . A compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt and/or hydrate thereof.
9 . A compound of claim 2 wherein R 6 is heteroaryl.
10 . A compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt and/or hydrate thereof.
11 . A compound of claim 1 wherein
12 . A compound of claim 11 wherein R 5 is a substituent independently selected from hydrogen, halogen, haloalkyl and haloalkoxy, r is 1 and the sum of j and k is 1, 2 or 3.
13 . A compound of claim 11 wherein R 6 is (C 1 -C 6 )alkylSO 2 —, (C 3 -C 7 )cycloalkylSO 2 —, or —SO 2 NR 9 R 10 .
14 . A compound of the formula
or a pharmaceutically acceptable salt and/or hydrate thereof.
15 . A compound of claim 11 wherein R 6 is heteroarylC(O)—, (C 1 -C 6 )alkylC(O)— or (C 3 -C 7 )cycloalkylC(O)—.
16 . A compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt and/or hydrate thereof.
17 . A compound of claim 11 wherein R 6 is heteroaryl.
18 . A compound of claim 1 selected from the structural formulas set forth in the following table, and the pharmaceutically acceptable addition salts and/or hydrates thereof:
Y
R 1
R 2
R 3
R 4
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
2-F
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—CH 2 CONH 2
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
—H
—CH 3
—H
19 . A pharmaceutical composition comprising a compound of formula I as defined in claim 1 and a pharmaceutically acceptable carrier.
20 . A method of treating metabolic or eating disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 of said compound.
21 . The method of claim 20 wherein said metabolic disorder is obesity.
22 . The method of claim 20 wherein said eating disorder is hyperphagia.
23 . A method of treating disorders associated with obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.
24 . The method of claim 23 wherein said disorders associated with obesity are Type II Diabetes, insulin resistance, hyperlipidemia and hypertension.
25 . A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising:
a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an anti-obesity and/or anorectic agent, a thryomimetic agent or an NPY antagonist; and a pharmaceutically acceptable carrier.
26 . The pharmaceutical composition of claim 25 wherein the anorectic agent is a β 3 agonist.
27 . A method of treating a metabolic and eating disorder which comprises administering to a mammal in need of such treatment
an amount of a first compound, said first compound being a compound of claim 1 , or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an anti-obesity and/or anorectic agent, a thryomimetic agent or an NPY antagonist; wherein the amounts of the first and second compounds result in a therapeutic effect.
28 . The pharmaceutical composition of claim 27 wherein the anorectic agent is a B 3 agonist.
29 . A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising:
a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin, an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and a pharmaceutically acceptable carrier therefor.Join the waitlist — get patent alerts
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