Neuropeptide Y Y5 receptor antagonists

• US 6,667,319 B2
• Filed: 07/24/2002
• Issued: 12/23/2003
• Est. Priority Date: 07/26/2001
• Status: Expired due to Fees

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering-Plough Corporation (Merck & Co., Inc.)
• Inventors: Li, Guoqing, Huang, Ying, Stamford, Andrew W.
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US10/202,239
• Publication Number:
  US 20030207860A1
• Time in Patent Office: 517 Days
• Field of Search: 546/224, 514/329, 514/330, 514/426, 514/212, 514/210, 540/605, 548/557, 548/950
• US Class Current: 514/329
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/96 Sulfur atom
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention discloses compounds which, are novel receptor antagonists for NPY Y5 as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such NPY Y5 receptor antagonists as well as methods of using them to treat obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes.

Claims

1. A compound represented by the structural formula

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is C;

Z is independently NR⁸ or CR³R⁹;

D is independently H, —

OH, -alkyl or substituted -alkyl;

E is independently H, -alkyl or substituted -alkyl, or D and E can independently be joined together via a —

(CH₂)_p—

bridge;

Q is independently H, -alkyl or substituted -alkyl;

g, j, k, m and n can be the same or different and are independently selected;

g is 0 to 3 and when g is 0, the carbons to which (CH₂)_g is shown connected are no more linked;

j and k are independently 0 to 3 such that the sum of j and k is 0, 1, 2 or 3;

m and n are independently 0 to 3 such that the sum of m and n is 1, 2,3, 4 or 5;

p is 1 to 3;

R¹ is 1 to 5 substituents which can be the same or different, each R¹ being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —

NR⁵R⁶, —

NO₂, —

CONR⁵R⁶, —

NR⁵COR⁶, —

NR⁵CONR⁵R⁶ where the two R⁵ moieties can be the same or different, —

NR⁶C(O)OR⁷, —

C(O)OR⁶, —

SOR⁷, —

SO₂R⁷, —

SO₂NR⁵R⁶, aryl and heteroaryl;

R² is 1 to 6 substituents which can be the same or different, each R² being independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy;

R³ is independently hydrogen, -alkyl or substituted -alkyl;

R⁴ is 1 to 6 substituents which can be the same or different, each R⁴ being independently selected from hydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy, with the proviso that when Z is NR⁸ and R⁴ is hydroxy or alkoxy, R⁴ is not directly attached to a carbon adjacent to the NR⁸;

R⁵ and R⁶ are independently hydrogen, -alkyl, substituted -alkyl or -cycloalkyl;

R⁷is independently -alkyl, substituted -alkyl or -cycloalkyl;

R⁸ is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —

SO₂R¹⁰, —

SO₂NR⁵R¹¹, —

C(O)R¹¹, —

C(O)NR⁵R¹¹ and —

C(O)OR¹⁰;

R⁹ is independently hydrogen, -alkyl, substituted -alkyl, hydroxy, alkoxy, —

NR⁵R¹¹, aryl, or heteroaryl;

or R³ and R⁹ can be joined together and with the carbon to which they are attached form a carbocyclic or heterocyclic ring having 3 to 7 ring atoms;

R¹⁰ is -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl or heteroaryl; and

R¹¹ is independently hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, aryl or heteroaryl.

2. A compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt or solvent of said compound.

3. A compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt or solvate of said compound.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

8. A method of treating a metabolic disorder, eating disorder or diabetes comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.

9. 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 or a pharmaceutically acceptable salt of said compound.

10. The method of claim 8 wherein said metabolic disorder is obesity.

11. The method of claim 8 wherein said eating disorder is hyperphagia.

12. 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.

13. The method of claim 12 wherein said disorders associated with obesity are Type II Diabetes, insulin resistance, hyperlipidemia and hypertension.

14. 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 such as a 3 agonist, a thryomimetic agent, an anorectic agent or an NPY antagonist; and

a pharmaceutically acceptable carrier thereof.

15. A method of treating a metabolic or 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 such as a β

₃ agonist, a thryomimetic agent, an anorectic agent or an NPY antagonist;

wherein the amounts of the first and second compounds result in a therapeutic effect.

16. 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 (including orally bioavailable insulin preparations), 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.

4. A compound represented by the structural formula

or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹ is 1 to 5 substituents which can be the same or different, each R¹ being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —

NR⁵R⁶, —

NO₂, —

CONR⁵R⁶, —

NR⁵COR⁶, —

NR⁵CONR⁵R⁶ where the two R⁵ moieties can be the same or different, —

NR⁶C(O)OR⁷, —

C(O)OR⁶, —

SOR⁷, —

SO₂R⁷, —

SO₂NR⁵R⁶, aryl and heteroaryl;

R³ is independently hydrogen or -alkyl; and

R⁸ is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —

SO₂R¹⁰, —

SO₂NR⁵R¹¹, —

C(O)R¹¹, —

C(O)NR⁵R¹¹ and —

C(O)OR¹⁰.

5. A compound of claim 4 selected from the group consisting of

or a pharmaceutically acceptable salt or solvate of said compound.

6. A compound represented by the structural formula

or a pharmaceutically acceptable salt or solvate there of, wherein

R¹ is 1 to 5 substituents which can be the same or different, each R¹ being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —

NR⁵R⁶, —

NO₂, —

CONR⁵R⁶, —

NR⁵COR⁶, —

NR⁵CONR⁵R⁶ where the two R⁵ moieties can be the same or different, —

NR⁶C(O)OR⁷, —

C(O)OR⁶, —

SOR⁷, —

SO₂R⁷, —

SO₂NR⁵R⁶, aryl and heteroaryl;

R³ is independently hydrogen or -alkyl; and

R⁸ is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —

SO₂R¹¹, —

SO₂NR⁵R¹¹, —

C(O)R¹, —

C(O)NR⁵R¹¹ and —

C(O)OR¹⁰.