N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists

• US 7,153,868 B2
• Filed: 04/16/2003
• Issued: 12/26/2006
• Est. Priority Date: 04/18/2002
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Inventors: Szekeres, Helen Jane, Chambers, Mark Stuart, Jones, Philip
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US10/417,360
• Publication Number:
  US 20040002504A1
• Time in Patent Office: 1,350 Days
• Field of Search: 514/255, 514/256, 514/319, 514/320, 514/324, 514/326, 546/192, 546/195, 546/196, 546/205, 546/207, 546/212, 544/333, 544/336
• US Class Current: 514/326
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• 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 provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I:

wherein, generally,

• • Q is

• • R¹ is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C_1-4alkyl or halogen, such as methyl, fluorine or bromine;
  • R² is hydrogen or C_1-4alkyl such as methyl;
  • R³ is phenyl;
  • R⁴ is hydrogen;
  • R⁵ is hydrogen or C_1-6alkylcarbonyl such as methylcarbonyl;
  • X is —SO₂— or —C(O)N(R²)SO₂— where R² is preferably hydrogen;
  • Y is a bond, CH₂ or Z¹ where Z¹ is —N(R^f)— in which R^f is C_1-6alkylcarbonyl such as ethylcarbonyl; and
  • R⁶ is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C_1-6alkyl and benzyl, such as methyl, ethyl and benzyl;
  • or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of the formula I:

2. The compound of claim 1 wherein R⁶ is 1,3-dimethylpyrazol-5-yl or 1-ethyl-3-benzylpyrazol-5yl.

3. The compound of claim 1 wherein Y is a single bond.

4. The compound of claim 1 wherein X is —

C(═

O)N(R²)SO₂—

where R² is hydrogen.

5. The compound of claim 1 wherein R¹ is phenyl or thiophen-2-yl.

8. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable excipient.

10. A method of treatment of schizophrenia in a human patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. A compound which is selected from the group consisting of:

N-{3-[4-(2-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}-benzenesulfonamide;

(R)-N-{3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}-N-methylbenzenesulfonamide;

N-{1-(4-chlorophenyl)-3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]propyl}-N-methylbenzenesulfonamide;

4-bromo-N-{3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

3-bromo-N-{3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenyipropyl}benzenesulfonamide;

N-{3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}-4-fluorobenzenesulfonamide;

N-{3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}-N-phenylmethanesulfonamide;

1-methyl-1H-imidazole-4-sulfonic acid {3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-piperidin-1-yl]-1-phenylpropyl}amide;

5-bromothiophene-2-sulfonic acid {3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}amide;

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising an effective amount of the compound of claim 6 and a pharmaceutically acceptable excipient.

11. A method of treatment of schizophrenia in a human patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 6 or a pharmaceutically acceptable salt thereof.

7. A compound which is:

(R)-N-{3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-1-phenylpropyl}-N-methylbenzenesulfonamide;

or a pharmaceutically acceptable salt thereof.