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

• US 20040002504A1
• Filed: 04/16/2003
• Published: 01/01/2004
• Est. Priority Date: 04/18/2002
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Inventors: Chambers, Mark Stuart, Jones, Philip, Szekeres, Helen Jane
• Granted Patent: US 7,153,868 B2
• Time in Patent Office: Days
• US Class Current: 514/255.05
• 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 method of treatment of a subject suffering from a disease 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):

2. A method according to claim 1 where the disease treated is selected from CNS disorders such as anxiety, psychosis, depression, Huntington'"'"'s Disease, epilepsy, schizophrenia, panic, movement and convulsive disorders and Parkinson'"'"'s disease.

3. A method according to claim 1 wherein the compound:

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.

4. A method according to claim 3 in which X is SO₂.

5. A method according to claim 1 where the compound is chosen from:

N-{3-[4-(1,3-dimethyl-1H-pyrazol-5-yl)-1-piperidinyl]-1-phenylpropyl}benzenesulfonamide;

N-{3-[4-(1,3-dimethyl-1H-pyrazol-5-yl)-1-piperidinyl]-1-phenylpropyl}-2-thiophenesulfonamide;

N-{3-[4-(1,3-dimethyl-1H-pyrazol-5-yl)-1-piperidinyl]-1-phenylpropyl}-N-methyl-2-thiophenesulfonamide;

N-{1-phenyl-3-[4-(phenylmethyl)-1-piperidinyl]propyl}benzenesulfonamide;

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

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

N-{(1S)-3-[4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl]-1-phenylpropyl}thiophene-2-sulfonamide, bis trifluoroacetate salt;

4-(3-benzyl-1-ethyl-1H-pyrazol-1-ium-5-yl)-1-[(3S)-3-phenyl-3-({[(phenylsulfonyl)amino]carbonyl}amino)propyl]piperidinium bis(trifluoroacetate);

N-{1-[3-(benzenesulfonylmethylamino)-3-phenylpropyl]piperidin-4-yl}-N-phenylpropionamide;

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}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 hydrochloride;

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

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

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

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 hydrochloride;

N-{3-[4-(pyrimidin-3-yl)piperidin-1-yl]-1-phenylpropyl}-4-methylbenzenesulfonamide;

N-{3-[4-(pyridin-3-yl)piperidin-1-yl]-1-phenylpropyl}-4-methylbenzenesulfonamide;

N-methyl-N-{3-[4-(1,3-dimethylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzesulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

(S)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

(S)-N-methyl-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

N-{3-[4-(benzimidazolon-1-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

N-[3-(4-methylcarbonyl-4-phenyl)piperidin-1-phenylpropyl]benzenesulfonamide;

(R)-N-{3-[4-(1-ethyl-3-benzylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}thiophen-2-ylsulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}-2-fluorophenylsulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}-3-fluorophenylsulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}-4-fluorophenylsulfonamide; and

N-methyl-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

and the pharmaceutically acceptable salts thereof.

6. A compound of formula I:

7. A compound according to claim 6 which is chosen from:

N-{1-[3-(benzenesulfonylmethylamino)-3-phenylpropyl]piperidin-4-yl}-N-phenylpropionamide;

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}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 hydrochloride;

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

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

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

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 hydrochloride;

N-{3-[4-(pyrimidin-3-yl)piperidin-1-yl]-1-phenylpropyl}-4-methylbenzenesulfonamide;

N-{3-[4-(pyridin-3-yl)piperidin-1-yl]-1-phenylpropyl}-4-methylbenzenesulfonamide;

N-methyl-N-{3-[4-(1,3-dimethylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzesulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

(S)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

(S)-N-methyl-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

N-{3-[4-(benzimidazolon-1-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

N-[3-(4-methylcarbonyl-4-phenyl)piperidin-1-phenylpropyl]benzenesulfonamide;

(R)-N-{3-[4-(1-ethyl-3-benzylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}thiophen-2-ylsulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}-2-fluorophenylsulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}-3-fluorophenyl sulfonamide;

(R)-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}-4-fluorophenylsulfonamide; and

N-methyl-N-{3-[4-(1-ethyl-3-methylpyrazin-5-yl)piperidin-1-yl]-1-phenylpropyl}benzenesulfonamide;

and the pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a compound as defined in claim 6 and a pharmaceutically acceptable excipient.