Aminoalcohol derivatives as beta-3 adrenergic receptor agonists

1 . A compound of the formula [I]:

wherein

R 1 and R 5 are each independently hydrogen, halogen, lower alkyl, mono(or di or tri)halo(lower)alkyl or cyano,

R 2 is hydrogen or an amino protective group,

X is bond, —O—, —O—CH 2 —,

—(CH 2 ) q — (in which q is 1 to 3),

—CH═CH—, —C≡C—, —NH—, —S— or —SO 2 —,

Y is

in which Z is bond, —O—(CH 2 ) m — (in which m is 1 to 4), lower alkylene or lower alkenylene,

R 3 is lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl, (lower alkylsulfonyl)carbamoyl, (phenylsulfonyl)carbamoyl, (benzylsulfonyl)carbamoyl or tetrazolyl, and

R 4 is hydrogen, halogen, hydroxy, phenoxy, lower alkyl, lower alkoxy, cyclo(lower)alkyloxy, 3,4,5,6-tetrahydro-2H-pyranyloxy, phenoxy, nitro, cyano or

 in which

R 6 is hydrogen or lower alkyl, and

R 7 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, benzyloxycarbonyl, benzoyl, furoyl, lower alkylcarbamoyl, phenylcarbamoyl, lower alkylsulfonyl, 3,4,5,6-tetrahydro-2H-pyranyl or phenyl, or

R 6 and R 7 are combined to form pyrrolidino or piperidino together with the nitrogen atom which may be substituted with oxo, and

n is 0, 1 or 2,

or a salt thereof.

2 . A compound of claim 1 , wherein

R 1 is hydrogen or halogen,

R 2 is hydrogen,

X is bond, —O—, —O—CH 2 —,

(CH 2 ) q — (in which q is 1 or 2),

—CH═CH—, —C≡C—, —NH—, —S— or —SO 2 —,

Y is

in which Z is bond, —O—(CH 2 ) m — (in which m is 1 to 4), lower alkylene or lower alkenylene,

R 3 is lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl, (lower alkylsulfonyl)carbamoyl, (phenylsulfonyl)carbamoyl, (benzylsulfonyl)carbamoyl or tetrazolyl, and

R 4 is hydrogen, halogen, hydroxy, phenoxy, lower alkyl, lower alkoxy, cyclo(lower)alkyloxy, 3,4,5,6-tetrahydro-2H-pyranyloxy, phenoxy, nitro, cyano or

 in which

R 6 is hydrogen or lower alkyl, and

R 7 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, benzyloxycarbonyl, benzoyl furoyl, lower alkylcarbamoyl, phenylcarbamoyl, lower alkylsulfonyl, 3,4,5,6-tetrahydro-2H-pyranyl or phenyl, or

R 6 and R 7 are combined to form pyrrolidino or piperidino together with the nitrogen atom which may be substituted with oxo, and

n is 0, 1 or 2.

3 . A compound of claim 2 , wherein

R 1 is halogen,

R 5 is hydrogen,

R 2 is hydrogen,

X is bond, —O— or —O—CH 2 —,

Y is

in which Z is bond, —O—(CH 2 ) m — (in which m is 1 or 2) or lower alkenylene,

R 3 is lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl or tetrazolyl, and

R 4 is hydrogen or lower alkoxy, and

n is 1 or 2.

4 . A compound of claim 3 , wherein

R 1 is chloro,

X is bond or —O—,

Y is

in which Z is bond or lower alkenylene,

R 3 is carboxy, and

R 4 is hydrogen or lower alkoxy, and

n is 1.

5 . A compound of claim 4 , which is

(1) 3-[[(7S)-7-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]benzoic acid;

(2) 2-[[(7S)-7-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]nicotinic acid;

(3) 3-[2-[[(7S)-7-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-5,6,7,8-tetrahydro-2-naphthalenyl]-oxy]-3-pyridyl]-2-propenoic acid;

(4) 3-[6-[[(7S)-7-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-5,6,7,8-tetrahydro-2-naphthalenyl]-oxy]-3-pyridyl]-2-propenoic acid;

(5) 4-[(7S)-7-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-amino]-5,6,7,8-tetrahydro-2-naphthalenyl]benzoic acid;

(6) 4-[(7S)-7-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-amino]-5,6,7,8-tetrahydro-2-naphthalenyl]-2-methoxybenzoic acid; or

(7) 5-[[(7S)-7-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]-2-methoxybenzoic acid,

or a salt thereof.

6 . A process for preparing a compound of claim 1 ,

or a salt thereof,

which comprises,

(i) reacting a compound [II] of the formula:

wherein

 R 1 and R 5 are each as defined in claim 1 , with a compound [III] of the formula:

wherein R 2 , X, Y and n are each as defined in claim 1 , or a salt thereof, to give a compound [I] of the formula:

wherein

 R 1 , R 5 , R 2 , X, Y and n are each as defined in claim 1 ,

or a salt thereof,

(ii) subjecting a compound [Ia] of the formula

Wherein

 R 1 , R 5 , X, Y and n are each as defined in claim 1 , and

R a 2 is an amino protective group,

or a salt thereof, to elimination reaction of the amino protective group, to give a compound [Ib] of the formula:

wherein

 R 1 , R 5 , X and Y are each as defined in claim 1 ,

or a salt thereof,

(iii) reacting a compound [IV] of the formula:

wherein

 R 1 , R 5 , R 2 and n are each as defined in claim 1 ,

or a salt thereof, with a compound [V] of the formula:

(HO) 2 B—Y  [V]

wherein Y is as defined in claim 1 ,

or a salt thereof, to give a compound [Ic] of the formula:

wherein

 R 1 , R 5 , R 2 , Y and n are each as defined in claim 1 ,

or a salt thereof,

(iv) reacting a compound [IV] of the formula:

wherein

 R 1 , R 5 , R 2 and n are each as defined in claim 1 ,

or a salt thereof, with a compound [VI] of the formula:

X 1 —Y  [VI]

wherein Y is as defined in claim 1 , and

X 1 is a leaving group,

or a salt thereof, to give a compound [IC] of the formula:

wherein

 R 1 , R 5 , R 2 , Y and n are each as defined in claim 1 ,

or a salt thereof, and

(v) reacting a compound [VII] of the formula:

wherein

 R 1 , R 5 , R 2 and n are each as defined in claim 1 ,

X 2 is a leaving group,

or a salt thereof, with a compound [V] of the formula:

(HO) 2 B—Y  [V]

wherein Y is as defined in claim 1 ,

or a salt thereof, to give a compound [Id] of the formula:

wherein

 R 1 , R 1 , R 5 , R 2 Y and n are each as defined in claim 1 ,

or a salt thereof.

7 . A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients.

8 . Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

9 . A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

10 . A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as selective β 3 adrenergic receptor agonists.

11 . A method for the prophylactic and/or the therapeutic treatment of pollakiuria, urinary incontinence, obesity or diabetes, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.