Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists

1. A compound of the formula:

wherein

Y is bond or lower alkylene,

R 1 is aryl which may have substituent(s),

R 2 is aryl or indolyl, each of which may have substituent(s),

R 3 is hydrogen or lower alkyl,

R 4 is pyridyl(lower)alkylamino(lower)alkynyl;

N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino-(lower)alkyl;

hydroxy(lower)alkoxy(lower)alkyl;

lower alkanoyl(lower)alkoxy(lower)alkyl;

phenyl(lower)alkyl which has hydroxy(lower)alkyl or morpholinyl(lower)alkyl;

ar(lower)alkoxycarbonyl;

(2-pyridyl) (lower)alkyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;

(3-pyridyl)propyl which may have lower alkoxy or amino;

(3-pyridyl)butyl which may have lower alkoxy or amino;

pyridyl(lower)alkenyl which may have lower alkoxy or amino;

(2-pyridyl) (lower)alkynyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;

(3-pyridyl) (lower) alkynyl which may have lower alkoxy or amino;

pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituent(s);

imidazolyl(lower)alkyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

pyrazolyl(lower)alkyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl;

thiazolyl(lower)alkyl which may have lower alkyl;

piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy;

morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;

morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl;

(3,5-dimethylmorpholino)(lower)alkyl;

morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl;

(2- or 3-morpholinyl) (lower)alkenyl which may have lower alkoxycarbonyl;

pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;

morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl;

morpholinyl(lower)alkynyl which has methyl and lower alkoxy;

(dimethylmorpholino)(lower)alkynyl;

homomorpholinyl(lower)alkynyl which have halogen;

(morpholinylamino)propyl which may have lower alkanoyl;

thiomorpholinyl(lower)alkynyl which may have substituent(s);

homomorpholinylamino(lower)alkyl;

thiomorpholinylamino(lower)alkyl; or

saturated heterocyclicimino(lower)alkyl, saturated heterocyclicaminocarbonyl(lower)alkyl or saturated heterocyclic(lower)alkoxy(lower)alkyl, each of which may have substituent(s),

provided that when

R 4 is 2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl,

3-(3-pyridyl)propyl,

3-(3-pyridyl)-2-propynyl,

4-[(2-methoxymethyl)pyrrolidino]-2-butynyl,

4-thiomorpholino-2-butynyl,

3-(morphlinoamino)propyl,

4-morpholino-2-butenyl,

4-morpholino-2-butynyl, or

4-(3,3-dimethylmorpholino)-2-butynyl, then

R 1 is not 3,5-bis(trifluoromethyl)phenyl,

and a salt thereof.

2. The compound of claim 1 , in which

Y is lower alkylene,

R 1 is C 6 -C 10 aryl which may have 1 or 2 substituent(s) selected from the group consisting of mono(or di or tri)halo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro,

R 2 is C 6 -C 10 aryl or indolyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino,

R 3 is hydrogen, and

R 4 is pyridyl(lower)alkylamino(lower)alkynyl;

(2-pyridyl)propyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;

pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, ar(lower)alkyl and pyridyl(lower)alkyl;

imidazolyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

(2-methyl-1H-imidazol-4-yl) (lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of isopropyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

(5-methyl-1H-imidazol-4-yl) (lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of isopropyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy;

morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;

morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl;

(3,5-dimethylmorpholino) (lower)alkyl;

morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl;

(2- or 3-morpholinyl) (lower)alkenyl which may have lower alkoxycarbonyl;

pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;

morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl;

morpholinyl(lower)alkynyl which has methyl and lower alkoxy(lower)alkyl;

(dimethylmorpholino) (lower)alkynyl; or

homomorpholinyl(lower)alkynyl which may have halogen.

3. The compound of claim 2 , in which

Y is lower alkylene,

R 1 is phenyl which has 1 -or 2 substituent(s) selected from the group consisting of trihalo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro,

R 2 is phenyl or indolyl, each of which have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, trihalo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino,

R 3 is hydrogen, and

R 4 is (2-pyridyl)propyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen;

morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;

morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl.

4. A compound of claim 3 , which is selected from the group consisting of

(1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-ethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine,

(2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((2S)-2-methoxymethylmorpholino)ethyl]piperazine,

(3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R)-3-methoxymethylmorpholino)ethyl]piperazine,

(4) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl[-2-(3,4-dimethylbenzyl)-4-[2-((2R)-2-methoxymethylmorpholino)ethyl]piperazine,

(5) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-((2S)-2-methoxymethylmorpholino)ethyl]piperazine, and

(6) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-((3R)-3-ethylmorpholino)ethyl]-2-[(1H-indol-3-yl)-methyl]piperazine

or a pharmaceutically acceptable salt thereof.

5. A process for the preparation-of the compound of claim 1 or a salt thereof, which comprises,

(1) reacting a compound of the formula (II):

wherein R 1 , R 2 , R 3 and Y are each as defined in claim 1 , or a salt thereof, with a compound of the formula (III):

W 1 —R 4   (IV)

wherein R 4 is as defined in claim 1 and

W 1 is a leaving group,

or a salt thereof to give a compound of the formula (I):

wherein R 1 , R 2 , R 3 , R 4 and Y are each as defined in claim 1 , or a salt thereof,

(2) subjecting a compound of the formula (Ia):

wherein R 1 , R 2 , R 3 and Y are each as defined above,

R 5 is 2-pyridyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen; or 3-pyridyl which may have lower alkoxy or amino, and

Z 1 is lower alkynylene,

or a salt thereof to a reduction reaction to give a compound of the formula (Ib):

wherein R 1 , R 2 , R 3 , Y and R 5 are each as defined above, and

X 1 is lower alkylene,

or a salt thereof,

(3) reacting a compound of the formula (III):

wherein R 1 , R 2 , R 3 and Y are each as defined above, and

X 2 is lower alkylene,

or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula (V):

H 2 N—R 6   (V)

wherein R 6 is saturated heterocyclic which may have substituent(s),

or a salt thereof to give a compound (Ic):

wherein R 1 , R 2 , R 3 , R 6 , X 2 and Y are each as defined above,

(4) reacting a compound of the formula (VI):

wherein R 1 , R 2 , R 3 and Y are each as defined above,

X 3 is lower alkylene and

W 2 is a leaving group,

or a salt thereof with a compound of the formula (VII):

H—R 7   (VII)

wherein R 7 is pyridyl(lower)alkylamino;

N-(lower alkyl)-N-[pyridyl(lower)alkyl]-amino;

1-imidazolyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

1-pyrazolyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl;

piperidino which may have hydroxy(lower)alkyl or lower alkoxy;

morpholino which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;

morpholino which has lower alkyl and lower alkoxy(lower)alkyl;

3,5-dimethylmorpholino;

morpholinylamino which may have lower alkanoyl;

homomorpholinylamino; or

thiomorpholinylamino,

or a salt thereof to give a compound of the formula (Id):

wherein R 1 , R 2 , R 3 , R 7 , X 3 and Y are each as defined above,

or a salt thereof,

(5) reacting a compound of the formula (VIII):

wherein R 1 , R 2 , R 3 and Y are each as defined above,

Z 2 is lower alkenylene, and

W 3 is a leaving group,

or a salt thereof with a compound of the formula (IX):

H—R 8   (IX)

wherein R 8 is morpholino which may have lower alkyl or lower alkoxy(lower)alkyl,

or a salt thereof to give a compound of the formula (Ie):

wherein R 1 , R 2 , R 3 , R 8 , Y and Z 2 are as defined as above,

or a salt thereof,

(6) reacting compound of the formula (X):

wherein R 1 , R 2 , R 3 and Y are each as defined above,

Z 3 is a lower alkynylene and

W 4 is a leaving group,

or a salt thereof with a compound of the formula (XI):

H—R 9   (XI)

wherein R 9 is pyrrolidino which may have lower alkoxy(lower) alkyl;

morpholino which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl;

morpholino which has methyl and lower alkoxy;

dimethylmorpholino; or

homomorpholino which has halogen,

or a salt thereof to give a compound of the formula (If):

wherein R 1 , R 2 , R 3 , R 9 , Y and Z 3 are each as defined above,

or a salt thereof.

6. 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.

7. A method for treating Tachykinin-mediated diseases which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animals.