Quinoline derivatives

1. A compound of formula (I):

wherein A, B, C, D, and T are the same or different from one another and each represents methine or nitrogen, provided that one and only one of them represents nitrogen;

the bond represented by the following formula:

- - - - -

represents a single or double bond;

Y and Z are the same or different from each other and each represents methine, nitrogen, a group represented by the following formula:

or a group represented by the following formula:

provided at least one of them represents nitrogen;

R 1 and R 2 are the same or different from each other and each represents hydrogen, halogeno, hydroxy, lower alkylsulfonylaminoalkyl, lower halogenated-alkylsulfonylaminoalkyl, 2-pyrrolidinon- 1 -yl, 1-hydroxy-1- (methoxypyridyl)methyl, methoxypyridylcarbonyl, 1,3-propanesultum-2-yl, lower hydroxypiperidyl -carbonylalkyl, lower hydroxyalkylamidoalkyl, lower halogenated-alkylamidoalkyl, lower dihalogenatedalkylamidoalkyl, lower hydroxyalkylamidoalkyl, optionally substituted amino, nitro, lower alkyl, lower alkoxy, lower acyl, lower alkoxyalkoxy, cyano, lower alkylsulfonyl, sulfonylamido, hydroxy-lower alkyl, hydroxy-lower alkoxy, lower alkoxycarbonylamino, lower alkylsulfonylamino, N-lower alkylalkylsulfonylamino, lower acylamino, optionally substituted aminoalkyl, optionally N-substituted lower acylaminoalkyl, optionally substituted aryl, optionally substituted arylsulfonylamino, lower alkylsulfonyloxy, hydroxyiminomethyl, (2-pyrrolidonl-yl) methyl, (2-piperidon-1-yl) methyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, cycloalkylcarbonylaminoalkyl, optionally substituted ureido, optionally substituted ureido-lower alkyl, succinimido, (succinimido-1-yl)-lower alkyl, amido, optionally substituted carbamoyl, optionally substituted carbamoyl-lower alkyl, optionally substituted thiocarbamoyllower alkyl, formyl, aromatic acyl, heteroarylcarbonyl, halogenated lower alkyl, (2-imidazolidinon -1-yl)methyl, (2,4-imidazolidinedion-3-yl)methyl, (2-oxazolidon3-yl) methyl, (glutarimido-1-yl)methyl, optionally substituted heteroarylhydroxyalkyl, cyano-lower alkyl, 1-hydroxy lower cycloalkyl, (2,4-thiazolidinedion-3-yl)methyl, optionally substituted 4-piperidylmethyl, heteroarylacyl, pyrrolidinylcarbonyl-lower alkyl, optionally substituted aminosulfonylalkyl, carboxy-lower alkyl, or lower alkylamidoalkyl; or alternatively optionally substituted heterocycle or alkylenedioxy, provided these rings may be substituted;

R 3 represents hydrogen, halogeno, lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy, formyl, optionally substituted aralkyloxy, hydroxy-lower alkoxy, optionally substituted sulfamoyl, or optionally N-substituted sulfamoyl-lower alkyl;

R 4 represents hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxyalkyl, optionally aryl-substituted aryloxyalkyl, or optionally aryl-substituted aralkyloxyalkyl;

R 5 represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromatic acyl, or a group represented by the following formula:

-Q 1 -(CH 2 ) s -Q 2 -R 6

wherein Q 1 and Q 2 are both single bonds, or one of them is a single bond while the other represents oxygen, carbonyl, a group represented by —NHCO—, a group represented by —NHSO 2 —, or a group represented by >CH—R 7 , wherein R 7 represents hydroxy, lower alkyl or halogeno:

s represents 0 or an integer of 1 to 6; and

R 6 represents optionally substituted aryl, optionally substituted benzoheteroaryl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzothiazolyl, or cyano;

n represents 1;

m represents 0 or an integer of 1 to 6; and

p represents an integer of 1 to 3,

or a pharmacologically acceptable salt thereof.

2. A compound of formula:

wherein R represents a substituent of the formula:

wherein the bond represented by the following formula:

- - - - -

and R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z, m, and p are each as defined in claim 1 , and pharmacologically acceptable salts thereof.

3. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein m is 0 and p is 2.

4. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein Y is methine and Z is nitrogen.

5. The compound of claim 1 or a pharmacologically acceptable salt thereof, which is a compound selected from among the following ones:

(267) 1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(268) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydro-quinoline,

(269) 1-[1-(4-cyanopropyl)piperidin-4-yl]-7-methoxy-1,2,3,4-tetrahydroquinoline,

(270) 1-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-1-7-methoxy-1,2,3,4-tetrahydroquinoline,

(271) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-dimethoxy- 1,2,3,4-tetrahydroquinoline,

(272) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-methylenedioxy-1,2,3,4-tetrahydroquinoline,

(273) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-8-methyl-1,2,3,4-tetrahydroquinoline,

(274) 1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(275) 1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,

(276) 1-{1-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline, and

(283) 5-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydroisoquiline.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or its salt in combination with a pharmaceutically acceptable carrier.

7. An agent for treating and ameliorating diseases against which serotonin antagonism is efficacious, which contains as the active ingredient the compound of claim 1 or a pharmacologically acceptable salt thereof.

8. A compound for treating and ameliorating spastic paralysis, which comprises as the active ingredient an effective amount of the compound of claim 1 or a pharmacologically acceptable salt thereof.

9. A muscle relaxant composition which contains as the active ingredient an effective amount of the compound of claim 1 or a pharmacologically acceptable salt thereof.

10. A process for producing a compound of the formula:

wherein the bond represented by the following formula:

-----

and A, B, C, D, R 1 , R 2 , R 3 , R 4 , R 5 , n, and p are each as defined in claim 1 , which comprises removing, if necessary, the protecting group from a 1,4-substituted cyclic amine derivative (IX) represented by the following formula:

wherein the bond represented by the following formula:

-----

and A, B, C, D, R 1 , R 2 , R 3 , R 4 , n, and p are each as defined in claim 1 ; and Pr.G represents hydrogen or a protecting group, and then reacting the same with L-R 5 wherein R 5 is as defined in claim 1 ; and L represents a leaving group.

11. A process for producing a compound of claim 1 , which comprises reacting a fused cyclic amine represented by the following formula:

wherein the bond represented by the following formula:

-----

and A, B, C, D, R 1 , R 2 , R 3 and n are each as defined in claim 1 with a cyclic ketone (VIII) represented by the following formula:

wherein R 4 , p, and Pr.G are each as defined in claim 1 in the presence of a reducing agent to thereby give a 1,4-substituted cyclic amine derivative (IX), removing, if necessary, the protecting group therefrom and further reacting the same with L-R 5 .

12. A compound of the formula:

wherein the bond represented by the following formula:

-----

and A, B, C, D, R 1 , R 2 , R 3 , R 4 , n, and p are each as defined in claim 1 , provided that the case where R 1 , R 2 , R 3 and R 4 are all hydrogen atoms is excluded.

13. A method for antagonizing serotonin, which comprises administering an effective dose of the compound of claim 1 , or a pharmacologically acceptable salt thereof, to a person in need of such treatment.

14. The compound of claim 1 , in which the bond represented by the following formula in the formula (I):

-----

is a single bond, represented by the formula (XXI)

or a pharmacologically acceptable salt thereof.

15. The compound of claim 1 , which m is 0 in the formula (I), represented by the formula (XXII)

or a pharmacologically acceptable salt thereof.

16. The compound of claim 1 , in which m is 1 to 6 in the formula (I) or a pharmacologically acceptable salt thereof.

17. A compound of the formula (XXIII)

or a pharmacologically acceptable salt thereof.

18. The compound of claim 1 , in which the bond represented by the following formula in the formula (I):

-----

is a double bond, represented by the formula (XXIV):

or a pharmacologically acceptable salt thereof.

19. The compound of claim 1 , in which the T is nitrogen.