JP4596792B2 - Drugs having both 5-HT1A agonistic action and 5-HT3 antagonistic action - Google Patents

Description

The present invention combines a serotonin receptor subtype 1A (5-HT _1A ) agonistic action and a serotonin receptor subtype 3 (5-HT ₃ ) antagonistic action of a piperazinylpyridine derivative represented by the following formula (I). In particular, the present invention relates to a therapeutic agent such as irritable bowel syndrome (hereinafter referred to as “IBS”) containing the piperazinylpyridine derivative as an active ingredient.

  IBS is a disease mainly having stool abnormalities such as diarrhea and constipation and abdominal pain, and is a functional disease in which no organic lesions of the intestine are recognized. IBS is formed by intestinal motility abnormalities, visceral hypersensitivity, and psychological and social factors interrelated.

Although the intestinal There are various serotonin receptor subtypes, of which, 5-HT ₃ intestinal contraction, intestinal fluid secretion, peristalsis, are involved in the contents such as transportation. Therefore, diarrhea symptoms caused by IBS may be ameliorated by 5-HT ₃ antagonists. In fact, 5-HT ₃ antagonist alosetron has been approved as an IBS therapeutic agent in the United States.

In Patent Document 1 and Patent Document 2, various 5-HT ₃ antagonists such as ondansetron, allosetron, tropisetron, or granisetron are useful as IBS therapeutic agents. It is described.

Non-Patent Document 1 describes a piperazinyl pyrazine derivative having selective affinity for the 5-HT ₃ receptor, but the piperazinyl pyridine derivative described in Non-Patent Document 1 The action on the 5-HT ₃ receptor is an agonistic action.

  On the other hand, since psychological and social factors are involved in IBS, anxiolytic drugs may show some usefulness in the treatment of IBS. Based on this possibility, benzodiazepine anxiolytic In some cases, the drug is used for the purpose of treating IBS. Recently, serotonergic anxiolytic drugs including non-benzodiazepine compounds with fewer side effects have been developed, and their usefulness in the treatment of IBS is expected.

In Japan, the 5-HT _1A agonist tandospirone is marketed for the indication of stress peptic ulcer and the like. However, the compound has no indication for IBS.

Non-Patent Document 2 discloses a pyrimidinone derivative having selective affinity for the 5-HT _1A receptor. In this document, the selectivity for the 5-HT _1A receptor is examined in comparison with the selectivity for the α ₁ receptor.

Patent Documents 3 and 4 disclose aryl piperazine derivatives having affinity for the 5-HT _1A receptor. In these documents, a mental action based on the action of arylpiperazines on 5-HT _1A receptors is examined.

As described above, various 5-HT ₃ antagonists or 5-HT _1A agonists have been proposed so far, and these compounds have both 5-HT _1A agonistic action and 5-HT ₃ antagonistic action. Whether or not to have both is not considered. In addition, since 5-HT ₃ antagonists or 5-HT _1A agonists that have been developed or marketed so far are unidirectional in their action, sufficient treatment for IBS having multiple causes is possible. It has not yet reached its effect.

Non-Patent Document 3 discloses a benzimidazole-allyl piperazine derivative having affinity for both 5-HT _1A and 5-HT ₃ receptors. However, this document only describes the action of the derivative on the nervous system, and describes that both 5-HT ₃ antagonistic action and 5-HT _1A acting action are exerted on IBS. Not.
PCT International Publication WO 99/17755 Pamphlet US Pat. No. 6,284,770 European Patent Publication No. 343050 JP 2001-97978 A J. et al. Med. Chem. , 42, 4362-4379 (1999) J. et al. Med. Chem. , 40, 574-585 (1997) Bioorg. Med. Chem. Lett. , 13, 3177-3180 (2003)

The main object of the present invention is to provide a drug having both 5-HT _1A agonistic action and 5-HT ₃ antagonistic action.

  Another object of the present invention is to provide a therapeutic agent such as IBS containing the antagonist as an active ingredient.

According to the invention, the formula (I)

Where
A ring is optionally a halogen atom, a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom) an amino group, a lower alkyl group A benzene ring optionally substituted with an amino group, a di-lower alkylamino group, a lower alkylthio group, a lower alkylsulfinyl group or an aminosulfonyloxy group, or optionally a pyridine optionally substituted with a halogen atom or a lower alkyl group, Represents a heterocyclic ring selected from furan and thiophene,
R ¹ represents a hydrogen atom, a halogen atom or a lower alkyl group,
R ² represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, a lower alkyl group or a lower alkoxy group), an amino lower alkyl group (of this group The amino moiety is optionally mono- or di-substituted with a lower alkyl group or may form a cyclic imide group) or a phenylcycloalkyl group (the phenyl portion of this group is optionally a halogen atom, lower alkyl group) Or R ³ may be substituted with a lower alkoxy group, and R ³ represents a hydrogen atom or a lower alkyl group, or R ² and R ³ together may optionally be a hydroxy group, a lower alkoxy group or a phenyl group. Forming a residue of a pyrrolidine ring or piperidine ring optionally substituted with a lower alkoxy group; You may,
R ⁴ represents a hydrogen atom or a lower alkyl group,
A drug having both 5-HT _1A agonistic activity and 5-HT ₃ antagonistic activity, comprising a piperazinylpyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient is provided: .

According to the present invention, there is also provided a treatment agent such as IBS containing the above drug as an active ingredient.
In the present specification, the term “lower” means that the group to which the word is attached has 6 or less carbon atoms, preferably 4 or less.

  Accordingly, examples of the “lower alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like. Of these, methyl, ethyl, n-propyl and isopropyl groups are preferred. Examples of the “lower alkoxy group” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, n-hexyloxy group and the like. Among them, methoxy, ethoxy, n-propoxy and isopropoxy groups are preferable.

  In the present specification, “phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom)” refers to a lower alkoxy substituted with an unsubstituted or substituted phenyl group. Means a group such as benzyloxy, phenylethoxy, phenylpropyloxy, phenylbutoxy, 2-chlorobenzyloxy, 2-bromobenzyloxy, 2-fluorobenzyloxy, 3-bromobenzyloxy, 4-fluorobenzyloxy, 2,4-dichlorobenzyloxy, 1- (4-fluorophenylmethyl) ethoxy group and the like can be mentioned. Among these, a benzyloxy group which is unsubstituted or substituted with one halogen atom is particularly preferable.

  In the formula (I), the “lower alkylamino group” in the definition of the A ring is an amino group substituted with one lower alkyl group, and examples thereof include N-methylamino, N-ethylamino, Nn. -Propylamino, N-sec-butylamino group and the like can be mentioned, and N-methylamino and N-ethylamino groups are particularly preferable. The “di-lower alkylamino group” in the definition of the A ring is an amino group substituted with two identical or different lower alkyl groups, and examples thereof include N, N-dimethylamino, N, N-diethylamino. , N, N-diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-tert-butylamino group, etc., particularly N, N-dimethylamino and N, N-diethylamino groups Is preferred.

  Further, the “lower alkylthio group” in the definition of the A ring in the formula (I) is a thio group substituted with a lower alkyl group, and examples thereof include methylthio, ethylthio, isobutylthio group and the like. Of these, a methylthio group is particularly preferred. Further, the “lower alkylsulfinyl group” in the definition of the A ring is a sulfinyl group substituted with a lower alkyl group, and examples thereof include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl groups and the like. A sulfinyl group is preferred.

In the formula (I), when the A ring represents a “benzene ring”, the compound of the formula (I) is represented by the following formula (III)

Where
R ¹ , R ² , R ³ and R ⁴ have the meanings given above,
R ⁵ represents a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom), an amino group, A lower alkylamino group, a di-lower alkylamino group, a lower alkylthio group, a lower alkylsulfinyl group or an aminosulfonyloxy group;
Can be expressed as

  Furthermore, in the formula (I), when the A ring represents a “heterocycle selected from pyridine, furan and thiophene”, it is a heterocycle formed by condensation with the pyridine ring in the formula (I). Are, for example, 1,6-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, 1,7-naphthyridine, furo [3,2-c] pyridine, furo [3,4-c] pyridine, furo [ Examples include 2,3-c] pyridine, thieno [3,2-c] pyridine, thieno [3,4-c] pyridine, and thieno [2,3-c] pyridine. Among them, 1,6-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, 1,7-naphthyridine, furo [3,2-c] pyridine, furo [2,3-c] pyridine, thieno [3] , 2-c] pyridine and thieno [2,3-c] pyridine are preferred, especially 1,6-naphthyridine, 1,7-naphthyridine, furo [2,3-c] pyridine and thieno [2,3-c. Pyridine is preferred.

“Phenyl lower alkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, lower alkyl group or lower alkoxy group)” used in the definition of R ² is a substituted or unsubstituted phenyl group. A substituted lower alkyl group, and examples of the substituent on the phenyl group include 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 3-bromo, 4-bromo. 4-iodo, 2-methyl, 3-methyl, 4-methyl, 2-ethyl, 3-ethyl, 3-n-propyl, 4-isopropyl, 2-methoxy, 3-methoxy, 4-methoxy, 3-ethoxy , 4-isopropyloxy, 3,4-methylenedioxy group and the like, among which 4-fluoro, 4-chloro, 4-bromo, 3-methyl, 3- Ethyl, 3-methoxy, 3-ethoxy and 3,4-methylenedioxy groups are preferred. Moreover, as said lower alkyl group, a methyl, ethyl, n-propyl, and n-butyl group is suitable, for example. Thus, preferred specific examples of the “phenyl lower alkyl group” include benzyl, 4-fluorobenzyl, 2- (4-chlorophenyl) ethyl, 3- (4-bromophenyl) -n-propyl, 3-methylbenzyl, 3 Mention may be made of-(3-ethylphenyl) -n-butyl, 3-methoxybenzyl, 4- (3-methoxyphenyl) -n-butyl and (3,4-methylenedioxyphenyl) methyl groups.

As used in the definition of R ² , “amino lower alkyl group (the amino portion of this group may optionally be mono- or di-substituted with a lower alkyl group or form a cyclic imido group)” A lower alkyl group substituted with a group, wherein “amino” means not only an unsubstituted amino group but also an amino group substituted with one or two lower alkyl groups and an amino group forming a cyclic imido group Is included. The lower alkyl group which may be substituted on the amino group preferably includes methyl, ethyl, n-propyl and n-butyl groups. Thus, preferred specific examples of “amino lower alkyl group (the amino portion of this group may optionally be mono- or di-substituted with a lower alkyl group or form a cyclic imide group)” include amino Methyl, 2-aminoethyl, 3-amino-n-propyl, 4-amino-n-butyl, 2- (N-methylamino) ethyl, 3- (N, N-dimethylamino) -n-propyl and 3- Mention may be made of the phthalimino-n-propyl group.

As used in the definition of R ² , “phenylcycloalkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, lower alkyl group or lower alkoxy group)” is optionally a halogen atom, lower alkyl group Or a cycloalkyl group substituted by a phenyl group which may be substituted with a lower alkoxy group, wherein the substituent on the phenyl group is the phenyl group of the “phenyl lower alkyl group” in the definition of R ² above. The same substituents as described in the substituent can be given. Examples of the cycloalkyl group include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Among them, a cyclohexyl group is preferable. Furthermore, the substitution position of the phenyl group in the “phenylcycloalkyl group” is preferably the 3-position for the cyclopentyl group, the 4-position for the cyclohexyl group and the cycloheptyl group, and the 5-position for the cyclooctyl group. Thus, preferred examples of “phenylcycloalkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, a lower alkyl group or a lower alkoxy group)” include 4- (4-fluorophenyl) Cyclohexyl, 4- (4-chlorophenyl) cyclohexyl, 4- (4-bromophenyl) cyclohexyl, 4- (3-methylphenyl) cyclohexyl, 4- (3-ethylphenyl) cyclohexyl, 4- (3-methoxyphenyl) cyclohexyl , 4- (3-ethoxyphenyl) cyclohexyl and 4- (3,4-methylenedioxyphenyl) cyclohexyl groups.

In the present specification, examples of the substituent on the benzene ring in the isoquinoline ring formed when the A ring represents a benzene ring, that is, the group represented by R ⁵ in the formula (III) include 5- Chloro, 6-chloro, 7-chloro, 8-chloro, 5-fluoro, 7-fluoro, 5-bromo, 7-bromo, 5-iodo, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-ethyl, 5-n-propyl, 5-sec-butyl, 5-phenyl, 6-phenyl, 7-phenyl, 8-phenyl, 5-hydroxy, 6-hydroxy, 7-hydroxy, 8-hydroxy, 5- Methoxy, 6-methoxy, 7-methoxy, 8-methoxy, 5-ethoxy, 7-ethoxy, 5-isopropyloxy, 5-tert-butyloxy, 5-benzyloxy, 7-benzyl Ruoxy, 5- (2-phenyl) ethyloxy, 5- (4-fluorophenyl) methoxy, 7- (4-fluorophenyl) methoxy, 5- (2-chlorophenyl) methoxy, 5- (3-bromophenyl) methoxy, 5- (2-fluoro-4-chlorophenyl) methoxy, 6- (2,4-dichlorophenyl) ethoxy, 5-amino, 6-amino, 7-amino, 8-amino, 5- (N-methylamino), 7 -(N-methylamino), 5- (N-ethylamino), 5- (N-isobutylamino), 6- (N-tert-butylamino), 5- (N, N-dimethylamino), 7- (N, N-dimethylamino), 5- (N, N-diisopropylamino), 6- (N-methyl-Nn-butylamino), 5-methylthio, 6-methylthio, 7-methylthio 8-methylthio, 5-ethylthio, 5-n-propylthio, 5-isobutylthio, 6-isopropylthio, 5-methylsulfinyl, 6-methylsulfinyl, 7-methylsulfinyl, 8-methylsulfinyl, 5-ethylsulfinyl, 6 -Isopropylsulfinyl, 7-tert-butylsulfinyl, 8-n-pentylsulfinyl, 5-aminosulfonyloxy, 6-aminosulfonyloxy, 7-aminosulfonyloxy, 8-aminosulfonyloxy group, etc. -Chloro, 6-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl, 7-phenyl, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 7-ethoxy, 7-benzyl Oxy, 7- (4-fluorophenyl) methoxy, 7 (N-methylamino), 7- (N, N-dimethylamino), 7-methylthio, 7-methylsulfinyl and 7-aminosulfonyloxy groups are preferred, especially 6-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl, 7-hydroxy, 7-methoxy, 7-ethoxy, 7-benzyloxy, 7- (4-fluorophenyl) methoxy, 7- (N, N-dimethylamino), 7-methylthio group Is preferred.

In the present specification, examples of the substituent on the pyridine ring in the isoquinoline ring formed when the A ring represents a benzene ring, that is, the group represented by R ¹ in the formula (I) include 3 -Fluoro, 4-fluoro, 3-chloro, 4-chloro, 3-bromo, 4-bromo, 3-iodo, 4-iodo, 3-methyl, 4-methyl, 3-ethyl, 4-ethyl, 3-n -Propyl, 4-isopropyl, 3-tert-butyl, 4-n-butyl, 3-isopentyl, 4- (1,2-dimethyl-n-butyl) group and the like, among which 3-chloro, 4- Chloro, 3-methyl and 4-methyl groups are preferred. Thus, preferred substituents on the isoquinoline ring formed when the A ring represents a benzene ring include 5-chloro, 6-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl, 7- Phenyl, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 7-ethoxy, 7-benzyloxy, 7- (4-fluorophenyl) methoxy, 7- (N-methylamino), 7- (N , N-dimethylamino), 7-methylthio, 7-methylsulfinyl, 7-aminosulfonyloxy, 3-methyl-5-chloro, 4-methyl-6-chloro, 3-methyl-7-chloro, 3-methyl- 7-fluoro, 3,7-dimethyl, 3-methyl-7-hydroxy, 4-chloro-7-methoxy, 4-methyl-7-benzyloxy, 3-chloro-7- (4-fluoro Enyl) methoxy, 3-chloro-7- (N-methylamino), 4-chloro-7- (N, N-dimethylamino), 3-methyl-7-methoxy, 4-methyl-7-methoxy and 3- Mention may be made of the chloro-7-methyl group.

  In this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 1,6-naphthyridine ring, examples of the substituent on the 1,6-naphthyridine ring include 2 -Chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 2-bromo, 3-bromo, 2-iodo, 2-methyl, 3-methyl, 4-methyl, 2-ethyl, 2-n -Propyl, 2-sec-butyl, 2,7-dichloro, 2,8-dichloro, 3,7-dichloro, 3,8-dichloro, 4,7-dichloro, 4,8-dichloro, 8-chloro-4 -Fluoro, 2,7-dimethyl, 2,8-dimethyl, 3,7-dimethyl, 3,8-dimethyl, 4,7-dimethyl, 4,8-dimethyl, 2-methyl-7-ethyl, 2-chloro -7-methyl, 3-chloro-7-methyl, -Chloro-2-methyl, 7-chloro-3-methyl and the like can be mentioned, among which 2-chloro, 3-chloro, 3-fluoro, 3-bromo, 3-methyl and 3chloro-7-methyl A group is preferred.

  Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 2,6-naphthyridine ring, examples of the substituent on the 2,6-naphthyridine ring include 5 -Chloro, 7-chloro, 8-chloro, 5-fluoro, 7-fluoro, 5-bromo, 7-bromo, 5-iodo, 5-methyl, 7-methyl, 8-methyl, 5-ethyl, 7-n -Propyl, 8-sec-butyl, 3,5-dichloro, 3,7-dichloro, 3,8-dichloro, 4,5-dichloro, 4,7-dichloro, 4,8-dichloro, 4-chloro-8 -Fluoro, 3,5-dimethyl, 3,7-dimethyl, 3,8-dimethyl, 4,5-dimethyl, 4,7-dimethyl, 4,8-dimethyl, 3-chloro-5-methyl, 3-chloro -7-methyl, 3-chloro-8-methyl 4-chloro-5-methyl, 4-chloro-7-methyl, 4-chloro-8-methyl, 5-chloro-3-methyl, 5-chloro-4-methyl, 7-chloro-3-methyl, 7- Chloro-4-methyl, 8-chloro-3-methyl, 8-chloro-4-methyl group and the like can be mentioned, among which 5-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl And 3,7-dichloro groups are preferred.

  Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 2,7-naphthyridine ring, examples of the substituent on the 2,7-naphthyridine ring include 5 -Chloro, 6-chloro, 8-chloro, 5-fluoro, 6-fluoro, 5-bromo, 6-bromo, 5-iodo, 5-methyl, 6-methyl, 8-methyl, 5-ethyl, 6-n -Propyl, 8-sec-butyl, 3,5-dichloro, 3,6-dichloro, 3,8-dichloro, 4,5-dichloro, 4,6-dichloro, 4,8-dichloro, 4-chloro-8 -Fluoro, 3,5-dimethyl, 3,6-dimethyl, 3,8-dimethyl, 4,5-dimethyl, 4,6-dimethyl, 4,8-dimethyl, 5-chloro-3-methyl, 5-chloro -4-methyl, 6-chloro-3-methyl 6-chloro-4-methyl, 8-chloro-3-methyl, 8-chloro-4-methyl, 3-chloro-5-methyl, 3-chloro-6-methyl, 3-chloro-8-methyl, 4- Chloro-5-methyl, 4-chloro-6-methyl, 4-chloro-8-methyl group and the like can be mentioned, among which 5-chloro, 6-chloro, 6-fluoro, 6-bromo, 6-methyl 3,6-dichloro and 3,6-dimethyl groups are preferred.

  Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 1,7-naphthyridine ring, examples of the substituent on the 1,7-naphthyridine ring include 2 -Chloro, 3-chloro, 4-chloro, 2-fluoro, 4-fluoro, 2-bromo, 4-bromo, 4-iodo, 2-methyl, 3-methyl, 4-methyl, 4-ethyl, 3-n -Propyl, 2-sec-butyl, 2,5-dichloro, 2,6-dichloro, 3,5-dichloro, 3,6-dichloro, 4,5-dichloro, 4,6-dichloro, 5-chloro-2 -Fluoro, 2,5-dimethyl, 2,6-dimethyl, 3,5-dimethyl, 3,6-dimethyl, 4,5-dimethyl, 4,6-dimethyl, 2-chloro-5-methyl, 2-chloro -6-methyl, 3-chloro-5-methyl 3-chloro-6-methyl, 4-chloro-5-methyl, 4-chloro-6-methyl, 5-chloro-2-methyl, 6-chloro-2-methyl, 5-chloro-3-methyl, 6- Examples include chloro-3-methyl, 5-chloro-4-methyl, 6-chloro-4-methyl group, among which 2-chloro, 4-chloro, 2-fluoro, 2-bromo, 2-methyl And 2,6-dichloro groups are preferred.

  Furthermore, in the present specification, when the heterocyclic ring formed when the A ring represents a furan ring is furo [3,2-c] pyridine, the substitution on the furo [3,2-c] pyridine is performed. Examples of the group include the same substituents as described in the above-mentioned “substituents on the pyridine ring in the isoquinoline ring when A represents a benzene ring”, for example, 2-chloro, 3-chloro, 2-fluoro, 2 -Bromo, 2-iodo, 2-methyl, 3-methyl, 2-ethyl, 3-n-propyl, 2,6-dichloro, 2,7-dichloro, 3,6-dichloro, 3,7-dichloro, 2 , 6-dimethyl, 2,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, 7-chloro-3-fluoro, 2-chloro-6-methyl, 3-chloro-6-methyl, 2-chloro -7-methyl, 3-chloro-7- Til, 6-chloro-2-methyl, 6-chloro-3-methyl, 7-chloro-2-methyl, 7-chloro-3-methyl and the like can be mentioned, among which 2-chloro, 3-chloro 2-bromo, 2-methyl, 3-methyl, 6-chloro-2-methyl, 6-chloro-3-methyl, 2,6-dimethyl, 3,6-dimethyl and 7-chloro-3-methyl groups Is preferred.

  Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a furan ring is furo [3,4-c] pyridine, the substitution on the furo [3,4-c] pyridine is performed. Examples of the group include 1-chloro, 3-chloro, 1-fluoro, 1-bromo, 1-iodo, 1-methyl, 3-methyl, 1-ethyl, 3-n-propyl, 1,6-dichloro, 3,6-dichloro, 1,7-dichloro, 3,7-dichloro, 7-chloro-3-fluoro, 1,6-dimethyl, 1,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, 1-chloro-6-methyl, 1-chloro-7-methyl, 3-chloro-6-methyl, 3-chloro-7-methyl, 6-chloro-1-methyl, 6-chloro-3-methyl, 7- Examples include chloro-1-methyl, 7-chloro-3-methyl group, etc. 1-chloro, 3-chloro, 1-bromo, 1-methyl, 3-methyl, 6-chloro-1-methyl, 3-chloro-6-methyl and 6-chloro-3-methyl groups Is preferred.

  Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a furan ring is furo [2,3-c] pyridine, the substitution on the furo [2,3-c] pyridine Examples of the group include 2-chloro, 3-chloro, 3-fluoro, 3-bromo, 3-iodo, 2-methyl, 3-methyl, 3-ethyl, 2-n-propyl, 2,4-dichloro, 2,5-dichloro, 3,4-dichloro, 3,5-dichloro, 4-chloro-2-fluoro, 2,4-dimethyl, 2,5-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 3-chloro-4-methyl, 3-chloro-5-methyl, 4-chloro-2-methyl, 4-chloro-3-methyl, 5- Listed are chloro-2-methyl, 5-chloro-3-methyl, etc. Among them, 2-chloro, 3-chloro, 3-bromo, 3-methyl, 2-methyl, 2-chloro-5-methyl, 5-chloro-2-methyl and 5-chloro-3-methyl groups Is preferred.

  Furthermore, in the present specification, when the heterocyclic ring formed when the A ring represents a thiophene ring is thieno [3,2-c] pyridine, the substituent on the thieno [3,2-c] pyridine As, for example, 2-chloro, 3-chloro, 2-fluoro, 2-bromo, 2-iodo, 2-methyl, 3-methyl, 2-ethyl, 3-n-propyl, 2,6-dichloro, , 7-dichloro, 3,6-dichloro, 3,7-dichloro, 2,6-dimethyl, 2,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, 7-chloro-3-fluoro, 2 -Chloro-6-methyl, 3-chloro-6-methyl, 2-chloro-7-methyl, 3-chloro-7-methyl, 6-chloro-2-methyl, 6-chloro-3-methyl, 7-chloro -2-methyl, 7-chloro-3-methyl group, etc. Among them, 2-chloro, 3-chloro, 2-bromo, 2-methyl, 3-methyl, 6-chloro-2-methyl, 6-chloro-3-methyl, 2,6-dimethyl, 3 , 6-Dimethyl and 7-chloro-3-methyl groups are preferred.

  Further, in the present specification, when the heterocyclic ring formed when the A ring represents a thiophene ring is thieno [3,4-c] pyridine, the substituent on the thieno [3,4-c] pyridine. As, for example, 1-chloro, 3-chloro, 1-fluoro, 1-bromo, 1-iodo, 1-methyl, 3-methyl, 1-ethyl, 3-n-propyl, 1,6-dichloro, 3 , 6-dichloro, 1,7-dichloro, 3,7-dichloro, 7-chloro-3-fluoro, 1,6-dimethyl, 1,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, -Chloro-6-methyl, 1-chloro-7-methyl, 3-chloro-6-methyl, 3-chloro-7-methyl, 6-chloro-1-methyl, 6-chloro-3-methyl, 7-chloro -1-methyl, 7-chloro-3-methyl group, etc. 1-chloro, 3-chloro, 1-bromo, 1-methyl, 3-methyl, 6-chloro-1-methyl, 3-chloro-6-methyl and 6-chloro-3-methyl, among others A group is preferred.

  Furthermore, in the present specification, when the heterocyclic ring formed when the A ring represents a thiophene ring is thieno [2,3-c] pyridine, the substituent on the thieno [2,3-c] pyridine As, for example, 2-chloro, 3-chloro, 3-fluoro, 3-bromo, 3-iodo, 2-methyl, 3-methyl, 3-ethyl, 2-n-propyl, 2,4-dichloro, 2 , 5-dichloro, 3,4-dichloro, 3,5-dichloro, 4-chloro-2-fluoro, 2,4-dimethyl, 2,5-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 2 -Chloro-4-methyl, 2-chloro-5-methyl, 3-chloro-4-methyl, 3-chloro-5-methyl, 4-chloro-2-methyl, 4-chloro-3-methyl, 5-chloro -2-methyl, 5-chloro-3-methyl group, etc. Among others, 2-chloro, 3-chloro, 3-bromo, 3-methyl, 2-methyl, 2-chloro-5-methyl, 5-chloro-2-methyl and 5-chloro-3-methyl A group is preferred.

In the present specification, it is preferable that R ² and R ³ “form together a pyrrolidine ring or a piperidine ring optionally substituted with a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group”. Examples of such a ring include a pyrrolidine ring, and examples of the substituent on the pyrrolidine ring or piperidine ring include a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, a benzyloxy group, and a (2-phenyl) ethoxy group. Among them, hydroxy, methoxy and benzyloxy groups are preferable.

  Furthermore, the “halogen atom” includes fluorine, chlorine, bromine and iodine atoms. Among them, preferred are fluorine, chlorine and bromine atoms.

A preferred group of compounds in the present invention is a compound of the formula (I) when the A ring represents a benzene ring optionally substituted with a halogen atom, a hydroxy group or a lower alkoxy group, that is, R ⁵ is a halogen atom, a hydroxy A compound of formula (III) in the case of a group or a lower alkoxy group

Another group of compounds preferred in the present invention are the compounds of formula (I) when R ¹ represents a hydrogen atom.

Yet another group of compounds preferred in the present invention are compounds of formula (I) when R ² represents a hydrogen atom or a lower alkyl group.

Yet another group of compounds preferred in the present invention are compounds of formula (I) when R ³ and R ⁴ both represent a hydrogen atom.

  Typical examples of the compound of the formula (I) constituting the drug provided by the present invention include the following.

7-piperazin-1-ylfuro [2,3-c] pyridine,
6-methyl-7-piperazin-1-ylfuro [2,3-c] pyridine,
7- (3-methylpiperazin-1-yl) furo [2,3-c] pyridine,
7- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine,
4-piperazin-1-ylfuro [3,2-c] pyridine,
4- (3-methylpiperazin-1-yl) furo [3,2-c] pyridine,
3-chloro-4- (3-methylpiperazin-1-yl) furo [3,2-c] pyridine,
4- (4-methylpiperazin-1-yl) furo [3,2-c] pyridine,
4-piperazin-1-ylfuro [3,4-c] pyridine,
7-piperazine-1-ylthieno [2,3-c] pyridine,
7- (3-methylpiperazin-1-yl) thieno [2,3-c] pyridine,
3-chloro-7- (3-methylpiperazin-1-yl) thieno [2,3-c] pyridine,
7- (4-methylpiperazin-1-yl) thieno [2,3-c] pyridine,
4-piperazin-1-ylthieno [3,2-c] pyridine,
4-piperazin-1-ylthieno [3,4-c] pyridine,
4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
6-chloro-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride,
2-bromo-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-bromo-6-methyl-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-methyl-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride,
2-methyl-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine dihydrochloride,
2-methyl-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine dihydrochloride,
3-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride,
3-bromo-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
3-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
3-chloro-1-piperazin-1-ylisoquinoline dihydrochloride,
3-chloro-7-methoxy-1-piperazin-1-ylisoquinoline,
3-chloro-1- (4-methylpiperazin-1-yl) isoquinoline dihydrochloride,
7- (4-ethylpiperazin-1-yl) thieno [2,3-c] pyridine,
4- (4-ethylpiperazin-1-yl) thieno [3,2-c] pyridine,
5-piperazin-1-yl-1,6-naphthyridine,
7-chloro-5-piperazin-1-yl-1,6-naphthyridine,
5- (4-ethylpiperazin-1-yl) -1,6-naphthyridine,
8-piperazin-1-yl-1,7-naphthyridine,
8- (4-ethylpiperazin-1-yl) -1,7-naphthyridine,
1-piperazin-1-yl-2,6-naphthyridine,
1-piperazin-1-yl-2,7-naphthyridine,
2-methyl-piperazin-1-ylfuro [3,2-c] pyridine,
7-methoxy-3-methyl-1-piperazin-1-ylisoquinoline,
7-methoxy-3,4-dimethyl-1- (4-methylpiperazin-1-yl) isoquinoline,
7-methoxy-4-methyl-1-piperazin-1-ylisoquinoline,
7-methoxy-4-methyl-1- (4-methylpiperazin-1-yl) isoquinoline,
7-bromo-1-piperazin-1-ylisoquinoline,
7-bromo-1- (4-methylpiperazin-1-yl) isoquinoline,
7-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -7-methoxyisoquinoline,
7-methoxy-1-piperazin-1-ylisoquinoline,
1-piperazin-1-ylisoquinoline,
1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) isoquinoline,
7-methoxy-1- (3-methylpiperazin-1-yl) isoquinoline,
1- (3,5-dimethylpiperazin-1-yl) -7-methoxy-isoquinoline,
6-methoxy-1-piperazin-1-ylisoquinoline,
6-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -6-methoxyisoquinoline,
5-methoxy-1-piperazin-1-ylisoquinoline,
5-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -5-methoxyisoquinoline,
7-methyl-1-piperazin-1-ylisoquinoline,
7-methyl-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -7-methylisoquinoline,
7-chloro-1-piperazin-1-ylisoquinoline,
7-chloro-1- (4-methylpiperazin-1-yl) isoquinoline,
7-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline,
7-fluoro-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -7-fluoroisoquinoline,
1- (4-methylpiperazin-1-yl) -7-phenylisoquinoline,
1- (4-ethylpiperazin-1-yl) -7-phenylisoquinoline,
7-phenyl-1-piperazin-1-ylisoquinoline,
6-chloro-1-piperazin-1-ylisoquinoline,
6-chloro-1- (4-methylpiperazin-1-yl) isoquinoline,
6-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline,
5-chloro-1-piperazin-1-ylisoquinoline,
5-chloro-1- (4-methylpiperazin-1-yl) isoquinoline,
5-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline,
7-fluoro-1-piperazin-1-ylisoquinoline,
7-chloro-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline,
7-methoxy-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline,
7-chloro-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline,
7-methoxy-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline,
1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline,
7-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline,
8-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,7-naphthyridine,
5-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,6-naphthyridine,
7-chloro-1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline,
1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline,
3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline,
3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methylisoquinoline,
7-chloro-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline,
7-methoxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline,
7-methylthio-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline,
7-methylsulfinyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline,
7-hydroxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline,
1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-hydroxyisoquinoline,
1-octahydropyrido [1,2-a] pyrazin-2-yl-7-sulfamoyloxyisoquinoline,
1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-sulfamoyloxyisoquinoline,
1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline,
1- (4-benzylpiperazin-1-yl) -7-dimethylaminoisoquinoline,
7-methylamino-1-piperazin-1-ylisoquinoline,
7-ethylamino-1-piperazin-1-ylisoquinoline,
7-dimethylamino-1-piperazin-1-ylisoquinoline,
7-dimethylamino-1- (4-methylpiperazin-1-yl) isoquinoline,
7-methylamino-1- (4-methylpiperazin-1-yl) isoquinoline,
1- [4- (4-fluorobenzyl) piperazin-1-yl] -7-methoxyisoquinoline,
1- [4- (4-fluorobenzyl) piperazin-1-yl] isoquinoline,
7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride,
7-hydroxy-1- (4-methylpiperazin-1-yl) isoquinoline,
7-ethoxy-1-piperazin-1-ylisoquinoline,
7- (4-fluorobenzyloxy) -1-piperazin-1-ylisoquinoline,
7-benzyloxy-1-piperazin-1-ylisoquinoline,
7-sulfamoyloxy-1-piperazin-1-ylisoquinoline hydrochloride, etc.

  Most of the compounds of the formula (I) in the present specification are known compounds described in the literature (for example, J. Med. Chem., 42, 4362-4379 (1999), etc.). Even if it is a compound, it can be easily synthesized according to the synthesis method described in the literature or the like or the production examples described later.

  The compounds of formula (I) according to the invention can also form salts, examples of which include salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. A salt with an organic acid such as acetic acid, succinic acid, citric acid, lactic acid, tartaric acid or p-toluenesulfonic acid; an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal such as calcium salt or magnesium salt; Salts; salts with organic bases such as triethylamine, dicyclohexylamine, pyrrolidine, morpholine, pyridine; ammonium salts, and the like. Among them, pharmaceutically acceptable salts are preferable.

The agent of the present invention is used for the treatment and treatment of diseases associated with both 5-HT _1A and 5-HT ₃ , such as irritable bowel syndrome, anxiety, stress urinary incontinence, urgency in humans and other mammals. Urinary incontinence, depression, prostate cancer, schizophrenia, frequent urination, schizophrenia, overactive bladder syndrome, psychosis, lower urinary tract disease, senile dementia, dysuria associated with benign prostatic hyperplasia, Alzheimer's disease, Interstitial cystitis, addiction / withdrawal symptoms, chronic prostatitis, cognitive impairment, ischemia resulting from acute stroke, Huntington's disease, transient ischemic attack, Parkinson's disease, head or spinal cord trauma, muscle atrophic side Cord sclerosis, fetal hypoxia, AIDS dementia, non-ulcer dyspepsia, chronic neurodegenerative diseases such as retinal disease, reflux esophagitis, addiction to alcohol or cocaine, stimulus-responsive bowel syndrome, extrapyramidal disorders, Apnea or Respiratory disease, panic syndrome, tremor, short-term memory impairment, nausea or vomiting, alcoholism, epilepsy, nicotine dependence, sleep disorder, drug addiction, pain, eating disorders, sexual dysfunction, traumatic stress disorder, obesity Childhood autism, cough, nerve compression syndrome, fascia syndrome, neuropathy, tendomyosis, painful dystrophy, tendinosis, agitation, insertion tendonpathy, attack Hostility, bursal disease, obsessive compulsive disorder, periarthropathy, cognitive enhancement, intramuscular overload syndrome, sexual dysfunction, premenstrual tension syndrome, autonomic ataxia, Essential hypertension, Physical disease, convulsions, peptic ulcer, gonorrhea, gastritis, migraine, half-moon injury, chronic polyarthritis, arthritic trauma, paraneoplastic symptoms, locally severe osteochondritis, tumor-induced inflammatory disease, osteonecrosis , Cloudy exudation, articular chondromatosis, collagen disease, chronic obstructive pulmonary disease (COPD), post-infection arthritis, adult respiratory distress syndrome (ARDS), seronegative spinal arthritis, bronchitis, vasculitis, pneumoconiosis, sarcoidosis It is useful for the treatment and treatment of arthropathy, laryngeal spasm, pulmonary vasculitis, pulmonary granuloma, exogenous allergic alveolitis, chronic fatigue syndrome or glaucoma.

The 5-HT _1A agonistic action and 5-HT ₃ antagonism of the drug of the present invention can be shown by the experiments described below.
(1) Determination of the affinity of a compound for human 5-HT _1A receptor (in vitro):
CHO cell membrane specimen expressing human 5-HT _1A receptor (purchased from Packard Bioscience) 0.25 mL (about 50 units) 24.75 mL incubation buffer A solution (50 mmol / L Tris) -An aqueous solution of a mixture of hydrochloric acid, 10 mmol / L magnesium sulfate, 0.5 mmol / L EDTA and 0.1% ascorbic acid, adjusted to pH 7.4 at 27 ° C with 1N aqueous sodium hydroxide) In addition, a membrane specimen suspension A solution was obtained. Each test compound was made into a 270 μmol / L DMSO solution, and then diluted to a predetermined concentration using incubation buffer A solution to obtain a compound solution.

In a polypropylene tube, 20 μL of incubation buffer A solution of [ ³ H] 8-OH-DPAT (8-hydroxy-2- (di-N-propylamino) tetralin; purchased from Daiichi Chemical Co., Ltd.) The concentration of [ ³ H] 8-OH-DPAT is adjusted so that the concentration of [ ³ H] 8-OH-DPAT in the mixture is 0.25 nmol / L) and 20 μL of the compound solution are added. 500 μL of suspension A solution was added and incubated at 27 ° C. for 60 minutes. Using a Brandel cell harvester, the reaction was stopped by rapidly filtering with a GF / C filter that had been pre-soaked in a solution of polyethyleneimine to a concentration of 0.3% in incubation buffer A solution. After that, the filter was washed with about 5 mL of 50 mmol / L Tris-hydrochloric acid cooled to 4 ° C., and the filter was washed again by the same operation.

The radioactivity remaining on the filter was measured with a liquid scintillation counter (manufactured by Aloka, LSC-5100). Inhibition rate (%) of each test compound with respect to the binding of [ ³ H] 8-OH-DPAT to 5-HT _1A receptor at a concentration of 0.25 nmol / L, that is, each test target for 5-HT _1A receptor. The affinity of the test compound can be calculated by the following formula. The ratio of non-specific binding was calculated by measuring the radioactivity when 8-OH-DPAT having a concentration of 10 μmol / L was used, and the measured value of each test compound was corrected accordingly.

(2) Measuring the affinity of a compound for human 5-HT ₃ receptor (in vitro):
Human 5-HT ₃ (purchased from Bio Links Ltd) receptor was expressed HEK-293 cell membranes sample 0.05 mL (about 50 microassay) the 24.95mL incubation buffer B solution (50 mmol / L of Tris- hydrochloric acid Membrane sample suspension B was added to an aqueous solution of a mixture of 5 mmol / L magnesium chloride and 1 mmol / L EDTA, adjusted to pH 7.5 at 25 ° C. using a 1N-sodium hydroxide aqueous solution). A liquid was used. Each test compound was made into a 270 μmol / L DMSO solution, and then diluted to a predetermined concentration using incubation buffer B solution to obtain a compound solution.
In a polypropylene tube, 20 μL of an incubation buffer B solution of [ ³ H] BRL-43694 (purchased from Daiichi Chemical Co., Ltd.) (however, the concentration of [ ³ H] BRL-43694 in the reaction mixture is 0.5 nmol / L). Then, the concentration of [ ³ H] BRL-43694 was adjusted in advance) and 20 μL of the compound solution were added, and 500 μL of the membrane sample suspension B solution was further added, followed by incubation at 25 ° C. for 60 minutes. Using a Brandel cell harvester, the reaction was stopped by rapid filtration with a GF / B filter pre-soaked in a solution of polyethyleneimine to 0.5% concentration in incubation buffer B. After that, the filter was washed with about 5 mL of 50 mmol / L Tris-hydrochloric acid cooled to 4 ° C., and the filter was washed again by the same operation.
The radioactivity remaining on the filter was measured with a liquid scintillation counter (manufactured by Aloka, LSC-5100). Inhibition rate (%) of each test compound for binding of [ ³ H] BRL-43694 to 5-HT ₃ receptor at a concentration of 0.5 nmol / L, ie, each test compound against 5-HT ₃ receptor The affinity can be calculated by the following equation. The ratio of non-specific binding was calculated by measuring the radioactivity when tropisetron (ICS205-930) at a concentration of 10 μmol / L was used, and the measured value of each test compound was corrected accordingly. .

Table A below shows the affinity of each test compound at a concentration of 100 nmol / L for the 5-HT _1A receptor and 5-HT ₃ receptor. BRL-43694 and tropistron (ICS205-930) used for measuring the affinity of a compound for 5-HT ₃ receptor are represented by the following structural formulas.

(3) Measurement of 5-HT _1A receptor agonist effect on rats (in vivo):
Seven-week-old SD male rats were divided into 4-5 animals per group. This was acclimated twice to the experimental environment, placed in a transparent plastic case one week after the second acclimation, and 10 mg / kg of the test compound (dissolved in 1N hydrochloric acid and then diluted with an appropriate amount of physiological saline) ) Was administered intraperitoneally. Immediately before the administration of the compound and 5, 10, 20 and 30 minutes after the administration, behavioral observations were made on lower lip retraction (LLR) and flat body posture (FBP), which were classified into four stages (0: no response, 1: slight). Reaction, 2: moderate reaction, 3: maximum reaction). And the maximum value of evaluation of each group in each measurement point was calculated | required. The results are shown in Table B below.

(4) Measurement of 5-HT ₃ receptor antagonism on rats (in vivo):
270-410 g SD male rats were intranasally injected with urethane 1.25 g / kg (dissolved in distilled water) and anesthetized, then the left carotid artery was used for blood pressure and heart rate measurement, and the right jugular vein was compounded Each administration catheter was inserted. After stabilization of blood pressure and heart rate, 300 μg / kg of 5-hydroxytryptamine creatinine sulfate (hereinafter referred to as serotonin) was rapidly administered intravenously, and a bradycardia reaction (BC1) that was transiently expressed was observed. Next, when the blood pressure and heart rate are stabilized again after serotonin administration, a test compound is administered intravenously, and 10 minutes after administration, a transient gradual expression that occurs when serotonin 300 μg / kg is rapidly intravenously administered again. A pulse (BC2) was observed. The bradycardia suppression rate of each test compound, that is, the BJ reflection suppression rate can be calculated by the following equation.

  Table C below shows the rate of suppression of bradycardia for each test compound.

Thus, it has both 5-HT _1A agonistic action and 5-HT ₃ antagonistic action characterized by including the piperazinylpyridine derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof. The drug can be administered orally or parenterally (for example, intramuscular injection, intravenous injection, rectal administration, transdermal administration, etc.) for the treatment and treatment of humans and other mammals.

  The drug of the present invention is in a solid form (for example, tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche tablet, etc.) with non-toxic additives depending on its use. It can be prepared and used in any pharmaceutical form in a semi-solid form (eg, suppository, ointment, etc.) or liquid form (eg, injection, emulsion, suspension, lotion, spray, etc.). Examples of non-toxic additives that can be used in the above preparation include starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, and gum arabic. , Polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The formulation can also contain other therapeutically useful agents.

  The content of the piperazinyl pyridine derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof in the preparation varies depending on the dosage form and the like, but is generally solid and semi-solid. In the case of the form, it is desirable to contain it at a concentration of 0.1 to 50% by weight, and in the case of the liquid form, it is contained at a concentration of 0.05 to 10% by weight.

  The dose of the drug of the present invention can vary widely depending on the type of warm-blooded animals including human beings, administration route, severity of symptoms, doctor's diagnosis, etc. It can be in the range of 01-5 mg / kg, preferably 0.02-2 mg / kg. However, as described above, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit depending on the severity of the patient's symptoms, the diagnosis of the doctor, and the like. The above dose can be administered once a day or divided into several times.

Hereinafter, the present invention will be described in more detail with reference to formulation examples and production examples.
Formulation Example 1
tablet:
mg / tablet
Active ingredient 5.0
Starch 10.0
Lactose 73.0
Carboxymethylcellulose calcium 10.0
Talc 1.0
Magnesium stearate 1.0
100.0
The active ingredient is ground to a particle size of 70 μm or less, starch, lactose and carboxymethylcellulose calcium are added and mixed well. 10% starch paste is added to the above mixed powder and mixed by stirring to produce granules. After drying, the particle size is adjusted to about 1000 μm, and talc and magnesium stearate are mixed therein and tableted.

Production example

Production Example 1

8.6 g of anhydrous piperazine was dissolved in 100 ml of ethylene glycol, 7-chlorofuro [2,3-c] pyridine was added, and the mixture was stirred at 140 ° C. overnight. After cooling, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.52 g (75%) of 7-piperazin-1-ylfuro [2,3-c] pyridine.
¹ H-NMR (CDCl ₃ ) δ: 7.96 (d, J = 5.5 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 5. 4 Hz, 1 H), 6.72 (d, J = 1.9 Hz, 1 H), 3.83 to 3.80 (m, 4 H), 3.06 (t, J = 5.0 Hz, 4 H)
Mass, m / e: 203 (M ⁺ ), 135 (base)
Production Example 2
In the same manner as in Production Example 1, 7- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.95 (d, J = 5.3 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 5. 4 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 3.88 (t, J = 5.0 Hz, 4H), 2.59 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H)
Mass, m / e: 217 (M ⁺ ), 147 (base)
Production Example 3
In the same manner as in Production Example 1, 4-piperazin-1-ylfuro [3,2-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.05 (d, J = 5.8 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 0. 8 Hz, 5.8 Hz, 1 H), 6.81 (dd, J = 1.2 Hz, 2.3 Hz, 1 H), 3.67 (t, J = 5.0 Hz, 4 H), 3.05 (t, J = 5.0Hz, 4H)
Mass, m / e: 203 (M ⁺ ), 135 (base)
Production Example 4
In the same manner as in Production Example 1, 4- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.05 (d, J = 5.8 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 1. 2 Hz, 5.8 Hz, 1 H), 6.81 (dd, J = 1.2 Hz, 2.3 Hz, 1 H), 3.74 (t, J = 5.0 Hz, 4 H), 2.59 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H)
Mass, m / e: 217 (M ⁺ ), 147 (base)
Production Example 5
In the same manner as in Production Example 1, 7-piperazin-1-ylthieno [2,3-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.58 (d, J = 5.4 Hz, 1H), 7.32 (d, J = 5. 4Hz, 1H), 7.25 (d, J = 5.4Hz, 1H), 3.64 (t, J = 5.0Hz, 4H), 3.09 (t, J = 5.0Hz, 4H)
Mass, m / e: 219 (M ⁺ ), 151 (base)
Production Example 6
In the same manner as in Production Example 1, 7- (4-methylpiperazin-1-yl) thieno [2,3-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.13 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 5. 4 Hz, 1H), 7.24 (d, J = 5.4 Hz, 1H), 3.71 (t, J = 5.0 Hz, 4H), 2.63 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H)
Mass, m / e: 233 (M ⁺ ), 163 (base)
Production Example 7
In the same manner as in Production Example 1, 4-piperazin-1-ylthieno [3,2-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.09 (d, J = 5.8 Hz, 1H), 7.42-7.35 (m, 3H), 3.50 (t, J = 5.0 Hz, 4H), 3.11 (t, J = 5.0 Hz, 4H)
Mass, m / e: 219 (M ⁺ ), 151 (base)
Production Example 8
In the same manner as in Production Example 1, 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.41-7.33 (m, 3H), 3.57 (t, J = 5.0 Hz, 4H), 2.64 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H)
Mass, m / e: 233 (M ⁺ ), 163 (base)
Production Example 9
In the same manner as in Production Example 1, 2-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.67 (d, J = 5.8 Hz, 1H) , 3.72 (br s, 4H), 2.59 (br s, 4H)
Mass, m / e: 297 (M ⁺ ), 229 (base)
Production Example 10
In the same manner as in Production Example 1, 2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.05 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 0.8 Hz, 1H), 7.19 (dd, J = 0. 8Hz, 5.8Hz, 1H), 3.53 (t, J = 5.0Hz, 4H), 2.63 (t, J = 5.0Hz, 4H), 2.39 (s, 3H)
Mass, m / e: 311 (M ⁺ ), 83 (base)
Production Example 11
In the same manner as in Production Example 1, 2-methyl-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 7.94 (d, J = 6.2 Hz, 1H), 7.76 (d, J = 6.2 Hz, 1H), 7.55 (s, 1H) , 3.91 (br s, 4H), 2.59 (br s, 4H), 2.64 (s, 3H)
Mass, m / e: 233 (M ⁺ ), 177 (base)
Production Example 12
In the same manner as in Production Example 1, 2-methyl-4- (4-methylpiperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 7.96 (d, J = 6.2 Hz, 1H), 7.73 (d, J = 5.8 Hz, 1H), 7.50 (s, 1H) , 4.20 (d, J = 5.9 Hz, 3H), 3.57 (brs, 4H), 3.30-3.27 (m, 4H), 2.84 (d, J = 4.3 Hz) , 3H)
Mass, m / e: 247 (M ⁺ ), 177 (base)
Production Example 13
In the same manner as in Production Example 1, 3-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 8.17 (d, J = 5.4 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J = 5.8 Hz, 1H) 3.56 to 3.32 (m, 8H)
Mass, m / e: 297 (M ⁺ ), 229 (base)
Production Example 14
In the same manner as in Production Example 1, 3-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 8.17 (d, J = 5.4 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H) 3.59 to 3.51 (m, 4H), 3.37 to 3.27 (m, 4H), 2.87 (m, 3H)
Mass, m / e: 311 (M ⁺ ), 83 (base)
Production Example 15
In the same manner as in Production Example 1, 3-chloro-1-piperazin-1-ylisoquinoline dihydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 8.08 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.78-7.75 ( m, 1H), 7.64 to 7.62 (m, 1H), 7.60 (s, 1H), 3.60 to 3.57 (m, 4H), 3.29 (brs, 4H)
Mass, m / e: 247 (M ⁺ ), 179 (base)
Production Example 16
In the same manner as in Production Example 1, 3-chloro-1- (4-methylpiperazin-1-yl) isoquinoline dihydrochloride was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.02 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.79-7.75 (m, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.61 (s, 1H), 3.98 to 3.52 (m, 4H), 3.52 to 3.32 (m, 4H), 2.86 (m, 3H)
Mass, m / e: 261 (M ⁺ ), 83 (base)
Production Example 17
In the same manner as in Production Example 1, 7- (4-ethylpiperazin-1-yl) -thieno [2,3-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.12 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 5. 4 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 3.73 (t, J = 5.0 Hz, 4H), 2.67 (t, J = 5.0 Hz, 4H), 2.52 (q, J = 7.3 Hz, 2H), 1.53 (t, J = 7.3 Hz, 3H)
Mass, m / e: 247 (M ⁺ ), 163 (base)
Production Example 18
In the same manner as in Production Example 1, 4- (4-ethylpiperazin-1-yl) -thieno [3,2-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.41-7.33 (m, 3H), 3.59 (t, J = 5.0 Hz, 4H), 2.68 (t, J = 5.0 Hz, 4H), 2.52 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H)
Mass, m / e: 247 (M ⁺ ), 163 (base)
Production Example 19
In the same manner as in Production Example 1, 5-piperazin-1-yl- [1,6] naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.9 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.39 (dd, J = 1.2 Hz, 8.5 Hz, 1H), 8. 34 (d, J = 6.2 Hz, 1H), 7.48 (d, J = 6.2 Hz, 1H), 7.42 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 3.42 To 3.39 (m, 4H), 3.16 to 3.14 (m, 4H)
Mass, m / e: 214 (M ⁺ ), 146 (base)
Production Example 20
In the same manner as in Production Example 1, 5- (4-methylpiperazin-1-yl)-[1,6] naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.98 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.39-8.36 (m, 1H), 8.33 (d, J = 6.2 Hz, 1H), 7.48 (dd, J = 0.8 Hz, 5.8 Hz, 1H), 7.41 (dd, J = 4.3 Hz, 5.8 Hz, 1H), 3.49 (t , J = 5.0 Hz, 4H), 2.69 (t, J = 5.0 Hz, 4H), 2.41 (s, 3H)
Mass, m / e: 228 (M ⁺ ), 158 (base)
Production Example 21
In the same manner as in Production Example 1, 5- (4-ethylpiperazin-1-yl)-[1,6] naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.97 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.38 to 8.35 (m, 1H), 8.32 (d, J = 5.8 Hz, 1H), 7.46-7.45 (m, 1H), 7.40 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 3.49 (t, J = 5.0 Hz) 4H), 2.71 (t, J = 5.0 Hz, 4H), 2.54 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H)
Mass, m / e: 242 (M ⁺ ), 158 (base)
Production Example 22
In the same manner as in Production Example 1, 8-piperazin-1-yl- [1,7] naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.82 (dd, J = 1.9 Hz, 4.3 Hz, 1H), 8.13 (d, J = 5.4 Hz, 1H), 8.00 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.47 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 7.04 (d, J = 5.8 Hz, 1H), 3.93. (T, J = 5.0 Hz, 4H), 3.13 (t, J = 5.0 Hz, 4H)
Mass, m / e: 214 (M ⁺ ), 146 (base)
Production Example 23
In the same manner as in Production Example 1, 8- (4-methylpiperazin-1-yl)-[1,7] naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.82 (dd, J = 1.9 Hz, 4.3 Hz, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.80 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.47 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 4.01 (Br s, 4H), 2.67 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H)
Mass, m / e: 228 (M ⁺ ), 158 (base)
Production Example 24
In the same manner as in Production Example 1, 8- (4-ethylpiperazin-1-yl)-[1,7] naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.81 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.16 (d, J = 5.4 Hz, 1H), 7.99 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.47 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 4.03 (T, J = 4.6 Hz, 4H), 2.71 (t, J = 4.6 Hz, 4H), 2.51 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3Hz, 3H)
Mass, m / e: 242 (M ⁺ ), 158 (base)
Production Example 25
In the same manner as in Production Example 1, 2-methyl-piperazin-1-ylfuro [3,2-c] pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.93 (d, J = 5.8 Hz, 1H), 6.86 (dd, J = 1.2 Hz, 5.8 Hz, 1H), 6.38 (s, 1H), 3.60 (t, J = 5.0 Hz, 4H), 3.03 (t, J = 5.0 Hz, 4H), 2.43 (d, J = 1.2 Hz, 3H)
Mass, m / e: 217 (M ⁺ ), 161 (base)
Production Example 26
In the same manner as in Production Example 1, 7-methoxy-3-methyl-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.58 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 2. 3 Hz, 8.9 Hz, 1 H), 7.05 (s, 1 H), 3.92 (s, 3 H), 3.36 to 3.32 (m, 4 H), 3.18 to 3.14 (m, 4H), 2.54 (s, 3H)
Mass, m / e: 257 (M ⁺ ), 188 (Base)
Production Example 27
In the same manner as in Production Example 1, 7-methoxy-3,4-dimethyl-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.82 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.27 (dd, J = 2. 7Hz, 9.2Hz, 1H), 3.93 (s, 3H), 3.41 to 3.34 (m, 4H), 2.73 to 2.68 (m, 4H), 2.56 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H)
Mass, m / e: 285 (M ⁺ ), 215 (base), 202
Production Example 28
In the same manner as in Production Example 1, 7-methoxy-4-methyl-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.92 (d, J = 0.7 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 2. 7 Hz, 1H), 7.40 (dd, J = 2.7 Hz, 9.2 Hz, 1H), 3.95 (s, 3H), 3.31 to 3.26 (m, 4H), 3.18- 3.14 (m, 4H), 2.49 (d, J = 0.7 Hz, 3H)
Mass, m / e: 257 (M ⁺ ), 201, 188 (base)
Production Example 29
In the same manner as in Production Example 1, 7-methoxy-4-methyl-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.90 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7 .33 (dd, J = 2.7 Hz, 9.3 Hz, 1H), 3.95, (s, 3H), 3.48 to 3.39 (m, 4H), 2.75 to 2.66 (m , 4H), 2.49 (s, 3H), 2.41 (s, 3H)
Mass, m / e: 305 (M ⁺ ), 235, 83 (base)
Production Example 30
In the same manner as in Production Example 1, 7-bromo-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.24-8.22 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.67 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.26-7.19 (m, 1H), 3.36-3.32 (m, 4H), 3. 16-3.12 (m, 4H)
Mass, m / e: 292 (M ⁺ ), 235, 223 (base)
Production Example 31
In the same manner as in Production Example 1, 7-bromo-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.23 to 8.21 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.67 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 0.8 Hz, 5.8 Hz), 3.47-3.39 (m, 4H) ), 2.76-2.26 (m, 4H), 2.41 (s, 3H)
Mass, m / e: 305 (M ⁺ ), 235, 83 (base)
Production Example 32
In the same manner as in Production Example 1, 7-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 2. 7 Hz, 1H), 7.29 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H), 3. 48-3.40 (m, 4H), 2.77-2.69 (m, 4H)
Mass, m / e: 257 (M ⁺ ), 187 (base)
Production Example 33
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 2. 5 Hz, 1H), 7.31-7.25 (m, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.48-3.39 (m, 4H), 2.79- 2.69 (m, 4H), 2.55 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H)
Mass, m / e: 271 (M ⁺ ), 187 (base)
Production Example 34
In the same manner as in Production Example 1, 7-methoxy-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 2. 6 Hz, 1 H), 7.29 (dd, J = 2.6 Hz, 9.2 Hz, 1 H), 7.23 (d, J = 5.5 Hz, 1 H), 3.94 (s, 3 H), 3. 37-3.30 (m, 4H), 3.20-3.13 (m, 4H)
Mass, m / e: 243 (M ⁺ ), 174 (base)
Production Example 35
In the same manner as in Production Example 1, 1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.9 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8. 1 Hz, 1 H), 7.61 (ddd, J = 1.1 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.51 (ddd, 1.1 Hz, 7.0 Hz, 8.4 Hz, 1 H), 7 .25 (d, J = 5.9 Hz, 1H), 3.41-3.34 (m, 4H), 3.18-3.13 (m, 4H)
Mass, m / e: 213 (M ⁺ ), 145 (base)
Production Example 36
In the same manner as in Production Example 1, 1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.9 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8. 1 Hz, 1 H), 7.60 (ddd, J = 1.1 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.50 (ddd, 1.1 Hz, 7.0 Hz, 8.4 Hz, 1 H), 7 .24 (d, J = 5.9 Hz, 1H), 3.51 to 3.41 (m, 4H), 2.74 to 2.66 (m, 4H), 2.42 (s, 3H)
Mass, m / e: 227 (M ⁺ ), 157 (base)
Production Example 37
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.9 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8. 1 Hz, 1 H), 7.60 (ddd, J = 1.1 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.50 (ddd, 1.1 Hz, 7.0 Hz, 8.4 Hz, 1 H), 7 .23 (d, J = 5.9 Hz, 1H), 3.51-3.44 (m, 4H), 2.77-2.69 (m, 4H), 2.55 (q, J = 7. 3Hz, 2H), 1.17 (t, J = 7.3Hz, 3H)
Mass, m / e: 241 (M ⁺ ), 157 (base)
Production Example 38
In the same manner as in Production Example 1, 7-methoxy-1- (3-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1H), 7.29 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H), 3. 70 to 3.62 (m, 2H), 3.30 to 3.17 (m, 3H), 3.08 to 2.99 (m, 1H), 2.80 to 2.71 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H)
Mass, m / e: 257 (M ⁺ ), 175 (base)
Production Example 39
In the same manner as in Production Example 1, 1- (3,5-dimethylpiperazin-1-yl) -7-methoxy-isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1H), 7.29 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.93 (s, 3H), 3. 70 to 3.62 (m, 2H), 3.33 to 3.23 (m, 2H), 2.66 to 2.57 (m, 2H), 1.17 (d, J = 6.6 Hz, 6H) )
Mass, m / e: 271 (M ⁺ ), 187 (base)
Production Example 40
In the same manner as in Production Example 1, 6-methoxy-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, J = 5.9 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 5. 9 Hz, 1 H), 7.13 (dd, J = 2.6 Hz, 9.2 Hz, 1 H), 7.02 (d, J = 2.6 Hz, 1 H), 3.93 (s, 3 H), 3. 38 to 3.32 (m, 4H), 3.18 to 3.12 (m, 4H)
Mass, m / e: 243 (M ⁺ ), 187 (base)
Production Example 41
In the same manner as in Production Example 1, 6-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.09 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 5. 9 Hz, 1H), 7.12 (dd, J = 2.6 Hz, 9.2 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H), 3. 48-3.38 (m, 4H), 2.74-2.64 (m, 4H), 2.41 (s, 3H)
Mass, m / e: 257 (M ⁺ ), 187 (base)
Production Example 42
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -6-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.09 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 5. 9 Hz, 1H), 7.11 (dd, J = 2.6 Hz, 9.2 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H), 3. 48-3.38 (m, 4H), 2.76-2.67 (m, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz) , 3H)
Mass, m / e: 271 (M ⁺ ), 187 (base)
Production Example 43
In the same manner as in Production Example 1, 5-methoxy-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.16 (d, J = 6.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.63 (dd, J = 0. 8 Hz, 5.8 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 6.94 (d, J = 7.7 Hz, 1 H), 3.99 (s, 3 H), 3. 39 to 3.31 (m, 4H), 3.18 to 3.11 (m, 4H)
Mass, m / e: 243 (M ⁺ ), 174 (base)
Production Example 44
In the same manner as in Production Example 1, 5-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.16 (d, J = 5.8 Hz, 1H), 7.65 (dd, J = 0.8 Hz, 8.5 Hz, 1H), 7.62 (dd, J = 0.8 Hz, 5.8 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 3.98 (s, 3H) ), 3.50 to 3.38 (m, 4H), 2.74 to 2.63 (m, 4H), 2.41 (s, 3H)
Mass, m / e: 257 (M ⁺ ), 187 (base)
Production Example 45
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -5-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 5. 8 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 3.98 (s, 3H), 3.50-3. 40 (m, 4H), 2.77 to 2.68 (m, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H)
Mass, m / e: 271 (M ⁺ ), 187 (base)
Production Example 46
In the same manner as in Production Example 1, 7-methyl-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, J = 5.8 Hz, 1H), 7.88 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7 .45 (dd, J = 1.5 Hz, 8.1 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 3.39 to 3.32 (m, 4H), 3.20 to 3.13 (m, 4H)
Mass, m / e: 227 (M ⁺ ), 159 (base)
Production Example 47
In the same manner as in Production Example 1, 7-methyl-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.09 (d, J = 5.8 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7 .44 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.51 to 3.38 (m, 4H), 2.77 to 2.64 (m, 4H), 2.54 (s, 3H), 2.42 (s, 3H)
Mass, m / e: 241 (M ⁺ ), 171 (base)
Production Example 48
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-methylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.09 (d, J = 5.8 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7 .44 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 3.50 to 3.40 (m, 4H), 2.80 to 2.69 (m, 4H), 2.59 to 2.52 (m, 5H), 1.17 (t, J = 7.3 Hz, 3H)
Mass, m / e: 255 (M ⁺ ), 171 (base)
Production Example 49
In the same manner as in Production Example 1, 7-chloro-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.16 (d, J = 5.8 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8. 5 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 3.41 to 3.33 (m, 4H) ), 3.20-3.14 (m, 4H)
Mass, m / e: 247 (M ⁺ ), 179 (base)
Production Example 50
In the same manner as in Production Example 1, 7-chloro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8. 5 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 3.48-3.40 (m, 4H) ), 2.77-2.70 (m, 4H), 2.42 (s, 3H)
Mass, m / e: 261 (M ⁺ ), 83 (base)
Production Example 51
In the same manner as in Production Example 1, 7-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8. 5 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.49-3.40 (m, 4H) ), 2.79-2.69 (m, 4H), 2.56 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H)
Mass, m / e: 275 (M ⁺ ), 97 (base)
Production Example 52
In the same manner as in Production Example 1, 7-fluoro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.73-7.66 (m, 1H) , 7.42 to 7.35 (m, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.48 to 3.37 (m, 4H), 2.76 to 2.64 ( m, 4H), 2.42 (s, 3H)
Mass, m / e: 245 (M ⁺ ), 175 (base)
Production Example 53
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-fluoroisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.73-7.67 (m, 1H) , 7.42 to 7.36 (m, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.49 to 3.39 (m, 4H), 2.79 to 2.70 ( m, 4H), 2.56 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H)
Mass, m / e: 259 (M ⁺ ), 175 (base)
Production Example 54
In the same manner as in Production Example 1, 1- (4-methylpiperazin-1-yl) -7-phenylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.30-8.27 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.90-7.80 (m, 2H) , 7.72-7.67 (m, 2H), 7.55-7.48 (m, 2H), 7.44-7.39 (m, 1H), 7.29-7.25 (m, 1H), 3.55 to 3.49 (m, 4H), 2.76 to 2.66 (m, 4H), 2.42 (s, 3H)
Mass, m / e: 303 (M ⁺ ), 233 (base)
Production Example 55
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-phenylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.30-8.27 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.89-7.80 (m, 2H) , 7.72-7.67 (m, 2H), 7.55-7.49 (m, 2H), 7.44-7.39 (m, 1H), 7.28-7.24 (m, 1H), 3.58 to 3.48 (m, 4H), 2.81 to 2.72 (m, 4H), 2.56 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3Hz, 3H)
Mass, m / e: 317 (M ⁺ ), 233 (base)
Production Example 56
In the same manner as in Production Example 1, 7-phenyl-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.30 (s, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.90-7.80 (m, 2H), 7.72 ˜7.67 (m, 2H), 7.54 to 7.48 (m, 2H), 7.44 to 7.39 (m, 1H), 7.28 (d, J = 5.8 Hz, 1H) 3.47-3.38 (m, 4H), 3.21-3.14 (m, 4H)
Mass, m / e: 289 (M ⁺ ), 220 (base)
Production Example 57
In the same manner as in Production Example 1, 6-chloro-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.16 (d, J = 5.8 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 1. 9 Hz, 1H), 7.44 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.16 (d, J = 5.8 Hz, 1H), 3.40 to 3.34 (m, 4H) ), 3.17-3.12 (m, 4H)
Mass, m / e: 247 (M ⁺ ), 179 (base)
Production Example 58
In the same manner as in Production Example 1, 6-chloro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 1. 9 Hz, 1 H), 7.43 (dd, J = 1.9 Hz, 8.9 Hz, 1 H), 7.14 (d, J = 5.8 Hz, 1 H), 3.45 (t, J = 4.6 Hz) , 4H), 2.69 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H)
Mass, m / e: 261 (M ⁺ ), 83 (base)
Production Example 59
In the same manner as in Production Example 1, 6-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 1. 9 Hz, 1H), 7.42 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.14 (d, J = 5.8 Hz, 1H), 3.46 (t, J = 4.6 Hz) , 4H), 2.72 (t, J = 4.6 Hz, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H)
Mass, m / e: 275 (M ⁺ ), 83 (base)
Production Example 60
In the same manner as in Production Example 1, 5-chloro-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.25 (d, J = 5.8 Hz, 1H), 8.04 (td, J = 1.2 Hz, 8.5 Hz, 1H), 7.69 (dd, J = 1.2 Hz, 7.3 Hz, 1H), 7.64 (dd, J = 1.2 Hz, 5.8 Hz, 1H), 7.42 (dd, J = 7.3 Hz, 8.5 Hz, 1H) , 3.41-3.35 (m, 4H), 3.18-3.13 (m, 4H)
Mass, m / e: 247 (M ⁺ ), 179 (base)
Production Example 61
In the same manner as in Production Example 1, 5-chloro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.24 (d, J = 5.8 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 1. 2 Hz, 7.3 Hz, 1 H), 7.62 (dd, J = 1.2 Hz, 5.8 Hz, 1 H), 7.41 (dd, J = 7.3 Hz, 8.5 Hz, 1 H), 3.45 (T, J = 4.6 Hz, 4H), 2.69 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H)
Mass, m / e: 261 (M ⁺ ), 83 (base)
Production Example 62
In the same manner as in Production Example 1, 5-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.24 (d, J = 5.8 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 0. 8 Hz, 7.3 Hz, 1 H), 7.61 (d, J = 6.2 Hz, 1 H), 7.40 (t, J = 8.1 Hz, 1 H), 3.47 (t, J = 4.6 Hz) , 4H), 2.73 (t, J = 4.6 Hz, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H)
Mass, m / e: 275 (M ⁺ ), 97 (base)
Production Example 63
In the same manner as in Production Example 1, 7-fluoro-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.79-7.69 (m, 2H), 7.43-7.37 (m, 1H) 7.27-7.24 (m, 1H), 3.38-3.32 (m, 4H), 3.19-3.14 (m, 4H)
Mass, m / e: 231 (M ⁺ ), 163 (base)
Production Example 64
In the same manner as in Production Example 1, 1- (2,5-diazabicyclo [2.2.2] octan-1-yl) -7-methoxyisoquinoline was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 7.97 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 6.2 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1 H), 7.48 (s, 1 H), 7.42 (d, J = 6.2 Hz, 1 H), 4.63 (br s, 1 H), 4.42 to 4.31 (m) , 1H), 4.10 to 3.98 (m, 1H), 3.96 (s, 3H), 3.96 to 3.27 (m, 3H), 2.48 to 2.37 (m, 1H) ), 2.28 to 2.13 (m, 1H), 2.08 to 1.92 (m, 2H)
Mass, m / e: 269 (M ⁺ ), 175 (base)
Production Example 65
In the same manner as in Production Example 1, 7-chloro-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.06 (m, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7 .56 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.26 (t, J = 3.9 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.75-6.69 (m, 2H), 3.86 (s, 3H), 3.39 (t, J = 5.0 Hz, 4H), 2.69 ( t, J = 4.8 Hz, 4H), 2.59 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H), 1.75 to 1.50 (m , 4H)
Mass, m / e: 409 (M ⁺ ), 191 (base), 121, 107
Production Example 66
In the same manner as in Production Example 1, 7-methoxy-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.17 (d, J = 5.9 Hz, 1H), 8.08 (s, 1H), 7.20 (d, J = 8.9 Hz, 1H), 7 .13 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.04 (t, J = 3.9 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.79-6.65 (m, 2H) 3.96 (s, 3H), 3.89 (s, 3H), 3.42 (t, J = 4.8 Hz) 4H), 2.73 (t, J = 4.8 Hz, 4H), 2.63 (t, J = 6.9 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1 .78 to 1.47 (m, 4H)
Mass, m / e: 405 (M ⁺ ), 187 (base), 121, 107
Production Example 67
In the same manner as in Production Example 1, 7-chloro-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 8.03 (m, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7 .55 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.76 to 6.72 (m, 2H), 3.80 (s, 3H), 3.59 (t, J = 5.0 Hz, 4H), 2.97 ( t, J = 4.8 Hz, 4H), 2.53 to 2.47 (m, 2H), 2.21 to 2.10 (m, 4H), 2.09 to 2.00 (m, 4H)
Mass, m / e: 435 (M ⁺ ), 420, 191 (base), 121, 107
Production Example 68
In the same manner as in Production Example 1, 7-methoxy-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, J = 5.7 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.20 (d, J = 5. 7 Hz, 1 H), 7.14 (d, J = 5.7 Hz, 1 H), 7.11 (dd, J = 2.7 Hz, 9.3 Hz, 1 H), 7.01 (d, J = 2.7 Hz) , 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.78 to 6.72 (m, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.43 (m, 4H), 2.87 (t, J = 4.4 Hz, 4H), 2.50 to 2.47 (m, 2H), 2.16 to 2.10 (m, 4H), 2.06-1.98 (m, 4H)
Mass, m / e: 431 (M ⁺ ), 416, 187 (base), 121
Production Example 69
In the same manner as in Production Example 1, 1- [4- (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -piperazin-1-yl] -7-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.06 (d, J = 5.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 2. 3 Hz, 1 H), 7.22 (d, J = 5.4 Hz, 1 H), 7.28 (dd, J = 2.3 Hz, 8.8 Hz, 1 H), 6.89 (dd, J = 4.6 Hz) , 9.6 Hz, 1H), 6.84 (dd, J = 3.4 Hz, 5.8 Hz, 1H), 4.41 to 4.35 (m, 2H), 4.05 (dd, J = 7. 4 Hz, 11.2 Hz, 1 H), 3.94 (s, 3 H), 3.41 (t, J = 4.5 Hz, 4 H), 2.92 to 2.85 (m, 2 H), 2.83 2.73 (m, 4H)
Mass, m / e: 391 (M ⁺ ), 376, 282, 187 (base), 174
Production Example 70
In the same manner as in Production Example 1, 1- [1,4] diazepan-1-yl-7-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.02 to 7.99 (m, 2H), 7.11 to 7.09 (m, 2H), 7.00 (d, J = 2.3 Hz, 1H) , 3.92 (s, 3H), 3.76 (t, J = 5.4 Hz, 2H), 3.72 (t, J = 5.8 Hz, 2H), 3.27 (t, J = 5. 4 Hz, 2H), 3.16 (t, J = 5.7 Hz, 2H), 2.75 (brs, 1H), 2.00 to 1.95 (m, 2H)
Mass, m / e: 257 (M ⁺ ), 242, 201, 187 (base)
Production Example 71
In the same manner as in Production Example 1, 1- (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -7-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 5. 8 Hz, 1 H), 7.09 (dd, J = 2.7 Hz, 9.3 Hz, 1 H), 7.00 (d, J = 2.7 Hz, 1 H), 6.91 (s, 1 H), 6. 77 (t, J = 7.2 Hz, 2H), 5.94 (s, 2H), 3.91 (s, 3H), 3.53 (s, 2H), 3.39 (m, 4H), 2 .69 (t, J = 4.5Hz, 4H)
Mass, m / e: 377 (M ⁺ ), 187 (base), 174, 135
Production Example 72
In the same manner as in Production Example 1, 1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1 H), 7.29 (dd, J = 2.3 Hz, 8.9 Hz, 1 H), 7.21 (d, J = 5.4 Hz, 1 H), 3.94 (s, 3 H), 3. 87-3.84 (m, 1H), 3.79-3.75 (m, 2H), 3.22-3.16 (m, 2H), 2.93-2.88 (m, 1H), 2.64 to 2.58 (m, 1H), 2.40 to 2.38 (m, 1H), 2.29 (q, J = 8.5 Hz, 1H), 1.94 to 1.76 (m , 3H), 1.65 to 1.52 (m, 1H)
Mass, m / e: 283 (M ⁺ ), 96 (base)
Production Example 73
In the same manner as in Production Example 1, 7-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 8. 9 Hz, 1H), 7.55 to 7.52 (m, 1H), 7.19 (d, J = 5.4 Hz, 1H), 3.87 to 3.83 (m, 1H), 3.78 to 3.73 (m, 1H), 3.24 to 3.16 (m, 3H), 2.93 to 2.87 (m, 1H), 2.63 to 2.60 (m, 1H), 2. 38 to 2.25 (m, 2H), 1.93 to 1.83 (m, 3H), 1.63 to 1.51 (m, 1H)
Mass, m / e: 287 (M ⁺ ), 96 (base)
Production Example 74
In the same manner as in Production Example 1, 8-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,7-naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.83 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.13 (d, J = 5.4 Hz, 1H), 8.01 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.48 (dd, J = 4.3 Hz, 8.5 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 4.96. ˜4.90 (m, 2H), 3.32 to 3.25 (m, 1H), 3.19 to 3.15 (m, 2H), 2.97 to 2.92 (m, 1H), 2 .62 to 2.56 (m, 1H), 2.34 to 2.33 (m, 1H), 2.25 (q, J = 8.9 Hz, 1H), 1.96 to 1.85 (m, 2H), 1.82-1.75 (m, 1H), 1.56-1.50 (m, 1H)
Mass, m / e: 254 (M ⁺ ), 96 (base)
Production Example 75
In the same manner as in Production Example 1, 5-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,6-naphthyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.98 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.40-8.37 (m, 1H), 8.33 (d, J = 5.8 Hz, 1H), 7.47-7.40 (m, 2H), 3.93 (td, J = 2.3 Hz, 8.3 Hz, 1H), 3.82 (dd, J = 2.7 Hz) , 11.8 Hz, 1H), 3.32 to 3.25 (m, 1H), 3.21 to 3.16 (m, 2H), 2.97 to 2.93 (m, 1H), 2.59. (Dt, J = 2.7 Hz, 11.2 Hz, 1H), 2.37 to 2.25 (m, 2H), 1.94 to 1.75 (m, 3H), 1.55 to 1.50 ( m, 1H)
Mass, m / e: 254 (M ⁺ ), 96 (base)
Production Example 76
In the same manner as in Production Example 1, 7-chloro-1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8. 9 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.86 (td, J = 2.3 Hz) , 11.6 Hz, 1H), 3.80 to 3.75 (m, 1H), 3.25 to 3.17 (m, 3H), 2.94 to 2.88 (m, 1H), 2.65. ˜2.59 (m, 1H), 2.39 to 2.34 (m, 1H), 2.28 (t, J = 8.9 Hz, 1H), 1.95 to 1.84 (m, 2H) , 1.84 to 1.75 (m, 1H), 1.55 to 1.48 (m, 1H)
Mass, m / e: 287 (M ⁺ ), 96 (base)
Production Example 77
In the same manner as in Production Example 1, 1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.06 (d, J = 5.8 Hz, 1H), 7.66 (dd, J = 3.4 Hz, 8.9 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 2.3 Hz, 8.9 Hz, 1H), 7.19 (d, J = 5.4 Hz, 1H), 3.93 (s, 3H) ), 3.85 (td, J = 2.3 Hz, 12.0 Hz, 1H), 3.77-3.74 (m, 1H), 3.20-3.15 (m, 3H), 2.89 (T, J = 10.8 Hz, 1H), 2.60 (t, J = 11.2 Hz, 1H), 2.39 to 2.37 (m, 1H), 2.32 to 2.25 (m, 1H), 1.93 to 1.83 (m, 2H), 1.80 to 1.76 (m, 1H), 1.59 to 1.51 (m, 1H)
Mass, m / e: 283 (M ⁺ ), 96 (base)
Production Example 78
In the same manner as in Production Example 1, 3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.00 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.60-7.56 (m, 1H), 7.46-7.42 (m, 1H), 7.22 (s, 1H), 3.99 (td, J = 2.3 Hz, 12.3 Hz, 1H), 3.93-3. 89 (m, 1H), 3.24 (dt, J = 2.7 Hz, 12.0 Hz, 1H), 3.18 to 3.13 (m, 2H), 2.95 to 2.90 (m, 1H) ), 2.61-1.23 (m, 2H), 1.93-1.83 (m, 1H), 1.81-1.74 (m, 2H), 1.53-1.47 (m) , 1H)
Mass, m / e: 287 (M ⁺ ), 96 (base)
Production Example 79
In the same manner as in Production Example 1, 3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.55 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.19 (s, 1H), 3.95 (td, J = 2.3 Hz, 12.3 Hz, 1H), 3.90 to 3.86 (m, 1H), 3.25 to 3.13 (m, 2H), 2. 95-2.89 (m, 1H), 2.62-2.57 (m, 1H), 2.51 (s, 3H), 2.35-2.24 (m, 2H), 1.91- 1.83 (m, 2H), 1.79 to 1.76 (m, 1H), 1.56 to 1.51 (m, 1H)
Mass, m / e: 301 (M ⁺ ), 96 (base)
Production Example 80
In the same manner as in Production Example 1, 7-chloro-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8. 9 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.72 (qd, J = 2.7 Hz) , 12.3 Hz, 1H), 3.56 (td, J = 2.7 Hz, 12.3 Hz, 1H), 3.23 (dt, J = 2.7 Hz, 12.3 Hz, 1H), 2.97- 2.84 (m, 3H), 2.63 (dt, J = 2.7 Hz, 11.6 Hz, 1H), 2.33 to 2.16 (m, 2H), 1.87 to 1.78 (m , 1H), 1.75 to 1.57 (m, 3H), 1.45 to 1.28 (m, 2H)
Mass, m / e: 301 (M ⁺ ), 110 (base)
Production Example 81
In the same manner as in Production Example 1, 7-methoxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.4 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1H), 7.28 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H), 3. 72 (qd, J = 2.7 Hz, 12.3 Hz, 1H), 3.57 (td, J = 2.7 Hz, 12.3 Hz, 1H), 3.26 to 3.16 (m, 1H), 2 .98 to 2.84 (m, 3H), 2.63 (dt, J = 2.7 Hz, 11.6 Hz, 1H), 2.35 to 2.25 (m, 1H), 2.25 to 2. 15 (m, 1H), 1.84 to 1.54 (m, 4H), 1.42 to 1.32 (m, 2H)
Mass, m / e: 297 (M ⁺ ), 110 (base)
Production Example 82
In the same manner as in Production Example 1, 7-methylsulfanyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, J = 5.8 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 8. 5 Hz, 1H), 7.50 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.18 (d, J = 5.8 Hz, 1H), 3.91 to 3.84 (m, 1H) ), 3.82 to 3.75 (m, 1H), 3.25 to 3.15 (m, 3H), 2.94 to 2.85 (m, 1H), 2.59 (s, 3H), 2.43 to 2.24 (m, 2H), 1.97 to 1.73 (m, 3H), 1.66 to 1.47 (m, 2H)
Mass, m / e: 299 (M ⁺ ), 96 (base)
Production Example 83

First, in the same manner as in Production Example 1, 285 mg of 7-methylsulfanyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline was obtained. To this was added 1 ml of 30% aqueous hydrogen peroxide and 0.5 ml of acetic acid, and the mixture was stirred at room temperature for 15 minutes, made alkaline with aqueous ammonia, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 4) and 235 mg (78 of 7-methanesulfinyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline (78 %).
¹ H-NMR (CDCl ₃ ) δ: 8.43-8.40 (m, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.77-7.73 (m, 1H), 7.28-7.25 (m, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.89-3. 81 (m, 1H), 3.33 to 3.23 (m, 1H), 3.23 to 3.14 (m, 2H), 3.02 to 2.91 (m, 1H), 2.79 ( d, J = 1.5 Hz, 3H), 2.70-2.60 (m, 1H), 2.46-2.25 (m, 2H), 1.97-1.75 (m, 3H), 1.62-1.46 (m, 1H)
Mass, m / e: 315 (M ⁺ ), 96 (base)
Production Example 84

First, in the same manner as in Production Example 1, 610 mg of 7-methoxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline was obtained. To this, 8 ml of a 47% hydrobromic acid aqueous solution was added and heated to reflux for 2 hours. After cooling, the mixture was neutralized with 5N aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (saturated aqueous ammonia: methanol: chloroform = 0.5: 5: 45) and 7-hydroxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline 500 mg. (86%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.03 (dd, J = 1.2 Hz, 5.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.27 to 7.21 (m, 1H), 7.20 (d, J = 5.8 Hz, 1H), 3.711 to 3.63 (m, 1H), 3.58 to 3.51 (m, 1H), 3.27 to 3.17 (m, 1H), 2.95 to 2.83 (m, 3H), 2.60 to 2.50 (m, 1H) ), 2.31 to 2.07 (m, 2H), 1.82 to 1.54 (m, 4H), 1.39 to 1.26 (m, 2H)
Mass, m / e: 283 (M ⁺ ), 110 (base)
Production Example 85
In the same manner as in Production Example 84, 1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-hydroxyisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.02 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 2. 3 Hz, 1H), 7.29 to 7.25 (m, 1H), 7.23 (d, J = 5.4 Hz, 1H), 3.71 to 3.58 (m, 2H), 3.32 to 3.23 (m, 1H), 3.21 to 3.13 (m, 2H), 3.01 to 2.85 (m, 3H), 2.55 to 2.46 (m, 1H), 1. 98 to 1.79 (m, 3H), 1.59 to 1.49 (m, 1H)
Mass, m / e: 269 (M ⁺ ), 96 (base)
Production Example 86
105 mg of 7-hydroxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline synthesized in Production Example 84 was dissolved in 3 ml of N-methylpyrrolidone, and 1.00 g of sulfamoyl chloride was added thereto. The mixture was further stirred at room temperature for 1 hour. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (25% aqueous ammonia: methanol: chloroform = 1: 10: 90), and 1-octahydropyrido [1,2-a] pyrazin-2-yl-7-sulfamoyl. 85 mg (75%) of isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.05 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 8. 9 Hz, 1H), 7.57 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.14 (d, J = 5.8 Hz, 1H), 3.62 to 3.49 (m, 2H) ), 3.05 (dt, J = 2.7 Hz, 12.3 Hz, 1H), 2.94 to 2.72 (m, 3H), 2.54 (dt, J = 3.1 Hz, 11.6 Hz, 1H), 2.27 (t, J = 10.8 Hz, 1H), 2.21 to 2.12 (m, 1H), 1.83 to 1.54 (m, 4H), 1.43 to 1. 21 (m, 2H)
Mass, m / e: 362 (M ⁺ ), 110 (base)
Production Example 87
In the same manner as in Production Example 86, 1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-sulfamoylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 8. 9Hz, 1H), 7.57 (dd, J = 2.3Hz, 8.9Hz, 1H), 7.17 (d, J = 5.8Hz, 1H), 3.85 to 3.78 (m, 1H) ), 3.73 to 3.65 (m, 1H), 3.18 to 3.05 (m, 3H), 2.86 to 2.78 (m, 1H), 2.63 to 2.54 (m) , 1H), 2.43 to 2.24 (m, 2H), 1.95 to 1.74 (m, 3H), 1.53 to 1.41 (m, 1H)
Mass, m / e: 348 (M ⁺ ), 96 (base)
Production Example 88
Step 1: Synthesis of 1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline.

A mixture of 3.96 g of 1,7-dichloroisoquinoline and 10.50 g of benzylpiperazine was stirred at 150 ° C. for 3 hours. Water was added to the residue, and the mixture was extracted with chloroform, washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4.78 g (71%) of 1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline.
¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.4 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8. 5 Hz, 1 H), 7.53 (dd, J = 2.3 Hz, 8.8 Hz, 1 H), 7.39 to 7.23 (m, 5 H), 7.20 (d, J = 5.8 Hz, 1 H) ), 3.64 (s, 2H), 3.41 (t, J = 5.6 Hz, 4H), 2.73 (t, J = 4.8 Hz, 4H)
Mass, m / e: 337 (M ⁺ ), 191, 159, 91 (base)
Step 2: Synthesis of 1- (4-benzylpiperazin-1-yl) -7-dimethylaminoisoquinoline.

After dissolving 1.01 g of 1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline synthesized in Step 1 above in 30 ml of tetrahydrofuran, 20 mg of palladium acetate and 2- (di-tert-butylphosphino) were added thereto. ) 48 mg of biphenyl, 450 mg of sodium-tert-butoxide and 5 ml of 2.0 M dimethylamine tetrahydrofuran solution were added and sealed, and the mixture was stirred at 80 ° C. for 16 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give 1- (4-benzylpiperazin-1-yl) -7- 261 mg (25%) of dimethylaminoisoquinoline was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.94 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.45 to 7.20 (m, 6H), 7.18 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 3.69 (s, 2H), 3.49 (t, J = 4.8 Hz, 4H), 3.06 (s, 6H), 2.77 (t, J = 5.0 Hz, 4H)
Mass, m / e: 346 (M ⁺ ), 330, 200 (base), 187, 91
Step 3: Synthesis of 7-dimethylamino-1-piperazin-1-ylisoquinoline.

250 mg of 1- (4-benzylpiperazin-1-yl) -7-dimethylaminoisoquinoline synthesized in Step 2 above was dissolved in 20 ml of ethanol, 50 mg of 10% palladium on carbon was added thereto, and the mixture was brought to room temperature under a hydrogen atmosphere. And stirred for 16 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to obtain 46 mg (25%) of 7-dimethylamino-1-piperazin-1-ylisoquinoline.
¹ H-NMR (CDCl ₃ ) δ: 7.95 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.27 (dd, J = 2. 3 Hz, 8.9 Hz, 1 H), 7.16 (d, J = 5.4 Hz, 1 H), 7.12 (d, J = 2.3 Hz, 1 H), 3.39 (t, J = 5.0 Hz) , 4H), 3.19 (t, J = 5.0 Hz, 4H), 3.07 (s, 6H)
Mass, m / e: 256 (M ⁺ ), 200, 187 (base)
Production Example 89
The compound obtained in Production Example 88 was methylated by a conventional method to obtain 7-dimethylamino-1- (4-methylpiperazin-1-yl) isoquinoline.

¹ H-NMR (CDCl ₃ ) δ: 7.95 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 2. 8 Hz, 9.0 Hz, 1 H), 7.21 (d, J = 5.4 Hz, 1 H), 7.12 (d, J = 2.8 Hz, 1 H), 3.45 (t, J = 5.0 Hz) , 4H), 3.07 (s, 6H), 2.71 (t, J = 5.0 Hz, 4H), 2.42 (s, 3H)
Mass, m / e: 270 (M ⁺ ), 200, 187 (base)
Production Example 90
In the same manner as in Production Example 88, 7-methylamino-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.93 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 5. 4 Hz, 1 H), 7.01 (dd, J = 1.3 Hz, 8.9 Hz, 1 H), 6.90 (d, J = 1.9 Hz, 1 H), 3.56 (t, J = 5.0 Hz) , 4H), 3.33 (t, J = 5.0 Hz, 4H), 2.94 (s, 3H)
Mass, m / e: 242 (M ⁺ ), 198, 186, 173 (base)
Production Example 91
In the same manner as in Production Example 89, 7-methylamino-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.94 (d, J = 5.7 Hz, 1H), 7.55 (d, J = 9.5 Hz, 1H), 7.21 (d, J = 9. 2 Hz, 1 H), 7.07 (dd, J = 2.6 Hz, 5.1 Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H), 3.44 (t, J = 4.8 Hz) , 4H), 2.95 (s, 3H), 2.72 (t, J = 5.0 Hz, 4H), 2.42 (s, 3H)
Mass, m / e: 256 (M ⁺ ), 186 (base), 173, 157
Production Example 92
Step 1: Synthesis of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine.

Under an argon atmosphere, 17.5 ml of a 1.58M n-butyllithium-n-hexane solution was added dropwise to a mixture of 25 ml of tetrahydrofuran and 2.78 g of diisopropylamine under ice cooling, followed by stirring for 30 minutes. To this, under ice-cooling, a solution of 1-tert-butoxycarbonyl-3-oxopiperazine (produced with reference to Tetrahedron Lett, 1980, 21, 3019-3020) 2.50 g of tetrahydrofuran was added dropwise. After stirring for 3 hours as it was, a solution of 2.30 g of 5-chloromethyl-benzo [1,3] dioxole in 20 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred as it was for 1 hour. The reaction solution was allowed to come to room temperature and stirred for 18 hours, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.84 g (68%) of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine.
¹ H-NMR (CDCl ₃ ) δ: 6.67 (s, 1H), 6.65 (d, J = 1.3 Hz, 2H), 5.90 (s, 2H), 4.52 to 4.43 (M, 1H), 4.12 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 5.1 Hz, 2H), 2.57 (t, J = 5.8 Hz, 2H) , 1.45 (s, 9H)
Mass, m / e: 334 (M ⁺ ), 278, 144, 57 (base)
Step 2: Synthesis of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine.

2.00 g of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine synthesized in the above step was dissolved in 50 ml of tetrahydrofuran, and 1.00 g of lithium aluminum hydride was added thereto. The mixture was heated to reflux for 16 hours. A 10% aqueous potassium hydroxide solution was added to the reaction solution, insoluble matter was filtered off, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to obtain 1.27 g (66%) of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine. .
¹ H-NMR (CDCl ₃ ) δ: 6.68 (s, 1H), 6.65 (d, J = 0.5 Hz, 2H), 5.90 (s, 2H), 4.02 to 3.87 (M, 3H), 3.78 to 3.54 (m, 2H), 2.96 to 2.77 (m, 2H), 2.65 to 2.51 (m, 2H), 1.45 (s , 9H)
Mass, m / e: 320 (M ⁺ ), 219, 57 (base)
Step 3: Synthesis of 1- (2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl) -7-methoxyisoquinoline.

A mixture of 320 mg of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine synthesized in the above step, 200 mg of 1-chloro-7-methoxyisoquinoline and 110 mg of triethylamine was added in 2 ml of ethylene glycol. Stir at 150 ° C. for 18 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1), and 1- (2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl ) -7-methoxyisoquinoline (210 mg, 44%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.05 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.26 (dd, J = 2. 1 Hz, 9.1 Hz, 1 H), 7.22 (d, J = 5.4 Hz, 1 H), 7.08 (d, J = 2.1 Hz, 1 H), 6.92 (s, 1 H), 6. 79 (d, J = 1.3 Hz, 1H), 5.94 (s, 2H), 3.93 (s, 3H), 3.33 to 3.26 (m, 2H), 3.21 to 3. 14 (m, 2H), 2.80-2.66 (m, 3H), 1.45 (s, 9H)
Mass, m / e: 477 (M ⁺ ), 342 (base), 187, 135
Step 4: Synthesis of 1- (3-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -7-methoxyisoquinoline.

150 mg of 1- (2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl) -7-methoxyisoquinoline synthesized in the above step was added to 10 ml of 4N hydrochloric acid dioxane solution. Stir for 18 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9), and 1- (3-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -7-methoxyisoquinoline 69 mg (58 %).
¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.33 to 7.30 (m, 1H), 7.25 to 7.18 (m, 2H), 6.74 (s, 1H), 6.72 (d, J = 0.8 Hz, 1H), 5.93 (s, 2H), 3 .84 (s, 3H), 3.66 to 3.59 (m, 2H), 3.30 to 3.18 (m, 2H), 3.15 to 3.10 (m, 2H), 2.80 ~ 2.64 (m, 3H)
Mass, m / e: 377 (M ⁺ ), 242 (base), 187, 135
Production Example 93

To 10 ml of acetone, 50 mg of 7-methoxy-1-piperazin-1-ylisoquinoline, 100 mg of 4-fluorobenzyl bromide and 100 mg of triethylamine were added and heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give 52 mg of 1- [4- (4-fluorobenzyl) piperazin-1-yl] -7-methoxyisoquinoline. (79%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.41-7.32 (m, 3H), 7.30-7.26 (m, 1H), 7.21 (d, J = 5.5 Hz, 1H), 7.06-6.99 (m, 2H), 3.93 (s, 3H), 3.61 (s, 2H), 3.45 to 3.35 (m, 4H), 2.77 to 2.67 (m, 4H)
Mass, m / e: 351 (M ⁺ ), 187 (base)
Production Example 94
In the same manner as in Production Example 93, 1- [4- (4-fluorobenzyl) piperazin-1-yl] isoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, J = 5.8 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8. 1 Hz, 1 H), 7.59 (ddd, J = 1.2 Hz, 6.9 Hz, 8.1 Hz, 1 H), 7.49 (ddd, 1.2 Hz, 6.9 Hz, 8.5 Hz, 1 H), 7 .38 to 7.32 (m, 2H), 7.23 (d, J = 5.8 Hz, 1H), 7.06 to 6.99 (m, 2H), 3.61 (s, 2H), 3 .47-3.40 (m, 4H), 2.75-2.68 (m, 4H)
Mass, m / e: 321 (M ⁺ ), 157 (base)
Production Example 95
Step 1: Synthesis of 1- (4-tert-butoxycarbonylpiperazin-1-yl) -7-hydroxyisoquinoline.

A mixture of 4.00 g of 7-methoxy-1-piperazin-1-ylisoquinoline and 40 ml of 47% aqueous hydrobromic acid solution was heated to reflux for 2 hours. After cooling, the mixture was alkalified with 5N aqueous sodium hydroxide solution, 30 ml of 1,4-dioxane and 3.94 g of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to obtain 4.63 g (85%) of 1- (4-tert-butoxycarbonylpiperazin-1-yl) 7-hydroxyisoquinoline.
¹ H-NMR (CDCl ₃ ) δ: 8.03 (d, J = 5.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2. 6 Hz, 1H), 7.30 to 7.23 (m, 2H), 3.72 to 3.64 (m, 4H), 3.34 to 3.26 (m, 4H), 1.51 (s, 9H)
Mass, m / e: 329 (M ⁺ ), 173 (base)
Step 2: Synthesis of 7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride.

A mixture of 70 mg of 1- (4-tert-butoxycarbonylpiperazin-1-yl) 7-hydroxyisoquinoline synthesized in the above step and 3 ml of 4N ethyl acetate solution was stirred at room temperature for 1 hour. The crystals were collected by filtration and washed with ethyl acetate to obtain 43 mg (yield 78%) of 7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride.
¹ H-NMR (CD ₃ OD) δ: 8.02 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.72 (d, J = 6 .6 Hz, 1H), 7.64 to 7.56 (m, 2H), 4.06 to 3.98 (m, 4H), 3.68 to 3.59 (m, 4H)
Mass, m / e: 229 (M ⁺ ), 173 (base)
Production Example 96

A mixture of 795 mg of 7-methoxy- (4-methylpiperazin-1-yl) isoquinoline and 8 ml of 47% aqueous hydrobromic acid solution was heated to reflux for 2.5 hours. After cooling, the mixture was neutralized with 20% aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (saturated aqueous ammonia: methanol: chloroform = 1: 10: 90) to obtain 673 mg (80%) of 7-hydroxy-1- (4-methylpiperazin-1-yl) isoquinoline.
¹ H-NMR (CDCl ₃ ) δ: 8.01 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 2. 7 Hz, 1H), 7.26-7.19 (m, 2H), 3.48-3.35 (m, 4H), 2.70-2.55 (m, 4H), 2.33 (s, 3H)
Mass, m / e: 243 (M ⁺ ), 173 (base)
Production Example 97

After dissolving 105 mg of 1- (4-tert-butoxycarbonylpiperazin-1-yl) -7-hydroxyisoquinoline in 10 ml of acetone, 93 mg of potassium carbonate and 55 mg of ethyl iodide were added, and the mixture was heated to reflux for 2 hours. After adding 55 mg of ethyl iodide and refluxing for 2 hours, 48 mg of potassium carbonate and 55 mg of ethyl iodide were added, and the mixture was further refluxed overnight. After cooling, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain 102 mg (90%) of 1- (4-tert-butoxycarbonylpiperazin-1-yl) -7-ethoxyisoquinoline. .
Next, this was stirred in 3 ml of 4N hydrochloric acid dioxane solution at room temperature for 30 minutes. The mixture was made alkaline with a 10% aqueous sodium hydroxide solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 4) to obtain 67 mg (93%) of 7-ethoxy-1-piperazin-1-ylisoquinoline.
¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 3 Hz, 1 H), 7.28 (dd, J = 2.3 Hz, 8.9 Hz, 1 H), 7.22 (d, J = 5.8 Hz, 1 H), 4.17 (q, J = 6.9 Hz) , 2H), 3.38 to 3.32 (m, 4H), 3.20 to 3.14 (m, 4H), 1.51 (t, J = 6.9 Hz, 3H)
Mass, m / e: 257 (M ⁺ ), 188 (base)
Production Example 98
In the same manner as in Production Example 97, 7- (4-fluorobenzyloxy) -1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.49 to 7.42 (m, 2H), 7.41-7.38 (m, 1H), 7.38-7.33 (m, 1H), 7.22 (d, J = 5.8 Hz, 1H), 7.12-7. 06 (m, 2H), 5.20 (s, 2H), 3.29 to 3.22 (m, 4H), 3.13 to 3.06 (m, 4H)
Mass, m / e: 337 (M ⁺ ), 109 (base)
Production Example 99
In the same manner as in Production Example 97, 7-benzyloxy-1-piperazin-1-ylisoquinoline was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.06 (d, J = 5.8 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.50-7.29 (m, 7H), 7.21 (d, J = 5.8 Hz, 1H), 5.25 (s, 2H), 3.24 to 3.18 (m, 4H), 3.08 to 3.02 (m, 4H)
Mass, m / e: 319 (M ⁺ ), 91 (base)
Production Example 100
In the same manner as in Production Example 97, 7- [4- (1,3-dioxo-1,3-dihydroisoindol-2-yl) butoxy] -1-piperazin-1-ylisoquinoline hydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 7.97 to 7.91 (m, 2H), 7.89 to 7.80 (m, 4H), 7.57 to 7.48 (m, 2H) 7.38 (d, J = 2.3 Hz, 1H), 4.25 to 4.16 (m, 4H), 3.79 to 3.63 (m, 8H), 1.87 to 1.77 ( m, 4H)
Mass, m / e: 430 (M ⁺ ), 160 (base)
Example 101
In the same manner as in Example 97, 7-sulfamoyloxy-1-piperazine-1-isoquinoline hydrochloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 8.19 to 8.11 (m, 3H), 8.07 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 2. 3Hz, 1H), 7.69 (dd, J = 2.3Hz, 8.9Hz, 1H), 7.57 (d, J = 5.8Hz, 1H), 3.65 to 3.57 (m, 4H) ), 3.40 to 3.31 (m, 4H)

Claims (4)

Formula (I)

Where
A ring is optionally a halogen atom, a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom), an amino group, a lower group A benzene ring optionally substituted with an alkylamino group, di-lower alkylamino group, lower alkylthio group, lower alkylsulfinyl group or aminosulfonyloxy group, or optionally a pyridine optionally substituted with a halogen atom or a lower alkyl group Wherein the condensed ring formed when the A ring represents a pyridine ring is 1,7-naphthyridine,
R ¹ represents a hydrogen atom, a halogen atom or a lower alkyl group,
R ² and R ³ together form a residue of a pyrrolidine ring or piperidine ring optionally substituted with a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group;
R ⁴ represents a hydrogen atom or a lower alkyl group,
A therapeutic agent for irritable bowel syndrome, comprising as an active ingredient a piperazinylpyridine derivative represented by the formula: or a pharmaceutically acceptable salt thereof. The treatment agent according to claim 1, wherein the A ring represents a benzene ring which may be substituted with a halogen atom, a hydroxy group or a lower alkoxy group. The treatment agent according to claim 1 or 2, wherein R ¹ represents a hydrogen atom. The pharmaceutical composition for the treatment of irritable bowel syndrome including piperazinyl pyridine derivatives or pharmaceutically acceptable Shio及beauty pharmaceutical acceptable carrier according to any one of claims 1 to 3 .