JP2012067054A - Sulfonamide derivative compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent and/or a prophylactic agent for gastrointestinal disorder and the like.SOLUTION: There are provided a compound expressed by general formula (I) or a pharmaceutically allowable salt thereof. In general formula (I), A represents a replaceable phenylene group; B represents a replaceable aryl group having 6 to 10 carbon atoms, a replaceable cycloalkyl group having 3 to 10 carbon atoms, or a replaceable heterocyclic group; Rrepresents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; Rrepresents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; Rrepresents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a 1-3C alkoxy, a 1-3C alkyl group, or the like; Rrepresents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; and n is an integer of 1 to 4.

Description

  The present invention relates to novel sulfonamide derivative compounds having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various injuries.

  Furthermore, the present invention provides a gastrointestinal disorder associated with decreased motility, particularly gastroesophageal reflux disease (GERD), functional dyspepsia (FD), constipation-type irritable intestine, containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient. Functional bowel disorders such as syndrome (IBS-C), diabetic gastric paresis, constipation (diabetic neuropathy / chronic constipation), opioid-induced bowel dysfunction, paralytic ileus, postoperative bowel obstruction, etc. And / or a preventive drug (preferably a therapeutic and / or preventive drug for functional bowel disorder such as constipation-type irritable bowel syndrome (IBS-C), diabetic gastric paralysis, constipation).

  Furthermore, the present invention provides a preventive or therapeutic agent for the above-mentioned diseases containing the above compound as an active ingredient, a composition for preventing or treating the above-mentioned diseases containing the above compound as an active ingredient, and for preventing or treating the above-mentioned diseases. The present invention relates to a method for preventing or treating the above-mentioned diseases, which comprises using the above-mentioned compound for producing a pharmaceutical, or administering a pharmacologically effective amount of the above-mentioned compound to a mammal (preferably a human).

  Compounds that have been described for their usefulness in the treatment of gastrointestinal disorders are described in Patent Literatures 1 to 3 and the like. Moreover, the evaluation method of the gastrointestinal disorder by the test using rabbit Magnus is described in Non-Patent Document 1.

International Publication No. 2008/729 pamphlet (corresponding US publication number: 2008/27065, 2009/192160) International Publication No. 2007/144400 pamphlet (corresponding US Publication No. 2009/131453) International Publication No. 2009/68552 pamphlet

Pharmacology, 79 (3), pp137-148, 2007

  As a result of intensive research, the present inventors have found that the compound represented by the following formula (I) has unexpectedly superior activity based on its specific chemical structure, and further has a pharmaceutical product such as stability. It has also been found to be a safe and useful drug as a prophylactic / therapeutic agent for pathologic conditions or diseases related to gastrointestinal disorders, etc. based on these findings. completed.

  That is, the present invention relates to gastrointestinal disorders associated with decreased motility, particularly functional bowel disorders such as GERD, functional dyspepsia (FD), constipation irritable bowel syndrome (IBS-C), It is useful as a prophylactic / therapeutic agent for diseases such as (diabetic neuropathy / chronic constipation), opioid-induced bowel dysfunction, paralytic ileus, postoperative bowel obstruction.

The present invention
(1) The following general formula (I)

[Wherein, A represents a phenylene group (C1-3 alkyl group, C1-3 alkoxy group, optionally substituted with 1-3 halogen atoms);
B is a C6-10 aryl group (the aryl group may be substituted with 1 to 5 groups selected from the substituent group α), a C3-10 cycloalkyl group (the cycloalkyl group is a substituent) 1 to 5 optionally substituted with a group selected from group α), a 4-10 membered heterocyclic group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur ( The heterocyclic group may be substituted with 1 to 5 groups selected from the substituent group α.
R ¹ represents a hydrogen atom or a C1-3 alkyl group,
R ² represents a hydrogen atom or a C1-3 alkyl group,
R ³ represents a C1-6 alkyl group, a C3-10 cycloalkyl group, a C1-3 alkoxy C1-3 alkyl group or a C1-3 hydroxyalkyl group,
R ⁴ represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom,
n represents an integer of 1 to 4.

(Substituent group α)
A halogen atom, a C1-C6 alkyl group (the alkyl group is a carboxyl group, a C1-C6 alkoxycarbonyl group or a 4-10 member containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur) 1 to 3 substituents may be substituted with a heterocyclic group), a C3-C10 cycloalkyl group (the cycloalkyl group is the same or selected from a carboxyl group, a C1-C6 alkoxycarbonyl group, nitrogen, oxygen and sulfur) Optionally substituted by 1 to 3 4 to 10-membered heterocyclic groups containing 1 to 4 different heteroatoms), C1-C6 haloalkyl group (the haloalkyl group is a carboxyl group, C1-C6 alkoxycarbonyl) A C1-C6 hydroxyalkyl group, optionally substituted by 1 to 3 heterocyclic groups containing the same or different 1-4 heteroatoms selected from the group or nitrogen, oxygen and sulfur) (Hydroxyal 1 to 3 substituents are substituted with a carboxyl group, a C1-C6 alkoxycarbonyl group, or a 4-10 membered heterocyclic group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. C1-C6 alkoxy C1-C6 alkyl group (wherein the alkoxyalkyl group is a carboxyl group, and the C1-C6 alkoxycarbonyl group is the same or different 1-4 selected from nitrogen, oxygen and sulfur) 1 to 3 substituted with a 4-10 membered heterocyclic group containing a heteroatom), a 4-10 member containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur Heterocyclic group, C1-C6 aminoalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 hydroxyalkoxy group, C6-C10 aryloxy group, C1-C6 alkylthio group, carboxy group, C1-C6 Alkoxycarbonyl group, hydroxyl group, C1-C6 fat Group acyl group, amino group, C1-C6 alkylamino group, C3-C10 cycloalkylamino group, C1-C6 dialkylamino group, C1-C6 alkoxyamino group, C1-C6 aliphatic acylamino group, cyano group, nitro group, C1-C6 alkylsulfonyl group, C1-C6 dialkylaminosulfonyl group, C6-C10 aryl group] or a pharmacologically acceptable salt thereof,
(2) The compound according to the above (1), wherein A is a phenylene group which may be substituted by 1-3 C1-3 alkyl groups,
(3) The above (1) or (2), wherein B is a C6-10 aryl group (the aryl group may be substituted by 1 to 5 groups selected from the substituent group α) Compound,
(4) The compound according to any one of (1) to (3) above, wherein R ¹ is a C1-3 alkyl group, or a pharmacologically acceptable salt thereof,
(5) The compound according to any one of (1) to (4), wherein R ² is a hydrogen atom,
(6) The compound according to any one of (1) to (5) above, wherein R ³ is a C 1-6 alkyl group,
(7) The compound according to any one of (1) to (6), wherein R ⁴ is a hydrogen atom or a C 1-6 alkyl group,
(8) The compound according to any one of (2) to (7) above, wherein n is an integer of 1 or 2.
(9) 1- (cyclohexylsulfonyl) -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, 1- [(4-chlorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, 1- [ (5-Chloro-2-thienyl) phenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4- Carboxamide, N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) -1- (piperidin-1-ylsulfonyl) piperidine-4-carboxamide 1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, 1- [ (4-Fluorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[[ (3S) -3-Methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, N-ethyl-1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[ (3S) -3-Methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide.
(10) A pharmacologically acceptable salt of the compound according to any one of (2) to (9) above (11) The compound or pharmacologically according to any one of (1) to (8) above A pharmaceutical containing an acceptable salt as an active ingredient.

In the present invention, the “C1-C3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl, ethyl, or n-propyl group. Can do. The substituent for the phenylene group of R ¹ , R ² and A is preferably a methyl group.

In the present invention, the “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, as an example of the “C1-3 alkyl group”, Listed groups or n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 Mention may be made of -dimethylbutyl or 2-ethylbutyl groups. R ³ and R ⁴ are preferably a methyl group. In the substituent group α, an alkyl group having 1 to 3 carbon atoms is preferable, and a methyl group is most preferable.

  In the present invention, the `` C3-C10 cycloalkyl group '' is a 3- to 10-membered saturated cyclic hydrocarbon group which may be condensed, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, Mention may be made of adamantyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H-benzo [7] annulenyl group. M is preferably a 3- to 7-membered saturated cyclic hydrocarbon group or a C3-C7 cycloalkyl group condensed with a phenyl group, and more preferably cyclohexyl, 2,3-dihydroindenyl, 1,2, 3,4-tetrahydronaphthalenyl or 6,7,8,9-tetrahydro-5H-benzo [7] annulenyl group, preferably 3 to 7-membered saturated cyclic hydrocarbon in B and substituent group α More preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

In the present invention, the “C1-C6 haloalkyl group” is a group in which a halogen atom is substituted for the “C1-6 alkyl group”, and examples thereof include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, Fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 2,2-dibromoethyl , 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl group. R ¹ is preferably a trifluoromethyl group or a difluoroethyl group, and the substituent group α is preferably a trifluoromethyl group or a difluoromethyl group.

  In the present invention, the “C1-C6 aminoalkyl group” is a group in which an amino group is substituted on the “C1-6 alkyl group”, and examples thereof include aminomethyl, aminoethyl, aminopropyl, and aminobutyl groups. In the substituent group α, aminomethyl is preferable.

In the present invention, the “C1-C3 hydroxyalkyl group” is a group in which a hydroxyl group is substituted on the “C1-3 alkyl group”, and examples thereof include hydroxymethyl, hydroxyethyl, 1-hydroxyethyl, and hydroxypropyl groups. R ³ is preferably a hydroxymethyl group or a 1-hydroxyethyl group.

  In the present invention, the “C1-C6 hydroxyalkyl group” is a group obtained by substituting a hydroxyl group for the “C1-6 alkyl group”, for example, the group mentioned as an example of the “C1-3 hydroxyalkyl group”, or Examples thereof include a hydroxybutyl group, a hydroxypentyl group, and a hydroxyhexyl group. The substituent group α is preferably a hydroxymethyl group or a 1-hydroxyethyl group.

  In the present invention, the “C1-C3 alkoxy group” is a group in which the “C1-3 alkyl group” is bonded to an oxygen atom. For example, the carbon number is 1 such as methoxy, ethoxy, n-propoxy, isopropoxy. There may be mentioned up to 3 linear or branched alkoxy groups. In A, it is preferably a methoxy or ethoxy group.

  In the present invention, the “C1-C6 alkoxy group” is a group in which the “C1-6 alkyl group” is bonded to an oxygen atom, for example, the group mentioned as an example of the “C1-3 alkoxy group”, or n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1 to 6 carbon atoms such as 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy And a straight chain or branched chain alkoxy group. In the substituent group α, a methoxy or ethoxy group is preferable.

  In the present invention, the “C1-C6 haloalkoxy group” is a group in which the “C1-6 haloalkyl group” is bonded to an oxygen atom, such as trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy. And groups such as fluoromethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-dibromoethoxy The substituent group α is preferably a trifluoromethoxy group or a difluoromethoxy group.

In the present invention, the “C1-C3 alkoxy C1-C3 alkyl group” is a group in which the “C1-3 alkoxy group” is bonded to the “C1-3 alkyl group”. For example, methoxymethyl, methoxyethyl, Mention may be made of ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl groups. R ³ is preferably a methoxymethyl group.

  In the present invention, the “C1-C6 alkoxy C1-C6 alkyl group” is a group in which the “C1-6 alkoxy group” is bonded to the “C1-6 alkyl group”. For example, the “C1-C3 alkoxy group” A group listed as an example of `` C1-C3 alkyl group '' or n-butoxymethyl, isobutoxymethyl, s-butoxymethyl, tert-butoxymethyl, n-pentoxymethyl, isopentoxymethyl, 2-methylbutoxymethyl, Neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methylpentoxymethyl, 2-methylpentoxymethyl, 3,3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1, Mention may be made of groups such as the 1-dimethylbutoxymethyl group. In the substituent group α, a methoxymethyl group is preferred.

  In the present invention, the “C1-C6 hydroxyalkoxy group” is a group in which a hydroxyl group is bonded to the “C1-6 alkoxy group”, and examples thereof include groups such as hydroxymethoxy and hydroxyethoxy. In the group α, a hydroxymethoxy group is preferable.

  In the present invention, the “C1-C6 alkylthio group” is a group in which the “C1-6 alkyl group” is bonded to a sulfur atom, and examples thereof include methylthio, ethylthio, and t-butylthio groups. In group α, it is preferably a methylthio group.

  In the present invention, the “C6-C10 aryl group” is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include phenyl, indenyl, naphthyl, and biphenyl groups. B and substituent groups α is preferably a phenyl group.

  In the present invention, the “C6-C10 aryloxy group” is a group in which the “C6-C10 aryl group” is bonded to an oxygen atom, and examples thereof include phenyloxy, indenyloxy, and naphthyloxy groups. In the group α, a phenyloxy group is preferable.

  In the present invention, the “4- to 10-membered heterocyclic group containing 1-4 heteroatoms which are the same or different selected from nitrogen, oxygen and sulfur” refers to 1 to 3 sulfur atoms, oxygen atoms or nitrogen atoms. 4- to 10-membered heterocyclic group including Pairs with aromatic heterocyclic groups such as, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl and groups such as morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl Corresponding partial or fully reduced groups can be mentioned. The above “4- to 10-membered heterocyclic group” may be condensed with other cyclic groups, such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, Phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, isoindolinyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-1H-isochromenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -A tetrahydroisoquinolinyl group can be mentioned. B is preferably a 4- to 10-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom, such as pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, Aromatic heterocyclic groups such as isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl Examples thereof include partially or completely reduced groups corresponding to these groups such as piperazinyl and tetrahydropyranyl, and more preferably pyridyl, pyrimidyl, pyrazolyl, pyrrolidi Nyl, piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl groups. B is preferably an aromatic heterocyclic group. Substituent group α, substituent of C1-C6 alkyl group of substituent group α, substituent of C3-C10 cycloalkyl group of substituent group α, substituent of C1-C6 haloalkyl group of substituent group α, substituent The substituent of the C1-C6 hydroxyalkyl group of the group α and the substituent of the C1-C6 alkoxy C1-C6 alkyl group of the substituent group α are preferably aromatic heterocyclic groups.

  In the present invention, the “C1-C6 alkoxycarbonyl group” is a group in which the “C1-6 alkoxy group” is bonded to a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, n-hexyloxycarbonyl, 4-methyl Pentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, Examples thereof include straight-chain or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as 2,3-dimethylbutoxycarbonyl, and substituents of substituent groups α and C1-C6 alkyl groups of substituent group α. A substituent of the C3-C10 cycloalkyl group of the substituent group α, a substituent of the C1-C6 haloalkyl group of the substituent group α, a substituent of the C1-C6 hydroxyalkyl group of the substituent group α, of the substituent group α The substituent of the C1-C6 alkoxy C1-C6 alkyl group is preferably a methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl group.

  In the present invention, the “C1-C6 aliphatic acyl group” is a group in which an aliphatic hydrocarbon group having 1 to 6 carbon atoms is bonded to a carbonyl group, such as formyl, acetyl, propionyl, butyryl, isobutyryl, Alkylcarbonyl groups such as pentanoyl, pivaloyl, valeryl and isovaleryl groups, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, (E) And an unsaturated alkylcarbonyl group such as -2-methyl-2-butenoyl. In the substituent group α, a formyl group, an acetyl group, and a trifluoroacetyl group are preferable.

  In the present invention, the “C1-C6 alkylamino group” is a group in which the “C1-6 alkyl group” is bonded to an amino group, such as methylamino, ethylamino, n-propylamino, isopropylamino, n -Butylamino, isobutylamino, s-butylamino, tert-butylamino, n-pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, n-hexylamino, isohexylamino 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1 , 2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, or 2-ethylbutylamino group, In substituent group alpha, preferably a methylamino group, an ethylamino group, an isopropylamino group.

  In the present invention, the “C3-C10 cycloalkylamino group” is a group in which the “C3-C10 cycloalkyl” is bonded to an amino group, such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, Examples include cycloheptylamino, norbornylamino, and adamantylamino groups. In the substituent group α, a 3- to 7-membered saturated cyclic hydrocarbon amino group is preferable.

  In the present invention, the “C1-C6 dialkylamino group” is a group obtained by substituting two of the above-mentioned “C1-6 alkyl groups”, which are the same as or different from each other, for example, N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, N, N-di-n-butylamino, N, N-diisobutylamino, N, N-di-s-butylamino, N, N-ditert-butylamino, N, N-di-n-pentylamino, N, N-diisopentylamino, N, N-di2-methylbutylamino, N, N-dineopentylamino, N, N -Di-1-ethylpropylamino, N, N-di-n-hexylamino, N, N-diisohexylamino, N, N-di4-methylpentylamino, N, N-di3-methylpentylamino, N , N-di-2-methylpentylamino, N, N-di1-methylpentylamino, N, N-ethylmethylamino, N, N-isopropylmethylamino groups, and in substituent group α , Preferably a dimethylamino or diethylamino group.

  In the present invention, the “C1-C6 alkoxyamino group” is a group in which the “C1-6 alkoxy group” is bonded to an amino group, such as methoxyamino, ethoxyamino, n-propoxyamino, isopropoxyamino, n-butoxyamino, isobutoxyamino, s-butoxyamino, tert-butoxyamino, n-pentoxyamino, isopentoxyamino, 2-methylbutoxyamino, neopentoxyamino, n-hexyloxyamino, 4-methyl Pentoxyamino, 3-methylpentoxyamino, 2-methylpentoxyamino, 3,3-dimethylbutoxyamino, 2,2-dimethylbutoxyamino, 1,1-dimethylbutoxyamino, 1,2-dimethylbutoxyamino, List linear or branched alkoxyamino groups having 1 to 6 carbon atoms such as 1,3-dimethylbutoxyamino and 2,3-dimethylbutoxyamino Can do. In the substituent group α, a methoxyamino group, an ethoxyamino group, and an n-propoxyamino group are preferable.

  In the present invention, the “C1-C6 aliphatic acylamino group” is an aliphatic hydrocarbon group having 1 to 6 carbon atoms or a group in which a hydrogen atom is bonded to a carbonylamino group, such as formylamino, acetylamino, Alkylcarbonylamino groups such as propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, pivaloylamino, valerylamino, isovalerylamino groups, chloroacetylamino, dichloroacetylamino, trichloroacetylamino, trifluoroacetylamino, etc. Examples thereof include a halogenated alkylcarbonylamino group, a lower alkoxyalkylcarbonylamino group such as methoxyacetylamino, and an unsaturated alkylcarbonylamino group such as (E) -2-methyl-2-butenoylamino. In the substituent group α, an acetylamino group is preferred.

  In the present invention, the “C1-C6 alkylsulfonyl group” is a group to which the “C1-6 alkyl group” is bonded via a sulfonyl group, such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropane. Sulfonyl, n-butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl, tert-butanesulfonyl, n-pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, n-hexanesulfonyl, 4-methylpentanesulfonyl, 3 -Methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonyl , 2,3-dimethylbutanesulfonyl group it can. In the substituent group α, a linear or branched alkanesulfonyl group having 1 to 4 carbon atoms is preferable, and a methanesulfonyl group is most preferable.

  In the present invention, the “C1-C6 dialkylaminosulfonyl group” is a group to which the “C1-C6 dialkylamino group” is bonded via a sulfonyl group, such as N, N-dimethylaminosulfonyl, N, N -Diethylaminosulfonyl, N, N-di-n-propylaminosulfonyl, N, N-diisopropylaminosulfonyl, N, N-di-n-butylaminosulfonyl, N, N-diisobutylaminosulfonyl, N, N-dis-butyl Aminosulfonyl, N, N-ditert-butylaminosulfonyl, N, N-di-n-pentylaminosulfonyl, N, N-diisopentylaminosulfonyl, N, N-di2-methylbutylaminosulfonyl, N, N -Dineopentylaminosulfonyl, N, N-di1-ethylpropylaminosulfonyl, N, N-di-n-hexylaminosulfonyl, N, N-diisohexylaminosulfonyl, N, N-di4-methylpentylamino Sulfonyl, N, N- 3-methylpentylaminosulfonyl, N, N-di-2-methylpentylaminosulfonyl, N, N-di-1-methylpentylaminosulfonyl, N, N-ethylmethylaminosulfonyl, N, N-isopropylmethylaminosulfonyl groups In the substituent group α, a dimethylaminosulfonyl or diethylaminosulfonyl group is preferable.

In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in the substituents and substituent group α of the phenylene group of R ⁴ and A, preferably a chlorine atom or It is a fluorine atom.

  In the present invention, the term “pharmacologically acceptable salt” refers to a case where a basic group such as an amino group is reacted with an acid, and a case where an acidic group such as a carboxyl group is present. By reacting with a base, it can be converted into a salt, so that salt is shown.

  The salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid. Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aliquots such as benzene sulfonate and p-toluene sulfonate Organic acid salts such as sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt, lysine Mention may be made of amino acid salts such as salts, arginine salts, ornithine salts, glutamates, aspartates. Preferably, it is a hydrohalide salt or an inorganic acid salt.

  On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt. Metal salt; inorganic salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane Organic salts such as salt And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate.

The sulfonamide derivative compound having the general formula (I) may have various isomers. In the above general formula (I), all of these isomers and equivalent and unequal mixtures of these isomers are represented by a single formula. Accordingly, the present invention includes all of these isomers and mixtures of these isomers in various proportions. The present invention also relates to various radioisotopes [tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), etc.] or non-radioactive isotopes [deuterium ( ² H), etc.]. Also includes labeled compounds.

  In addition, the present invention includes all of the cyclohexane derivative compound having the general formula (I) and a salt thereof when a solvate (for example, a hydrate) is formed.

  Furthermore, the present invention includes all compounds that are metabolized in vivo and converted into the sulfonamide derivative compound having the general formula (I) or a salt thereof.

  A is preferably a phenylene group optionally substituted by 1 to 3 C1 alkyl groups.

  B is preferably a C6-10 aryl group (the aryl group may be substituted with 1 to 5 groups selected from the substituent group α).

R ¹ is preferably a C 1-3 alkyl group.

R ² is preferably a hydrogen atom.

R ³ is preferably a C 1-6 alkyl group.

R ⁴ is preferably a hydrogen atom or a C 1-6 alkyl group.

  n is preferably 1 or 2.

  Substituent group α is preferably a halogen atom, a C1-C6 alkyl group (wherein the alkyl group is substituted by 1 to 3 C1-C6 alkoxycarbonyl groups when the C6-C10 aryl group of B is substituted. Or a C1-C6 alkoxy group or a cyano group, and more preferably a halogen atom.

Substituent group α is preferably substituted with a halogen atom or a C1-C6 alkyl group when the C3-C10 cycloalkyl group of B is substituted (the alkyl group is substituted with 1 to 3 C1-C6 alkoxycarbonyl groups). Or a C1-C6 alkoxy group or a cyano group.
Substituent group α is preferably a halogen atom, C1- when a 4- to 10-membered heterocyclic group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur of B is substituted. A C6 alkyl group (the alkyl group may be substituted by 1 to 3 C1-C6 alkoxycarbonyl groups), a C1-C6 alkoxy group, a cyano group, and more preferably a halogen atom.
L ⁵ is preferably a t-butoxycarbonyl group.
L ¹ is preferably a substituted benzenesulfonyl group.
L ² is preferably a halogen atom, and more preferably a chlorine atom.
L ³ is preferably a trifluoromethanesulfonyl group.
L ⁴ is preferably a 1-6 alkyl group, and more preferably methyl.

  The compound having the following general formula (I) of the present invention can be produced, for example, by the following method using a known compound as a starting material.

In the above formula and the following description, A, B, n, R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above.
Method A: Intermediate production method

Method B: Intermediate production method

Method C Method C-1

  C-2 method

  C-3 method

In the above process and the following description, L ¹ and L ⁵ represent an amine protecting group, L ² represents a leaving group such as a halogen atom, and L ³ represents a hydroxyl protecting group such as a halogenated aromatic sulfonyl group. L ⁴ represents a protecting group for a carboxyl group such as a 1-6 alkyl group.

In the above process and the following description, the amine protecting group in the definition of L ¹ and L ⁵ is not particularly limited as long as it is a group used in the field of organic synthetic chemistry, but preferably 2-nitrobenzenesulfonyl And substituted benzenesulfonyl group such as t-butoxycarbonyl group.

  The step of producing the compound (I) of the present invention can be selected from the above-mentioned method C depending on the desired compound.

Hereinafter, each step will be described.
(Method A)
(Process A-1)
In this step, compound (1a) is produced by protecting the piperidinyl group of compound (1) with a halogenated aromatic sulfonyl or the like in the presence of a base.

  The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphorotriamide, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone, water or the like A mixed solvent may be mentioned, and a mixed solvent of ketone and water is preferable.

  The halogenated aromatic sulfonyl is preferably 2-nitrobenzenesulfonyl.

  Bases include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; lithium hydride, sodium hydride and hydrogenated Alkali metal hydrides such as potassium; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal fluorides such as sodium fluoride and potassium fluoride Inorganic bases such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, alkali metal alkoxides such as lithium methoxide; mercaptan alkoxides such as methyl mercaptan sodium and ethyl mercaptan sodium Metals and the like, preferably an alkali metal bicarbonate salt.

  The reaction temperature is 0 ° C. to 100 ° C., preferably room temperature.

  The reaction time is 1 to 24 hours, and preferably 5 to 10 hours.

(Method B)
(Process B-1)
In this step, compound (2a) is produced by adding compound (3) to compound (2) in the presence of a base.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene are suitable.

  The base is not particularly limited as long as it is used as a base in a normal reaction. Preferably, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, hydrogen carbonate Alkali metal hydrogen carbonates such as potassium and lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Alkali metal hydroxides; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide Alkali metal alkoxides such as lithium methoxide; Mercaptan alkali metals such as mercaptan sodium and ethyl mercaptan sodium; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4 -(N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3 Organic bases such as .0] nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) Or organometallic bases such as butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and more preferably It is a base.

  The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.

  The reaction time is 0.5 to 24 hours, and preferably 1 to 5 hours.

(Process B-2)
In this step, compound (2a) is enolized in the presence of a base to produce compound (2c).

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether. Ethers, and tetrahydrofuran is preferred.

  The enol scavenger is preferably N-phenylbis (trifluoromethanesulfonimide), 2- [N, N-bis (trifluoromethanesulfonyl) amino] -5-chloropyridine and the like.

  The base is preferably a bistrimethylsilylamide metal salt such as sodium bistrimethylsilylamide, lithium bistrimethylsilylamide, or a diisopropylamide metal salt such as lithium diisopropylamide, and more preferably sodium bistrimethylsilylamide.

  The reaction temperature is -78 ° C to room temperature.

  The reaction time is 0.5 hour to 12 hours, and preferably 1 hour to 5 hours.

(Process B-3)
In this step, compound (2b) is subjected to a carbon increase reaction using carbon monoxide in the presence of a base and a palladium catalyst to produce compound (2c).

  The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol, isopropanol, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethyl Amides such as phosphorotriamide or a mixed solvent of alcohols and amides are preferable, and a mixed solvent of methanol and dimethylformamide is more preferable.

  The base is preferably N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N- Dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5 Organic bases such as -ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); Preferable is triethylamine.

  Preferable examples of the palladium catalyst include 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride, bis (triphenylphosphine) palladium (II) dichloride, and the like.

  The reaction temperature is from room temperature to 100 ° C.

  The reaction time is 1 to 24 hours, and preferably 1 to 5 hours.

(Process B-4)
In this step, compound (2c) is reduced to produce compound (2d).

  The reduction reaction can be achieved according to a reduction method well known in the field of synthetic organic chemistry. A hydrogenation reaction performed in the presence of a catalyst and hydrogen gas is preferred.

  The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol and isopropanol are preferred, and methanol is more preferred.

  The catalyst to be used is not particularly limited as long as it is usually used for catalytic reduction reaction, but preferably palladium carbon, palladium black, palladium hydroxide, Raney-nickel, platinum oxide, platinum black. Rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used. Preferable is palladium carbon or palladium hydroxide.

  The pressure is not particularly limited, but is usually 1 to 10 atmospheres.

  The reaction temperature is from room temperature to 100 ° C.

  The reaction time is 1 to 24 hours, and preferably 1 to 5 hours.

(Process B-5)
In this step, the ester of compound (2d) is hydrolyzed in the presence of a base to produce compound (2e).

  The hydrolysis of the ester can be achieved according to a reduction method well known in the field of synthetic organic chemistry, but is preferably a hydrolysis reaction carried out in the presence of an acid.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, Examples thereof include alcohols such as cyclohexanol and methyl cellosolve, water or a mixed solvent thereof, and methanol is preferable.

  Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide, and sodium hydroxide is preferable.

  The reaction temperature is from room temperature to 80 ° C.

  The reaction time is 1 hour to 12 hours, and preferably 1 hour to 5 hours.

(Method C)
(C-1 method)
(Process C-1-1)
In this step, compound (4) and compound (2e) are condensed to produce compound (5).

  The condensation can be achieved according to a method well known in the field of organic synthetic chemistry, but is preferably a reaction performed in the presence of a dehydrating condensing agent.

  The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide Preferred examples include amides such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve. Is dimethylformamide or ethanol.

  Examples of the dehydrating condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, diphenylphosphoryl azide, 4- (4,6-dimethoxy-1,3, 5-triazin-2-yl) -4-methylmorpholium hydrate, and the like, preferably 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) chloride- 4-methylmorpholium hydrate.

  The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.

  The reaction time is 0.5 to 24 hours, preferably 10 to 20 hours.

(Process C-1-2)
In this step, L ⁵ which is a protecting group for piperazine in compound (5) is deprotected to produce compound (I).

  The deprotection can be achieved according to a method well known in the field of synthetic organic chemistry, but is preferably a hydrolysis reaction carried out in the presence of an acid.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene are suitable.

  Examples of the acid include organic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and trifluoroacetic acid is preferable.

  The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.

The reaction time is 0.5 to 6 hours, preferably 1 to 2 hours.
(C-2 method)
(Process C-2-1)
In this step, compound (2e) is converted to an acid halide and then condensed with compound (4a) in the presence of a base to produce compound (5a).

  Although acid halide formation can be achieved according to a method well known in the field of organic synthetic chemistry, acid chloride formation using thionyl chloride or oxalyl chloride is preferred. The acid halide may be carried out in a solvent, and preferably a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene is used as a solvent.

  The solvent at the time of condensation is not particularly limited as long as it does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, benzene, toluene, Aromatic hydrocarbons such as xylene are exemplified, and aromatic hydrocarbons are preferred.

  The base is preferably N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N- Dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5 Organic bases such as -ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); Preferable is triethylamine.

  The reaction temperature is 0 ° C. to 80 ° C., preferably 0 ° C. to room temperature.

  The reaction time is 0.5 to 3 hours, preferably 1 to 2 hours.

(Process C-2-2)
In this step, compound (5a) is alkylated with an alkylating agent in the presence of a base to produce compound (5).

  The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide Examples of such amides include dimethylformamide.

  Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, and sodium hydride is preferred.

  The alkylating agent preferably includes an alkyl halide, and more preferably an alkyl iodide.

  The reaction temperature is 0 ° C. to 100 ° C., preferably room temperature to 60 ° C.

The reaction time is 0.5 to 24 hours, preferably 1 to 4 hours.
(C-3 method)
(Process C-3-1)
In this step, compound (4a) and compound (1a) are condensed to produce compound (5c).

  The condensation can be achieved according to a method well known in the field of organic synthetic chemistry, but is preferably a reaction performed in the presence of a dehydrating condensing agent.

  The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide Preferred examples include amides such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve. Is dimethylformamide or ethanol.

  Examples of the dehydrating condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, diphenylphosphoryl azide, 4- (4,6-dimethoxy-1,3, 5-triazin-2-yl) -4-methylmorpholium hydrate, and the like, preferably 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) chloride- 4-methylmorpholium hydrate.

  The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.

  The reaction time is 1 to 24 hours, preferably 6 to 12 hours.

(Step C-3-2)
In this step, compound (5c) is alkylated with an alkylating agent in the presence of a base to produce compound (5d).

  The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide Examples of such amides include dimethylformamide.

  Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, and sodium hydride is preferred.

  The alkylating agent preferably includes an alkyl halide, and more preferably an alkyl iodide.

  The reaction temperature is 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.

(Process C-3-3)
In this step, L ¹ which is a protecting group for piperidine in compound (5d) is deprotected to produce compound (5e).

  Although deprotection can be achieved according to a method well known in the field of synthetic organic chemistry, it is preferably a nucleophilic addition reaction performed using thiols in the presence of a base.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, acetonitrile, nitriles such as isobutyronitrile, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethyl Amides such as phosphorotriamide are mentioned, and acetonitrile is preferred.

  Examples of the base include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide, Alkali metal carbonates are preferred.

  Examples of thiols include thiophenol and thioglycolic acid.

  The reaction temperature is room temperature to 80 ° C., preferably room temperature.

  The reaction time is 1 to 24 hours, preferably 3 to 10 hours.

(Step C-3-4)
In this step, compound (5) is produced by adding compound (3) to compound (5e) in the presence of a base.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene are suitable.

  The base is preferably N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N- Dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5 Organic bases such as -ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); Preferable is triethylamine.

  The reaction temperature is 0 ° C to 50 ° C.

  The reaction time is 1 to 12 hours.

  After completion of the reaction in each of the above steps, the target compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.

  If necessary, the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.

  Furthermore, if necessary, the optically active substance can be separated and purified by a chiral column.

  The sulfonamide derivative compound having the general formula (I) and the pharmacologically acceptable salt thereof of the present invention are administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acid, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally. Oral administration is preferred.

  These various preparations are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.

  In molding into tablets, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binder such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, Class Ammonius Absorption accelerators such as bases, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. A lubricant can be exemplified. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.

  In molding into the form of suppository, conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.

  When prepared as injections, the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation. Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.

  Furthermore, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals as needed.

  The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

  The dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.

  The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective. The combination may be administered simultaneously or separately in succession or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

  The compound of the present invention, a cyclohexane derivative compound and a pharmacologically acceptable salt thereof, have excellent gastrointestinal disorder-mediated gastric action, etc., and gastrointestinal disorders associated with decreased mobility, particularly gastroesophageal reflux disease (GERD), Functional dyspepsia (FD), functional bowel disorders such as constipation irritable bowel syndrome (IBS-C), diabetic gastric paralysis, constipation (diabetic neuropathy / chronic constipation), opioid-induced bowel dysfunction, It is useful as a therapeutic or prophylactic agent for paralytic ileus and postoperative bowel obstruction.

  EXAMPLES Next, although an Example etc. are given and this invention is demonstrated further in detail, this invention is not limited to these.

Example 1 1- (Cyclohexylsulfonyl) -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide

(1A) 1-[(2-Nitrophenyl) sulfonyl] piperidine-4-carboxylic acid Piperidine-4-carboxylic acid (12.9 g, 99.9 mmol) and sodium bicarbonate (8.40 g, 100 mmol) in acetone (50 mL) And water (100 mL), 2-nitrobenzenesulfonyl chloride (22.2 g, 100 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting solid was washed with water, acetone and hexane to obtain the title object compound as a white solid (9.43 g, yield 30%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.90-1.78 (2H, m), 2.07-1.98 (2H, m), 2.54-2.44 (1H, m), 3.02-2.92 (2H, m), 3.76 (2H , td, J = 8.6, 4.3 Hz), 7.64-7.60 (1H, m), 7.73-7.68 (2H, m), 8.03-7.98 (1H, m).
(1B) (2S) -2-methyl-4- {2-methyl-4- [methyl (piperidin-4-ylcarbonyl) amino] benzyl} piperazine-1-carboxylate tert-butyl is a known compound (2S) Tert-butyl-4-[(4-aminophenyl) methyl] -2-methylpiperazine-1-carboxylate (1.47 g, 4.60 mmol) was dissolved in dimethylformamide (23 mL) and prepared in (1A) 1 -[(2-Nitrophenyl) sulfonyl] piperidine-4-carboxylic acid (1.73 g, 5.50 mmol) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methyl chloride Morpholium hydrate (1.73 g, about 5.52 mmol) was added at room temperature and stirred at room temperature overnight.

  A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was dissolved in dimethylformamide (23 mL), and sodium hydride (60%, 221 mg, 5.53 mmol) was added at 0 ° C. After stirring at 0 ° C. for 10 minutes in a nitrogen atmosphere, methyl iodide (429 μL, 6.89 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product.

The obtained crude product and cesium carbonate (1.79 g, 5.49 mmol) were dissolved in acetonitrile (25 mL), thiophenol (760 mg, 6.90 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours.
Water was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography (hexane: ethyl acetate: methanol = 100: 0: 0-0: 100: 0-0: 80: 20, v / v / v) for the title purpose. The compound was obtained as a pale yellow oil (1.44 g, yield 70%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.22 (3H, d, J = 6.7 Hz), 1.46 (9H, s), 1.57 (2H, d, J = 13.7 Hz), 1.77-1.63 (2H, m) , 2.08-1.99 (1H, m), 2.21 (1H, dd, J = 11.3, 3.9 Hz), 2.41-2.31 (6H, m), 2.59 (1H, d, J = 11.0 Hz), 2.73 (1H, d , J = 10.2 Hz), 3.12-2.98 (3H, m), 3.23 (3H, s), 3.43 (2H, s), 3.82 (1H, d, J = 13.7 Hz), 4.26-4.16 (1H, m) , 6.99-6.91 (2H, m), 7.30 (1H, d, J = 7.82 Hz).
(1C) 1- (Cyclohexylsulfonyl) -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide (1B) (2S) -2-Methyl-4- {2-methyl-4- [methyl (piperidin-4-ylcarbonyl) amino] benzyl} piperazine-1-carboxylate (67.0 mg, 0.151 mmol) prepared in And triethylamine (23.0 mg, 0.227 mmol) were dissolved in dichloromethane (1.5 mL), cyclohexanesulfonyl chloride (33.0 mg, 0.181 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour.

The solvent of the reaction solution was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the resulting residue, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography {silica gel in which aminopropylsilane was chemically bonded to a silica surface silanol group (ethyl acetate: methanol = 100: 0-80: 20, v / v)} The title object compound was obtained as a colorless oil (39.0 mg, yield 53%).
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.04 (3H, d, J = 6.3 Hz), 1.30-1.16 (3H, m), 1.52-1.38 (2H, m), 1.89-1.61 (8H, m), 2.13-2.02 (3H, m), 2.42-2.32 (4H, m), 3.01-2.62 (8H, m), 3.23 (3H, s), 3.45 (2H, s), 3.74-3.64 (2H, m), 6.96-6.91 (2H, m), 7.33 (1H, d, J = 7.4 Hz).

Example 2 1-[(4-Chlorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine- 4-carboxamide

(2A) 1-[(4-Chlorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4- Carboxamide (2S) -2-Methyl-4- {2-methyl-4- [methyl (piperidin-4-ylcarbonyl) amino] benzyl} piperazine-1-carboxylate tert-butyl prepared in Example (1B) ( 67.0 mg, 0.151 mmol) and triethylamine (23.0 mg, 0.227 mmol) are dissolved in dichloromethane (1.5 mL). 4-Chlorobenzenesulfonyl chloride (38.0 mg, 0.180 mmol) is added at room temperature, and at room temperature for 1 hour under nitrogen atmosphere. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour.

The solvent of the reaction solution was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the resulting residue, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography (ethyl acetate: methanol = 100: 0-80: 20, v / v) to give the title object compound as a white solid (60.0 mg, 77% yield) Obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.01 (3H, d, J = 6.3 Hz), 1.76-1.60 (3H, m), 1.96-1.83 (2H, m), 2.10-2.01 (1H, m), 2.27-2.12 (3H, m), 2.33 (3H, s), 2.74-2.67 (2H, m), 2.98-2.79 (3H, m), 3.19 (3H, s), 3.41 (2H, s), 3.72- 3.63 (2H, m), 6.91-6.85 (2H, m), 7.29-7.26 (1H, m), 7.48-7.43 (2H, m), 7.67-7.62 (2H, m).

Example 3 1-[(5-Chloro-2-thienyl) phenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] Methyl} phenyl) piperidine-4-carboxamide

(3A) 1-[(5-Chloro-2-thienyl) phenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} Phenyl) piperidine-4-carboxamide (2S) -2-methyl-4- {2-methyl-4- [methyl (piperidin-4-ylcarbonyl) amino] benzyl} piperazine-1-prepared in Example (1B) Dissolve tert-butyl carboxylate (67.0 mg, 0.151 mmol) and triethylamine (23.0 mg, 0.227 mmol) in dichloromethane (1.5 mL), and add 5-chlorothiophene-2-sulfonyl chloride (39.0 mg, 0.180 mmol) at room temperature. In addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product.
The obtained crude product was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour.

The solvent of the reaction solution was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the resulting residue, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography (ethyl acetate: methanol = 100: 0-80: 20, v / v) to give the title object compound as a colorless oil (51.0 mg, yield 64%) Got as.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.02 (3H, d, J = 6.3 Hz), 1.78-1.64 (3H, m), 2.00-1.87 (2H, m), 2.11-2.02 (1H, m) , 2.33-2.22 (3H, m), 2.35 (3H, s), 2.76-2.68 (2H, m), 3.00-2.80 (3H, m), 3.20 (3H, s), 3.43 (2H, s), 3.73 -3.64 (2H, m), 6.94-6.88 (3H, m), 7.25 (1H, d, J = 4.3 Hz), 7.30 (1H, d, J = 8.2 Hz).

Example 4 N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) -1- (piperidin-1-ylsulfonyl) piperidine- 4-carboxamide

  Piperidine hydrochloride (1.10 g, 9.05 mmol) was dissolved in acetonitrile (9 mL), sulfuryl chloride (4.05 g, 30.0 mmol) was added at room temperature, and the mixture was stirred overnight under heating and refluxing in a nitrogen atmosphere. The solvent of the reaction solution was distilled off under reduced pressure, diethyl ether was added to the resulting residue to remove insoluble components, and then the solvent was distilled off under reduced pressure to obtain a crude product.

  Next, tert- (2S) -2-methyl-4- {2-methyl-4- [methyl (piperidin-4-ylcarbonyl) amino] benzyl} piperazine-1-carboxylic acid prepared in Example (1B) was used. Butyl (67.0 mg, 0.151 mmol) and triethylamine (46.0 mg, 0.454 mmol) are dissolved in dichloromethane (1.5 mL), and the resulting crude product (55.0 mg) is added at room temperature, and at room temperature for 1 hour under nitrogen atmosphere. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product.

The obtained crude product was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the resulting residue, and the organic matter was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography (ethyl acetate: methanol = 100: 0-80: 20, v / v) to give the title object compound as a colorless oil (43.0 mg, 58% yield) Got as.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.05 (3H, d, J = 6.3 Hz), 1.88-1.49 (11H, m), 2.13-2.04 (1H, m), 2.35-2.25 (1H, m) , 2.37 (3H, s), 2.56-2.46 (2H, m), 2.79-2.70 (2H, m), 3.02-2.83 (3H, m), 3.19-3.13 (4H, m), 3.23 (3H, s) , 3.45 (2H, s), 3.62-3.54 (2H, m), 6.96-6.90 (2H, m), 7.33 (1H, d, J = 7.4 Hz).

Example 5 1-[(4-Fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide

(5A) 2,2-Dimethylpiperazin-4-one
To a solution of 2,2-dimethyl-4-oxopiperazine-1-carboxylate-tert-butyl (1.0 g, 4.40 mmol) in tetrahydrofuran (1 mL) at room temperature was added 4N hydrochloric acid in dioxane (10 mL, 40 mmol). The mixture was stirred at 70 ° C. for 1 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure to obtain the title compound as an oily substance.
(5B) 1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethylpiperidin-4-one 2,2-dimethylpiperazin-4-one (764 mg, 4.67 mmol) synthesized in Example (5A) Triethylamine (2.0 mL, 14.0 mmol) and 4-fluorobenzenesulfonyl chloride (1.0 g, 5.14 mmol) were added to a dichloromethane (50 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Thereafter, water was added to the reaction solution, followed by extraction once with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-50: 50, v / v) to give the title compound as an oily substance (401 mg, Yield: 30%).
¹ H NMR (400MHz, CDCl ₃ ) δppm: 7.86 (2H, m), 7.20 (2H, t, J = 9.0Hz), 3.84 (2H, t, J = 6.0Hz), 2.51 (2H, s), 2.49 (2H, s), 1.45 (6H, s).
(5C) 1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonic acid 1- [synthesized in Example (5B) (4-Fluorophenyl) sulfonyl] -2,2-dimethylpiperidin-4-one (402 mg, 1.40 mmol) in tetrahydrofuran (14 mL) at −78 ° C. with sodium bis (trimethylsilyl) amide in 1N tetrahydrofuran (1.69 mL) , 1.68 mmol) and N-phenylbis (trifluoromethanesulfonimide) (604 mg, 1.68 mmol) were added and stirred at the same temperature for 1 hour. Thereafter, the reaction solution was warmed to room temperature and stirred for 1 hour. Thereafter, a saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-50: 50, v / v) to give the title compound as an oily substance (429 mg, Yield: 73%).
¹ H NMR (400MHz, CDCl ₃ ) δppm: 7.83-7.80 (2H, m), 7.20-7.17 (2H, m), 5.86-5.84 (1H, m), 4.35 (2H, q, J = 3.2Hz), 2.25-2.25 (2H, m), 1.36 (6H, s).
(5D) methyl 1-[(4-fluorophenyl) sulfonyl] -2,2-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxylate

1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonic acid (429 mg, 1.03 mmol) synthesized in Example (5C) In methanol (60 mL) -N, N-dimethylformamide (40 mL), triethylamine (0.3 mL, 2.05 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (25.2 mg, 0.03 mmol) ) And stirred at 80 ° C. for 5 hours under a carbon monoxide atmosphere. Thereafter, water was added to the reaction solution, followed by extraction once with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-50: 50, v / v) to give the title compound as an oily substance (290 mg, Yield: 82%).
¹ H NMR (CDCl ₃ , 400MHz) δ: 7.83-7.80 (2H, m), 7.16 (2H, t, J = 9 Hz), 6.93-6.93 (1H, m), 4.32 (2H, q, J = 3 Hz), 3.75 (3H, s), 2.26-2.25 (2H, m), 1.29 (6H, s).
(5E) 1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid

Methyl 1-[(4-fluorophenyl) sulfonyl] -2,2-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxylate (290 mg, 0.84 mmol) synthesized in Example (5D) 10% palladium hydroxide (30 mg) was added to a methanol (10 mL) solution, and the mixture was stirred at 70 ° C. for 5 hours under a hydrogen atmosphere. Thereafter, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-50: 50, v / v). The title compound was obtained as an oily substance (290 mg, yield: 100%).
¹ H NMR (400MHz, CDCl ₃ ) δppm: 7.83-7.80 (2H, m), 7.17-7.15 (2H, m), 4.04 (1H, dt, J = 13.1, 4.2Hz), 3.68 (3H, s), 3.14 (1H, ddd, J = 14.1,12.3,2.5Hz), 2.67-2.59 (1H, m), 2.06-2.03 (1H, m), 1.70-1.67 (3H, m), 1.43 (3H, s), 1.25 (3H, s).
(5F) 1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethylpiperidine-4-carboxylic acid

1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid (290 mg, 0.84 mmol) synthesized in Example (5E) in methanol ( 10 ml) 2N sodium hydroxide (0.8 mL, 1.60 mmol) was added to the solution and stirred at 60 ° C. for 3 hours. Thereafter, 2N hydrochloric acid (1.0 mL, 2 mmol) was added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was roughly purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 50: 50, v / v) to give the title compound as a crude product. It was.
(5G) (2S) -4- {4-[({1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethylpiperidin-4-yl} carbonyl) (methyl) amino] -2-methylbenzyl } -2-Methylpiperazine-1-carboxylic acid-tert-methyl

1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethylpiperidine-4-carboxylic acid (212 mg, 0.63 mmol) synthesized in Example (5F) and (2S) -2-methyl- 4- (4-Methyl-4- (methylamino) benzyl] piperazine-1-carboxylate-tert-butyl (200 mg, 0.63 mmol) in N, N-dimethylformamide (10 mL) in 4- (4,6- Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorphonium chloride hydrate (224.2 mg, 0.76 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 17 hours. Thereafter, water was added to the reaction solution, followed by extraction once with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20-50: 50, v / v) to give the title compound as an oily substance (192 mg, (Yield: 47%).
¹ H NMR (CDCl ₃ , 400MHz) δppm: 7.78 (2H, dd, J = 9.0, 5.2Hz), 7.30 (1H, d, J = 8.2Hz), 7.13 (2H, t, J = 9.0Hz), 6.95 -6.93 (2H, m), 4.20 (1H, brs), 4.05 (1H, s), 3.96 (1H, s), 3.84 (3H, m), 3.72 (1H, t, J = 5.0Hz), 3.42- 3.40 (2H, m), 3.22 (3H, s), 3.04 (1H, m), 2.88 (1H, m), 2.69 (1H, m), 2.56 (2H, m), 2.39 (3H, s), 2.19 (1H, m), 2.01 (1H, m), 1.76 (3H, m), 1.47 (9H, s), 1.19 (3H, dd, J = 9.1, 7.4Hz), 0.88 (2H, d, J = 5.2 Hz).
(5H) 1-[(4-Fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide

(2S) -4- {4-[({1-[(4-Fluorophenyl) sulfonyl] -2,2-dimethylpiperidin-4-yl} carbonyl) (methyl) amino] synthesized in Example (5G) -2-Methylbenzyl} -2-methylpiperazine-1-carboxylic acid-tert-methyl (192 mg, 0.30 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (10 mL) at room temperature and 30 Stir for minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 100: 0-90: 10, v / v) to give the title compound as an oily substance (132 mg Yield: 81%).
¹ H NMR (CDCl ₃ , 400MHz) δppm: 7.77 (2H, dd, J = 9.0, 5.5Hz), 7.29 (1H, d, J = 8.2Hz), 7.13 (2H, t, J = 9.1Hz), 6.96 -6.94 (2H, m), 3.95 (1H, s), 3.85 (2H, t, J = 5.0z), 3.73 (1H, t, J = 5Hz), 3.51 (2H, s), 3.22 (3H, s ), 3.15-3.12 (2H, m), 2.89-2.86 (1H, m), 2.78-2.75 (3H, m), 2.34 (3H, s), 2.07-2.04 (1H, m), 1.75-1.72 (3H , m), 1.34 (3H, s), 1.18 (3H, d, J = 7.0Hz), 0.87 (3H, s).

Example 6 1-[(4-Fluorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine -4-carboxamide and its hydrochloride

(6A) (2S) -4- {4-[({1-[(4-Fluorophenyl) sulfonyl] piperidin-4-yl} carbonyl) (methyl) amino] -2-methylbenzyl} -2-methylpiperazine Tert-butyl-1-carboxylate
1-[(4-Fluorophenyl) sulfonyl] piperidine-4-carboxylic acid (137 mg, 0.476 mmol) is dissolved in dichloromethane (5 mL), and oxalyl chloride (130 μL, 1.43 mmol), catalytic amount of dimethylformamide is added. The mixture was added at 0 ° C. and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The residue obtained by evaporating the solvent under reduced pressure was dissolved in dichloromethane (15 mL), and (2S) -2-methyl-4- [2-methyl-4- (methylamino) benzyl] piperazine-1-carboxyl was dissolved. Tert-butyl acid (158 mg, 0.474 mmol) and triethylamine (200 μL, 1.43 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.

Water was added to the reaction solution at room temperature, and the organic matter was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-0: 100, v / v) to give the title object compound as a colorless oil (259 mg, yield 90%). Obtained.
¹ H NMR (CDCl ₃ , 500MHz): δ 1.18 (3H, d, J = 6.8Hz), 1.47 (9H, s), 1.64 (2H, d, J = 10.7Hz), 1.85-1.91 (2H, m ), 1.99-2.05 (1H, m), 2.18-2.22 (4H, m), 2.34 (3H, s), 2.55 (1H, d, J = 11.2Hz), 2.69 (1H, d, J = 11.2Hz) , 3.01-3.07 (1H, m), 3.19 (3H, s), 3.39 (2H, s), 3.66-3.69 (2H, m), 3.79-3.82 (1H, m), 4.20 (1H, br s), 6.88 (1H, d, J = 7.8Hz), 6.91 (1H, s), 7.17 (2H, t, J = 8.8Hz), 7.27 (1H, d, J = 7.8Hz), 7.71-7.74 (2H, m ).
(6B) 1-[(4-Fluorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4 -Carboxamide (2S) -4- {4-[({1-[(4-Fluorophenyl) sulfonyl] piperidin-4-yl} carbonyl) (methyl) amino] -2-methyl prepared in Example (6A) Benzyl} -2-methylpiperazine-1-carboxylate tert-butyl (259 mg, 0.430 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and nitrogen atmosphere at room temperature was added. Stir for 1 hour. Toluene (10 mL) was added to the reaction solution, the solvent was evaporated under reduced pressure, 2N aqueous sodium hydroxide solution was added to the resulting residue, and the organic matter was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography (hexane: ethyl acetate: methanol = 100: 0: 0-0: 100: 0-0: 80: 20, v / v / v) for the title purpose. The compound was obtained as a white solid (110 mg, 51% yield).
¹ H NMR (CDCl ₃ , 500 MHz): δ 1.10 (3H, d, J = 6.3 Hz), 1.64 (2H, br d, J = 16.1 Hz), 1.72 (1H, t, J = 10.3 Hz), 1.85 -1.93 (2H, m), 2.02-2.07 (1H, m), 2.16-2.24 (3H, m), 2.33 (3H, s), 2.70 (1H, d, J = 11.2Hz), 2.83-2.95 (3H , m), 3.19 (3H, s), 3.41 (2H, s), 3.66-3.69 (2H, m), 6.88 (1H, d, J = 7.8Hz), 6.89 (1H, s), 7.16 (2H, t, J = 8.8Hz), 7.28 (1H, d, J = 7.8Hz), 7.71-7.74 (2H, m).
(6C) 1-[(4-Fluorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4 1-[(4-Fluorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] prepared with 1-carboxamide hydrochloride (6B) Methyl} phenyl) piperidine-4-carboxamide (450 mg, 0.895 mmol) was dissolved in ethyl acetate (10 mL), 1N hydrochloric acid diethyl ether solution (895 μL, 0.895 mmol) was added at room temperature, and the solid was filtered. Obtained. The obtained solid was redissolved in methanol (5 mL), the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to give the title object compound as a white solid (286 mg, yield 59%).
MS (ESI) m / z: 503 (M + H) ⁺ .

<Example 7> N-ethyl-1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine -4-carboxamide and its hydrochloride

(7A) (2S) -4- {4-[({1-[(4-Fluorophenyl) sulfonyl] piperidin-4-yl} carbonyl) amino] -2-methylbenzyl} -2-methylpiperazine-1- Tert-butyl carboxylate
1-[(4-Fluorophenyl) sulfonyl] piperidine-4-carboxylic acid (210 mg, 0.731 mmol) is dissolved in dichloromethane (10 mL), and oxalyl chloride (200 μL, 2.19 mmol) and a catalytic amount of dimethylformamide are added. The mixture was added at 0 ° C. and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The residue obtained by evaporating the solvent under reduced pressure was dissolved in dichloromethane (15 mL), and (2S) -4- (4-amino-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert- Butyl (158 mg, 0.474 mmol) and triethylamine (200 μL, 1.43 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere.

Water was added to the reaction solution at room temperature, and the organic matter was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-0: 100, v / v) to give the title object compound as a colorless oil (419 mg, 97% yield) Obtained.
¹ H NMR (CDCl ₃ , 500 MHz): δ 1.17 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 1.89-2.04 (5H, m), 2.12-2.15 (1H, m), 2.18 -2.24 (1H, m), 2.34 (3H, s), 2.49-2.55 (3H, m), 2.66-2.68 (1H, m), 2.98-3.04 (1H, m), 3.35 (2H, s), 3.75 -3.80 (2H, m), 4.16 (1H, br s), 7.02 (1H, s), 7.15-7.30 (4H, m), 7.78-7.81 (2H, m).
(7B) (2S) -4- {4- [Ethyl ({1-[(4-fluorophenyl) sulfonyl] piperidin-4-yl} carbonyl) amino] -2-methylbenzyl} -2-methylpiperazine-1 Tert-butyl carboxylate

(2S) -4- {4-[({1-[(4-Fluorophenyl) sulfonyl] piperidin-4-yl} carbonyl) amino] -2-methylbenzyl} -2- prepared in Example (7A) Methylpiperazine-1-carboxylate tert-butyl (419 mg, 0.712 mmol) was dissolved in dimethylformamide (10 mL) and sodium hydride (63%, 35 mg, 0.93 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes under a nitrogen atmosphere, ethyl iodide (114 μL, 1.42 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-0: 100, v / v) to give the title object compound as a colorless oil (370 mg, 84% yield).
¹ H NMR (CDCl ₃ , 500MHz): δ1.06 (3H, t, J = 7.3Hz), 1.18 (3H, d, J = 6.8Hz), 1.47 (9H, s), 1.63 (2H, d, J = 13.2Hz), 1.84-2.00 (2H, m), 2.00-2.05 (1H, m), 2.12-2.21 (4H, m), 2.34 (3H, s), 2.55 (1H, d, J = 11.2Hz) , 2.69 (1H, d, J = 11.2Hz), 3.02-3.08 (1H, m), 3.39 (2H, s), 3.64-3.68 (4H, m), 3.80 (1H, d, J = 14.2Hz), 4.20 (1H, br s), 6.85 (1H, d, J = 7.8Hz), 6.87 (1H, s), 7.17 (2H, t, J = 8.3Hz), 7.27 (1H, d, J = 7.8Hz) , 7.71-7.74 (2H, m).
(7C) N-ethyl-1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4 -Carboxamide

(2S) -4- {4- [Ethyl ({1-[(4-fluorophenyl) sulfonyl] piperidin-4-yl} carbonyl) amino] -2-methylbenzyl} -2 prepared in Example (7B) -Methylpiperazine-1-carboxylate tert-butyl (370 mg, 0.600 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. . Toluene (10 mL) was added to the reaction solution, and then the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the organic matter was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by NH silica gel column chromatography (hexane: ethyl acetate: methanol = 100: 0: 0-0: 100: 0-0: 80: 20, v / v / v) for the title purpose. The compound was obtained as a colorless amorphous substance (242 mg, yield 78%).
¹ H NMR (CDCl ₃ , 400 MHz): δ1.11 (3H, d, J = 6.3 Hz), 1.06 (3H, t, J = 7.0 Hz), 1.61 (2H, m), 1.71 (1H, t, J = 10.2Hz), 1.83-1.93 (2H, m), 2.02-2.19 (4H, m), 2.33 (3H, s), 2.69-2.72 (2H, m), 2.80-2.97 (3H, m), 3.41 ( 2H, s), 3.63-3.68 (4H, m), 6.83-6.86 (2H, m), 7.16 (2H, t, J = 8.6Hz), 7.28 (1H, d, J = 8.6Hz), 7.71-7.74 (2H, m).
(7D) N-ethyl-1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4 -Carboxamide hydrochloride (7C) N-ethyl-1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] Methyl} phenyl) piperidine-4-carboxamide (242 mg, 0.468 mmol) was dissolved in ethyl acetate (5 mL), 1N hydrochloric acid diethyl ether solution (460 μL, 0.468 mmol) was added at room temperature, and the solvent was distilled under reduced pressure. Left. After dissolving in water (8 mL), it was cooled to −78 ° C. and frozen. This was lyophilized with a lyophilizer to give the title object compound as a white solid (240 mg, 93% yield).
MS (ESI) m / z: 517 (M + H) ⁺ .

<Test Example 1> [Biological activity test (measurement of intestinal contractile activity)]
(1) Animals used Male NZW rabbits (body weight 2.5-3.0 kg, Kitayama Labes Co., Ltd., Nagano) were used.
(2) Reagent Carbachol (carbamylcholine chloride, Sigma-Aldrich Japan) was purchased and used. In-house compounds were dissolved in dimethyl sulfoxide (DMSO, Sigma-Aldrich Japan) and suspended in physiological saline. Carbachol was dissolved in physiological saline.
(3) Experimental method / results Rabbits were administered pentobarbital sodium (Kyoritsu Pharmaceutical Co., Ltd., Osaka) from the auricular vein, exsanguinated under anaesthesia, euthanized, and the duodenal site was removed and promptly removed with Krebs solution (NaCl 120.0 mM, It was washed with KCl 4.7 mM, CaCl ₂ 2.4 mM, KH ₂ PO ₄ 1.0 mM, MgSO ₄ 1.2 mM, NaHCO ₃ 24.5 mM, glucose 5.6 mM, pH 7.4). Create a strip (10mm long, 3mm wide) in the longitudinal muscle direction of the duodenal smooth muscle layer from which the mucosal layer has been peeled off, and attach the strip to the Magnus device to suppress excessive spontaneous movement. It was immersed in 20 mL of a Krebs solution containing O ₂ and 5% CO ₂ and 1 g of tension was added. The Krebs solution was changed every 15 minutes until the strips were stabilized, and then left to stand for 1 hour or more. Before starting the experiment, repeated stimulation was performed until reproducible contraction was obtained with carbachol 10 μM stimulation. Contractile activity was measured with a FD pickup (TB-611T, Nihon Kohden Co., Ltd., Tokyo) and recorded with a pen recorder (RECTI HORIZ-8K, Sanei, Tokyo). The test compound was added to the Krebs solution to 0.01 nM to 10 μM, and the strip was contracted by cumulative administration. The contractile activity at each concentration was determined with the contractile activity at 10 μM carbachol stimulation as 100%, and the EC50 value of each test compound was determined. EC50 values are shown below.

Claims (11)

The following general formula (I)

[Wherein, A represents a phenylene group (C1-3 alkyl group, C1-3 alkoxy group, optionally substituted with 1-3 halogen atoms);
B is a C6-10 aryl group (the aryl group may be substituted with 1 to 5 groups selected from the substituent group α), a C3-10 cycloalkyl group (the cycloalkyl group is a substituent) 1 to 5 optionally substituted with a group selected from group α), a 4-10 membered heterocyclic group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur ( The heterocyclic group may be substituted with 1 to 5 groups selected from the substituent group α.
R ¹ represents a hydrogen atom or a C1-3 alkyl group,
R ² represents a hydrogen atom or a C1-3 alkyl group,
R ³ represents a C1-6 alkyl group, a C3-10 cycloalkyl group, a C1-3 alkoxy C1-3 alkyl group or a C1-3 hydroxyalkyl group,
R ⁴ represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom,
n represents an integer of 1 to 4.
(Substituent group α)
A halogen atom, a C1-C6 alkyl group (the alkyl group is a carboxyl group, a C1-C6 alkoxycarbonyl group or a 4-10 member containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur) 1 to 3 substituents may be substituted with a heterocyclic group), a C3-C10 cycloalkyl group (the cycloalkyl group is the same or selected from a carboxyl group, a C1-C6 alkoxycarbonyl group, nitrogen, oxygen and sulfur) Optionally substituted by 1 to 3 4 to 10-membered heterocyclic groups containing 1 to 4 different heteroatoms), C1-C6 haloalkyl group (the haloalkyl group is a carboxyl group, C1-C6 alkoxycarbonyl) A C1-C6 hydroxyalkyl group, optionally substituted by 1 to 3 heterocyclic groups containing the same or different 1-4 heteroatoms selected from the group or nitrogen, oxygen and sulfur) (Hydroxyal 1 to 3 substituents are substituted with a carboxyl group, a C1-C6 alkoxycarbonyl group, or a 4-10 membered heterocyclic group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. C1-C6 alkoxy C1-C6 alkyl group (wherein the alkoxyalkyl group is a carboxyl group, and the C1-C6 alkoxycarbonyl group is the same or different 1-4 selected from nitrogen, oxygen and sulfur) 1 to 3 substituted with a 4-10 membered heterocyclic group containing a heteroatom), a 4-10 member containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur Heterocyclic group, C1-C6 aminoalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 hydroxyalkoxy group, C6-C10 aryloxy group, C1-C6 alkylthio group, carboxy group, C1-C6 Alkoxycarbonyl group, hydroxyl group, C1-C6 fat Group acyl group, amino group, C1-C6 alkylamino group, C3-C10 cycloalkylamino group, C1-C6 dialkylamino group, C1-C6 alkoxyamino group, C1-C6 aliphatic acylamino group, cyano group, nitro group, C1-C6 alkylsulfonyl group, C1-C6 dialkylaminosulfonyl group, C6-C10 aryl group] or a pharmacologically acceptable salt thereof,   The compound according to claim 1, wherein A is a phenylene group which may be substituted by 1-3 C1-3 alkyl groups.   The compound according to claim 1 or 2, wherein B is a C6-10 aryl group (the aryl group may be substituted with 1 to 5 groups selected from the substituent group α). The compound according to any one of claims 1 to 3, wherein R ¹ is a C1-3 alkyl group. The compound according to any one of claims 1 to 4, wherein R ² is a hydrogen atom. The compound according to any one of claims 1 to 5, wherein R ³ is a C1-6 alkyl group. The compound according to any one of claims 1 to 6, wherein R ⁴ is a hydrogen atom or a C 1-6 alkyl group.   The compound according to any one of claims 2 to 7, wherein n is an integer of 1 or 2.   1- (cyclohexylsulfonyl) -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, 1-[(4 -Chlorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, 1-[(5- Chloro-2-thienyl) phenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, N -Methyl-N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) -1- (piperidin-1-ylsulfonyl) piperidine-4-carboxamide, 1- [(4-Fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, 1-[(4- Fluorophenyl) sulfonyl] -N-methyl-N- (3-methyl-4-{[(3S) -3- Tilpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide, N-ethyl-1-[(4-fluorophenyl) sulfonyl] -N- (3-methyl-4-{[(3S) -3- Methylpiperazin-1-yl] methyl} phenyl) piperidine-4-carboxamide.   A pharmacologically acceptable salt of the compound according to any one of claims 2 to 9.   A medicament comprising the compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt as an active ingredient.