JPH11217377A - New alkylamino derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new alkylamino derivative having an excellent affinity to a σ-bonding site and useful as a treating agent and/or a preventive agent of a disease induced and acelerated by a nerve controlling action of the σ-ligand, e.g. central nervous system disease. SOLUTION: This derivative is a compound expressed by the formula: X-Q- C(R<1> )(R<2> )-Z R<1> and R<2> are each hydrogen, an alkynyl, etc.; Z is formula I or II [R<3> is an alkyl, a cycloalkyl, etc.; (p) is 3 to 8; R<4> and R<5> are each hydrogen, an alkyl, etc.; B is formula III (R<6> and R<7> are each hydrogen, nitro, etc.; D is sulfur, oxygen, etc.)]; when X is an aryl, Q is CO, etc., and when X is a dicyclic heteroaryl having 8-10 membered cycles containing 1-2 heteroatoms, Q is a single bond}, its salt, their hydrate or solvate, e.g. (R, S)-1-(1- adamantyl)-2-[4-(6-chloro-2-iminobenzothiazolin-3-ylmethyl)piperidin-1- yl]ethanol.dihydrochloride. The compound is obtained from a compound of formula IV (Z' is a halogen, etc.; Q' is a single bond, etc).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound acting as a ligand for a sigma receptor / binding site, and a medicament containing the compound as an active ingredient.

[0002]

2. Description of the Related Art Brain sigma receptors /
Binding sites are important targets for developing antipsychotics that overcome the side effects of currently available antipsychotics with dopamine D2 receptor antagonism (JM Walke
r, WD Bowen, FO Walker, RR Matsumoto, B. de
Costa and KC Rice, Pharmacological Reviews, 42,
pp.355-402, 1990; G. Debonnel, J. Psychiatr. Neuro
sci., 18, 4, pp.157-172,1993; G. Debonnel and C. d
e Montigny, Life Sciences, 58, 9, pp.721-734,199
6). In addition, data have been reported that suggest that sigma ligands (sometimes referred to herein as "sigma receptor ligands") and their receptors regulate signaling systems by controlling calcium levels in synaptosomes ( PJ Brent, H. Saunders and PR
Dunkley, Neurosci. Lett., 211, pp.138-142, 1996)
.

The term "receptor" as used herein refers to membrane-bound receptors and other binding sites, but the presence of at least two sigma receptor subtypes, sigma 1 and sigma 2, has been confirmed. A classification method for sigma binding sites has been proposed (R. Qui
rion, WD Bowen, Y. Itzhak, JL Junien, JM Mus
acchio, RB Rothman, TP Su, W. Tam and DP Tay
lor, TiPS, 13, pp85-86, 1992). The sigma 1 binding site is characterized by a high affinity for (+) benzomorphanes such as haloperidol, di-o-tolyl guanidine (DTG) and (+) pentazocine, while the sigma 2 binding site Is characterized by high affinity for haloperidol and DTG, but low affinity for (+) benzomorphan.

[0004] The sigma 1 ligand has an effect on the gastrointestinal tract, and the sigma 1 site seems to mediate the inhibition of the muscarinic acetylcholine receptor phosphoinositide response by the sigma ligand. The sigma1 binding site is present not only in the brain but also on spleen cells (Y. Lin, BB Whitlock, JA Pu
ltz and SA Wolfe Jr, J. Neuroimmunol., 58, pp.14
3-154, 1995), such sigma ligands may suppress the immune system (HH Garza, S. Mayo, WDB
owen, BR DeCosta and DJJ Carr, J. of Immunolo
gy, 151, 9, pp. 4672-4680, 1993).

[0005] The sigma 2 binding site is located in the liver (AE Bruc
e, SB Hellewell and WD Bowen, Neurosci. Abstr.,
16, 370, 1990; AS Basile, IA Paul and B. DeCos
ta, Eur. J. Pharmacol. Mol. Pharm. Sect., 227, pp.
95-98, 1992; C. Torrence-Campbell and WDBowen, Eu
r. J. Pharmacol., 304, pp. 201-210, 1996), renal
(WDBowen, G. Feinstein and JSOrringer, Soc. Neu
rosci. Abstr., 18, 456, abstract 195.8, 1992) and intracardiac (M. Dumontand S. Lemaire, Eur. J. Pharmaco
l., 209, pp. 245-248, 1991).

[0006] The sigma-2 binding site in the brain is located in the hypothalamus, cerebellum, and in the pons, pons medulla.
In the hippocampus, frontal lobe, and occipital lobe in the rat brain, sigma 1
Abundant than binding site (DJ Mc Cann, AD W
eissmann and TP Su, Soc. Neurosci. abstr. 18, 2
2, abstract 16.5, 1992). Guinea pig hippocampal synaptosomes also have a sigma2 binding site that is selectively labeled by [ ³ H] BIMU (DW Bonhaus, DN Louie).
ry, LB Jakeman, Z. To, A. DeSouza, RM Eglen an
d EHF Wong, J. Pharmacol. Exp. Ther., 267, 2, p
p.961-970, 1993). The relationship between the sigma2 binding site and the cortex and limbic system has provided support for the usefulness of compounds used in the treatment of psychosis (DC Mash and CP Zabetian, S
ynapse, 12, pp. 195-205, 1992).

[0007] The sigma 2 binding site has been thought to be involved in motor activity, especially dystonia (RR Matsumoto,
MK Hemstreet, NL Lai, A. Thurkauf, BR DeCost
a, KCRice, SB Hellewell, WD Bowen and JM W
alker, Pharmacol. Biochem. Behav., 36, pp. 151-155,
1990). However, there is no evidence of such an effect in primate models of extrapyramidal dysfunction (LT
Meltzer, CL Christoffersen, KA Serpa, TA Pu
gsley, A. Razmpour and TG Heffner, Neuropharmaco
logy, 31, 9, pp. 961-967, 1992).

Although haloperidol, a clinically effective dopaminergic antipsychotic, has a high affinity for these two sigma subtypes, the reduced metabolite of haloperidol acting on the central nervous system is compared to haloperidol. And has better affinity and selectivity for sigma 2 receptor than dopamine D2 (JC Jaen. BWC
aprathe, TA Pugsley, LD Wise and H. Akunne, J.
Med. Chem., 36, pp. 3929-3936, 1993). In fact, the pharmacological significance, distribution, and function of the sigma 2 binding site have not been elucidated because a selective drug is not available. On the other hand, recent studies have shown that sigma 2 sites play a role in regulating ileal function (G.
G. Kinney, EW Haris, R. Ray and TJ Hudzik, Eur
op. J. Pharmacol., 294, pp. 547-553, 1995). These data suggest that the selective sigma2 ligand is useful for treating irritable bowel syndrome.

Although there is much literature on heteroarylalkylamino derivatives, there is little data on compounds in which the heteroaryl moiety is benzothiazoline and its analogs. Several polyfluoroalkoxy-2-iminobenzothiazolines have been reported as compounds having an anti-glutamic acid action. (P. Jimone
t P., F. Audiau, M. Barreau, F. Beaudoin, J.-C. Bl
anchard, G. Dutruc-Rosset, C. Gueremy, P. Laduron,
J. Le Blevec, S. Mignani, C. Nemecek, J. Rataud a
nd J.-M. Stutzmann, presented at XIIth International
al Symposium onMedicinal Chemistry, Basel, Switzer
land, 1992; P. Jimonet P., M. Barreau, J.-C. Blanc
hard, A. Boireau, A. Doble, P. Laduron, J. Lavayr
e, C. Malgouris, O. Piot, J. Pratt, J. Rataud, M.
Reibaud, S. Mignani and J.-M. Stutzmann, Bioorg. A
nd Med. Chem., 2, 8, pp. 793-798, 1994).

[0010] Also, Japanese Patent Application No. 58-180481, international publication
WO 87/02359, WO 87/02035 and WO 87/02666, and U.S. Pat. No. 4,215,119 describe benzimidazole methylpiperidine derivatives. European Patent Publication No. 546,388 discloses a heteroarylmethylpiperidine derivative of chroman, but there is no illustration of a benzothiazoline derivative. The International Publication WO 93/22309 4- India-methyl-1- [2'-phenyl-2'-oxoethyl] piperidines have been disclosed as serotonin 5-HT ₂ antagonist. U.S. Patent No. 5,500,433 describes piperidinoethanone as a dopamine and serotonin antagonist. However, the above compounds are not known to have an affinity for the sigma binding site.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound having excellent affinity for a sigma binding site. Another object of the present invention is to provide a medicament containing a compound having the above-mentioned characteristics as an active ingredient, and being useful for treating and / or preventing a disease caused or promoted by the neuromodulating action of a sigma ligand. is there.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above problems, and as a result, a group of compounds represented by the following formulas has a high affinity for the sigma binding site. A low inhibition constant Ki for sigma 1 and / or sigma 2; and these compounds have a completely different selective binding profile as compared with conventionally known compounds; Is useful for the treatment and / or prevention of diseases caused or promoted by The present invention has been completed based on these findings.

That is, the present invention provides the following formula (I): XQC (R
¹ ) (R ² ) -Z wherein R ¹ and R ² are each independently a hydrogen atom,
Z represents an alkyl group, a cycloalkyl group, a hydroxyalkyl group, or an alkenyl group;

Embedded image [Wherein, R ³ represents an alkyl group, a cycloalkyl group, a hydroxyalkyl group, or an alkenyl group; p represents an integer of 3 to 8; R ⁴ and R ⁵ each independently represent a hydrogen atom or an alkyl group Or R ⁴ and R ⁵ together with other intervening atoms represent a 5- to 7-membered heterocyclic ring;

Embedded image (Wherein R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a cycloalkyl group, an alkenyl group, a halogenated alkyl group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, an alkoxycarbonyl group A phenyl group, a substituted or unsubstituted amino group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted carbamoyl group, an acyl group, a cyano group, and an alkynyl group. A substituent selected from the group; D represents a sulfur atom, an oxygen atom, or a group represented by NR ⁸ (wherein R ⁸ is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-substituted alkyl group, an alkenyl group) , Halogenated alkyl group, hydroxyalkyl group, alkoxyalkyl group, alkoxy Carbonyl group, phenyl group,
Alkylsulfinyl, alkylsulfonyl, substituted or unsubstituted sulfamoyl, alkylsulfonylamino, alkylcarbonylamino, substituted or unsubstituted carbamoyl, acyl, cyano, and alkynyl; X represents a monocyclic or polycyclic cycloalkyl group, a cycloalkyl-substituted alkyl group, an aryl group, or a heterocyclic group, which may be substituted with an alkyl group. When it represents an aryl group, Q represents -CO-, -C (= NO
A group represented by H)-or -C (Y) (A)-, wherein Y is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a monocyclic or polycyclic cycloalkyl group, or a cycloalkyl-substituted group; A represents an alkyl group, an aryl group, an aryl-substituted alkyl group, a heteroaryl group, or a heteroaryl-substituted alkyl group, and A represents a group represented by -OR ⁹ (R ⁹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, X represents an alkyl group, an alkenyl group, an aryl group, an aryl-substituted alkyl group, a hydroxyalkyl group, or an acyl group), and X is an 8- to 10-membered bicyclic heterocyclic group containing 1 or 2 heteroatoms. In the case where it represents an aryl group, Q represents a single bond], a salt thereof, or a hydrate or solvate thereof.

From another viewpoint, the above-mentioned compound and a salt thereof,
And a medicament containing, as an active ingredient, a substance selected from the group consisting of hydrates and solvates thereof. In a preferred embodiment, a disease caused or promoted by the neuromodulating action of sigma ligand (for example, central nervous system) Systemic disease, gastrointestinal disease, or heart defect system disease) and / or
Alternatively, the above-mentioned medicine for use in prevention is provided. Further, the present invention provides a sigma ligand comprising a substance selected from the group consisting of the above compounds and salts thereof, and hydrates and solvates thereof.

From a further aspect, it is selected from the group consisting of the above-mentioned compounds, salts thereof, and hydrates and solvates thereof for the manufacture of the above-mentioned medicaments, preferably in the form of pharmaceutical compositions. And a method for treating and / or preventing a disease caused or promoted by the neuromodulatory action of a sigma ligand, comprising the above compound and a salt thereof,
And a method comprising administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of hydrates and solvates thereof.

[0016]

In the above formula (I), R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group or an alkenyl group.
Among these, it is preferable that both R ¹ and R ² are hydrogen atoms.

As used herein, the term "alkyl group" or the term "alkyl" used for a group containing an alkyl group as a constituent is, for example, 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms. 1
And from 4 straight or branched chain alkyl groups. More specifically, as the alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
An isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, an n-hexyl group, and the like can be used.

As used herein, the term "cycloalkyl group" or the term "cycloalkyl" used for a group containing a cycloalkyl group as a constituent includes, for example, a 3- to 8-membered ring, preferably a 3- to 8-membered ring.
And a cycloalkyl group having about 6 to 6 members (unless otherwise specified, a monocyclic cycloalkyl group). These cycloalkyl groups may have one or more alkyl groups on the ring. More specifically, as a cycloalkyl group, for example, a cyclopropyl group, a methylcyclopropyl group, a cyclobutyl group, a cyclopentyl group,
A cyclohexyl group, a methylcyclohexyl group, a dimethylcyclohexyl group, or the like can be used.

The term "hydroxyalkyl group" as used herein includes alkyl groups having one or more, preferably one, hydroxyl group.
As the hydroxyalkyl group, a hydroxyalkyl group having 2 to 6 carbon atoms can be preferably used, and more specifically, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 4-hydroxybutyl group, -Hydroxypentyl group, 6-hydroxyhexyl group and the like can be used.

As used herein, the term "alkenyl" refers to, for example, a straight or branched alkenyl group having 2 to 6, preferably 3 to 6, carbon atoms, Or an alkenyl group containing two or more, preferably one, double bond. Examples of the alkenyl group include a 1-propenyl group, an allyl group, an isopropenyl group, a 1-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 1 A -hexenyl group, a 2-hexenyl group, or the like can be used. The double bond present in the alkenyl group may be in either cis or trans configuration.

In the above group represented by Z, R ³ represents an alkyl group, a cycloalkyl group, a hydroxyalkyl group, or an alkenyl group; p represents an integer of 3-8. Also, R ⁴
And R ⁵ each independently represent a hydrogen atom or an alkyl group, or R ⁴ and R ⁵ together with other intervening atoms are 5-7
Represents a membered heterocycle. Among these, a compound in which R ³ is an alkyl group and p is 3 to 6, and a compound in which R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group are preferred. R ³ is preferably a methyl group, p is preferably ^4, and both R ⁴ and R ⁵ are preferably hydrogen atoms.

In the above group represented by B, R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a cycloalkyl group, an alkenyl group, a halogenated alkyl group, a hydroxyl group, an alkoxy group, a halogen atom. Alkoxy group, alkoxycarbonyl group, phenyl group, substituted or unsubstituted amino group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, substituted or unsubstituted sulfamoyl group, substituted or unsubstituted carbamoyl group, acyl group, cyano group And a substituent selected from the group consisting of an alkynyl group.

In the present specification, the term "halogen" or "halogenated" may be any of a fluorine, chlorine, bromine or iodine atom. As used herein, the term "halogenated alkyl group" includes, for example, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a pentafluoroethyl group, a monochloromethyl group, a dichloromethyl group. , A trichloromethyl group and the like, and a preferred example is a trifluoromethyl group.

As used herein, the term "alkoxy group" or the term "alkoxy" used for a group containing an alkoxy group as a constituent is, for example, 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms. 1-4 straight or branched alkoxy groups are included. More specifically, as the alkoxy group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, or n-hexyloxy group Etc. can be used. As the halogenated alkoxy group, for example, a trifluoromethoxy group, a trifluoroethoxy group, a monochloromethoxy group, a trichloromethoxy group, or the like can be used.

As the alkoxycarbonyl group, for example, an alkoxycarbonyl group constituted by the above-mentioned alkoxy group can be used. More specifically, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group And the like. Examples of the alkylthio group include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, an n-pentylthio group, and an n-hexylthio group.

Examples of the substituted amino group include an alkylamino group such as a monoalkylamino group or a dialkylamino group, an acylamino group such as an alkanoylamino group or an arylcarbonylamino group, an aralkylamino group, and an alkylsulfonylamino group. be able to. More specifically, a monomethylamino group,
Alkylamino groups such as dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, butylamino, pentylamino, hexylamino; acetylamino, trifluoroacetylamino Acylamino groups such as a group, propionylamino group, benzoylamino group and p-methoxybenzoylamino group; aralkylamino groups such as a benzylamino group and a paramethoxybenzylamino group;
Examples thereof include alkylsulfonylamino groups such as methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, and n-hexylsulfonylamino group.

Examples of the alkylsulfinyl group include a methylsulfinyl group, an ethylsulfinyl group, an n-propylsulfinyl group, an n-butylsulfinyl group, an n-pentylsulfinyl group, and an n-hexylsulfinyl group. Examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group,
Examples thereof include an n-propylsulfonyl group, an n-butylsulfonyl group, an n-pentylsulfonyl group, and an n-hexylsulfonyl group. Examples of the substituted sulfamoyl group include a sulfamoyl group substituted with one or two alkyl groups, and more specifically, a methylaminosulfonyl group, a dimethylaminosulfonyl group, an ethylaminosulfonyl group, or a diethylamino group. A sulfonyl group or the like can be used.

Examples of the substituted carbamoyl group include a carbamoyl group substituted with one or two alkyl groups, and more specifically, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group and the like are used. be able to. Examples of the acyl group include an alkanoyl group (such as an alkylcarbonyl group and a halogenated alkylcarbonyl group), an arylcarbonyl group, and a heteroarylcarbonyl group. More specifically, a formyl group, an acetyl group, a propionyl group, a trifluoromethylcarbonyl group, a pentafluoroethylcarbonyl group, a benzoyl group, a p-methoxybenzoyl group, a 3-pyridylcarbonyl group, and the like can be used. Alkynyl groups include 2 to 6 carbon atoms,
Preferably a straight or branched alkynyl group having 3 to 6 carbon atoms, for example, 2-propynyl group, 3-butynyl group,
Examples thereof include a 4-pentynyl group and a 5-hexynyl group.

Among them, R ⁶ and R ⁷ are preferably each independently a substituent selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group and an alkoxy group, and R ⁶ is hydrogen. More preferably, it is an atom. R ⁶ is a hydrogen atom, R ⁷ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a trifluoromethyl group, or a compound is preferably a methoxy group,
Particularly preferred are compounds in which R ⁶ is a hydrogen atom and R ⁷ is a chlorine or bromine atom. The substitution position of R ⁶ and R ⁷ is not particularly limited, but when R ⁶ is a hydrogen atom and R ⁷ is a group other than a hydrogen atom, R ⁷ is benzothiazolin-3-yl represented by B It is preferably substituted at the 6-position of the group.

[0030] In the group represented by B in the above equation, D is a sulfur atom, an oxygen atom, or a group represented by NR ^8, R ⁸
Is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-substituted alkyl group, an alkenyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxycarbonyl group, a phenyl group, an alkylsulfinyl group, an alkylsulfonyl group, a substituted or And a substituent selected from the group consisting of an unsubstituted sulfamoyl group, an alkylsulfonylamino group, an alkylcarbonylamino group, a substituted or unsubstituted carbamoyl group, an acyl group, a cyano group, and an alkynyl group.

As the cycloalkyl-substituted alkyl group,
Examples include a cyclopropylmethyl group, a methylcyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a dimethylcyclohexylmethyl group. Can be. As the alkoxyalkyl group, for example,
Examples thereof include a 2-methoxyethyl group, a 3-methoxypropyl group, a 2-ethoxyethyl group, a 3-ethoxypropyl group, and a 3-propoxypropyl group.

As the alkoxycarbonyl group, alkylsulfinyl group, alkylsulfonyl group, substituted sulfamoyl group, alkylsulfonylamino group, alkylcarbonylamino group, substituted carbamoyl group, acyl group and alkynyl group, those exemplified above can be used. Can be. Of these, R ⁸ is preferably a hydrogen atom, an alkyl group, a halogenated alkyl group, and a substituent selected from the group consisting of an acyl group, and R ⁸ is a hydrogen atom, a methyl group, an ethyl group, More preferably, they are a 1,2-trifluoroethyl group and an acetyl group.

In the above formula (I), X is a monocyclic or polycyclic cycloalkyl group optionally substituted with an alkyl group;
Represents a cycloalkyl-substituted alkyl group, an aryl group, or a heteroaryl group, and Q is -CO-, -C (= NOH)-, or
A group represented by -C (Y) (A)-(wherein Y is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a monocyclic or polycyclic cycloalkyl group, a cycloalkyl-substituted alkyl group,
A represents an aryl group, an aryl-substituted alkyl group, a heteroaryl group, or a heteroaryl-substituted alkyl group;
A group represented by OR ⁹ (R ⁹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-substituted alkyl group, an alkenyl group, an aryl group, an aryl-substituted alkyl group, a hydroxyalkyl group, or an acyl group) Is shown.
Alternatively, X is from 8 to containing 1 or 2 heteroatoms
It represents a 10-membered bicyclic heteroaryl group, and Q represents a single bond. When Q is a group other than a single bond, -CH (OH)-
Or -CO-.

Examples of the polycyclic cycloalkyl group include a 5- to 12-membered polycycloalkyl group such as a norbornyl group and an adamantyl group, and preferably an adamantyl group. As the cycloalkyl-substituted alkyl group, those exemplified above can be used. As the aryl group, a 1 to 3 ring aryl group can be used, for example, a phenyl group,
In addition to a 1-naphthyl group and a 2-naphthyl group, a phenanthryl group, an anthracenyl group and the like can be used.

As the heteroaryl group, a 5- to 10-membered 1 to 3 ring heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms is used. be able to. For example, a furyl group (furan ring), a benzofuranyl group (benzofuran ring), an isobenzofuranyl group (isobenzofuran ring),
Thienyl group (thiophene ring), benzothiophenyl group (benzothiophene ring), pyrrolyl group (pyrrole ring),
Imidazolyl group (imidazole ring), pyrazolyl group (pyrazole ring), thiazolyl group (thiazole ring), benzothiazolyl group (benzothiazole ring), isothiazolyl group (isothiazole ring), benzoisothiazolyl group (benzoisothiazole ring), triazolyl Group (triazole ring), tetrazolyl group (tetrazole ring), pyridyl group (pyridine ring), pyrazinyl group (pyrazine ring), pyrimidinyl group (pyrimidine ring), pyridazinyl group (pyridazine ring), isodolyl group (indole ring), isoindolyl group (Isoindole ring), benzimidazolyl group (benzimidazole ring), purinyl group (purine ring),
Quinolyl group (quinoline ring), isoquinolyl group (isoquinoline ring), dihydroisoquinolyl group (dihydroquinoline ring), phthalazinyl group (phthalazine ring), naphthyridinyl group (naphthyridine ring), quinoxalinyl group (quinoxaline ring), cinnolyl group (cinnoline) Ring), pteridinyl group (pteridine ring), oxazolyl group (oxazole ring), isoxazolyl group (isoxazole ring), benzoxazolyl group (benzoxazole ring), benzoisoxazolyl group (benzoisoxazole ring), furzanil Groups (furazan ring) and the like can be used.

In the present specification, when an “aryl group” or a “heteroaryl group” is not particularly specified, the aryl group or the heteroaryl group has one or more substituents on its ring. And such substituents include a halogen atom, a nitro group,
Alkyl group, cycloalkyl group, alkenyl group, halogenated alkyl group, hydroxyl group, alkoxy group, halogenated alkoxy group, carboxyl group, alkoxycarbonyl group, phenyl group, substituted or unsubstituted amino group, alkylthio group, alkylsulfinyl group, Examples include an alkylsulfonyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted carbamoyl group, an acyl group, a cyano group, and an alkynyl group. As these substituents, those described above can be preferably used.

In the group -C (Y) (A)-represented by Q, Y represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a monocyclic or polycyclic cycloalkyl group, a cycloalkyl-substituted alkyl group, or an aryl group. , An aryl-substituted alkyl group, a heteroaryl group, or a heteroaryl-substituted alkyl group. A represents a group represented by -OR ^9, wherein R ⁹ is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-substituted alkyl group, alkenyl group, aryl group, aryl-substituted alkyl group, a hydroxyalkyl group, or an acyl Represents a group.

In the above Y and A, an alkynyl group,
As the polycyclic cycloalkyl group, cycloalkyl-substituted alkyl group, aryl group, heteroaryl group, and acyl group, those described above can be used. Examples of the aryl-substituted alkyl group include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a 2-phenylpropyl group, a 3-phenylpropyl group,
Examples thereof include a 1-naphthylmethyl group and a 2-naphthylmethyl group. As the heteroaryl-substituted alkyl group, an alkyl group substituted by the above-mentioned heteroaryl group can be used. More specifically, for example, 2-furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 1-imidazolylmethyl group, 2-imidazolylmethyl group, 2-thiazolylmethyl group, 1- A pyridylmethyl group, a 2-pyridylmethyl group, a 3-pyridylmethyl group, a 4-pyridylmethyl group, a 1-quinolylmethyl group, a 2-quinolylmethyl group, and the like can be used.

When X represents an 8- to 10-membered bicyclic heteroaryl group containing one or two heteroatoms, Q represents a single bond. As the 8- to 10-membered bicyclic heteroaryl group, in addition to a bicyclic fused heteroaromatic group, a heteroaryl group in which one ring is saturated or partially reduced can be used. For example, benzofuranyl group, indolyl group, benzoisothiazolyl group, benzothiazolyl group,
Benzoisoxazolyl group, benzoxazolyl group, benzimidazolyl group, isoquinolinyl group, quinolinyl group, 1,2,3,4-tetrahydroisoquinolinyl group, 1,2,3,4-
A tetrahydroquinolyl group or the like can be used. X
Specific examples of preferred groups are shown below.

[0040]

Embedded image

Of the compounds included in the above formula (I),
As a preferred group of compounds, (1) R ¹ and R ² are each independently a hydrogen atom or an alkyl group, R ³ is an alkyl group, p is 4, R ⁴ and R ⁵ are both hydrogen atoms. ,
R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a substituent selected from the group consisting of an alkoxy group, R ⁸ is a hydrogen atom, an alkyl group, a halogenated alkyl group, And X is a substituent selected from the group consisting of an acyl group; X is a monocyclic or polycyclic cycloalkyl group optionally substituted with an alkyl group, a substituted or unsubstituted phenyl group (the substituent is a halogen atom, An alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, and one or more substituents selected from the group consisting of a substituted or unsubstituted aminosulfonyloxy group). the, Q is -CO -, - C (= NOH ) -, or -C (Y) (a) - group represented by (wherein, Y is hydrogen atom, a is represented by -OR ⁹ group (R ⁹ is a hydrogen atom, an alkyl And X is an 8- to 10-membered bicyclic heteroaryl group containing 1 or 2 heteroatoms, and a compound wherein Q is a single bond can be mentioned. .

[0042] As a further preferred group of compounds, (2) R ³ is an alkyl group, R ⁴ and R ⁵ are both hydrogen atoms, R ⁶
Is a hydrogen atom, R ⁷ is a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a substituent selected from the group consisting of an alkoxy group, X is a monocyclic or an alkyl group may be substituted Polycyclic cycloalkyl group,
A substituted or unsubstituted phenyl group (the substituent is selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, and a substituted or unsubstituted aminosulfonyloxy group A group represented by -CO-, -C (= NOH)-, or -C (Y) (A)-, wherein Y is Is a hydrogen atom, and A is a group represented by —OR ⁹ (R ⁹ is a hydrogen atom, an alkyl group, or an acyl group).

As a particularly preferred group of compounds, (3) the compounds of the above (2), wherein X is a substituted or unsubstituted phenyl group;
(4) The compound of the above (3), wherein X is a p-fluorophenyl group; (5) R ⁶ is a hydrogen atom and R ⁷ is a halogen atom (preferably substituted at the 6-position of a benzothiazolin-3-yl group) (3) or (4), wherein D is an oxygen atom or a group represented by NR ⁸ (where R ⁸ is a hydrogen atom or an alkyl group); Q is -CO- or -CH (OH)-
And the compounds of the above (3) to (5).

More specifically, X is a p-fluorophenyl group, R ⁷ is a chlorine atom, D is NH, and Q is -C
The above compound which is O- or -CH (OH)-; X is a p-fluorophenyl group, R ⁷ is a chlorine atom, D is NCH ₃ ,
The above compound wherein Q is -CO- or -CH (OH)-; X is a p-fluorophenyl group, R ⁷ is a fluorine atom, D is NH, and Q is -CO- or -CH ( OH)-, wherein X is p-
X is a p-fluorophenyl group, wherein R ⁷ is a trifluoromethyl group, D is NH, and Q is -CO- or -CH (OH)-; ⁷ is a bromine atom, D is an oxygen atom, and Q is -CO- or -CH (O
X) is a p-fluorophenyl group, R ⁷ is a chlorine atom, D is an oxygen atom, and Q is -C
The above compound which is O- or -CH (OH)-; X is a p-fluorophenyl group, R ⁷ is a fluorine atom, D is an oxygen atom, and Q is -CO- or -CH (OH) And X is-
Is an unsubstituted phenyl group, R ⁷ is a bromine atom, D
Is an oxygen atom, and Q 2 is —CO— or —CH (OH) —. However, the compound of the present invention is not limited to these preferred compounds.

Specific examples of particularly preferred compounds of the present invention are shown in the following table, but the compounds of the present invention are not limited to these. In the compound group shown below, R ¹ and
R ² is both hydrogen atoms. In the table, for example, for X, the title of “pFC ₆ H ₄ −” indicates that X is a parafluorophenyl group, and for R ⁷ , the title of “6-Cl” indicates that 6 is of the benzothiazolin-3-yl group. Indicates that a chlorine atom is substituted at the position, and the same applies to other notations. Table 1 shows compounds of methylene type, and Table 2 shows compounds of piperidine type. Besides these, the compounds specifically disclosed in the examples of the present specification are also particularly preferred compounds of the present invention.

[0046]

[Table 1]

[0047]

[Table 2]

The compound of the present invention represented by the above formula (I) may have one or more asymmetric carbon atoms, and can exist as an optical isomer. Both the racemic and pure forms of the optical isomers, as well as mixtures of any optical isomers, are within the scope of the present invention. Racemates can be separated into optical isomers in pure form by methods well known to those skilled in the art. Also, diastereoisomers based on two or more asymmetric carbons or any mixtures thereof are included in the scope of the present invention. Acid addition salts of the compounds of the present invention represented by the above formula (I), preferably pharmacologically acceptable acid addition salts, hydrates, and any solvates are also included in the scope of the present invention. .

The salts which the compounds of the present invention can form include:
For example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate, succinate, acetate, glycolate, methanesulfonate, and toluenesulfonic acid Examples thereof include organic acid salts such as salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, and ammonium salts such as ammonium salts and alkylammonium salts.
Examples of the solvate solvent that can be formed by the compound of the present invention include methanol, ethanol, isopropanol, acetone, and ethyl acetate. However,
The form of the salt or solvate is not limited to those exemplified above.

The compounds of the present invention have a high affinity for the sigma binding site (as used herein, when a compound is referred to as a “sigma ligand”
Meaning that the compound has the properties described above). Accordingly, the compounds of the present invention can be used in mammals, including humans,
Preferably, it is useful as a medicament for treating and / or preventing various diseases and conditions caused or promoted by the neuromodulating action of sigma ligand in humans. Such disorders include, for example, central nervous system disorders, gastrointestinal disorders,
And cardiovascular diseases.

The central nervous system diseases include, for example, anxiety,
Depression or emotional disorders, schizophrenia, drug addiction or addiction, pain, dyskinesia, cerebrovascular disorders, epilepsy, dementia including Alzheimer's disease, Parkinson's syndrome, brain tumors, and attention deficit disorders. As gastrointestinal diseases, for example, irritable bowel syndrome, irritable colon,
Mention may be made of spastic colon, mucosal colitis, small bowel colitis, diverticulitis, and dysentery. In addition, examples of the cardiovascular disease include hypertension, arrhythmia, and angina. However, the target of application of the medicament of the present invention is not limited to these specific diseases and / or symptoms, and various diseases and / or diseases involving sigma ligands in vivo.
Or it can be applied to the treatment and / or prevention of symptoms.

As the active ingredient of the medicament of the present invention, one or more substances selected from the group consisting of the above compounds and salts thereof, and hydrates and solvates thereof can be used. The administration route of the medicament of the present invention is not particularly limited,
It can be administered orally or parenterally. As the medicament of the present invention, the above-mentioned substance may be administered to a patient as it is, but preferably as a preparation in the form of a pharmaceutical composition containing an active ingredient and a pharmacologically and pharmaceutically acceptable additive. Should be administered. Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases, solubilizers and the like. Dissolution aids, tonicity agents, pH adjusters, stabilizers, propellants, adhesives and the like can be used. Examples of formulations suitable for oral administration include, for example,
Tablets, capsules, powders, fine granules, granules, liquids, syrups and the like can be mentioned. Examples of preparations suitable for parenteral administration include injections, drops, ointments, creams, and transdermals. Examples include skin absorbents, eye drops, ear drops, inhalants, and suppositories, but the form of the preparation is not limited thereto.

Formulations suitable for oral administration include, as additives, excipients such as glucose, lactose, D-mannitol, starch or crystalline cellulose; disintegrants such as carboxymethylcellulose, starch or calcium carboxymethylcellulose; Disintegration aid; binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin;
Lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol or titanium oxide; groups such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat Agents can be used. Suitable preparations for injection or infusion include solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injections such as distilled water for injection, physiological saline and propylene glycol; glucose, sodium chloride, D-mannitol , Glycerin and the like; tonicity additives such as pH adjusters such as inorganic acids, organic acids, inorganic bases and organic bases.

The dosage of the medicament of the present invention should be appropriately increased or decreased according to the type of disease to be applied, the purpose of prevention or treatment, the age, weight, and symptoms of the patient. The daily dose for adults is approximately
It is about 0.05 to 500 mg. Generally, the above dose can be administered in one to several doses per day, but may be administered every few days.

The method for producing the compound of the present invention represented by the formula (I) is not particularly limited, but for example, it can be produced according to any of the following methods. Further, the examples of the present specification show more specifically the production methods for preferred compounds of the compounds of the present invention. Those skilled in the art will be able to refer to the following general description and the specific description of the examples, and if necessary, modify or modify the starting materials, reaction conditions, reaction reagents, and the like, so that they are included in the formula (I). Any of the compounds of the present invention can be prepared.

Scheme A:

Embedded image

A compound of the formula (II) wherein Z ′ is a halogen atom such as chlorine, bromine or iodine, or tosylate or mesylate;
Represents a single bond or -CO-) with a nucleophilic amino derivative (III) represented by HZ (Z is as defined above) to obtain a corresponding compound (I). Usually, this reaction may be performed in a polar solvent such as dimethylformamide, ethanol, or acetonitrile in the presence of a base such as triethylamine, sodium bicarbonate, or potassium carbonate.

When Q ′ is —CO—, the amino-keto derivative (I) can be reduced to obtain a hydroxy derivative in which A is a hydroxyl group and Y is a hydrogen atom in the formula (I ′). . Generally, reduction can be carried out using sodium borohydride in an organic solvent such as ethanol, methanol, or tetrahydrofuran at room temperature.
Even when the amino-keto derivative (I) is reacted with an organometallic reagent such as Y-MgBr, a compound in which A in Formula (I ') is a hydroxyl group can be produced.

The acyloxy and alkoxy compounds can be prepared by conventional methods starting from the free hydroxy derivatives. The O-alkyl derivative may be produced by solvolysis of a sulfonyl ester intermediate [Ad
vanced Organic Chemistry, J. March. John Wiley & so
ns, New York, pp. 264-317, 1985]. Chiral ethers can also be obtained by solvolysis of chiral sulfonyl ester derivatives such as camphorsulfonate. Q '
The oxime of the keto derivative (I) when is -CO- is Organic
Functional Group Preparation Vol. III, SR Sandle
r and W. Karo, Academic Press, London, pp. 430-481,
It can be produced by the oximation method as described in 1989.

As the compound of the formula (II), a commercially available compound may be used,
Alternatively, it can be obtained by halogenation using a methyl group (when Q is a single bond) or a methyl ketone group (when Q is -CO-) as a starting material, or a method analogous thereto.
In the synthesis of benzoisoxazoline derivatives and benzoisothiooxazoline derivatives, known literature [H. Un
o, M. Kurokawa, K. Natsuka, Y. Yamato and H. Nishi
mura, Chem. Pharm. Bull., 24 (4), pp.632-643, 1976;
H. Uno and M. Kurokawa, Chem. Pharm. Bull., 26 (1
2), pp. 3888-3891, 1978].

The starting compounds described in Scheme A above
The compound in which D is NR ⁸ in (III) can be produced by the method shown in the following scheme. In these schemes, the target derivative having a piperidine ring is described, but an acyclic compound can be produced in the same manner. The substituent P of the compound shown in the scheme is Protecti
ve Groups in OrganicSynthesis [TW Greene and P.
GM Wuts, John Wiley & Sons, New York, 1991], wherein the protecting group of the amino group is easily removed to give the piperidine compound of formula (III).

[0062]

Embedded image

N of the trifluoroacetamide precursor (V)
The alkylation is carried out using an activated derivative of the formula (IV), wherein Z ″ represents a halogen atom such as a chlorine, bromine or iodine atom, or tosylate or mesylate, etc. The N-alkylation reaction can be carried out preferably in dimethylformamide in the presence of sodium hydride as a base at a temperature of at least 50 ° C. If desired, the reaction may take up to 1 molar equivalent or less. An iodide salt (eg, Nal, KI) can be added as a catalyst, and the reaction can be carried out using toluene as a solvent, sodium hydroxide or potassium hydroxide as a base, and a catalytic amount of tetrabutylammonium sulfate. The N-alkylation of derivative (V) may be carried out by the Mitsunobu reaction (O. Mitsunobu, Synthesis, pp. 1-28, 1). 981)
It can be carried out directly using a hydroxy derivative of (IV) (wherein Z ″ = OH).

The trifluoroacetamide (V) can be produced by reacting a 2-aminobenzothiazole derivative with trifluoroacetic anhydride in the presence of one equivalent of a base. 2-Aminobenzothiazoles can be used commercially or can be synthesized by the method of R. Schubart et al. [R. Schubart, H. Kropf and F. Wohrle in M.
ethoden der Organischen Chemie, Houben-Weil, stutt
gart-New-York: Thieme, Band E-8b, pp.865-1062, 199
Four]. The imino group of the derivative (VI) can be converted to a carboxamide derivative, a urea derivative, or a carbamoyl derivative by a known method. Further, a 2-alkyliminobenzothiazoline derivative can be obtained by reducing the carboxamide derivative of (VI). Preferred reducing agents include borohydride salts and borane reagents. A sulfonamide derivative, a sulfonylurea derivative or a sulfamoyl derivative can be similarly produced from (VI).

[0065]

Embedded image

Another synthesis method of the benzothiazoline derivative represented by the general formula (VI ') is shown in the above scheme. The acylation of the aniline derivative (VII) is carried out by reacting the compound of the formula (IV ') ((IV')
Wherein Z ″ ′ represents a hydroxyl group or a halogen atom such as a chlorine atom, or a mesylate or the like) according to a known method. Using a reducing agent,
It can be performed in an organic solvent such as tetrahydrofuran,
An amino derivative represented by the formula (VIII) can be obtained.
The thiourea derivative represented by the formula (IX) is an amino derivative (V
It can be synthesized by the reaction of III) with isothiocyanates.

The synthesis of the benzothiazoline derivative (VI ') by oxidative cyclization of the thiourea derivative (IX) can be carried out by a method described in the literature [R. Schubart, H. Kropf and F. Wohrle in Methode.
n derOrganischen Chemie, Houben-Weil, stuttgart-Ne
w-York: Thieme, Band E-8b, pp. 865-1062, 1994]. Here, when R ⁸ is a hydrogen atom,
By reacting the intermediate (VIII) with a thiocyanate such as sodium thiocyanate, potassium thiocyanate or ammonium thiocyanate and bromine in a solvent such as methanol or acetic acid, the benzothiazoline derivative (V
I ′ where R ⁸ = H) can be obtained.

The starting compounds described in Scheme A above
In the case where D is an oxygen atom in (III), the synthesis is
It can be produced by the method shown in the following scheme.
In these schemes, the target derivative having a piperidine ring is described, but an acyclic compound can be produced in the same manner. Substituent P of the compound shown in the scheme
Protective Groups in Organic Synthesis [TWGr
eene and PGM Wuts, John Wiley & Sons, New York,
1991], wherein the protecting group is easily removed to give a piperidine compound of formula (III).

[0069]

Embedded image

N- of the 2-oxobenzothiazoline derivative (X)
Alkylation is carried out using an activated derivative of formula (IV), wherein Z '' represents a halogen atom such as chlorine, bromine or iodine, or tosylate or mesylate. It can be carried out. The N-alkylation reaction can be carried out preferably in dimethylimidazolidinone in the presence of sodium hydride as a base at a temperature above room temperature. If desired, up to one molar equivalent of an iodide salt (eg, NaI, KI) can be added to the reaction as a catalyst. This reaction may be carried out at a temperature of 50 ° C. or higher using dimethylformamide as a solvent and potassium carbonate as a base. N-alkylation of derivative (X) is carried out by the Mitsunobu reaction (O. Mitsunobu, Synthesis, p.
p. 1-28, 1981), the hydroxy derivative of formula (IV) ((I
V) where Z '' = OH).

The 2-oxobenzothiazoline derivative (X) is
Use commercially available ones or, using 2-aminobenzothiazoles as starting materials, according to the method of RR Gupta et al. (Synthetic Communications, 17 (2), 229-240 (198
7)), can be synthesized by reacting with 1,1′-carbonylbis-1H-imidazole, preferably in tetrahydrofuran, after leading to a 2-aminothiophenol derivative.

Scheme B:

Embedded image

Another synthetic route to the compound of formula (I ') wherein A is -OH is shown in Scheme B. The amination of an epoxy derivative is usually carried out by heating the reaction reagent in a solvent such as ethanol [NS Isaacs an.
d RE Parker, J., pp. 3497-3504, 1960], and metal salts may be used as catalysts [M. Chini P. Crotti and F. Ma
cchia, Tetrahedron Letters, 31 (32), pp.4661-4664,
1990]. The epoxy derivative (XII) can be produced by oxidizing an alkenyl derivative, dehydrohalogenating a halohydrin compound, or reacting carboxaldehyde with dimethylsulfonium methylide (T. Kutsuma, I. Nagayama, T. Ozaki. T.
Sakamoto, S. Akaboshi, Heterocycles, 8, pp.397-40
1, 1977]. When an optically active substance is used as the epoxy derivative (XII) as a starting material, an optically active amino alcohol compound (I ′) can be obtained.

Scheme C:

Embedded image

The compound represented by the formula (I ″) (wherein R ¹ ′ = R ² ′ = H) is a compound of the formula (XIII) (wherein Z ″ ″ is a hydroxyl group or a chlorine atom) Such as a halogen atom or a mesylate) and the amino derivative (III), followed by reduction of the resulting amide intermediate. The condensation reaction can be carried out by dicyclohexylcarbodiimide depending on the type of Z "" (In the case where Z is a hydroxyl group)
Or in the absence. The reduction reaction can be performed using a reducing agent such as borane dimethyl sulfide or aluminum hydride.

The compound used as a starting material in the above method may be a racemic compound or a desired optically active compound, and it is possible to produce a racemic or optically active compound correspondingly. It is also possible to produce a desired optically active substance by optical resolution according to a well-known and commonly used method. The basic compounds of the formula (I) are capable of forming acid addition salts with various inorganic and organic acids, preferably pharmaceutically acceptable salts. These salts can be readily prepared by treating a basic compound of formula (I) with a mineral or organic acid in a suitable organic solvent such as methanol, ethanol, isopropanol, or ethyl acetate.

[0077]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples.

Example 1 (R, S) -1- (1-adamantyl) -2
-[4- (6-Chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride (Compound 114 in Table 2) a) Piperidine-1,4-dicarboxylic acid, 1- tert-butyl ester isonipecotic acid (60 g, 464 mmol) and sodium hydroxide in 86 ml of water and 176 ml of tert-butyl alcohol
To a solution of (37.6 g, 940 mmol) was added di-tert-butyl dicarbonate (101.1 g, 464 mmol) with stirring.
After the addition is complete, add tert-butyl alcohol (10
(0 ml) and stirred at room temperature for 3 hours.
(200 ml) and extracted twice with 150 ml of pentane. The aqueous layer was acidified with 70 g of potassium hydrogen sulfate under cooling, and extracted with ethyl acetate. After standard work-up, 102.3 g (96% yield) of the title compound were obtained as a white powder. Melting point
144-146 ° C.

B) tert-Butyl 4- (hydroxymethyl) piperidine-1-carboxylate In the compound obtained in Example 1 (a) (13.74 g, 60 mmol) dissolved in 60 ml of 1,2-dimethoxyethane And under cooling (-15
C)), N-methylmorpholine (6.66 ml, 60 mmol) and isobutyl chloroformate (8.16 ml, 60 mmol) were successively added.After 10 minutes, the precipitate was filtered off, and 60 ml of 1,2-dimethoxyethane was added. And washed. An aqueous solution of sodium borohydride (3.42 g, 90 mmol) was added to the above filtrate under cooling in an ice-salt bath.
0 ml was carefully added dropwise. After the addition was completed, the mixture was stirred for 45 minutes, then 800 ml of water was added, and the desired alcohol compound was extracted with 400 ml of ethyl acetate.
Washed sequentially with 5N hydrochloric acid, water and a saturated aqueous solution of sodium bicarbonate. After drying, the solvent is distilled off under reduced pressure to give the title compound.
9.8 g (yield 75%) was obtained as a colorless oil. The oil gave a white solid upon standing at room temperature. 74-76 ° C.

C) tert-butyl 4- (methanesulfonyloxymethyl) piperidine-1-carboxylate Example 1 dissolved in 350 ml of dry tetrahydrofuran
Methanesulfonyl chloride (11.3 ml, 137.5 mmol) was added dropwise to a solution of the compound (26.8 g, 125 mmol) obtained in (b) and triethylamine (19.1 ml, 137.5 mmol) under ice cooling. After stirring for 20 minutes, water was added, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and subjected to standard work-up to give the title compound as a white solid. Rate: quantitative). Melting point 72-
74 ° C.

D) 6-chloro-2-trifluoroacetylaminobenzothiazole 2-amino-6-chlorobenzothiazole (51.3 g, 278 mm
ol) and triethylamine (44 ml, 306 mmol) were dissolved in a mixed solvent of ethyl acetate (450 ml) and tetrahydrofuran (350 ml), and trifluoroacetic anhydride (43.2 ml, 3
06 mmol) was added dropwise, and after completion of the addition, the mixture was returned to room temperature and stirred for 1 hour. Thereafter, 500 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate-hexane (3: 7) to give the title compound (69.6 g, yield 89%) as a white solid. 232-234 ° C.

E) tert-butyl 4- (6-chloro-2-trifluoroacetyliminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate The compound obtained in Example 1 (d) (28.05 g, 100 mmol) were dissolved in dimethylformamide (300 ml) and added to a solution of sodium hydride (60% content in oil, 4 g, 100 mmol) suspended in 80 ml of dimethylformamide. The reaction mixture was stirred for 20 minutes at room temperature under a nitrogen atmosphere, and then dissolved in dimethylformamide (200 ml).
Methanesulfonate obtained in 1 (c) (29.3 g, 100 mmo
l) The solution and sodium iodide (5 g, 33 mmol) were added and the reaction was heated and stirred at 85 ° C. for 28 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and standard work-up gave a brown solid. The obtained solid was washed with a mixed solvent of ethyl acetate-hexane (3: 7) to give the title compound as a white solid in a yield of 63%. Mp 197-199 ° C. Rf = 0.
45 (ethyl acetate / hexane 2: 8).

F) tert-Butyl 4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate The compound (27.4 g, 58 mmol) obtained in Example 1 (e) was obtained. It was dissolved in methanol (400 ml) and 200 ml of a mixed solution of 10% potassium carbonate in methanol-water (7: 3) was added. After stirring the reaction solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After the organic layer was dried over sodium sulfate, the solvent was distilled off to obtain the title compound as a white solid (yield: quantitative). Melting point 142
-144 ° C. Rf = 0.3 (ethyl acetate / hexane 3: 7). ¹ H-NMR (CDCl ₃ ): 7.23 (d, 1H), 7.16 (dd, 1H), 6.74 (d, 1
H), 4.1 (m, 2H), 3.8 (d, 2H), 2.65 (m, 2H), 2.1 (m, 1H),
1.64 (m, 2H), 1.45 (s, 9H), 1.25 (m, 2H).

G) 4- (6-Chloro-2-iminobenzothiazolin-3-ylmethyl) piperidine The compound (7.7 g, 19 mmol) obtained in Example 1 (f) was dissolved in 80 ml of ethyl acetate. 4N hydrochloric acid / ethyl acetate solution 15 m
l (60 mmol) was added and the reaction was stirred at reflux for 4 hours. After cooling, the resulting solid was filtered and washed with ethyl acetate to give the hydrochloride of the title compound as a white solid. Melting point 2
96-298 ° C. The hydrochloride was treated with a 0.5N aqueous sodium hydroxide solution, extracted with methylene chloride, dried over sodium sulfate, and the solvent was distilled off. 4.4 g of the title compound (89% yield)
Was obtained as a white solid. 115-117 ° C. ¹ H-NMR (CDCl ₃ ): 7.27 (d, 1H), 7.17 (dd, 1H), 6.74 (d, 1
H), 3.78 (d, 2H), 3.06 (m, 2H), 2.58 (dt, 2H), 2.05 (m, 1
H), 1.64 (m, 3H), 1.26 (dq, 2H).

H) 3-[[1- [2- (1-Adamantyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline Obtained in Example 1 (g) Compound (1.6 g, 5.7 mmol) and 1-
(Bromoacetyl) adamantane (1.54 g, 6 mmol) and potassium carbonate (866 mg, 6.3 mmol) in acetonitrile
(80 ml) The solution was stirred under reflux for 2 hours. After cooling, water was added and the mixture was extracted with methylene chloride. After the organic layer was dried over sodium sulfate, the solvent was distilled off to obtain the title compound as a foamy powder (yield: quantitative). Rf = 0.55 (methylene chloride / methanol 9: 1).

I) (R, S) -1- (1-adamantyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride Compound (2.9 g, 5.7 mmol) obtained in Example 1 (h) was dissolved in a mixed solvent of ethanol (50 ml) and tetrahydrofuran (30 ml), and sodium borohydride (1.2 g, 31.5 m
mol) was added. After stirring the reaction mixture at room temperature for 4 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
(Eluent: methylene chloride / methanol 9: 1, Rf = 0.4)
To give 2.1 g (yield 80%) of a free form of the title compound as a white solid. 120-123 ° C. ¹ H-NMR (CDCl ₃ ): 7.22 (d, 1 H), 7.17 (dd, 1 H), 6.74 (d,
1H), 3.78 (d, 2H), 3.47 (s, 2H), 3.17 (dd, 1H), 3.0 (d, 1
H), 2.80 (d, 1H), 2.24 (m, 3H), 1.95-1.38 (m, 20H).

The above free form was dissolved in ethanol and 4N
Hydrochloric acid / ethyl acetate solution was added to give the title compound as a white solid (yield 69%). Melting point> 250 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.04 (m, 2H), 9.61 (m, 1H), 8.13
(d, 1H), 7.88-7.77 (dd, 1H), 7.57 (dd, 1H), 5.33 (m, 1H),
4.55-4.36 (dd, 2H), 3.60-2.90 (m, 8H), 2.25-1.48 (m, 20
H). Elemental analysis (C ₂₅ H ₃₆ Cl ₃ N ₃ OS + H ₂ O) Calculated: C, 54.49%; H, 6.95%; N, 7.63%; Cl, 19.30%;
S, 5.82% found: C, 54.64%; H, 6.95%; N, 7.58%; Cl, 19.45%;
S, 5.63%

Example 2: 3-[[1- [2- (4-fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline dihydrochloride (Table Compound 103 of No. 2) In the presence of sodium iodide (200 mg, 1.3 mmol), the compound (1.6 g, 5.7 mmol) obtained in Example 1 (g) and 2-chloro-
The reaction was carried out using 4′-fluoroacetophenone (984 mg, 5.7 mmol) according to the method described in Example 1 (h), followed by silica gel column chromatography (eluent: methylene chloride / methanol 9: 1, Rf = 0.40). ) To give 2.1 g (80% yield) of a free form of the title compound as a foamy powder. ¹ H-NMR (CDCl ₃ ): 8.09-8.04 (m, 2H), 7.21-7.06 (m, 4H),
6.75 (d, 1H), 3.80 (d, 2H), 3.70 (s, 2H), 2.98-2.93 (m,
2H), 2.15-2.06 (m, 2H), 2.06-1.96 (m, 1H), 1.70-1.65
(m, 2H), 1.56-1.45 (m, 2H).

The above free form was dissolved in ethanol and 4N
Hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid. 240-245 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.02 (m, 2H), 10.06 (m, 1H), 8.25-
7.76 (m, 4H), 7.60 (m, 1H), 7.49-7.43 (m, 2H), 5.30-4.90
(m, 2H), 4.42 (m, 2H), 3.35-3.01 (m, 4H), 2.19 (m, 2H),
1.80-1.65 (m, 3H).

Example 3 (R, S) -1- (4-fluorophenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol Dihydrochloride (Compound 104 in Table 2) Using the free form of the compound obtained in Example 2,
The reaction was performed according to the method described in 1 (i), and purification was performed by silica gel column chromatography (eluent: methylene chloride / methanol 9: 1, Rf = 0.45) to obtain a free form of the title compound as a white solid. Rate 75%). 186-188
° C. ¹ H-NMR (CDCl ₃ ): 7.34-7.16 (m, 4H), 7.04-6.98 (m, 2H),
6.76 (d, 1H), 4.70 (dd, 1H), 3.82 (d, 2H), 3.14 (d, 1H),
2.80 (d, 1H), 2.49-2.34 (m, 3H), 1.99-1.96 (dt, 2H), 1.7
0 (m, 2H), 1.50 (m, 2H).

The above free form was dissolved in ethanol and 4N
Hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (83% yield). 225 ° C (decomposes). ¹ H-NMR (DMSO-d ₆ ): 10.95 (m, 2H), 10.05 (m, 1H), 8.13
(d, 1 H), 7.76 (m, 1H), 7.59-7.45 (m, 3H), 7.17 (m, 2H),
6.25 (m, 1H), 5.18 (m, 1H), 4.40 (m, 2H), 3.60-2.90 (m, 7
H), 2.25-1.85 (m, 4H). Elemental analysis (C ₂₁ H ₂₅ Cl ₃ FN ₃ OS + H ₂ O) Calculated: C, 49.37%; H, 5.3%; N, 8.22%; Cl, 20.8%;
F, 3.72%; S, 6.27% Found: C, 49.1%; H, 4.9%; N, 8.1%; Cl, 21.2%; F,
3.6%; S, 6.2%

Example 4: 3-[[1- [2- (4-fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-
Chloro-2-methyliminobenzothiazoline dihydrochloride (Compound 115 in Table 2) a) tert-butyl 4- (6-chloro-2-formyliminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate acetic anhydride Formic acid (acetic formic anhydride) is S. Krishn
amurthy et al. (Tetrahedron Lett., 23 (33), pp.33
15-3318, 1982). Acetic anhydride (13.5g, 130
98% formic acid (7.5 g, 160 mmol) was added dropwise thereto at 0 ° C, followed by heating and stirring at 50-60 ° C for 2 hours. After cooling to room temperature, tetrahydrofuran (60 ml) was added, followed by -30 ° C
The compound obtained in Example 1 (f) was cooled to (16.7 g, 44
mmol) in tetrahydrofuran (80 ml) was added dropwise.
After the reaction solution was stirred at -30 ° C for 30 minutes, ethyl acetate was added thereto, and the temperature was returned to room temperature. Subsequently, water was added thereto, and the organic layer was separated.The obtained organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate. did. After the organic layer was dried over sodium sulfate, the solvent was distilled off to obtain 16.2 g (yield 90%) of the title compound as a white solid. 168-170 ° C. Rf = 0.4 (ethyl acetate / hexane
4: 6).

B) tert-butyl 4- (6-chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidine-1-
Carboxylate The compound (12.5 g, 30.5 mmol) obtained in Example 4 (a) was suspended in tetrahydrofuran (45 ml), and the suspension was stirred at 0 ° C. under a nitrogen atmosphere.
In the above, 7.5 ml (75 mmol) of a borane dimethylsulfide solution was slowly added. After the addition is completed, return the reaction solution to room temperature.
Stir for 1.5 hours, then add tetrahydrofuran under ice-cooling
(120 ml) and a mixed solvent of methanol (12 ml) were slowly added. Subsequently, the reaction solution was stirred at 40 ° C. for 30 minutes, and then 9 ml of a 4N hydrochloric acid / ethyl acetate solution was added to the reaction solution under ice cooling. The resulting solid was filtered and washed with tetrahydrofuran to obtain 8.7 g (yield 66%) of the hydrochloride of the title compound. 180-182 ° C.

This compound was freed according to the method described in Example 1 (g) to obtain the title compound as a white solid.
(Yield: quantitative). 106-108 ° C. Rf = 0.3 (ethyl acetate / methylene chloride 2: 8). ¹ H-NMR (CDCl ₃ ): 7.31 (d, 1H), 7.16 (dd, 1H), 6.74 (d, 1
H), 4.1 (m, 2H), 3.76 (d, 2H), 3.07 (s, 3H), 2.64 (m, 2H),
2.07 (m, 1H), 1.64 (m, 2H), 1.45 (s, 9H), 1.22 (dq, 2H).

C) 4- (6-Chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 4 (b), react according to the method described in Example 1 (g). Was performed to obtain the title compound as a white solid (yield: 92%). Melting point 106-108 ° C ¹ H-NMR (CDCl ₃ ): 7.30 (d, 1H), 7.17 (dd, 1H), 6.75 (d, 1
H), 3.75 (d, 2H), 3.06 (m, 5H), 2.54 (dt, 2H), 2.04 (m, 1
H), 1.64 (m, 3H), 1.23 (dq, 2H).

D) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-methyliminobenzothiazoline dihydrochloride Sodium iodide (675 mg, 4.5 mmol), using the compound obtained in Example 4 (c) (5.5 g, 18.6 mmol) and 2-chloro-4'-fluoroacetophenone (3.45 g, 20 mmol), The reaction was carried out according to the method described in Example 1 (h) and purified by silica gel column chromatography (eluent: methylene chloride / methanol 19: 1, Rf = 0.30) to obtain 4.0 g of the title compound in a free form (yield: 50). %) As a foamy powder. ¹ H-NMR (CDCl ₃ ): 8.07 (m, 2H), 7.30 (d, 1H), 7.17-6.71
(m, 3H), 6.75 (d, 1H), 3.77 (d, 2H), 3.69 (s, 2H), 3.06
(s, 3H), 2.94 (m, 2H), 2.09 (dt, 2H), 1.95 (m, 1H), 1.61
(m, 2H), 1.47 (dq, 2H).

The above free form was dissolved in ethanol and 4N
Hydrochloric acid / ethyl acetate solution was added to give the title compound as a white solid (yield 66%). 228-234 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.87 (m, 1H), 10.16 (m, 1H), 8.25
(m, 2H), 8.06-7.82 (m, 2H), 7.64 (m, 1H), 7.42 (m, 2H),
5.33 (s, 1H), 5.02 (s, 1H), 4.56 (m, 2H), 3.60-3.05 (m, 1
. 0H), 2.43-1.71 (m, 4H) Elemental analysis _{(C 22 H 25 Cl 3 FN} 3 OS + 1.3H 2 O) Calcd: C, 50.02%; H, 5.26%; N, 7.95%; Cl , 20.13
%, F, 3.59%; S, 6.07% Found: C, 49.73%; H, 4.85%; N, 7.80%; Cl, 20.43
%; F, 3.38%; S, 5.79%

Example 5: (R, S) -1- (4-fluorophenyl) -2- [4- (6-chloro-2-methyliminobenzothiazoline
-3-ylmethyl) piperidin-1-yl] ethanol ・ 2
Hydrochloride (Compound 116 in Table 2) Using the free form of the compound obtained in Example 4,
The reaction was carried out according to the method described in 1 (i), and the obtained solid was washed with ethanol to obtain a free form of the title compound as a white solid (yield 79%). 183-187 ° C. Rf = 0.55 (methylene chloride / methanol 9: 1) ¹ H-NMR (CDCl ₃ ): 7.31 (m, 3H), 7.18 (dd, 1H), 7.04-6.9
8 (m, 2H), 6.76 (d, 1H), 4.66 (dd, 1H), 3.80 (d, 2H), 3.07
(d + s, 4H), 2.80 (d, 1H), 2.49-2.26 (m, 3H), 2.01-1.94
(m, 2H), 1.66 (m, 2H), 1.43 (m, 2H).

The above free compound was dissolved in ethanol / ethyl acetate, and a 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield: 78%). 218-232 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.7 (m, 1H), 10.1 (m, 1H), 8.25
(s, 1H), 7.90-7.43 (m, 4H), 7.17 (m, 2H), 6.25 (m, 1H), 5.
15 (m, 1H), 4.54 (m, 2H), 3.62-2.90 (m, 10H), 2.18-1.78
(m, 4H). Elemental analysis (C ₂₂ H ₂₇ Cl ₃ FN ₃ OS + H ₂ O) Calculated: C, 50.34%; H, 5.57%; N, 8.00%; Cl, 20.26%;
F, 3.62%; S, 6.10% Found: C, 49.94%; H, 5.22%; N, 7.82%; Cl, 20.23%;
F, 3.46%; S, 6.03%

Example 6: (R, S) -1- (3,4-difluorophenyl) -2- [4- (6-chloro-2-iminobenzothiazoline-3-
Ylmethyl) piperidin-1-yl] ethanol dihydrochloride a) 3-[[1- [2- (3,4-difluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2 -Iminobenzothiazoline Compound (1.69 g, 6.0 mmol) obtained in Example 1 (g) and 2-
Bromo-3 ', 4'-difluoroacetophenone (1.37 g, 6.
0 mmol) and purified by silica gel column chromatography (eluent: methylene chloride / methanol 19: 1, Rf = 0.40) to give the title compound as an oil. (Yield 69
%).

B) (R, S) -1- (3,4-difluorophenyl) -2-
[4- (6-Chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride Example 1 (i) using the compound obtained in Example 6 (a) The resulting solid was washed with ethanol to give a free form of the title compound as a white solid
(78% yield). 146-148 ° C. Rf = 0.45 (methylene chloride / methanol 9: 1). ¹ H-NMR (CDCl ₃ ): 7.23-7.02 (m, 5H), 6.76 (d, 1H), 4.64
(dd, 1H), 3.82 (d, 2H), 3.10 (d, 1H), 2.80 (d, 1H), 2.50-
2.28 (m, 3H), 2.0 (m, 2H), 1.71 (m, 2H), 1.46 (m, 2H).

The above free compound was dissolved in ethyl acetate, and a 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a pale yellow solid (yield: 83%). Mp 195-197 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.05 (m, 2H), 10.1 (m, 1H), 8.14 (d,
1H), 7.89-7.28 (m, 6H), 6.38 (m, 1H), 5.17 (m, 1H), 4.50
(m, 2H), 3.66-2.96 (m, 7H), 2.16-1.78 (m, 4H).

Example 7: (R, S) -1- (3-methoxyphenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol. Dihydrochloride a) 3-[[1- [2- (3-methoxyphenyl) -2-oxoethyl]-
4-Piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline Compound (1.69 g, 6.0 mmol) obtained in Example 1 (g) and 2-
Bromo-3'-methoxyacetophenone (1.37 g, 6.0 mmo
l) and purified by silica gel column chromatography (eluent: methylene chloride / methanol 19: 1, Rf = 0.40) to give the title compound as an oil. (Yield 78%).

B) (R, S) -1- (3-methoxyphenyl) -2- [4-
(6-Chloro-2-iminobenzothiazolin-3-ylmethyl)
Piperidin-1-yl] ethanol dihydrochloride Using the compound obtained in Example 7 (a), the reaction was carried out according to the method described in Example 1 (i), and the obtained solid was washed with ethanol. The free form of the title compound was obtained as a white solid.
(Yield 80%). 156-158 ° C. Rf = 0.4 (methylene chloride / methanol 9: 1). ¹ H-NMR (CDCl ₃ ): 7.26-7.16 (m, 3H), 6.94 (m, 2H), 6.75
(m, 2H), 4.67 (dd, 1H), 3.80 (m, 5H), 3.14 (d, 1H), 2.80
(d, 1H), 2.48-2.26 (m, 3H), 1.97 (m, 2H), 1.69 (m, 2H),
1.45 (m, 2H).

The above free form was dissolved in ethyl acetate and 4N
Hydrochloric acid / ethyl acetate solution was added to give the title compound as a pale orange solid (83% yield). 186-188 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.0 (m, 2H), 10.1 (m, 1H), 8.15 (d,
1H), 7.88-7.76 (m, 2H), 7.30-6.84 (m, 4H), 6.20 (m, 1H),
5.10 (m, 1H), 4.40 (m, 2H), 3.80-2.95 (m, 10H), 2.16-1.7
6 (m, 4H).

Example 8: (R, S) -1- (4-trifluoromethylphenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol·
Dihydrochloride (Compound 110 in Table 2) a) 3-[[1- [2- (4-trifluoromethylphenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-iminobenzo Thiazoline Compound (1.69 g, 6.0 mmol) obtained in Example 1 (g) and 2-
Bromo-4'-trifluoromethylacetophenone (1.6 g,
6.0 mmol) and purified by silica gel column chromatography (eluant: methylene chloride / methanol 19: 1, Rf = 0.45) to give the title compound as an oil. (56% yield).

B) (R, S) -1- (4-trifluoromethylphenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol Dihydrochloride Using the compound obtained in Example 8 (a), the solid obtained by performing the reaction according to the method described in Example 1 (i) was subjected to ethanol-
After washing with a mixed solvent of hexane (1: 1), a free form of the title compound was obtained as a pale yellow solid (yield 78%). Melting point 168
-170 ° C. Rf = 0.50 (methylene chloride / methanol 9: 1). ¹ H-NMR (CDCl ₃ ): 7.58 (d, 2H), 7.48 (d, 2H), 7.23 (d, 1
H), 7.17 (dd, 1H), 6.76 (d, 1H), 4.74 (dd, 1H), 3.83 (d,
2H), 3.14 (d, 1H), 2.80 (d, 1H), 2.50 (dd, 1H), 2.41-2.2
9 (m, 2H), 2.03 (m, 2H), 1.70 (m, 2H), 1.47 (m, 2H).

The above free form was dissolved in ethyl acetate and 4N
Hydrochloric acid / ethyl acetate solution was added to give the title compound as a white solid (86% yield). 202-204 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.0 (m, 2H), 10.15 (m, 1H), 8.14 (d,
1H), 7.95-7.57 (m, 7H), 6.42 (m, 1H), 5.32 (m, 1H), 4.40
. (m, 2H), 3.70-2.99 (m, 7H), 2.20-1.86 (m, 4H) Elemental analysis _{(C 22 H 25 Cl 3 F} 3 N 3 OS + 2H 2 O) Calculated: C, 46.90 %; H, 4.47%; N, 7.46%; Cl, 18.89%;
F, 10.12%; S, 5.69% Found: C, 47.19%; H, 4.56%; N, 7.38%; Cl, 19.51%;
F, 9.87%; S, 5.53%

Example 9 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-acetyliminobenzothiazoline hydrochloride a) tert-butyl 4- (6-chloro-2-acetyliminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Imino compound obtained in Example 1 (f) (6.10 g, 16 mmol)
And triethylamine (2.36 ml, 16.5 mmol) were dissolved in a mixed solvent of ethyl acetate (80 ml) and tetrahydrofuran (20 ml), and acetic anhydride (1.56 ml, 16.5 mmol) was added dropwise at 0 ° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Subsequently, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was distilled off, and the obtained solid was filtered.
Wash with a mixed solvent of ethyl acetate (7: 3) to give the title compound 6.0
g (88.5% yield) as a white powder. Rf = 0.7 (methylene chloride / ethyl acetate 8: 2).

B) 4- (6-Chloro-2-acetyliminobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 9 (a) according to the method described in Example 1 (g) Was performed to obtain the title compound as a white solid (yield: 80%). 183-185 ° C. ¹ H-NMR (CDCl ₃ ): 7.61 (d, 1H), 7.39 (dd, 1H), 7.20 (d, 1
H), 4.23 (d, 2H), 3.06 (m, 2H), 2.54 (dt, 2H), 2.33 (s, 3
H), 2.1 (m, 1H), 1.59 (m, 3H), 1.37 (dq, 2H).

C) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-acetyliminobenzothiazoline hydrochloride Example 9 ( Compound (1.24 g, 3.8 mmol) obtained in b) and 2-bromo-4'-fluoroacetophenone (825 mg, 3.8 mmol)
Using, the reaction according to the method described in Example 1 (h),
Purification by silica gel column chromatography (eluent: methylene chloride / ethyl acetate 1: 1, Rf = 0.40) gave a free form of the title compound (yield 75%) as a white solid. 168-170 ° C. ¹ H-NMR (CDCl ₃ ): 8.05 (m, 2H), 7.61 (d, 1H), 7.39 (dd, 1
H), 7.19-7.09 (m, 3H), 4.25 (d, 2H), 3.74 (s, 2H), 2.96
(m, 2H), 2.33 (s, 2H), 2.09 (m, 3H), 1.61 (m, 4H).

The above free form was treated with methylene chloride-methanol.
The compound was dissolved in a mixed solvent of (9: 1) and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (80% yield).
234-242 ° C. ¹ H-NMR (DMSO-d ₆ ): 10.10 (m, 1H), 8.28-8.00 (m, 3H), 7.
90-7.75 (m, 1H), 7.56-7.38 (m, 3H), 5.03 (m, 1H), 5.02
(s, 2H), 4.50 (m, 2H), 3.60-3.05 (m, 4H), 2.29 (s, 3H),
2.10-1.80 (m, 3H).

Example 10: (R, S) -1-phenyl-2- [4- (6-
Chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride (Compound 112 in Table 2) a) 3-[[1- (2-Phenyl-2-oxoethyl) -4- Piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline The compound (1.69 g, 6.00 mmol) obtained in Example 1 (g) and 2-
Using bromoacetophenone (1.20 g, 6.03 mmol),
The reaction was carried out according to the method described in Example 1 (h), and the mixture was purified by silica gel column chromatography (eluent: methylene chloride / methanol 19: 1) to give 2.32 g of the title compound (yield)
96.7%) as white crystals. ¹ H-NMR (CDCl ₃ ): 8.00 (m, 2H), 7.57 (m, 1H), 7.45 (m, 2
H), 7.23-7.15 (m, 2H), 6.76 (d, 1H), 3.81 (d, 2H), 3.78
(s, 2H), 3.00 (m, 2H), 2.17-1.96 (m, 3H), 1.71-1.51 (m, 4
H).

B) (R, S) -1-phenyl-2- [4- (6-chloro-2)
-Iminobenzothiazolin-3-ylmethyl) piperidine
-1-yl] ethanol dihydrochloride Using 2.32 g of the compound obtained in Example 10 (a), reduction was carried out according to the method described in Example 1 (i), followed by silica gel column chromatography (eluent: Purified with methylene chloride / methanol 92: 8) to give the free form of the title compound 1.08
g (46.3% yield) was obtained as a viscous oil. ¹ H-NMR (CDCl ₃ ): 7.38-7.16 (m, 7H), 6.78 (d, 1H), 4.72
(dd, 1H), 3.83 (d, 2H), 3.19 (d, 1H), 2.85 (d, 1H), 2.53-
2.24 (m, 3H), 2.03 (m, 2H), 1.70 (m, 2H), 1.50 (m, 2H). Dissolve the above free form in ethanol and add 4N hydrochloric acid / ethyl acetate solution to add the hydrochloride Was obtained in 95.5% yield as white crystals. 188-198 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.00 (m, 2H), 9.99 (m, 1 H), 8.14
(s, 1H), 7.85-7.31 (m, 7H), 6.24 (m, 1H), 5.13 (m, 1H), 4.
36 (m, 2H), 3.60-2.77 (m, 7H), 2.20-1.71 (m, 4H).

Example 11: (R, S) -1- (3-fluorophenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol. Dihydrochloride a) 2-Bromo-3'-fluoroacetophenone Bromine (1.65 ml, 32.1 mmol) was added dropwise to a solution of 3-fluoroacetonephenone (4.15 g, 30.0 mmol) in acetic acid (23 ml) at room temperature. For 1.5 hours. Add water,
The mixture was extracted with ethyl acetate, and the organic layer was washed with water, aqueous sodium hydrogen carbonate and saturated saline in this order, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 1:40) to obtain the title compound (4.64 g, yield 71.3%) as white crystals. ¹ H-NMR (CDCl ₃ ): 7.79 (dd, 1H), 7.70 (m, 1H), 7.48 (m, 1
H), 7.30 (m, 1H), 4.43 (s, 2H).

B) 3-[[1- [2- (3-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline Obtained in Example 1 (g) Using the obtained compound (1.69 g, 6.00 mmol) and 2-bromo-3′-fluoroacetophenone (1.31 g, 6.03 mmol) obtained in Example 11 (a), the method described in Example 1 (h) was used. Perform the reaction according to the method and perform silica gel column chromatography (eluent: methylene chloride / methanol 19: 1).
To give 2.25 g (yield 89.7%) of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ): 7.80 (m, 1H), 7.70 (m, 1H), 7.42 (m, 1
H), 7.30-7.15 (m, 3H), 6.76 (d, 1H), 3.81 (d, 2H), 3.73
(s, 2H), 2.97 (m, 2H), 2.17-1.96 (m, 3H), 1.71-1.50 (m, 4
H).

C) (R, S) -1- (3-fluorophenyl) -2- [4-
(6-Chloro-2-iminobenzothiazolin-3-ylmethyl)
Piperidin-1-yl] ethanol dihydrochloride Using 2.25 g of the ketone compound obtained in Example 11 (b), reduction was carried out according to the method described in Example 1 (i) to give the free compound of the title compound 1.95 g (yield 86.3%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.30-7.00 (m, 5H), 6.95 (m, 1H), 6.78
(d, 1H), 4.79 (dd, 1H), 3.83 (d, 2H), 3.21 (d, 1H), 2.92
(d, 1H), 2.58-2.34 (m, 3H), 2.08 (m, 2H), 1.74 (m, 2H),
1.50 (m, 2H). The above free compound was dissolved in ethanol, and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as white crystals in a yield of 94.9%. 183-191 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.00 (m, 2H), 10.00 (m, 1H), 8.15
(s, 1H), 7.87-7.12 (m, 6H), 6.39 (m, 1H), 5.20 (m, 1H), 4.
36 (m, 2H), 3.60-2.77 (m, 7H). 2.20-1.71 (m, 4H).

Example 12: (R, S) -1- (4-trifluoromethoxyphenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] Ethanol dihydrochloride a) 2-Bromo-4'-trifluoromethoxyacetophenone 4-trifluoromethoxyacetophenone (8.03 g, 39.3
(mmol) using the method described in Example 11 (a) to give 8.13 g (yield 73.1%) of the title compound as white crystals.

B) 3-[[1- [2- (4-Trifluoromethoxyphenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-
Chloro-2-iminobenzothiazoline Compound (1.41 g, 5.00 mmol) obtained in Example 1 (g) and 2-bromo-4′-trifluoromethoxyacetophenone (1.42 g) obtained in Example 12 (a) , 5.02 mmol) and purified by silica gel column chromatography (eluent: methylene chloride / methanol 97: 3) to give 2.05 g (yield) of the title compound. 84.7
%) As white crystals. ¹ H-NMR (CDCl ₃ ): 8.09 (d, 2H), 7.29-7.13 (m, 4H), 6.76
(d, 1H), 3.81 (d, 2H), 3.72 (s, 2H), 2.96 (m, 2H), 2.15-
1.95 (m, 3H), 1.71-1.44 (m, 4H).

C) (R, S) -1- (4-trifluoromethoxyphenyl) -2- [4- (6-chloro-2-iminobenzothiazoline-3-
Ilmethyl) piperidin-1-yl] ethanol dihydrochloride Using 2.05 g of the ketone compound obtained in Example 12 (b), reduction was carried out according to the method described in Example 1 (i), and the title compound was freed. 1.81 g of the compound (87.8% yield) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.38 (d, 2H), 7.27-7.15 (m, 4H), 6.77
(d, 1H), 4.70 (dd, 1H), 3.83 (d, 2H), 3.16 (d, 1H), 2.83
(d, 1H), 2.53-2.24 (m, 3H), 2.02 (m, 2H), 1.74 (m, 2H),
1.59-1.23 (m, 2H). The above free compound was dissolved in ethanol, and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as white crystals in a yield of 96.7%. 183-193 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.00 (m, 2H), 10.00 (m, 1H), 8.14
(s, 1H), 7.87-7.30 (m, 6H), 6.36 (m, 1H), 5.20 (m, 1H), 4.
36 (m, 2H), 3.60-2.80 (m, 7H), 2.25-1.70 (m, 4H).

Example 13: (R, S) -1- (4-methoxyphenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol. Dihydrochloride a) 3-[[1- [2- (4-methoxyphenyl) -2-oxoethyl]-
4-Piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline The compound obtained in Example 1 (g) (1.41 g, 5.00 mmol) and 2-
Bromo-4'-methoxyacetophenone (1.15 g, 5.02 mmo
Using l) to carry out the reaction according to the method described in Example 1 (h),
Purified by silica gel column chromatography (eluent: methylene chloride / methanol 97: 3) to give the title compound
1.96 g (yield 91.2%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 8.01 (d, 2H), 7.18 (m, 2H), 6.91 (d, 2
H), 6.76 (d, 1H), 3.87 (s, 3H), 3.81 (d, 2H), 3.71 (s, 2
H), 2.98 (m, 2H), 2.15-1.95 (m, 3H), 1.71-1.50 (m, 4H).

B) (R, S) -1- (4-methoxyphenyl) -2- [4-
(6-Chloro-2-iminobenzothiazolin-3-ylmethyl)
Piperidin-1-yl] ethanol dihydrochloride Using 1.96 g of the ketone compound obtained in Example 13 (a), reduction was carried out according to the method described in Example 1 (i), and 0.51 g of the free form of the title compound was obtained. (25.9% yield) as white crystals. ¹ H-NMR (CDCl ₃ ): 7.30-7.15 (m, 4H), 6.85 (d, 2H), 6.77
(d, 1 H), 4.66 (dd, 1H), 3.83 (d, 2H), 3.79 (s, 3H), 3.1
6 (d, 1H), 2.85 (d, 1H), 2.43 (m, 2H), 2.27 (m, 1H), 2.00
(m, 2H), 1.70 (m, 2H), 1.50 (m, 2H). Dissolve the above free form in ethanol and add 4N hydrochloric acid / ethyl acetate solution to give the title hydrochloride in 95.6% white. Obtained as crystals. 180-190 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.00 (m, 2H), 10.00 (m, 1H), 8.16
(s, 1H), 7.87-7.30 (m, 4H), 7.31 (d, 2H), 6.93 (d, 2H), 5.
09 (m, 1H), 4.36 (m, 2H), 3.70-2.80 (m, 7H), 2.25-1.70
(m, 4H).

Example 14: (R, S) -1- (4-methylphenyl) -2- [4- (6-chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol. Dihydrochloride (compound 108 in Table 2) a) 3-[[1- [2- (4-methylphenyl) -2-oxoethyl] -4-
Piperidinyl] methyl] -6-chloro-2-iminobenzothiazoline The compound (1.69 g, 6.00 mmol) obtained in Example 1 (g) and 2-
Bromo-4'-methylacetophenone (1.28 g, 6.01 mmol)
And purified by silica gel column chromatography (eluent: methylene chloride / methanol 97: 3) to give the title compound 2.20
g (88.6% yield) were obtained as white crystals. ¹ H-NMR (CDCl ₃ )
: 7.90 (d, 2H), 7.26-7.13 (m, 4H), 6.76 (d, 1H), 3.80
(d, 2H), 3.75 (s, 3H), 2.98 (m, 2H), 2.41 (s, 3H), 2.15-
1.95 (m, 3H), 1.71-1.50 (m, 4H).

B) (R, S) -1- (4-methylphenyl) -2- [4- (6-
Chloro-2-iminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride Using 1.04 g of the ketone compound obtained in Example 14 (a), the method described in Example 1 (i) was used. Reduction was carried out by the method to give 0.84 g (yield 80.5%) of a free form of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ): 7.27-7.12 (m, 6H), 6.77 (d, 1H), 4.67
(dd, 1H), 3.83 (d, 2H), 3.17 (d, 1H), 2.80 (d, 1H), 2.46-
2.20 (m, 3H), 2.33 (s, 3H), 2.00 (m, 2H), 1.70 (m, 2H), 1.
The above free compound was dissolved in ethanol and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as white crystals in a yield of 94.2%. Melting point 187-197 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.00 (m, 2H), 10.00 (m, 1H), 8.16
(s, 1H), 7.87-7.50 (m, 2H), 7.40-7.15 (m, 4H), 5.09 (m, 1
H), 4.35 (m, 2H), 3.70-2.80 (m, 7H), 2.29 (s, 3H), 2.25-
1.70 (m, 4H).

Example 15: 3-[[1- [2- (4-fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -2-iminobenzothiazoline dihydrochloride a) 2-trifluoro Acetylaminobenzothiazole According to the method described in Example 1 (d), starting from 2-aminobenzothiazole (7.51 g, 50.0 mmol), the title compound 11.
5 g (yield 93.4%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ): 7.75 (d, 1H), 7.61 (d, 1H), 7.4
7 (m, 1H), 7.36 (m, 1H) .b) tert-butyl 4- (2-trifluoroacetyliminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Obtained in Example 15 (a) The reaction was carried out using 493 mg of the resulting amide form according to the method described in Example 1 (e) to give the title compound 410
mg (yield 46.2%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.78 (d, 1H), 7.57 (m, 1H), 7.44 (m, 2
H), 4.39 (m, 2H), 4.12 (m, 2H), 2.67 (t, 2H), 2.18 (m, 1
H), 1.60-1.26 (m, 4H), 1.46 (s, 9H).

C) tert-Butyl 4- (2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Example 1 using 410 mg of the crystals obtained in Example 15 (b)
The reaction was performed according to the method described in (f), and the title compound (330 mg) was obtained.
(Yield: quantitative) was obtained as a foamy powder. Rf = 0.1 (ethyl acetate / hexane 1: 2). d) 4- (2-Iminobenzothiazolin-3-ylmethyl) piperidine Example 1 using 330 mg of the powder obtained in Example 15 (c)
The reaction was carried out according to the method described in (g), and 210 mg of the title compound was obtained.
(91.8% yield) as a foamy powder. ¹ H-NMR (CDCl ₃ ): 7.23 (m, 2H), 6.99 (dt, 1H), 6.86 (d, 1
H), 3.82 (d, 2H), 3.10 (m, 2H), 2.58 (m, 2H), 2.12 (m, 1
H), 1.75-1.23 (m, 5H).

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -2-iminobenzothiazoline dihydrochloride obtained in Example 15 (d). Compound 210 mg and 2-chloro-4'-
The reaction was carried out using 150 mg of fluoroacetophenone according to the method described in Example 1 (h), followed by silica gel column chromatography (eluent: methylene chloride / methanol 97:
Purified by 3) to give 230 mg of the free form of the title compound (yield 7
0.6%). ¹ H-NMR (CDCl ₃ ): 8.06 (m, 2H), 7.26-7.08 (m, 4H), 6.99
(dt, 1H), 6.86 (d, 1H), 3.84 (d, 2H), 3.71 (s, 2H), 2.96
(m, 2H), 2.16-2.00 (m, 3H), 1.70 (m, 2H), 1.50 (m, 2H). Dissolve the above free form in ethanol and add 4N hydrochloric acid / ethyl acetate solution to give the above hydrochloride. Was obtained as white crystals in a yield of 91.3%. Mp 185-195 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.00 (m, 2H), 10.13 (m, 1H), 8.28
(s, 1H), 8.07-7.40 (m, 7H), 5.32-5.02 (m, 2H), 4.53-4.4
2 (m, 2H), 3.70-3.00 (m, 4H), 2.50-1.60 (m, 5H).

Example 16: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-methoxy-2-iminobenzothiazoline dihydrochloride a) 6-methoxy-2-trifluoroacetylaminobenzothiazole Starting from 6-methoxy-2-aminobenzothiazole (7.21 g, 40.0 mmol) by the method described in Example 1 (d), 8.75 g of the title compound (yield 79%) as white crystals. b) tert-Butyl 4- (6-methoxy-2-trifluoroacetyliminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Performed using 8.75 g of the amide obtained in Example 16 (a). The reaction was carried out according to the method described in Example 1 (e) and the title compound 5.7
0 g (yield 38%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.35 (d, 1H), 7.26 (d, 1H), 7.12 (dd, 1
H), 4.40-4.30 (m, 2H), 4.20-4.05 (m, 2H), 3.89 (s, 3H),
2.66 (t, 2H), 2.22-2.10 (m, 1H), 1.70-1.32 (m, 4H), 1.46
(s, 9H).

C) tert-butyl 4- (6-methoxy-2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Example 1 using 5.70 g of the crystals obtained in Example 16 (b)
The reaction was carried out according to the method described in (f), and 4.52 g of the title compound was obtained.
(Yield: quantitative) was obtained as a foamy powder. ¹ H-NMR (CDCl ₃ ): 6.85 (d, 1H), 6.76-6.71 (m, 2H), 4.20
-4.05 (m, 2H), 3.85-3.68 (m, 2H), 3.78 (s, 3H), 2.65 (t, 2
H), 2.20-2.08 (m, 1H), 1.72-1.60 (m, 2H), 1.45 (s, 9H),
1.40-1.21 (m, 2H) .d) 4- (6-Methoxy-2-iminobenzothiazolin-3-ylmethyl) piperidine Example 1 using 4.52 g of the powder obtained in Example 16 (c)
The reaction was carried out according to the method described in (g), and 3.10 g of the title compound was obtained.
(94% yield) as a foamy powder.

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-methoxy-2-
Iminobenzothiazoline dihydrochloride 555 mg of the compound obtained in Example 16 (d) and 2-chloro-4'-
The reaction was carried out according to the method described in Example 1 (h) using 362 mg of fluoroacetophenone, followed by silica gel column chromatography (eluent: methylene chloride / methanol 97:
3) to give 778 mg of the free form of the title compound (yield 94
%). ¹ H-NMR (CDCl ₃ ): 8.15-8.03 (m, 2H), 7.10 (t, 2H), 6.84
(s, 1H), 6.76-6.70 (m, 2H), 3.86-3.74 (m, 2H), 3.78 (s, 3
H), 3.69 (s, 2H), 2.95 (m, 2H), 2.16-1.98 (m, 3H), 1.70
(m, 2H), 1.58-1.45 (m, 2H).

327 mg of the above free compound was dissolved in ethanol, and a 4N hydrochloric acid / ethyl acetate solution was added thereto to give the title hydrochloride.
mg (72% yield). 207-212 ° C. ¹ H-NMR (DMSO-d ₆ ): 10.67 (m, 2H), 10.07 (m, 1H), 8.27-
8.04 (m, 2H), 7.78-7.68 (m, 2H), 7.47 (t, 2H), 7.14 (m, 1
H), 5.29-4.80 (m, 2H), 4.46-4.35 (m, 2H), 3.81 (s, 3H),
3.51-3.34 (m, 2H), 3.34-2.85 (m, 2H), 2.49-1.57 (m, 5
H).

Example 17: (R, S) -1- (4-fluorophenyl) -2- [4- (6-methoxy-2-iminobenzothiazoline-3-
Ilmethyl) piperidin-1-yl] ethanol dihydrochloride Using 465 mg of the free form of the ketone obtained in Example 16 (e), reduction was carried out according to the method described in Example 1 (i) to give the title compound 417 mg (90% yield) of the free form was obtained. ¹ H-NMR (CDCl ₃ ): 7.35-7.28 (m, 2H), 7.00 (t, 2H), 6.85
(s, 1H), 6.78-6.75 (m, 2H), 4.67 (dd, 1H), 3.83-3.74 (m,
2H), 3.78 (s, 3H), 3.13 (m, 1H), 2.80 (m, 1H), 2.45-2.20
(m, 3H), 2.04-1.95 (m, 2H), 1.80-1.65 (m, 2H), 1.55-1.4
1 (m, 2H). The above free compound was dissolved in ethanol, and a 4N hydrochloric acid / ethyl acetate solution was added to obtain 400 mg of the title hydrochloride (yield: 82%).
Melting point 268-272 ° C ¹ H-NMR (DMSO-d ₆ ): 10.54 (m, 2H), 10.02 (m, 1H), 7.74-
7.25 (m, 4H), 7.25-7.10 (m, 3H), 6.28 (m, 1H), 5.18 (m, 1
H), 4.34 (m, 2H), 3.81 (s, 3H), 3.62-2.49 (m, 6H), 2.48-
1.70 (m, 5H).

Example 18: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-methyl-2-iminobenzothiazoline dihydrochloride a) 6-methyl-2-trifluoroacetylaminobenzothiazole By the method described in Example 1 (d), starting from 4.93 g of 6-methyl-2-aminobenzothiazole 2.16 g of the title compound
(Yield 28%) was obtained as white crystals. b) tert-butyl 4- (6-methyl-2-trifluoroacetyliminobenzothiazolin-3-ylmethyl) piperidine
-1-Carboxylate Using 1.98 g of the amide obtained in Example 18 (a), the reaction was carried out according to the method described in Example 1 (e), and the title compound 2.3
2 g (yield 68%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.57 (s, 1H), 7.38-7.30 (m, 2H), 4.40-
4.32 (m, 2H), 4.14-4.06 (m, 2H), 2.66 (t, 2H), 2.49 (s, 3
H), 2.17 (m, 1H), 1.61-1.33 (m, 4H), 1.46 (s, 9H).

C) tert-butyl 4- (6-methyl-2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Example 1 using 2.32 g of the crystals obtained in Example 18 (b)
The reaction was carried out according to the method described in (f), and 1.83 g of the title compound was obtained.
(Yield: quantitative) was obtained as a foamy powder. d) 4- (6-Methyl-2-iminobenzothiazolin-3-ylmethyl) piperidine Example 1 using 1.83 g of the powder obtained in Example 18 (c)
The reaction was carried out according to the method described in (g), and 1.69 g of the title compound was obtained.
(Yield: quantitative) was obtained as a foamy powder. ¹ H-NMR (CDCl ₃ ): 7.06-6.95 (m, 2H), 6.74 (d, 1H), 3.78
(m, 2H), 2.55 (t, 2H), 2.32 (s, 3H), 2.09 (m, 1H), 1.34
(m, 2H), 1.26 (m, 2H).

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-methyl-2-iminobenzothiazoline dihydrochloride Example 18 ( 1.69 g of the compound obtained in d) and 2-chloro-4'-
The reaction was carried out using 897 mg of fluoroacetophenone according to the method described in Example 1 (h), followed by silica gel column chromatography (eluent: methylene chloride / methanol 97:
Purified by 3) to give 1.92 g of the free form of the title compound (yield 95
%). ¹ H-NMR (CDCl ₃ ): 8.10-8.05 (m, 2H), 7.13-6.96 (m, 3H),
6.73 (d, 2H), 3.80 (d, 2H), 3.68 (s, 2H), 2.94 (m, 2H), 2.3
0 (s, 3H), 2.18-2.00 (m, 3H), 1.74-1.50 (m, 4H).

The above free form (993 mg) was dissolved in ethanol, and a 4N hydrochloric acid / ethyl acetate solution was added thereto to give the title hydrochloride (654 ml).
g (yield 56%) was obtained. Melting point 215-222 ° C. ¹ H-NMR (DMSO-d ₆ ): 10.80 (m, 2H), 10.09 (m, 1H), 8.28-
8.03 (m, 2H), 7.80-7.64 (m, 2H), 7.47 (t, 2H), 7.37 (m, 1
H), 5.29-4.97 (m, 2H), 4.58-4.40 (m, 2H), 3.56-3.28 (m,
2H), 3.28-2.96 (m, 2H), 2.39 (s, 3H), 2.37-1.60 (m, 5H).

Example 19: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-fluoro-2-iminobenzothiazoline dihydrochloride (Table 127) a) 6-Fluoro-2-trifluoroacetylaminobenzothiazole Starting from 5.05 g of 6-fluoro-2-aminobenzothiazole by the method described in Example 1 (d), 3.65 of the title compound
g (yield 46%) was obtained as white crystals. b) tert-butyl 4- (6-fluoro-2-trifluoroacetyliminobenzothiazolin-3-ylmethyl) piperidine
-1-Carboxylate Using 980 mg of the amide obtained in Example 19 (a), the reaction was carried out according to the method described in Example 1 (e) to give the title compound 1.0
6 g (yield 62%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.50 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1
H), 4.39-4.36 (m, 2H), 4.15-4.06 (m, 2H), 2.67 (t, 2H),
2.16 (m, 1H), 1.70-1.52 (m, 2H), 1.42-1.30 (m, 2H), 1.46
(s, 9H).

C) tert-butyl 4- (6-fluoro-2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Example 1 using 1.06 g of the crystals obtained in Example 19 (b)
The reaction was performed according to the method described in (f), and 841 mg of the title compound was obtained.
(Yield: quantitative) was obtained as a foamy powder. d) 4- (6-Fluoro-2-iminobenzothiazolin-3-ylmethyl) piperidine Example 1 using 841 mg of the powder obtained in Example 19 (c).
The reaction was performed according to the method described in (g), and the title compound (570 mg) was obtained.
(94% yield) as a foamy powder.

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-fluoro-2-
Iminobenzothiazoline dihydrochloride 570 mg of the compound obtained in Example 19 (d) and 2-chloro-4'-
The reaction was carried out according to the method described in Example 1 (h) using 371 mg of fluoroacetophenone, followed by silica gel column chromatography (eluent: methylene chloride / methanol 97:
Purify by 3) and give 803 mg of the free form of the title compound (yield
93%). ¹ H-NMR (CDCl ₃ ): 8.12-8.04 (m, 2H), 7.12-7.00 (m, 2H),
7.00-6.70 (m, 2H), 6.75 (m, 1H), 3.85-3.76 (m, 2H), 3.6
9 (s, 2H), 2.95 (m, 2H), 2.10 (t, 2H), 2.00 (m, 1H), 1.71-
1.45 (m, 4H).

The above free form (400 mg) was dissolved in ethanol, and a 4N hydrochloric acid / ethyl acetate solution was added thereto to give the above hydrochloride.
mg (25% yield). 217-221 ° C. ¹ H-NMR (DMSO-d ₆ ): 10.86 (m, 2H), 10.05 (m, 1H), 8.25
(m, 2H), 7.96-7.78 (m, 2H), 7.47 (m, 3H), 5.27-4.96 (m, 2
H), 4.48-4.36 (m, 2H), 3.51 (m, 2H), 3.31-2.95 (m, 2H),
2.29-2.17 (m, 2H), 2.09-1.65 (m, 3H).

Example 20: 3-[[1- [2- (4-fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-trifluoromethoxy-2-iminobenzothiazoline dihydrochloride a) 6-Trifluoromethoxy-2-trifluoroacetylaminobenzothiazole3.57 g of the title compound starting from 4.89 g of 6-trifluoromethoxy-2-aminobenzothiazole by the method described in Example 1 (d). Yield 52%) as white crystals. b) tert-Butyl 4- (6-trifluoromethoxy-2-trifluoroacetyliminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Using 2.0 g of the amide obtained in Example 20 (a), Example
The reaction was carried out according to the method described in 1 (e), and the title compound 1.64 was obtained.
g (yield 51%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): 7.67 (m, 1H), 7.48-7.40 (m, 2H), 4.39
(m, 2H), 4.16-4.05 (m, 2H), 2.67 (t, 2H), 2.17 (m, 1H),
1.61 (m, 2H), 1.45 (s, 9H), 1.45-1.23 (s, 9H).

C) tert-Butyl 4- (6-trifluoromethoxy-2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Performed using 1.64 g of the crystals obtained in Example 20 (b). Example 1
The reaction was carried out according to the method described in (f), and 1.34 g of the title compound was obtained.
(Yield: quantitative) was obtained as a foamy powder. d) 4- (6-trifluoromethoxy-2-iminobenzothiazolin-3-ylmethyl) piperidine Example 1 using 1.34 g of the powder obtained in Example 20 (c)
The reaction was carried out according to the method described in (g), and the title compound (1.03 g) was obtained.
(Yield: quantitative) was obtained as a foamy powder.

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-trifluoromethoxy-2-iminobenzothiazoline dihydrochloride 1.03 g of the compound obtained in 20 (d) and 2-chloro-4'-
The reaction was carried out according to the method described in Example 1 (h) using 537 mg of fluoroacetophenone, followed by silica gel column chromatography (eluent: methylene chloride / methanol 97:
Purify by 3) to give 965 mg of the free form of the title compound (yield
66%). ¹ H-NMR (CDCl ₃ ): 8.09-8.03 (m, 2H), 7.14-7.05 (m, 4H),
6.80 (d, 1H), 3.83 (d, 2H), 3.72 (s, 2H), 3.00-2.95 (m, 2
H), 2.13 (t, 2H), 1.99 (m, 1H), 1.73-1.65 (m, 2H), 1.60-
1.47 (m, 2H).

The above free compound (247 mg) was dissolved in ethanol, and a 4N hydrochloric acid / ethyl acetate solution was added thereto to give the hydrochloride (180 mg).
mg (63% yield). 202-206 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.07 (m, 2H), 10.04 (m, 1H), 8.26-
7.85 (m, 4H), 7.60 (m, 1H), 7.47 (t, 2H), 5.29-4.96 (m, 2
H), 4.51-4.35 (m, 2H), 3.55-2.95 (m, 4H), 2.30-2.15 (m,
2H), 1.98-1.63 (m, 3H).

Example 21: 3-[[1- [2- (4-aminosulfonylphenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-methyliminobenzothiazoline dihydrochloride a) 2-Bromo-4'-aminosulfonylacetophenone 4-aminosulfonylacetophenone (4.97 g, 25 mmol)
The title compound was prepared by the method described in Example 11 (a) using
3.9 g (57% yield) were obtained as a pale yellow solid. Melting point 14
6-149 ° C.

B) 3-[[1- [2- (4-Aminosulfonylphenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-methyliminobenzothiazoline dihydrochloride Example 1 using the compound (1.69 g, 5.7 mmol) obtained in 4 (c) and 2-bromo-4'-aminosulfonylacetophenone (1.6 g, 7.0 mmol) obtained in Example 21 (a). (h)
Perform the reaction according to the method described in (1) to obtain the free form of the title compound.
2.2 g (77% yield) were obtained as a pink solid. Melting point 1
78-180 ° C. Rf = 0.25 (methylene chloride / ethyl acetate / methanol 10: 9: 1). ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ): 8.1 (d, 2H), 8.01 (d, 2H), 7.
32 (d, 1H), 7.17 (dd, 1H), 6.87 (m, 2H), 6.80 (d, 1H), 3.78
(d, 2H), 3.73 (s, 2H), 3.05 (s, 3H), 2.92 (d, 2H), 2.1 (dt,
2H), 2.0 (m, 1H), 1.62 (m, 2H), 1.42 (m, 2H). Dissolve the above free form in ethanol / diethyl ether, add 4N hydrochloric acid / ethyl acetate solution to remove the hydrochloride. Obtained as a white solid (40% yield). Melting point 224-227 ° C. ¹ H-NMR
(DMSO-d ₆ ): 11.8 (m, 1H), 10.15 (m, 1H), 8.36-7.62 (m, 1H)
9H), 5.37 (m, 1H), 5.07 (m, 1H), 4.54 (m, 2H), 3.59-3.06
(m, 8H), 2.50-1.85 (m, 4H).

Example 22: (R, S) -1- (2,4-difluorophenyl) -2- [4- (6-chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidin-1-yl ] Ethanol dihydrochloride a) 2,4-Difluorophenyloxirane 2-chloro-2 ', 4'-difluoroacetophenone (2.26 g,
11.9 mmol) in 10 ml of isopropyl alcohol,
Sodium borohydride (0.3 g, 8 mmol) was added.
After stirring at room temperature for 2 hours, 1N aqueous sodium hydroxide solution (10
ml) and the mixture was further stirred at 60 ° C for 2 hours. After cooling, water was added to the reaction solution, which was extracted with diethyl ether. After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: hexane) to give the title compound (890 mg, yield 48%) as an oil. Rf = 0.85 (hexane / ethyl acetate 9: 1)

B) (R, S) -1- (2,4-difluorophenyl) -2-
[4- (6-Chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride Implemented with the compound obtained in Example 4 (c) (1.48 g, 5.0 mmol) Ethanol solution (30 ml) of 2,4-difluorophenyloxirane (790 mg, 5.0 mmol) obtained in Example 22 (a)
Was heated to reflux for 8 hours. After cooling, the solvent was distilled off, and the obtained solid was washed with ethanol to give a free form of the title compound.
7 g (69% yield) was obtained as a white solid. 161-163 ° C. Rf = 0.3 (methylene chloride / methanol 19:
1). ¹ H-NMR (CDCl ₃ ): 7.53 (q, 1H), 7.32 (d, 1H), 7.16 (dd, 1
H), 6.87 (dt, 1H), 6.75 (m, 2H), 4.95 (dd, 1H), 3.79 (d, 2
H), 3.12 (d, 1H), 3.08 (s, 3H), 2.79 (d, 1H), 2.58 (dd, 1
H), 2.30 (m, 2H), 2.0 (m, 2H), 1.67 (m, 2H), 1.43 (dq, 2
H). The above free form was dissolved in ethanol / diethyl ether, and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as a white solid. 233-244 ° C. ¹ H-NMR (DMSO-d ₆ ): 11.7 (m, 1H), 10.1 (m, 1H), 8.20-6.
80 (m, 6H), 6.30 (m, 1H), 5.35 (m, 1H), 4.47 (m, 2H), 3.64-
2.7 (m, 8H), 2.30-1.60 (m, 6H).

Example 23: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -2-imino-6-trifluoromethylbenzothiazoline dihydrochloride (Compound 151 of Table 2) a) 6-trifluoromethyl-2-trifluoroacetylaminobenzothiazole By the method described in Example 1 (d),
2-amino-6-trifluoromethylbenzothiazole (6.
Starting from 54 g, 30 mmol), 7.4 g of the title compound (yield 78
%) As white crystals. 200-202 ° C.

B) tert-butyl 4- (6-trifluoromethyl)
-2-trifluoroacetyliminobenzothiazoline-3-
Ilmethyl) piperidine-1-carboxylate Using the amide (6.28 g, 20 mmol) obtained in Example 23 (a), the reaction was carried out according to the method described in Example 1 (e), and silica gel column chromatography ( Eluent: Purification with methylene chloride / hexane / ethyl acetate 5: 4: 1) gave the title compound as white crystals (yield 42%). Melting point 136-1
37 ° C. c) tert-butyl 4- (6-trifluoromethyl-2-iminobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Using the compound (4.2 g, 8 mmol) obtained in Example 23 (b). The reaction was carried out according to the method described in Example 1 (f) to obtain the title compound as a foamy powder. Rf = 0.2 (hexane / ethyl acetate 7: 3).

D) 4- (6-Trifluoromethyl-2-iminobenzothiazolin-3-ylmethyl) piperidine Using the powder obtained in Example 23 (c) according to the method described in Example 1 (g) The reaction was performed to give the title compound as a white solid (yield 87%). 110-112 ° C. ¹ H-NMR (CDCl ₃ ): 7.47 (m, 2H), 7.0 (m, 1H), 6.90 (d, 1
H), 3.84 (d, 2H), 3.1 (d, 2H), 2.59 (dt, 2H), 2.08 (m, 1
H), 1.66 (m, 3H), 1.25 (dq, 2H).

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -2-imino-6-trifluoromethylbenzothiazoline dihydrochloride The compound (2.1 g, 6.7 mmol) obtained in 23 (d) and 2-
Bromo-4'-fluoroacetophenone (1.45 g, 6.7 mmo
The reaction was carried out using l) according to the method described in Example 1 (h) and purified by silica gel column chromatography (eluent: methylene chloride / ethyl acetate / methanol 5: 4.7: 0.3) to give the title compound free of charge. 2.2 g (yield 72%) of the product was obtained as a pale yellow foamy powder. ¹ H-NMR (CDCl ₃ ): 8.08 (m, 2H), 7.48 (s + d, 2H), 7.12 (m,
2H), 6.90 (d, 1H), 3.86 (d, 2H), 3.72 (s, 2H), 2.98 (d, 2
H), 2.1 (dt, 2H), 2.0 (m, 1H), 1.70 (m, 2H), 1.53 (dq, 2
H).

The above free form was dissolved in ethanol / diethyl ether, and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as a white solid (yield 77%). Melting point 213-221
° C. ¹ H-NMR (DMSO-d ₆ ): 11.4 (m, 2H), 10.1 (m, 1H), 8.4
9 (s, 1H), 8.30-7.87 (m, 4H), 7.42 (m, 2H), 5.33 (m, 1H),
5.03 (m, 1H), 4.54 (m, 2H), 3.59-3.05 (m, 5H), 2.48-1.74
(m, 4H).

Example 24: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2- (2,2,2-trifluoro Ethyl) iminobenzothiazoline dihydrochloride a) 6-Chloro-2- (2,2,2-trifluoroethyl) aminobenzothiazole Lithium aluminum hydride (2.65 g, 60 mmol) in tetrahydrofuran (150 ml ), A solution of 6-chloro-2-trifluoroacetylaminobenzothiazole (14.02 g, 50 mmol) obtained in Example 1 (d) in tetrahydrofuran
(150 ml) was added dropwise at room temperature, and then stirred for 12 hours. After cooling with ice, water (2.7 ml), a 1N aqueous sodium hydroxide solution (2.7 ml) and water (7 ml) were sequentially added to the reaction solution, and then the organic layer was separated and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 9: 1) to obtain 5.1 g (yield 38%) of the title compound as a white solid. Was. 147-148 ° C.

B) tert-Butyl 4- [6-chloro-2- (2,2,2-trifluoroethyl) iminobenzothiazolin-3-ylmethyl] piperidine-1-carboxylate Obtained in Example 24 (a) Using the obtained compound, the reaction was carried out according to the method described in Example 1 (e), and the compound was purified by silica gel column chromatography (eluent: hexane / ethyl acetate / methylene chloride 5: 1: 4) to give the title compound. Obtained as an orange solid (Yield: 21%). 104 ° C.

C) 4- [6-Chloro-2- (2,2,2-trifluoroethyl) iminobenzothiazolin-3-ylmethyl] piperidine Example using the compound obtained in Example 24 (b) The reaction was carried out by the method described in 1 (g) to give the title compound as a pale orange powder (yield 78%). Melting point 80-82 ° C ¹ H-NMR (CDCl ₃ ): 7.34 (d, 1H), 7.20 (dd, 1H), 6.83 (d, 1
H), 3.85 (d, 2H), 3.68 (q, 2H), 3.06 (d, 2H), 2.57 (dt, 2
H), 2.01 (m, 2H), 1.62 (m, 2H), 1.28 (dq, 2H).

D) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2- (2,
2,2-trifluoroethyl) iminobenzothiazoline ・ 2
Hydrochloride Compound (370 mg, 1.7 mmol) obtained in Example 24 (c)
2-Bromo-4'-fluoroacetophenone (350 mg, 1.6 mm
ol) and purified by silica gel column chromatography (eluent: methylene chloride / ethyl acetate 8: 2) to give 300 mg of the free form of the title compound (37% yield) as an oil. ¹ H-NMR (CDCl ₃ ): 8.07 (m, 2H), 7.34 (d, 1H), 7.22 (dd, 1
H), 7.11 (m, 2H), 6.83 (d, 1H), 3.87 (d, 2H), 3.72 (s, 2
H), 3.64 (q, 2H), 2.95 (d, 2H), 2.13 (dt, 2H), 1.92 (m, 1
H), 1.66 (m, 2H), 1.53 (dq, 2H).

The above free form was dissolved in ethyl acetate and 4N
The hydrochloric acid / ethyl acetate solution was added to give the title hydrochloride as an orange solid (87% yield). 125-142 ° C. ¹ H-NMR (DMSO-d ₆ ): 10.1 (m, 1H), 9.0-8.6 (m, 1H), 8.30
-7.82 (m, 3H), 7.48-7.34 (m, 4H), 5.18-5.02 (m, 2H), 4.1
9-3.02 (m, 7H), 2.15-1.76 (m, 6H).

Example 25: 3-[[1- [2- (2,4-difluorophenyl) -2-hydroxyiminoethyl] -4-piperidinyl] methyl] -6-chloro-2-methyliminobenzothiazoline Dihydrochloride a) 2-chloro-2 ', 4'-difluoroacetophenone oxime 2-chloro-2', 4'-difluoroacetophenone (3.51 g,
18.4 mmol), hydroxylamine hydrochloride (1.40 g, 20.1
mmol) and sodium acetate (1.70 g, 20.7 mmol) were dissolved in ethanol (30 ml), and the mixture was cooled under ice-cooling for 1 hour and then at room temperature.
Stirred for 24 hours. Thereafter, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and dried over sodium sulfate, the solvent was distilled off to obtain 3.76 g (yield 99%) of the title compound. ¹ H-NMR (CDCl ₃ ): 8.73 (s, 1H), 7.55-7.47 (m, 1H), 6.97
-6.85 (m, 1H), 4.62 (s, 2H).

B) 3-[[1- [2- (2,4-difluorophenyl)-
2-hydroxyiminoethyl] -4-piperidinyl] methyl] -6-chloro-2-methyliminobenzothiazoline dihydrochloride The compound obtained in Example 4 (c) in the presence of sodium iodide (1.61 g , 5.44 mmol) and the 2-chloro-2 ', 4'-difluoroacetophenone oxime obtained in Example 25 (a) (1.
Using 50 g (7.30 mmol) of the title compound, the reaction was carried out according to the method described in Example 1 (h), and purified by silica gel column chromatography (eluent: methylene chloride / methanol 50: 1) to give the title compound free of charge. 2.05 g of the compound (81% yield) was obtained as an oil. ¹ H-NMR (CDCl ₃ ): 9.23 (s, 1H), 7.33-7.25 (m, 2H), 7.14
(dd, 1H), 6.94-6.74 (m, 3H), 3.73 (d, 2H), 3.32 (s, 2H),
3.04 (s, 3H), 2.86 (d, 2H), 2.00-1.89 (m, 3H), 1.62-1.56
(m, 2H), 1.35-1.22 (m, 2H).

The above free form was dissolved in ethyl acetate and 4N
The hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as a white solid (yield: 88.5%). 230 ° C (decomposes). ¹ H-NMR (DMSO-d ₆ ): 12.1 (1H), 11.8 (1H), 10.3 (1H),
8.25 (s, 1H), 7.76-7.18 (m, 5H), 4.49 (m, 4H), 3.55-3.45
(m, 2H), 3.10 (s, 3H), 2.93-2.89 (m, 2H), 2.12-1.68 (m, 5
H).

Example 26: 3-[[1-[(6-Fluoro-1,2-benzisoxazol-3-yl) methyl] -4-piperidinyl] methyl] -6-chloro-2-methyliminobenzo Thiazoline dihydrochloride Free form of the compound obtained in Example 25 (b) (1.12 g, 2.
A solution of sodium methoxide in methanol (0.54 ml, 2.66 mmol) was added to a solution of 41 mmol) in methanol (60 ml).
Stirred at C for 22 hours. Thereafter, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and dried over sodium sulfate, the solvent was distilled off to obtain 845 mg (yield: 79.0%) of a free form of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ): 7.92-7.87 (m, 1H), 7.32-7.03 (m, 4H),
6.75 (d, 1H), 3.86 (s, 2H), 3.78 (d, 2H), 3.06 (s, 3H),
2.89 (d, 2H), 2.11-2.02 (m, 2H), 1.94-1.88 (m, 1H), 1.66-
1.61 (m, 2H), 1.48-1.38 (m, 2H).

The above free form was dissolved in ethyl acetate and 4N
The hydrochloric acid / ethyl acetate solution was added to obtain the title hydrochloride as a white solid (yield 92.0%). 178-183 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ): 11.7-11.4 (m, 2H), 8.32-8.25 (m, 2
H), 7.86-7.63 (m, 3H), 7.44-7.38 (m, 1H), 3.58 (d, 2H),
3.10 (s, 3H), 2.13-1.77 (m, 5H).

Example 27: (R) -1- (4-fluorophenyl) -2- [4- (6-chloro-2-methyliminobenzothiazoline
-3-ylmethyl) piperidin-1-yl] ethanol ・ 2
Hydrochloride a) 2-Chloro-1- (4-fluorophenyl) ethanol 2-Chloro-4'-fluoroacetophenone (25 g, 145 mmo
l) was dissolved in methanol (250 ml) and sodium borohydride (3.78 g, 100 mmol) was added. After stirring the reaction mixture at room temperature for 5 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (eluent:
Methylene chloride) to give the title compound 18.5 g (73% yield)
Was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ): 7.35 (m, 2H), 7.06 (m, 2H), 4.88 (m, 2
H), 3.64 (m, 2H), 2.70 (s, 1H).

B) (R)-(-)-2-chloro- (4-fluorophenyl) ethanol and (S)-(+)-2-chloro- (4-fluorophenyl) ethanol acetate The title compound Tetrahedron Asymmetry, 2, pp.113 (1
The compound was synthesized according to the method described in 991). That is, the embodiment
The compound (1.0 g, 5.73 mmol) obtained in 27 (a) was dissolved in diethyl ether (15 ml), and then isopropenyl acetate was dissolved.
(2.2 ml, 20 mmol), Lipase PS (Amano, immobilize
d Lipase PS on diatomite, 2.0 g) was added and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate 10: 1) to give (R)-(-)-2-chloro- (4-fluorophenyl) ethanol 393 mg (Yield 39%), (S)-(+)-2-
Chloro- (4-fluorophenyl) ethanol acetate
511 mg (41% yield) were each obtained as a colorless oil.

(R)-(-)-2-chloro- (4-fluorophenyl)
Ethanol ¹ H-NMR (CDCl ₃ ): 7.35 (m, 2H), 7.06 (m, 2H), 4.88 (m, 2
H), 3.64 (m, 2H), 2.70 (s, 1H).> 99% ee (HPLC: Daicel CHIRALCEL OJ, UV 254 nm,
Hexane / ethanol = 95/5) (S)-(+)-2-chloro- (4-fluorophenyl) ethanol
Acetate ¹ H-NMR (CDCl ₃ ): 7.35 (m, 2H), 7.06 (m, 2H), 5.93 (m, 1
H), 3.75 (m, 2H), 2.13 (s, 3H) .97% ee (HPLC: Daicel CHIRALCEL OJ, UV 254 nm, hexane / ethanol = 95/5)

C) (R) -1- (4-fluorophenyl) -2- [4- (6-
Chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride (R)-(-)-2-chloro- (4-fluoro) obtained in Example 27 (b) Phenyl) ethanol (340 mg, 1.95 mmol) was dissolved in ethanol (10 ml) and 4- (6-chloro-2-methyliminobenzothiazolin-3-ylmethyl) obtained in Example 4 (c) was obtained.
Piperidine (577 mg, 1.95 mmol) and potassium carbonate (270
mg, 1.95 mmol) and stirred at 60 ° C. for 4 hours. The precipitated solid was collected by filtration and washed with ethanol. The obtained solid was washed in ethanol-water (1: 1, 20 ml) at 60 ° C. for 1 hour, filtered, washed with ethanol, and free of the title compound (534 mg, 63% yield). Was obtained as a white solid. Melting point
211-212 ° C ¹ H-NMR (CDCl ₃ ): 7.31 (m, 3H), 7.18 (dd, 1H), 7.01 (m, 2
H), 6.77 (d, 1H), 4.67 (dd, 1H), 3.80 (d, 2H), 3.12 (d, 1
H), 3.08 (s, 3H), 2.81 (d, 1H), 2.44 (m, 2H), 2.27 (m, 1
H), 1.98 (m, 2H), 1.67 (m, 2H), 1.43 (m, 2H).

The above free form was dissolved in ethyl acetate and 4N
Hydrochloric acid / ethyl acetate solution was added to obtain 508 mg of the title compound as a white solid (96% yield). Melting point 220-223 ° C ¹ H-NMR (DMSO-d ₆ ): 11.7 (m, 1H), 10.1 (m, 1H), 8.25 (s,
1H), 7.90-7.43 (m, 4H), 7.17 (m, 2H), 6.25 (m, 1H), 5.15
(m, 1H), 4.54 (m, 2H), 3.62-2.90 (m, 10H), 2.18-1.78 (m,
4H) .99% ee (HPLC: Shinwa Kako ULTRON ES-PhCD, UV 254 n
m, 20mM KH ₂ PO ₄ (pH3.0) / CH ₃ CN = 60/40)

Example 28: (S) -1- (4-fluorophenyl) -2- [4- (6-chloro-2-methyliminobenzothiazoline
-3-ylmethyl) piperidin-1-yl] ethanol ・ 2
Hydrochloride (a) (S) -4-fluorostyrene oxide (S)-(+)-2-chloro- (4-fluorophenyl) ethanol acetate obtained in Example 27 (b) (565 mg, 2.61 mmo
l) was dissolved in methanol (10 ml) and water (5 ml), and sodium hydrogen carbonate (500 mg) was added. 60 reaction mixture
After stirring at 1 ° C. for 1 hour, the solvent was distilled off under reduced pressure, water was added to the residue, and extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 300 mg (yield 83%) of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ): 7.25 (m, 2H), 7.04 (m, 2H), 3.85 (t, 1
H), 3.14 (m, 1H), 2.70 (s, 1H).

(B) (S) -1- (4-fluorophenyl) -2- [4-
(6-Chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol dihydrochloride The compound (300 mg, 2.17 mmol) obtained in Example 28 (a) was treated with ethanol (10 ml). ), And obtained in Example 4 (c).
Add (6-chloro-2-methyliminobenzothiazolin-3-ylmethyl) piperidine (642 mg, 2.17 mmol), and add
For 4 hours. The precipitated solid was collected by filtration and washed with ethanol. The obtained solid was dissolved in ethanol-water (1: 1, 10
After washing for 1 hour at 60 ° C., the precipitate was collected by filtration and washed with ethanol to give 438 mg (yield 47%) of the free form of the title compound as a white solid. Melting point 211-212 ° C ¹ H-NMR (CDCl ₃ ): 7.31 (m, 3H), 7.18 (dd, 1H), 7.01 (m, 2
H), 6.77 (d, 1H), 4.67 (dd, 1H), 3.80 (d, 2H), 3.12 (d, 1
H), 3.08 (s, 3H), 2.81 (d, 1H), 2.44 (m, 2H), 2.27 (m, 1
H), 1.98 (m, 2H), 1.67 (m, 2H), 1.43 (m, 2H).

The above free form was dissolved in ethyl acetate and 4N
Hydrochloric acid / ethyl acetate solution was added to obtain 423 mg of the title compound as a white solid (yield 95%). 227-230 ° C ¹ H-NMR (DMSO-d ₆ ): 11.7 (m, 1H), 10.1 (m, 1H), 8.25 (s,
1H), 7.90-7.43 (m, 4H), 7.17 (m, 2H), 6.25 (m, 1H), 5.15
(m, 1H), 4.54 (m, 2H), 3.62-2.90 (m, 10H), 2.18-1.78 (m,
4H) .99% ee (HPLC: Shinwa Kako ULTRON ES-PhCD, UV 254 n
m, 20mM KH ₂ PO ₄ (pH3.0) / CH ₃ CN = 60/40)

Example 29: 3- [4- [N- [2- (4-fluorophenyl) -2-oxoethyl] -N-methylamino] butyl] -6-chloro-2-methyliminobenzothiazoline-2 Hydrochloride (Compound 13 in Table 1) a) 4- (N-tert-butyloxycarbonyl-N-methylamino) butyric acid Example 4 was performed using 4-methylaminobutyric acid hydrochloride (30 g, 200 mmol). The reaction was carried out according to the method described in (a) to obtain 44.08 g (quantitative) of the title compound as an oil. 1H-NMR (CDCl ₃ ): 3.28 (t, 2H), 2.85 (s, 3H), 2.36 (t, 2
H), 1.85 (m, 2H), 1.45 (s, 9H).

B) 4- (N-tert-butyloxycarbonyl-N
-Methylamino) butanol Using 42.4 g of the compound obtained in Example 29 (a), 33.1 g (yield 83%) of the title compound was obtained as an oily substance according to the method described in Example 1 (b). 1H-NMR (CDCl ₃ ): 3.67 (t, 2H), 3.24 (t, 2H), 2.84 (s, 3
H), 1.60-1.54 (m, 4H), 1.45 (s, 9H).

C) 4- (N-tert-butyloxycarbonyl-N
-Methylamino) butanol methanesulfonate Using 33.1 g of the compound obtained in Example 29 (b), the reaction was carried out according to the method described in Example 1 (c) to give the title compound 4
0.9 g (89% yield) was obtained as an oil. 1H-NMR (CDCl ₃ ): 4.26 (t, 2H), 3.27 (t, 2H), 3.02 (s, 3
H), 2.84 (s, 3H), 1.78-1.55 (m, 4H), 1.46 (s, 9H) .d) 3- [4- (N-tert-butyloxycarbonyl-N-methylamino) butyl]- 6-chloro-2-trifluoroacetyliminobenzothiazoline 4.3 g of the compound obtained in Example 29 (c) and Example 1 (d)
Using 4.3 g of the compound obtained in the above, the reaction was carried out according to the method described in Example 1 (e), followed by crystallization in ethyl acetate-hexane to obtain 3.98 g (yield 56%) of the title compound as a white solid. Was. 1H-NMR (CDCl ₃ ): 7.76 (s, 1H), 7.51 (m, 2H), 4.53 (t, 2
H), 3.32 (m, 2H), 2.83 (s, 3H), 1.84 (m, 2H), 1.66 (m, 2
H), 1.46 (s, 9H)

E) 3- [4- (N-tert-butyloxycarbonyl)
-N-methylamino) butyl] -6-chloro-2-iminobenzothiazoline 3.30 g of the title compound using 3.94 g of the compound obtained in Example 29 (d) and according to the method described in Example 1 (f). Was obtained as an oil (yield: quantitative). 1H-NMR (CDCl ₃ ): 7.22 (m, 2H), 6.83 (m, 1H), 3.95 (t, 2
H), 3.27 (m, 2H), 2.82 (s, 3H), 1.67 (m, 4H), 1.45 (s, 9
H).

F) 3- [4- (N-tert-butyloxycarbonyl)
-N-methylamino) butyl] -6-chloro-2-formyliminobenzothiazoline Using 3.13 g of the compound obtained in Example 29 (e), the reaction was carried out according to the method described in Example 4 (a). , The title compound
3.44 g was obtained as an oil (yield: quantitative). 1H-NMR (CDCl ₃ ): 9.05 (s, 1H), 7.66 (s, 1H), 7.43 (m, 2
H), 4.43 (t, 2H), 3.32 (m, 2H), 2.83 (s, 3H), 1.82 (m, 2
H), 1.65 (m, 2H), 1.46 (s, 9H).

G) 3- [4- (N-tert-butyloxycarbonyl)
-N-methylamino) butyl] -6-chloro-2-methyliminobenzothiazoline Example 4 (b) using the compound obtained in Example 29 (f)
The title compound was obtained according to the method described in (yield 32%
). 1H-NMR (CDCl ₃ ): 7.32 (m, 1H), 7.16 (dd, 1H), 6.82 (m, 1
H), 3.91 (t, 2H), 3.24 (m, 2H), 3.07 (s, 3H), 2.82 (s, 3
H), 1.65 (m, 4H), 1.44 (s, 9H).

H) 3- (4-methylaminobutyl) -6-chloro-2
-Methyliminobenzothiazoline Using the compound obtained in Example 29 (g), Example 1 (g)
The title compound was obtained as an oily substance (yield: 91%). 1H-NMR (CDCl ₃ ): 7.32 (d, 1H), 7.16 (dd, 1H), 6.76 (d, 1
H), 3.90 (t, 2H), 3.07 (s, 3H), 2.61 (t, 2H), 2.42 (t, 2
H), 2.42 (s, 3H), 1.76-1.53 (m, 4H).

I) 3- [4- [N- [2- (4-fluorophenyl) -2-
Oxoethyl] -N-methylamino] butyl] -6-chloro-2-
Methyliminobenzothiazoline dihydrochloride 723 mg of the compound obtained in Example 29 (h) and 2-chloro-4 '
-Example 1 using 440 mg of fluoroacetophenone
The reaction was carried out according to the method described in (h), followed by silica gel chromatography (eluent: methylene chloride / methanol 50:
1) Purify with 815 mg of the free form of the title compound (yield
76%) as an oil. 1H-NMR (CDCl3): 8.02 (m, 2H), 7.31 (d, 1H), 7.13 (m, 3
H), 6.77 (d, 1H), 3.90 (t, 2H), 3.73 (s, 2H), 3.07 (s, 3
H), 2.52 (t, 2H), 2.32 (s, 3H), 1.76-1.54 (m, 4H).

The above compound was dissolved in ethyl acetate, and a 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield 83%). Melting point 142-152 ° C 1H-NMR (DMSO-d ₆ ): 11.66 (bs, 1H), 10.09 (bs, 1H), 8.2
5 (bs, 1H), 8.08 (m, 2H), 7.81 (m, 1H), 7.67 (m, 1H), 7.48
(m, 2H), 5.08 (m, 2H), 4.44 (m, 2H), 3.18 (m, 2H), 3.12 (s,
3H), 2.90 (s, 3H), 1.97 (m, 2H), 1.76 (m, 2H).

Example 30: (R, S) -1- (4-fluorophenyl) -2-[[N- [4- (6-chloro-2-methyliminobenzothiazolin-3-yl) butyl]- N-methyl] amino] ethanol dihydrochloride (Compound 14 in Table 1) Using 385 mg of the free form of the compound obtained in Example 29, a reaction was carried out according to the method described in Example 1 (i), and Purified by silica gel chromatography (eluent: methylene chloride / methanol 50: 1) to give the free form of the title compound
163 mg (42% yield) was obtained as an oil. 1H-NMR (CDCl ₃ ): 7.33 (m, 3H), 7.26 (dd, 1H), 7.02 (m, 2
H), 6.77 (d, 1H), 4.66 (m, 1H), 3.93 (t, 2H), 3.08 (s, 3
H), 2.57 (m, 1H), 2.41 (m, 3H), 2.32 (s, 3H), 1.84-1.55
(m, 4H).

The above compound was dissolved in ethyl acetate, and a 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield: 42%). Melting point 149-155 ° C 1H-NMR (DMSO-d ₆ ): 11.67 (bs, 1H), 9.80 (m, 1H), 8.24 (b
s, 1H), 7.79 (m, 1H), 7.66 (m, 1H), 7.51 (m, 2H), 7.22 (m, 2
H), 6.30 (bs, 1H), 5.15 (m, 1H), 4.44 (m, 2H), 3.61 (m, 2
H), 3.21 (m, 2H), 3.12 (s, 3H), 2.87 (s, 3H), 1.98-1.70
(m, 4H).

Example 31: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-bromo-2-oxobenzothiazoline hydrochloride (Table 2) Compound 175) a) tert-butyl 4- (6-bromo-2-oxobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate 6-bromo-2-oxobenzothiazoline (1.50 g, 6.52
mmol) dissolved in 16 mL of dimethylimidazolidinone, and NaH suspended in 3 mL of dimethylimidazolidinone.
(60% content in oil, 287 mg, 7.17 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour,
Thereafter, the methanesulfonate obtained in Example 1 (c) (1.
91 g, 6.51 mmol) and sodium iodide (977 mg, 6.
52 mmol), and the reaction solution was heated and stirred at 80 ° C. for 2.5 hours. After cooling to room temperature, the reaction solution was poured into water, and the precipitated solid was filtered and washed with water to give 2.4 g of the title compound (86% yield).
I got ¹ H-NMR (CDCl ₃ ): 7.57 (d, 1H), 7.43 (dd, 1H), 6.90 (d,
1H), 4.11 (m, 2H), 3.80 (m, 2H), 2.64 (t, 2H), 2.01
(m, 1H), 1.63 (d, 2H), 1.45 (s, 9H), 1.28 (dq, 2H).

B) 4- (6-Bromo-2-oxobenzothiazolin-3-ylmethyl) piperidine The compound obtained in Example 31 (a) (2.75 g, 6.43 mmol) was dissolved in 26 mL of dichloromethane, and dissolved in 4N of 4N. Hydrochloric acid / ethyl acetate solution (8.0 mL, 32.2 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The precipitated solid was filtered and washed with ethyl acetate to obtain a hydrochloride of the title compound. The hydrochloride was treated with a 0.5N aqueous sodium hydroxide solution, extracted with dichloromethane, dried over sodium sulfate, and the solvent was distilled off to obtain 1.89 g (yield: 90%) of the title compound. ¹ H-NMR (CDCl ₃ ): 7.55 (d, 1H), 7.42 (dd, 1H), 6.91 (d,
1H), 3.80 (d, 2H), 3.08 (dt, 2H), 2.54 (dt, 2H), 1.9
6 (m, 1H), 1.64 (d, 2H), 1.27 (dq, 2H).

C) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-bromo-2-oxobenzothiazoline Obtained in Example 31 (b) 14.19 g (43.4 mmol) of the obtained compound and 2-
Chloro-4'-fluoroacetophenone (7.49 g, 43.4 m
mol) and triethylamine (5.27 g, 52.1 mmol) in dimethylformamide (100 mL) were stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and then diluted with water.
It was washed once with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent is distilled off to give the title compound
19.23 g (96% yield) were obtained. ¹ H-NMR (CDCl ₃ ): 8.06 (m, 2H), 7.55 (d, 1H), 7.42 (dd, 1
H), 7.11 (m, 2H), 6.90 (d, 1H), 3.81 (d, 2H), 3.71 (s, 2
H), 2.95 (d, 2H), 2.09 (dt, 2H), 1.88 (m, 1H), 1.65 (d, 2
H), 1.50 (dq, 2H).

D) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-bromo-2-oxobenzothiazoline hydrochloride Example 31 (c )) Is dissolved in ethanol,
A 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield: 75%). 233-240 ° C. ^{1 H-NMR (DMSO-d} 6): 9.92 (m, 1H), 8.14-7.99 (m, 3H), 7.5
9-7.33 (m, 4H), 5.10-4.99 (m, 2H), 3.96-3.80 (m, 2H), 3.
54-2.98 (m, 4H), 2.08 (m, 1H), 1.87-1.68 (m, 4H).

Example 32: (R, S) -1- (4-fluorophenyl) -2- [4- (6-bromo-2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol. Hydrochloride (Compound 176 in Table 2) a) (R, S) -1- (4-fluorophenyl) -2- [4- (6-bromo-2-
(Oxobenzothiazolin-3-ylmethyl) piperidine-1
-Il] ethanol The compound (1.00 g, 2.16 mmol) obtained in Example 31 (c) was dissolved in a mixed solvent of 14 mL of ethanol and 3 mL of dichloromethane, and sodium borohydride (82 mg, 2.16 mmol) was dissolved.
Was added and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off to obtain 0.97 g (yield: 97%) of the title compound. ¹ H-NMR (CDCl ₃ ): 7.57 (d, 1H), 7.43 (dd, 1H), 7.32 (m, 2
H), 7.02 (m, 2H), 6.92 (d, 1H), 4.67 (dd, 1H), 3.84 (d, 2
H), 3.15 (d, 1H), 2.82 (d, 1H), 2.48-2.34 (m, 2H), 2.27
(dt, 1H), 1.99 (dt, 1H), 1.87 (m, 1H), 1.68 (m, 2H), 1.48
(dq, 2H).

B) (R, S) -1- (4-fluorophenyl) -2- [4-
(6-Bromo-2-oxobenzothiazolin-3-ylmethyl)
Piperidin-1-yl] ethanol / hydrochloride The compound obtained in Example 32 (a) was dissolved in ethanol,
The title compound was obtained as a white solid by adding a 4N hydrochloric acid / ethyl acetate solution (80% yield). 135-138 ° C. ^{1 H-NMR (DMSO-d} 6): 9.85 (m, 1H), 7.99 (d, 3H), 7.59-7.4
0 (m, 4H), 7.22 (t, 2H), 6.28 (d, 1H), 5.14 (m, 1H), 3.40-
3.88 (m, 2H), 3.67-2.91 (m, 6H), 2.04 (m, 1H), 1.88-1.62
(m, 4H).

Example 33: 3-[[1- [2- (4-fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-oxobenzothiazoline hydrochloride (Table 2) Compound of
185) 2-Amino-5-chlorothiophenol 2-amino-6-chlorobenzothiazole (3.00 g, 16.25
was dissolved in 30 mL of a 50% aqueous NaOH solution, and the reaction solution was heated and stirred at 100 ° C. for 6 hours under a nitrogen stream. After cooling to room temperature, the reaction solution was poured into 50 ml of acetic acid containing ice, and the precipitated solid was filtered, washed with water, and 2.43 g of the title compound (94% yield).
) Got. ¹ H-NMR (CDCl ₃ ): 7.15-7.11 (m, 2H), 6.67-6.63 (m, 1H),
4.32 (br s, 2H)

6-Chloro-2-oxobenzothiazoline 1,1′-carbonylbis-1H-imidazole was added to a solution of 2.43 mg (15.0 mmol) of the compound obtained in Example 33 (a) in tetrahydrofuran (60 mL). And stirred at room temperature for 3.5 hours. The precipitated solid was separated by filtration, and the obtained mother liquor was concentrated, subjected to silica gel column chromatography, and subjected to ethyl acetate.
A mixture was obtained from a stream of / hexane (1/4), and the precipitated solid was collected by filtration to obtain 475 mg (yield 28%) of the title compound. ¹ H-NMR (DMSO-d ₆ ): 12.04 (br s, 1H), 7.76 (d, 1H), 7.33
(dd, 1H), 7.12 (d, 1H).

Tert-Butyl 4- (6-chloro-2-oxobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate Using the compound obtained in Example 33 (b), Example 31 (a)
The reaction was carried out according to the method described in (1) to obtain the title compound (yield: 38%). _{^{1 H-NMR (CDCl 3)}} : 7.43 (d, 1H), 7.30-7.26 (m, 1H), 6.95
(d, 1H), 4.12 (br d, 2H), 3.81 (br d, 2H), 2.65 (br t, 2
H), 2.05-1.97 (m, 1H), 1.66-1.61 (br d, 2H), 1.45 (s, 9
H), 1.35-1.13 (m, 2H).

D) 4- (6-Chloro-2-oxobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 33 (c), Example 31 (b)
The reaction was carried out by the method described in (1) to obtain the title compound (yield: 95%). _{^{1 H-NMR (CDCl 3)}} : 7.42 (d, 1H), 7.30-7.27 (m, 1H), 6.96
(d, 1H), 3.80 (d, 2H), 3.09 (br d, 2H), 2.54 (td, 2H), 2.
00-1.93 (m, 1H), 1.64 (br d, 2H), 1.28 (ddd, 2H).

E) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-oxobenzothiazoline Obtained in Example 33 (d) Using the obtained compound, Example 31 (c)
The reaction was carried out according to the method described in (1) to obtain the title compound (yield 93%). ¹ H-NMR (CDCl ₃ ): 8.08 (m, 2H), 7.42 (d, 1H), 7.28 (dd, 1
H), 7.15-7.09 (m, 2H), 6.96 (d, 1H), 3.82 (d, 2H), 3.74
(s, 2H), 2.98 (br d, 2H), 2.16-2.08 (m, 2H), 1.99-1.81
(m, 1H), 1.66 (br d, 2H), 1.59-1.51 (m, 2H).

F) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-chloro-2-oxobenzothiazoline hydrochloride Example 33 (e Using the compound obtained in Example 31 (d)
The reaction was carried out by the method described in (1) to obtain the title compound (yield: 66%). 216-229 ° C. ^{1 H-NMR (DMSO-d} 6): 9.85 (br s, 1H), 8.18-8.02 (m, 2H),
7.85 (s, 1H), 7.47-7.41 (m, 4H), 5.17-4.96 (m, 2H), 3.97
-3.88 (m, 2H), 3.56-3.48 (m, 2H), 2.97 (br s, 2H), 2.07 (b
rs, 1H), 1.86 (m, 2H).

Example 34: 1- (4-fluorophenyl) -2-
[4- (2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol ・ hydrochloride a) tert-butyl 4- (2-oxobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate 2- The reaction was carried out using oxobenzothiazoline by the method described in Example 31 (a) to give the title compound (yield:
quantitative). ¹ H-NMR (CDCl ₃ ): 7.43 (d, 1H), 3.32 (t, 1H), 7.17 (t, 1H),
7.03 (d, 1H), 4.15-4.08 (m, 2H), 3.84-3.82 (m, 2H), 2.6
4 (br t, 2H), 2.04-1.99 (m, 1H), 1.67-1.62 (m, 2H), 1.45
(s, 9H), 1.36-1.23 (m, 2H).

B) 4- (2-oxobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 34 (a), Example 31 (b)
The title compound was obtained (yield: 76%). ¹ H-NMR (CDCl ₃ ): 7.42 (dd, 1H), 7.31 (dd, 1H), 7.12 (t, 1
H), 7.03 (d, 1H), 3.82 (d, 2H), 3.10 (br d, 2H), 2.55 (td,
2H), 2.06-1.96 (m, 1H), 1.67 (br d, 2H), 1.32 (ddd, 2H).

C) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] 2-oxobenzothiazoline Using the compound obtained in Example 34 (b). Example 31 (c)
The title compound was obtained (98% yield). ¹ H-NMR (CDCl ₃ ): 8.06 (dd, 2H), 7.43 (d, 1H), 7.31 (t, 1
H), 7.18-7.02 (m, 4H), 4.12 (d, 2H), 3.72 (s, 2H), 2.96
(d, 2H), 2.16-2.04 (m, 2H), 1.95-1.89 (m, 1H), 1.71-1.6
6 (m, 2H), 1.60-1.52 (m, 2H).

D) 1- (4-Fluorophenyl) -2- [4- (2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol Using the compound obtained in Example 34 (c) Example 32 (a)
The title compound was obtained (71% yield). _{^{1 H-NMR (CDCl 3)}} : 7.44 (d, 1H), 7.43-7.30 (m, 3H), 7.20
(t, 1H), 7.06-6.99 (m, 3H), 4.75 (dd, 1H), 3.86 (d, 2H),
3.15 (br d, 1H), 2.82 (br d, 1H), 2.49-2.38 (m, 3H), 2.07
-1.94 (m, 3H), 1.72-1.68 (m, 2H), 1.56-1.37 (m, 2H).

1- (4-Fluorophenyl) -2- [4- (2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol / hydrochloride The compound obtained in Example 34 (d) was used. Using, Example 32 (b)
And the title compound was obtained (yield: 91%). 222-235 ° C. ¹ H-NMR (DMSO-d ₆ ): 9.71 (br s, 1H), 7.69 (d, 1H), 7.54-
7.37 (m, 4H), 7.29-7.20 (m, 3H), 6.28 (d, 1H), 5.12 (br
s, 1H), 4.01-3.89 (m, 2H), 3.68-3.55 (m, 2H), 3.27-3.1
2 (m, 2H), 2.96-2.88 (m, 2H), 2.07-1.61 (m, 3H).

Example 35: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-nitro-2-oxobenzothiazoline hydrochloride tert-butyl 4- (6-nitro-2-oxobenzothiazoline
Example using -3-ylmethyl) piperidine-1-carboxylate 6-nitro-2-oxobenzothiazoline
The reaction was carried out according to the method described in 31 (a) to obtain the title compound (yield: 95%). ¹ H-NMR (CDCl ₃ ): 8.39 (d, 1H), 8.26 (dd, 1H), 7.14 (d, 1
H), 4.13 (br s, 2H), 3.90 (br d, 2H), 2.66 (br t, 2H),
2.06-2.00 (m, 1H), 1.66-1.62 (m, 2H), 1.47 (s, 9H), 1.39
(ddd, 2H).

B) 4- (6-Nitro-2-oxobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 35 (a), Example 31 (b)
The reaction was carried out according to the method described in (1) to obtain the hydrochloride of the title compound (yield: 92%). ^{1 H-NMR (DMSO-d} 6): 8,91 (br s, 1H), 8.75 (d, 1H), 8.64 (b
rs, 1H), 8.26 (dd, 1H), 7.64 (d, 1H), 3.95 (d, 2H), 3.22
(br d, 2H), 2.76 (br dd, 2H), 2.10-2.04 (m, 1H), 1.74 (br
d, 2H), 1.44 (br dd, 2H). The hydrochloride was reacted according to the method described in Example 31 (b) to give the title compound (yield 98%). ¹ H-NMR (CDCl ₃ ): 8.37 (d, 1H), 8.25 (dd, 1H), 7.13 (d, 1
H), 3.88 (d, 2H), 3.09 (dt, 2H), 2.53 (td, 2H), 2.01-1.
96 (m, 1H), 1.65 (br s, 2H), 1.37-1.21 (m, 2H).

C) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-nitro-2-oxobenzothiazoline Obtained in Example 35 (b) Using the obtained compound, Example 31 (c)
The title compound was obtained (97% yield). _{^{1 H-NMR (CDCl 3)}} : 8.37 (d, 1H), 8.28 (dd, 1H), 8.07-8.02
(m, 2H), 7.16-7.09 (m, 3H), 3.91 (d, 2H), 3.73 (s, 2H),
2.98 (br d, 2H), 2.18-2.10 (m, 2H), 1.93-1.88 (m, 1H),
1.68-1.52 (m, 4H) .d) 3-[[1- [2- (4-fluorophenyl) -2-oxoethyl]-
4-Piperidinyl] methyl] -6-nitro-2-oxobenzothiazoline hydrochloride Example 31 (d) using the compound obtained in Example 35 (c)
The reaction was carried out according to the method described in (1) to obtain the title compound (yield: 82%). 213-226 ° C. ^{1 H-NMR (DMSO-d} 6): 10.09 (br s, 1H), 8.77 (d, 1H), 8.28
(br d, 1H), 8.18-8.05 (m, 2H), 7.70 (d, 1H), 7.46 (br t,
2H), 5.15-5.01 (m, 2H), 4.07-3.99 (m, 2H), 3.52-3.02
(m, 6H), 2.13 (br s, 1H), 1.99-1.73 (m, 2H).

Example 36: 1- (4-fluorophenyl) -2-
[4- (6-Nitro-2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol ・ hydrochloride a) 1- (4-Fluorophenyl) -2- [4- (6-nitro-2 -Oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol Using the compound obtained in Example 35 (c), Example 32 (a)
The reaction was carried out by the method described in (1) to obtain the title compound (yield: 68%). _{^{1 H-NMR (CDCl 3)}} : 8.39 (d, 1H), 8.26 (dd, 1H), 7.35-7.30
(m, 2H), 7.15 (d, 1H), 7.05-6.99 (m, 2H), 4.68 (dd, 1H),
3.93 (d, 2H), 3.17 (br d, 1H), 2.84 (br d, 1H), 2.49-
2.23 (m, 4H), 2.07-1.41 (m, 5H).

B) 1- (4-Fluorophenyl) -2- [4- (6-nitro-2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol hydrochloride Example 36 (a) Using the compound obtained in Example 32 (b)
And the title compound was obtained (yield: 80%). 243-252 ° C. ^{1 H-NMR (DMSO-d} 6): 9.68 (br s, 1H), 8.75 (d, 1H), 8.27
(d, 1H), 7.47-7.43 (m, 2H), 7.24-7.12 (m, 3H), 5.13 (br
s, 1H), 4.00-3.98 (m, 2H), 3.64-2.67 (m, 6H), 2.12-1.93
(m, 1H), 1.16-1.04 (m, 5H).

Example 37: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-fluoro-2-oxobenzothiazoline hydrochloride (Table 2) Compound 195) Using tert-butyl 4- (6-fluoro-2-oxobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate 6-fluoro-2-oxobenzothiazoline as described in Example 31 (a) The reaction was carried out according to the method described to obtain the title compound (yield: 75%). ¹ H-NMR (CDCl ₃ ): 7.19 (dd, 1H), 7.03 (m, 1H), 6.96 (dd, 1
H), 4.12 (m, 2H), 3.82 (d, 2H), 2.65 (t, 2H), 2.02 (m, 1
H), 1.64 (d, 2H), 1.45 (s, 9H), 1.29 (dq, 2H).

4- (6-Fluoro-2-oxobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 37 (a), Example 31 (b)
The reaction was carried out by the method described in (1) to obtain the title compound (yield 72%). ¹ H-NMR (CDCl ₃ ): 7.19 (dd, 1H), 7.03 (m, 1H), 6.97 (dd, 1H)
H), 3.81 (d, 2H), 3.09 (dt, 2H), 2.55 (dt, 2H), 1.98 (m, 1
H), 1.65 (d, 2H), 1.28 (dq, 2H).

3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-fluoro-2-oxobenzothiazoline Obtained in Example 37 (b) Using the compound, Example 31 (c)
The reaction was carried out by the method described in (1) to obtain the title compound (yield: quantitative). ¹ H-NMR (CDCl ₃ ): 8.06 (m, 2H), 7.18 (dd, 1H), 7.12 (t, 2
H), 7.04 (m, 1H), 6.97 (dd, 1H), 3.83 (d, 2H), 3.73 (s, 2
H), 3.83 (d, 2H), 2.12 (dt, 2H), 1.88 (m, 1H), 1.67 (d, 2
H), 1.52 (dq, 2H).

D) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-fluoro-2-
Oxobenzothiazoline hydrochloride Using the compound obtained in Example 37 (c), Example 31 (d)
The title compound was obtained (63% yield). 205-215 ° C ¹ H-NMR (DMSO-d ₆ ): 8.20 (m, 1H), 8.20-8.05 (m, 2H), 7.7
1 (dd, 1H), 7.52-7.44 (m, 3H), 7.28 (dt, 1H), 5.16-5.03
(m, 2H), 4.02-3.90 (m, 2H), 3.56-3.02 (m, 4H), 2.11 (m, 1
H), 1.91-1.67 (m, 4H).

Example 38: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-methyl-2-oxobenzothiazoline hydrochloride a) 6 Example using 2-methyl-2-oxobenzothiazoline 2-amino-6-methylbenzothiazole
The reaction was carried out according to the method described in 33 (a) (b) and crystallized in diethyl ether to give the title compound as a white solid. 1H-NMR (CDCl ₃ ): 11.76 (bs, 1H), 7.37 (s, 1H), 7.08 (d, 1
H), 6.99 (d, 1H), 2.30 (s, 3H).

B) tert-Butyl 4- (6-methyl-2-oxobenzothiazolin-3-ylmethyl) piperidine-1-carboxylate The compound (450 mg, 2.72 mmol) obtained in Example 38 (a) was obtained. The reaction was carried out according to the method described in Example 31 (a) to give the title compound as a yellow oil. The obtained title compound was used for the next reaction without purification.

C) 4- (6-Methyl-2-oxobenzothiazolin-3-ylmethyl) piperidine Using the compound obtained in Example 38 (b), Example 31 (b)
And 550 mg of the title compound was obtained as an oil (yield 77%, two steps). 1H-NMR (CDCl ₃ ): 7.24 (s, 1H), 7.11 (d, 1H), 6.93 (d, 1
H), 3.80 (d, 2H), 3.09 (m, 2H), 2.57 (m, 2H), 2.37 (s, 3
H), 1.80 (m, 1H), 1.65 (m, 2H), 1.28 (m, 2H).

D) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-methyl-2-oxobenzothiazoline hydrochloride Example 38 (c Using the compound obtained in the above, the reaction was carried out according to the method described in Example 31 (c), followed by silica gel column chromatography (eluent: methylene chloride / methanol 5).
0: 1) to give the free form of the title compound as an oil (61% yield). 1H-NMR (CDCl ₃ ): 8.09-8.04 (m, 2H), 7.23 (s, 1H), 7.14-
7.09 (m, 3H), 6.92 (d, 1H), 3.81 (d, 2H), 3.72 (s, 2H), 2.
98-2.94 (m, 2H), 2.37 (s, 3H), 2.14-2.06 (dt, 2H), 1.92
(m, 1H), 1.69 (2H, d), 1.55-1.45 (m, 2H).

The above free compound was dissolved in ethyl acetate, and a 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield 57%). 212-217 ° C 1H-NMR (DMSOd ₆ ): 9.87 (bs, 1H), 8.20-8.02 (m, 2H), 7.49
-7.41 (m, 3H), 7.30 (d, 2H), 7.18 (d, 1H), 5.12-4.94 (m, 2
H), 3.90-3.84 (m, 2H), 3.48-2.95 (m, 4H), 2.32 (s, 3H),
2.06 (m, 1H), 1.80-1.72 (m, 4H).

Example 39: 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -5-chloro-2-oxobenzothiazoline hydrochloride (Table 2) Compound of
213) tert-butyl 4- (5-chloro-2-oxobenzothiazoline
Example using -3-ylmethyl) piperidine-1-carboxylate 5-chloro-2-oxobenzothiazoline
The reaction was carried out by the method described in 31 (a) to obtain the title compound (yield: 68%). ¹ H-NMR (CDCl ₃ ): 7.35 (d, 1H), 7.15 (dd, 1H), 7.02 (d, 1
H), 4.13 (m, 2H), 3.80 (d, 2H), 2.67 (t, 2H), 2.02 (m, 1
H), 1.64 (d, 2H), 1.45 (s, 9H), 1.29 (dq, 2H).

4- (5-chloro-2-oxobenzothiazoline)
-3-ylmethyl) piperidine Using the compound obtained in Example 39 (a), Example 31 (b)
The reaction was carried out according to the method described in (1) to obtain the title compound (yield 99%). ¹ H-NMR (CDCl ₃ ): 7.35 (d, 1H), 7.15 (dd, 1H), 7.03 (d, 1
H), 3.80 (d, 2H), 3.16 (m, 2H), 2.60 (dt, 2H), 1.20 (m, 1
H), 1.69 (d, 2H), 1.37 (dq, 2H).

3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -5-chloro-2-oxobenzothiazoline Obtained in Example 39 (b) Using the compound, Example 31 (c)
The reaction was carried out according to the method described in (1) to obtain the title compound (yield: 93%). ¹ H-NMR (CDCl ₃ ): 8.07 (m, 2H), 7.34 (d, 1H), 7.16-7.09
(m, 3H), 7.03 (d, 1H), 3.80 (d, 2H), 3.72 (s, 2H), 2.97
(d, 2H), 2.13 (dt, 2H), 1.89 (m, 1H), 1.67 (d, 2H), 1.52
(dq, 2H).

D) 3-[[1- [2- (4-Fluorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -5-chloro-2-oxobenzothiazoline hydrochloride Example 39 (c Using the compound obtained in Example 31 (d)
The reaction was carried out by the method described in (1) to obtain the title compound (yield: quantitative). ¹ H-NMR (DMSO-d ₆ ): 9.95 (m, 1H), 8.07 (m, 2H), 7.33 (d, 1
H), 7.65 (d, 1H), 7.47 (t, 2H), 7.29 (dd, 1H), 4.99 (m, 2
H), 3.93 (d, 2H), 3.54-3.02 (m, 4H), 2.12 (m, 1H), 1.91-
1.68 (m, 4H).

Example 40: (R, S) -1- (4-fluorophenyl) -2- [4- (5-chloro-2-oxobenzothiazolin-3-ylmethyl) piperidin-1-yl] ethanol Hydrochloride (Compound 214 in Table 2) a) (R, S) -1- (4-fluorophenyl) -2- [4- (5-chloro-2-
(Oxobenzothiazolin-3-ylmethyl) piperidine-1
-Yl] ethanol Example 32 (a) was prepared using the compound obtained in Example 39 (b).
The reaction was carried out according to the method described in (1) to obtain the title compound (yield: 94%). ¹ H-NMR (CDCl ₃ ): 7.37-7.31 (m, 3H), 7.16 (dd, 1H), 7.05
-6.99 (m, 3H), 7.02 (m, 2H), 4.68 (dd, 1H), 3.83 (d, 2H),
3.16 (d, 1H), 2.83 (d, 1H), 2.49-2.35 (m, 2H), 2.29 (dt, 1
H), 2.02 (dt, 1H), 1.92 (m, 1H), 1.69 (m, 2H), 1.48 (dq, 2
H).

B) (R, S) -1- (4-fluorophenyl) -2- [4-
(5-chloro-2-oxobenzothiazolin-3-ylmethyl)
Piperidin-1-yl] ethanol / hydrochloride Example 32 (b) using the compound obtained in Example 40 (a)
The reaction was carried out by the method described in (1) to obtain the title compound (yield: 68%). Melting point 220 ° C ¹ H-NMR (DMSO-d ₆ ): 9.79 (m, 1H), 7.73 (d, 1H), 7.64 (d, 1
H), 7.51-7.42 (m, 2H), 7.30-7.19 (m, 3H), 6.28 (d, 1H),
5.14 (m, 1H), 4.00-3.89 (m, 2H), 3.68-2.90 (m, 6H), 2.07
(m, 1), 1.91-1.61 (m, 4H).

Example 41: 3-[[1- (2-Phenyl-2-oxoethyl) -4-piperidinyl] methyl] -6-bromo-2-oxobenzothiazoline hydrochloride (compound 181 in Table 2) The compound obtained in Example 31 (b) was reacted with 2-bromoacetophenone according to the method described in Example 31 (c), and subjected to silica gel column chromatography (eluent: methylene chloride / methanol 30: 1). Purification afforded the free form of the title compound as an oil.

The above free form was treated with ethyl acetate-ethanol.
(3: 1), and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield 48%, two steps). Melting point
217-223 ° C 1H-NMR (DMSOd ₆ ): 9.84 (bs, 1H), 8.09-7.95 (m, 3H), 7.76
(t, 1H), 7.65-7.56 (m, 3H), 7.43 (d, 1H), 5.13-4.98 (m, 2
H), 3.99-3.91 (m, 2H), 3.52 (d, 2H), 3.06-2.91 (m, 2H),
2.08 (m, 1H), 1.91-1.58 (m, 4H).

Example 42: 3-[[1- [2- (4-Chlorophenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-bromo-2-oxobenzothiazoline hydrochloride (Table 2 Compound 177) The compound obtained in Example 31 (b) was reacted with 2-bromo-4′-chloroacetophenone according to the method described in Example 31 (c), followed by silica gel column chromatography (eluent: Purification with methylene chloride / methanol (30: 1) gave the free form of the title compound as an oil.

The above free form was treated with ethyl acetate-ethanol.
(3: 1), and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield 48%, two steps). Melting point
210-218 ° C 1H-NMR (DMSOd ₆ ): 9.90 (bs, 1H), 8.09-7.95 (m, 3H), 7.71
(d, 2H), 7.58 (dd, 1H), 7.42 (d, 1H), 5.12-4.94 (m, 2H),
4.01-3.88 (m, 2H), 3.54-3.48 (m, 2H), 3.15-2.94 (m, 2H),
2.08 (m, 1H), 1.91-1.68 (m, 4H).

Example 43: 3-[[1- [2- (4-methoxyphenyl) -2-oxoethyl] -4-piperidinyl] methyl] -6-bromo-2-oxobenzothiazoline hydrochloride (Table 2) Compound 179) The compound obtained in Example 31 (b) was reacted with 2-bromo-4′-methoxyacetophenone according to the method described in Example 31 (c), and subjected to silica gel column chromatography (eluent). : Methylene chloride / methanol 30: 1) to give the free form of the title compound as an oil.

The above free form was treated with ethyl acetate-ethanol.
(3: 1), and 4N hydrochloric acid / ethyl acetate solution was added to obtain the title compound as a white solid (yield 78%, two steps). Melting point
165-170 ° C 1H-NMR (DMSOd ₆ ): 9.84 (bs, 1H), 8.97-7.93 (m, 3H), 7.60
(dd, 1H), 7.43 (d, 1H), 7.13 (d, 2H), 5.07-4.93 (m, 2H),
3.99-3.89 (m, 2H), 3.88 (s, 3H), 3.54-3.48 (m, 2H), 3.08
-2.94 (m, 2H), 2.08 (m, 1H), 1.91-1.68 (m, 4H).

Test Example: Sigma Binding Site Binding Inhibition Experiment Sigma 2 selective receptor binding inhibition experiment was performed using [ ³ H] -di-o-tolylguanidine (DTG, 1 nM final concentration, 37 Ci / mmol, New Zealand) as a radioligand. England Nuclear, Dupont de N
emours). Male rat (Sprague-Dawley
A crude P2 membrane fraction was prepared from the liver of the (system) by the method described in the literature (X. He, et al., J. Med. Chem., 36, pp. 566-571, 1).
993). In the presence of 500 nM pentazocine and various concentrations of the control compound (halopedol (10 ^-10 to 10 ^-6 M) or the test ligand (10 ^-10 to 10 ^-5 M) and the radioligand, the P2 fraction (0.4 ml) at 25 ° C with 50 mM Tris-
Incubated in HCl (pH 7.4, final volume 0.5 ml) for 2 hours. Prior to use, the reaction solution was rapidly filtered through a Brandel cell harvester using Whatman GF / B filter paper immersed in 0.5% polyethyleneimine for 1 hour to terminate the reaction.
The filter paper was washed four times with ice-cold incubation buffer. Non-specific results were assessed using 1 μM haloperidol and scintillation and curve analyzes were performed as described above. The Kd value of [ ³ H] -DTG was 6.9 nM.

[0227]

[Table 3]

Formulation Examples The pharmaceutical composition of the present invention can be produced by using methods and additives for pharmaceutical preparations commonly used in the art. Typical formulation examples of the drug of the present invention are shown below, but the pharmaceutical composition of the present invention is not limited thereto. 1) Tablets Compound of Example 2 5 to 50 mg Calcium phosphate 20 mg Lactose 30 mg Talc 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

2) Suspension Water was added to 1 to 5 mg of the compound of Example 2, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, and 500 mg of sorbitol, and a total amount of 1 ml of an aqueous suspension for oral administration was added. To manufacture. 3) Injection 1.5% by weight of the compound of Example 2 as an active ingredient was mixed and stirred with a mixture of 10% by volume of propylene glycol and distilled water for injection, and the obtained solution was sterilized by filtration through a membrane filter and injected. To produce a composition for use.

4) Ointment Compound of Example 2 5-1,000 mg Stearyl alcohol 3 g Lanolin 5 g White petrolatum 15 g Water ad 100 g

[0231]

The compounds of the present invention have a high affinity for the sigma binding site. Therefore, the compound of the present invention is useful as a sigma ligand for the treatment and / or prevention of various diseases and conditions involving the sigma ligand.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/425 603 A61K 31/425 603 31/445 614 31/445 614 C07D 277/70 C07D 277/70 277/82 277/82 417/06 211 417/06 211 417/14 211 417/14 211 (72) Inventor Kenichi Saito 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Rinichi Abe Kanagawa 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi, Japan Inside Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Masahiro Okuyama 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa prefecture Mitsubishi Chemical Corporation Yokohama Research Laboratory

Claims (19)

[Claims] 1. The following formula: XQC (R ¹ ) (R ² ) -Z wherein R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, or an alkenyl group. Z is one of the following groups: [Wherein, R ³ represents an alkyl group, a cycloalkyl group, a hydroxyalkyl group, or an alkenyl group; p represents an integer of 3 to 8; R ⁴ and R ⁵ each independently represent a hydrogen atom or an alkyl group Or R ⁴ and R ⁵ together with other intervening atoms represent a 5- to 7-membered heterocycle; B is of the following formula: (Wherein R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a cycloalkyl group, an alkenyl group, a halogenated alkyl group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, an alkoxycarbonyl group A phenyl group, a substituted or unsubstituted amino group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted carbamoyl group, an acyl group, a cyano group, and an alkynyl group. A substituent selected from the group; D represents a sulfur atom, an oxygen atom, or a group represented by NR ⁸ (wherein R ⁸ is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-substituted alkyl group, an alkenyl group) , Halogenated alkyl group, hydroxyalkyl group, alkoxyalkyl group, alkoxy Carbonyl group, phenyl group,
Alkylsulfinyl, alkylsulfonyl, substituted or unsubstituted sulfamoyl, alkylsulfonylamino, alkylcarbonylamino, substituted or unsubstituted carbamoyl, acyl, cyano, and alkynyl; X represents a monocyclic or polycyclic cycloalkyl group, a cycloalkyl-substituted alkyl group, an aryl group, or a heterocyclic group, which may be substituted with an alkyl group. When it represents an aryl group, Q represents -CO-, -C (= NO
A group represented by H)-or -C (Y) (A)-, wherein Y is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a monocyclic or polycyclic cycloalkyl group, or a cycloalkyl-substituted group; A represents an alkyl group, an aryl group, an aryl-substituted alkyl group, a heteroaryl group, or a heteroaryl-substituted alkyl group, and A represents a group represented by -OR ⁹ (R ⁹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, X represents an alkyl group, an alkenyl group, an aryl group, an aryl-substituted alkyl group, a hydroxyalkyl group, or an acyl group), and X is an 8- to 10-membered bicyclic heterocyclic group containing 1 or 2 heteroatoms. And when Q represents an aryl group, Q represents a single bond], a salt thereof, or a hydrate or solvate thereof. Wherein R ¹ and R ² are both hydrogen atoms, R ³ is an alkyl group, p is 4, R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group, R ⁶ And R ⁷ are each independently a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a halogenated alkyl group, a substituent selected from the group consisting of an alkoxy group, R ⁸ is a hydrogen atom, an alkyl group,
X is a substituent selected from the group consisting of a halogenated alkyl group and an acyl group, wherein X is a monocyclic or polycyclic cycloalkyl group optionally substituted with an alkyl group, or a substituted or unsubstituted phenyl group ( The substituent is one or more substituents selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, and a substituted or unsubstituted aminosulfonyloxy group. Is a group represented by -CO-, -C (= NOH)-, or -C (Y) (A)-(where Y is a hydrogen atom, and A is Is a group represented by -OR ⁹ (R ⁹ is a hydrogen atom, an alkyl group, or an acyl group), and X is an 8- to 10-membered bicyclic heteroaryl group containing one or two hetero atoms. 2. The compound of claim 1, wherein, in some cases, Q is a single bond. Or its salt,
Or hydrates or solvates thereof. 3. R ³ is an alkyl group, R ⁴ and R ⁵ are both hydrogen atoms, R ⁶ is a hydrogen atom, R ⁷ is a hydrogen atom,
X is a substituent selected from the group consisting of a halogen atom, a nitro group, an alkyl group, a halogenated alkyl group, and an alkoxy group, and X is a monocyclic or polycyclic cycloalkyl group which may be substituted with an alkyl group, An unsubstituted phenyl group (the substituent is one selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, and a substituted or unsubstituted aminosulfonyloxy group Or two or more substituents), and Q is -CO-, -C (= NOH)-
Or a group represented by —C (Y) (A) — (wherein Y is a hydrogen atom, and A is a group represented by —OR ⁹ (R ⁹ is a hydrogen atom, an alkyl group, or an acyl group) 3. The method according to claim 2, wherein
Or a salt or hydrate or solvate thereof. 4. Z is the following formula: 4. The compound according to claim 3, which is a group represented by or a salt thereof, or a hydrate or solvate thereof. 5. The compound according to claim 4, wherein X is a substituted or unsubstituted phenyl group, a salt thereof, or a hydrate or solvate thereof. 6. The method according to claim 2, wherein R ⁶ is a hydrogen atom, R ⁷ is a halogen atom, and D is a group represented by NR ⁸ (wherein R ⁸ is a hydrogen atom or an alkyl group). 6. The compound according to any one of 1 to 5, or a salt thereof, or a hydrate or solvate thereof. 7. The compound according to any one of claims 2 to 5, wherein R ⁶ is a hydrogen atom, R ⁷ is a halogen atom, and D is an oxygen atom, or a salt thereof, or a hydration thereof. Or solvate. 8. The compound or a salt thereof according to claim 2, wherein Q is —CO— or —CH (OH) —.
Or hydrates or solvates thereof. 9. X is a p-fluorophenyl group, R ⁷ is a chlorine atom, D is NH, and Q is -CO- or -CH (OH)-
The compound according to claim 4, which is or a salt thereof, or a hydrate or solvate thereof. 10. X is a p-fluorophenyl group, and R ⁷
Is a chlorine atom, D is NCH ₃ and Q is -CO- or -CH
The compound according to claim 4, which is (OH)-, or a salt thereof,
Or hydrates or solvates thereof. 11. X is a p-fluorophenyl group and R ⁷
Is a fluorine atom, D is NH, and Q is -CO- or -CH (O
The compound according to claim 4, which is H)-, a salt thereof, or a hydrate or solvate thereof. 12. X is a p-fluorophenyl group, and R ⁷
Is a trifluoromethyl group, D is NH, and Q is -C
The compound according to claim 4, which is O- or -CH (OH)-, a salt thereof, or a hydrate or solvate thereof. 13. X is a p-fluorophenyl group, and R ⁷
Is a bromine atom, D is an oxygen atom, and Q is -CO- or
The compound according to claim 4, which is -CH (OH)-, a salt thereof, or a hydrate or solvate thereof. 14. X is a p-fluorophenyl group, and R ⁷
Is a chlorine atom, D is an oxygen atom, and Q is -CO- or
The compound according to claim 4, which is -CH (OH)-, a salt thereof, or a hydrate or solvate thereof. 15. X is a p-fluorophenyl group, and R ⁷
Is a fluorine atom, D is an oxygen atom, and Q is -CO- or -CH (OH)-, or a salt thereof, or a hydrate or solvate thereof. 16. X is an unsubstituted phenyl group, R ⁷ is a bromine atom, D is an oxygen atom, and Q is -CO- or -C
The compound or a salt thereof according to claim 4, which is H (OH)-,
Or hydrates or solvates thereof. 17. A medicament comprising as an active ingredient a substance selected from the group consisting of the compound according to any one of claims 1 to 16, a salt thereof, and a hydrate or solvate thereof. 18. The medicament according to claim 17, which is used for treating and / or preventing a disease caused or promoted by the neuromodulatory action of a sigma ligand. 19. A sigma ligand comprising a compound selected from the group consisting of the compound according to claim 1 and a salt thereof, and a hydrate and a solvate thereof.