WO2003101490A1 - Drug composition containing calcium channel antagonist - Google Patents

Abstract

A drug composition comprising a calcium channel antagonist exhibiting intestinal tract selectivity that is used for treating Alzheimer disease, mental illness, adolescent insanity, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or obesity; and a serotonin liberation inhibitor comprising a calcium channel antagonist exhibiting intestinal tract selectivity.

Description

 Description Pharmaceutical composition containing calcium channel antagonist

 The present invention has calcium channel antagonism, and has Alzheimer's disease, psychosis, premature dementia, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia BACKGROUND OF THE INVENTION The present invention relates to a pharmaceutical composition useful for treating epilepsy or obesity

For example, EP 0404359 A1 discloses that 5,11-dihydrodibenzo [b, e] [1,4] thiazepine derivatives are useful as calcium channel antagonists having selectivity for the gastrointestinal tract. ing. Also, Quinn, P. et al., Brit. J. Pharmacol., 1994, 112 (Suppl.) ₅ Abst. 573P and Perris et al. (Wallis, M. et al.), Brit. J. Pharmacol., 1994, U2 (S Lord 1.), Abst. 574P shows that one of the above derivatives is (S) -5- [C1- (4-methoxyphenyl) ethyl] pyrrolidine-12-ylmethyl] 15,11-dihydrodiben Zo [b, e] [1, 4] discloses that thiazepine maleate has a similar effect. However, one of the drawbacks is that these compounds do not have sufficient activity and selectivity for the gastrointestinal tract, and have an anticholinergic effect that contributes to side effects such as blood loss and mydriasis. . In addition, International Patent Nos. 9733885 A1 and 991 2925 A1 disclose 5- (2-pyridinylmethyl) -5,11-dihydrodibenzo [b, e] [1,4] as an agent for improving gastrointestinal motility dysfunction. An oxazepine derivative has been disclosed. Further, International Patent No. 0040570 A1 discloses that 5-alkyl-1,5,11-dihydrodibenzo [b, e] [1,4] oxo is used as an agent for improving gastrointestinal motility dysfunction. Sazepine derivatives are disclosed.

On the other hand, serotonin receptor subtypes include 5-HT1 (5-ΗΤ1Α _Ν 5-HT1B, 5-HT1 D ヽ 5-HT1Es 5-HT1F), 5-HT2 (5-HT2A ヽ 5-HT2B, 5-HT2C ), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6, 5-HT7, and the like. The stimulatory effects of various serotonin receptors include: appetite enhancement, anorexia, anxiety 'Anxiety, depressive', antidepressant, suppression of extrapyramidal symptoms, increased sexual behavior, suppression, aggressive behavior, hypothermia, arteriovenous contraction, Pulmonary artery contraction, vasoconstriction, atrial adrenaline release, smooth muscle contraction, platelet aggregation, gastric atrophy, penile erection, analgesia, nausea, vomiting, gastrointestinal tract constriction, neurotransmitter release (noradrenaline is suppressed), memory and cognitive function Improvement, steroid secretion, cardiac arrhythmia, cardiac contractility enhancement, intestinal motility hyperactivity, acetylcholine release, sleep cycle, pain, bronchial relaxation, memory impairment, dysrhythmia, aldosterone secretion, coronary vasodilation, vascular relaxation, hypotension, Colonic relaxation, tachycardia, etc. are known. In relation to various serotonin receptors and diseases, anxiety, depression, migraine, strong Disorders, depression, psychomotor arousal, hallucinations, schizophrenia negative symptoms, urinary incontinence cognitive impairment, pain, peripheral vascular disorders, hypertension, neurogenic inflammation, schizophrenia, etc. are known (Pharmaceutical Journal, Vol. 36, No. 5, 2000, p 1383-1388). Disclosure of the invention

 The present invention treats Alzheimer's disease, mental illness, premature dementia, manic depression, migraine, lactation, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or obesity. To provide an excellent pharmaceutical composition for the same.

The present invention treats Alzheimer's disease, mental illness, premature dementia, manic depression, migraine, lactation, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or obesity. And a pharmaceutical composition containing a calcium channel antagonist having intestinal selectivity. The present invention also provides a serotonin release inhibitor containing a calcium channel antagonist having intestinal selectivity. BRIEF DESCRIPTION OF THE FIGURES

 FIGS. 1 and 2 show the effect of the test compound on serotonin released from the isolated intestinal tract of mice. BEST MODE FOR CARRYING OUT THE INVENTION

 As the “calcium channel antagonist” as the active ingredient of the present invention, a drug that acts on calcium channels present in skeletal muscle, cardiac muscle, vascular smooth muscle, brain, endocrine and kidney and inhibits influx of potassium is used. can do. In particular, calcium channel antagonists having intestinal selectivity are preferred. The calcium channel antagonist having intestinal selectivity refers to a compound having a calcium channel antagonistic activity whose antagonistic action on calcium channels present in the intestinal tract is stronger than that of calcium channels present in cardiac blood vessels. Further, it preferably has a serotonin release inhibitory action.

 Examples of the “calcium channel antagonist having intestinal selectivity” used in the present invention include compounds represented by the following (I) to (V) or pharmaceutically acceptable salts thereof.

(I) 5,11-dihydrodiaryl [b, e] CI, 4) oxazepine derivative represented by the following general formula [I], a stereoisomer thereof, a pharmacologically acceptable salt thereof, Hydrate or solvate of

[Wherein, rings G, J, and K each represent a benzene ring or a nitrogen-containing aromatic ring. R ¹ R ⁸ may be the same or different, and represent a halogen atom or a hydrogen atom; R ⁹ to R ¹³ may be the same or different; a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower group; Represents an alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group, a cyclic alkylamino group, or R ⁹ and R ^{1 ()} , or R ^1Q and R ¹¹ Connected together 0 (CH ₂ ) n

0— represents a group (n is 1, 2 or 3). A is any of CH ₂ , CHOH, C〇, or 0, B is CH ₂ , CHOH, or CO, or A—B represents CH = CH, D is CH ₂ , CH ₂ —CH ₂ Or CH ₂ — CH ₂ — CH ₂ , or BD represents CH ₂ . X and Z are joined to each other CH ₂ - CH ₂ or CH ₂ - CH ₂ - represents either CH _2, Y represents a hydrogen atom at that time. Alternatively, Y and Z are joined to each other CH ₂ - CH ₂ - CH ₂ or _{CH 2 - CH 2 - CH 2} - CH 2 , whichever is represents, X at that time represent a hydrogen atom. When X and Z, and Y and Z are not bonded to each other, X and Y represent a hydrogen atom, and Z represents a lower alkyl group. However, when any of R ^{9 to} R ¹³ is a cyclic amino group represented by the formula [E], any of R ¹ to R ⁸ may be a halogen atom or a hydrogen atom, but any of H ⁹ to R ¹³ also within the case is not cyclic amino group represented by the formula [E] is 1 ^ to 11 ⁸ or 1 connected to 2 Tsugano the other a mouth Gen atoms denote the hydrogen atom.

 [In the formula, n and m represent 1 or 2, and W represents a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom which may be substituted with a lower alkyl group. ]

 (II) 5, 11-dihydrodibenzo [b, e] represented by the following general formula [2]

[1, 4] thiazepine derivatives, stereoisomers, pharmacologically acceptable salts thereof, hydrates or solvates thereof;

[2]

(Where

 k, m and n are 1, 2 or 3, respectively;

 P is 0, 1 or 2;

X is 0, S or a linking group; when X is 0 or S, n is 2 or 3; R ¹ is H or —C ₄ alkyl; and

R ² is

(a)

(Wherein, and R ⁴ are each independently H, C—C ₄ alkyl, d—C ₄ alkoxy, —OH, —NiCi—C ₄ alkyl) ₂ , halo, or —CF ₃ . ) (b)

 (Where q is 1, 2 or 3;

X ¹ and X ² are each independently selected from 〇 and —CH ₂ —), or

(c) pyridinyl, pyridazinyl, pyrimidinyl, a Birajiniru or thienyl group, wherein said groups, CI- C ₄ alkyl and C ^ - to separate from C ₄ alkoxy substituted by selection Bareru 2 following substituents Is also good. )

 (III) 5- (2-pyridinylmethyl) -5,11-dihydrodibenzo [b, e] CI, 4] oxazepine derivative represented by the following general formula [3], its stereoisomer, pharmacology Pharmaceutically acceptable salts, hydrates or solvates thereof;

[3]

[Wherein, R ¹ and may be the same or different, and represent a hydrogen atom, a halogen atom, Represents a cyano group, a hydroxy group or a lower alkoxy group, or R ¹ and R ² together represent a — 0 (CH ₂ ) _n 0 — group (n is 1, 2 or 3), and R ³ is hydrogen Represents an atom or a hydroxy group, R ⁴ and may be the same or different, represent a hydrogen atom or a hydroxy group, or together represent = 0. ]

 (IV) 5-alkyl-1,5,11-dihydrodibenzo [b, e] [1, '4] oxazepine derivatives represented by the following general formula [4], stereoisomers thereof, and pharmacologically acceptable Salts thereof, hydrates or solvates thereof; and

 [Four]

[Wherein, may be the same or different and represents a hydrogen atom, a lower alkoxy group, an amino group, or an alkylamino group, and at least one of them represents an amino group or an alkylamino group, and R ⁶ and R ⁷ may be the same or different and represents a hydrogen atom or a hydroxy group, or together represent = 0, and Y ¹ represents a methylene, dithiol atom or hydroxymethine. ]

(V) a 5-alkyl-5,11-dihydrodibene represented by the following general formula [5]: Zo! b, e] [1, 4] oxazepine derivative, stereoisomer, pharmacologically acceptable salt thereof, hydrate or solvate thereof.

 [Five]

[In the formula, 1 ^ to ¹⁵ may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group. , Or: R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , or R ⁴ and R ⁵ together form a (CH ₂ ) nO— group (n is 1, 2 or 3) R ⁶ represents hydrogen or a lower alkyl group, Y represents a methylene, oxygen atom, zeo atom, or alkylamino group, A represents any of CH ₂ , CHOH, CO or 0, and B represents CH ₂ , represents either CHOH or CO, or A—B represents CH = CH, D represents either CH ₂ , CH ₂ —CH ₂ or CH ₂ —CH ₂ —CH ₂ , or Β'— D represents CH _2. ]

In the present invention, a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the general formula [I], a stereoisomer thereof, a pharmacologically acceptable salt thereof, Particularly preferred are calcium channel antagonists, which are hydrates or solvates of Good. The oxazepine derivative represented by the general formula [I] is disclosed in WO 02/096991 A1, which was published after the priority date of the present application. Are all included in this specification.

As the nitrogen-containing aromatic ring of 璟 G, J, and K in the general formula [I], a 6-membered ring is desirable, and examples thereof include a pyridine ring, a pyrimidine ring, a virazine ring, and a pyridazine ring. However, in 璟 0, J, there is no aromatic ring nitrogen atom on the oxazepine ring, and when any of 1 ^ to ¹⁸ is a halogen atom, the halogen atom is replaced with the aromatic ring nitrogen atom. Does not combine. In ring K, the aromatic ring nitrogen atom does not bond to A and has no substituent on the nitrogen atom.

 Regarding the rings G, J, and K in the general formula [I], (i) when both G and J are benzene rings, (ii) one of the rings G and J is pyridine, and the other is (Iii) In the case of the above (i) or (ii), in which ring K is a benzene ring, (iv) あ る K is a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring. In the case of (i) or (ii), or (v ^^ G, J and K are preferably all benzene rings. The same applies to the general formulas [XV] and [XVI].

Examples of the halogen atom of ¹ to! ^ In the above general formula include a fluorine atom, a chlorine atom, a bromine atom and the like, and a fluorine atom or a chlorine atom is preferable. Of ^{Ri~R 8, R 2, R 3} , any one of R \ R ⁷ is a full Uz atom or a chlorine atom, and more preferably other is a hydrogen atom. Examples of the halogen atom of R ^{9 to} R ¹³ include a fluorine atom, a chlorine atom, a bromine atom, and the like.Examples of the lower alkyl group include a methyl group, an ethyl group, a lower alkyl group having 1 to 5 carbon atoms such as a propyl group, Examples of the lower alkoxy group include a lower alkoxy group having 1 to 5 carbon atoms such as a methoxy group, an ethoxy group, and a propoxy group, and examples of the lower alkylamino group include a carbon atom such as a monomethylamino group, a monoethylamino group, and a monopropylamino group. Examples include lower alkylamino groups of the numbers 1 to 5. Amino groups and lower acyl forms of these lower alkylamino groups; Formylamino, acetylamino, propionylamino, formylmethylamino, formylethylamino, formylpropylamino, acetylmethylamino, acetylethylamino, acetylpropylamino, Examples thereof include fatty acid acyl groups having 1 to 3 carbon atoms, such as a pionylmethylamino group, a propionylethylamino group, and a propionylpropylamino group. Examples of the dialkylamino group include a lower alkylamino group having a total of 2 to 7 carbon atoms such as a dimethylamino group, a acetylamino group, and a methylethylamino group.Examples of the cyclic alkylamino group include an azetidino group, a pyrrolidino group, a piperidino group, and a homopiperidino group. Examples of the 4- to 7-membered amino group such as a piperazino group and a morpholino group, and a 10 (CH ₂ ) ηθ- group include a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group. Among these, a fluorine atom and a chlorine atom are preferable as the halogen atom, and a lower alkyl group having 1 to 3 carbon atoms is preferable as the lower alkyl group. As the lower alkoxy group, a lower alkoxy group having 1 to 3 carbon atoms is preferable. The monoalkylamino group is preferably a lower alkylamino group having 1 to 3 carbon atoms, and the dialkylamino group is preferably one having a total of 2 to 6 carbon atoms in the alkyl group. The cyclic alkylamino group is preferably one having 4 to 6 ring members. As the amino group or the lower acyl group of these lower alkylamino groups, a formyl group such as a formyl group is preferred. Here, it is preferred that R ^{9 to} R ¹³ are not simultaneously hydrogen atoms.

 In the above general formula [I], the following are preferable, and the same applies to the general formulas [XV] and [XVI].

(i) and X and Z are bonded to each other CH ₂ - CH ₂ or CH ₂ - CH ₂ - represents CH _2, Y is a hydrogen atom,

(ii) Y and Z are bonded to each other CH ₂ - CH ₂ - CH ₂ or CH ₂ - CH ₂ - CH ₂ shows one CH _2, X is a hydrogen atom, (i ii) X and Y are hydrogen atoms, Ζ is a lower alkyl group,

(iv) one or both of R ¹⁰ _s R ¹¹ are methoxy groups, or R ^lfl and R ¹¹ together represent a methylenedioxy group, and R ^9, R ¹² and R ¹³ are water Elementary atom,

(v) R ¹¹ is a methoxy group, R ⁹ , R and R ¹² , R ¹³ are a hydrogen atom,

(vi) ^{one of} R ^{1 Q} and R ¹¹ is an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group or a cyclic alkylamino group, and the other is a hydrogen atom,

(vii) all of R ^{1 to} R ⁸ are hydrogen atoms,

(viii) ^{one of} R ^{1 to} R ⁸ is a fluorine atom or a chlorine atom, and the other is a hydrogen atom

(ix) one of R \ RR ⁶ and R ⁷ is a fluorine atom or a chlorine atom, the other is a hydrogen atom,

(x) Both A and B—D are CH ₂ ,

 (xi) the absolute configuration of the carbon atom to which X is bonded is R-form,

(xi i) The absolute configuration of the carbon atom bonded to X is S-form,

 (xi i i) The absolute configuration of the carbon atom bonded to Y is R-form,

(xiv) The absolute configuration of the carbon atom to which Y is bonded is S-configuration.

Examples of the cyclic amino group represented by the formula [E] include a azetidino group, a pyrrolidino group, a pyridino group and the like containing one nitrogen atom, a piperazino group, a morpholino group, a nitrogen atom, an oxygen atom, and the like. Examples thereof include a cyclic amino group containing a heteroatom atom, and preferred are a pyrrolidino group and a morpholino group. Among R ^{9 to} R ″, it is more preferable that one of R ^{1 ()} and R ¹¹ is a cyclic amino group and the other is a hydrogen atom.

A— B— D is CH ₂ — CH ₂ , CO— CH ₂ , CHOH— CH ₂ , CHOH-CH ₂ _CH ₂ , CH ₂ -CHOH-CH ₂ , CH = CH— CH ₂ , CO-CH ₂ -CH ₂ , 0 — CH ₂ , CH ₂ — CO— CH ₂ , or CH ₂ — CH ₂ — CH ₂ Either is preferred.

In the present invention, among these, preferred compounds are, for example, compounds represented by the following formula [II]. In the formula, the aromatic ring ^{G, J, K, ~ 3} , A, B, D represent the same as the formula [I], r is representative of 1 or 2.

Examples of the compound represented by [II] include 2-fluoro-5,11-dihydric 5- (1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl) dibenzo [b, e [1,4] oxazepine, 2-fluoro-5,11-dihydro-1- [1- (3-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2- Fluoro-5,11-dihydro-1-5- [1-1 (3,4-methylenedioxyphenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11 —Jihid Mouth 5- [1-1- (4-aminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1 5-[1- (3-aminophenethyl ) Pyrrolidine_2-ylmethyl] dipento [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1- (4-methylaminophenethyl) pyrrolidine-1-ylmethyl] dipento [B, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-methylaminophenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 , 1 1 dihydromono 5— [1-(3—dimethyl Laminophenethyl) pyrrolidine-1-2-ylmethyl] dipenza [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1-(4-pyrrolidinophenethyl) pyrrolidine-1 2 —Ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1- (3-pyrrolidinofphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidine-1-ylmethyl] dipento [b, e] [1,4] oxazepine, 2 —Fluoro-5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidine-1-2-methyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1 5-[1-(4-fluorophenethyl) Loridine-1-2-ylmethyl] dipento [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1-1 (3-fluorophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [ 1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidine-1-ylmethyl] dipento [b, e] CI , 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-a-cetylaminophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro 1,5-dihydro-5- [1- (4-Methoxyphenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,] oxazepine, 3-chloro-5,1 1-dihydro-5 [1— (3-Methoxyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5— [1- (3,4-methylenedi) Oxyphenethyl) pyrrolidine-1-ylmethyl] dipento [b, e] [1,4] oxazepine, 3-chloro-1,5-dihydro-1-5- [1- (4-aminophenethyl) pyrrolidine-1-ylmethyl] dipento (B, e) (1, 4) oxazepine, 3 Chloro-5,11-dihydro-5- [1- (3-aminophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- ( 4-Methylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-1--5,11-dihydro-5- [1- (3-methylaminophenyl Enetyl) pi-Lysine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazebine, 3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) P-lysine-1-2-methyl] dibenzo [b, e] CI, 4} oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-dimethylaminophenethyl) p-lysine 2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-1,5-dialdehyde Rho 5— [1— (4-Pyrrolidinophenetyl) pyrrolidin-1-ylmethyl] dibenzo [b, e] [1, 4] oxazebine, 3-chloro-1-5, 11-dihydro-5— [1 -(3-Pyrrolidinophenetyl) pyrrolidine —2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) ) Pyrrolidine 2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [ b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (4-fluorophenethyl) pyrrolidine-12-ylmethyl] dipenza [b, e] [1, 4] oxazepine , 3-chloro-1,5-dihydro-5- [1- (3-fluorophenethyl) pyrrolidine-1,2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-1,5 , 11-Dihydro-1-5- [1- (4-acetylaminophenethyl) pyrrolidine-1-2-ylmethyl] dipento [b, e] [1,4] oxazepine, 3-chloro-1,5-dihydro 1- [1- (3-Acetylaminophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] 1, 4] Okisazepin, 5, 11-dihydro-5- [1- (4 one pyrrolidinium Nof energy chill) pyrrolidine one 2- Irumechiru] Jipenzo [b, e]

[1,4] oxazebine, 5,11-dihydro-1-5- [1- (3-pyrrolidinopheneethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro- 5— [1- (4-Piperidinophenetyl) pyrrolidin-1-ylmethyl] dipenza [b, e] [1,4] oxazepine, 5,11 dihydro-5- [1-(3-piperidinoff Enethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5-

[1— (4-morpholinophenetyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-1 5 -— [1 -— (3-morpholinov) Netyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine and its halogen-substituted regioisomers, pharmaceutically acceptable salts or hydrates, and solvates thereof Can be

The compound [II] that can be used in the present invention has one or more asymmetric carbon atoms, and may have optical isomers. These optical isomers, those Any mixtures or racemates are included in the compounds of the present invention. Among them, it is preferable that the configuration at the 2-position of the pyridine ring or the pyridine ring bonded to the dihydroxybenzoxazepine ring via methylene is R-form.

 Other preferred compounds are, for example, compounds represented by the following formula (III):

However, in the formula, the aromatic rings G, J, K, R′-R ¹³ , A, B, and D represent the same as in the formula [I], and r represents 1 or 2. Examples of the compound represented by the formula [III] include, for example, 2-fluoro-5,11-dihydro-1-5- [1- (4-methoxyphenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazebine, 2-fluoro-5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1 , 4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1-1- (3,4-methylenedioxyphenethyl) pyrrolidin-13-yl] dibenzo [b, e] [1,4 Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-aminophenethyl) pyrrolidine-3-yl ] Dibenzo [b, e] [1, 4] oxazepine, 2_fluoro-5,11-dihydro 5- [1-(3-aminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1, 4] Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 , 11 Dihydro-5- [1- (3-Methylaminophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [ 1- (4-Dimethylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazebine, 2-fluoro-5,11-dihydro-5- [1- (3-dimethyl) Minophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-pyrrolidino phenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11- Dihydro-5- [1— (3-pyrrolidinophenyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11 dihydro-5- [1- ( 4-morpholinophenethyl) pi-lysine-3-yl] dibenzo [b, e] [1, 4] oxazepine, 2-fluoro 1-, 11-dihydro-1- 5-—1- (3-morphoyl Nophenethyl) pyrrolidin-1-yl] dipenza [b, e] [1,4] oxazepine, 2-fluoro-5,11 dihydro-5- [1- (4-fluorophenethyl) pyrrolidine-3-yl] Dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5, 11 dihidroh 5-— [1-(3-fluorofur Enethyl) pyrrolidine-1-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [11- (4-acetylaminophenethyl) pyrrolidine-1 3 —Yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1- (3-acetylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [ b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazepine , 3-chloro-5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazepine,

3-chloro-1,5-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazebine, 3_chloro 1,5-dihydro-5- [1- (4-aminophenethyl) pyrrolidin-13-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5 — [1— (3-Aminophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- [1 -— (4-methyl Aminophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5-

[1- (3-Methylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1— (

4-dimethylaminophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-dimethylamine Phenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,] oxazepine, 3-chloro-1,5-dihydro-5- [1- (4- (pyrrolidinophenetyl) pyrrolidine-1 3-] L] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-1-5- [1- (4-morpholinophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] Oxazepine, 3-chloro-5,11-dihydro-1-5- [1- (3-morpholinophenethyl) pyrrolidine-1-yl] di Down zone [b, e] [1, 4] Okisazepin, 3-chloro 5, 11 Dihydro-5- [1- (4-fluorophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-1-5,11 dihydro-5- [1- ( 3-Fluorophenethyl) pyrrolidine-1-3-yl] dipenza [b, e]

[1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1-1 (4-acetylaminophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] Oxazepine, 3-chloro-1,5-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1, 4] oxazepine, 5 , 11-dihydro-5- [1- (4-pyrrolidinophenetyl) pi-lysine-13-yl] dibenzo [b, e] [1,4] oxazebine, 5,11-dihydro-5- [1 -(3-Pyrrolidinophenetyl) pyrrolidine-1-3-yl] dibenzo [b, e] CI, 4) oxazepine, 5, 11-dihydro-5- [1- (4-piperidinophenethyl) pyrrolidine 1,3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-1-5- (1-1- (3-piperidinophenethyl) pyrrolidine-1 3- Dibenzo [b, e] [1,4] oxazepine, 5,11 dihydro-5- [1- (4-morpholinophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4 Oxazepine, 5, 11-dihydro-5-

[1- (3-morpholinophenetyl) pyrrolidine-1-yl] dibenzo [b, e] [1, 4] oxazepine and its halogen-substituted positional isomers, pharmacologically acceptable salts thereof Or hydrates and solvates.

 The compound [III] that can be used in the present invention has one or more asymmetric carbon atoms, and may have optical isomers. These optical isomers, arbitrary mixtures or racemates thereof are included in the compounds of the present invention. Among these, it is preferable that the configuration at the 2-position of the pyrrolidine ring or the piperidine ring bonded to the dihydrodibenzoxazepine ring is R-form.

Other preferred compounds are, for example, compounds represented by the following formula [IV]. However, it represents wherein the aromatic rings G, J, K, Ri R 13 A, B, D are the same as the formula [I], R ¹⁴ represents a lower alkyl group having 1 to 3 carbon atoms.

Examples of the compound represented by the formula [IV] include 2-fluoro-5,11-dihydro-5- {2- [N- (4-methoxyphenethyl) -1-N-methyl] aminoethyl} dibenzo [ b, e] [1, 4] oxazebine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-methoxyphenethyl) -N-methyl] aminoethyl} dibenzo [b, e [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3,4-methylenedioxyphenethyl) -1-N-methyl] aminoethyl} dibenzo [b , e] [1,4] oxazepine, 2-fluoro 1,5-dihydro-5- {2- [N- (4-aminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1 , 4] oxazepine, 2-fluoro-1,5-dihydro-5- {2- [N- (3-aminophenethyl) -N-methyl] aminoethyl} dipe Zo [b, e] [1, 4] Okisazepin, 2 Furuo port one 5, 11- dihydro 5- {2- [N- (4- methylamino-off energy Chill) Single N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- (N— (3-methylaminoaminoethyl) —N-methyl ] Aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-dimethylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [ b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- (N- (3-dimethylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b , e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- (N- (4-pyrrolidinophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- (N- (3-pyrrolidino Enetyl) 1 N-methyl] aminoethyl} dibenzo [b, Θ] [1, 4] oxazepine, 2-fluoro-5, 11-dihydro-1- 5- {2- [N- (4-morpholinophenethyl) 1 N-methyl] aminoethyl} dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-l 5- {2- (N- (3-morpholinophenethyl) 1 N- Methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [2- [N- (4-fluorophenethyl) -N-methyl] aminoethyl } Dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-fluorophenethyl) -1-N-methyl] aminoethyl} diben Zo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- (N- (4-acetylamino Enethyl) 1-N-methyl] aminoethyl} dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-acetylaminophene) Tyl) 1-N-methyl] aminoethyl} dibenzo [b, e] [1, 4] oxazebine, 3-chloro-5,11-dihydro-1 5 -— {2- [N- (4-methoxyphenethyl) 1 N-methyl] Minoethyl} dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5, 1 1 dihydro-5- {2- [N- (3-methoxyphenethyl) 1 N-methyl] aminoethyl} dibenzo [ b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- {2- [N- (3,4-methylenedioxyphenethyl) -1-N-methyl] amino Ethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-aminophenyl) -1-N-methyl] aminoethyl} dibenzo [b , E] [1,4] oxazepine, 3-chloro-1,5-dihydro-5- {2- [N- (3-aminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1 , 4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-methylaminophenethyl) -1-N-methyl] aminoethyl} Benzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-methylaminophenethyl) -N-methyl] aminoethyl} Dibenzo [b, e] [1, 4] oxazepine, 3-1,5-dihydro-5-{2- [N- (4-dimethylaminophenethyl)-1 N-methyl] aminoethyl} dibenzo [B, e] [1, 4] oxazepi, 3-chloro-1,5-dihydro-5- {2- [N- (3-dimethylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- {2- (N- (4-pyrrolidinophenetyl) -N-methyl] aminoethyl} dibenzo [b, e] [1, 4 Oxazepine, 3-chloro-5,11-dihydro-5- {2- (N- (3-pyrrolidinophenethyl) -1-N-methyl] aminoethyl} Benzo [b, e] [1,4] oxazebine, 3-chloro-5,11-dihydro-1-5- {2- [N- (4-morpholinophenethyl) -N-methyl] aminoethyl} dibenzo [b , e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- (N- (3-morpholinophenetyl) -N-methyl] aminoethyl} dibenzo [b, e ] [ 1,4] oxazebine, 3-chloro-5,11-dihydro-5- {2- (N- (4-fluorophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine 5,11-dihydro-5- {2- (Ν- (3-fluorophenethyl) -1-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazebine, 3-chloro 1,5,11-dihydro-5- {2- [N- (4-acetylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5 , 11-Dihydro-1-5-N- [N- (3-acetylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-1 5— {2— [N-methyl—N— (4-pyrrolidinophenethyl)] aminoethyl} dipenza [b, e] CI, 4] oxazepine, 5, 11— Hydro-5- {2-[{-methyl-1- (3-pyrrolidinophenethyl)] aminoethyl} dibenzo [b, e] [1, 4] oxazepine, 5, 11-dihydro-5— {2- [N-methyl-N— (4-piberidi-nophenethyl)] aminoethyl} dibenzo [b, e] [1, 4] oxazepine, 5, 11-dihydro-5- {2- [N-methyl-1-N— (3-piperidinophenetyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-1-5— {2- [N-methyl-1-N— (4-morpho Nophenethyl)] aminoethyl} Dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [N-methyl-N- (3-morpholinophenethyl)] aminoethyl } Dibenzo [b, e] [1, 4] oxazepine and its halogen-substituted isomers, pharmacologically acceptable salts or Hydrates, and solvates. In the present invention, (i) one of R ⁹ to R ¹³ is a cyclic amino group represented by the formula [E], the other is a hydrogen atom, and all of Ri R ⁸ are a hydrogen atom A derivative of the formula [I], (ii) one of R ^{9 to} R ¹³ is a linear amino group represented by the formula [E], the other is a hydrogen atom, and one of R ^{1 to} R ⁸ One or two is a fluorine atom or a chlorine atom, Other represents derivatives of the formula [I] is a hydrogen atom, a (iii) none of R ⁹ to R ¹³ is other than cyclic Amino groups Table by formula [E] group, R ¹ ~: 1 of R ⁸ A derivative of the formula [I] in which one or two are a fluorine atom or a chlorine atom and the other is a hydrogen atom is preferred.

In the above general formulas [XV] and [XVI], 1) to ¹⁸ may be the same or different and each represents a fluorine atom, a chlorine atom or a hydrogen atom, and one L ₂ is CH ₂ or CH ₂ — represents CH _2, Y and Z are CH ₂ bonded to each other - CH ₂ - CH ₂ or CH ₂ -CH ₂ -CH ₂ or represents -CH _2, and / or (ii) R ⁹ ~ ³ are the same However, they may be different from each other, and preferably represent a hydrogen atom, an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group, or a cyclic alkylamino group.

 Specifically, (R) — {[2- (3- (1-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidine] -11-yl} —2 — (4-Dimethylaminophenyl) ethanone, (R) —1— [(4-Dimethylaminophenyl) acetyl] pyrrolidine-l- 2-carboxylic acid [2- (2-promo — 4-chloropentyloxy) phenyl] Amide, (R) — {(2- (2-Fluoro 5,11-dihydrodibenzo [b, e] [1,4] oxazepine-l 5-force rubonyl) pyrrolidine] — 1-yl}- 2- (4-pyrrolidinophenyl) phenyl, (R) — 1— ((4-pyrrolidinophenyl) acetyl] pyrrolidine—2-force rubonic acid [2 -— (2-bromo-5— Fluoropendiloxy) phenyl] amide, and their stereoisomers and salts are preferred.

Examples of the pharmacologically acceptable salt of the compound [I] that can be used in the present invention include mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate and phosphate, and acetic acid. Organic salts such as salts, lactate, fumarate, maleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate can be mentioned. Among the compounds [I] that can be used in the present invention, the compound represented by the formula [II] is, for example, according to the method disclosed in International Patent No. 9733885A1 It can be produced by the following method (reaction formula 1). Note that the entire contents of this patent document are included in this specification.

Reaction formula 1>

[Wherein, aromatic rings G, J, K, R ¹ to: ¹³ , A, B, and D are the same as those in the formula (I), r represents 1 or 2, W is a chlorine atom, a bromine atom, Represents a halogen atom such as an iodine atom. ]

By reacting compound [V] with a compound represented by the above general formula [VI] in a solvent in the presence of a base, compound [II] usable in the present invention can be produced. Examples of the reaction solvent in the above reaction include amides such as dimethylsulfoxide, N, N-dimethylformamide, ethers such as tetrahydrofuran, dimethyl ether, dioxane, 1,2-dimethoxyethane, etc., acetonitrile, toluene and xylene. , Benzene and the like can be suitably used. Examples of the base include sodium carbonate, potassium carbonate, sodium hydrogen hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide, and potassium pentoxide. The reaction temperature is usually 0 ° C to 150 ° C, preferably Is carried out at room temperature to 10 oc. The reaction time depends on the reaction temperature and the type of solvent, but usually:! ~ 50 hours. The amount of the compound [VI] and the base to be used is 0.5 to 5 molar equivalents, preferably 0.8 to 2 molar equivalents, based on the amount of the compound [V] used, respectively.

 The compound [V] used as a starting material for the reaction can be produced by a known method [J. Med. Chem., Ί, 609 (1964)].

The halide represented by the general formula [VI] can be reduced by using proline and homoproline as raw materials in accordance with the method disclosed in EP 0 440 359 A1. N-alkylation of the resulting alcohol, followed by halogenation of the hydroxyl group with methanesulfonyl chloride, tosyl chloride, etc., enables the production with ring expansion. Note that the entire contents of this patent document are included in this specification. 'Further, the compound [II] which can be used in the present invention can also be produced by the following method (reaction formula 2) according to the method disclosed in International Patent No. 9912925A1. . Note that the entire contents of this patent document are included in this specification.

 Reaction formula 2>

[In the formula, aromatic. , J, K, 1 ^ ~1 1 3, A, B, D are as defined above, r is 1 or 2, V and V 'is a chlorine atom, a bromine atom, an iodine atom, Toshiruoki sheet group, U represents a leaving group such as a mesyloxy group, and U represents a protecting group for an amino group such as a t-butyloxycarbonyl group, a benzyloxycarbonyl group, and a tosyl group. The compound [V] is reacted in the presence of a base by dropwise addition of Nt-butoxycarbonyl-12-piperidylmethyl tosylate represented by the above general formula [VII], and the compound of the general formula [VIII] is reacted. The compound is then prepared and then deprotected to give a compound of the general formula [IX], and the compound of the general formula [X] is reacted in the presence of a base to give a compound [II] which can be used in the present invention. Can be manufactured. As the reaction solvent and base from [V] to [VIII] and from [IX] to [II], the same solvents and bases as those in the above Reaction Formula 1 can be used. Among the compounds [I] that can be used in the present invention, the compound represented by the formula [III] can be prepared, for example, according to the method disclosed in International Patent Application No. (Reaction formula 3). The contents of this patent document are all included in this specification.

 Reaction formula 3>

[In the formula, aromatic rings K, R ^{9 to} R ¹³ , A, B, D, V and r represent the same as those in Reaction Scheme 2. ]

By reacting compound [V] with a compound represented by the above general formula [XI] in a solvent in the presence of a base, compound [III] usable in the present invention can be produced. Examples of the reaction solvent in the above reaction include amides such as dimethyl sulfoxide, N, N-dimethylformamide, ethers such as tetrahydrofuran, dimethyl ether, dioxane, 1,2-dimethoxyethane, etc., acetonitrile, toluene, xylene , Benzene and the like can be suitably used. Examples of the base include sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide, potassium t-butoxide and the like. The reaction temperature is usually in the range of 0 ° C to 150 ° C, preferably room temperature to 100 ° C. The reaction time varies depending on the reaction temperature or the type of the solvent, but is usually 1 to 50 hours. The amount of the compound [XI] and the base used is based on the amount of the compound [V] used. And 0.5 to 10 molar equivalents, preferably 0.8 to 5 molar equivalents.

 The compound represented by the above general formula [XI] reacts N-alkylated 3-hydroxypyrrolidine and 3-hydroxypiperidine, and then acts on oxyphosphorus chloride, thionyl chloride, tosyl chloride, methanesulfonyl chloride, and the like. Can be obtained.

 Among the compounds (I) that can be used in the present invention, the compound represented by the formula (IV) is, for example, according to the method disclosed in International Patent Application No. It can be produced by the following method (Reaction Scheme 4).

 Reaction formula 4>

[In the formula, aromatic rings G, J, K, ³ , A, B, D and V are the same as described above, and R ¹⁴ represents a lower alkyl group. ] That is, the compound [V] is converted to a compound represented by the above general formula [XII], and reacted with the compound of the general formula [XIII] in the presence of a base. Examples of the reaction solvent in this reaction include amides such as dimethyl sulfoxide and N, N-dimethylformamide, ethers such as tetrahydrofuran, getyl ether, dioxane, 1,2-dimethoxyethane, acetonitrile, toluene, Xylene, benzene, etc. can be suitably used. Examples of the base include sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide, and potassium t-ptoxide. The reaction temperature is usually in the range of 0 ° C. to 150 ° C., preferably in the range of room temperature to 100 ° C. The reaction time varies depending on the reaction temperature or the type of the solvent, but is usually 1 to 50 hours. The amount of the base to be used is 1 mol or more, preferably 1 to 5 mol, per mol of the compound [XII], and the ratio of the compound [XII] to [XIII] is 0.5 to 2 mol, preferably. Or 0.7 to 1.5 times.

 Alternatively, the compound [V] is converted to a compound represented by the general formula [XIV], and then condensed with the compound [X] in the presence of a base to produce a compound [IV] that can be used in the present invention. be able to. As the reaction solvent and base in the condensation reaction, the same ones as in the above reaction can be used, and the same applies to the reaction temperature and reaction time. The amount of the base to be used is equimolar or more, preferably 1 to 5 moles, relative to compound (XIV), and the ratio of the compounds (XIV) to (X) is 0.5 to 2 moles, preferably It is 0.7 to 1.5 times.

Compound [XII] is obtained by alkylating compound [V] with a monohaloacetic acid ester and reducing it to an alcohol, and further converting the hydroxyl group to a leaving group, or using a 2-haloethanol having a protected hydroxyl group. It can be easily produced by combining known methods such as alkylating the conjugated product [V] and converting the hydroxyl group to a leaving group after deprotection. Compound (XIII) is disclosed in International Patent Application No. Various reactions such as alkylation reaction of primary amine with corresponding halide, reductive alkylation reaction of primary amine with corresponding aldehyde, reduction of amine after acylation with corresponding carboxylic acid, etc. It can be easily manufactured by a known method.

 The compound [XIV] can be prepared by various known methods such as alkylation of the compound [V] with a haloacetate ester followed by amidation and reduction as disclosed in International Patent Publication No. It can be easily manufactured by the method described above.

In addition to the above, among the compounds [I] that can be used in the present invention, the compound represented by the formula [II] or the formula [IV] is described in International Patent Publication No. The compound can be produced via a compound represented by the following formulas [XVI] and [XV] by a method similar to the method described in (1). That is, when the compound represented by the formula (II) is represented by the formula (11-1), and the compound represented by the formula (IV) is represented by the formula (IV-1), these are represented by the formula (XVI) according to the reaction formula 5. The compound represented by the formula is converted into an intramolecular aryl to obtain the compound represented by the formula [XV], and then reduced to obtain the corresponding intermediate.

<Reaction formula 5>

[Wherein the aromatic rings G, J, K, Ri R ¹⁴ L ₁ L ₂ are the same as those in the formula [XV], r represents 1 or 2, Y and Z are bonded to each other and CH ₂ — CH ₂ - CH ₂ or CH ₂ - Y when CH ₂ or represents -CH _Z -CH _2, or Y and Z are not bound to each other represents a hydrogen atom, Z is a lower alkyl group. ]

Here, examples of the reaction solvent in the present reduction reaction include ethers such as getyl ether, dioxane, tetrahydrofuran, and 1,2-dimethoxyethane. The solvent may contain 0 to 50% of benzene, toluene, xylene and the like. Examples of the reducing agent include diborane, borane ammonia complex, borane-tert-butylamine complex, borane-N, N-getylaniline complex , Borane N, N-diisoprovirethylamine complex, borane dimethylamine complex, borane 4- (dimethylamino) pyridine complex, borane diphenylphosphine complex, borane 4-ethyl morpholine complex, borane 1-2, 6-lutidine complex, borane 4-methyl morpholine complex, borane dimethyl sulfide complex, porane morpholine complex, borane-1,4-oxathiane complex, borane 1-4-phenylmorpholine complex, borane pyridine complex, borane tetrahydrofuran complex, borane triptyl Borane compounds such as phosphine complexes, borantrietylamine complexes, boranetrimethylamine complexes, and borantrifenylphosphine complexes; aluminum hydride; and metal hydrides such as sodium borohydride and lithium borohydride. These alkyl, alkoxy or acyl substituents are exemplified. Alternatively, a reducing agent may be prepared in a reaction vessel by adding an acid or the like to these metal hydrides. Examples of the acids used herein include, for example, Bronsted acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesnoleic acid, paratoluenesulfonic acid, camphorsulfonic acid, acetic acid, and trifluoroacetic acid; boron trifluoride; Examples thereof include Lewis acids such as boron chloride and aluminum trichloride and complexes thereof. Among these reducing agents, for example, a method using diborane, borane tetrahydrofuran complex or the like, or adding a methanesulfonic acid, boron trifluoride and a complex thereof to sodium borohydride to prepare a reducing agent in a reaction vessel. The production method can be suitably used. The reaction temperature depends on the boiling point of the solvent, but is usually 5 ° C to 100 ° C, preferably 30 ° C! It is carried out in the range of up to 60 ° C. The reaction time varies depending on the type of the reducing agent, the reaction temperature or the type of the solvent, but is usually 4 to 70 hours. The amount of the reducing agent used depends on the type of the reducing agent, but the amount of hydride that can be generated is 4 times or more, preferably 7 times or more. The compound [11-1] or compound [IV-1] obtained by the reaction can be purified by silica gel column chromatography or crystallization. In addition, compound [11-1] or compound [ IV-1] may be obtained by crystallization in the form of a salt with an appropriate acid. Examples of the salt with an appropriate acid include mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate, phosphate, and nitrate, and acetate, lactate, fumarate, and maleate. Organic acid salts such as acid, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate.

 Compound [XV] used as a raw material for the reduction reaction can be produced by subjecting compound [XVI] to intramolecular arylation with a metal catalyst in the presence of a base. Here, the reaction solvent in this reaction includes, for example, benzene and its substituted product, pyridine and its substituted product, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone And amides. Among these reaction solvents, for example, toluene, pyridine, picoline, N-methylpyrrolidone and the like can be suitably used. Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate, metal alkoxides such as sodium methoxide, sodium t-butoxide and potassium t-butoxide, trimethylamine, Examples include amines such as triethylamine, diisopropylethylamine, and N-methylmorpholine. Among these bases, for example, sodium carbonate, potassium carbonate, cesium carbonate and the like can be suitably used. Examples of the metal catalyst include copper, copper catalysts such as copper chloride (I), copper bromide (I), copper iodide (I), palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine). Palladium catalysts such as palladium or complexes thereof, or platinum catalysts such as platinum and platinum chloride and complexes thereof. Among these metal catalysts, for example, copper, copper (I) bromide and the like can be suitably used. These metal catalysts may also be prepared in a reaction vessel. The reaction temperature depends on the boiling point of the solvent,

, Usually from room temperature to 200 ° C, preferably 100 ° C! It is performed in a range of up to 150 ° C. The reaction time varies depending on the type of the base or metal catalyst, the reaction temperature or the type of the solvent. But usually 8 to 200 hours. The amount of the base to be used varies depending on the kind thereof, but is usually 1 to 10 mol, preferably 1 to 4 mol. The amount of the metal catalyst to be used varies depending on the kind thereof, but is usually 0.001 times to 1 times, preferably 0.005 times to 0.2 times the mole. The compound [XV] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography or crystallization, and used in the next reaction, or can be used as it is in the next reaction. Here, the present compound [XV] may be obtained in the form of a salt with an appropriate acid. Here, the salt with an appropriate acid includes, for example, mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, fumarate, Organic acid salts such as oleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate can be mentioned.

 The compound [XVI] used as a starting material for the intramolecular arylation reaction can be produced by the following method (reaction formula 6).

[Wherein the aromatic rings G, J, K, ~ 1 ^ ³ , L _ls L ₂ are the same as those in the formula [XVI], and Y and Z are mutually bonded to form CH ₂ — CH ₂ — CH ₂ or CH ₂ — CH ₂ — CH ₂ — represents CH ₂ , or Y and Z are not bonded to each other, Y represents a hydrogen atom, and Ζ is lower Represents a alkyl group. ]

 That is, compound [XVI] can be produced by condensing compound [XVII] and compound [XVIII]. Here, the condensation reaction refers to, for example, an amidation reaction using N, N, -dicyclohexylcarbodiimide or N-dimethylaminopropyl-N, -ethylcarbodiimide or a salt thereof, or the compound [XVIII] being acid anhydride. The method can be selected from known methods such as an acid anhydride method of condensing after that, and a method via an acid chloride or acid bromide of compound [XVIII]. The compound [XVI] obtained in the reaction can be extracted from the reaction solution, purified by silica gel column chromatography, or purified by crystallization, etc., and used in the next reaction, but can also be used as it is in the next reaction. Here, the present compound [XVI] may be obtained in the form of a salt with an appropriate acid. Examples of the salt with an appropriate acid include, for example, mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate, phosphate, and nitrate, acetate, lactate, fumarate, and maleate. Organic acid salts such as phosphate, malate, tartrate, citrate, oxalate, aspartate, and mesylate sulfonate.

 Compound [XVII] used as a starting material in the above Reaction Scheme 6 can be produced by a known method [J. Med. Chem., 7, 609 (1964)].

Compound [XVIII] can be produced by the following method (reaction formula 7).

 <Reaction formula 7>

[Wherein, aromatic rings K, R ^{9 to} R ¹³ , Lj and L ₂ are the same as above, and Y and Z are bonded to each other to form CH ₂ —CH ₂ —CH ₂ or CH ₂ —CH ₂ — CH ₂ — represents CH ₂ , or When Y and Z do not bond to each other, Y represents a hydrogen atom, and Z represents a lower alkyl group. ]

That is, compound [XVIII] can be produced by condensing compound [XIX] and compound [XX]. Here condensation reaction with, for example, New, New '- to not hexyl carbodiimide dicyclohexyl Ν- dimethyl § amino propyl one New ⁵ - E chill carbonitrile di imide and amine de reactions and the like salts thereof, compound [XIX Is converted to an acid anhydride and then condensed, or a known method such as a method via an acid chloride or an acid bromide of compound [XIX]. The compound [XVIII] obtained by the reaction can be used in the next reaction by extracting the reaction solution, purifying it by silica gel column chromatography or crystallization, etc., but can also be used in the next reaction as it is. Compound (XVI II) may also be produced by protecting the carboxylic acid moiety of compound (XX) with an appropriate protecting group, followed by deprotection after the same condensation reaction as described above with compound (XIX). . Suitable protecting groups here include, for example, methyl, ethyl, η-propyl, is ο-propyl, n-butyl, iso_butyl, tert-butyl, or an ester thereof or a substituted product thereof, trimethylsilyl, triethylsilyl, tert And silyl esters with monobutyldimethylsilyl and the like. Further, among the compounds [I] that can be used in the present invention, the compound represented by the formula [III] can also be produced by the following method (reaction formula 8).

<Reaction formula 8>

[Wherein, aromatic rings G, J, K, 1 ^ to 11 ¹³ , AB, D, V and r are the same as above]

That is, compound [III] can also be produced by subjecting compound [XXI] to intramolecular arylation with a metal catalyst in the presence of a base. Examples of the reaction solvent in this reaction include amides such as benzene and its substituted products, pyridine and its substituted products, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, and the like. And the like. Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, and cesium carbonate; metal alkoxides such as sodium methoxide, sodium t-butoxide, and potassium t-butoxide; trimethylamine, triethylamine; Examples include amines such as diisopropylpyrethylamine and N-methylmorpholine. Foreword 3 gold Examples of the metal catalyst include copper catalysts such as copper, salted copper (I), salted copper (I), copper iodide (I), palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine). Palladium catalysts such as palladium or complexes thereof, and platinum catalysts such as platinum and shiridani platinum and complexes thereof. These metal catalysts may also be prepared in a reaction vessel. The reaction temperature depends on the boiling point of the solvent, but is usually in the range of room temperature to 200 ° C, preferably 80 ° C to: 160 ° C. The reaction time varies depending on the type of the base or the metal catalyst, the reaction temperature or the type of the solvent, but is usually 5 to 150 hours. The amount of the base to be used varies depending on its kind, but it is usually 1 to 20 mol, preferably 1.5 to 8 mol. The amount of the metal catalyst to be used varies depending on the type thereof, but is usually from 0.1 to 1 mol, preferably from 0.005 to 0.3 mol. The compound [III] obtained by the reaction can be purified from the reaction solution by extraction, silica gel column chromatography, high performance liquid chromatography or crystallization. The compound [III] that can be used in the present invention may be obtained by crystallization in the form of a salt with an appropriate acid. Examples of the salt with an appropriate acid include, for example, mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate, phosphate, and nitrate, and acetate, lactate, and fumarate. And organic acid salts such as maleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate.

 Compound [XXI] used as a raw material for the intramolecular arylation reaction can be produced by alkylating an amino group of compound [XVII] with a conjugate [XI]. Here, the alkylation reaction includes, for example, an alkylation reaction in the presence of a base.

. That is, it can be produced by reacting compound [XVII] and compound [XI] in an appropriate solvent in the presence of a base. Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium methoxide, sodium t-toxide, and potassium t-toxide. Any metal alkoxides, amines such as trimethylamine, triethylamine, disopropylethylamine, N-methylmorpholine and the like can be mentioned. The compound [XXI] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography, etc. and used for the next reaction, but can also be used for the next reaction as it is.

 When the compound that can be used in the present invention is used as a pharmaceutical preparation or a pharmaceutical composition, pharmaceutically acceptable excipients, carriers, diluents, and other formulation auxiliaries are appropriately mixed, and tablets and capsules are prepared in a conventional manner. It can be administered orally or parenterally in the form of granules, fine granules, powders, pills, syrups, suspensions, emulsions, ointments, suppositories or injections. In the present invention, a pharmaceutical preparation or a pharmaceutical composition containing the compound of the present invention as an active ingredient and a pharmaceutically acceptable carrier and / or diluent is preferable. Here, examples of the carrier and the diluent include glucose, sucrose, lactose, talc, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water and oils and fats.

 The dose and frequency of administration of the compound that can be used in the present invention can be appropriately selected according to the type of the disease, the age and weight of the patient, and the like. For example, the pharmaceutical composition of the present invention may be used to treat Alzheimer's disease, psychosis, premature dementia, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy. Orally, when administered orally as a therapeutic agent for obesity, about 0.1 to 100 mg per day may be administered to an adult in one to several divided doses.

In the present invention, a compound represented by the following formula, a stereoisomer thereof, a pharmacologically acceptable salt thereof, and a calcium channel antagonist which is a hydrate or solvate thereof are further particularly preferred.

Next, the production method of the compound described in the present invention will be described in more detail by reference examples, but the present invention is not limited to these reference examples.

 (Reference Example 1)

 (R) —3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride

 (R) —3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine

Under a stream of argon, 60% sodium hydride (44 mg, 1.1 mmol) was washed with hexane, suspended in dimethyl sulfoxide (5 ml), stirred at room temperature for 30 minutes, and then treated with 3-fluoro-5,11-dihydrodibenzo. ! b, e] [1, 4] oxazepine (0.22 g, 1.0 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for an additional 30 minutes, the solution was added to (R) -3-chloro-1- (4-methoxyphenethyl) piperidine (0.25 g, 1.Ommol, International Patent No. 9 733885A1). (2ml)) The solution was added dropwise, and the mixture was stirred at 50 ° C for 6 hours. The reaction solution was partitioned between saturated saline and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (7: 3). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -3-fluoro-5,11-dihydro-1-5- [1- (4-methoxyphenethyl) piberidin-2-ylmethyl] Dibenzo [b, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.30 g, 70%).

ES I / Mas s: 433 [M + H ⁺ ]

NMR (CDC13) δ: 1.60-1 · 90 (4Η, m), 2.27 (1H ₃ m), 2.50-2.60 (1H, m), 2.70-2.82 (3H,), 2.98-3.10 (lH, m), 3 ・ 18 ・ 3 ・ 24 (1Η, m), 3.35 (1H ₅ dd, J = 9.3, 12.9Hz), 3.82 (3H, s), 4.02 (1H, dd, J = 3.60, 13.2Hz), 5.20 (1H, d, J = 12.0Hz), 5.27 (1H, d, J = 12.0Hz), 6.70-6.95 (6H, m), 6.98-7.05 (lH ₃ m) ₅ 7.15-7.30 (4H, m)

 () 1-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenyl) piperidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride

 (R) —3-Fluoro-5,11-dihydro-5- [1-1- (4-methoxyphenethyl) piperidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (300 mg, 0 To a solution of 0.7 mmol 1) in dichloromethane (5 ml) was added 0.3 ml of 4M hydrogen chloride Z-dioxane, and after stirring for 30 minutes, the solvent was distilled off under reduced pressure. The obtained residue was solidified using a mixed solvent of hexane and ethyl acetate, and the precipitated solid was separated by filtration to obtain the title compound as a brown solid (257 mg, 79%).

 ES I / Mas s: 433 [M + H +]

NMR (CDC13) δ: 1.90-2.06 (1H, m), 2.06-2.30 (3H ₃ m), 2.74-2.86 (lH ₅ m), 2.90-3.20 (2H, m), 3.25-3.40 (lH, m), 3.42-3.68 (2H ₃ m), 3.80 (3H, s), 3.85-4.00 (1H, m), 4.24 (1H, dd ₃ J _{= 7.8 5 14.1Hz), 4.62 (} 1H, dd, J = 5.7, 14.1Hz), 5.12 (1H, d, J = 12.3Hz), 5.32 (1H 5 d, J = 12.3Hz), 6.72-7.03 (8H _{5 m), 7.12 (2H,} d, J = 8.4Hz), 7.18- 7.25 (1H, m)

 (Reference Example 2)

 (R) 18-Fluoro-1,5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride

 3-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazebine Instead of 8-fluoro-5,11 dihydrodibenzo [b, e] [1,4] oxazepine And (R) -8-fluoro-5,11 dihydro-1-5- [1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e [1, 4] oxazepine was obtained. Pale yellow solid. Yield 19%.

 ES I / Mas s: 433 [M + H +]

NMR (CDC13) δ: 1.58-1.88 (4H, m), 2.22-2.30 (1Η, m), 2.48-2.58 (1H, m), 2.68-2.82 (3H, m), 2 ・ 99-3 ・ 08 ( 1Η, m), 3.21-3.36 ₅ 2H ₃ m), 3.81 (3H ₃ s) ₃ 4.00-

4.05 (1H, m), 5.20 (1H, d, J = 13.0Hz) ₃ 5.34 (1H ₃ d, J = 13.0Hz), 6.47-6.50 (2H, m), 6.9-6.93 (3H, m) ₃ 7.02-7.18 (4H, m), 7.26-7.34 (2H ₃ m)

 This was treated with 4 M hydrochloric acid Z-dioxane in the same manner as in Reference Example 1 to obtain the title compound as a brown solid. Yield 81%.

 E S I / M a s s: 433 [M + H +]

NMR (CDC13) δ: 1.90-2 · 32 (4Η, m), 2.75-2.88 (1Η, m), 2.94-3.23 (2Η, m), 3.28-3.60 (3Η ₃ m), 3.81 (3H, s) , 3.91-4.00 (1H, m), 4.14-4.30 (1H, m), 4.58- 4.73 (1H, m), 5.17 (1H ₃ d, J = 13.0 Hz), 5.34 (1H, d, J = 13.0 Hz) ) ₃ 6.50- 6.60 (2H, m), 6.81-7.00 (3H ₃ m), 7.08-7.39 (6H ₃ m)

 (Reference Example 3)

 (R) — 2-Chloro-5,11-dihydro-5- [1- (4-methoxyphenethylpyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine

Instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, use 2_chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine. And (R) -2-chloro-5,11-dihydro-1-5- [1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e [1, 4] oxazepine was obtained. Pale yellow solid. Yield 44%.

 E S I / Mas s: 449 [M + H +]

NMR (CDC13) δ: 1.60-1 · 87 (4Η, m) ₅ 2.20-2.28 (1Η, m), 2048-2.56 (1H, m), 2.67-2.82 (3H, m), 2.93-3.06 (lH ₅ m) ₃ 3.16-3.23 (1H ₅ m), 3.34 (1H ₅ dd, J = 10.3, 14.7 Hz), 3.8K3H, s), 4.04 (1H ₃ dd, J = 4.0, 14.7 Hz), 5.15 ( 1H, d, J = 13.OHz), 5.25 (1H, J = 13.0Hz), 6.75-6.89 (5H, m), 6.97-7.04 (2H, m), 7.10-7,16 (2H, m), 7.22-7.30 (2H ₅ m)

 This was treated with 4 M salt / hydrogen / dioxane in the same manner as in Reference Example 1 to obtain the title compound as a brown solid. 90% yield.

ES I / Mas s: 449 [M + H +]

NMR (CDC13) δ: 1.92-2.28 (4H, m), 2.72-2.88 (1H, m), 2.93-3.13 (2H, m), 3.26-3.38 (1H, m), 3.43-3.6. (2H, m _{) 3 3.81 (3H, s)} , 3.83-3.98 (1H 5 m), 4.20 - 4.35 (1H, m), 4.61-4.74 (1H, m), 5.11 (1H, d, J = 14.0Hz), 5.27 ( 1H ₅ d ₃ J = 14. OHz), 6.87- 6.92 (5H, m), 7.01-7.16 (3H, m), 7.22-7.30 (3H, m)

(Reference Example 4) (R) —3-chloro-5,11-dihydro-5- [1- (4-methoxyphenyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine

Instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, use 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine. By the same operation as in Reference Example 1, (R) -3-3-chloro-5,11-dihydro-1-5- [1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b , E] [1, 4] oxazepine. Pale yellow solid. Yield 55%. '

ES I / Mas s: 449 [M + H +]

NMR (CDC13) δ: 1.60-1.90 (4H ₅ m), 2.22- 2.30 (1H, m), 2.52-2.62 (1Η, m), 2.68-2.82 (3H, m), 2.97-3.07 (lH, m) , 3.16-3.22 (1H ₅ m), 3.35 (1H, dd, J = 10.3, 14.7 Hz), 3.81 (3H ₅ s), 4.03 (1H, dd, J = 4.0, 14.7 Hz), 5.20 (1H ₅ d, J = 13.7 Hz), 5.23 (1H, d, J = 13.7 Hz), 6.75-6.90 (5H, m), 6.96-7.02 (2H, m), 7.10-7.20 (4H, m)

 This was treated with 4 M salt / hydrogen / dioxane in the same manner as in Reference Example 1 to obtain the title compound as a brown solid. 86% yield.

ES I / Mas s: 449 [M + H +]

NM (CDC13) δ: 1.92-2.03 (1H, m), 2.10-2.30 (3H, m), 2.75- 2.84 (lH, m), 2.96-3.12 (2H, m), 3.24-3.34 (lH ₅ m) ₃ 3.44-3.60 (2H ₃ m), 3.81 (lH, s) 3.87-3.981 H, m), 4.24 (lH ₃ dd ₅ J = 8.7,15.3Hz), 4.62 (lH, dd, J = 6.3,15.3Hz ), 5.12 (lH, d, J = 14.0 Hz), 5.35 (lH, d, J = 14.0 Hz), 6.83-6.96 (3H ₃ m), 6.84 (2H, d, J = 9.3 Hz), 7.01- 7.19 (4H ₃ m) ₅ 7.12 (2H, d ₅ J = 9.3Hz)

 (Reference Example 5)

(R) 1 7-chloro-1,5-dihydro-5- [1— (3,4-methylenedi Xyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1, 4] oxazepine hydrochloride

 (R) — 3-methyl-1- (3,4-methylenedioxyphenethyl) piperidine in acetonitrile (50 ml), (R) -2-hydroxymethylpyrrolidine, (505 mg, 5.00 mmo l), 3,4-methylenedioxyphenethyl mesylate (1.34 g, 5.5 Ommo 1), sodium carbonate (585 mg, 5.5 Ommo 1), sodium iodide (5 Om :, 0. After adding 33 mmo 1) and heating under reflux at 90 ° C. for 13.5 hours, the solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 25 ml of dichloromethane, and 712 mg (5.5 mmo 1) of diisopropylethylamine and 63 Omg (5.5 mmo 1) of methanesulfonyl chloride were added while stirring under ice cooling. The mixture was stirred for 1 hour under ice-cooling and further for 2 hours at room temperature. The reaction solution was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (15: 1) as eluents. The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -3-1-chloro-1- (3,4-methylenedioxyphenethyl) biperidine as a pale yellow oil. (1.02g, 76%).

^{NMR (CDC13) ό 1: 1.55-1.68} (3H, m), 1.75-1.87 (1H 3 m), 2.12- 2.20 (2H, m), 2.55-2.64 (2H, m), 2.69-2.78 (3H, m ), 3.08-3.18 (lH, m), 3.98-4.06 (lH, m), 5.93 (2H ₃ s), 6.63-6.75 (3H, m)

(R) — 7-chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] CI, 4oxazepine Under an argon stream, 60% sodium hydride (48 mg, 1.2 mmol) was washed with hexane, suspended in dimethyl sulfoxide (8 ml), and stirred at room temperature for 30 minutes. —Dihydrodibenzo [b, e] [1,4] oxazepine (232 mg, lmmo 1) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for 30 minutes, the (R) -3-chloro-1- (3,4-methylenedioxyphenethyl) bipyridine (308 mg, 1.15 mmol 1) was added to the solution. A solution of methyl sulfoxide (3 ml) was added dropwise, and the mixture was stirred at 50 ° C for 4 hours. The reaction solution was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (10: 1) as eluents. The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -7-chloro-5,11-dihydro-1-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-1 —Ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow solid (362 mg, 78%).

ES I / Mas s: 463 [M + H +]

NMR (CDC13) δ: 1.60-1.84 (4Η, m), 2.20-2.30 (1Η, m), 2.49-2.59 (1Η ₅ m), 2.65- 2.78 (3Η, m), 2.95-3.05 (lH, m) , 3.13-3.21 (lH, m) ₃ 3.34 (1H ₅ dd, J = 10.3, 13.0Hz), 4.00 (1H ₃ dd, J = 3.3, 13.0Hz), 5.15 (1H, d, J = 13.0Hz), _{5.23 (1H 5 d, J =} 13.0Hz), 5.95 (2H 5 s), 6.63-6.78 (5H 5 m), 6.96 (1H, s), 7.02-7.13 (2H, m), 7.26-7.37 (2H, m)

 (R) —7-chloro-5,11-dihydro-5- [1-1 (3,4-methylenedioxy xyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1, 4] oxazepine hydrochloride

(R) 1 7-chloro-5,11-dihydro-5- [1— (3,4-methylenedioxyphenethyl) pyrrolidine_2-ylmethyl] dibenzo [b, e] [1, 4 To a solution of oxazepine (0.63 g) in dichloromethane (5 ml) was added 3.0 ml of 2 M hydrogen chloride / getyl ether, and the mixture was stirred for 2 hours, and the solvent was distilled off under reduced pressure. The resulting residue was stirred in hexane to give the title compound as a pale brown solid (348mg, 89%).

ESI / Mass: 463 [M + H ⁺ ]

NM (CDC13) δ: 1.92-2.33 (4H, m), Z.74-3.16 (3H, m) ₅ 3.24-3.37 (lH, m), 3.44-3.58 (2H, m), 3.88-3.98 (1H, _{m), 4.15-4.28 (1H 3 m} ), 4.60-4.72 (lH, m), 5.19 (1H, d 3 J = 14.0Hz), 5.27 (1H, d, J = 14.0Hz), 5.98 (2H, s ), 6.64-6.77 (5H

, M), 6.80-6.88 (lH, m), 6.98 (1H ₅ s), 7.09-7.20 (2H, m), 7.28-7.38 (2H ₅ m)

(Reference Example 6)

 (R) 1-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride

 (R) —2-Hydroxymethyl-1- (4-dimethylaminophenethyl) pyrrolidine

In acetonitrile (50 ml), D-prolinol (2.02 g, 20.0 mmo 1), 4-dimethylamino phenethyl mesylate, (5.35 g, 22. Ommo 1), sodium carbonate (2 65 g, 25. Ommo 1) and sodium iodide (300 mg, 2. Ommo 1) were added, and the mixture was heated under reflux at 90 ° C for 13.5 hours, cooled to room temperature, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. 1M hydrochloric acid was added to the organic layer to maintain the pH of the aqueous layer at 1, and the desired product was extracted into the aqueous layer. 4Mzk sodium chloride was added to the aqueous layer, the pH of the aqueous layer was adjusted to 14, and the resulting precipitate was extracted with ethyl acetate. After the extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, (R) -2-hydroxymethyl-1- (4-dimethylaminophenethyl) pyrrolidine was obtained as a pale yellow oil ( Four. (91 g, 99%) o

NMR (CDC13) δ: 1.69-1.90 (4H ₅ m), 2.29-2.38 (1H ₃ m), 2.45-2.54 (1H, m), 2.56-2.64 (lH, i), 2.66-2.74 (2H, m) , 2.88-2.94 (lH ₅ m), 2.9 ms), 3.2

3- 3.30 (1H,), 3.3K1H, dd, J = 2.7, 12.0Hz), 3.58 (1H, dd, J = 4.0, 12.0Hz), 6.70 (2H, d, J = 9.7Hz), 7.07 (2H , d, J = 9.7Hz)

 (R) —3-Chloro-1 -— (4-dimethylaminophenethyl) piperidine

 (R) —2-Hydroxymethyl-1- (4-dimethylaminophenethyl) pyrrolidine (4.91 g, 19.8 mmo 1) was dissolved in 6 mL of dichloromethane and stirred under ice-cooling. Add 3.1 g (24.4 mmo1) of disopropylethylamine and 2.75 g (24.Ommol) of methanesulfonyl chloride, and cool for 1 hour under ice-cooling and then at room temperature. Stir for 2 hours. The reaction solution was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (9: 1) as eluents. The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -3-chloro-1- (4-dimethylaminophenethyl) piperidine as a pale yellow solid (3.03 g, 57 %

) o

NMR (CDC13) δ: 1.50-1.68 ( 3H, m), 1.76- 1.88 (1H, m), 2.09-2.20 (2H, m), 2.55-2.62 (2H 3 m), 2.66-2.73 (2H 3 m) , 2.75-2.84 (lH, m), 2.91 (6H, s), 3.08 -3.17 (1H ₅ m), 3.98-4.08 (lH, m), 6.69 (2H, d, J = 9.7 Hz), 7.06 (2H , d, J = 9.7H z)

 (R) 11-Fluoro-5,1 1-dihydro-1-5- [1- (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine

Under an argon stream, 60% sodium hydride (35 mg, 0.88 mmo 1) After washing with hexane, the suspension was suspended in dimethyl sulfoxide (5 ml), stirred at room temperature for 30 minutes, and then treated with 1-fluoro-1,5,11-dihydrodibenzo [b, e] [1,4] oxazepine (0.17 g, (0.80 mmol) and stirred at room temperature for 30 minutes. After stirring at 50 ° C for 30 minutes, this solution was added to (R) _3-chloro-1- (4-dimethylaminophenethyl) piperidine (0.18 g, 0.8 Ommo 1) dimethyl sulfoxide ( 2 ml) solution was added dropwise and stirred at 50 ° C. for 6 hours. The reaction solution was partitioned between saturated saline and ethyl acetate, the organic layer was dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (6: 4). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -1-fluoro-5,11-dihydro-5- [1_ (4-dimethylaminophenethyl) piperidine-12-ylmethyl] Givenzo [b, e] CI, 4] oxazepine was obtained as a pale yellow oil (0.23 g, 64%).

 E S I / Ma s s: 446 [M + H +]

NMR (CDC13) δ: 1.60-1.90 (4Η, m), 2.20-2.30 (1Η, m), 2.48-2.55 (ΙΗ, m), 2.70-2.80 (3H ₃ m) ₅ 2.94 (6H ₃ s), 2.98 -3.08 (1H, m), 3.16-3.25 (1H, m), 3.38 (1H, dd, J = 9.3, 13.0Hz), 4.10 (1H, dd, J = 3.60, 13.0Hz), 5.35 (1H, d , J = 12.0 Hz), 5.42 (1H ₅ d, J = 12.0 Hz), 6.70-6.78 (3H, m), 6.80-6.90 (4H, m), 7.00-7.15 (3H ₅ m), 7.18 -7.28 (1H, m)

 (R) 11-Fluoro-5,11-dihydro-1-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride

(R) ― 1-Fluoro-5,11-dihydro-5- [1- (4-Dimethylaminophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (228mg, 0.5mmo 1 ) In dichloromethane (5ml) solution After adding 0.5 ml of 4 M hydrogen chloride / dioxane and stirring for 30 minutes, the solvent was distilled off under reduced pressure. The obtained residue was solidified using a mixed solvent of hexane and ethyl acetate, and the precipitated solid was separated by filtration to obtain the title compound as a brown solid (170 mg, 64%

) o

ESI / Ma ss: 446 [M + H ⁺ ]

NMR (CDC13) δ: 1.92-2.30 (3H, m), 2.78-2.90 (1H, m), 2.91-3.16 (3H, m), 3.16 (6H, s), 3.38-3.50 (2H, m), 3.62 -3.75 (IH, m) ₃ 3.82-3.95 (1H, m), 4.28

(IH, dd, J = 6.3, 14.7Hz), 4.77 (1H ₃ dd, J = 6.0, 14.7Hz), 5.24 (2H, s), 6.76 (

IH, t, J = 8.1Hz), 6.90-7.12 (5H ₃ m), 7.21-7.30 (1H, m), 7.37 (2H, d, J = 8.4Hz)

), 7.71 (2H, d, J = 8.4Hz)

 (Reference Example 7)

 (R) 13-Fluoro-5,11-dihydro-5- [1- (4-Dimethylaminophenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride

 Reference using 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 1-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine By the same operation as in Example 6, (R) -3-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] CI, 4) oxazepine Was obtained as a pale yellow oil (0.24 g, 53%).

ES I / Mas s: 446 [M + H +]

NMR (CDC13) δ: 1.60-1.90 ( 4Η 5 m), 2.22- 2.32 (1Η, m), 2.50- 2.60 (1Η, m), 2.70- 2.82 (3Η, m), 2.94 (6Η, s), 2.98 -3.08 (1Η, m), 3.15-3.25 (1Η ₃ m) ₃ 3.34 (IH, dd, J = 9.3, 13.0Hz), 4.05 (1H, dd, J = 3.60, 13.0Hz), 5.20 (1H ₅ d , J = 12.0 Hz), 5.26 (1H ₅ d ₃ J = 12, 0 Hz), 6.68-6.90 (7H, m), 6.97-7.04 (lH ₅ m), 7.08-7. 15 (2H, m), 7.20-7.25 (1H, m)

 This was treated with 4 M salt / hydrogen / dioxane in the same manner as in Reference Example 6 to give the title compound as a pale brown solid (100%).

E S I / Mas s: 446 [M + H +]

NMR (CDC13) δ: 1.95-2.30 (3H, m), 2.80-300 (1Η, m), 3.00-325 (9Η, m), 3.42-3.60 (2Η, m), 3.60-3.75 ( lH ₅ m), 3.85- 3.98 (1H, m), 4.19-4.28 (1H ₅ m), 4.58-4.68 (lH, m), 5.11 (1H, d, J = 12.6 Hz), 5.35 (1H, d, J = 12.6Hz), 6.76 (1H

, T, J = 8.1Hz), 6.80-7.08 (5H, m), 7.20 (1H, dd, J = 6.3, 8.1Hz), 7.43 (2H, d, J = 6.9Hz), 7.75 (2H, d, (J = 6.9Hz)

 (Reference Example 8)

 (R) —3-chloro-1,5-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine · 2 Hydrochloride

 1-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] Instead of oxazepine, 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] Using (x) azepine in the same manner as in Reference Example 6, (R) -3-chloro-1,5-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-ylmethyl] dibe Anzo [b, e] [1, 4] oxazepine oxazepine was obtained. Pale yellow oil. Yield 67%.

E S I / Mas s: 462 [M + H +]

NMR (CDC13) δ: 1.50-1.91 (4H, m), 2.23-2.32 (1Η, m), 2.51-2.60 (1H ₅ m), 2.65-2.83 (3H, m), 2.93 (6H, s), 2.97 -3.07 (lH ₃ m), 3.15-3.23 (1H, m), 3.34 (1H, dd, J = 10.3, 14.3 Hz), 4.06 (1H, dd, J = 4.0 ₃ 14.3 Hz) ₅ 5.22 (2H ₅ s ), 6.72 (2H, d, J = 10.0Hz), 6.75-6.85 (3H ₃ m), 6.98- 7.01 (2H, m) ₃ 7.09-7.19 (2H, m), 7.1K2H, d, J = 10.0Hz ) (R) — 3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazezepinoxa Dissolve Zepin (306 mg, 0.662 mmo 1) in 6.0 ml of a mixed solvent of ethyl acetate and ethanol (2: 1), and add 2 M hydrogen chloride Z ether (0.73 ml, 1.46 mmo 1). Then, 2.0 ml of ethyl acetate was added, and the mixture was stirred at room temperature. After leaving it at room temperature for 2 days, it was filtered and dried to obtain the title compound as white crystals (96%).

ES I / Mass: 462 [M + H +]

NMR (CDC13) δ: 2.02-2.28 (4Η, m), 2.80-2.90 (1Η, m), 2.98-3.24 (2H, m), 3.17 (6H, s), 3.44-3.56 (2H, m) , 3.59-3.69 (lH, m), 3.88-3.98 (lH 3 m), 4.23

(1H, dd ₃ J = 7.7, 15.7Hz), 4.64 (1H ₃ dd, J = 6.3, 15.7Hz), 5.11 (1H ₅ d, J = 14.0

Hz), 5.33 (1H, d, J = 14.0Hz), 6.85-6.97 (3H, m), 7.02-7.07 (2H, m), 7.12-7.1

8 (2H, m), 7.4K2H , d, J two _{9.3Hz), 7.75 (2H 5 d} , J = 9.3Hz)

 (Reference Example 9)

 () -2-Fluoro-5,11-dihydro-5- [1- (4-Pyrrolidinopheneethyl) pyrrolidine-1--2-methyl] dibenzo [b, e] [1,4] oxazepine.2 hydrochloride

 4-pyrrolidinophenetyl alcohol

Dried palladium acetate (270 mg, 1.20 mmol), 2- (di-t-butylphosphino) biphenyl (720 mg, 2.40 mmol), sodium t-butoxide (14.42 g, 150 mm ol) and 2- (4-promophenethoxy) tetrahydro-1H-pyran (28.01 g, 98.39 mmol) in toluene (100 ml) and pyrrolidine (9.93 ml, 119 mmol 1), and add 70 ° The mixture was stirred at C for 12 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The product was extracted from the organic layer with 1 M hydrochloric acid. Neutralize the aqueous layer with aqueous sodium hydroxide solution, Extracted with ethyl acetate. The organic layer was dried to obtain 4-pyrrolidinophenethyl alcohol as a pale yellow solid. (16.4 lg 87%)

NMR (CDC13) δ: 1.97-2.01 ( 4H, m), 2.77 (2H 5 t, J = 7.3Hz), 3.24-3.29 (4H 5 m), 3.79 (2H, q, J = 6.7Hz), 6.53 ( 2H, d, J = 9.3Hz), 7.03 (2H, d, J = 9.35Hz)

4-pyrrolidinopheneethyl mesylate

 4-Pyrrolidinophenetyl alcohol (16.41 g, 85.9 mmol) is dissolved in dichloromethane (150 ml), and disopropylethylamine (19.0 ml, 108 mmol) and methanesulfonyl are dissolved at 0 ° C. Chloride (8.40 ml, 108 mmol) was added and stirred overnight. The reaction solution was partitioned between a 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (7: 3). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to obtain 4-pyrrolidinophenethyl mesylate as a white solid (21.14 g, 80%).

ES I / Mas s: 270 [M + H +]

NMR (CDC13) δ: 1.98-2.01 (4Η, m), 2.84 (3Η, s), 2.95 (2Η, t, J = 8.0 Hz), 3.24-3.28 (4H ₅ m), 4.46 (2H, t, J _{= 8.0Hz), 6.52 (2H 5} d, J = 9.3Hz), 7.07 (2H 3 d, J = 9.3Hz)

(R)-2-Hydroxymethyl-1- (4-pyrrolidinophenetyl) pyrrolidine D-prolinol, (2.72 g, 25.0 mmol), 4-pyrrolidinoff in acetonitrile (150 ml) Enethyl mesylate, (6.06 g, 22.5 mmol 1) and potassium carbonate (3.45 g, 25.Ommol) are added, and 90. After heating at reflux for 3.5 hours with C, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. 1M hydrochloric acid was added to the organic layer, the pH of the aqueous layer was kept at 1, and the desired product was extracted into the aqueous layer. 4M acid sodium for water layer Was added to adjust the pH of the aqueous layer to 14, and the resulting precipitate was extracted with ethyl acetate. After the extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, (R) -2-hydroxymethyl-1-1 (4-pyrrolidinofphenethyl) pyrrolidine was obtained as a pale yellow oily substance ( 4.96 g, 85%) o

NMR (CDC13) δ ·: 1.70-1.91 (4H, m), 1.95 - 2 · 04 (4Η, m), 2.26-2.36 (1Η 5 m), 2.42-2.56 (1H, m), 2.57-2.77 (4H _{5 m), 2.87-2.96 (lH,} m), 3.18-3.27 (4H, m), 3.28 (1H, dd, J = 2.7, 12.0Hz), 3.57 (1H, dd, J = 4.0, 12.0Hz), 6.51 (2H, d, J

_{= 9.3Hz), 7.05 (2H 5} d, J = 9.7Hz)

 (R) —3—Chloro 1— (4—Viroridinophenetyl) piperidine

 (R) — 2-Hydroxymethyl-1- (4-pyrrolidinofphenethyl) pyrrolidine (4.96 g, 19. lmmo 1) is dissolved in 70 ml of dichloromethane, and the mixture is stirred under ice-cooling while stirring for diisopropyl ester. 3.21 g (24.8 mmol) of tilamine and 2.84 g (24.8 mmol) of methanesulfonyl chloride were added, and the mixture was stirred for 1 hour under ice cooling and further for 2 hours at room temperature. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1) as eluents. The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -3-3-chloro-1- (4-pyrrolidinopheneethyl) piperidine as a pale yellow solid (3.23 g, 61%). ES I / Mas s: 293 [M + H +]

NMR (CDC13) δ: 1.50-1.70 (3Η, m), 1.78-1.87 (1Η, m), 1.96-2.01 (4Η ₃ m), 2.10-2.20 (2Η, m), 2.54-2.6Κ2Η, m), 2.65- 2.72 (2H, m), 2.75-2.85 (1H, m), 3.10-3.17 (1H, m), 3.23-3.28 (4H, m), 3.96-4.06 (lH ₅ m), 6.51 (2H, d , J = 9.7

Hz), 7.05 (2H ₃ d, J = 9.7Hz)

(R) —2-Fluoro-5,1 1-dihydro-1-5-—1- (4-pyrrolidinofe Netyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine ''

 Under an argon stream, 60% sodium hydride (348 mg, 8.7 mmol) was washed with hexane, suspended in dimethyl sulfoxide (50 ml), and stirred at room temperature for 30 minutes. The mixture was charged with 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine (1.70 g, 7.9 Ommo 1) and stirred at room temperature for 30 minutes. After stirring at 50 ° C for another 30 minutes, dimethyl sulfoxide of (R) -3-chloro-1- (4-pyrrolidinofphenethyl) piperidine (2.64 g, 9.02 mm o 1) was added to the solution. (25 ml) The solution was added dropwise. The mixture was stirred with C for 3 hours. The reaction solution was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate, the organic layer was dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (6: 1) first, followed by hexane and ethyl acetate (1: 1) as the eluent. . The appropriate fractions were collected and the solvent was distilled off under reduced pressure. b, e] C 1, 4] oxazepine obtained as a pale yellow oil (2.29 g, 68%)

E S I / Mas s: 472 [M + H +]

NMR (CDC13) δ: 1.59- 1.86 (4H, m), 1.96-2.02 (4H, m), 2.21-2.29 (lH 5 m), 2. 46-2.55 (lH 5 m), 2.60-2.78 (3H, m) ₅ 2.97- 3.06 (lH, m), 3.19- 3.31 (6H, m), 4.08 (1 H, dd, 3.7, 14.3 Hz), 5.16 (lH ₅ m), 5.30 (lH, d, J = 13.0 Hz), 6.54 (2H, d , J = 9.0Hz), 6 .75-6.85 (3H 3 m) 5 6.95-7.09 (4H, m), 6.99 (2H, d, J = 9.0Hz)

(R) —2-Fluoro-1,5,11-dihydro_5 -— [1- (4-Pyrrolidinopheneethyl) pyrrolidine-1-ylmethyl] dipento [b, e] [1,4] oxazepine dihydrochloride (R) —2-Fluoro-5,11-dihydro-5- [1- (4-Pyrrolidinoff enetyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (2.29 g) Was added to a dichloromethane (30 ml) solution of 2M, and the mixture was stirred for 2 hours, and the solvent was distilled off under reduced pressure. The obtained residue was stirred in hexane, solidified and filtered off, to give the title compound as a pale brown solid (2.1 g, 81%).

ESI / Mass: 472 [M + H +]

NMR (CDC13) δ: 1.95-2.36 ( 8Η 3 m), 2.84-2.96 (1Η 5 m), 3.03-3.27 (3Η, m), 3.40-3.72 (6Η 5 m), 3.82-3.93 (1Η 5 m) _{, 4.21 (1Η 3 dd, J} = 8.7, 15.7Hz), 4.63 (1 H, dd, J = 6.3 5 15.7Hz), 5.13 (1H, d 5 J = 14.0Hz), 5.33 (1H 3 d, J = 14.0Hz), 6.8 1-7.03 (6H ₅ m), 7.11- 7.14 (1H, m), 7.37 (2H, d, J = 9.0Hz), 7.60 (2H, d, J = 9.0 Hz)

 (Reference Example 10)

 (R) —3-Fluoro-5,11-dihydro-5- [1- (4-Pyrrolidinophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, Θ] [1, 4] oxazepine dihydrochloride

 Use 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazebin and (R) -3-chloro-1- (4-virolidinophenethyl) piperidine. And the same operation as in Reference Example 6) 1-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinofphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.19 g, 50%).

ES I / Mas s: 472 [M + H ⁺ ]

NMR (CDC13) ό ": 1.55-1.90 (4H, m) ₅ 1.95-2.06 (4H, i) ₅ 2.20-2.3 (1H, m), 2.48-2.60 (lH ₃ m), 2.70-2.82 (3H, m ), 2.95-3.10 (1H, m), 3.18-3.40 (6H, m) , 4.06 (1H, m), 5.20 (1H, d, J = 12.0Hz), 5.26 (1H, d, J = 12.0Hz), 6.54 (2H, d, J = 8.7Hz), 6.68-6.85 (5H, m), 6.95-7.03 (lH ₃ m), 7.08 (2H, d, J = 8.7 Hz), 7.2 0-7.30 (lH, m)

 This was treated with 4 M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to give the title compound as a pale brown solid (90%).

ESI / Mass: 472 [M + H ⁺ ]

NMR (CDC13) δ: 1.95-2.30 (4H, m), 2.34 (4Η, m), 2.82-2.95 (1H, m), 3.00-3.24 (2H, m), 3.39-3.78 (7H, m) , 3.82-3.95 (1H, m), 4.21 (1H ₅ dd, J = 7.2, 14 • 1Hz), 4.62 (1H ₃ dd, J = 5.7, 14.1Hz), 5.11 (1H, d, J = 12.6Hz) , 5.34 (1H, d, J = 12.6Hz), 6.76 (1H, t, J = 8.1Hz), 6.80-7.05 (5H, m), 7.19 (1H, t, J = 8.1Hz), 7.37 (2H, d, J = 8.4Hz), 7.64 (2H, d, J = 8.4Hz)

 (Reference Example 11)

 (R) -7-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinopheneethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride

 Using 7-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) —3-chloro-1- (4-pyrrolidinophenethyl) piperidine, By the same operation as in Reference Example 6, (R) -7-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow oil (0.19 g, 51%).

ESI / Mass: 472 [M + H ⁺ ]

NMR (CDC13) δ: 1.58-1.90 (4H, m), 1.95-2.06 (4H ₅ m), 2.20-2.32 (1H, m), 2.48-2.60 (lH, m), 2.68-2.82 (3H, m) , 2.98-3.08 (lH, m), 3.18-3.40 (6H, m), 4.05 (1H ₃ dd, J = 5.8, 13.2 Hz) ₃ 5.14 (1H ₅ d, J = 12.0 Hz) ₅ 5.31 (1H ₃ d , J = 12.0H z), 6.45-6.58 (3H, m), 6.68-6.78 (2H, m), 7.02-7.13 (4H, m), 7.28-7.35 (2H ₅ m)

 This was treated with 4 M salt / hydrogen / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a brown solid (98%).

E S I / Mas s: 472 [M + H +]

NMR (CDC13) 6: 1.95-2.30 ( 4H, m), 2.34 (4H, m), 2.78-2.92 (1Η 5 m), 2.94 -3.25 (2H 3 m), 3.40-3.76 (7H, m), 3.83 -3.94 (1H, m), 4.23 (1H 3 dd, J = 7.2, 14 .4Hz), 4.66 (1H, dd, J = 6.0, 14.4Hz) 3 5.13 (1H 5 d, J = 12.9Hz), 5.24 (1H ₅ d, J = 12.9 Hz), 6.58-6.63 (lH, m), 6.72-6.82 (2H, m), 7.05-7.25 (4H ₅ m), 7.35 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J-8.4Hz)

 (Reference Example 12)

 () _ 8-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinopheneethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine.2 hydrochloride

 Uses 8-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazebin and (R) -3-chloro-1- (4-pyrrolidinophenethyl) biperidine Then, by the same operation as in Reference Example 6, (R) -8-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [B, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.13 g, 32%).

 ES I / Mas s: 472 [M + H +]

NMR (CDC13) δ: 1.58-1.90 (4Η, m), 1.95-2006 (4Η, m), 2.18-2.34 (1Η, m), 2.45-2.58 (1Η, m), 2.65-2.80 (3Η, m) _{m), 2.95-3.10 (1Η 5 m} ), 3.14-3.38 (6Η, m), 4.05-4.14 (1Η 5 m), 5.21 (1Η 3 d, J = 11.7Hz), 5.35 (1H, d, J = 11.7Hz), 6.48-6.

58 (4H, m), 6.88-6.95 (1H ₃ m) ₃ 7.02- 7.12 (4H, m), 7.24-7.35 (2H ₅ m) This was treated with 4 M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a brown solid (98%).

 ES I / Mas s: 472 [M + H +]

NMR (CDC13) ό: 1.95-2.30 (4H, m), 2.35 (4H, m), 2.78-2.94 (1H, m), 2.95-3.10 (1H, m), 3.10-3.25 (1H, m), 3.40-3.80 (7H, m), 3.80-3.95 (1H 5 m), 4.19 (1H, dd, J = 7.8, 14.1Hz), 4.64 (1H, dd, J = 4.2 5 14.1Hz) 5 5.16 (1H 5 d, J = 12.3 Hz), 5.44 (1H ₃ d, J = 12.3Hz) ₃ 6.50-6.61 (2H, m), 6.88-7.00 (1H, m), 7.05-7.1 8 (2H, m), 7.30- 7.41 (4H ₅ m), 7.64 (2H ₅ d, J = 7.8 Hz)

 (Reference Example 13)

 (R) —3-Chloro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine.2 hydrochloride

 Using 3-monochloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R)-3-chloro-1- (4-pyrrolidinophenethyl) piperidine for reference (R) — 3-Chloro-5,11-dihydro-5 — [1- (4-Pyrrolidinophenetyl) pyrrolidine-12-ylmethyl] dibenzo Cb, e] [1,4 Oxazepine was obtained as a pale yellow oil (0.18 g, 68%).

 ES I / Mas s: 488 [M + H +]

NMR (CDC13) δ: 1.50-1.90 (4Η, m), 1.95-2.06 (4Η, m), 2.20-2.34 (1Η, m), 2.50-2.62 (1Η, m), 2.65-2.82 (3Η ₃ m) ₅ 2.90- 3.10 (1Η, m), 3.16-3.40 (6Η ₅ m), 4.05-4.14 (1Η, m), 5.22 (2Η, s), 6.54 (2Η ₃ d, J = 8.7Hz), 6.75 -6.88 (3H, m),

6.96- 7.04 (2H, d, J = 8.7 Hz) ₃ 7.05-7.14 (3H ₅ m), 7.18 (1H ₅ d, J = 8. Etc.) 4M salted hydrogen / dioxane as in Reference Example 6. To give the title compound as a brown solid (91%). ES I / Mas s: 488 [M + H ⁺ ]

NMR (CDC13) δ: 1.95-2.30 (4H, m), 2.34 (4H, m), 2.78- 2.92 (1H, m) ₃ 2.92 -3.25 (2H ₅ m), 3.40- 3.81 (7H, m), 3.83 _{-3.99 (1H 5 m), 4.21} (1H, dd, J = 6.9, 14 .1Hz), 4.63 (1H, dd, J = 6.3 3 14.1Hz), 5.10 (1H, d, J = 12.9Hz), 5.36 _{(1H 3 d, J = 12.9Hz} ) 5 6.85-7.06 (5H, m), 7.15 (2H, t, J = 8.1Hz) 5 7.35 (2H 5 d, J = 8.7Hz), 7.62 (2H 5 d, J = 8.7Hz)

 (Reference Example 14)

 (R) —3-Chloro-5,11-dihydro-5— [1- (3-Pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1, 4] oxazepine dihydrochloride

 3-pyrrolidinophenethyl alcohol

 Dried palladium acetate (58 mg, 0.26 mmol), 2- (di-t-butylphosphino) biphenyl (136 mg, 0.46 mmol 1), t-butoxy sodium (3.23 g, 33.6 mmol) To 1), add a solution of 2- (3-bromophenethoxy) tetrahydro-1H-pyran (6.27 g ヽ 21.9 mmo 1) in toluene (15 ml) and pyrrolidine (2.2 ml, 26.4 mmol), and add 70 ° The mixture was stirred at C for 12 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the product was extracted from the organic layer with 1M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried to quantitatively obtain 3-pyrrolidinophenethyl alcohol as a pale yellow solid.

 NMR (CDC13) δ: 1.98-2.02 (4H, m), 2.82 (2H, t, J = 7.0Hz), 3.26-3.30 (4H, m), 3.86 (2H, q, J = 7.0Hz), 6.42- 6.54 (3H, m), 7.17 (1H, t, J = 8.3Hz)

3-pyrrolidinopheneethyl mesylate

3-Pyrrolidinophenetyl alcohol is dissolved in dichloromethane (20 ml), and triethylamine (3.7 ml ヽ 26.7 mmo 1) and methanesulfone are dissolved at 0 ° C. Nyl chloride (1.9 ml, 24.5 mmol) was added and stirred overnight. The reaction solution was partitioned between a 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (7: 3). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give 3-pyrrolidininophenethyl mesylate as a white solid (5.13 g, 87%).

 ESI / Mass: 270 [M + H +]

NMR (CDC13) δ: 1.98-2.03 (4Η, m), 2.86 (3Η, s), 2.98 (2Η, t, J = 7.3Hz), 3.25-3.30 (4H, m), 4.43 (2H, t, J = 7.3Hz) ₅ 6.40-6.53 (3H ₃ m), 7.16 (1H, t, J = 8.7Hz)

 (R) —3-Chloro-1- (3-pyrrolidinophenethyl) piperidine

 The compound was synthesized in the same manner as in Reference Example 13 using 3-pyrrolidinophenethyl mesylate instead of 4-pyrrolidinophenethyl mesylate. Yield 50%. E S I / Mas s: 293 [M + H +]

NMR (CDC13) δ: 1.55-1.70 (2H ₅ m), 1.78-1.88 (2H, m), 1.95-2.03 (4H, m), 2.10- 2.22 (2H, m), 2.30 (1H, t, J = 10.5Hz) ₅ 2.60- 2.67 (2H, m), 2.67-2.82 (2H, m), 3.16 (1H, m), 3.22-3.30 (4H, m), 4.02 (1H, m), 6.40 (2H ₃ m ), 6.49 (1H, d, J = 7,5Hz), 7.13 (1H 5 t, J = 7.5Hz)

 (R) —3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazebin

3-chloro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine and (R) — 3-chloro-1- (3-pyrrolidinophenethyl) biperidine Then, by the same operation as in Reference Example 6, (R) -3-chloro-1,5-dihydro-15- [1- (3-pyrrolidinophenethyl) pyrrolidine-12-ylmethyl] dibenzo [B, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.21 g, 45%).

 E SI / Ma SS: 488 [M + H +]

NMR (GDC13) δ: 1.50-1.90 (4Η, m), 1.95-2.06 (4Η, m), 2.24-2.34 (1Η ₅ m) ₃ 2.55-2.70 (lH, m), 2.70-2.88 (3H, m) , 3.02-3.15 (lH, m), 3.16-3.40 (6H 3 m) 3 4.02- 4.14 (1H, m), 5.23 (2H, s), 6.40-6.58 (3H, m), 6.75-6.88 (3H 5 m), 6.96

-7.04 (2H, m), 7.10-7.20 (3H, m)

 (R) —3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazebin dihydrochloride

 This was treated with 4M salt / hydrogen / dioxane in the same manner as in Reference Example 6 to give the title compound as a brown solid (88%).

E SI / Ma SS: 488 [M + H +]

NMR (CDC13) δ: 1.95-230 (4 (, m), 2.32 (4H, m), 2.77-2.90 (1H, m), 3.00-3.30 (2H, m) ₅ 3.38-3,78 (7H, m) ₅ 3.80-3.92 (1H ₃ m), 4.21 (1H, dd, J = 6.6, 14.1 Hz), 4.64 (1H ₃ dd, J = 5.7, 14.1 Hz) ₅ 5.10 (1H, d, J2 12.9 Hz), 5.33 (1H, d , J = 12.9Hz), 6.82-7.08 (5H 5 m), 7.14 (2H, t, J = 8.4Hz), 7.20-7.30 (lH, m), 7.38 -7.53 (2H , m), 7.60-7.70 (lH, m)

 (Reference Example 15)

 (R) — 3-chloro-5,11-dihydro-5- [1- (4-morpholinophenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1, 4] oxazepine.2 hydrochloric acid salt

 4-Morpholinopheneethyl alcohol

Dried palladium acetate (32.3 mg, 0.14 mmol), 2- (G-t-butylphosphino) biphenyl (86. Omgs 0.39 mmol), t- Butoxy sodium (1.73 g, 18 mmo 1) in 2- (4-Bromophenoxy) tetrahydro-2H-pyran (3.42 g, 12. Ommo 1) in toluene (9. Oml) solution and morpholine ( 1.22 g, 14 mmo l) and add 70

The mixture was stirred at ° C for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the product was extracted from the organic layer with 1M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried to give 4-morpholinophenethyl alcohol as a pale yellow solid (2.35 g, 95%).

NMR (CDC13) δ: 2.80 (2H ₃ t, J = 8.7 Hz), 3.13 (4H, t, J = 6.8), 3.78-3.88 (6 H.m), 6.88 (2H, d, J = 11.7 Hz) , 7.14 (2H ₅ d, J = 11.7Hz)

 4-Morpholinophene ethyl mesylate

4 Dissolve morpholinophenethyl alcohol (2.35 g, 11.3 mmo 1) in dichloromethane (20 ml), and add diisopropylethylamine (2.60 ml, 14.8 mmo 1) at 0 ° C. Methanesulfonyl chloride (1.1 ml, 14.8 mmol) was added and stirred for 4 hours. The reaction solution was partitioned between 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel gel column chromatography, and eluted with hexane and ethyl acetate (3: 1) first, and then changed to the same solvent (1: 1). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give 4-morpholinophenethyl mesylate as a white solid (2.60 gs 81%). NMR (CDC13) δ: 2.86 ( 3H, s), 2.98 (2H 5 t, J = 9.3Hz), 3.14 (4H, m), 3.86 (4H, m), 4.38 (2H, t, J = 9.3Hz) , 6.87 (2H, d, J = 11.7Hz), 7.14 (2H, d, J = 11.7Hz)

 (R) — 3—Mouth 1— (4—Morpholinophenetyl) piperidine

Acetonitrile (20 ml) in 4-morpholinopheneethyl mesylate (0.43 g, 1.51 mmo 1) and D-prolinol (0.17 g, 1.66 mmo 1) ) And potassium carbonate (0.40 g, 2.89 mmol) were added, and the mixture was stirred at 70 ° C overnight. After cooling, the mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the obtained residue was partitioned between water and ethyl acetate. The desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After the organic layer was dried, the solvent was distilled off under reduced pressure to obtain (R) -2-hydroxymethyl-1- (4-morpholinophenethyl) pyrrolidin as a pale yellow solid (0.44 g, 1 5 mmol, 100%). This was dissolved in dichloromethane (10 ml), and triethylamine (0.29 ml, 2. lmmo 1) and methanesulfonyl chloride (0.15 ml, 1.9 mmo 1) were added at 0 ° C. Stirred for hours. The reaction solution was partitioned between a 5% sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel gel chromatography, and eluted with hexane and ethyl acetate (1: 1). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -3-chloro-1- (4-morpholinophenethyl) piperidine as a white solid (0.30 g, 64 %).

E S I / Ma s s: 309 [M + H +]

NMR (CDC13) δ: 1.50-1.86 (4Η, m), 2.10-2.20 (2Η, m), 2.28 (1Η, t, J = 7.8 Hz), 2.55- 2.64 (2H, m), 2.65-2.80 (3H , m) ₃ 3.10-3.18 (4H, m), 3.80- 3.88 (4H, m), 3.96- 4.04 (1H, m), 6.82-6.88 (2H ₅ m), 7.10-7.20 (2H, m)

 (R) — 3-chloro-5,11-dihydro-5- [1- (4-morpholinophenyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine.2 hydrochloride

(R) — 3-chloro-1- (4-morpholinophenethyl) piperidine and 3-chloro-1,5,11-dihydrodibenzo [b, e] CI, 4] oxazepine By the same operation as in Example 6, (R) -3-chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [ b, e] [1, 4] oxazebin. Pale yellow oil. Yield 46%.

ES I / Mas s: 504 [M + H +]

NMR (GDC13) δ: 1.60-1.95 ( 4H 5 m), 2.22-2.31 (1Η 5 m), 2.52- 2.61 (1H, m), 2.69-2.80 (3H 3 m), 2.98-3.07 (lH 3 m) , 3.01- 3.19 (1H, m), 3.15 (4H, t, J = 5.3Hz), 3.35 (1H ₃ dd, J = 10,3, 14.7Hz), 3.87 (4H, t, J = 5.3Hz) ₃ 4.03 (1H, dd, J = 4.0, 14.7Hz), 5.2K1H, d, J = 13.3Hz), 5.23 (1H, d, J = 13.3Hz) ₃ 6.76-6.90 (3H, m), 6.88 (2H , D, J = 9.7 Hz) ₃ 6.97-7.01 (2H, m), 7.09-7.19 (2H, m), 7.14 (2 H, d, J 2 9.7 Hz)

 This was treated with 4 M salt / hydrogen / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a pale brown solid. 96% yield.

E S I / Mas s: 504 [M + H +]

NMR (CDC13) ό-: 1.98-2.33 (4H, m), 2.83-3.30 (4H, m), 3.38-3.70 (6Η, m), 3.87-3.98 (1H, m), 4.15-4.42 (5H , m), 4.60-4.70 (1H, m), 5.12 (1H, d, J = 14.0Hz), 5.39 (1H, d, J = 14.0Hz), 6.84-6.93 (3H, m), 7.04-7.19 (4H, m) ₃ 7.43 (2 H, s), 7.78 (2H, s)

 (Reference Example 16)

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazepine

Under an argon stream, 60% sodium hydride (100 mg, 2.5 mmol) was washed with hexane and then suspended in dimethyl sulfoxide (8 ml). After stirring for 30 minutes at room temperature, 2-fluoro-5,11-dihydrodibenzo [b, e] [1 , 4] oxazepine (538 mg, 2.5 mmol 1) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C for 40 minutes. To this solution was added a solution of (S) -1- (4-dimethylaminophenethyl) -1,3-methanesulfonyloxypyrrolidine (312 mg, 1.0 mmol, prepared by the method described in International Patent No. 0040570A1) in dimethyl sulfoxide (3 ml). The mixture was added dropwise and stirred at 50 ° C for 13 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1) first as eluents, followed by hexane and ethyl acetate (1: 1). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -2-fluoro-1,5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-13-yl] dibenzo [ b, e] [1, 4] oxazepine was obtained as a pale yellow oil (140 mg, 32%).

ESI / Mass: 432 [M + H ⁺ ]

NMR (CDC13) δ1.74-1.84 (1H, m), 2.22-2.34 (1Η, m) ₅ 2.37-2.47 (lH, m), .48-2.71 (5H, m), 2.75-2.85 (lH, m), 2.90 (6H, s ), 3.18 (1H, dd, J two 7.7, 1 0.7Hz), 4.60-4.70 ( 1H, m), 5.25-5.40 (2H, bs), 6.37-6.49 (3H 3 m ), 6.72-6.87 (5H ₅ m), 6.95-7.24 (3H ₃ m),

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-Dimethylaminophenethyl) pyrrolidine-1-3-yl] dipenzo [b, e] [1,4] oxazepine dihydrochloride

(R) 1-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-3-yl] dipento [b, e] [1,4] oxazepine (140mg) (5 ml) To the solution was added 1.0 ml of 4 M hydrogen chloride / ethyl acetate, and after stirring for 1 hour, the solvent was distilled off under reduced pressure, and the residue was solidified by stirring in hexane and indicated by filtration. The compound was obtained as a pale yellow solid (145 ms 90%).

ESI / Mas s: 432 [M + H ⁺ ]

NMR (CD30D) δ: L90- 2.08 (1H, m), 2.10-2.30 (1H 3 m) 5 2.38-2.53 (lH 5 m), 2.60-2.73 (lH, m), 3.14 (2H 5 t, J = 8.0Hz) ₅ 3.26 (6H, s), 3.49 (2H, t, J = 8.0 Hz), 3.60-3.82 (2H ₃ m), 4.03-4.14 (lH, m), 4.95-5.03 (lH, m), 5.06-5.15 (1H ₃ m), 6.73-6.92 (3H ₃ m), 7.03-7.26 (4H, m), 7.47-7.59 (4H, m)

 (Reference Example 17)

 (R) —3-Fluoro-1,5,11-dihydro-5- [1-1- (4-dimethylaminophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine.2 hydrochloride

 Using 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine By the same operation as in Reference Example 16, (R) -3-fluoro-5,11-dihydro-1-5- [1- (4-dimethylaminophenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1, 4] oxazebine was obtained. Pale yellow solid. Yield 40%.

 ES I / Mas s: 432 [M + H +]

NMR CDC13) δ: 1.73-1.84 (1H, m), 2.21-2.30 (1H, m), 2.41-2.48 (1H, m), 2.50-2.71 (5H, m), 2.75-2.82 (lH, m), 2.90 (6H, s), 3.18 (1H ₅ dd, J = 7.7, 10.7Hz), 5.28 (1H, d, J = 12.0Hz), 5.40 (1H, d, J = 12.0Hz), 6.48-6.54 ( 1H ₃ m), 6.63-6.72 (4H, m), 7.01-7.12 (4H ₃ m), 7.25-7.34 (2H, m)

 This was treated with 4 M hydrogen chloride and ethyl acetate in the same manner as in Reference Example 16 to obtain the title compound as a pale brown solid. Yield 92%.

ES I / Mas s: 432 [M + H +]

NMR (CD30D) 6: 1.90-2.07 (1H, m), 2.14-2.27 (1H ₃ m), 2.42-2.52 (1H, m) , 2.63-2.77 (1H, m), 3.15 (2H, t, J = 9.0Hz), 3.26 (6H, s), 3.49 (2H, t, J = 9.0 Hz), 3.64-3.82 (2H, m), 4.07-4.16 (lH ₃ m), 4.97-5.06 (1H, m), 5.10-5.18 (1H, m), 6.72-6.94 (4H, m), 7.00-7.09 (2H, m) ₃ 7.43-7.65 (5H , m)

 (Reference Example 18)

 (R) — 3-chloro-1,5-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1, 4] oxazepine • dihydrochloride salt

 Instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazebin, 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine In the same manner as in Reference Example 16, (R) -3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-13-yl] dibenzo [b , e] [1, 4] oxazepine. Pale yellow oil. Yield 39%.

 ES I / Mas s: 448 [M + H +]

NM (CDC13) 6: 1.74-1.84 (1H, m), 2.22-2.34 (1 mm, m), 2.37-2.47 (1 mm, m), 2.48-2.71 (5H ₅ m), 2.75-2.85 (lH, m ), 2,90 (6H, s) , 3.18 (1H, dd, J = 7.7 3 10, 7Hz), 4.60-4.70 (1H, m), 5.25-5.40 (2H, bs), 6.68 (2H, d, J = 9.7Hz), 6.71-6.88 (4H, m), 6.92- 7.10 (3H, m) 7.04 (2H, d, J = 9.7Hz)

 This was treated with 4 M sodium chloride / ethyl acetate in the same manner as in Reference Example 16 to give the title compound as a brown solid. 90% yield.

ESI / Mass: 448 [M + H +]

NMR (CD30D) δ: 1.86-2.08 (1H, m), 2.10-2.27 (1H ₃ m), 2.40-2.53 (1H, m), 2.60-2.74 (1H, m) ₃ 3.12 (2H, t, J = 9.0Hz), 3.27 (6H, s), 3.50 (2H, t, J = 9.0 Hz), 3.64- 3.84 (2H, m), 4.06-4.16 (lH, m), 5.00-5.08 (lH, m), 5.10-5.19 (1H ₅ m), 6.73-7.07 (4H ₅ m) ₃ 7.17-7.42 (3H ₅ m), 7.47-7.67 (4H ₃ m) (Reference Example 19)

 (R) _ 3-Fluoro-5,11-dihydro-5- [1- (3-pyrrolidinophenyl) pyrrolidine-1-yl] dibenzo [b, e] [1,4] oxazepine 'dihydrochloride

 (S) —3-Methanesulfonyloxy-1- (3-pyrrolidinophenethyl) bi-lysine

 3-pyrrolidinophenethyl mesylate (1.80 g, 4.00 mmol), (S) -3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmol), potassium carbonate (1.70 g, 12 3mmo 1) was added to acetonitrile (2 Oml) and stirred at 100 ° C for 12 hours. After the acetonitrile was distilled off under reduced pressure, the mixture was separated into water and ethyl acetate. The desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After the organic layer was dried, the solvent was distilled off under reduced pressure to give (S) -3-hydroxy-1- (3-pyrrolidinophenetyl) pyrrolidine quantitatively as a pale yellow solid. Dissolve this in dichloromethane (10 ml), add triethylamine (0.76 ml, 5.49 mmol) and methanesulfonyl chloride (0.39 ml, 5.03 mmol) at 0 ° C and stir overnight. did. The reaction solution was partitioned between a 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with chloroform and methanol (95: 5). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -3-methanesulfonyloxy-1- (3-pyrrolidinofphenethyl) pyrrolidine as a pale yellow oil (1. 30g, 96%).

ES I / Mas s: 339 [M + H +]

NMR (CDC13) δ: 1.99 (4Η ₃ m), 2.03-2.15 (1Η, m), 2.25- 2.38 (1Η, m), 2.44-2.54 (1Η, m), 2.70-2.80 (4Η ₅ m), 2.80 -3.02 (3Η, m), 3.02 (3H, s), 3.23-3.30 (4H, m), 5.23 ( 1H, m), 6.42 (2H, m), 6.50 (1H, d, J = 7.5Hz), 7.14 (1H 3 t, J = 7 .5Hz)

 (R) —3-Fluoro-5,11-dihydro-5- [1- (3-Pyrrolidinophenethyl) pyrrolidine-1-3-yl] dipenzo [b, e] [1,4] oxazepine 60% hydrogen under argon stream Sodium chloride (88 mg, 2.2 mmol) was washed with hexane, suspended in dimethyl sulfoxide (10 ml), stirred at room temperature for 30 minutes, and then treated with 3-fluoro-5,11-dihydrodibenzo [b, e]. [1,4] Oxazepine (0.43 g, 2. Ommo 1) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for an additional 30 minutes, (S) 13-methanesulfonyloxy-1- (3-pyrrolidinophenethyl) pyrrolidine (0.34 g, 1. Ommo 1) dimethyl sulfoxide ( 4 ml) solution was added dropwise and stirred at 70 ° C. for 2 hours. The reaction solution was partitioned between saturated saline and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel gel chromatography, and eluted with hexane and ethyl acetate (1: 1). Appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -3-fluoro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidine-1-yl Dibenzo [b, e] CI, 4] oxazepine was obtained as a pale yellow oil (0.19 g, 42%).

 ES I / Mas s: 458 [M + H +]

NMR (CDC13) ό: 1.68-1.84 (1Η, m), 1.90-1.99 (4Η, m), 2.22-2.36 (1H, m), 2.40-2.48 (lH ₃ m), 2.50-2.76 (5H, m ), 2.76-2.86 (1H, m), 3.16- 3.28 (5H, m), 4.64 (1H ₃ m), 5.36 (2H ₃ m), 6.37-6.49 (3H, m), 6.72-6.87 (5H ₅ m ), 6.95 (1H, d, J = 6.6Hz), 7.12- 7.28 (1H, t, J = 7.5Hz), 7.28 (1H, d, J = 6.6Hz)

This was treated with 4 M sodium chloride / ethyl acetate in the same manner as in Reference Example 16 to give the title compound as a brown solid (69%). NMR (CD30D) δ: 1.90- 2.08 (1H, m), 2.10-2.30 (5H, m), 2.35-2.55 (lH, m), 2.60-2.78 (2H, m), 3.12 (2H 5 t, J = 8.1Hz), 3.30-3.48 (lH ₃ m), 3.53 (1H ₅ t, J = 8.1 Hz), 3.60-3.83 (6H ₃ m), 4.95-5.15 (2H ₅ m) ₅ 6.70-7.10 (6H ₃ m ), 7.25-7.53 (5H ₅ m)

 (Reference Example 20)

 (R) —3-chloro-5,11-dihydro-5- [1- (3-pyrrolidine-11-ylphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazepine '2HCl salt

 Using 3-chloro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-methylsulfonyl-1- (3-pyrrolidine-1-1-ylphenethyl) pyrrolidine By the same procedure as in Example 19, (R) — 3-chloro-1,5-dihydro-5- [1- (3-pyrrolidine-1-ylphenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow oil (0.20 g, 43%).

ES I / Mas s: 474 [M + H +]

NMR (CDC13) δ: 1.63-1.80 (1Η ₃ m), 1.92-2.00 (4Η ₅ m), 2.22-2.36 (1Η, m), 2.40- 2.48 (1Η, m), 2.52-2.75 (5Η, m), 2.75-2.86 (IH, m), 3.15-3.30 (5H, m), 4.60-4.70 (1H, m), 5.38 (2H ₅ brs), 6.37-6.49 (3H, m), 6.72-6.80 ( 3H,) ₅ 6.95 (1H ₃ dd, J = 1.8, 7.8 Hz), 7.04- 7.14 (3H, m), 7.24 (1H ₅ d, J = 7.8 Hz) Treatment with hydrogen chloride / ethyl acetate gave the title compound as a brown solid (93%).

ES I / Mas s: 474 [M + H +]

NMR (CD30D) δ: 1.90-2.10 (1H, m), 2.13-2.32 (5H ₅ m), 2.37-2.55 (1Η, m), 2.60-2.78 (2H, m), 3.10 (2H, t, J = 7.8Hz), 3.30-3.5 (IH, m), 3.53 (1H, t, J = 7.8Hz), 3.58-3.81 (5H, m), 4.00-4.12 (lH, m), 4.95-5.18 (2H , m), 6.70-7.1 0 (4H, m), 7.16-7.50 (7H, m)

 (Reference Example 21)

(R) -5 ₃₁ 1-Dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine.2 HCl salt

(R) -5,11-Dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-1-ylmethyl] dibenzo [b, e] [1,4] oxazebine

 In acetonitrile (2 Oml), (R) —5,11-dihydro-5- (2-birolidylmethyl) dibenzo [b, e] [1,4] oxazepine (240 mg, 0.85 mmo1, International Patent No. 99 12925) A 1), 3-pyrrolidinophenethyl mesylate (253 mg, 0.94 mmol), sodium carbonate (106 mg, 1.0 mmo 1), sodium iodide (1 mg, 0.07 mmo 1) ) And heated under reflux at 90 ° C for 6.5 hours, the solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluting first with hexane and ethyl acetate (15: 1) as eluents, and then eluting with hexane and ethyl acetate (2: 1). . The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -5,11-dihydro-5- [1- (3-pyrrolidinofphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow oil (208 mg, 54%).

ES I / Mas: 454 [M + H +]

NMR (CDC13) δ: 1.65-1.88 ( 4Η 5 m), 1.99- 2.05 (4Η, m), 2.23-2.32 (1Η 3 m), 2.55-2.64 (1Η, m), 2.71-2.84 (3Η,), 3.06- 3.16 (1Η, m), 3.19- 3.24 (1Η, m), 3.28-3.32 (4Η 3 m), 3.37 (1Η, dd, J = 11.0, 14.3Hz), 4.15 (1H 5 dd, J = 4.0 ₅ 14. Hz), 5.22 (1H ₅ d, J = 13.0 Hz), 5.34 (1H, d ₃ J = 13.0 Hz), 6.44-6.55 (3H ₃ m), 6. 75-6.83 (3H ₃ m), 7.00-7.20 (4H, m), 7.2.6-7.32 (2H, m)

 (R) —5,11-dihydro —5— [1- (3_Pyrrolidinophenetyl) pyrrolidin-1--2-methyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride (R) — 5,11-Dihydro-5- [1- (3-pyrrolidinofphenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] Oxazepine (208 mg) in dichloromethane (2 ml) After adding 2.0 ml of M shiridani hydrogen / getyl ether and stirring for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was solidified by stirring in hexane and filtered to give the title compound as a pale brown solid (220 mg, 91%).

ES I / Mas: 454 [M + H +]

NMR (CDC13) ό ": 1.90-2.42 (8Η, m), 2.98-3.30 (3Η, m), 3.40-3.90 (8H, m), 4.18-4.35 (1H ₅ m), 4.62-4.76 (lH, m ), 5.14 (1H, d, J = 13.0Hz), 5.30 (1H 3 d, J = 13.0Hz), 6.78- 6.94 (3H, m), 6.97-7.16 (3H, m), 7.20-7.40 (4H, m), 7.45 (1 H, s), 7.59 (1H ₅ s)

 (Reference Example 22)

 (R) — 5,11 dihydro-5- [1— (4-pyrrolidinofphenethyl) pyrrolidin-1-3-yl] dipenza [b, e] [1,4] oxazepine 'dihydrochloride

(S) — 3-Hydroxy-1- (4-pyrrolidinophenethyl) pyrrolidine acetonitrile (200ml) in 4-pyrrolidinophenethyl mesylate (13.45 gs 50. Ommo 1) and (S) — 3 _Pyrrolidinol hydrochloride (5.56 g, 45. Ommo 1) and potassium carbonate (18.63 g, 135 mmo 1) were added, and the mixture was stirred at 90 ° C for 3 hours. After cooling, the mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the obtained residue was partitioned between water and ethyl acetate. The desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After drying the organic layer and distilling off the solvent under reduced pressure, the (S) -3-hydroxy-1- (4-pyrrolidinofe (Netyl) Pyrrolidine was obtained as a pale yellow solid (6.30 g, 52%).

NMR (CDC13) δ: 1.74-1.84 (1H, m), 1.96-2.04 (4H ₅ m), 2.15-2.25 (1H ₅ m), 2.34-2.43 (1H, m) ₅ 2.55-2.63 (lH ₅ m) , 2.65-2.80 (5H ₃ m), 2.92-3.03 (lH, m), 3.23-3.28 (4H, m), 4.33-4.40 (lH, m), 6.51 (2H ₃ d, J = 9.3Hz), 7.06 (2H ₃ d, J two 9.3 Hz)

 (S) —3-Methanesulfonyloxy 1- (4-pyrrolidinophenethyl)

 (S) 13-Hydroxy-1- (4-pyrrolidinofphenethyl) pyrrolidine (6.30 g, 23.4 mmol 1) is dissolved in 10 mL of dichloromethane and diisopropylethylamine (0 ° C). 5. 28 ml, 30. Ommo 1) and methanesulfonyl chloride (2.34 ml, 30. Ommo 1) were added and stirred for 4 hours. The reaction solution was partitioned between 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with dichloromethane and methanol (10: 1). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (S) -3-methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pipalysine as a pale yellow oil ( 7.50g, 49%).

E S I / Mas s: 339 [M + H +]

NMR (CDC13) ό ": 1.96-2.00 (4Η, m), 2.04-2.16 (1Η ₃ m), 2.27-2.38 (1Η, m), 2.44-2.52 (1H, m), 2.65-2.74 (4H , M), 2.82-2.98 (3H, m), 3.02 (3H, s), 3.23 -3.28 (4H, m), 5.19-5.27 (1H ₅ m), 6.50 (2H ₃ d, J = 9.3 Hz), 7.05 (2H, d, J = 9.3H z)

 (R) -5,11-dihydro-5- [1- (4-pyrrolidinofphenethyl) pyrrolidin-1--3-yl] dibenzo! : b, e] CI, 4] oxazepine dihydrochloride

Under argon flow, 60% sodium hydride (132mg, 3.3mmo 1) After washing with hexane, the suspension was suspended in dimethyl sulfoxide (10 ml), stirred at room temperature for 30 minutes, and then 5,11-dihydrodibenzo [b, e] CI, 4] oxazepine (600 mg, 3. ) Was added and stirred at room temperature for 30 minutes. After stirring at 50 ° C for 30 minutes, this solution was added to (S)-3-methanesulfonyloxy-111- (4-pyrrolidinofphenethyl) pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml). The solution was added dropwise and stirred at 50 ° C for 42 hours. The reaction solution was partitioned between saturated saline and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -5,11-dihydro-1-5- [1- (4-pyrrolidinophenetyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazebin was obtained as a pale yellow oil (142 mg, 32%).

NMR (CDC13) δ: 1.72-1.84 (1H, m), 1.96-2.04 (4H, m), 2.22-2.1 (2H, m), 2.49-2.71 (5H, m), 2.80-2.89 (lH, m), 3.22-3.27 (5H, m), 4.67-4.74 (lH, m), 5.30-5.50 (2H, b), 6.48 (2H, d, J = 9.7Hz), 6.72-6.82 (3H, m) , 6.95- 7.13 (3H, m), 7.02 (2H, d, J = 9.7Hz), 7.26-7.33 (2H, m)

 This was treated with 2 M salt / hydrogen / jetilether in the same manner as in Reference Example 21 to give the title compound as a brown solid (83%).

ES I / Mas s: 440 [M + H +]

NMR (CD30D) δ: 1.90-2.08 (1H, m), 2.10-2.30 (5H ₃ m), 2.35-2.55 (1Η ₃ m), 2.60-2.78 (2H, m), 3.08 (2H, t, J = 10.0Hz), 3.23- 3.38 (1H, m), 3.47 (1H, t, J = 10.0Hz), 3.60-3.83 (5H, m), 4.02-4.11 (lH ₃ m), 4.99-5.08 (lH ₃ m ), 5.10-5

.18 (1H, m), 6,72-7.04 (4H, m), 7.15-7.24 (2H, m), 7.36-7.4 (6H ₅ m)

(Reference Example 23)

(R) -5,11-Dihydro-5- [1- (3-pyrrolidinophenetyl) pylori Gin-3-yl] dipenza [b, e] [1, 4] oxazepine 'dihydrochloride (S) —3-hydroxy-1- (3-pyrrolidinophenethyl) pyrrolidine acetonitrile (20 ml) Reference Example 21 3-pyrrolidinopheneethyl mesylate (1.80 g, 4.OO mmol) and (S) -3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmo 1), potassium carbonate (1.70 g, 12 3mmo 1) was added and the mixture was stirred at 100 ° C for 12 hours. After the acetonitrile was distilled off under reduced pressure, it was partitioned between water and ethyl acetate. The desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, neutralized, and then extracted again with ethyl acetate. After drying the organic layer and distilling off the solvent under reduced pressure, (S) -3-hydroxy-1- (3-pyrrolidinofphenethyl) pyrrolidine was obtained as a pale yellow solid (1.04 g, 100%). %).

NMR (CDC13) δ: 1.68-1.80 (1H, m), 1.91-2.02 (4H, m), 2.13-2.25 (1H ₅ m), 2.30-2.40 (lH ₃ m), 2.55-2.63 (lH, m) , 2.67-2.80 (5H, m), 2.89-2.98 (1H, m), 3.15-3.25 (4H ₃ m), 4.28-4.39 (1H, m), 6.39-6.42 (2H, m), 6.50 (1H, m d, J = 8.0 Hz), 7.13 (1H, t, J = 8.0Hz)

 (S) —3-Methanesulfonyloxy 1- (3-pyrrolidinophenethyl)

(S) —3-Hydroxy-1- (3-pyrrolidinophenethyl) Pyrrolidine (1.04 g, 4.0 Ommo 1) is dissolved in dichloromethane (1 Oml), and triethylamine (0. 76 ml, 5.49 mmo 1) and methanesulfonyl chloride (0.39 ml, 5.03 mmo 1) were added and stirred overnight. The reaction solution was partitioned between 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to gel chromatography on silica gel, and eluted with chloroform and methanol (95: 5). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (S) -3-methanesulfonyloxy-1- (3-pyrrolidinofphenethyl) pyrrolidine as a pale yellow oil. (1.30 g, 96%).

 E S I / Mas s: 339 [M + H +]

NMR (CDC13) δ: 1.96- 2.02 (4H, m), 2.03-2.15 (lH 5 m), 2.25- 2.38 (1H, m), 2.44-2.54 (1H 5), 2.70-2.80 (4H 3 m), 2.80-3.02 (3H ₅ m), 3.02 (3H, s), 3.23 -3.30 (4H, m), 5.20-5.28 (lH ₃ m), 6.42 (2H, m), 6.50 (1H ₃ d, J = 7.5 Hz) ₅ 7.14 (1H, t, J = 7.5Hz)

 (R) -5,11-Dihydro-5-CI- (3-pyrrolidinophenetyl) pyrrolidin-13-yl] dibenzo [b, e] [1,4] oxazepine 'dihydrochloride Under argon stream After washing 60% sodium hydride (132 mg, 3.3 mmo 1) with hexane, suspending it in dimethyl sulfoxide (10 ml), stirring at room temperature for 30 minutes, and adding 5,11-dihydrodibenzo! : b, e] [1,4] oxazepine (600 mg, 3.0 mmol) and stirred at room temperature for 30 minutes. After stirring at 50 ° C for 30 minutes, this solution was added to a solution of (S) -3-methanesulfonyloxy-1- (4-pyrrolidinofphenethyl) pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml). Was added dropwise, and the mixture was stirred at 50 ° C for 42 hours. The reaction solution was partitioned between saturated saline and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -5,11-dihydro-1-5- (1- (3-pyrrolidinophenetyl) pyrrolidine-13-yl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (225 mg, 51%).

ES I / Mas s: 440 [M + H +]

NMR (CDC13) δ: 1.74- 1,84 (1Η, m), 1.95-2.00 (4Η, m), 2.23-2.34 (1Η, m), 2.34-2.43 (1H, m), 2.49-2.57 (1H, m), 2.61-2.76 (5H, m ), 2.81-2.88 (1H, m), 3.23-3.29 (4H, m), 4.67-4.76 (lH, m), 5.30-5.50 (2H 3 bs), 6.34- 6.48 (3H, m) , 6.71-6.85 (3H ₅ m), 6.94-6.97 (1 mm, m), 7.04- 7.16 (3H, m), 7.25-7.32 (2H ₃ m) Treatment with hydrogen / jetilether afforded the title compound as a brown solid (78%).

ES I / Mas s: 440 [M + H +]

NMR (CD30D) δ: 1.90-2.08 (1H, m), 2.10-2.30 (5H ₅ m), 2.35-2.55 (1Η, m), 2.60-2.78 (1H, m), 3.10 (2H, t, J = 10.0Hz), 3.25-3.40 (lH, m ), 3.25 (2H 3 t, J = 10.0Hz), 3.60- 3.80 (5H, m), 4.03-4.12 (lH, m), 4.99-5.09 (1H,) , 5.11-5

.19 (1H, m), 6.70- 7.04 (5H, m), 7.14-7.47 (7H, i)

 (Reference Example 24)

 5,11-dihydro-5- [2- [N-methyl-1-N- (3-pyrrolidinophenyl) amino] ethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride acetonitrile ( 5,11-dihydro-5- [2_ (N-methylamino) ethyl] dibenzo [b, e] [1,4] oxazepine (254 mg, 1.00 mmol, International Patent No. 0040570 A1) ), 3-pyrrolidinophenethyl mesylate (296 mg, 1.10 O.mmol), sodium carbonate (138 mg, 1.3 Ommo 1), sodium iodide (2 Omg, 0 After adding 13 mmo 1) and heating under reflux at 90 ° C for 6.5 hours, the solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and hexane and ethyl acetate were first used as eluents.

Elution was performed using (10: 1) followed by hexane and ethyl acetate (3: 1). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give 5,11-dihydro-5- [2- [N-methyl-N- (3_pyrrolidinofphenethyl) amino] ethyl] dibenzo [b, e] [1, 4] oxazepine obtained as pale yellow oil

(33 lmg, 78%). ESI / Mas s: 428 [M + H ⁺ ]

NMR (CDC13) δ: 1.96-2.00 ( 4H, m), 2.32 (3H 5 s), 2.61 (4H, s), 2.66 (2H, t, J = 8.0Hz), 3.23-3.27 (4H, m), 3.90 (2H, t, J = 8.0Hz), 5.29 (2H, s), 6.32-6 .44 (3H, m) 5 6.77-6.84 (3H, m), 7.00-7.14 (4H 5 m), 7.25- 7.32 (2H ₃ m)

 This was treated with 2 M salt / hydrogen nodethyl ether in the same manner as in Reference Example 21 to give the title compound as a brown solid (81%).

ES I / Mas s: 428 [M + H +]

NMR (CDC13) δ: 2.28-2.40 (4H ₃ m) ₃ 2.85 (3H ₅ d, J = 4.3 Hz), 3.10-3.48 (6H, m), 3.55-3.74 (4H ₃ m), 4.23-4.35 (lH , m), 4. 0-4.52 (1H , m), 5.23 (1H, d 3 J = 14.3Hz), 5.25 (1H, d, J = 14.3Hz), 6.82- 6.93 (3H, m), 7.06- 7.11 (2H, m), 7.1 8 (1H, d, J = 8.7Hz) 3 7.24-7.44 (4H 3 m), 7.53 (1H, d, J = 8.7Hz), 7.78 (1H 3 m)

(Reference Example 25)

 (R) 1-3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine'2HCl Salt (Compound of Reference Example 8)

 (R) -N- [(4-dimethylaminophenyl) acetyl] 1-D-proline methyl ester

(4-Dimethylaminophenyl) Acetic acid (7.4 g, 41.3 mmol 1), D-proline methyl ester hydrochloride (7.19 g, 43.4 mmol) in methylene chloride (150 ml) solution Hydroxybenzotriazole monohydrate (6.1 g, 45.4 mmol) and N-dimethylaminopropyl-N'-ethylethylcarbodiimid hydrochloride (8.7 g, 45.4 mmol 1) were added. . After the mixture was stirred at room temperature for 6 hours, triethylamine (6.3 ml, 45.4 mmol) was added. The mixture was stirred overnight at room temperature, and the reaction solution was successively washed with water (200 ml), 5% aqueous sodium bicarbonate (20 Oml), and water (200 ml). The solvent is distilled off under reduced pressure The residue obtained was subjected to silica gel gel column chromatography, and eluted with methylene chloride and methanol (10: 1). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (11.0 g, 83%).

 ES I / Mas s: 291 [M + H +]

_{NMR (CDC1 3) (5:} 1.82-2.26 (4H, m), 2.82-2.98 (6H, m), 3.40-3.76 (2H 3 m), 3.60 (3H, s), 3.73 (2H, s), 4.41 -4.52 (1H, m), 6.64-6.74 (2H, m), 7.07-7.19 (2H, m)

 (R) — N— [(4-Dimethylaminophenyl) acetyl] 1-D-proline

 (R) -N-[(4-Dimethylaminophenyl) acetyl] 1-D-Proline methyl ester (1.0 g, 3.4 mmol) was dissolved in tetrahydrofuran (10 ml), and water (10 ml) and 1 M hydroxylated An aqueous sodium solution (3.7 ml, 3.7 mmo 1) was added. After stirring at room temperature overnight, a saturated aqueous solution of ammonium chloride (15 ml) was added, and the pH was adjusted to about 4 with 1 M hydrochloric acid. After distilling off the solvent from the mixture under reduced pressure, acetone was added and mixed. The filtrate was collected by filtration, the solvent was distilled off under reduced pressure, and the residue was dried to obtain the title compound as a yellow solid (0.91 g, 96%).

ES I / Mas s: 277 [M + H +]

_{NMR (CDC1 3) δ: 1.80-2.28} (3H, m), 2.45-2.58 (1H 5 m), 2.95 (6H, s), 3.42- 3.70 (2H, m), 3.65 (2H, s), 4.60- 4.68 (1H, m), 6.72-6.83 (2H, m), 7.08-7.19 (2H, m)

 (R) -1-[(4-Dimethylaminophenyl) acetyl] pyrrolidine-1-force rubonic acid [2- (2-bromo-4-cyclobenzyloxy) phenyl] amide

(R) -N-[(4-dimethylaminophenyl) acetyl] 1-D-proline (8.56 g, 31. Ommo 1) in toluene (111 ml), N-methylmorpholine (3. 85 ml, 35. Ommo 1) was added. Under ice-cooling, ethyl chloroformate (3.26 ml, 34. lmmol) was added thereto, and the mixture was stirred for 2 hours. Here, 21- (2-bromo-14-chlorobenzyloxy) aniline hydrochloride (10.8 g, 31.Ommo 1) and N-methylmorpholine (4.09 ml, 37.2 mmo 1) The mixture was stirred overnight at room temperature. Water (40 ml) was added to the reaction solution, and the organic layer was washed with water (40 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride and methanol (30: 1). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to obtain the title compound as a yellow solid (16.3 g, 92%).

 E S I / Ma s s: 572 [M + H +]

_{NMR (CDC1 3) ό-: 1.80-1.94} (1.2H 5 m), 1.96-2.06 (0.8H,), 2.08-2.36 (1.2H, m), 2.51-2.59 (0.8H 3 m), 2.79 and 2.92 (total 6. OH, each s), 3.45-3.75 (4 H, m), 4.53-4.59 (0.2 H ₅ m), 4.81-4.87 (0.8 H, m), 4.94-5.13 (0.3 H, m), 5.13 (1.7H, s), 6.47-6.69 (2. OH, m), 6.84-7.14 (5.1H, m), 7.19-7.26 (0.9H 5 m), 7. 51-7.68 (1.9H, m) , 8.26 (0.1H, br s), 8.35-8.42 (1. OH, m), 9.53 (1H, br s)

(R) — {[2- (3-Chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-15-carbonyl) pyrrolidine] -11-yl} -2- (4-dimethyla Minophenyl) ethanone

 (R) -1-[(4-Dimethylaminophenyl) acetyl] pyrrolidine-1-carboxylic acid [2- (2-promo 4-cyclopentyloxy) phenyl] amide (1.73 g, 3.003 mmo 1 ) With potassium carbonate (1.27 g, 9.19 mmol 1), copper (I) bromide (24. lmg ヽ 0.168 mmo 1), 4-picoline

(8.65 ml) was added. After heating at 145 ° C for 20 hours, the solution was filtered to obtain a filtrate, and the solvent was distilled off under reduced pressure. The residue obtained is silica gel The residue was subjected to chromatography, and eluted with methylene chloride and methanol (20: 1). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to obtain the title compound as a brown solid (0.97 g, 66%).

 ES I / Mas s: 490 [M + H +]

_{NMR (CDC1 3) 5:.} 1.52-2.34 (4H 5 m), 2.92 and 2.96 (total 6. OH, each s), 3 .44-3.77 (4.1H, m), 4.34-4 1 (0.2H, m), 4.65-4.72 (0.4H, m) ₅ 4.77-4.91 (1.1 H, m), 5.08-5.15 (0.2H, m), 5.50-5.67 (0.3H ₅ m), 6.34-6.1. H, m), 6.65- 7.03 (4.0H, m) ₅ 7.06-7.50 (6.5H, m), 7.59 (0.2H ₅ br s), 7.91-7.96 (0.2H ₃ m), 8.11 (0.1H, br s)

 (R) — 3-Chloro-5,11-dihydro-5- [1-1- (4-dimethylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine

(R)-{[2- (3-chloro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidine] —1-yl} —2— (4 —Dimethylaminophenyl) ethanone (0.97 g ヽ 1.98 mmo 1) is dissolved in tetrahydrofuran (19.4 ml), sodium borohydride (0.39 g, 10.4 mmo 1) is added, and then ice In a bath, boron trifluoride tetrahydrofuran complex (1.69 ml, 13.9 mmo 1) was added. After heating the reaction solution to 37 ° C for 42 hours, sodium borohydride (0.056 g, 1.5 mmo 1) and borotrifluoride tetrahydrofuran complex (0.24 ml, 1.99 mmol) were obtained. . After heating the reaction solution to 37 ° C for 24 hours, a 1.5 M aqueous sodium hydroxide solution (16 ml, 24 mmo 1) was added in an ice bath. After the reaction solution was heated to 60 ° C for 12 hours, it was partitioned between toluene (20 ml) and water (10 ml). An organic layer was obtained, and tetrahydrofuran was distilled off under reduced pressure. After washing with water (10 ml), the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography. The mixture was applied to a filter and eluted with methylene chloride and methanol (10: 1). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give the title compound as a brown solid (0.67 g, 74%) o

ES I / Mas s: 462 [M + H +]

_{NMR (CDC1 3) <5:} 1.59-1.90 (4H, m), Z.22-2.31 (1H, m), 2.50-2.59 (lH 3 m), 2.66-2.84 (3H 5 m), 2.93 (6H 5 s), 2.97-3.06 (1H, m), 3.16- 3.24 (1H, m), 3.34 (1H, dd, J = 13.0 ₅ 9.4Hz), 4.07 (1H ₅ dd, 13,0, 3.7Hz), 5.22 (2H, s), 6.70-6.75 (2H ₅ m), 6.75-6.86 (3H ₅ m), 6.97-7.02 (2H, m), 7.08-7.14 (3H, m), 7.17 (1 H, d , J = 7.9Hz)

 (R) 1,3-dichloro-5,11-dihydro-5- [1-1 (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride salt

 (R) —3—Chloro-1,11-dihydro-5— [1-1 (4-dimethylaminophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (10.6 g , 22.9mmo 1) was dissolved in 2-propanol (100ml), and 4M sodium chloride / 2-propanol (22.9ml) was added. The solvent was distilled off under reduced pressure, and to the resulting residue was added 4M sodium chloride / 2-propanol (11.5 ml). The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (12.9 g, 100%).

ES I / Ma ss: 462 [M + H +]

_{NMR (CDC1 3) 5: 2.00-} 2.21 (2H, m) 5 2.21-2.34 (2H 3 m), 2.86-2.98 (lH, m), 3.03-3.15 (1H, m), 3.19 (6H, s), 3.15-3.30 (1H, m), 3.47-3.70 (3H ₅ m), 3.90- 4.00 (1H, m), 4.24 (1H ₅ dd, J = 14.0, 7.2Hz), 4.65 (1H ₃ dd, J = 14.0 , 6.0Hz), 5.12 (1H, d, J = 12.7Hz), 5.40 (1H, d, 12.7Hz), 6.87 (1H, dd, J = 7.8, 1.9Hz), 6.89-7.00 (2H , m), 7.03-7.09 (2H, m), 7.14 (1H ₃ d, J = 1.9Hz) ₅ 7.18 (1H, d, J = 8 .0Hz), 7.45 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.6Hz)

 (Reference Example 26)

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-Pyrrolidinopheneethyl) pyrrolidine-1-ylmethyl] dipenza [b, e] [1,4] oxazepine dihydrochloride

 (4-pyrrolidinophenyl) acetic acid (= compound of Reference Example 9)

 Palladium acetate (22.3 mg, 0.10 mmol), (2-biphenyl) -di-tert-butylphosphine (59.8 mg, 0.2 Ommo 1), sodium-tert-butoxide (2.40 g, Toluene (1 Oml) was added to 25. Ommo 1), and (4-promophenyl) acetic acid (2.15 g, 10. Ommo 1) and pyrrolidine (1. 10 ml, 13.2 mmo 1) were added. . This mixture was heated at 70 ° C. for 46 hours, and then water (20 ml) was added. After the pH of the aqueous layer was adjusted to 2 or less, it was washed with toluene, and the pH of the aqueous layer was adjusted to 4 to 5. After stirring for a while in an ice bath, the mixture was filtered to obtain the title compound as a pale yellow solid (1.1 lg, 54%).

 ESI / Mass: 206 [M + H +]

NMR (DMSO- d6) 5: 1.90-1.95 (4H 5 m), 3.15-3.20 (4H 5 m), 3.38 (2H 3 s), 6. 47 (2H 5 d, J = 8.4Hz), 7.03 (2H , d, J = 8.4Hz)

 (R) — N— [(4-Pyrrolidinophenyl) acetyl] 1-D-proline methyl ester

Methylene chloride (2 Oml) was added to (4-pyrrolidinophenyl) acetic acid (2.05 g, 10. Ommol) and D-phosphorus methyl ester hydrochloride (1.66 g, 10. Ommo 1), and triethylamine was added. (1.55 ml, 11.1 mmol) and N-dimethylaminopropyl-N, monoethyl carbodiimide hydrochloride (2.11 g 11. Ommo 1) were added. The mixture was stirred at room temperature for 4 hours. The reaction solution was successively washed with water (10 ml), water (5 ml), a 5% aqueous solution of citric acid (5 ml), and a 5% aqueous solution of sodium bicarbonate (5 ml). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a pale red solid (3.06 g, 96%

) 0

_{NMR (CDC1 3) δ: 1.85-2.15} (8H, m), 3.23-3.28 (4H, m), 3.31-3.68 (4H, m), 3.68-3.75 (3H, m), 4.40- 4.53 (1H, m ), 6.45-6.54 (2H, m), 7.05- 7.14 (2H, m)

(R) -N- [(4-pyrrolidinophenyl) acetyl] D-proline

 (R) — N— [(4-Pyrrolidinophenyl) acetyl] 1-D-proline methyl ester (30.1: 94.2 mmol) was dissolved in tetrahydrofuran (150 ml), and water (134 ml) and 6 M sodium hydroxide aqueous solution (16.5 ml, 99.2 mmo 1) was added. After stirring at room temperature for 4 hours, 6M hydrochloric acid (

16.6 ml, 99.7 mmo 1) were added. After tetrahydrofuran was distilled off from the mixture under reduced pressure, the mixture was allowed to stand in a refrigerator. This was filtered and dried under reduced pressure to obtain the title compound as a pale purple solid (23.4 g, 82%

) o

 ESI / Mass: 303 [M + H +]

_{NMR (CDC1 3) (5-:} 1.85-2.05 (7H 5 m), 2.45-2.55 (1H, m), 3.23-3.29 (4H, m), 3.45-3.70 (4H, m), 4.60-4.64 (lH , m), 6.48-6.55 (2H, m), 7.07-7.11 (2H ₅ m) (R)-1-(4-pyrrolidinophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-1 Promote 5- (fluorobenzyloxy) phenyl] amide (R) — N— ((4-pyrrolidinophenyl) acetyl) -D-proline (2.90: 9.59 mmo1) and toluene ( 37.8 ml) and N-methylmorpholine (1.10 g, 10.8 mmol 1) were added, and ethyl chloroformate (1.14 g, 10.5 mmol) was added in an ice bath, followed by stirring for 2 hours. 2- (2-butane-5-fluorobenzyloxy) aniline hydrochloride (3.19 g, 9.59 m mo 1) and N-methylmorpholine (1.16 g, 11.5 mmol) were added, and the temperature was raised to room temperature over 16 hours. Water (30 ml), cunic acid (1.61 g) and toluene (10 ml) were added and partitioned. The organic layer was separated with water (10 ml), water (10 ml), 6.7% aqueous sodium bicarbonate (10 ml), 6. Washed sequentially with 7% aqueous sodium bicarbonate (10 ml), water (10 ml), and water (10 ml). It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (5.13 g

, 93%).

 ES I / Mas s: 580 [M + H +]

_{NMR (CDC1 3): 1.77-2.20 (} 7H, m), 2.48-2.57 (1H 5 m), 3.14-3.25 (4H, m), 3.42- 3.67 (4H, m), 4.80- 4.88 (1H, m) , 5.11 (2H, s), 6.29-6.46 (2H, m), 6.80-7.10 (6H ₃ m), 7.43-7.61 (2H ₃ m), 8.26- 8.39 (1H, m), 9.57 (1H ₃ s)

 (R) — {[2- (2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-l-carbonyl) pyrrolidine] 1-l-l-inole} -2- (4l-pyrroli Dinophenyl) ethanone

 ()-1-[(4-pyrrolidinophenyl) acetyl] pyrrolidine-1-carbonic acid [2- (2-promo 5-fluorobenzyloxy) phenyl] amide

(5.0 g, 8.6 lmmo 1) to potassium carbonate (3.58 g, 25.9 mmo 1), copper (I) bromide (63.5 mg, 0.443 mmo 1), 4-picoline (25 ml) Was added. After heating this at 145 ° C for 21 hours, filtration was performed to obtain a filtrate, and the solvent was distilled off under reduced pressure. This mixture was partitioned between toluene and a 9.5% aqueous citric acid solution, and the organic layer was washed twice with a 9.5% aqueous citric acid solution. It was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride / methanol (97: 3). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to obtain the title compound as a purple solid (4.16 g, 97%). ESI / Ma ss: 500 [M + H +]

_{NMR (CDC1 3) 0 ":} 1.60-2.40 (8H, m), 3.14-3.35 (4H 3 m), 3.39-3.75 (4H 3 m), 4.29-5.68 (3H, m) 5 6.32-6.60 (3H 3 m), 6.77-8.11 (8H, m)

 (R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinopheneethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine

 (R) — {[2— (2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidine] — 1-yl} 1 2 -— (4 Dinophenyl) ethanone (3.79 g, 7.59 mmol 1) was dissolved in tetrahydrofuran (48 ml), sodium borohydride (1.52 g, 40.2 mmol 1) was added, and the mixture was placed on an ice bath. Then, boron trifluoride tetrahydro tifuran complex (7.38 g, 49.5 mmol) was added. After the reaction solution was heated to 37 ° C for 66 hours, a 1.5 M aqueous sodium hydroxide solution (48 ml, 75 mmol) was added in an ice bath. After the reaction solution was heated to 60 ° C. for 13 hours, toluene (30 ml) was added. The organic layer was obtained, and the solvent was distilled off under reduced pressure to 21.0 g, and toluene (12 ml) was added. This was washed twice with water (10 ml), and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride and methanol (97: 3). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to obtain the title compound as a purple solid (2.95 g, 82%).

 ES I / Mas s: 472 [M + H +]

_{NMR (CDC1 3) (5:} 1.59-1.90 (4H 5 m), 1.90-2.10 (4H, m), 2.18- 2.30 (1H, m), 2.42-2.58 (1H, m), 2.62-2.83 (3H, m), 2.92-3.08 (lH, m), 3.12-3.38 (6H, m), 4.08 (1H, dd, J = 12.8, 3.0Hz), 5.16 (1H, d, J = 11.8Hz) ₃ 5.30 (1H _{5 d, J = 11.8Hz),} 6.54 (2H 5 d, J = 8.5Hz), 6.72-6.86 (3H 3 m), 6.93-7.12 (6H 5 m) (R) —2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinopheneethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-Pyrrolidinoff enetyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine (12.4 s 25.5 mmol 1) was dissolved in 2-propanol (250 ml), 4 M hydrogen chloride / 2-propanol (17.0 ml) was added, and the mixture was stirred at room temperature for 0.5 hours. The solvent was distilled off under reduced pressure. 2-Propanol (about 50 mL) was added to the obtained residue, and the solvent was distilled off under reduced pressure four times. Thus, the title compound was obtained as a pale red solid (14.89 g, 100% ) 0 ESI / Mas s: 472 [M + H +]

NMR (DMS0-d6) d: 1.76-2.19 (8H, m), 2.89-3.25 (4H 5 m), 3.33-3.54 (5H, m), 3.54-3.67 (2H, m) 3 4.10 (1H, dd, J = 13.6, 7.5Hz), 4.39 (1H, dd, J = 13.6, 6.5Hz), 5.18 (1H, d, J = 12.0Hz), 5.44 (1H, d, J2 12.1Hz), 6.72-6.78 _{(1H, m) 5 6 .83-6.90} (2H, m) 3 6.96-7.27 (6H, m), 7.31-7.38 (2H 5 m) ·

(Reference Example 27)

 (R) — 5, 11-dihydro- 1 5-CI- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1, 4] oxazepine (= compound of Reference Example 22) )

 (R) — N— [1— (4-pyrrolidinophenethyl) pyrrolidine-13-yl] 1-2- (2-bromobenzyloxy) aniline

Under an argon stream, 2- (2-bromobenzyloxy) aniline (1.15g, 4.13mmo1) and (S) -3-methanesulfonyloxy-1- (4-pyrrolidinofphenethyl) pyrrolidine (0.30g) : 0.98mmo 1) was added and dissolved in acetonitrile (50ml). Here potassium carbonate (1.62g, 11 .7mmo 1) was added and the mixture was refluxed for 85 hours. Thereafter, acetonitrile (15 ml) was added, and the mixture was further refluxed for 48 hours. The reaction solution was filtered through celite to obtain a filtrate, and the solvent was distilled off under reduced pressure to obtain the title compound as a brown oily mixture (1.40 g).

 ESI / Mas s: 520 [M + H +]

 (R) — 5,11-dihydro-5- [1- (4-pyrrolidinofphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine

 Under an argon stream, (R) -N- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] -12- (2-bromobenzyloxy) aniline (1.40 g, mixture) As) potassium carbonate (1.7 lg, 12. mmo 1), copper bromide (Ί)

(53 mg, 0.37 mmol) and toluene (3 Oml) were added. The reaction solution was refluxed for 53 hours under heating, and copper (I) bromide (60 mg, 0.42 mmol) was obtained. The reaction solution was refluxed for further 50 hours while heating, and further toluene (10 ml), potassium carbonate (1.04 g, 7.52 mmol) and copper (I) bromide (42 mg, 0.29 mmol) were added. The reaction solution was further refluxed for 48 hours while heating, filtered through Celite, and water was added to the filtrate. The organic layer was obtained, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 187 mg of the obtained residue (1.12 g) was subjected to high performance liquid chromatography, and eluted with acetonitrile and water (gradient from 20:80 to 70:30). The appropriate fractions were collected and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to thin-layer silica gel chromatography, and developed using hexane and ethyl acetate (1: 5). The silica gel at an appropriate site was collected and eluted with a mixed solvent of methylene chloride and methanol (3: 1). The eluate was collected and the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (25.5 mg, 39% in two steps). ES I / Mas s: 440 [M + H +]

_{NMR (CDC1 3) 5: 1.72-1.84} (1H, m) 3 1.92-2.05 (4H, m), 2.24-2.49 (2H, m), 2.49-2.77 (5H 5 m), 2.82- 2.94 (1H, m ), 3.18-3.36 (5H ₃ m), 4.68-4.79 (1H, m), 5.19-5.62 (2H ₃ m), 6.48 (2H ₃ d, J = 8.4 Hz) ₅ 6.70-6.85 (3H ₃ m), 6.95 (1H ₅ dd, J = 7.8, 1.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.03-7.14 (2H, m), 7.25-7.35 (2H, m) Same method as in Reference Example 1. Thus, instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, the compound [V] shown in Table 1 was converted to (: R) -1-chloro-11- (4-methoxy). By using the compound [VI] shown in Table 1 instead of phenethyl) biperidine, the compound [II] shown in Table 1 can be prepared.

(Reference Example 2 9)

In the same manner as in Reference Example 16, the compound [V] shown in Table 2 was used instead of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, instead of (S) Preparation of the compound [III] shown in Table 2 by substituting the compound [XI] shown in Table 2 for 1- (4-dimethylaminophenethyl) -l-methanesulfonyloxypyrrolidine Can be done.

(Reference Example 30)

In the same manner as in Reference Example 24, the compound [V] shown in Table 3 was used instead of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, to give 3-pyrrolidinophene The compound [IV] shown in Table 3 can be prepared by using the compound [X] shown in Table 3 instead of til mesylate.

Table 3

Raw material [V] Raw material] Product [IV]

. ^Μβ I

!

^M

> -o ^{/ _oMs}

F, <Formulation example>

 The formulation examples are described below.

 (Formulation Example 1)

 The following mixture was mixed in a conventional manner, and the mixture was tableted to give tablets containing 50 mg of the active drug per tablet.

 Compound of Reference Example 8 5 Omg

 Lactose 20 Omg

 Microcrystalline cellulose 4 Omg

 Magnesium stearate 5mg

 (Formulation Example 2)

 The following mixture was granulated according to a conventional method to obtain granules.

 Compound of Reference Example 8 ΰ Omg

 Lactose 9 Omg

 Corn starch 6 Omg

 Talc 3 Omg

 Magnesium stearate 1 Omg

Example

 Effects on serotonin release from isolated mouse intestinal tract in vitro.

SLC: excised ileum sites ICR male mice, a mixed gas _{(95% 0 2 -5% C0} 2) 37 ° C of modified Krebs nutrient solution was bubbled (NaCl 120 mM; C15.0 mM; CaCl 2 2.5 mM; MgC 1 ₂ 0.24 mM; appended to the nutrient solution tank filled with _{pH 7.4); Na¾P0 4 0.77 mM} ; NaHC0 3 25.0 mM; glucose 11.0 mM. The nutrient solution tank was perfused with a modified Krebs nutrient solution at a flow rate of 20/1 / min. After equilibration, the perfusion was continued with a serotonin release stimulating solution (5 mM Ca ²⁺ modified Krebs nutrient solution) in which the test compound was dissolved. Serotonin concentration in perfusate Was measured by HPLC-ECD. The test compound was evaluated by setting the amount of serotonin released during the equilibration time of 1 hour to 100%, and releasing it 1 hour after starting the perfusion of the 5 m Ca ^{2 +} modified Krebs nutrient solution in which the test conjugate was dissolved. Figures 1 and 2 show the serotonin content and increase). The voltage-dependent L-type calcium channel antagonist D1 iazem and the compound of Reference Example 8 suppressed the amount of serotonin released from the intestinal tract depending on the concentration. According to the present invention, Alzheimer's disease, psychosis, premature dementia, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or Obesity can be treated.

Claims

The scope of the claims

1. To treat Alzheimer's disease, mental illness, premature dementia, manic depression, migraine, breastfeeding disorders, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or obesity. A pharmaceutical composition comprising a calcium channel antagonist having intestinal selectivity.

 2. The pharmaceutical composition according to claim 1, wherein the calcium channel antagonist having intestinal selectivity is selected from the following group.

 (I) 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the following general formula [I], a stereoisomer thereof, a pharmacologically acceptable salt thereof , Their hydrates or solvates;

[Wherein, 0, J and K each represent a benzene ring or a nitrogen-containing aromatic ring. R ¹ R ⁸ may be the same or different and represent a halogen atom or a hydrogen atom; R ^{9 to} R ¹³ may be the same or different; a hydrogen atom, a halogen atom, a cyano group,

0 0 A xy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group, a cyclic alkylamino group, or R ⁹ and R ^1Q , or R ¹ ; And R ¹¹ together represent a —0 (CH ₂ ) n 0 — group (n is 1, 2 or 3). A is any of CH ₂ , CHOH, CO, or 0, B is CH ₂ , CHOH, or CO, or A_B represents CH = CH, D is CH ₂ , CH ₂ — CH ₂ or CH ₂ Any of CH ₂ —〇11 ₂ or B-D represents CH ₂ . X and Z are joined to each other CH ₂ - CH ₂ or C - CH ₂ represents either one CH _2, Y represents a hydrogen atom at that time. Alternatively, Y and Z are joined to each other CH ₂ - CH ₂ - CH ₂ or _{CH 2 - CH 2 - CH 2} - CH 2 , whichever is represents, X at that time represent a hydrogen atom. When X and Z ヽ and Y and Z are not bonded to each other, X and Y represent a hydrogen atom, and Z represents a lower alkyl group. However, when any of R ^{9 to} R ¹³ is a cyclic amino group represented by the formula [E], any of R ^{1 to} R ⁸ may be a halogen atom or a hydrogen atom, but any of R ^{9 to} R ¹³ When R 1 is not a cyclic amino group represented by the formula [E], one or two of Ri R ⁸ are a halogen atom, and the others represent a hydrogen atom.

[E]

 [In the formula, n and m represent 1 or 2, and W represents a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom which may be substituted with a lower alkyl group. ]

 (II) 5,11-dihydrodibenzo [b, e] [1, 4] thiazepine derivative represented by the following general formula [2], a stereoisomer thereof, a pharmacologically acceptable salt thereof,

Ten Hydrates or solvates thereof

[2]

(Where

 k, m and n are 1, 2 or 3, respectively;

 p is 0, 1 or 2;

X is 0, S or a linking group, but when X is 0 or S, n is 2 or 3; R ¹ is H or —C ₄ alkyl; and

R ² is

Wherein R ³ and R ⁴ are each independently H, Ci—C ₄ alkyl, d—C ₄ alkoxy, —OH, —Ni C —C ₄ alkyl) halo or —CF ₃ . ) (b)

 (Where q is 1, 2 or 3;

X ¹ and X ² are each independently selected from ◦ and —CH ₂ —), or

(c) a pyridinyl, pyridazinyl, pyrimidinyl, birazinyl or phenyl group, wherein the group may be substituted with 2 or less substituents independently selected from —C ₄ alkyl and Ci—C ₄ alkoxy . )

 (II I) 5- (2-pyridinylmethyl) -5,11-dihydrodibenzo [b, e] [1,4] oxazebine derivative represented by the following general formula [3], its stereoisomer, Pharmacologically acceptable salts, hydrates or solvates thereof;

 [3]

[In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group or a lower alkoxy group, or R ¹ and R ² represent-緖 Represents a (CH ₂ ) _n O— group (n is 1, 2 or 3); R ³ represents a hydrogen atom or a hydroxy group; R ⁴ and R ⁵ may be the same or different; Represents an atom or a hydroxy group, or represents together with = 〇. ]

 (IV) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [4], its stereoisomer, pharmacologically acceptable Salts, hydrates or solvates thereof; and

 [Four〗

[In the formula,! ^ To ⁵ may be the same or different, and represent a hydrogen atom, a lower alkoxy group, an amino group, or an alkylamino group, and at least one of them represents an amino or alkylamino group, and R ⁶ and R ⁷ are may be the same or different, 7_K atom or a hydroxy group, or represents a connexion = 0 such together, Upsilon ¹ represents methylene, an I O © atom or hydroxymethine. ]

(V) 5-alkyl-1,5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [5], its stereoisomer, its pharmacologically acceptable Salts, hydrates or solvates thereof.

[Five]

[In the formula, 1 ^ to ¹⁵ may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group. Or R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , or R ⁴ together represent a —0 (CH ₂ ) nO— group (n is 1, 2 or 3); R ⁶ represents hydrogen or a lower alkyl group; Y represents a methylene, an oxygen atom, a zeo atom, or an alkylamino group; A represents any of CH ₂ , CHOH, CO or 0; B represents CH ₂ , CH0H or represents either CO, or A- B is table a CH = CH, D is CH _2, CH ₂ - CH ₂ or CH ₂ - one of CH ₂ -〇_11 _2, or B_ D is CH ₂ Represents ]

 3. A calcium channel antagonist having intestinal selectivity is a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the general formula [I] according to claim 2, 3. The pharmaceutical composition according to claim 2, which is a stereoisomer, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof.

4. A calcium channel antagonist having intestinal selectivity is represented by the following general formula [II]. 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative, a stereoisomer, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof. Item 10. The pharmaceutical composition according to Item 1.

(Expressed in the formula, the aromatic ring G, J, K, Ri R 13 A, B, D are the same as the formula [I] according to claim 2, r is representative of 1 or 2.)

5. A calcium channel antagonist having intestinal selectivity is a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the following general formula [III], and its stereoisomer 2. The pharmaceutical composition according to claim 1, which is a pharmacologically acceptable salt, hydrate or solvate thereof.

(Wherein the aromatic ring G, J, K, 1 ^ ~11 13, Α, Β, D represents the same as the formula of claim 2, wherein [I],: gamma represents 1 or 2.)

 6. A calcium channel antagonist having intestinal selectivity is a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the following general formula [IV], a stereoisomer thereof, 2. The pharmaceutical composition according to claim 1, which is a pharmacologically acceptable salt, hydrate or solvate thereof.

07

(Wherein, aromatic rings G, J, K, R ¹ to R ¹ \ A and B _s D represent the same as those of the formula (I) according to claim 2, and R ¹⁴ has 1 to 3 carbon atoms. Represents a lower alkyl group.)

7. The calcium channel antagonist having intestinal selectivity is a compound represented by the following formula, a stereoisomer thereof, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof. The pharmaceutical composition according to claim 1.

8. Inhibition of serotonin release containing calcium channel antagonist with intestinal selectivity Agents.

 9. The serotonin release inhibitor according to claim 8, wherein the calcium channel antagonist having intestinal selectivity is selected from the following group.

 (I) a 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the following general formula [I], a stereoisomer thereof, a pharmacologically acceptable salt thereof, Hydrates or solvates thereof;

[Wherein, rings G, J, and K each represent a benzene ring or a nitrogen-containing aromatic ring. R ¹ H ⁸ may be the same or different and represent a halogen atom or a hydrogen atom; R ^{9 to} R ¹³ may be the same or different; a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl A lower alkoxy group, an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group, a cyclic alkylamino group, or R ⁹ and R ^{1 ()} , or R ^lfl and R ¹¹ together To 0 — (CH ₂ ) n

Represents a 0-group (n is 1, 2 or 3); A is either CH or CHOH, CO, or 0; B is either CH or CHOH or CO; or A—B is CH = CH

09 Represents, D is CH _2, CH ₂ - CH ₂ or CH ₂ - either CH ₂ -CH _2, or B - D represents CH _2. X and Z are joined to each other CH ₂ - CH ₂ or CH ₂ - CH ₂ - represents either CH _2, Y represents a hydrogen atom at that time. Alternatively, Y and Z are joined to each other CH ₂ - CH ₂ - CH ₂ or _{CH 2 - CH 2 - CH 2} - CH 2 , whichever is represents, X at that time represent a hydrogen atom. When X and Z, and Y and Z are not bonded to each other, X and Y represent a hydrogen atom, and Z represents a lower alkyl group. However, if any of R ⁹ to R ¹³ is a cyclic amino group represented by the formula ^{[E], 1 ~: R} 8 may be either a halogen atom or a hydrogen atom, R ⁹ ~: of R ¹³ When none of them is a cyclic amino group represented by the formula [E], one or two of Ri R ⁸ are a halogen atom, and the others represent a hydrogen atom.

[E]

 [In the formula, n and m represent 1 or 2, and W represents a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom which may be substituted with a lower alkyl group. '

 (II) 5,11-dihydrodibenzo [b, e] represented by the following general formula [2]

[1, 4] thiazepine derivatives, stereoisomers, pharmacologically acceptable salts thereof, hydrates or solvates thereof;

0

[2]

 (Where

 k, m and n are 1, 2 or 3, respectively;

 p is 0, 1 or 2;

X is 0, S or a linking group, but when X is 0 or S, n is 2 or 3, R ¹ is H or Ci—C ₄ alkyl, and

R ² is

(Wherein, R ³ and are each independently H, —C ₄ alkyl, Ci—C ₄ alkoxy, —OH, —NiCi—C ₄ alkyl), halo or —CF ₃ . )

11 (b)

 (Where q is 1, 2 or 3;

X ¹ and X ² are each independently selected from 0 and —CH ₂ —), or

(c) a pyridinyl, pyridazinyl, bilimidinyl, birazinyl or phenyl group, wherein the group may be substituted with 2 or less substituents independently selected from Ci—C ₄ alkyl and 1 C ₄ alkoxy . :)

 (I II) 5- (2-pyridinylmethyl) _5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [3], a stereoisomer thereof, Pharmacologically acceptable salts, hydrates or solvates thereof;

[3]

Wherein R ¹ and R ² may be the same or different and each represent a hydrogen atom, a halogen atom, a cyano group, a hydroxy group or a lower alkoxy group, or R ¹ and Represents a 0 (CH ₂ ) _n O— group (n is 1, 2 or 3); R ³ represents a hydrogen atom or a hydroxy group; R ⁴ and R ⁵ may be the same or different; Represents an atom or a hydroxy group, or, together, represents = 0. ]

 (IV) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [4], its stereoisomer, pharmacologically acceptable Salts, hydrates or solvates thereof; and

 [Four]

Wherein 1 ^ to 11 ⁵ may be the same or different, a hydrogen atom, a lower alkoxy group, and an amino group or alkylamino group, any one or more Amino groups or § alkylamino group, R ⁶ and R ⁷ may be the same or different and each represent a hydrogen atom or a hydroxy group, or together represent = 0, and Y ¹ represents a methylene, dithio atom or hydroxymethine. ]

(V) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [5], its stereoisomer, its pharmacologically acceptable Salts, hydrates or solvates thereof.

[Five]

[In the formula, 1 ^ to ¹⁵ may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group. Or R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , or R ⁴ and R ⁵ together form a — 0 (CH ₂ ) nO— group (n is 1, 2 or 3) R ⁶ represents hydrogen or a lower alkyl group, Y represents methylene, an oxygen atom, a zirconium atom, or an alkylamino group, A represents any of CH ₂ , CHOH, CO or ◦, and B represents CH ₂ represents either CH0H or CO, or A- B is table a CH = CH, D is CH _2, CH ₂ _CH ₂ or CH ₂ - CH ₂ - or a CH _2, or B- D is CH Represents ₂ . ]

 10. The calcium channel antagonist having intestinal selectivity is a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the general formula [I] according to claim 9, 10. The serotonin release inhibitor according to claim 9, which is a stereoisomer, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.

11. A calcium channel antagonist having intestinal selectivity is represented by the following general formula [II]. 5, 11-dihydrodiaryl [b, e] [1, 4] oxazebine derivative, its stereoisomer, its pharmacologically acceptable salt, its hydrate or solvate 9. The serotonin release inhibitor according to claim 8, wherein

(Expressed in the formula, the aromatic ring G, J, K, 1 ^ ~1 13, A, B, D are the same as the formula [I] according to claim 9, r is representative of 1 or 2.)

 12. A calcium channel antagonist having intestinal selectivity is a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the following general formula [III], and its stereoisomer 9. The serotonin release inhibitor according to claim 8, which is a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof.

15

(Wherein the aromatic ring G, J, K, 1 ^ ~11 1 3, Α, Β, D represents the same as the formula [I] according to claim 9, r is representative of 1 or 2.)

13. A calcium channel antagonist having intestinal selectivity is a 5,11-dihydrodiaryl [b, e] [1,4] oxazebin derivative represented by the following general formula [IV], and its steric form. 9. The serotonin release inhibitor according to claim 8, which is an isomer, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof.

R14

[IV]

(Wherein, aromatic rings G, J, K, 1 ^ to 11 ¹³ , Α, Β, and D represent the same as in the formula (I) according to claim 9, and R ¹⁴ has 1 to 3 carbon atoms. Represents a lower alkyl group.)

 14. The calcium channel antagonist having intestinal selectivity is a compound represented by the following formula, a stereoisomer thereof, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof. 9. The serotonin release inhibitor according to claim 8.

7