WO2003101489A1 - Medicinal composition for treatment for digestive tract disease - Google Patents

Abstract

A medicinal composition containing the calcium channel antagonist represented by the following formula or an analogue thereof. The composition is used for treatments for diseases accompanied by an organic change of the digestive tract. (1)

Description

 Description Pharmaceutical compositions for treating gastrointestinal disorders

 The present invention relates to a pharmaceutical composition having calcium channel antagonism and useful for treating a disease accompanied by an organic change in the digestive tract. Background of the Invention

For example, Japanese Patent No. 0404359A1 discloses that 5,11-dihydrodibenzo [b, e] [1,4] thiazepine derivatives have selectivity for the gastrointestinal tract and are useful as calcium channel antagonists. It is disclosed that there is. Also, Quinn et al. (Qunn, P. et al.), Brit. J. Pharmacol., 1994, 112 (Suppl.) ₅ Abst. 573P and Perris et al. (Wallis, RM et al.), Brit. J. Pharmacol., 1994, 112 (Suppl.) And Abst. 5 74P include (S) -5-[[1- (4-methoxyphenyl) ethyl] pyrrolidine-2-ylmethyl] -1,5— It discloses that dihydrodibenzo [b, e] [1,4] 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. Also, International Patent Nos. 9733885 A1 and 9912 925 A1 disclose 5- (2-pyridinylmethyl) -5,11-dihydrodibenzo! As a drug for improving gastrointestinal motility dysfunction. : b, e] [1,4] oxazepine derivatives are disclosed. Further, International Patent No. 004057 OA1 discloses a 5-alkyl-1,5,11-dihydrodibenzo [b, e] [1,4] oxazebine derivative as an agent for improving gastrointestinal motility dysfunction. However, these compounds have activity on the gastrointestinal tract. Sex and selectivity are not yet sufficient, and it has not been used as a drug.

 On the other hand, reports that calcium channel antagonists suppress 5-lipoxygenase in patients with active ulcerative colitis and can be expected to have a therapeutic effect (Alimentary Pharmacology & Therapeutics 6 (2): 163-168, 1992), There is a report that gastric protection and ulcer are improved in a gastric mucosal disorder model of ethanol-hydrochloride using ethanol (Japanese Journal of Pharmacology 78 (4): 435-441, 1998). Disclosure of the invention

 An object of the present invention is to provide an excellent pharmaceutical composition for treating a disease accompanied by a structural change in the digestive tract.

 The present invention provides a pharmaceutical composition for treating a disease associated with a structural change of the digestive tract, which comprises a calcium channel antagonist having intestinal selectivity.

 The present invention also provides a method of screening for a calcium channel binding compound,

 (a) Measure the amount of labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to the colon or ileum membrane specimen To do,

 (b) To a colon or ileum membrane specimen of a 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] labeled in the presence of a test compound Measuring the amount of binding of and

 (c) comparing the result obtained in step (a) with the result obtained in step (b).

'The present invention also provides the use of a calcium antagonist having intestinal selectivity for preparing a pharmaceutical composition for treating a disease associated with a structural alteration of the digestive tract. 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.

 The “calcium channel antagonist having intestinal selectivity” used in the present invention includes

And the following compounds (I) to (V) or pharmaceutically acceptable salts thereof.

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

[Wherein, rings G, J, and K each represent a benzene ring or a nitrogen-containing aromatic ring. 1 ^ to 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 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 ^1Q , or R ^{1 (1} and R ¹¹ are Connected together 0 (CH ₂ ) n

0—represents a group (η is 1, 2 or 3). Α is CH ₂ , CH0H, 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 One of CH ₂ — 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. X and Z, and Y and Z When 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 ^U 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-dihydrodibenzozo represented by the following general formula [2] [b, e]

[1, 4] thiazepine derivatives, stereoisomers thereof, 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, but when X is 0 or S, n is 2 or 3; R ¹ is H or 1 C ₄ alkyl; and

R ² is

(a)

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

(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, pyrimidinyl, vilazinyl or phenyl group, wherein the group may be substituted with 2 or less substituents independently selected from C ^ —C ₄ alkyl and —C ₄ alkoxy; Good. )

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

[3] [Wherein, R ¹ and 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 R ² together represent — 0 (CH ₂ ) _{n represents a} 0-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; a hydrogen atom or a hydroxy group Represents a group, or together represents = 0. ]

 (IV) 5-alkyl-1,5,11-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 ¹⁵ 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 group or an alkylamino group; R ⁶ and R ⁷ may be the same or different and represent a hydrogen atom or a hydroxy group, or together represent = 0, and Y ¹ represents methylene, O represents an 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]

Wherein 1 ^ to 11 ⁵ may be the same or different, a hydrogen atom, a halogen atom, shea Anomoto, hydroxy group, lower alkyl group, a lower alkoxy group, or 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 0, and B represents CH ₂ , CH OH or CO, or A—B represents CH = CH, D is either CH ₂ , CH ₂ —CH ₂ or CH ₂ —CH ₂ —CH ₂ , or B—D but it represents a CH _2. ] In the present invention, the calcium channel antagonist is a 5,11 dihydroaryl [b, e] [1,4] oxazepine derivative represented by the above general formula [I], a stereoisomer thereof, and a pharmacologically acceptable substance. Or a hydrate or solvate thereof. The oxazepine derivative represented by the general formula [I] is disclosed in International Patent Publication No. WO 02/096991 A1, which was published after the priority date of the present application. All contents are included in this specification.

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

As the nitrogen-containing aromatic ring of rings G, J, and K in the general formula [I], a 6-membered aromatic ring is desirable, and examples thereof include a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring. However, in rings G and J, there is no aromatic ring nitrogen atom on the oxazepine ring. When any of ^ ¹ to! ^ Is a halogen atom, the halogen atom does not bind to the aromatic ring nitrogen atom. In ring K, the aromatic ring nitrogen atom is not bonded 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 the rings G and J are benzene, (ii) one of the rings G and J is a pyridine ring, and

0 Is a benzene ring; (iii) ring K is a benzene ring; (i) or (ii) above; (iv) ring K is any one of a pyridine, pyrimidine, virazine and pyridazine ring In the case of the above (i) or (ii), or (V) It is preferable that all of the rings G, J and K are benzene rings. The same applies to general formulas [XV] and [XVI].

Examples of the halogen atom of the 1 ^ to 11 ⁸ in the above general formula, a fluorine atom, a chlorine atom, but can be given a bromine atom and the like, preferably Ru Oh a fluorine atom or a chlorine atom. Among 1 ^ to ¹⁸ , it is more preferable that one of R ² , R ³ , R ⁶ , and R ⁷ is a fluorine atom or a chlorine atom, and the other is a hydrogen atom. Examples of the halogen atoms of R ^{9 to} R ¹³ include a fluorine atom, a chlorine atom and the like, a bromine atom and the like, examples of the lower alkyl group include a lower alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group and 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. Examples of the lower alkylamino group include a monomethylamino group, a monoethylamino group, and a monopropylamino group. A lower alkylamino group having 1 to 5 carbon atoms is exemplified. Amino groups and lower acetyls of these lower alkylamino groups include formylamino, acetylamino, propionylamino, formylmethylamino, formylethylamino, formylpropylamino, acetylmethylamino, and α-amino. Fatty acid acyl compounds having 1 to 3 carbon atoms, such as a cetylethylamino group, an acetylpropylamino group, a propionylmethylamino group, a propionylethylamino group, a propionylpropylamino group, and the like. 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 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. Of these, a fluorine atom and a chlorine atom are preferred as the halogen atom. Preferably, the lower alkyl group is a lower alkyl group having 1 to 3 carbon atoms. 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. The amino group or the lower acyl group of these lower alkylamino groups is preferably a formyl group or an acetyl group. 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,

 (iii) X and Y are hydrogen atoms, Z is a lower alkyl group,

(iv) either one or both of R ¹⁰ s R ¹¹ is a methoxy group, or R ^lfl and R ¹¹ are 緖 to represent a methylenedioxy group, and R ^9, R ¹² and R ¹³ are Hydrogen atom,

(v) R ¹¹ is a methoxy group, R ⁹ , R ^1Q and R ¹² , R ¹³ are hydrogen atoms,

(vi) one of R ¹⁰ R ¹¹ is an amino group or a lower alkylamino group and a lower acyl group, a lower dialkylamino group, or a cyclic alkylamino group thereof, and the other is a hydrogen atom,

(Each of vi Ri R ⁸ is a hydrogen atom,

(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 \ R ³ , R ⁶ and R ⁷ is a fluorine atom or a chlorine atom, and 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,

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

 (xiii) 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 cyclic amino group containing one nitrogen atom such as an azetidino group, a pyrrolidino group, a pyridino group, a biperazino group, and a morpholino group. Although a cyclic amino group containing a hetero atom can be mentioned, a pyrrolidino group and a morpholino group are preferred. : R ⁹ ~! Of ^13, R ^lfl, any one of R ¹¹ is a cyclic amino group, the other is a more preferable this is a hydrogen atom.

A-B-D are 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- One of CH ₂ , 0—CH ₂ , CH ₂ —CO—CH ₂ , or CH ₂ —CH ₂ —CH ₂ is preferred.

In the present invention, among these, preferred compounds are, for example, compounds represented by the following formula [II]. However, where the aromatic璟^{0, J, K, ~ 3} , AB, D represents the same as the formula [I], r is representative of 1 or 2.

Three

Examples of the compound represented by [II] include 2-fluoro-5,11-dihydro 5- [1- (4-methoxyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazebine, 2-fluoro-5,11-dihydro-1-5- [1- (3-methoxyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2- Fluoro-5,11-dihydro-5-

[1- (3,4-Methylenedioxyphenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro 5 -— [1--( 4-Aminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] CI, 4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1- (3-aminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [ b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1, 4] Oxazepine, 2-fluoro-5,11-dihydro-5- [1 1- (3-Methylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenyl Enethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11 dihydro-1-5- [1-1 (3-dimethylaminophenethyl) pyrrolidine-1-2-ylmethyl ] Dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-1,5,11-dihydro-1-5- [1- (4-pyrrolidinofphenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] CI, 4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1- (3-pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dipento [b, e] [1,4] oxazepine, 2 —Fluoro-5, 1 1—dihydro-5— [1-(4 Morpholinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidine-1 2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-fluorophenethyl) pyrrolidine- 1 2-fluoromethyl] dibenzo [b, e] [ 1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-fluorophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,1 1-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5 — [1— (3-a cetylaminophene L) Pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [11- (4-methoxyphenethyl) pyrrolidine-l-2-ylmethyl] dipenzo [ b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (3-methoxyphenyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [ 1, 4] Oki Sazepine, 3-chloro mouth _5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,] oxazepine, 3-chloro-5 11-dihydro-5- [1- (4-aminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- ( 3-aminophenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidine-1 2 —Ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3 —chloro-1,5,11-dihydro-5- [1- (3- (methylaminophenethyl) pi-lysine-1-2-ylmethyl] dibenzo [B, e] [1, 4] oxazepine, 3-chloro-5, 11-1 Dihydro-1- [1- (4-dimethylaminophenethyl) pi-lysine-1-2-methyl] dibenzo [b, e] [1,4] oxazebine, 3-chloro-5,11-dihydro-5- [1-1- (3-dimethylaminophenethyl) p-lysine-l- 2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine, 3-c-chloro-5, 11-dihydro-5- [1--(4- Pyrrolidinophenetyl) Pyrrolidin-1-ylmethyl] dipenza [b, e] [1, 4] oxazebine, 3-chloro 1-, 11-dihydro-5- [1- (3-pyrrolidinophenethyl) Pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-1-5- [1- (4-morpholinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [ b, e] [1, 4] oxazepine, 3—chloro-1,5-dihydro-5— [1— (3-morpholinophenetyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1-(4-fluorophenethyl) pyrrolidine 1,2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-fluorophenethyl) pyrrolidine-1-ylmethyl] di Benzo [b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo! : b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5, 11-dihydro-5- [1- (4-pyrrolidinofphenethyl) pyrrolidine-12-ylmethyl] dipento [b, e] [1,4] oxazepine, 5, 11- Dihydro-5- [1— (3-pyrrolidinopheneethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5— [1-(4-piperidinophene Tyl) pyrrolidin-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11 dihydro-5- [1- (3-piperidinophenethyl) pyrrolidine-12-ylmethyl] dibenzo [b , E] [1,4] oxazepine, 5,11-dihydro-5- [1- (4-morpholinofe Tyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (3- (morpholinophenethyl)) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine and halogen-substituted regioisomers thereof, pharmacologically acceptable salts or hydrates and solvates thereof.

 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, 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 pyridine- or 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):

In the formula, the aromatic ring G, J, K, 1 ^ ~1 13, Α, Β, D represents the same as the formula [I], r is representative of 1 or 2. Examples of the compound represented by the formula [III] include 2-fluoro-1,5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidine_3-yl] dibenzo [b, e] [ 1,4] oxazepine, 2-fluor-5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidine—3-yl] dibenzo [b, e] [1,4] oxazepine, 2 —Fluoro-5,11-dihydro-5— [1- (3,4-methylenedioxyphenethyl) pyrrolidin-1-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 , 1 1 dihydro-5- [1- (4-aminophenethyl) pyrrolidine-3-yl] dipenza [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1— (3-aminophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1, 4] oxazepine, 2-fluoro -5,11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, Θ] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5 — [1- ( 3-Methylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1- (4-dimethylaminophenethyl) ) Pyrrolidine-1— ^ f1] dibenzo [b, e] [1, 4] oxazebine, 2-fluoro-5,11-dihydro-5- [1- (3- (dimethylaminoaminophenethyl) pyrrolidine-1 3-] Dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-1,5,11-dihydro-5- [1- (4-pyrrolidinophenyl) pyrrolidine-3-yl] dibenzo [ b, e] [1, 4] oxazepine, 2-fluoro-5, 11-dihydro- 1-5- (1- (3-pyrrolidinophenethyl) pyrrolidine-13-yl] dipenza [b, e] [1 , 4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-morpholinophenetyl) pi Lysine-3-yl] dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-1,5-dihydro-5- [11- (3-morpholinophenethyl) pyrrolidin-1 3- Yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11 dihydro-1-5- [1- (4-fluorophenethyl) pyrrolidine-3-yl:] dibenzo [b, e] [ 1,4] oxazepine, 2-fluoro-5,11-dihydro 5- [1- (3-fluorophenethyl) virolidine-l-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 1 1-Dihydro-5- [1- (4-Acetylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro_5- [1— (3-Acetylaminophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1, 4] Sazepine, 3-chloro-5,11-dihydro-5- [1- (4-Methoxyphenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro 1,5-dihydro-5- [1- (3-Methoxyphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro 5— [1— (3,4-methylenedioxyfue Netyl) pyrrolidine-1-3-yl] dipento [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-aminophenethyl) pyrrolidin-1-3-yl] dibenzo [B, e] CI,) oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-aminophenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazepine, 3 —Chloro-1,5—dihydric Chloro 5— [1-(4-Methylaminophenethyl) pyrrolidine-1 3-yl] dibenzo [b, e] CI, 4] oxazepine, 5, 11—dihydro-5—

[1- (3-Methylaminophenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (4-dimethyl Aminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (3-dimethylaminophenyl) Tyl) pyrrolidine-1-yl] dibenzo [b ₃ e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4- (pyrrolidinophenetyl) pyrrolidine-1-3-yl] dibenzo [ b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- [11- (3-pyrrolidinophenyl) pyrrolidine-13-yl] dibenzo [b, e] [1 , 4] oxazepine, 3-1,5-dihydro-5-[1- (4-morpholinophenethyl) pyrrolidine-1 3-yl] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidine-1-3-yl] dibenzo [b , e] CI, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (4-fluorophenethyl) pyrrolidine-1-yl] dibenzo [b, e] [1, 4] Oxazepine, 3-chloro-5,11-dihydro-5- [11- (3-fluorophenethyl) pyrrolidine-l-yl] dibenzo [b, e]

[1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1, 4] oxazepine, 3-chloro-1,5-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 5 , 11 Dihydro-5- [1- (4-pyrrolidinofphenethyl) pi-lysine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-1 dihydro-5- [1— (3-Pyrrolidinophenetyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (4-piperidinophenethyl) pyrrolidine 1,3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-1-5- (11- (3-piperidinophenethyl) pyrrolidine-13-yl] dibenzo [b , e] [1, 4] oxazepine, 5,

11-dihydro-5- [1- (4-morpholinophenetyl) pyrrolidine-1-3-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 piperidine ring bonded to dihydrodibenzoxoxazepine 璟 is R-form.

Other preferred compounds are, for example, compounds represented by the following formula [IV]. In the formula, the aromatic ring G, J, K, 1 ^ ~1 13, A, B, D represent 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, for example, 2-fluoro-5,11-dihydro-1-5- {2- [N- (4-methoxyphenethyl) -1-N-methyl] aminoethyl} dibenzo [ b, e] [1, 4] oxazepine, 2-fluoro-1,5,11-dihydro-5- {2- [N- (3-methoxyphenethyl) -1-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) -N-methyl] aminoethyl} dibenzo [b, e] [1 , 4] oxazepine, 2-fluoro-1,5-dihydro-5- {2- [N- (3-aminophenethyl) -1-N-methyl] aminoethyl} Dibenzo [b, e] [1, 4] oxazepine, 2-fluoro-1,5-dihydro-5- {2- [N- (4-methylaminophenethyl) -N-methyl] aminoethyl} dibenzo [ b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- (N- (3-methylaminophenetene) 1) 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-1,5,11-dihydro-5— {2— [N— (3-dimethylaminophenyl) -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-1- 5- {2- [N- (3-pyrrolidinophenetyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2 -— [N— (4-morpho Nopenetyl) 1 N-methyl] aminoethyl} dibenzo [b, e] CI, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-morpholinophenethyl) -N-methyl ] Aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-fluorophenethyl) -1-N-methyl] aminoethyl} di Benzo [b, e] [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-fluorophenethyl) -1-N-methyl] aminoethyl} dibenzo [b , e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-acetylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N— (3-acetylaminoaminophen Tyl) — N—methyl] aminoethyl} dibenzo [b, e] [1, 4] oxazebine, 3-chloro-1,5-dihydro-5- {2- [N- (4-methoxyphenethyl) 1) N-methyl] aminoethyl} dibenzo [b, e] CI, 4] oxazepine, 3-chloro-5, 1 1 dihydro-5- {2— [N— (3-methoxyphenethyl) 1 N —Methyl] Minoethyl} dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro- 1-5- {2- [N- (3,4-methylenedioxyphenethyl) 1N-methyl] Aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,1 1-dihydro-5- {2- [N- (4-aminophenethyl) -1-N-methyl] aminoethyl} dibenzo [ b, e] (1, 4) oxazebine, 3-chloro-1,5-dihydro-5- {2- (N- (3-aminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e ] [1,4] oxazepine, 3-clo mouth —5,11-dihydro-1-5- {2- [N- (4-methylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e [1,4] oxazebine, 3-chloro-5,11-dihydro-5- {2- [N- (3-methylaminophenethyl) -N-methyl] aminoethyl} Dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-dimethylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b , e] [1,4] oxazebin, 3-chloro-5,11-dihydro-5- {2_ [N- (3-dimethylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1, .4] oxazepine, 3-chloro-1,5-dihydro-5- {2- [N- (4-pyrrolidinophenetyl) -1-N-methyl] aminoethyl} dibenzo [b, e [1 , 4] oxazebine, 3-chloro-5,11-dihydro-5- {2- (N- (3-pyrrolidinophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine , 3-Chemical 1,5 1-Dihydro-5- {2- (N- (4-morpholinophenetyl) -N-methyl] aminoethyl} Dibenzo [b, e] [1, 4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-morpholinophenethyl) -N-methyl] aminoethyl} dibenzo [b , e] [1,4] oxazepine, 3-chloro-1,5-dihydro_5 -— {2- [N- (4-fluorophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1 , 4] oxazepine, 3-chloro-1,5-dihydro-5- {2- [N- (3-fluorophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3 1,5-dihydro-5- {2- (N- (4-acetylaminophenethyl) -1-N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3 —Chloro-1,5—dihydro-5— {2— [N— (3-acetylaminophenethyl) -1-N—methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5 , 11 dihydro-5- {2-[N-methyl-1-N- (4-pyrrolidinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11 dihydro-5- {2— [Ν-methyl- ー — (3-pyrrolidinophenethyl)] aminoethyl} dipenza [b, e] [1, 4] oxazepine, 5 , 11-Dihydro-5- {2- [N-methyl-N- (4-piberidinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [N-methyl-N- (3-piperidinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [N-methyl- N— (4-morpholinophenetyl)] aminocetyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro—5— {2- [N-methyl-N— (3-morph Orinophenethyl)] aminoethyl} dibenzo [b, e] [1, 4] oxazepine and their halogen-substituted isomers, pharmacologically acceptable salts or hydrates, and solvates thereof. Can be In the present invention, (i) is any 1 Exemplary ethynylphenylbiadamantane derivatives cyclic amino group represented by [E] of R ⁹ to R ^13, the other is a hydrogen atom, none of the 1 ^ to 11 ⁸ are hydrogen atoms A derivative of a formula [I], (ii) one of R ⁹ to R ¹³ is a cyclic amino group represented by the formula [E], the other is a hydrogen atom, and R ^{1 to} R ⁸ are A derivative of the formula [I] wherein one or two are a fluorine atom or a chlorine atom and the other is a hydrogen atom; (iii) R ⁹ to R ¹³ are all cyclic represented by the formula [E] Represents a group other than an amino group, wherein one or two of R ¹ to ⁸ are a fluorine atom or Preference is given to derivatives of the formula [I] which are chlorine atoms and the others are hydrogen atoms.

In the above-described general formula [XV] and [XVI],) 1 ^ to 11 ⁸ may be the different from one in the same, represents a fluorine atom, a chlorine atom or a hydrogen atom, L ₂ is CH ₂ or CH ₂ - CH represents _2, Y and Z are joined to each other CH ₂ - CH ₂ - CH ₂ or (11 ₂ - (11 ₂ - (11 ₂ - (11 or represents a _2, and / or (ii) R ⁹ ~ R ¹³ may be the same or different, and preferably represents 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-chloro-1,5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidine] -1-yl} —2— (4-Dimethylaminophenyl) ethanone, (R) -1-[(4-dimethylaminophenyl) acetyl] pyrrolidine-1-carboxylic acid [2- (2-bromo-4-cyclobenzyloxy) phenyl: n-nil] Amide, (R) ― {(2- (2-fluoro-1,5,11-dihydrodibenzo [b, e] [1,4] oxazebine-5-force rubonyl) pyrrolidine] -1-yl} -2 -(4-bilirolidinophenyl) benzoyl, (R)-1-[(4-pyrrolidinophenyl) acetyl] pyrrolidine- 1-force rubonic acid [2_ (2-promo-5-fur Orobenzyloxy) 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 salt, lactate, fumarate, maleate, malate, tartrate, citrate, oxalate, aspartate, methanesulfonate and the like 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. 9733885 A1. 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 the aromatic璟, J, K, I ^ R 1 3 A, B, D are the same as the formula [I], r is 1 or 2, W is a chlorine atom, a bromine atom, an iodine atom Represents a halogen 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 dimethyl sulfoxide, N, N-dimethylformamide, ethers such as tetrahydrofuran, dimethyl ether, dioxane, 1,2-dimethoxyethane, etc., acetonitrile, toluene, xylene, and 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, potassium t-butoxide and the like. The reaction is carried out usually at a temperature 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 amounts of compound (VI) and base used are And 0.5 to 5 molar equivalents, preferably 0.8 to 2 molar equivalents, based on the amount of compound [V] used.

 The compound [V] used as the starting material for the reaction can be produced by a known method [J. Med. Chem., 7, 609 (1964)].

 Further, according to the method disclosed in European Patent No. 0 440 359 A1, the halide represented by the above general formula [VI] can be produced by using proline and homoproline as raw materials. By subjecting the alcohol obtained by the reduction to alkylalkylation and then halogenating the hydroxyl group using methanesulfonyl chloride, tosyl chloride or the like, the compound can be produced with ring expansion. Note that the entire contents of this patent document are included in this specification.

The compound [II] that 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>

(Wherein, aromatic rings G, J, K, ~ ³ , A, B, and D are the same as above, represents 1 or 2, and V and V 'are chlorine, bromine, iodine, and tosyloxy. And 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 2-piperidylmethyl tosylate represented by the above general formula [VI I], and the like. The compound is prepared and then deprotected to obtain a compound of the general formula (IX), which is reacted with a compound of the general formula (X) in the presence of a base to obtain a compound (II) which can be used in the present invention. ] Can be produced. As the solvent and the base for the reaction 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>

[Wherein, aromatic rings K, R ⁹ -R ¹³ , A, B, D ヽ V and: r represent the same as those in Reaction Formula 2. ]

The compound [III] which can be used in the present invention can be produced by reacting the compound [V] with the compound represented by the above general formula [XI] in a solvent in the presence of a base. 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 preferably used. Examples of the base include hydrogenated sodium, hydrogenated hydrogen, lithium disopropylamide, n-butyllithium, sodium methoxide, potassium t-butoxide and the like. The reaction is carried out usually at a temperature 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 compound [XI] and the base used is based on the amount of 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] is obtained by N-alkylating 3-hydroxypyrrolidine and 3-hydroxypiperidine, and then adding oxysulfonyl chloride, thionyl chloride, tosyl chloride, methanesulfonyl chloride. It can be obtained by acting on

 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>

[Where the fragrance is 0, J, K,! ^{^ 1 ~: ^ 1 3,} A, B, D and V are as defined above 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, geethylether, dioxane, 1,2-dimethoxyethane, etc., acetonitrile, toluene, Xylene, benzene, etc. can be suitably used. Examples of the base include sodium carbonate, carbonated carbonate, 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 base to be used is 1 mole or more, preferably 1 to 5 moles, per 1 mole of the compound [XII], and the ratio of the amounts of the compounds [XII] and [XIII] is 0.5 to 2 moles, preferably. Or 0.7 to 1.5 times.

 Alternatively, compound (V) is converted to a compound represented by the above general formula (XIV), and then condensed with compound (X) in the presence of a base to produce 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 1 mole or more, preferably 1 to 5 moles, per 1 mole of the compound [XIV], and the ratio of the conjugates [XIV] and [X] is 0.5 to 2 moles. Preferably, it is 0.7 to 1.5 times.

The compound [XII] is obtained by alkylating the compound [V] with a -haloacetic 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. V] can be easily produced by a combination of known methods such as alkylation of the compound of formula (I) and conversion of the hydroxyl group to a leaving group after deprotection. Compound (XIII) is disclosed in International Patent Application No. As described above, alkylation reaction of primary amine with corresponding halide, reductive alkylation reaction of primary amine with corresponding aldehyde, corresponding reduction of amine after acylation with corresponding carboxylic acid, etc. It can be easily manufactured by the known method described above.

 Compound (XIV) is, as disclosed in International Patent Application No. 2004/570 A1, after alkylating the compound (V) with a haloacetic acid ester, amidating and reducing, etc. It can be easily manufactured by various known methods.

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 [XV 1] The compound represented by is converted into a compound represented by the formula [XV] by intramolecular arylation, and then reduced to obtain the corresponding intermediate.

Reaction formula 5>

Wherein the aromatic ring G, J, K, 1 ^ ~1 14, L have L ₂ is the same as the formula [XV], r is 1 or 2, Y and Z are joined to each other CH ₂ — CH ₂ — CH ₂ or CH ₂ — CH ₂ —CH ₂ —CH ₂ , or when Y and Z are not bonded to each other, Y represents a hydrogen atom, and Z represents a lower alkyl group. ]

Here, as the reaction solvent in the present reduction reaction, for example, ethers such as diethyl ether, siloxane, tetrahydrofuran, 1,2-dimethoxyethane and the like can be mentioned. 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-diisopropylethylamine complex, borane dimethylamine complex, borane 4- (dimethylamino) pyridine complex, borane diphenylphosphine complex, borane 4-ethylethyl morpholine complex, borane 1, 2, 6— Lutidine complex, borane 4-methylmorpholine complex, borane dimethyl sulfide complex, borane morpholine complex, borane 1,4-oxatiane complex, borane 4-phenylphenyl morpholine complex, borane pyridine complex, borane tetrahydrofuran complex, borane triptylphosphine Complex, boranetriethylamine complex, boranetrimethylamine complex, borane compound such as boranetriphenylphosphine complex, aluminum hydride, metal hydride such as sodium borohydride, lithium borohydride, etc. These alkyl, alkoxy or Ashiru substitution products thereof. 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 here include hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid and other Prensted acids, boron trifluoride, and trichloride. Examples thereof include Lewis acids such as boron and trichloride aluminum 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 in the range of 5 ° C to 100 ° C, preferably 30 ° C to 60 ° C. The reaction time is usually 4 to 70 hours, although the type of reducing agent and the reaction temperature vary depending on the type of solvent. 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. 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. Acid Salts: Examples include organic acid salts such as 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-ptoxide; and trimethylamine. And amines such as triethylamine, diisopropylethylamine and N-methylmorpholine. Of these bases, for example, sodium carbonate, potassium carbonate, cesium carbonate and the like can be suitably used. Examples of the metal catalyst include copper horn media such as copper, copper chloride (I), copper bromide (I), copper iodide (I), palladium, palladium chloride, palladium acetate and tetrakis (trif). Enylphosphine) 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, but is usually in the range of room temperature to 200 ° C, preferably 100 ° C 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. However, it is usually 8 to 200 hours. The amount of the base to be used varies depending on the kind thereof, but it is usually 1 to 10 mol, preferably 1 to 4 mol. The amount of the metal catalyst used varies depending on the type thereof, but is usually 0.001 to 1 times, preferably 0.005 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, hydrogen bromide, sulfate, phosphate, and nitrate, and acetates lactate, fumarate, Organic acid salts such as oleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate can be mentioned.

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

[Wherein the aromatic rings G, J, I 1 ^ to 11 ¹³ , L i and L ₂ are the same as those in the formula [XVI], and Y and Z are bonded to each other to form CH ₂ — CH ₂ — CH ₂ Or CH ₂ — CH ₂ — CH ₂ — CH ₂ , or Y and Z are not bonded to each other, Y is 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 and a salt thereof, and the compound [XVIII] is subjected to acid anhydride. The method can be selected from known methods such as an acid anhydride method of condensing the compound and then condensing the compound, and a method via an acid chloride or an acid bromide of the compound [XVIII]. The compound [XVI] 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 [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>

[Wherein the aromatic rings K, R ⁹ -R ¹³ , L 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, the condensation reaction refers to, for example, an amidation reaction using N, N, 1-dicyclohexylcarbodiimide or N-dimethylaminopropyl-1-N'-ethylcarbodiimide, a salt thereof, and the like, compound [XIX] Can be selected from known methods such as an acid anhydride method in which is converted to an acid anhydride and then condensation, and a method via an acid chloride or an acid bromide of the 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). . Here, suitable protecting groups include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and esters thereof, and trimethylsilyl, triethylsilyl, tert-butyl. And silyl esters with butyldimethylsilyl and the like. In addition, 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).

Wherein the aromatic ring G, J, K, 1 ^ ~1 13, A, B, D, V and r are as defined above o

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, and N-methylpyrrolidone. 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. The gold Examples of the group catalyst include copper catalysts such as copper, copper chloride (I), copper bromide (I), copper iodide (I), palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine) palladium. And platinum complexes such as platinum and platinum chloride 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 used varies depending on its type, but is usually 1 to 20 times, preferably 1.5 to 8 times the molar amount.o The amount of the metal catalyst used is The molar ratio varies depending on the type, but it is usually from 0.01 to 1 mole, preferably from 0.005 to 0.3 mole. 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. Here, the salt with an appropriate acid includes, for example, mineral salts (inorganic salts) such as hydrochloride, hydrogen chloride, sulfate, phosphate, nitrate, etc., acetate, lactate, and fumarate. And organic acid salts such as maleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate.

Compound [XXI] used as a starting material for the intramolecular arylation reaction can be produced by alkylating the amino group of compound [XVII] with compound [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, and cesium carbonate, sodium methoxide, sodium t-butoxide, and potassium t-butoxide. Any metal alkoxides, amines such as trimethylamine, triethylamine, diisopropylethylamine, 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, the carrier and diluent include glucose, sucrose, lactose, talc, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water and oils and fats. Is raised.

 The dose and frequency of administration of the pharmaceutical composition of 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, when the pharmaceutical composition of the present invention is orally administered as a therapeutic agent for a disease associated with a structural change in the gastrointestinal tract, such as gastric ulcer, duodenal ulcer, reflux esophagitis, ulcerative colitis or Crohn's disease, the like. Approximately 0 per day for adults 1100 mg may be administered once or several times.

 A method for screening a calcium channel binding compound in the present invention,

(a) The amount of binding of the 5,11 dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the general formula [I] to the colon or ileum membrane specimen was determined. Measuring,

(b) In the presence of the test compound, the labeled 5,11-dithiophene represented by the general formula [I] Measuring the amount of drodiaryl [b, e] [1, 4] oxazepine derivative bound to the colon or ileum membrane specimen; and

 (c) comparing the result obtained in step (a) with the result obtained in step (b).

Process (a)

In the present invention, the method for labeling the 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the general formula [I] includes, for example, a method for labeling a hydrogen atom in the derivative. Is substituted with ³ H, or the carbon atom in the derivative is substituted with ¹⁴ C, which can be used without particular limitation.

 The preparation of the membrane specimen can be performed, for example, as follows. First, the longitudinal muscles of the colon and ileum are minced and suspended in ice-cold Tris buffer. Thereafter, the suspension is homogenized. Next, the obtained homogenizing solution is centrifuged, and the obtained supernatant is centrifuged again. Finally, a huge sample can be prepared by resuspending the obtained precipitate in Tris buffer.

 The labeled derivative can be bound to the membrane specimen thus obtained, for example, by incubating in a Tris buffer. The compound represented by the general formula [I] used in the present invention has a higher affinity for the colon and ileum than for the aorta, and furthermore, in the colon and ileum, the binding site of existing calcium channel antagonists Because of having different binding sites, calcium channel binding compounds that act selectively on the intestinal tract can be screened by using the method of the present invention.

Here, it is preferable to use the labeled derivative in an amount sufficient to bind to all binding sites of the receptor. Then, the reaction is stopped by suction filtration using a glass fiber filter paper or the like, and the filter paper is washed with a Tris buffer or the like. The amount of the labeled inducer in the obtained filtrate was measured using, for example, a liquid scintillation counter for radioactivity / dose (dpm ), It is possible to measure the amount of binding to the colon or ileum membrane specimen.

Process (b)

 By binding the labeled derivative to the membrane sample in the presence of the test compound, it is possible to determine whether the test derivative inhibits the binding of the labeled derivative to the membrane sample. . The test compound may be brought into contact with the membrane specimen together with the labeled derivative, or may be introduced after the labeled derivative has been bound to the sample. It is desirable to use the same amount of the test compound as the labeled derivative. The treatment after binding the test compound and the labeled compound to the membrane sample can be performed in the same manner as described in the step (a).

Process)

 By reducing the amount of the labeled derivative whose binding was inhibited by the test compound obtained in step (b) from the total amount of the labeled compound obtained in step (a) to the membrane specimen It can be determined whether the test compound has a calcium channel binding ability.

 In the present invention, by using a 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative as a receptor ligand, even at a low concentration, specifically, 1 to 2 OnM, The calcium channel binding compound can be efficiently screened. 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-methoxyphenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepi Hydrochloride

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

 Under a stream of argon, 60% sodium hydride (44 mg, 1. lmmol) 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-dihydrodiamine. Benzo [b, e] [1, 4] oxazepine (0.22 g, 1. Ommol) was added and 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 733885 A prepared by the method described in A1) in dimethyl sulfoxide (2 ml) 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) biveridin-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 (1Η, m), 2.50- 2.60 (1Η, m), 2.70 -2.82 (3Η, m), 2.98-3.10 (1Η, m), 3.18 _{-3.24 (1Η 5 m), 3.35} (1Η, dd, J = 9.3, 12 .9Hz), 3.82 (3H, s), 4.02 (1H, dd, J = 3.60 5 13.2Hz), 5.20 (1H, d, J = 12.0Hz), 5.27 (1H ₃ d, J = 12.0Hz), 6.70-6.95 (6H, m), 6.98-7.05 (lH, m), 7.15-7.30 (4H, m)

(R) —3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphen) Netyl) piperidine-2-ylmethyl] dipenza [b, e] [1, 4] oxazepine hydrochloride

 (R) —3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) piperidine-1-2-ylmethyl] dipento [b, e] [1,4] oxazepine (300mg, 0.7mmo To a solution of 1) in dichloromethane (5 ml) was added 0.3 ml of 4M hydrogen chloride / dioxane, and the mixture was stirred for 30 minutes, and then 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%).

 E S I / M a s s: 433 [M + H +]

NMR (CDC13) δ: 1.90-2.06 (1Η, m), 2006-2.30 (3Η, m), 2.74-2.86 (1Η ₃ m), 2.90-3.20 (2Η ₅ m), 3.25-3.40 ( 1Η ₃ m), 3.42-3.68 (2Η, m), 3.80 (3Η ₃ s), 3.85-4.00 (1Η, m), 4.24 (1H, dd, J = 7.8, 14.1 Hz), 4.62 (1H ₅ dd, J = 5.7, 14.1Hz), 5.12 (1H, d, J = 12.3Hz) 5 5.32 (1H 5 d, J = 12.3Hz), 6.72-7.03 (8H, m), 7.12 (2H, d, J = 8.4 Hz), 7.18-7.25 (1H, m)

 (Reference Example 2)

 () -8-Fluoro-5,11-dihydro-5- [1- (4-Methoxyphenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride

Instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, add 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%. ESI / Mas s: 433 [M + H ⁺ ]

NM (GDC13) δ: 1.58- 1.88 (4H, m), 2.22-2.30 (lH ₃ m), 2.48-2.58 (1H, m) ₃ 2.68-2.82 (3H, m), 2.99- 3.08 (1H, m) , 3.21-3.36, 2H, m), 3.81 (3H, s), 4.00-

4.05 (1H, m), 5.20 (1H ₅ d, J = 13.0 Hz) ₅ 5.34 (1H ₃ d, J = 13.0 Hz), 6.47-6.50 (2H ₅ m), 6.79-6.93 (3H ₅ m) ₃ 7.02 -7.18 (4H, m), 7.26-7.34 (2H ₅ 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 / Mas s: 433 [M + H +]

NMR (CDC13) δ: 1.90- 2.32 (4H, m), 2.75- 2.88 (1H, m), 2.94-3.23 (2H 5 m), 3.28-3.60 (3H, m), 3.81 (3H 5 s) 3 3.91 -4.00 (1H, m), 4.14- 4.30 (1H, m), 4.58-

4.73 (1H, m), 5.17 (1H 3 d, J = 13.0Hz) 5 5.34 (1H 5 d, J = 13.0Hz), 6.50- 6.60 (2H, m), 6.81-7.00 (3H, m), 7.08 -7.39 (6H, m)

 (Reference Example 3)

 (R) _2-Chloro-1,11-dihydro_5-C 1-(4-Methoxyphenyl) pyrrolidine-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 the same procedure as in Reference Example 1 was repeated to obtain (R) -2-chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b , e] [1, 4] oxazepine. Pale yellow solid. Yield 44%.

 E S I / Mas s: 449 [M + H +]

NMR (CDG13) δ: 1.60- 1.87 (4H, m), 2.20- 2.28 (1H, m), 2048-2.56 (1H, m), 2.67-2.82 (3H 3 m), 2.93-3.06 (lH, m) , 3.16-3.23 (1H ₅ m) ₅ 3.34 (1H, dd, J = 10 .3, 14.7Hz), 3.81 (3H, s), 4.04 (1H, dd, J = 4.0, 14.7Hz), 5.15 (1H, d, J = 13.OHz), 5.25 (1H, J = 13.0Hz) , 6.75-6.89 (5H ₃ m), 6.97-7.04 (2H, m) ₃ 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.

E S I / Mas s: 449 [M + H +]

NMR (CDC13) δ: 1.92-2.28 (4H, m), 2.72-2.88 (1Η, m), 2.93-3.13 (2H, m), 3.26-3.38 (lH ₃ m), 3.43-3.6. (2H ₃ m ), 3.81 (3H ₅ s), 3.83-3.98 (1H, 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 = 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- [1-1- (4-methoxyphenyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine

3-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] Instead of oxazepine, 3-chloro-5,11-dihydrodibenzo! b, e] [1, 4] Using oxazepine, the same procedure as in Reference Example 1 was carried out to give (R) -3-chloro-1,5-dihydro-5- [1- (4-methoxyphenyl). Enetyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine. Pale yellow solid. Yield 55%.

 ESI / Mass: 449 [M + H +]

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

E S I / Mas s: 449 [M + H +]

NMR (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) ₅ 3.24- 3.34 (lH, m) , 3.44-3.60 (2H ₅ m), 3.81 (lH, s) 3.87-3.981 H, m), 4.24 (lH ₅ dd ₅ J = 8.7 ₅ 15.3 Hz) ₅ 4.62 (lH ₃ dd ₅ J = 6.3 ₅ 15.3 Hz _{) 5 5.12 (lH, d,} J = 14.0Hz), 5.35 (lH, d 5 J = 14.0Hz) 3 6.83- 6.96 (3H, m), 6.84 (2H 3 d, J = 9.3Hz), 7.01- 7.19 (4H, m), 7.12 (2H, d, J = 9.3Hz)

 (Reference Example 5)

 () -Achloro-1,5-dihydro-5- [1- (3,4-Methylenedioxyphenyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride

 (R) — 3—Mouth 1— (3,4-Methylenedioxyphenethyl) piberidine

In acetonitrile (50 ml), (R) -2-hydroxymethylpyrrolidine, (505 mg, 5.00 mmol), 3,4-methylenedioxyphenethyl mesylate (1.34 g, 5.5 Ommo 1), Sodium carbonate (585 mg, 5.5 Ommo 1) Sodium iodide (50 mg, 0.33 mmo 1) was added, and the mixture was heated under reflux at 90 ° C for 13.5 hours. The solvent was distilled off under reduced pressure. 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 while stirring under ice-cooling, 712 mg (5.5 mmo 1) of diisopropylethylamine and 63 Omg (5.5 mmo 1) of metacisulfonyl chloride were added, and ice was added. The mixture was stirred for 1 hour under cooling and further for 2 hours at room temperature. Dilute the reaction mixture with dichloromethane Partitioned into aqueous sodium bicarbonate. 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) -3-3-chloro-1- (3,4-methylenedioxyphenethyl) piperidine as a pale yellow oil. (1.02g, 76%).

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

 () 1-7-chloro-5,11-dihydro-5- [1— (3,4-methylenedioxyphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4]

Under an argon stream, 60% sodium hydride (48 mg, 1.2 mmol) was washed with hexane, suspended in dimethylsulfoxide (8 ml), stirred at room temperature for 30 minutes, and then treated with 7-chloro 11-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, this solution was added to the solution of (R) -3-chloro-1- (3-, 4-methylenedioxyphenethyl) piperidine (308 mg, 1.15 mmol). 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- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-1 —Ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow solid (3 62 mg, 78%).

 ES I / Mas s: 463 [M + H +]

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

 (R) —7-chloro-1,5-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine hydrochloride

(R) —7-chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-2-ylmethyl] dibenzo [b ₃ e] [1,4] oxazepine (0.63 To a solution of g) in dichloromethane (5 ml) was added 3 M of 2 M hydrogen chloride / getyl ether, and the mixture was stirred for 2 hours. Then, 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%).

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

NMR (CDC13) δ: 1.92-2.33 (4H, m), 2.74-3.16 (3H ₅ m), 3.24-3.37 (lH, m), 3.44-3.58 (2H, m), 3.88-3.98 (1H, m) , 4.15-4.28 (1H, m), 4.60- 4.72 (1H, m), 5.19 (1H, d, J = 14.0Hz), 5.27 (1H 5 d, J = 14.0Hz) 3 5.98 (2H, s), 6.64-6.77 (5H

, m), 6.80-6.88 (lH ₃ m), 6.98 (1H, s), 7.09-7.20 (2H, m), 7.28-7.38 (2H, m)

(Reference Example 6)

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

 In acetonitrile (5 Oml), D-prolinol (2.02: 20.0 mmol), 4-dimethylaminophenethyl mesylate, (5.35 g, 22.Ommo1), Add sodium carbonate (2.65 g, 25. Ommo 1) and sodium iodide (300 mg, 2. Ommo 1), and add 90. After heating under reflux with C for 13.5 hours, 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 to keep the pH of the aqueous layer at 1, and the desired product was extracted into the aqueous layer. 4M 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 ( 4.91 g, 99%).

NMR (CDC13) δ: 1.69-1.90 (4H, in), 2.29-2.38 (1H, m) ₅ 2.45-2.54 (1H, m), 2.56-2.64 (lH, m), 2.66-2.74 (2H, m) , Z.88-2.94 (1H, m), 2.91 (6H, ms), 3.2

3-3.30 (lH, m), 3.31 (1H, dd, J = 2.7, 12.0Hz), 3.58 (1H ₅ dd, J = 4.0 ₃ 12.0Hz), 6.70 (2H, d, 9.7Hz), 7.07 (2H ₍₃ 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) in 6 Oml of dichloromethane and stirring under ice-cooling, 3.11 g (24.4 mm o 1) of diisopropylethylamine and 2.75 g of methanesulfonyl chloride g (24. Ommol) was added, and 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, 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 the eluent was The mixture was eluted with hexane and ethyl acetate (9: 1). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -3-3-chloro-1- (4-dimethylaminophenethyl) piperidine as a pale yellow solid (3.03 g, 57%

) o

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

 (R) — 1-fluoro-5,11-dihydro-5_ [1- (4-dimethylaminophenethyl) pyrrolidine-l-^^ methyl] dibenzo [b, e] [1, 4] oxazepine

Under an argon stream, 60% sodium hydride (35 mg, 0.88 mmol) was washed with hexane, suspended in dimethyl sulfoxide (5 ml), stirred at room temperature for 30 minutes, and then treated with 1-fluoro-5,11-dihydrodiamine. Benzo [b, e] [1, 4] oxazepine (0.17 g, 0.8 Ommo 1) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for 30 minutes, dimethyl sulfoxide of (R) -3-3-chloro-1- (4-dimethylaminophenethyl) piperidine (0.18 g, 0.8 Ommo 1) was added to this solution. (2 ml) 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, 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-1-ylmethyl] dibenzo [B, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.23 g, 64%). ESI / Mas s: 446 [M + H ⁺ ]

NMR (CDC13) δ: 1.60-1.90 ( 4H, m), 2.20-2.30 (lH, m), 2.48-2.55 (1H 3 m), 2.70-2.80 (3H, m), 2.94 (6H 5 s), 2.98 -3.08 (1H, m), 3.16- 3.25 (1H, m), 3.38 (1H ₅ dd, J = 9.3, 13.0Hz), 4.10 (1H, dd, J = 3.60, 13.OHz), 5.35 (1H ₅ d, J = 12.0 Hz), 5.42 (1H, d, J = 12.0 Hz), 6.70-6.78 (3H, m), 6.80-6, 90 (4H, m), 7.00-7.15 (3H, m ), 7.18- 7.28 (1H, m)

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

 (R) — 1-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (228 mg, 0.5 mmo 1 ) Was added to a dichloromethane (5 ml) solution, and 0.5 M of 4 M salt / hydrogen / dioxane was added. 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 (170 mg, 64%

) o

ESI / Mas s: 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) ₅ 3.62 -3.75 (lH ₅ m), 3.82-3.95 (1H, m), 4.28 (1H ₃ dd, J = 6.3, 14.7Hz), 4.77 (1H, dd, J = 6.0, 14.7Hz), 5.24 (2H, s ), 6.76 (1H, t, J = 8.1Hz) 5 6.90-7.12 (5H 3 m), 7.21-7.30 (1H, m), 7.37 (2H, d, J = 8.4Hz), 7.7K2H, d, J = 8.4Hz)

 [Reference Example 7] *

(R) 13-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxo Sazepine dihydrochloride

 1-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine is replaced by 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine And (R) -3-fluoro-5,11 dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (0.24 g, 53%).

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

NMR (CDC13) δ: 1.60-1.90 ( 4Η 5 m), 2.22-2.32 (1Η 5 m), 2.50-2.60 (1Η, m), 2.70-2.82 (3Η, m), 2.94 (6H 5 s), 2.98 -3.08 (lH, m), 3.15-3.25 (1H, m), 3.34 (1H, dd, J = 9.3, 13.0Hz), 4.05 (1H, dd, J2 3.60, 13.0Hz), 5.20 (1H, d , J = 12.0 Hz), 5.26 (1H ₅ d, J 2 12.0 Hz), 6.68-6.90 (7H, m), 6.97-7.04 (1H, m), 7.08-7.15 (2H ₅ m), 7.20 -7.25 (lH, 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%).

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

NMR (CDC13) δ: 1.95-2.30 (3H, m), 2.80-3.00 (1Η, m), 3.00-3.25 (9H ₅ m), 3.42-3.60 (2H, m), 3.60-3.75 (lH, m) , 3.85-3.98 (1H, m), 4.19-4.28 (1H 3), 4.58-4.68 (1H, m), 5.11 (1H, d, J = 12.6Hz), 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-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-l-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride 1-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine Instead of 3-chloro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine In the same manner as in Reference Example 6 by using (R) -3-3-chloro-1,5-dihydro-1-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [ 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 ₅ m) ₅ 2.23-2.32 (1H, m), 2.51-2.60 (1H ₃ m), 2.65-2.83 (3H ₅ m) ₃ 2.93 (6H, s), 2.97 -3.07 (lH, m), 3.15-3.23 (1H, m), 3.34 (1H, dd, J = 10.3, 14.3Hz), 4.06 (1H, dd, J = 4.0, 14.3Hz), 5.22 (2H, s ), 6.72 (2H, d, J = 10.0Hz), 6.75-6.85 (3H 5 m), 6.98-7.01 (2H, m), 7.09-7.19 (2H, m), 7.11 (2H 3 d, J = 10.0 Hz)

 (R) — 3-chloro-1,5-dihydro-5— [1— (4 dimethylaminophenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1, 4] oxazepinoxazebine (306 mg, 0.662 mmo 1) was dissolved in 6.0 ml of a mixed solvent of ethyl acetate and ethanol (2: 1), and 2 M hydrogen chloride Z ether (0.73 ml, 1.46 mmo 1) was added. After that, 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 / Mas s: 462 [M + H +]

NMR (CDC13): 2.02-2.28 (4H , m), 2.80- 2.90 (1H, m), 2.98-3.24 (2H, m), 3.17 (6H 5 s), 3.44-3.56 (2H, m), 3.59- _{3.69 (lH 3 m), 3.88-3.98} (lH 5 m), 4.23 (1H, dd, J = 7.7, 15.7Hz), 4.64 (1H, dd, J = 6.3 3 15.7Hz), 5.11 (1H, d, J = 14.0 Hz), 5.33 (1H, d, J = 14.0Hz), 6.85-6.97 (3H, m), 7.02-7.07 (2H, m), 7.12-7.18 (2H, m), 7.4K2H, d , J = 9.3Hz), 7.75 (2H ₃ d, J = 9.3Hz) (Reference Example 9)

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

 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, 15 Ommo 1) A solution of 2- (4-bromophenethoxy) tetrahydro- 1H-pyran (28.01 g, 98.39 mmol) in toluene (10 Oml) and pyrrolidine (9.93 ml. 119 mmol) were added to the mixture at 70 ° C. Stir for 12 hours. Water was added to the reaction solution, and extracted with ethyl acetate. 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-pyrrolidinofphenethyl alcohol as a pale yellow solid. (16.41 g, 87%)

NM (CDC13) δ: 1.97- 2.01 (4H, m), 2.77 (2H ₃ t, J = 7.3Hz), 3.24-3.29 (4H, 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 diisopropylethylamine (19 Oml, 108 mmol 1) and methanesulfonyl are dissolved at 0 ° C. Chloride (8.4 Oml, 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). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give 4-pyrrolidinophenethyl mesylate as a white solid ( 21. 1 80%).

ES I / Mas s: 270 [M + H ⁺ ]

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

 (R) -2-Hydroxymethyl-1- (4-pyrrolidinophenethyl) pyrrolidin

 In acetonitrile (15 Oml), D-prolinol, (2.72 g 25.Ommol), 4-pyrrolidinopheneethyl mesylate, (6.06 g, 22.5 mmo1), potassium carbonate (3 45 g, 25. Ommol) was added, and the mixture was heated under reflux at 90 ° C for 3.5 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, the pH of the aqueous layer was kept at 1, and the desired product was extracted into the aqueous layer. The pH of the aqueous layer was adjusted to 14 by adding 4ΜτΚ sodium salt to the aqueous layer, and the resulting precipitate was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (R) -2-hydroxymethyl-1- (4-pyrrolidinophenetyl) pyrrolidine as a pale yellow oily substance. (4. 96 g, 85%).

NMR (CDC13) δ: 1.70-1.91 (4H ₅ m), 1.95-2.04 (4H, m), 2.26-2.36 (lH, m), 2.42-2.56 (1H, m), 2.57-2.77 (4H, 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 (ZH, d, J = 9.7Hz)

 (R) — 3-chloro-1- (4-pyrrolidinophenetyl) piperidine

(R)-2-hydroxymethyl-one 1- (4 one pyrrolidinium Nof energy chill) pyrrolidine down the _{(4. 96 g s 19. lmmo 1} ) was dissolved in dichloromethane 7 OML, while stirring under ice cooling, diisopropyl 3.21 g (24.8 mmo 1 ) 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 was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. 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-chloro-1- (4-pyrrolidinopheneethyl) piperidine as a pale yellow solid (3.23 g, 61 %). ESI / Ma ss: 293 [M + H +]

NMR (CDC13) ό ·: 1.50-1.70 (3Η, m), 1.78-1.87 (1Η, m), 1.96-2.01 (4Η, m), 2.10-2.20 (2Η ₃ m), 2.54-2.61 (2Η, m ), 2.65-2.72 (2Η, m), 2.75-2.85 (1H, m), 3.10-3.17 (1H, m), 3.23-3.28 (4H, m) ₅ 3.96- 4.06 (1H, m), 6.51 (2H , d, J = 9.7

Hz), 7.05 (2H, d, J = 9.7Hz)

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

Under an argon stream, 60% sodium hydride (348 mg, 8.7 mmol) was washed with hexane, then suspended in dimethyl sulfoxide (50 ml), and stirred at room temperature for 30 minutes. To this was added 2-fluoro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine (1.70 g, 7.9 Ommo 1), and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for another 30 minutes, add (R) -3-3-chloro-1- (4-pyrrolidinofphenethyl) piperidine (2.64 g, 9.02 mmo 1) to the solution. A solution of dimethyl sulfoxide (25 ml) was added dropwise, and the mixture was stirred at 50 ° 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. First, hexane and ethyl acetate (6: 1) were used as eluents, and then hexane and vinegar were used. Elution was performed by changing to ethyl acetate (1: 1). The appropriate fractions are collected and the solvent is distilled off under reduced pressure to give (R) -2-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinofphenethyl) pyrrolidine-1-ethyl] Dibenzo [b, e] [1, 4] oxazepine was obtained as a pale yellow oil (2.29 g, 68%)

ES 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, m), 2.46-2.55 (lH, m), 2.60-2.78 (3H ₃ m), 2.97- 3.06 (lH, m), 3.19-3.31 (6H, m), 4.08 (1H, dd, 3.7,14.3Hz), 5.16 (lH, m), 5.30 (lH, d, J = 13.0 Hz), 6.54 (2H, d , J = 9.0Hz), 6 .75- 6.85 (3H, m), 6.95-7.09 (4H, m) 5 6.99 (2H, d 3 J = 9.0Hz)

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-Pyrrolidinoff enetyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazebine dihydrochloride

 (R) —2-Fluoro-5,11-dihydro-5— [1- (4-Pyrrolidinoff enetyl) pyrrolidine-1-ylmethyl] dipenza [b, e] [1,4] oxazepine (2.29 g) in dichloromethane (30 ml), 20 ml of 2 M salt / hydrogen / ethyl ether was added to the solution, and after stirring for 2 hours, 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%).

ES I / Mas s: 472 [M + H +]

NMR (CDC13) δ:. 1.95-2.36 (8H, m), 2.84- 2 · 96 (1Η, m), 3.03-3.27 (3H, m), 3.40-3 2 (6H 5 m), 3.82-3.93 ( 1H, m), 4.21 (1H , dd, J = 8.7, 15.7Hz), 4.63 (1 H, dd, J = 6.3, 15.7Hz), 5.13 (1H, d, J = 14.0Hz), 5.33 (1H 5 d, J = 14.0Hz), 6.8 1-7.03 (6H, m), 7.11-7.14 (1H, m), 7.37 (2H ₅ d, J = 9.0Hz), 7.60 (2H, d, J = 9.0

Hz) (Reference Example 10)

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

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

 E S I / M a s s: 472 [M + H +]

NMR (CDC13) δ: 1.55-1.90 (4Η ₃ m), 1.95-2.06 (4Η ₅ m), 2.20-2.32 (1Η, m), 2.48-2.60 (1Η, m), 2.70-2.82 (3H, m) , 2.95- 3.10 (1H, m), 3.18-3.40 (6H ₃ m), .06 (1H, m), 5.20 (1H, d, J = 12.0 Hz), 5.26 (1H ₅ d, J = 12.0 Hz) , 6.54 (2H ₅ d, J = 8.7 Hz) ₅ 6.68-6.85 (5 H, m), 6.95-7.03 (lH ₅ m), 7.08 (2H ₃ 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%).

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

NMR (CDC13) (5: 1.95-230 (4Η, m) ₅ 2.34 (4H, m), 2.82-2.95 (1H, m), 3.00-3.24 (2H, m), 3.39-3.78 (7H ₅ m ), 3.82- 3.95 (1H, m), 4.21 (1H, dd, J = 7.2, 14.1Hz), 4.62 (1H, dd, J = 5.7, 14.1Hz), 5.11 (1H, d, J = 12.6Hz) ), 5.34 (1H, d, J = 12.6Hz) 5 6.76 (1H 5 t, J = 8.1Hz), 6.80-7.05 (5H, m), 7.19 (1H, t, J = 8.1Hz), 7.37 (2H _{5 d, 8.4Hz), 7.64 (} 2H, d, J = 8.4Hz)

[: Reference example 1 1] (R) —7-Fluoro-5,1 1-dihydro-5- [1- (4-Pyrrolidinopheneethyl) pyrrolidine-l-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 Then, by the same operation as in Reference Example 6, (: R) -7-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-1f-methyl] diazine Zo [b, e] [1,4] oxazepine was obtained as a pale yellow oil (0.19 g, 51%).

 E S I / Mas s: 472 [M + H +]

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

 This was treated with 4M 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) δ: 1.95-2.30 (4H, m), 2.34 (4H, m), 2.78-2.92 (1H, m), 2.94-3.25 (2H, 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) ₅ 5.13 (1H ₃ d, J = 12.9Hz), 5.24 (1H, d, J = 12.9Hz ) 3 6.58- 6.63 (1H, m), 6.72-6.82 (2H, m), 7.05-7.25 (4H 5 m), 7.35 (2H, d, J = 8.4Hz), 7.60 (2H, d, J = 8.4Hz)

 (Reference Example 12)

(R) 18-Fluoro-5,11-dihydro-5- [1— (4-pyrrolidinofe Netyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine ■ dihydrochloride

 Using 8-fluoro-5,11-dihydrodibenzo [b, e] [1, 4] oxazepine and (R) — 3-chloro-1- (4-pyrrolidinophenethyl) piperidine By the same procedure as in Reference Example 6, (R) -8-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinofphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow oil (0.13 g, 32%).

 ES I / Ma s s: 472 [M + H +]

NM (CDC13) δ: 1.58- 1.90 (4H, m), 1.95-2.06 (4H ₃ m), 2.18-2.34 (1H, m) ₃ 2.45-2.58 (lH, m), 2.65-2.80 (3H ₃ i) , 2.95-3.10 (lH, m), 3.14-3.38 (6H 5 m), 4.05-4.14 (lH 5 m), 5.21 (1H, d, J two 11.7Hz), 5.35 (1H, d , J = 11.7Hz ) ₃ 6.48-6.

58 (4H, m), 6.88-6.95 (1H, m), 7.02-7.12 (4H ₃ m), 7.24-7.35 (2H ₅ m)

 This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to give 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), 2.35 (4H, m), 2.78-2.94 (1Η 3 m), 2.95 -3.10 (1H, m), 3.10-3.25 (1H 5 m), 3.40 -3.80 (7H ₅ m), 3.80-3.95 (1H, m), 4.19 (1H, dd, J = 7.8, 14.1 Hz), 4.64 (1H, dd, J = 4.2, 14.1 Hz), 5.16 (1H, d , J = 12.3 Hz), 5.44 (1H, d, J = 12.3Hz), 6.50-6.61 (2H ₅ m), 6.88-7.00 (lH, m), 7.05-7.1 8 (2H, m), 7.30-7.4 K4H, m), 7.64 (2H, d, J = 7.8Hz)

 (Reference Example 13)

(R) —3-chloro-1,5-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-2-ylmethyl] dipento [b, e] [1,4] oxazepine.2 hydrochloride Using 3-chloro _5, 11-dihydrodibenzo [b, e] [1, 4] oxazepine and (R) -3-chloro- 1-(4-pyrrolidinofphenethyl) piperidine By the same procedure as in Example 6, (R) -3-3-chloro-1,5-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, 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 ₃ m), 2.20- 2.34 (1Η, m), 2.50-2.62 (1Η ₅ m), 2.65- 2.82 (3Η, m) , 2.90- 3.10 (1Η, m), 3.16- 3.40 (6Η, m), 4.05-4.14 (1Η ₃ m), 5.22 (2Η, s), 6.54 (2Η, d, J = 8.7Hz), 6.75-6.88 (3H, m),

6.96-7.04 (2H, d, J = 8.7Hz), 7.05- 7.14 (3H, m), 7.18 (1H, d, J = 8.4Hz) Similar to Reference Example 6, this was treated with 4M salt / hydrogen Z dioxane. Treatment gave 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), 2.92 -3.25 (2H, m), 3.40-3.81 (7H 5 m), 3.83 -3.99 (1H, m), 4.21 (1H ₃ dd, J = 6.9, 14lHz), 4.63 (1H ₃ dd, J = 6.3, 14.1Hz), 5.10 (1H, d, J = 12.9Hz), 5.36 (1H, d, J = 12.9Hz ), 6.85-7.06 (5H 5 m), 7.15 (2H 5 t, J = 8.1Hz), 7.35 (2H, d, J = 8.7Hz), 7.62 (2H, d, J = 8.7Hz)

 (Reference Example 14)

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

 3-pyrrolidinophenethyl alcohol

Dried palladium acetate (58mg, 0.26mmol), 2- (di-toop) Tylfosfuino) Biphenyl (136 mg, 0.46 mmol), t-peptoxy sodium (3.23 g, 33.6 mmo 1) in 2- (3-promophenetoxy) tetrahydro-1H-pyran (6.27 g, 21.9 mmo 1) ) In toluene (15 ml) and pyrrolidine (2.2 ml, 26.4 mmol) were added, and the mixture was stirred at 70 ° 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 1 M 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) ό ": 1.98-2.02 (4H, m) ₅ 2.82 (2H ₅ t, J = 7.0 Hz) ₃ 3.26-3.30 (4H ₅ m), 3.86 (2H, q, J = 7.0 Hz), 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, 26.7 mmol) and methanesulfonyl chloride (1.9 ml, 24.5 mmol) are added at 0 ° C. In addition, the mixture was 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%).

E S I / Mas s: 270 [M + H +]

NMR (CDC13) ό ": 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), 6.40-6.53 (3H 3 m), 7.16 (1H, t, J = 8.7Hz)

 (R) — 3-chloro-1- (3-pyrrolidinophenetyl) piperidine

4-pyrrolidinopheneethylmethacrylate instead of 3-pyrrolidinopheneethylmethacrylate It was synthesized in the same manner as in Reference Example 13 using silate. Yield 50%. ES I / Mas s: 293 [M + H +]

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

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

 Using 3-chloro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine and (R) —3-chloro-1- (3-pyrrolidinophenethyl) piperidine By the same operation as in Reference Example 6, (R) -3-chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (0.21 g, 45%).

 ES I / Mas s: 488 [M + H +]

NMR (CDC13) δ: 1.50-1.90 (4H, m), 1.95-2.06 (4H ₃ m), 2.24-2.34 (lH ₅ m), 2.55-2.70 (lH, m), 2.70-2.88 (3H, m) , 3.02-3.15 (lH, m), 3.16- 3.40 (6H, m), 4.02-4.14 (lH, m), 5.23 (2H 5 s), 6.40-6.58 (3H 5 m), 6.75-6.88 (3H, m), 6.96

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

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

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 brown solid (88%). ESI / Mas s: 488 [M + H +]

NMR (CDC13) δ: 1.95-2.30 (4H, m), 2.32 (4H, m) ₅ 2.77-2.90 (lH ₅ m) ₅ 3.00 -3.30 (2H ₃ m), 3.38-3.78 (7H ₃ m), 3.80 -3.92 (1H, m), 4.21 (1H, dd, J = 6.6, 14 .lHz), 4.64 (1H 5 dd, J = 5.7, 14.1Hz), 5.10 (1H 3 d, J = 12.9Hz), 5.33 (1H, d, J two 12.9Hz), 6.82- 7.08 (5H, m), 7.14 (2H 5 t, J = 8.4Hz), 7.20-7.30 (lH 5 m), 7.38 -7.53 (2H, m), 7.60-7.70 (lH ₅ m)

 (Reference Example 15)

 (R) — 3-Chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidine—2— ^ fmethyl] dibenzo [b, e] [1,4] oxazepine · 2 Hydrochloride.

 4-Morpholinophenetyl alcohol

 Dried palladium acetate (32.3 mg, 0.14 mmol), 2- (di-t-butylphosphino) biphenyl (86.Omg, 0.39 mmol), t-butoxy sodium (1.73 g) , 1 111111110 1) 2- (4-bromophenethoxy) tetrahydro- 1H-pyran (3.42 g, 12.Ommol) in toluene (9. Oml) solution and morpholine (1.22 g, 14 mmol) And stirred at 70 ° 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) ό ": 2.80 (2H, t, J = 8.7 Hz), 3.13 (4H, t, J = 6.8), 3.78-3.88 (6 H.m) ₃ 6.88 (2H, d, J = 11.7 Hz) ), 7.14 (2H, d, J = 11.7Hz)

 4-morpholinopheneethyl mesylate

Dissolve 4-morpholinophenethyl alcohol (2.35 11.3 mmo 1) in dichloromethane (20 ml) and diisopropylethylamine (2. 60 ml, 14.8 mmo 1) and methanesulfonyl chloride (1.1 ml, 14.8 mmo 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 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 g, 81%). NMR (CDC13) ό ": 2 · 86 (3Η, s), 2.98 (2Η, t, J = 9.3Hz), 3.14 (4H, m), 3.86 (4H, m), 4.38 (2H 5 t, J = 9.3Hz), 6.87 (2H, d , J = 11.7Hz), 7.14 (2H 5 d, J = 11.7H z)

 (R) —3—Black mouth — 1— (4-Morpholinopenitene) piperidine

Acetonitrile (2 Oml) in 4-morpholinophenethyl mesylate (0.4 '3 g, 1.5 lmmo 1) and D-prolinol (0.1 Ίg 1.66 mmo 1), potassium carbonate (0.40 g, 2.89 mmo 1) and 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) -12-hydroxymethyl-11- (4-morpholinophenethyl) pyrrolidin as a pale yellow solid (0.44 g, 1 5 mmo 1, 100%). This was dissolved in dichloromethane (10 ml), and triethylamine (0.29 ml, 2. lmmo 1) and methanesulfonyl chloride (0.15 ml, 1.9 mMol) 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 chromatography and eluted with hexane and ethyl acetate (1: 1). Collect the appropriate fractions and evaporate the solvent under reduced pressure This gave (R) _3-chloro-1- (4-morpholinopheneethyl) piperidine as a white solid (0.30 g, 64%).

 ES I / Mas 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 ₅ m), 3.10-3.18 (4H, m), 3.80-3.88 (4H, m), 3.96-4.04 (lH, m), 6.82-6.88 (2H, m), 7.10-7.20 (2H, m)

 (R) — 3-chloro-1,5-dihydro-5- [1- (4-morpholinopheneethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1, 4] oxazepine dihydrochloride salt

 (R) _3-Chloro-1- (4-morpholinopheneethyl) piperidine and 3-chloro-5,11 dihydrodibenzo [b, e] [1,4] Reference using oxazepine By the same procedure as in Example 6, (R) -3-3-chloro-1,5-dihydro-1-5- [1- (4-morpholinophenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [ 1, 4] oxazebine was obtained. Pale yellow oil. Yield 46%.

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

NMR (CDC13) δ: 1.60-1.95 (4H ₃ m), 2.22-2.31 (1Η, m), 2.52-2.61 (1Η ₅ m), 2.69-Z.80 (3H, m) ₅ 2.98-3.07 (lH ₃ m), 3.01-3.19 (1H, m ), 3.15 (4H 5 t, J = 5. 3Hz), 3.35 (1H, dd, J = 10 3 3, 14.7Hz), 3.87 (4H, t, J = 5.3 Hz) ₃ 4.03 (1H, dd, J = 4.0, 14.7Hz), 5.21 (1H, d, J = 13.3Hz), 5.23 (1H, d, J = 13.3Hz), 6.76-6.90 (3H, m), 6.88 (2H, d, J = 9.7Hz), 6.97-7.01 (2H, m), 7.09-7.19 (2H, m), 7.14 (2H, d, J = 9.7Hz)

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

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

NMR (CDC13) δ: 1.98-2.33 (4H, m), Z.83-3.30 (4H ₃ m) ₃ 3.38-3.70 (6H, m), 3.87-3.98 (1H, m), 4.15-4.42 (5H, m), 4.60-4.70 (lH, m), 5.12 (1H, d, J = 14. 0Hz), 5.39 (1H 3 d 5 J = 14.0Hz ), 6.84-6.93 (3H, m), 7.04-7.19 (4H ₃ m), 7.43 (2 H, s), 7.78 (2H, s)

 (Reference Example 16)

 (R) -2-Fluoro-1,5,11-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-1-3-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 at room temperature for 30 minutes, 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine (538 mg, 2.5 mmo 1) is added, and the mixture is added at room temperature for 30 minutes and then at 50 ° Stirred at C for 40 minutes. To this solution was added a solution of (S) -1- (4-dimethylaminophenethyl) 1-3-methanesulfonyloxypyrrolidine (312 mg, 1.0 mm 01, prepared by the method described in International Patent No. 0040570A1) in dimethyl sulfoxide (3 ml). Was added dropwise, and the mixture was 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-dimethylaminoaminophenethyl) pyrrolidine-13-yl] dibenzo [b , e] [1,4] oxazepine was obtained as a pale yellow oil (140 mg, 32%). ES I / Mas s: 432 [M + H +]

NMR (CDC13) δ: 1.74-1.84 (1H ₃ m) ₅ 2.22- 2.34 (1 H, m), 2.37-2.47 (lH ₃ m), 2.48-2.71 (5H ₃ m), 2.75-2.85 (lH ₅ m) , 2.90 (6H, s), 3.18 (1H, dd 5 J = 7.7 5 1 0.7Hz), 4.60-4.70 (lH, m), 5.25-5.40 (2H 3 bs), 6.37-6.49 (3H 3 m), 6.72-6.87 (5H, m), 6.95-7.24 (3H, m),

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

 (R) —2-Fluoro-5,11-dihydro-5- [1- (4-Dimethylaminophenethyl) pyrrolidine_-3-yl] dianzo [b, e] [1, 4] oxazepine (140mg) The dichloromethane (5 ml) solution was charged with 1.0 ml of 4 M hydrogen chloride / ethyl acetate, stirred for 1 hour, the solvent was distilled off under reduced pressure, and the residue was solidified by stirring in hexane and filtered. Separately, the title compound was obtained as a pale yellow solid (145 mg, 90%).

 E S I / Mas s: 432 [M + H +]

NMR (CD30D) δ: 1.90-2.08 ( 1Η 3 m), 2.10-2.30 (1Η 3 m), 2.38- 2.53 (1Η, m), 2.60-2.73 (1H, m), 3.14 (2H, t, J = 8.0Hz), 3.26 (6H, s ), 3.49 (2H, t 3 J = 8.0 Hz), 3.60-3.82 (2H, m), 4.03-4.14 (lH, m), 4.95-5.03 (lH 5 m), 5.06-5.15 (1H ₃ i), 6.73-6.92 (3H, m), 7.03-7.26 (4H ₃ m), 7.47-7.59 (4H ₅ m)

 (Reference Example 17)

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

2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] Instead of oxazepine, 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] (R) —3-Fluoro-5,11-dihydro-1-5- [1- (4-dimethylaminophenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1, 4] oxazepine was obtained. Pale yellow solid. Yield 40%.

 ES I / Mas s: 432 [M + H +]

NMR (CDC13) δ: 1.73-1.84 (1H ₃ m), 2.21-2.30 (1H, m), 2.41- 2.48 (1H, m), 2.50-2.71 (5H, m), 2.75-2.82 (lH ₅ m ), 2.90 (6H ₅ s), 3.18 (1H, dd, J = 7.7, 10 • 7 Hz), 5.28 (1H ₃ d, J = 12.0 Hz), 5.40 (1H, d, J = 12.0 Hz), 6.48- _{6.54 (lH, m) 5 6} .63-6.72 (4H 5 m), 7.01-7.12 (4H 5 m), 7.25-7.34 (2H, m)

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

ESI / Mass: 432 [M + H +]

NMR (CD30D) δ: 1.90-2.07 (1Η, m), 2.14-2.27 (1Η, m), 2.2-2.52 (IH, m), .63-2.77 (1Η, m) ₃ 3.15 (2H ₅ t, J = 9.0 Hz), 3.26 (6H, s), 3.49 (2H ₅ t, J = 9.0 Hz), 3.64-3.82 (2H, m), 4.07-4.16 (IH, m), 4.97- 5.06 (lH ₃ m), 5.10-5.18 (1H ₅ m), 6.72-6.94 (4H, m), 7.00-7.09 (2H, m), 7.43-7.65 (5H ₅ m)

 (Reference Example 18)

 (R) — 3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1,4] oxazebine • dihydrochloride

Reference example using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine By the same operation as in (16), (R) -3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1,4 Oxazepine was obtained. Pale yellow oil. Yield 39%.

 ES I / Mas s: 448 [M + H +]

^{NMR (CDC13) ό 1: 1.74-1.84} (1H, m), 2.22- 2.34 (1H, m), 2.37-2.47 (lH, m), 2.48-2.7K5H, m), 2.75-2.85 (lH 3 m) , 2.90 (6H, s), 3.18 (1H, dd, J = 7.7, 10.7Hz), 4.60-4.70 (lH, m), 5.25-5.40 (2H, bs), 6.68 (2H, d, J = 9.7 Hz) ₃ 6.71-6.88 (4H, m), 6.92-7.10 (3H ₃ m) 7.04 (2H, d, J = 9.7Hz)

 This was treated with 4 M salt / hydrogen Z ethyl acetate in the same manner as in Reference Example 16 to obtain the title compound as a brown solid. 90% yield.

E S I / Mas s: 448 [M + H +]

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

 (Reference Example 19)

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

Dihydrochloride

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

3-pyrrolidinophenethyl mesylate (1.80 g, 4.00 mmol), (S) -3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmol), potassium carbonate (1.70 g, 12.3 mmo 1) was added to acetonitrile (20 ml), 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, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After drying the organic layer, the solvent is distilled off under reduced pressure. S) 1-3-Hydroxy-1- (3-pyrrolidinofphenethyl) pyrrolidine was obtained quantitatively as a pale yellow solid. This was dissolved in dichloromethane (10 ml), triethylamine (0.76 ml, 5.49 mmol) and methanesulfonyl chloride (0.39 ml, 5.03 mmol) were added at 0 ° C, and the mixture was 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 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%).

 E S I / Mas s: 339 [M + H +]

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

(R) —3-Fluoro-5,11-dihydro-5- [1— (3-pyrrolidinopenetyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1, 4] oxazepine 60% hydrogen under argon stream Sodium chloride (88 mg, 2.2 mmo 1) 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, 2.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for another 30 minutes, dimethyl sulfoxide of (S) -3-methanesulfo'dioxy-1- (3-pyrrolidinophenethyl) pyrrolidine (0.34: 1. Ommol) was added to this solution. (4 ml) solution was added dropwise, and the mixture was stirred at 70 ° C for 2 hours. The reaction solution was partitioned between saturated saline and ethyl acetate. After drying the organic layer, dissolve The medium was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (1: 1). The 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-3-yl] Dipenza [b, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.19 g, 42%).

 E S I / Mas s: 458 [M + H +]

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

 This was treated with 4 M hydrogen 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 (1Η, m

), 2.60-2.78 (2H, m), 3.12 (2H ₃ t, J = 8.1 Hz), 3.30-3.48 (1H, m), 3.53 (1H ₅ t

, J = 8.1Hz), 3.60-3.83 ( 6H, m), 4.95-5.15 (2H 3 m), 6.70-7.10 (6H 5 m), 7.25-7

.53 (5H, m)

 (Reference Example 20)

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

Using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) —3-methylsulfonyl-1- (3-pyrrolidine-1-1-ylphenethyl) pyrrolidine, By the same operation as in Reference Example 19, (R) —3-chloro-1,5-dihydro-1-5- [1- (3-pyrrolidine-1-ylphenethyl) pyro Lysine-3-yl] dibenzo [b, e] [1, 4] oxazepine was obtained as a pale yellow oil (0.20 g, 43%) o

ESI / Mass: 474 [M + H +]

NMR (CDC13) ό ": 1.63- 1.80 (1Η, m), 1.92- 2.00 (4Η, m), 2.22-2.36 (1Η, m), 2.40-2.48 (1Η, m), 2.52-2.75 (5Η 3 m ), 2.75- 2.86 (1Η, m), 3.15-3.30 (5Η, m), 4.60-4.70 (1Η ₃ m), 5.38 (2H, brs), 6.37-6.49 (3H, m), 6.72-6.80 (3H _{, m) 5 6 .95 (1H} , dd, J two 1.8, 7.8Hz), 7.04-7.14 (3H , m), 7.24 (1H, d, J = 7.8Hz) which in the same manner as in reference example 16 4 M Treatment with hydrogen chloride / ethyl acetate afforded the title compound as a brown solid (93%).

ESI / Mass: 474 [M + H +]

NMR (CD30D) δ: 1.90-2.10 (1H, m), 2.13-2.32 (5H, m), 2.37-2.55 (1H, m), 2.60-2.78 (2H, m), 3.10 (2H, t, J = 7.8Hz), 3.30-3.45 (lH, m), 3.53 (1H, t, J = 7.8Hz) ₅ 3.58-3.81 (5H, m), 4.00-4.12 (lH, m), 4.95-5.18 (2H ₃ m ), 6.70-7.1 0 (4H, m), 7.16-7.50 (7H ₃ m)

 (Reference Example 21)

 (R) — 5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-1--2-methyl] dibenzo [b, e] [1, 4] oxazepine dihydrochloride (R)- 5, 11-dihydro-5- [1- (3-pyrrolidinofphenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1, 4] oxazepine

(R) -5,11-dihydro-5- (2-pyrrolidylmethyl) dibenzo [b, e] [1,4] oxazepine (240 mg, 0.85 mmo1, International Patent No. 9912925) in acetonitrile (20 ml) A 1), 3-pyrrolidinophenethyl mesylate (253 mg, 0.94 mmol), sodium carbonate (106 mg, 1. Ommo 1), sodium iodide (1 Omg, 0.07 mmo 1) After heating at 90 ° C for 6.5 hours under reflux, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. 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 eluted with hexane and ethyl acetate (15: 1) first, then hexane and ethyl acetate (2: 1) as eluents . The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -5,11-dihydro-1-5- [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 (CDG13) δ: 1.65-1.88 (4Η, m), 1.99-2.05 (4Η ₅ m), 2.23-2.32 (1Η, m), 2.55-2.64 (1Η, m), 2.71-2.84 (3Η, m) , 3.06-3.16 (1Η, m), 3.19-3.24 (1Η, m), 3.28-3.32 (4Η, m), 3.37 (1H, dd, J = 11.0, 14.3Hz), 4.15 (1H, dd, J = 4.0, 14.

3Hz), 5.22 (1H, d, J = 13.0Hz), 5.34 (1H, d, J = 13.0Hz), 6.44-6.55 (3H, m), 6.

75-6.83 (3H, m), 7.00-7.20 (4H, m), 7.26-7.32 (2H ₅ m)

 (R) — 5, 1 1-Dihydro-5— [1-(3-Pyrrolidinophenetyl) pyrrolidin-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride (R) — 5, 1 1 Dihydro-5- [1- (3-Pyrrolidinophenetyl) pyrrolidine-1-2-ylmethyl] dipento [b, e] [1, 4] Oxazepine (208 mg) in dichloromethane (2 ml) To 2 M hydrogen chloride / getyl ether 2.

After adding 0 ml 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%).

 E S I / Mas s: 454 [M + H +]

NMR (CDC13) δ: 1.90-2.42 (8Η ₃ m) ₅ 2.98- 3.30 (3Η, m), 3.40-3.90 (8Η, m), 4.18-4.35 (1Η, m), 4.62-4.76 (1H, m) , 5.14 (1H, d, J = 13.0Hz) ₅ 5.30 (1H, d, J = 13.0Hz) ₃ 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, s)

 (Reference Example 22

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

 (S) —3-Hydroxy-1- (4-pyrrolidinophenethyl) pyrrolidine acetonitrile (200 ml) in 4-pyrrolidinophenethyl mesylate (13.45 g, 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, (S) -3-hydroxy-1- (4-pyrrolidinopheneethyl) 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, m) 5 2.34-2 3 (1H, m), 2.55-2.63 (lH 3 m), 2.65-2.80 (5H ₃ m), 2.92- 3.03 (1H, m), 3.23-3.28 (4H ₅ m), 4.33-4.40 (lH ₅ m), 6.51 (2H, d, J = 9.3Hz) , 7.06 (2H ₃ d, J = 9.3Hz)

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

(S) —3-Hydroxy-1- (4-pyrrolidinophenethyl) pyrrolidine (6.30 g, 23.4 mmol 1) was dissolved in 10 Oml of dichloromethane, and diisopropylethylamine (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. Organic layer After drying, 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-11- (4-pyrrolidinofphenethyl) pyrrolidine as a pale yellow oil (7.50 g, 49%).

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

NMR (CDC13) δ: 1.96-2.00 (4Η, m), 2.04-2.16 (IH, m), 2.27-2.38 (1Η ₃ m), 2.44-2.52 (IH, 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, m), 6.50 (2H, d, J = 9.3Hz), 7.05 (2H ₃ d, J = 9.3H z)

(R) —5,11—Dihydro-5-CI— (4-Pyrrolidinophenetyl) pyrrolidine-1-3-yl] dibenzo [b, e] [1, 4] Oxazepine 'dihydrochloride Under argon stream , 60% sodium hydride (132 mg, 3.3 mmol 1) was washed with hexane, suspended in dimethyl sulfoxide (10 ml), stirred at room temperature for 30 minutes, and then treated with 5,11-dihydrodibenzo [b, e [1,4] oxazepine (600 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C for 30 minutes, this solution was added with (S) -3-methanesulfonyloxy-1- (4-pyrrolidinofphenethyl) pyrrolidine (34 Omg, 1. Ommol) in dimethyl sulfoxide (5 ml) The solution 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- (4-pyrrolidinophenetyl) pyrrolidine-13-yl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (142 mg, 32%). NMR (CDC13) δ: 1.72-1.84 (1H ₅ m), 1.96-2.04 (4H, m), 2.22- 2.41 (2H, m) ₅ 2.49-2.71 (5H ₅ m), 2.80-2.89 (lH, m) , 3.22-3.27 (5H ₅ m), 4.67-4.74 (1H, m), 5.30-5.50 (2H, b), 6.48 (2H, d, J = 9.7 Hz), 6.72-6.82 (3H, m), 6.95 -7.13 (3H ₃ m), 7.02 (2H, d, J = 9.7Hz), 7.26-7.33 (2H, m)

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

E S I / Mas s: 440 [M + H +]

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

.18 (1H, m), 6.72-7.04 (4H, m), 7.15-.7.24 (2H ₃ m), 7.36- 7.44 (6H, m)

(Reference Example 23)

 (R) — 5, 1 1—Dihydro-5- [1-(3-pyrrolidinophenetyl) pyrrolidin-1-yl] dibenzo [b, e] [1, 4] oxazepine '2 Hydrochloride

 (S) -3-Hydroxy-11- (3-pyrrolidinophenethyl) pyrrolidine acetonitrile (20 ml) synthesized in Reference Example 21 with 3-pyrrolidinophenethyl mesylate (1.80 g, 4. OOmmol) And (S) -3-pyrrolidinol hydrochloride (0.50 g, 4. O 5 mmol) and potassium carbonate (1.70 g, 12.3 mmol 1) were 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, the solvent was distilled off under reduced pressure to obtain (S) -3-hydroxy-11- (3-pyrrolidinophenethyl) pyrrolidine as a pale yellow solid (1.04 g, 100% ) o

NMR (CDC13) δ: 1.68-1.80 (1H, m), 1.91- 2.02 (4H, m), 2.13-2.5 (1H, m) ₅

2.30- 2.40 (1H, m), 2.55-2.63 (lH ₃ m), 2.67-2.80 (5H, m), 2.89-2.98 (lH ₃ m), 3.15-3.25 (4H ₃ m), 4.28-4.39 (lH, m) ₃ 6.39-6.42 (2H, m), 6.50 (1H, d, J = 8.0 Hz), 7.13 (1H, t, J = 8.0 Hz)

 (S) 1-Methanesulfonyloxy 1- (3-pyrrolidinophenetyl) pyrrolidine

 (S) —3-Hydroxy-1- (3-pyrrolidinofphenethyl) pyrrolidine (1.04 g, 4.0 Ommo 1) is dissolved in dichloromethane (1 Oml) and triethylamine (0 ° C) is dissolved. 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-methanesulfonyloxyl- (3-pyrrolidinofphenethyl) pyrrolidine as a pale yellow oil. 30g, 96%).

ESI / Mass: 339 [M + H ⁺ ]

NMR (CDC13) δ: 1.96-2.22 (4Η, m), 2.03-2.15 (1Η ₅ m), 2.25-2.38 (lH ₅ m), 2.44-2.54 (lH ₅ m) ₃ 2.70- 2.80 (4H, m), 2.80-3.02 (3H ₅ m), 3.02 (3H, s), 3.23-3.30 (4H ₅ m), 5.20-5.28 (lH ₅ m), 6.42 (2H, m), 6.50 (1H, d, J = 7.5Hz), 7.14 (1H, t, J = 7.5Hz)

(R) —5,11—dihydro-5-CI— (3-pyrrolidinophenethyl) pyrrolidin-1-yl] dibenzo! : b, e] [1, 4] oxazebine dihydrochloride 60% sodium hydride (132 mg, 3.3 mmo 1) was washed with hexane under an argon stream, suspended in dimethyl sulfoxide (10 ml), and then suspended at room temperature. After stirring for 30 minutes, 5,11-dihydrodibenzo [b, e] [1,4] oxazepine (600 mg, 3. Ommo 1) was added, and the mixture was stirred at room temperature for 30 minutes. 50 ° C After stirring for 30 minutes, a solution of (S) —3-Methanesulfonyloxy-1- (4-pyrrolidinofphenethyl) pyrrolidine (340 mg, 1. Ommo 1) in dimethylsulfoxide (5 ml) was added dropwise to the solution. Then, 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 ₃ m), 2.34-2.43 (ΙΗ, m), 2.49-2.57 (1H, m) , 2.61-2.76 (5H, m), 2.81-2.88 (1H, m), 3.23-3.29 (4H ₅ m), 4.67-4.76 (lH ₅ m), 5.30-5.50 (2H ₅ bs), 6.34-6.48 ( 3H, m)

, 6.71-6.85 (3H, m), 6.94-6.97 (1H, m), 7.04-7.16 (3H, m), 7.25-7.32 (2H, m) / Jetil ether to give the title compound as a brown solid (78%).

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

NMR (CD30D) δ: 1.90-2008 (1Η, m), 2.10-2.30 (5H, m), 2.35-2.55 (1Η ₃ m), 2.60-2.78 (1H, m), 3.10 (2H, t, J = 10.0Hz), 3.25-3.40 (1H, m), 3.25 (2H ₅ t, J = 10.0Hz), 3.60- 3.80 (5H, m) ₅ 4.03-4.12 (lH, m), 4.99-5.09 (1H , M), 5.11-5

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

 (Reference Example 24)

5,11-dihydro-5- [2- [N-methyl-N- (3-pyrrolidinophenyl) amino] ethyl] dibenzo [b, e] [1,4] oxazepine 'dihydrochloride acetonitrile (20ml) Among them, 5, 11-dihydro-5- [2- (N-me (Cilamino) ethyl] dipenza [b, e] [1, 4] oxazepine (254 mg, 1.00 mmol, prepared by the method described in International Patent No. 0040570A1), 3-pyrrolidinophenethyl mesylate (296 mg, 1. l Ommo l), sodium carbonate (138 mg, 1.3 Ommo 1), and sodium iodide (2 Omg, 0.13 mmo 1) were added, and the mixture was heated under reflux at 90 ° C for 6.5 hours and then under reduced pressure. The solvent was distilled off, 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 carried out 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 / Mass: 428 [M + H +]

NMR (CDC13) δ: 1.96-2.00 (4Η, m), 2.32 (3Η, s), 2.61 (4Η, s), 2.66 (2Η, 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), 6.77-6.84 (3H, m), 7.00-7.14 (4H 3 m), 7.25- 7.32 (2H, m)

 This was treated with 2 M salt / hydrogen / getyl 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, m), 2.85 (3H ₃ d, J = 4.3 Hz), 3.10-3.48 (6H, m), 3.55-3.74 (4H, m) ₃ 4.23-4.35 ( lH ₃ m) ₃ 4.40-4.52 (1H, m), 5.23 (1H, d, J = 14.3Hz), 5.25 (1H, d, J = 14.3Hz), 6.82-6.93 (3H, m), 7.06-7.11 (2H ₃ m), 7.18 (1H, d, J = 8.7 Hz), 7.24-7.44 (4H, m), 7.53 (1H, d, J = 8.7 Hz), 7.78 (1H, m) (Reference Example 25)

 (R) —3-chloro-1,5-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine · 2 Hydrochloride (= 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) and D-proline methyl ester hydrochloride (7.19 g, 43.4 mmol) in methylene chloride (150 ml) solution , 1-hydroxybenzotriazo-mono-hydrate (6.1 g, 45.4 mmol), and N-dimethylaminopropyl-N, ethylcarbodiimid hydrochloride (8.7 g, 45.4 mmol 1) Was added. After the mixture was stirred at room temperature for 6 hours, triethylamine (6.3 ml, 45.4 mmol) was added. This was stirred overnight at room temperature, and the reaction solution was washed successively with water (200 ml), 5% aqueous sodium bicarbonate (200 ml), and water (200 ml). The residue obtained by evaporating the solvent under reduced pressure was subjected to silica 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) ό ·:} 1.82-2.26 (4Η 5 m), 2.82-2.98 (6Η, m), 3.40-3.76 (2Η, m), 3.60 (3H, s), 3.73 (2H 5 s), 4.41 -4.52 (1H ₃ m), 6.64-6.74 (2H, m), 7.07-7.19 (2H, m)

 (R) — N— C (4-dimethylaminophenyl) acetyl] -D-proline

(R) — N— ((4-Dimethylaminophenyl) acetyl) 1-D-proline methyl ester (1.0 g, 3.4 mmol 1) in tetrahydrofuran (10 ml) And water (10 ml) and a 1 M aqueous sodium hydroxide solution (3.7 ml, 3.7 mmol) were 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) d: 1.80-2.28} (3H, m), 2.45-2.58 (1H, m), 2.95 (6H 3 s), 3.42- 3.70 (2H, m), 3.65 (2H 3 s), 4.60- 4.68 (1H ₅ m), 6.72-6.83 (2H, m), 7.08-7.19 (2H ₃ m)

 (R) -1-(4-Dimethylaminophenyl) acetyl] pyrrolidine-2-force rubonic acid [2- (2-promo 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 mls 35. 0 mmo 1) was added. Under ice bath, ethyl chloroformate (3.26 mls 34. lmmo 1) was added thereto, and the mixture was stirred for 2 hours. To this, add 2- (2-promo 4-cyclohexylbenzyloxy) aniline hydrochloride (10.8 g, 31.Ommo 1) and N-methylmorpholine (4.09 ml, 37.2 mmo 1), and add room temperature. And stirred overnight. 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%).

ES I / Mas s: 572 [M + H +] _{NMR (CDC1 3) (5:} 1.80- 1.94 (1.2H, m), 1.96-2.06 (0.8H, m), 2.08-2.36 (1.2H, m), 2.51-2.59 (0.8H 5 m), 2.79 and 2.92 (total 6.OH, each s), 3.45-3.75 (4

H, m), 4.53-4.59 (0.2H, m), 4.81- 4.87 (0.8H, m), 4.94-5.13 (0.3H ₃ m), 5.13 (

I.7H, s), 6.47-6.69 (2.0H ₃ m), 6.84-7.14 (5.1H, m), 7.19-7.26 (0.9H ₃ m), 7.51-7.68 (1.9H, m), 8.26 (0.1H, br s), 8.35-8.2 (1.OH, m), 9.53 (1H ₅ br s)

(R) ― {[2- (3-chloro-1,5-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidine] — 1-yl} 1 2— ( 4-dimethylaminophenyl) ethanone

 (R) — 1— [(4-Dimethylaminophenyl) acetyl] pyrrolidine-1-carboxylic acid [2- (2-bromo-4 monobenzyloxy) phenyl] amide (1.73 g, 3.03 mmo 1 ) To potassium carbonate (1.27 g, 9.19 mmo 1), copper (I) bromide (24. lmg, 0.168 mmol), 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 obtained residue was subjected to silica gel column 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%).

E S I / Mas s: 490 [M + H +]

_{NMR (CDC1 3) δ: 1.52-2.34} (4Η 3 m), 2.92 and 2.96 (total 6. OH, each s) 3 3 .44-3.77 (4.1H, m), 4.34 - 4.41 (0.2H, m) , 4.65-4.72 (0.4H, m), 4.77-4.91 (1.1 H, m), 5.08-5.15 (0.2H ₅ m) ₅ 5.50-5.67 (0.3H ₅ m), 6.34-6.41 (0.7H ₃ m) ₃ 6.65- 7.03 (4.0H ₅ m), 7.06-7.50 (6.5H ₅ m), 7.59 (0.H, br s), 7.91-7.96 (0.2H, m), 8.11 (0.1H ₅ br s)

(R) 13-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e] [1,4] oxa Zepin

 (R) 1 {[2- (3-Chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidine] 1-yl} — 2 -— (4-dimethyla Minophenyl) ethanone (0.97 g, 1.98 mmol) was dissolved in tetrahydrofuran (19.4 ml), sodium borohydride (0.39 g, 10.4 mmol) was added, and the mixture was placed in an ice 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 mmol) and borotrifluoride tetrahydrofuran complex (0.24 ml, 1.99 mmol) were added. . After the reaction solution was heated to 37 ° C. for 24 hours, a 1.5 M aqueous sodium hydroxide solution (16 ml, 24 mmo 1) was added in a water 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 was subjected to silica gel column chromatography, 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

ESI / Mass: 462 [M + H ⁺ ]

NMR (CDCl ₃ ) d: 1.59-1.90 (4H, m), 2.22-2.31 (1H ₅ m), 2.50-2.59 (1H, m), 2.66- 2.84 (3H, m), 2.93 (6H ₃ s), 2.97-3.06 (lH ₅ m), 3.16-3.24 (1H, m), 3.34 (1H ₅ dd, J = 13.0, 9.4Hz), 4.07 (1H, dd, J = 13.0 ₃ 3.7Hz), 5.22 (2H, s), 6.70-6.75 (2H, m), 6.75-6.86 (3H, m), 6.97-7.02 (2H, m), 7.08-7.14 (3H ₅ m), 7.17 (1H, d, J = (7.9Hz)

(R) — 3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-2-ylmethyl] dipenza [b, e] [1,4] oxa Zepinedihydrochloride

 (R) — 3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidine-1-2-ylmethyl] dipento [b, e] [1,4] oxazepine (10. 6 g, 22.9 mmo 1) was dissolved in 2-propanol (10 Oml), and 4 M Shiridani hydrogen / 2-propanol (22.9 ml) was added. The solvent was distilled off under reduced pressure, and to the obtained 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%)

ESI / Mass: 462 [M + H ⁺ ]

_{NMR (CDC1 3) 5: 2.00-2.2K2H} , m), 2.21-2.34 (2H, m), 2.86-2.98 (1H 5 m), 3.03-3.15 (lH, m), 3.19 (6H, s), 3.15 -3.30 (1H, m), 3.47-3.70 (3H, m), 3.90-4.00 (1H, m), 4.24 (1H ₅ dd, J = 14.0, 7.2Hz), 4.65 (1H, dd, J = 14.0, 6.0Hz), 5 .12 (1H, d, J = 12.7Hz) 3 5.40 (1H, d, 12.7Hz) 5 6.87 (1H, dd, J = 7.8, 1.9Hz), 6 .89-7.00 (2H 5 m), 7.03-7.09 (2H ₃ m), 7.14 (1H ₃ d, J = 1.9 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.6Hz)

 (Reference Example 26)

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

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

Palladium acetate (22.3m: 0.10mmol), (2-biphenyl) di-tert-butylphosphine (59.8mg, 0.2 Ommo 1), sodium tert-butoxide (2.40g, 25. Ommo) Toluene (1 Oml) was added to 1), and (4-bromophenyl) acetic acid (2.15 gs 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 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 in an ice bath for a while, the mixture was filtered to obtain the title compound as a pale yellow solid (1.1 gs, 54%).

 ESI / Mass: 206 [M + H +]

 NMR (DMS0_d6) 0 ": 1.90-1.95 (4H, m), 3.15-3.20 (4H, m), 3.38 (2H, s), 6.47 (2H, d, J = 8.4Hz), 7.03 (2H, d, J = 8.4Hz)

 (R) 1 N— ((4-pyrrolidinophenyl) acetyl) 1 D-proline methyl ester

 Methylene chloride (20 ml) was added to (4-pyrrolidinophenyl) acetic acid (2.05 g, 10. Ommo 1) and D-propyl methyl ester hydrochloride (1.66 g, 10. Ommo 1), and triethylamine ( 1. 55 ml, 11. lmmo 1) and N-dimethylaminopropyl-N′-ethylcarposimide hydrochloride (2.11 g 11. Ommo 1) were added. After stirring this mixture at room temperature for 4 hours, the reaction solution was successively washed with water (1 Oml), water (5 ml), 5% aqueous solution of citric acid (5 ml), and 5% aqueous 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%

) o

NMR (CDCl ₃ ) d: 1.85-2.15 (8H, m), 3.23-3.28 (4H ₅ m), 3.31-3.68 (4H, m), 3.68-3.75 (3H, m), 4.40-4.53 (1H ₃ m ), 6.45-6.54 (2H, m), 7.05-7.14 (2H ₃ m)

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

(R) 1-N-[(4-Pyrrolidinophenyl) acetyl] -D-proline methyl ester (30.lg, 94.2 mmol) was dissolved in tetrahydrofuran (150 ml), and water (134 ml) and 6M water were dissolved. An aqueous sodium chloride solution (16.5 mi 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 (CDCl 3) c5: 1.85-} 2.05 (7H, m), 2.45-2.55 (1H, m), 3.23-3.29 (4H, m), 3.45-3.70 (4H 3 m), 4.60-4.64 (1H, m ) ₅ 6.48-6.55 (2H, m), 7.07-7.11 (2H ₃ m) (R) — 1— [(4-Pyrrolidinophenyl) acetyl] pyrrolidine-l- 2-carboxylic acid [2-— (2-promo 5-Fluorobenzyloxy) phenyl] amide (R) — N — [(4-pyrrolidinophenyl) acetyl] -D-proline (2.90 g, 9.59 mmol 1) and toluene (37. 8 ml) and N-methylmorpholine (1.10 g :, 10.8 mmol) were added. Ethyl chloroformate (1.14 g, 10.5 mmol 1) was added in an ice bath, and the mixture was stirred for 2 hours. Here, 2- (2-butamate-5-fluorobenzyloxy) aniline hydrochloride (3.19: 9.59 mmol) and N-methylmorpholine (1.16 g, 11.5 mmol) 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, and the organic layer was separated with water (10 ml), water (10 ml), and 6.7% aqueous sodium bicarbonate (10 ml). , 6.7% aqueous sodium bicarbonate (10 ml), water (10 ml), and water (10 ml). The extract 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) 0-: 1.77-2.20} (7H, m), 2.48-2.57 (1H, m), 3.14-3.25 (4H, m), 3.42-3.67 (4H 3 m), 4.80-4.88 (lH, m), 5.11 (2H, s), 6.29-6.46 (2H, m), 6.80-7.10 (6H, m) ₃ 7.43-7.61 (2H, m), 8.26- 8.39 (1H, m), 9.57 (1H, s) (R) — {[2 -— (2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-1 5-carbonyl) pyrrolidine] -1-yl} —2 -— (4-pyrroli Dinophenyl) ethanone

 (R) —1— [(4-Pyrrolidinophenyl) acetyl] pyrrolidine-1-carbonic acid [2- (2-bromo-5-fluoropentyloxy) phenyl] amide

(5.0 g, 8.6 lmmo 1) and potassium carbonate (3.58 g, 25.9 mmo 1), copper (I) bromide (63.5 mgs 0.443 mmol), 4-picoline (25 ml) 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. After drying over sodium sulfate, 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 (4.16 g, 97%).

E S I / Mas s: 500 [M + H +]

_{NMR (CDC1 3) δ:.} 1.60-2 0 (8Η, m), 3.14-3.35 (4H 5 m), 3.39-3.75 (4H 5 m), 4.29-5.68 (3H, m), 6.32-6.60 (3H , m), 6.77-8.11 (8H, m)

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

(R) — {[2- (2-Fluoro-1,5,11-dihydrodibenzo [b, e] [1,4] oxazepine-1-5-carbonyl) pyrrolidine] -11-yl} —2 -— (4-pyrroli Jinofueniru) ethanone _{(3. 79 g s 7. 59mmo 1} ) was dissolved in Tetorahido port furan (48 ml), was added to sodium borohydride (1. 52g, 40. 2mmo 1 ), in an ice bath Tetrahydrofuran tetraborane complex (7. 38 g, 49.5 mmo 1) 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. Og, 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%).

 E S I / Mas s: 472 [M + H +]

_{NMR (CDC1 3) δ: 1.59-} 1.90 (4Η, m), 1.90-2.10 (4Η, m), 2.18- 2.30 (1Η, m), 2.42-2.58 (1Η 5 m), 2.62-2.83 (3Η, m ), 2.92- 3.08 (1H, m), 3.12-3.38 (6H, m), 4.08 (1H ₅ dd, J = 12.8, 3.0Hz), 5.16 (1H, d, J = 11.8Hz), 5.30 (1H, d, J = 11.8Hz), 6.54 (2H, d, J = 8.5Hz), 6.72-6.86 (3H, m), 6.93- 7.12 (6H, m)

 (R) —2-Fluoro-5,11-dihydro-5- [1-1 (4-pyrrolidinofphenethyl) pyrrolidine-2-ylmethyl] dibenzo [b, e]. Dihydrochloride

 (R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinopheneethyl) pyrrolidine-2-ylmethyl] dipenzo [b, e] [1,4] oxazepine (12.04 :, 25 .5mmo1) was dissolved in 2-propanol (250ml), 4M hydrogen chloride 2-propanol (17.0ml) 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 to obtain the title compound as a pale red solid (14.89 g, 100%). .

ES I / Mass: 472 [M + H ⁺ ] NMR (DMS0-d6) d: 1.76-2.19 (8H, m) ₃ 2.89-3.25 (4H ₅ m), 3.33-3.54 (5H, m 3.54-3.67 (2H ₃ m), 4.10 (1H, dd, J = 13.6, 7.5Hz) ₅ 4.39 (1H, dd, J = 13.6 ₅ 6.5Hz), 5.18 (1H, d, J = 12.0Hz), 5.44 (1H, d, J = 12.1Hz) ₃ 6.72-6.78 (1H , M), 6.83-6.90 (2H, m), 6.96-7.27 (6H, m), 7.31-7.38 (2H, m)

 (Reference Example 27)

 (R) — 5,11-Dihydro-5-CI- (4-pyrrolidinophenethyl) pyrrolidin-1-yl] dibenzo [b, e] [1,4] oxazebine (= Compound of Reference Example 22) )

 (R) — N— C1-(4-Pyrrolidinophenetyl) pyrrolidine-3-yl] -2-1- (2-propybenzyloxy) aniline

 Under an argon stream, 2- (2-bromobenzyloxy) aniline (1.15 g, 4.13 mmol 1) and (S) —3-methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pyrrolidine (0. 30: 0.98 mmo 1) was added and dissolved in acetonitrile (50 ml). Potassium carbonate (1.62 g, 11.7 mmo 1) was added thereto, 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.

(1.40g).

 E S I / Mas s: 520 [M + H +]

 (R) —5,11-dihydro-5- [11- (4-pyrrolidinofphenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazebine

Under an argon stream, (R) -N- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] -12- (2-bromobenzyloxy) aniline (1.40 g, as a mixture) ), Potassium carbonate (1.71 g, 12.4 mmol 1), copper (I) bromide (53 mg, 0.37 mmol 1) and toluene (30 ml) were added. Reaction liquid Was refluxed for 53 hours while heating, and copper (I) bromide (60 mg, 0.42 mmol) was added. The reaction solution was refluxed for another 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).

E S I / Ma s s: 440 [M + H +]

_{NMR (CDC1 3) δ:.} 1.72-1.84 (1H 5 m), 1.92- 2 · 05 (4Η, m), 2.24-2.49 (2Η, m), 2.49-2 7 (5Η 3 m), 2.82- 2.94 (1Η, m), 3.18-3.36 ( 5Η 3 m), 4.68-4.79 (1Η 5 m), 5.19-5.62 (2Η 5 m), 6.48 (2Η, d, J = 8.4Hz), 6.70-6.85 (3H , M), 6.95 (1H, dd, J = 7.8, 1.6 Hz), 7.02 (2H ₅ d, J = 8.6 Hz), 7.03-7.14 (2H, m), 7.25-7.35 (2H, m) Reference Example 1 The compound [V] shown in Table 1 was used in place of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine by the same method as in — (4-Methoxyphenethyl) The compound [II] shown in Table 1 can be prepared by using the compound [VI] shown in Table 1 instead of piperidine.

(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) —11- (4-Dimethylaminophenethyl) —Preparing the compound [III] shown in Table 2 by using the compound [XI] shown in Table 2 instead of 3-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 in place of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, to give 3-pyrrolidinophenethylmethic acid. By using the compound [X] shown in Table 3 instead of the rate, the compound [IV] shown in Table 3 can be prepared.

<Formulation example>

 The formulation examples are described below.

 Reference 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 ingredient 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

 Example of magnesium stearate 1 Omg

Preparation of smooth fascia sample:

The longitudinal muscles of the colon, ileum or aorta of Wistar rats (8 to 12 weeks old, os) are minced, suspended in water-cooled Tris buffer, and homogenized using a Teflon® homogenizer and polytron. did. This was centrifuged, and the supernatant was centrifuged with a cooled ultracentrifuge. The pellet obtained here was resuspended in Tris buffer and used for binding experiments. Protein quantification was performed using Protein Assay Kit (Bio-Rad), using pepsin albumin as a standard solution. [ ³ H] The compound of Reference Example 8 was used as a receptor ligand, and the compound of Reference Example 8, verapamil, diltiazem, and nicardipine were used as Ca antagonists.

After incubating the membrane preparation, Tris buffer, each Ca antagonist, and labeled ligand, the reaction was stopped by suction filtration using glass fiber filter paper (Whatman GF / C). After washing the filter paper with Tris buffer, the radioactivity / radiation dose (dpm) was measured in a liquid scintillation counter. [ ³ H] The specific binding amount of the compound of Reference Example 8 is a value obtained by subtracting the non-specific binding amount obtained when 10 zM of the compound of Reference Example 8 is added from the total binding amount of the receptor ligand. Asked. All experiments were performed with n = 4. The dissociation constant (Kd value), maximum binding number (Bmax), and 50% binding inhibition concentration (IC ₅₀ ) by each Ca antagonist were calculated using the analysis software GraphPad Prism (registered trademark). Table 4 shows the results. Table 4

[ ³ H] The compound of Reference Example 8 shows higher affinity in the colon and ileum than the aorta, and the ability of each compound to inhibit the binding of [ ³ H] Reference Example 8 compound to the compound of Reference Example 8>>verapami>diltiazem> nicardipine.

[ ³ H] The binding of the compound of Reference Example 8 to each tissue was inhibited at the lowest concentration by the compound of Reference Example 8 among the four Ca antagonists used. It was suggested that there is a binding site specific to the compound of Reference Example 8 different from the well-known dihydropyridine binding site, diltiazem binding site, and verapamil binding site. According to the present invention, it is possible to treat a disease accompanied by an organic change in the digestive tract without showing any side effects.

Claims

The scope of the claims

1. A pharmaceutical composition for treating a disease associated with an organic change in the digestive tract, comprising a calcium channel antagonist having intestinal selectivity.

 2. The pharmaceutical composition according to claim 1, wherein the disease associated with a structural change in the digestive tract is gastric ulcer, duodenal ulcer, reflux esophagitis, ulcerative colitis or Crohn's disease.

 3. 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 Hydrates or solvates thereof;

[Wherein, rings G, J and K each represent benzene or nitrogen-containing aromatic group]. 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, ⑩ Wisteria '

WO 03/101489 PCT / JP03 / 06845 represents 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 ^lfl , or R ^1Q and R ¹¹ together represent a —0 (CH ₂ ) n 〇— group (n is 1, 2 or 3). A is any of CH ₂ , CHOH, CO, or 0; B is any of CH ₂ , CHOH, or CO; or A—B represents CH = CH; D is CH ₂ , CH ₂ —CH ₂ or CH ₂ — CH ₂ — Any of 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 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, the 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 ^{3 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 ″ In the case where is not a cyclic amino group represented by the formula [E], one or two of 1 ^ to ¹⁸ are halogen atoms, and the others represent hydrogen atoms.

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

 WO 03/101489 PCT / JP03 / 06845 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, and when X is 0 or S, n is 2 or 3. R ¹ is H or d—C ₄ alkyl; and

R ² is

(a)

(Wherein, R ³ and R ⁴ are each independently H, one C ₄ alkyl, C -! C ₄ alkoxy, -OH, - W Ci- C ₄ alkyl) ₂ヽhalo or - is CF _3. )

0 5 ⑩

 WO 03/101489 PCT / JP03 / 06845

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

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

[3]

[Wherein 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 together ⑩: 禱.

WO 03/101489 PCT / JP03 / 06845-0 (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 and represent a hydrogen atom or a hydroxy group, or together represent = 0. ]

 (IV) 5-alkyl-1,5,11-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 Ri to R 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 group or an alkylamino group; ⁶ and R ⁷ may be the same or different and represent a hydrogen atom or a hydroxy group, or together represent = 〇, and Y ¹ represents a methylene, iodide 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. ⑩

 WO 03/101489 PCT / JP03 / 06845

[Five]

[Wherein, R ¹ to R ⁵ may be the same or different, and represent 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—— 0 (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 2 CH, and D represents either CH ₂ , CH ₂ —CH ₂ or CH ₂ —CH ₂ —CH ₂ , or B—D but it represents a CH _2. ]

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

5. A calcium channel antagonist with intestinal selectivity is represented by the following general formula [II]. ·

 WO 03/101489 PCT / JP03 / 06845 5,11 Dihydrodiaryl [b, e] [1,4] oxazepine derivative, stereoisomer, pharmacologically acceptable salt thereof, The pharmaceutical composition according to claim 1, which is a hydrate or a solvate.

(Wherein the aromatic ring G, J, K,:, ^ ~1 1 3, A, B D represent the same as the formula of claim 3, wherein [I],: r is 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 [III], its stereoisomer 2. The pharmaceutical composition according to claim 1, which is a body, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof.

0 9

(In the formula, the aromatic rings G, J, K, ~ ³ , A, B, and D represent the same as in the formula [I] according to claim 3, and r represents 1 or 2.)

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

(Wherein fragrance璟., J, K, 1 ^ ~1 13, A, B, D are the same as. Things as formula of claim 3, wherein [I], R ^{1 4} is 1 to 3 carbon atoms Represents a lower alkyl group.)

8. 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.

9. A method of screening for a calcium channel binding compound,

(a) a 5,11-dihydrodiamine represented by the general formula [I] according to claim 3, which is labeled; Measuring the amount of the aryl [b, e] [1,4] oxazepine derivative bound to the colon or ileum;

 (b) a colon of a 5,11-dihydrodiaryl [b, e] [1, 4] oxazepine derivative represented by the general formula [I] according to claim 3, which is labeled in the presence of a test compound; Or measuring the amount of binding to the ileal membrane specimen; and

 (c) comparing the result obtained in step (a) with the result obtained in step (b).

 10. Use of a calcium channel antagonist having intestinal selectivity for preparing a pharmaceutical composition for treating a disease involving an organic change in the digestive tract.