JPWO2016167318A1 - Memory improver and use thereof - Google Patents

Abstract

A memory-improving agent and a composition for improving memory, which comprise a compound that is an inverse agonist of an opioid δ receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, represented by the following formula (5): Or a pharmaceutically acceptable salt thereof, or a solvate thereof. [Chemical 1]

Description

  The present invention relates to memory improving agents and uses thereof. More specifically, the present invention relates to a memory improving agent, a memory improving composition and a novel compound. This application claims priority based on Japanese Patent Application No. 2015-084402 for which it applied to Japan on April 16, 2015, and uses the content here.

  An opioid receptor is a cell surface receptor protein involved in expression of the action of a morphine-like substance (opioid), and is at least μ (hereinafter referred to as “opioid μ receptor”), κ (hereinafter referred to as “opioid κ receptor”). ) (Hereinafter referred to as “opioid δ receptor”), three subtypes are known.

  Stimulating opioid mu receptors in the cerebral cortex and thalamus activates the descending inhibitory system and indirectly exerts analgesic action. Moreover, when the opioid μ receptor present in the dorsal horn of the spinal cord is stimulated, nociceptive transmission is directly suppressed and an analgesic action is exhibited. In addition to these, opioid μ receptors are known to have actions such as reduction of gastrointestinal motility, miosis, euphoria, bradycardia, and suppression of neurotransmitters.

  Many opioid κ receptors are present in the hypothalamus and spinal cord, and it is known that when the opioid κ receptor in the spinal cord is activated, analgesia, sedation, miosis, and bradycardia occur.

  Many opioid δ receptors are present in the extrapyramidal pathway and are involved in the regulation and dependence of emotions and neurotransmitters, and are considered to have a weak analgesic effect. As ligands of opioid δ receptors, naltolindole (NTI), naltriben (NTB), 7-benzylidene naltrexone (BNTX) and the like are known (see, for example, Non-Patent Documents 1 to 3).

Portoghese P. S., et al., Application of the message-address concept in the design of highly potent and selective non-peptide delta opioid receptor antagonists, J. Med. Chem., 31 (2), 281-282, 1988. Sofuoglu M., et al., Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for delta opioid receptor subtypes, J. Pharmacol. Exp. Ther., 257 (2), 676-680 , 1991. Portoghese P. S., et al., A highly selective delta 1-opioid receptor antagonist: 7-benzylidenenaltrexone, Eur. J. Pharmacol., 218 (1), 195-196, 1992.

  An object of the present invention is to provide a novel use of an inverse agonist of an opioid δ receptor. The present invention also aims to provide novel compounds.

The present invention is as follows.
[1] A memory improving agent comprising, as an active ingredient, a compound that is an inverse agonist of an opioid δ receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式（１）中、Ｒ^１は、いずれも置換されていてもよい、炭素数１〜５のアルキル基、炭素数４〜７のシクロアルキルアルキル基、炭素数５〜７のシクロアルケニルアルキル基、炭素数６〜１２のアリール基、炭素数６〜１２のヘテロアリール基、炭素数７〜１３のアラルキル基、炭素数４〜７のアルケニル基、アリル基、炭素数１〜５のフラン−２−イルアルキル基、炭素数１〜５のチオフェン−２−イルアルキル基、炭素数１〜６のハロゲン化アルキル基、炭素数１〜６のアルキルカルボニル基、炭素数１〜６のシクロアルキルカルボニル基、炭素数７〜１３のアリールカルボニル基、炭素数６〜１２のヘテロアリールカルボニル基、炭素数６〜１２のアリールアルキルカルボニル基、炭素数６〜１２のヘテロアリールアルキルカルボニル基、炭素数１〜６のアルケニルカルボニル基を表し、Ｒ^２及びＲ^３は、それぞれ独立に、水素原子、ヒドロキシ基、炭素数１〜５のアルカノルオキシ基、炭素数１〜５のアルコキシ基、炭素数７〜１３のアリールカルボニルオキシ基又は炭素数７〜１３のアラルキルオキシ基を表し、Ｘは、下記式（２）

［式（２）中、Ｒ^４は、水素原子、炭素数１〜５のアルキル基若しくは炭素数７〜１３のアラルキル基を表し、Ｒ^５、Ｒ^６及びＲ^７は、それぞれ独立に、水素原子、フッ素原子、塩素原子、臭素原子、ヨウ素原子、ニトロ基、イソチオシアナト基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、フェニル基、アミノ基、炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜３のヒドロキシアルキル基、炭素数３〜７のシクロアルキル基、ＳＲ^８、ＳＯＲ^８、ＳＯ_２Ｒ^８、（ＣＨ_２）_ｍＣＯ_２Ｒ^８（但し、ｍは０〜３の整数、Ｒ^８は炭素数１〜５のアルキル基を表す。）、ＳＯ_２ＮＲ^９Ｒ^１０、ＣＯＮＲ^９Ｒ^１０若しくは（ＣＨ_２）_ｎＮＲ^９Ｒ^１０（但し、ｎは０〜３の整数、Ｒ^９、Ｒ^１０はそれぞれ独立に水素原子、炭素数１〜５のアルキル基若しくは炭素数４〜６のシクロアルキルアルキル基を表す。）を表すか、又はＲ^７は前記定義に同じでかつ、Ｒ^５及びＲ^６を結合して（１）炭素数３〜６のアルキレン基（但し、アルキレン部の水素はＲ^１１（Ｒ^１１は炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜５のアルカノイル基、炭素数１〜５のヒドロキシアルキル基、ＳＲ^８、ＳＯＲ^８、ＳＯ_２Ｒ^８、（ＣＨ_２）_ｍＣＯ_２Ｒ^８、ＳＯ_２ＮＲ^９Ｒ^１０、ＣＯＮＲ^９Ｒ^１０、（ＣＨ_２）_ｎＮＲ^９Ｒ^１０（但し、ｍ、ｎ、Ｒ^８、Ｒ^９及びＲ^１０は前記定義に同じである。））で置換されていてもよく、かつアルキレン基はベンゼン環の隣接する炭素に結合して環を形成する。）、若しくは（２）−Ｓ＝Ｔ−Ｕ＝Ｖ−（Ｓ、Ｔ、Ｕ及びＶは窒素原子若しくはＣＨ（但し、水素原子はＲ^１２（Ｒ^１２はフッ素原子、塩素原子、臭素原子、ヨウ素原子、ニトロ基、イソチオシアナト基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、フェニル基、炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜３のヒドロキシアルキル基、ＳＲ^８、ＳＯＲ^８、ＳＯ_２Ｒ^８、（ＣＨ_２）_ｍＣＯ_２Ｒ^８、ＳＯ_２ＮＲ^９Ｒ^１０、ＣＯＮＲ^９Ｒ^１０若しくは（ＣＨ_２）_ｎＮＲ^９Ｒ^１０（但し、ｍ、ｎ、Ｒ^８、Ｒ^９及びＲ^１０は前記定義に同じである。））で置換されていてもよく、かつベンゼン環の隣接する炭素に結合して環を形成する。）を表す。］又は下記式（３）

［式（３）中、Ｒ^１３及びＲ^１４は、それぞれ独立に、水素原子、フッ素原子、塩素原子、臭素原子、ニトロ基、アミノ基、炭素数１〜５のアルキル基若しくは炭素数１〜５のアルコキシ基を表すか、又はＲ^１３及びＲ^１４が一緒になってベンゾ基を表す。］又は下記式（４）

［式（４）中、Ｒ^５、Ｒ^６及びＲ^７は前記定義に同じである。］を表す。］[2] The memory improving agent according to [1], wherein the inverse agonist is a compound represented by the following formula (1).

[In the formula (1), R ¹ is an optionally substituted alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms, and a cycloalkenylalkyl group having 5 to 7 carbon atoms. An aryl group having 6 to 12 carbon atoms, a heteroaryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an alkenyl group having 4 to 7 carbon atoms, an allyl group, and furan-2 having 1 to 5 carbon atoms. -Ylalkyl group, thiophen-2-ylalkyl group having 1 to 5 carbon atoms, halogenated alkyl group having 1 to 6 carbon atoms, alkylcarbonyl group having 1 to 6 carbon atoms, cycloalkylcarbonyl group having 1 to 6 carbon atoms , An arylcarbonyl group having 7 to 13 carbon atoms, a heteroarylcarbonyl group having 6 to 12 carbon atoms, an arylalkylcarbonyl group having 6 to 12 carbon atoms, and a heteroarylalkylcarbon having 6 to 12 carbon atoms R ² and R ³ each independently represent a hydrogen atom, a hydroxy group, an alkanoloxy group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms. Group, an arylcarbonyloxy group having 7 to 13 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, and X represents the following formula (2)

[In Formula (2), R ⁴ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 7 to 13 carbon atoms, and R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom. , Fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, isothiocyanato group, trifluoromethyl group, trifluoromethoxy group, cyano group, phenyl group, amino group, alkyl group having 1 to 5 carbon atoms, carbon number 1 ˜5 alkoxy group, C 1-3 hydroxyalkyl group, C 3-7 cycloalkyl group, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ (where m Is an integer of 0 to 3, R ⁸ represents an alkyl group having 1 to 5 carbon atoms), SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ or (CH ₂ ) _n NR ⁹ R ¹⁰ (where n is 0 An integer of ~ 3, R ⁹ And R ¹⁰ each independently represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a cycloalkylalkyl group having 4 to 6 carbon atoms), or R ⁷ is the same as defined above, and R ⁵ And R ⁶ (1) an alkylene group having 3 to 6 carbon atoms (provided that the hydrogen in the alkylene portion is R ¹¹ (R ¹¹ is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, alkanoyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon _{^{atoms, SR 8, SOR 8, SO}} 2 R 8, (CH 2) m CO 2 R 8, SO 2 NR 9 R 10, CONR 9 R ¹⁰ , (CH ₂ ) _n NR ⁹ R ¹⁰ (where m, n, R ⁸ , R ⁹ and R ¹⁰ are the same as defined above)), and the alkylene group is a benzene ring Bonded to adjacent carbons to form a ring Or (2) -S = TU = V- (S, T, U and V are nitrogen atoms or CH (however, hydrogen atoms are R ¹² (R ¹² is fluorine atom, chlorine atom, bromine) Atom, iodine atom, nitro group, isothiocyanato group, trifluoromethyl group, trifluoromethoxy group, cyano group, phenyl group, alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, 1 to 3 carbon atoms Hydroxyalkyl group, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ or (CH ₂ ) _n NR ⁹ R ¹⁰ (provided that m, n, R ⁸ , R ⁹ and R ¹⁰ are the same as defined above. )) And may be substituted with the adjacent carbon of the benzene ring to form a ring. ). ] Or the following formula (3)

[In Formula (3), R ¹³ and R ¹⁴ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, an amino group, an alkyl group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms. Or R ¹³ and R ¹⁴ together represent a benzo group. ] Or the following formula (4)

[In the formula (4), R ⁵ , R ⁶ and R ⁷ are the same as defined above. ]. ]

[3] R ¹ may be any substituted benzyl group, heteroarylmethyl group, fluoroalkyl group having 1 to 6 carbon atoms, cycloalkylcarbonyl group having 1 to 6 carbon atoms, 7 to 7 carbon atoms The memory improving agent according to [1] or [2], which is a 13 arylcarbonyl group or a heteroarylcarbonyl group having 6 to 12 carbon atoms.

[4] A memory improving composition comprising the memory improving agent according to any one of [1] to [3] and a pharmaceutically acceptable carrier.

［式（５）中、Ｒ^１ｂは、いずれも置換されていてもよい、炭素数１〜６のアルキルカルボニル基、炭素数１〜６のシクロアルキルカルボニル基、炭素数７〜１３のアリールカルボニル基、炭素数６〜１２のヘテロアリールカルボニル基、炭素数６〜１２のアリールアルキルカルボニル基、炭素数６〜１２のヘテロアリールアルキルカルボニル基、炭素数１〜６のアルケニルカルボニル基を表し、Ｒ^２ｂ、Ｒ^３ｂ及びＸ^ｂは、それぞれ前記式（１）におけるＲ^２、Ｒ^３及びＸの定義に同じである。］[5] A compound represented by the following formula (5), a pharmaceutically acceptable salt thereof, or a solvate thereof.

[In Formula (5), R ^1b is an optionally substituted alkylcarbonyl group having 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 1 to 6 carbon atoms, and an arylcarbonyl group having 7 to 13 carbon atoms. Represents a heteroarylcarbonyl group having 6 to 12 carbon atoms, an arylalkylcarbonyl group having 6 to 12 carbon atoms, a heteroarylalkylcarbonyl group having 6 to 12 carbon atoms, an alkenylcarbonyl group having 1 to 6 carbon atoms, R ^2b , R ^3b and X ^b are the same as the definitions of R ² , R ³ and X in the formula (1), respectively. ]

  ADVANTAGE OF THE INVENTION According to this invention, the novel use of the inverse agonist of an opioid delta receptor can be provided. In addition, novel compounds can be provided.

6 is a graph showing the results of [ ³⁵ S] GTPγS binding assay in Experimental Example 1. 6 is a graph showing the results of [ ³⁵ S] GTPγS binding assay in Experimental Example 1. 6 is a graph showing the results of [ ³⁵ S] GTPγS binding assay in Experimental Example 1. 6 is a graph showing the results of [ ³⁵ S] GTPγS binding assay in Experimental Example 1. 6 is a graph showing the results of [ ³⁵ S] GTPγS binding assay in Experimental Example 1. In Experimental example 2, it is a graph which shows the result of having examined the learning function of the mouse | mouth under restraint stress. In Experimental example 3, it is a graph which shows the result of having examined the learning function of the mouse | mouth under restraint stress.

[Memory improver]
In one embodiment, the present invention provides a memory improving agent comprising, as an active ingredient, a compound that is an inverse agonist of an opioid δ receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof.

  As will be described later, the inventors have found that an inverse agonist of the opioid δ receptor has an effect of improving memory. Although it is known that a psychiatric disorder related to the onset of stress such as depression and anxiety disorder causes a decrease in memory, the memory improving agent of the present embodiment has an effect of improving such symptoms.

  In the present specification, the memory improvement effect means an effect of improving a decrease in memory that is known to occur in a mental illness related to the onset of stress such as depression and anxiety disorder, and an improvement effect of learning function, It can also be said to be an anti-stress effect and an effect of improving the learning function under stress.

  Examples of the compound that is an inverse agonist of the opioid δ receptor include compounds represented by the following formula (1).

In formula (1), R ¹ may be any substituted alkyl group having 1 to 5 carbon atoms, cycloalkylalkyl group having 4 to 7 carbon atoms, cycloalkenylalkyl group having 5 to 7 carbon atoms, C6-C12 aryl group, C6-C12 heteroaryl group, C7-C13 aralkyl group, C4-C7 alkenyl group, allyl group, C1-C5 furan-2- An ylalkyl group, a thiophen-2-ylalkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 1 to 6 carbon atoms, C7-13 arylcarbonyl group, C6-C12 heteroarylcarbonyl group, C6-C12 arylalkylcarbonyl group, C6-C12 heteroarylalkylcarbonyl Group, an alkenylcarbonyl group having 1 to 6 carbon atoms, R ² and R ³ each independently represent a hydrogen atom, a hydroxy group, an alkanoloxy group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms. Represents an arylcarbonyloxy group having 7 to 13 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, and X represents the following formula (2), the following formula (3) or the following formula (4).

式（２）中、Ｒ^４は、水素原子、炭素数１〜５のアルキル基若しくは炭素数７〜１３のアラルキル基を表し、Ｒ^５、Ｒ^６及びＲ^７は、それぞれ独立に、水素原子、フッ素原子、塩素原子、臭素原子、ヨウ素原子、ニトロ基、イソチオシアナト基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、フェニル基、アミノ基、炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜３のヒドロキシアルキル基、炭素数３〜７のシクロアルキル基、ＳＲ^８、ＳＯＲ^８、ＳＯ_２Ｒ^８、（ＣＨ_２）_ｍＣＯ_２Ｒ^８（但し、ｍは０〜３の整数、Ｒ^８は炭素数１〜５のアルキル基を表す。）、ＳＯ_２ＮＲ^９Ｒ^１０、ＣＯＮＲ^９Ｒ^１０若しくは（ＣＨ_２）_ｎＮＲ^９Ｒ^１０（但し、ｎは０〜３の整数、Ｒ^９、Ｒ^１０はそれぞれ独立に水素原子、炭素数１〜５のアルキル基若しくは炭素数４〜６のシクロアルキルアルキル基を表す。）を表すか、又はＲ^７は前記定義に同じでかつ、Ｒ^５及びＲ^６を結合して（１）炭素数３〜６のアルキレン基（但し、アルキレン部の水素はＲ^１１（Ｒ^１１は炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜５のアルカノイル基、炭素数１〜５のヒドロキシアルキル基、ＳＲ^８、ＳＯＲ^８、ＳＯ_２Ｒ^８、（ＣＨ_２）_ｍＣＯ_２Ｒ^８、ＳＯ_２ＮＲ^９Ｒ^１０、ＣＯＮＲ^９Ｒ^１０、（ＣＨ_２）_ｎＮＲ^９Ｒ^１０（但し、ｍ、ｎ、Ｒ^８、Ｒ^９及びＲ^１０は前記定義に同じである。））で置換されていてもよく、かつアルキレン基はベンゼン環の隣接する炭素に結合して環を形成する。）、若しくは（２）−Ｓ＝Ｔ−Ｕ＝Ｖ−（Ｓ、Ｔ、Ｕ及びＶは窒素原子若しくはＣＨ（但し、水素原子はＲ^１２（Ｒ^１２はフッ素原子、塩素原子、臭素原子、ヨウ素原子、ニトロ基、イソチオシアナト基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、フェニル基、炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、炭素数１〜３のヒドロキシアルキル基、ＳＲ^８、ＳＯＲ^８、ＳＯ_２Ｒ^８、（ＣＨ_２）_ｍＣＯ_２Ｒ^８、ＳＯ_２ＮＲ^９Ｒ^１０、ＣＯＮＲ^９Ｒ^１０若しくは（ＣＨ_２）_ｎＮＲ^９Ｒ^１０（但し、ｍ、ｎ、Ｒ^８、Ｒ^９及びＲ^１０は前記定義に同じである。））で置換されていてもよく、かつベンゼン環の隣接する炭素に結合して環を形成する。）を表す。

In formula (2), R ⁴ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 7 to 13 carbon atoms, and R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom, Fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, isothiocyanato group, trifluoromethyl group, trifluoromethoxy group, cyano group, phenyl group, amino group, alkyl group having 1 to 5 carbon atoms, 1 to carbon atoms 5 alkoxy groups, C 1-3 hydroxyalkyl groups, C 3-7 cycloalkyl groups, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ (where m is An integer of 0 to 3, R ⁸ represents an alkyl group having 1 to 5 carbon atoms), SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ or (CH ₂ ) _n NR ⁹ R ¹⁰ (where n is 0 to 0) 3 of integer, ^{R 9} R ¹⁰ each independently represent a hydrogen atom, or represents a representative.) The cycloalkylalkyl group having 4 to 6 alkyl or C1-5 atoms, or R ⁷ and the same as defined above, R ⁵ and R ⁶ is bonded to (1) an alkylene group having 3 to 6 carbon atoms (provided that hydrogen in the alkylene part is R ¹¹ (R ¹¹ is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, carbon C 1-5 alkanoyl group, C 1-5 hydroxyalkyl group, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , (CH ₂ ) _n NR ⁹ R ¹⁰ (wherein m, n, R ⁸ , R ⁹ and R ¹⁰ are the same as defined above)), and the alkylene group is a benzene ring Bond to adjacent carbon to form a ring Or (2) -S = TU = V- (S, T, U and V are nitrogen atoms or CH (however, hydrogen atoms are R ¹² (R ¹² is fluorine atom, chlorine atom, bromine atom) , Iodine atom, nitro group, isothiocyanato group, trifluoromethyl group, trifluoromethoxy group, cyano group, phenyl group, alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, 1 to 3 carbon atoms Hydroxyalkyl group, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ or (CH ₂ ) _n NR ⁹ R ¹⁰ (provided that m , N, R ⁸ , R ⁹ and R ¹⁰ are the same as defined above. )) And may be substituted with the adjacent carbon of the benzene ring to form a ring. ).

式（３）中、Ｒ^１３及びＲ^１４は、それぞれ独立に、水素原子、フッ素原子、塩素原子、臭素原子、ニトロ基、アミノ基、炭素数１〜５のアルキル基若しくは炭素数１〜５のアルコキシ基を表すか、又はＲ^１３及びＲ^１４が一緒になってベンゾ基を表す。

In formula (3), R ¹³ and R ¹⁴ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, an amino group, an alkyl group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms. Represents an alkoxy group, or R ¹³ and R ¹⁴ together represent a benzo group;

式（４）中、Ｒ^５、Ｒ^６及びＲ^７は前記定義に同じである。

In formula (4), R ⁵ , R ⁶ and R ⁷ are the same as defined above.

  The compound represented by the formula (1) may be a free form or a pharmaceutically acceptable salt. Further, it may be a free solvate or a salt solvate. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloride, sulfate, hydrobromide, hydroiodide, phosphate, nitrate, benzoate, methanesulfone Acid salt, 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleic acid Examples include salts, fumarate, malate, mandelate and the like. The solvate is not particularly limited as long as it is a pharmaceutically acceptable solvate, and examples thereof include hydrates and organic solvates.

In the memory improving agent of the present embodiment, as a more limited example of the compound that is an inverse agonist of the opioid δ receptor, in the compound represented by the above formula (1), all of R ¹ are substituted. Benzyl group, heteroarylmethyl group, fluoroalkyl group having 1 to 6 carbon atoms, cycloalkylcarbonyl group having 1 to 6 carbon atoms, arylcarbonyl group having 7 to 13 carbon atoms or heteroaryl having 6 to 12 carbon atoms The compound which is a carbonyl group is mentioned. Examples of the substituent for R ¹ include halogen atoms such as fluorine atom and chlorine atom; hydroxy group and the like.

  Here, examples of the optionally substituted heteroarylmethyl group include a 2-pyridylmethyl group, a 3-pyridylmethyl group, and a 4-pyridylmethyl group.

  Examples of the optionally substituted fluoroalkyl group having 1 to 6 carbon atoms include a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a pentafluoroethyl group, and a heptafluoropropyl group. , Pentafluoropropyl group, hexafluoroisopropyl group and the like.

  Examples of the optionally substituted cycloalkylcarbonyl group having 1 to 6 carbon atoms include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, and a cycloheptylcarbonyl group.

  Moreover, as a C7-C13 arylcarbonyl group which may be substituted, a benzoyl group, a benzylcarbonyl group, etc. are mentioned, for example.

  Moreover, as a C6-C12 heteroaryl carbonyl group which may be substituted, a pyridyl carbonyl group, a pyrimidyl carbonyl group, etc. are mentioned, for example.

(Method for synthesizing compound represented by formula (1))
The compound represented by the above formula (1) can be synthesized, for example, according to the synthesis scheme (1) shown below. As an example, among the compounds represented by the above formula (1), R ² is a methoxy group, X is the compound (1-1) of the above formula (2), and R ² is a hydroxy group, A method for synthesizing the compound (1-2) in which is the formula (2) will be described below.

In the synthesis scheme ^{(1), R 1a} of R 1a -COOH is as defined for ^{R 1} in the formula ^{(1), L} 1 represents a leaving group typical acylating agents, Ar ¹ is phenyl R ¹⁵ represents an alkyl group or two R ¹⁵ together to represent an alkylene group. Ar ¹ is ^R 5, may be substituted by ^{R 6} and ^{R 7,} wherein ^R 5, the definition of ^{R 6} and ^{R 7} are as defined for ^R 5, ^{R 6} and ^{R 7} in the formula (2) It is.

  In Synthesis Scheme (1), compound A-1 was synthesized by Peter G. et al. M.M. Wuts and Thododora W. It can be synthesized from noroxycodone using the general acetalization conditions described in "Green's Protective Groups in Organic Synthesis" (5th edition, published by John Wiley & Son's).

Compound A-2 is optionally synthesized in the presence of an additive such as 1-hydroxybenzotriazole (HOBT) and a base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP), and the like. Acid (R ^1a —COOH), and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1- (3 A condensing agent such as -diethylaminopropyl) -3-ethylcarbodiimide (EDCI), N, N'-dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent) in a suitable solvent It can be synthesized by acting.

Alternatively, compound A-2 is prepared by reacting compound A-1 with an acylating agent (R ^1a such as carboxylic acid halide or carboxylic anhydride) in the presence of a base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP). It can also be synthesized by reacting —COL ¹ ) in a suitable solvent.

  Compound A-3 can be synthesized by reducing compound A-2 in a suitable solvent with a reducing agent such as borane or lithium aluminum hydride.

  Compound A-4 was prepared by Peter G. et al. M.M. Wuts and Thododora W. It can be synthesized from compound A-3 using the general deacetalization conditions described in "Green's Protective Groups in Organic Synthesis" (5th edition, published by John Wiley & Son's).

Compound (1-1) is an inorganic acid such as hydrochloric acid or sulfuric acid; a carboxylic acid such as acetic acid or trifluoroacetic acid; a compound A-4 and hydrazine in the presence of an acid such as sulfonic acid such as camphorsulfonic acid or methanesulfonic acid. It can be synthesized by reacting (Ar ¹ NHNH ₂ ) in a suitable solvent. At this time, hydrazine may be either a free base or an acid adduct.

  Compound (1-2) was prepared according to Peter G. et al. M.M. Wuts and Thododora W. Can be synthesized from compound (1-1) using general demethylation conditions described in “Green's Protective Groups in Organic Synthesis” (5th edition, published by John Wiley & Son's) by Green .

  Compound A-3 in the synthesis scheme (1) can also be synthesized according to the synthesis scheme (2) shown below.

In the synthesis scheme ^{(2), R 1a} of R 1a -CHO is as defined for ^{R 1} in the formula ^{(1), L} 1 represents a leaving group typical alkylating ^{agent, R 15} is alkyl A group or two R ¹⁵ together represent an alkylene group.

In Synthesis Scheme (2), Compound A-3 is obtained by reacting Compound A-1 with an aldehyde (R ^1a -CHO), sodium borohydride, trihydride in the presence of an additive such as acetic acid as necessary. It can be synthesized by reacting a reducing agent such as sodium acetoxyborohydride or sodium cyanoborohydride in an appropriate solvent. The above reduction reaction may be a catalytic hydrogenation reaction using palladium or the like as a catalyst.

Alternatively, the compound A-3 is obtained by appropriately using an alkylating agent (R ¹ -L ¹ ) such as an alkyl halide or an alkylsulfonic acid ester in the presence of a base such as triethylamine or diisopropylethylamine with respect to the compound A-1. It can also be synthesized by acting in a solvent. At this time, an additive such as sodium iodide may be added.

  Compound (1-1) in the above synthesis scheme (1) can also be synthesized by the following synthesis scheme (3).

In the synthesis scheme ^{(3), R 1a} of R 1a -CHO is as defined for ^{R 1} in the formula ^{(1), L} 1 represents a leaving group typical alkylating agents, Ar ¹ is phenyl Represents a group. Ar ¹ is ^R 5, may be substituted by ^{R 6} and ^{R 7,} wherein ^R 5, the definition of ^{R 6} and ^{R 7} are as defined for ^R 5, ^{R 6} and ^{R 7} in the formula (2) It is.

In the synthesis scheme (3), the compound A-5 can be synthesized in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid; a carboxylic acid such as acetic acid or trifluoroacetic acid; an acid such as sulfonic acid such as camphorsulfonic acid or methanesulfonic acid; It can be synthesized by reacting oxycodone and hydrazine (Ar ¹ NHNH ₂ ) in a suitable solvent. At this time, hydrazine may be either a free base or an acid adduct.

Compound (1-1) is an aldehyde (R ^1a -CHO) and sodium borohydride, sodium triacetoxyborohydride, hydrogen in the presence of an additive such as acetic acid as necessary with respect to compound A-5. It can be synthesized by reacting a reducing agent such as sodium cyanoborohydride in an appropriate solvent. The above reduction reaction may be a catalytic hydrogenation reaction using palladium or the like as a catalyst.

Alternatively, the compound (1-1) is obtained by adding an alkylating agent (R ¹ -L ¹ ) such as an alkyl halide or an alkylsulfonic acid ester to the compound A-5 in the presence of a base such as triethylamine or diisopropylethylamine. It can also be synthesized by acting in an appropriate solvent. At this time, an additive such as sodium iodide may be added.

  The compound (1-1) in the synthesis scheme (1) can also be synthesized via the compound (1-3) as in the synthesis scheme (4) shown below.

In Synthesis Scheme ^{(4), R 1a} of R 1a -COOH is as defined for ^{R 1} in the formula ^{(1), L} 1 represents a leaving group typical acylating agents, Ar ¹ is phenyl Represents a group. Ar ¹ is ^R 5, may be substituted by ^{R 6} and ^{R 7,} wherein ^R 5, the definition of ^{R 6} and ^{R 7} are as defined for ^R 5, ^{R 6} and ^{R 7} in the formula (2) It is.

In the synthesis scheme (4), compound (1-3) is compound A-5, carboxylic acid (R ^1a -COOH) in the presence of an additive such as HOBT and a base such as triethylamine, diisopropylethylamine, and DMAP as necessary. ), And a condensing agent such as HATU, EDCI, DCC, BOP reagent and the like in a suitable solvent.

Alternatively, the compound (1-3) is obtained by reacting the compound A-5 with an acylating agent (R ^1a -COL ¹ ) such as a carboxylic acid halide or carboxylic anhydride in the presence of a base such as triethylamine, diisopropylethylamine, or DMAP. It can also be synthesized by acting in an appropriate solvent.

  Compound (1-1) can be synthesized by reducing compound (1-3) in a suitable solvent with a reducing agent such as borane or lithium aluminum hydride.

Among the compounds represented by the formula (1), the compound (1-4) in which R ² is a hydroxy group and X is the formula (3) is synthesized according to the synthesis scheme (5) shown below. be able to.

In the synthesis scheme (5), R ¹ is the same as the definition of R ¹ in the above formula (1), and Ar ² represents a phenyl group. Ar ² may be substituted by ^{R 13} and ^{R 14,} wherein in the definition of ^{R 13} and ^{R 14} is as defined for ^{R 13} and ^{R 14} in the formula (3).

  In synthesis scheme (5), compound A-6 was synthesized by Peter G. et al. M.M. Wuts and Thododora W. It can be synthesized from compound A-4 using the general demethylation conditions described in "Green's Protective Groups in Organic Synthesis" (5th edition, published by John Wiley & Son's).

Compound (1-4) is described, for example, in J. Am. Med. Chem. 1991, 34, 1715. It can be synthesized by reacting compound A-6 and reagent Ar ² -ONH ₂ using the reaction conditions described. At this time, the reagent Ar ² -ONH ₂ may be either a free base or an acid adduct.

Among the compounds represented by the above formula (1), the compound (1-5) in which R ² is a hydroxy group and X is the above formula (4) is synthesized by the synthesis scheme (6) shown below. Can do.

In the synthesis scheme (6), R ¹ is the same as the definition of R ¹ in the above formula (1), and Ar ¹ represents a phenyl group. Ar ¹ is ^R 5, may be substituted by ^{R 6} and ^{R 7,} wherein ^R 5, the definition of ^{R 6} and ^{R 7} are as defined for ^R 5, ^{R 6} and ^{R 7} in the formula (2) It is.

In the synthesis scheme (6), the compound (1-5) is, for example, J.I. Med. Chem. 1991, 34, 1292. Or Bioorg. Med. Chem. Lett. 2012, 22, 5174. Can be synthesized by reacting compound A-6 with aldehyde Ar ¹ -CHO using the reaction conditions described in ¹ .

Among the compounds represented by the formula (1), the compound (1-8) in which R ² is hydrogen can be synthesized by the synthesis scheme (7) shown below.

In the synthesis scheme (7), R ¹ and X are the same as the definitions of R ¹ and X in the above formula (1). Compound (1-7) is compound (1-6), trifluoromethanesulfonic acid halide, trifluoromethanesulfonic anhydride, and N-phenylbis (trifluoromethanesulfonimide) in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine. ) And other trifluoromethanesulfonylating agents (Tf-L ² ) can be synthesized in a suitable solvent. Compound (1-8) can be synthesized by subjecting compound (1-7) to a reduction reaction using a palladium catalyst in an appropriate solvent. As palladium, palladium (II) compounds such as palladium chloride and palladium acetate, and palladium (0) compounds such as tetrakis (triphenylphosphine) palladium and bis (dibenzylideneacetone) palladium can be used. As the hydrogen source, formic acid, sodium borohydride, triethylsilane, or the like can be used. Monodentate phosphine ligands such as triphenylphosphine and tri (tert-butyl) phosphine, 1,3-bis (diphenylphosphino) propane (dppp), 1,4-bis (diphenylphosphino) butane (dppb), Bidentate phosphine ligands such as 1,1′-bis (diphenylphosphino) ferrocene (dppf), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) You may react.

[Memory improving composition]
In one embodiment, the present invention provides a memory improving composition comprising the above memory improving agent and a pharmaceutically acceptable carrier.

  The composition for improving memory of the present embodiment is, for example, orally in the form of tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, etc. It can be administered parenterally in the form of an agent, an external preparation for skin and the like.

  Examples of the pharmaceutically acceptable carrier include excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, diluents, solvents for injections, and the like. A pharmaceutically acceptable carrier can be used alone or in combination of two or more.

  The memory improving composition of the present embodiment may further contain additives such as preservatives, antioxidants, pH adjusters, fragrances, and coloring agents. An additive can be used individually by 1 type or in mixture of 2 or more types.

  Examples of the excipient include organic excipients and inorganic excipients. Examples of the organic excipient include sugar derivatives such as lactose and sucrose; starch derivatives such as corn starch and potato starch; cellulose derivatives such as crystalline cellulose; gum arabic and the like. Examples of inorganic excipients include sulfates such as calcium sulfate.

  Examples of the binder include gelatin, polyvinyl pyrrolidone, polyethylene glycol and the like.

  Examples of the disintegrant include starch or cellulose derivatives such as croscarmellose sodium and carboxymethyl starch sodium; and cross-linked polyvinyl pyrrolidone.

  Examples of the lubricant include talc; stearic acid; colloidal silica; waxes such as beeswax and geirow; sulfates such as sodium sulfate; lauryl sulfates such as sodium lauryl sulfate and the like.

  Examples of the emulsifier include colloidal clays such as bentonite and bee gum; anionic surfactants such as sodium lauryl sulfate; cationic surfactants such as benzalkonium chloride; nonionic surfactants such as polyoxyethylene alkyl ether And (poly) glyceryl fatty acid ester surfactants such as polyglyceryl stearate-10, polyglyceryl distearate-10, polyglyceryl tristearate-10 and polyglyceryl-10 pentastearate.

  Examples of the stabilizer include parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol; phenols such as phenol and cresol.

  Examples of the diluent include water, ethanol, propylene glycol and the like.

  Examples of the solvent for injection include water, ethanol, glycerin, physiological saline, glucose solution and the like.

(Method of administration)
The administration method of the memory-improving agent or the memory-improving composition is not particularly limited, and may be appropriately determined according to the patient's symptoms, body weight, age, sex, and the like. For example, tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions and the like are administered orally. Injectables are administered alone or mixed with normal fluids such as glucose and amino acids, and administered intravenously, and further administered intraarterially, intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. Suppositories are administered rectally. The external preparation for skin is applied, affixed or sprayed on the affected area.

(Dose)
The dosage of the memory-improving agent or the composition for improving memory varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but in the case of oral administration, for example, 1 μg to 10 g per day, for example What is necessary is just to administer the active ingredient of 0.01-2000 mg per day. In the case of injections, for example, 0.1 μg to 1 g per day, for example 0.001 to 200 mg per day, may be administered. In the case of a suppository, for example, 1 μg to 10 g per day, for example, 0.01 to 2000 mg per day may be administered. In the case of an external preparation for skin, for example, 1 μg to 10 g per day, for example, 0.01 to 2000 mg per day may be administered.

  In one embodiment, the present invention provides a method for improving memory comprising the step of administering a compound represented by the above formula (1) to a mammal. Here, the improvement of memory can also be called suppression of a decrease in memory under stress, improvement of a learning function, improvement of a learning function under stress, and so on.

  In one embodiment, the present invention provides a compound represented by formula (1) above for the treatment of memory loss. Here, the decrease in memory means a decrease in memory that is known to occur in a mental disease related to the onset of stress.

  In one embodiment, the present invention provides the use of a compound represented by the above formula (1) for producing a memory improving agent.

[New compound]
In one embodiment, the present invention provides a novel compound represented by the following formula (5), a pharmaceutically acceptable salt thereof, or a solvate thereof.

式（５）中、Ｒ^１ｂは、いずれも置換されていてもよい、炭素数１〜６のアルキルカルボニル基、炭素数１〜６のシクロアルキルカルボニル基、炭素数７〜１３のアリールカルボニル基、炭素数６〜１２のヘテロアリールカルボニル基、炭素数６〜１２のアリールアルキルカルボニル基、炭素数６〜１２のヘテロアリールアルキルカルボニル基、炭素数１〜６のアルケニルカルボニル基を表し、Ｒ^２ｂ、Ｒ^３ｂ及びＸ^ｂは、それぞれ上記式（１）におけるＲ^２、Ｒ^３及びＸの定義と同じである。

In Formula (5), R ^1b may be any substituted alkyl group having 1 to 6 carbon atoms, cycloalkyl carbonyl group having 1 to 6 carbon atoms, arylcarbonyl group having 7 to 13 carbon atoms, Represents a heteroarylcarbonyl group having 6 to 12 carbon atoms, an arylalkylcarbonyl group having 6 to 12 carbon atoms, a heteroarylalkylcarbonyl group having 6 to 12 carbon atoms, and an alkenylcarbonyl group having 1 to 6 carbon atoms, R ^2b , R ^3b and ^Xb are the same as the definitions of R ² , R ³ and X in the above formula (1), respectively.

  The novel compound of this embodiment is useful, for example, as a memory improving agent. In the present specification, the improvement of memory means an improvement of a decrease in memory that is known to occur in a mental illness related to the onset of stress such as depression, anxiety disorder, etc. It can also be called suppression, improvement of learning function, improvement of learning function under stress, and anti-stress.

  EXAMPLES Next, although an Example is shown and this invention is demonstrated further in detail, this invention is not limited to a following example.

<Experimental example 1>
[Synthesis of compounds]
(Synthesis Example 1)
6,7-didehydro-4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 5 )

<< Step 1 >> Synthesis of 4,5α-epoxy-6,6-ethylenedioxy-17- (2,2,2-trifluoroethyl) -3-methoxymorphinan-14β-ol (Compound 3)

  Nagase H. et al., Investigation of Beckett-Casy model 2: synthesis of novel 15-16 nornaltrexone derivatives and their pharmacology, Bioorg. Med. Chem. Lett., 20, 3726-3729, 2010 Compound 1 (130 mg, 0.38 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic anhydride (TFAA) (159 μL, 1.13 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. An aqueous sodium hydride solution was added. The mixture was extracted three times with chloroform, and the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product of compound 2 was used in the next reaction without purification.

  The crude product of compound 2 (135 mg, 0.31 mmol) was dissolved in tetrahydrofuran (THF) (3 mL), a 1.0 M THF solution of borane-THF complex (1.83 mL, 1.83 mmol) was added and heated for 1 hour. Refluxed. After allowing to cool, 4M aqueous sodium hydroxide solution (2 mL) was added under ice-cooling, and the mixture was stirred for 3 hours at room temperature. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, hexane: ethyl acetate = 4: 1) to give the title compound 3 (151 mg, 2-step yield 88%) as a white powder material.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45-1.62 (m, 4H), 2.19-2.36 (m, 2H), 2.50 (dt, J = 3.8, 11 .9 Hz, 1H), 2.62-2.70 (m, 1H), 2.75-2.84 (m, 1H), 2.91-3.14 (m, 4H), 3.75-3 .82 (m, 1H), 3.85-3.94 (m, 1H), 3.87 (s, 3H), 3.99-4.05 (m, 1H), 4.16-4.22 (M, 1H), 4.50 (d, J = 2.1 Hz, 1H), 4.57 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.76 (d , J = 8.2 Hz, 1H).
MS (ESI): m / z 450 [M + Na] ⁺ .

<< Step 2 >> Synthesis of 4,5α-epoxy-17- (2,2,2-trifluoroethyl) -14β-hydroxy-3-methoxymorphinan-6-one (Compound 4)

  Compound 3 (399 mg, 0.97 mmol) was dissolved in methanol (5 mL), 2M hydrochloric acid (5 mL) was added, and the mixture was refluxed for 2 hours. After allowing to cool, 4M aqueous sodium hydroxide solution (4 mL) and purified water were added to the reaction solution, followed by extraction three times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, Concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform: hexane = 1: 1-2: 1) to give the title compound 4 (329 mg, 94%) as a white amorphous.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.55-1.65 (m, 2H), 1.85-1.92 (m, 1H), 2.29 (dt, J = 3.1, 14) .4 Hz, 1H), 2.41-2.55 (m, 2H), 2.69-2.83 (m, 2H), 2.96-3.18 (m, 5H), 3.89 (s) 3H), 4.57 (d, J = 1.7 Hz, 1H), 4.66 (s, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1 H).
MS (ESI): m / z 406 [M + Na] ^< +>.

<< Step 3 >> 6,7-didehydro-4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β- Synthesis of all (compound 5)

  Compound 4 (179 mg, 0.49 mmol) was dissolved in acetic acid (5 mL), phenylhydrazine hydrochloride (143 mg, 0.98 mmol) was added, and the mixture was refluxed for 1 hour. After cooling, the mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (5 mL) and purified water were added, extracted three times with chloroform, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. . The resulting crude product was purified by silica gel column chromatography (40-100 μm, hexane: ethyl acetate = 4: 1-3: 1) to give the title compound 5 (209 mg, 90%) as a brown amorphous.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.80-1.87 (m, 1H), 2.47 (dt, J = 5.5, 12.7 Hz, 1H), 2.58-2.73 (M, 2H), 2.73-2.83 (m, 1H), 2.94 (d, J = 5.6 Hz, 1H), 3.01-3.20 (m, 4H), 3.22 -3.30 (m, 1H), 3.77 (s, 3H), 4.38 (d, J = 1.8 Hz, 1H), 5.86 (s, 1H), 6.61-6.68 (M, 2H), 7.01-7.07 (m, 1H), 7.12-7.20 (m, 1H), 7.23-7.36 (m, 1H), 7.40-7 .47 (m, 1H), 8.22 (s, 1H).
MS (ESI): m / z 457 [M + H] ^< +>.

(Synthesis Example 2)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2,2,2-trifluoroethyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 6)

  Compound 5 (209 mg, 0.47 mmol) was dissolved in dichloromethane (10 mL), 1M boron tribromide-dichloromethane solution (2.8 mL, 2.8 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 25% aqueous ammonia (5 mL) and purified water under ice-cooling, followed by extraction three times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. did. The resulting crude product was purified by preparative TLC (0.5 mm, ammonia-saturated chloroform: methanol = 20: 1) to give the title compound 6 (87 mg, 43%) as a brown amorphous.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.74-1.82 (m, 1H), 2.45 (dt, J = 5.5, 12.7 Hz, 1H), 2.58-2.71 (M, 2H), 2.75 (dd, J = 5.0, 11.4 Hz, 1H), 2.93 (d, J = 15.8 Hz, 1H), 2.97-3.19 (m, 4H), 3.23 (d, J = 5.6 Hz, 1H), 4.47 (d, J = 1.6 Hz, 1H), 5.40-5.46 (brs, 1H), 5.71 ( s, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 7.01-7.06 (m, 1H), 7 .12-7.18 (m, 1H), 7.23-7.29 (m, 1H), 7.39-7.43 (m, 1H), 8.24 (s, 1H).
MS (ESI): m / z 443 [M + H] ^< +>.

(Synthesis Example 3)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2,2-difluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 10)

<< Step 1 >> Synthesis of (4,5α-epoxy-6,6-ethylenedioxy-14β-hydroxy-3-methoxymorphinan-17-yl) -2,2-difluoroethane-1-one (Compound 7)

  Compound 1 (200 mg, 0.58 mmol) was dissolved in dichloromethane (5 mL), and difluoroacetic acid (354 μL, 5.80 mmol), EDCI hydrochloride (1.10 g, 5.80 mmol), DMAP (851 mg, 6.96 mmol) were added. In addition, after stirring at room temperature for 1 hour, a 10% aqueous citric acid solution (5 mL) and purified water were added to the reaction solution. The mixture was extracted three times with chloroform, and the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform: methanol = 100: 0-100: 1) to give the title compound 7 (263 mg, quantitative) as a colorless amorphous.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.41-1.78 (m, 4H), 1.90-2.13 (m, 1H), 2.29-2.52 (m, 1H) 2.68-3.37 (m, 4H), 3.74-4.21 (m, 5H), 3.88 (s, 3H), 4.31-4.87 (m, 2H), 6 .16 (t, J = 55.2 Hz, 0.54H), 6.30 (t, J = 55.2 Hz, 0.46H), 6.63-6.67 (m, 1H), 6.79 ( d, J = 8.1 Hz, 1H).
MS (ESI): m / z 446 [M + Na] ^< +>.

<< Step 2 >> Synthesis of 4,5α-epoxy-6,6-ethylenedioxy-17- (2,2-difluoroethyl) -3-methoxymorphinan-14β-ol (Compound 8)

  Compound 7 (263 mg) was dissolved in THF (3 mL), borane-THF complex and 1.0 M THF solution (3.1 mL, 3.10 mmol) were added, and the mixture was refluxed for 2 hours. After allowing to cool, 2M hydrochloric acid (1 mL) and 4M aqueous sodium hydroxide solution (3 mL) were added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 12 hours. After concentration, purified water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, hexane: ethyl acetate = 5: 1-4: 1) to give the title compound 8 (203 mg, 80%) as a white amorphous.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.45-1.63 (m, 4H), 2.17-2.33 (m, 2H), 2.40 (dt, J = 3.3, 12) .0Hz, 1H), 2.54-2.61 (m, 1H), 2.70-2.92 (m, 4H), 3.02 (d, J = 18.3 Hz, 1H), 3.74. -3.82 (m, 1H), 3.86-3.94 (m, 1H), 3.87 (s, 3H), 3.97-4.06 (m, 1H), 4.15-4 .23 (m, 1H), 4.57, (s, 1H), 4.61-4.65 (m, 1H), 5.84 (tt, J = 4.2, 55.8 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H).
MS (ESI): m / z 432 [M + Na] ^< +>.

<< Step 3 >> Synthesis of 4,5α-epoxy-17- (2,2-difluoroethyl) -14β-hydroxy-3-methoxymorphinan-6-one (Compound 9)

  The title compound 9 (88%) was obtained as a white amorphous form from the compound 8 by the same method as the synthesis method of the compound 4 described in Synthesis Example 1 and Step 2.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.54-1.63 (m, 2H), 1.83-1.92 (m, 1H), 2.30 (dt, J = 3.2, 14) .5Hz, 1H), 2.36-2.47 (m, 2H), 2.58-2.66 (m, 1H), 2.73 (dd, J = 5.9, 18.5 Hz, 1H) 2.80-2.94 (m, 2H), 2.94-3.10 (m, 3H), 3.89 (s, 3H), 4.66 (s, 1H), 4.70 (d , J = 1.7 Hz, 1H), 5.88 (tt, J = 4.1, 57.3 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H).
MS (ESI): m / z 388 [M + Na] ^< +>.

<< Step 4 >> 6,7-didehydro-4,5α-epoxy-17- (2,2-difluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 10) Synthesis

  The title compound 10 (87%) was obtained as a brown amorphous form from the compound 9 by a method similar to the method for synthesizing the compound 5 described in Synthesis Example 1 and Step 3.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.79-1.87 (m, 1H), 2.43 (dt, J = 5.4, 12.6 Hz, 1H), 2.53-2.75 (M, 3H), 2.84-3.04 (m, 4H), 3.12-3.22 (m, 2H), 3.76 (s, 3H), 4.50 (s, 1H), 5.69 (s, 1H), 5.92 (tt, J = 4.4, 58.2 Hz, 1H), 6.61-6.68 (m, 2H), 7.00-7.07 (m , 1H), 7.12-7.18 (m, 1H), 7.26-7.30 (m, 1H), 7.38-7.43 (m, 1H), 8.28 (s, 1H) ).
MS (ESI): m / z 439 [M + H] ^< +>.

(Synthesis Example 4)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2,2-difluoroethyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 6)

  The title compound 11 (74%) was obtained as a brown amorphous form from the compound 10 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.59-1.71 (m, 1H), 2.28-2.40 (m, 1H), 2.40-2.50 (m, 1H), 2.50-2.58 (m, 1H), 2.62 (d, J = 15.6 Hz, 1H), 2.71-2.97 (m, 4H), 3.06 (d, J = 18) .5Hz, 1H), 3.15 (d, J = 6.1 Hz, 1H), 4.43-4.97 (brs, 1H), 5.72 (s, 1H) 5.86 (tt, J = 4.2, 55.9 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H), 6.98-7.05 (m , 1H), 7.07-7.15 (m, 1H), 7.15-7.23 (m, 1H), 7.36-7.43 (m, 1H), 8.49 (s, 1H) ), 1 proton OH) it is not observed.
MS (ESI): m / z 425 [M + H] ^< +>.

(Synthesis Example 5)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2-fluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 14)

<< Step 1 >> Synthesis of 4,5α-epoxy-6,6-ethylenedioxy-17- (2-fluoroethyl) -3-methoxymorphinan-14β-ol (Compound 12)

  Compound 1 (200 mg, 0.58 mmol) was dissolved in acetonitrile (5 mL) and 2-fluoroethyl p-toluenesulfonate (773 μL, 4.33 mmol), potassium carbonate (611 mg, 4.33 mmol), and sodium iodide ( 651 mg, 4.34 mmol) was added and refluxed for 2 hours. After allowing to cool, suction filtration was performed, and after concentration, 5% aqueous sodium hydroxide solution (35 mL) was added. The mixture was extracted three times with chloroform, and the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform: methanol = 100: 0-100: 1) to give the title compound 12 (187 mg, 79%) as a white amorphous.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.40-1.62 (m, 4H), 2.16-2.35 (m, 3H), 2.52-2.59 (m, 1H), 2.62-2.96 (m, 4H), 3.07 (d, J = 18.3 Hz, 1H), 3.74-3.83 (m, 1H), 3.84-3.94 (m , 1H), 3.87 (s, 3H), 3.97-4.07 (m, 1H), 4.15-4.23 (m, 1H), 4.53 (td, J = 5.0 , 47.5, Hz, 2H), 4.57 (s, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 1 Proton (OH) not observed.
MS (ESI): m / z 414 [M + Na] ^< +>.

<< Step 2 >> Synthesis of 4,5α-epoxy-17- (2-fluoroethyl) -14β-hydroxy-3-methoxymorphinan-6-one (Compound 13)

  The title compound 13 (91%) was obtained as a white amorphous form from the compound 12 by the same method as the synthesis method of the compound 4 described in Synthesis Example 1 and Step 2.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.52-1.67 (m, 2H), 1.82-1.91 (m, 1H), 2.23-2.34 (m, 2H), 2.42 (dt, J = 4.5, 12.3 Hz, 1H), 2.67-3.14 (m, 7H), 3.88 (s, 3H), 4.45-4.67 (m 3H), 4.80-5.02 (brs, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H).
MS (ESI): m / z 370 [M + Na] ^< +>.

<< Step 3 >> 6,7-didehydro-4,5α-epoxy-17- (2-fluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 14) Synthesis of

  The title compound 14 (66%) was obtained as a brown amorphous form from the compound 13 in the same manner as in the synthesis method of the compound 5 described in Synthesis Example 1 and Step 3.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.80-1.86 (m, 1H), 2.36-2.53 (m, 2H), 2.61-2.72 (m, 2H), 2.80-3.00 (m, 4H), 3.18-3.26 (m, 2H), 3.77 (s, 3H), 4.61 (td, J = 4.9, 47.5) Hz, 2H), 5.72 (s, 1H), 6.64-6.66 (m, 2H), 7.03 (dt, J = 0.8, 8.0 Hz, 1H), 7.15 ( dt, J = 1.2, 6.9 Hz, 1H), 7.24-7.30 (m, 1H), 7.39-7.45 (m, 1H), 8.38 (s, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 421 [M + H] ^< +>.

(Synthesis Example 6)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2-fluoroethyl) -indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 6)

  The title compound 15 (21%) was obtained as a brown amorphous form from the compound 14 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.86-1.87 (m, 1H), 2.34-2.55 (m, 3H), 2.55-2.79 (m, 2H), 2.79-3.07 (m, 4H), 3.12-3.40 (m, 2H), 4.63 (td, J = 4.8, 47.3 Hz, 2H), 5.81 (s) , 1H), 6.49 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 7.03-7.38 (m, 3H), 7.42 -7.51 (m, 1H), 8.51 (s, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 407 [M + H] ⁺ .

(Synthesis Example 7)
Synthesis of 17-benzyl-6,7-didehydro-4,5α-epoxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 18)

<< Step 1 >> Synthesis of 6,7-didehydro-4,5α-epoxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 17)

  Compound 1 (804 mg, 2.32 mmol) was dissolved in methanol (5 mL), 2M hydrochloric acid (5 mL) was added, and the mixture was refluxed for 1.5 hours. After allowing to cool, 4M aqueous sodium hydroxide solution (3 mL) was added under ice cooling, and the mixture was extracted 3 times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained compound 16 was used for the next reaction without purification.

  The crude product of compound 16 (527 mg, 1.75 mmol) was dissolved in acetic acid (15 mL), and phenylhydrazine hydrochloride (328 mg, 2.27 mmol) was added and refluxed for 2 hours. After allowing to cool, acetic acid was removed by azeotropic distillation with toluene, a saturated aqueous sodium hydrogen carbonate solution was added to adjust pH = 9, and the mixture was extracted 3 times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform: methanol = 100: 4-100: 6-100: 8) to give the title compound 17 (562 mg, 2-step yield 84 as a brown amorphous). %).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70-1.78 (m, 1H), 2.35 (dt, J = 5.4, 12.5 Hz, 1H), 2.60 (d, J = 15.1 Hz, 1H), 2.75-2.90 (m, 2H), 2.85 (d, J = 15.8 Hz, 1H), 3.08 (d, J = 17.4 Hz, 1H) , 3.23-3.35 (m, 2H), 3.75 (s, 3H), 5.62 (s, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.64. (D, J = 8.2 Hz, 1H), 7.00-7.05 (m, 1H), 7.10-7.17 (m, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 8.39 (s, 1H), 2 protons (OH, NH) not observed.
MS (ESI): m / z 375 [M + H] ^< +>.

<< Step 2 >> Synthesis of 17-benzyl-6,7-didehydro-4,5α-epoxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 18)

  Compound 17 (171 mg, 0.46 mmol) was dissolved in DMF (5 mL), benzyl bromide (162 μL, 1.37 mmol) and potassium carbonate (189 mg, 1.37 mmol) were added, and the mixture was stirred at room temperature. Purified water was added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform) to give the title compound 18 (206 mg, 97%) as a white amorphous.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.73-1.83 (m, 1H), 2.31-2.43 (m, 2H), 2.55-2.64 (m, 2H), 2.80-2.90 (m, 2H), 3.16 (d, J = 5.6 Hz, 1H), 3.32 (d, J = 18.6 Hz, 1H), 3.70 (s, 2H) ), 3.74 (s, 3H), 5.68 (s, 1H), 6.64 (s, 2H), 6.99 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.22-7.40 (m, 7H), 8.37 (s, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 465 [M + H] ^< +>.

(Synthesis Example 8)
Synthesis of 17-benzyl-6,7-didehydro-4,5α-epoxyindolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 19)

  The title compound 19 (63%) was obtained as a white oil from the compound 18 in the same manner as in the synthesis of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-1.73 (m, 1H), 2.23-2.37 (m, 2H), 2.45-2.55 (m, 1H), 2.59 (d, J = 15.8 Hz, 1H), 2.77 (dd, J = 6.5, 18.6 Hz, 1H), 2.83 (d, J = 15.8 Hz, 1H), 3 .12 (d, J = 6.3 Hz, 1H), 3.24 (d, J = 18.6 Hz, 1H), 3.62-3.70 (m, 2H), 5.71 (s, 1H) , 6.42 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 7.05 ( t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.28-7.40 (m, 6H), 8.38 (s, 1H), 2 protons (OHX2 ) Not observed.
MS (ESI): m / z 451 [M + H] ⁺ .

(Synthesis Example 9)
(6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) -3,3,3-trifluoropropane- Synthesis of 1-one (compound 20)

  The title compound 20 (160 mg, 66%) was obtained from the compound 17 in the same manner as in the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-1.78 (m, 1H), 2.32 (dt, J = 5.0, 12.9 Hz, 0.4H), 2.48 (dt , J = 5.0, 12.8 Hz, 0.6H), 2.55-2.80 (m, 2H), 2.81-2.95 (m, 2H), 2.98-3.12 ( m, 1H), 3.15-3.60 (m, 4H), 3.65-3.75 (m, 3H), 4.13 (d, J = 6.6 Hz, 0.4H), 5. 19 (d, J = 6.6 Hz, 0.6H), 5.52 (s, 0.4H), 5.60 (s, 0.6H), 6.61 (d, J = 8.1 Hz, 1H) ), 6.66 (d, J = 8.0 Hz, 1H), 7.00-7.09 (m, 1H), 7.11-7.22 (m, 1H), 7.28 (d, J = 8.1 Hz, 1 H), 7.3 1-7.41 (m, 1H), 8.57 (s, 0.6H), 8.65 (s, 0.4H).
MS (ESI): m / z 507 [M + Na] ^< +>.

(Synthesis Example 10)
6,7-didehydro-4,5α-epoxy-17- (3,3,3-trifluoropropyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 21 ) Synthesis

  The title compound 21 (76%) was obtained from the compound 20 in the same manner as in the synthesis method of the compound 8 described in Synthesis Example 3 and Step 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.80-1.85 (m, 1H), 2.30-2.43 (m, 4H), 2.58-2.69 (m, 2H), 2.72-2.96 (m, 3H), 2.90 (d, J = 16.0 Hz, 1H), 3.14 (d, J = 6.9 Hz, 1H), 3.17 (d, J = 18.9 Hz, 1H), 3.73 (s, 1H), 3.75 (s, 3H), 5.69 (s, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.98-7.05 (m, 1H), 7.09-7.17 (m, 1H), 7.26 (d, J = 8 .2 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 1 H), 8.31 (s, 1 H).
MS (ESI): m / z 471 [M + H] ⁺ .

(Synthesis Example 11)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (3,3,3-trifluoropropyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 21)

  The title compound 22 (22%) was obtained as a white oil from the compound 21 in the same manner as in the synthesis of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70-1.80 (m, 1H), 2.26-2.43 (m, 4H), 2.50-2.58 (m, 1H), 2.63 (d, J = 15.6 Hz, 1H), 2.70-2.95 (m, 3H), 2.86 (dd, J = 6.2, 18.4 Hz, 1H), 3.12 (D, J = 18.4 Hz, 1H), 3.13 (d, J = 6.4 Hz, 1H), 5.74 (s, 1H), 6.45 (d, J = 8.2 Hz, 1H) 6.53 (d, J = 8.1 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.24 (D, J = 8.3 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H), 2 protons (OHX2) not confirmed.
MS (ESI): m / z 457 [M + H] ^< +>.

(Synthesis Example 12)
(6,7-dihydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) -2,2,3,3,3- Synthesis of pentafluoropropan-1-one (compound 23)

  The title compound 23 (57%) was obtained as a white oil from the compound 17 in the same manner as in the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70-1.80 (m, 1H), 2.45 (dt, J = 5.2, 12.7 Hz, 1H), 2.65 (d, J = 15.8 Hz, 1H), 2.87-3.05 (m, 1H), 3.16-3.35 (m, 3H), 3.60 (dd, J = 5.1, 13.2 Hz, 1H), 3.73 (s, 3H), 4.64-4.75 (m, 2H), 5.63 (s, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6 .60 (d, J = 8.3 Hz, 1H), 7.00-7.08 (m, 1H), 7.10-7.18 (m, 1H), 7.28 (d, J = 8. 1 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 1 H), 8.43-8.58 (m, 1 H).
MS (ESI): m / z 543 [M + Na] ^< +>.

(Synthesis Example 13)
6,7-didehydro-4,5α-epoxy-17- (2,2,3,3,3-pentafluoropropyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 25) Synthesis

  The title compound 24 is obtained as a white oily substance from the compound 23 in the same manner as the synthesis method of the compound 8 described in Synthesis Example 3 and Step 2, and the compound 6 described in the Synthesis Example 2 is synthesized without purification. The title compound 25 (2 step yield 36%) was obtained as a white oily substance in the same manner as in the above method.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.68-1.77 (m, 1H), 2.41 (dt, J = 5.6, 12.4 Hz, 1H), 2.60 (d, J = 15.6 Hz, 1H), 2.57-2.72 (m, 2H), 2.92 (d, J = 15.6 Hz, 1H), 2.94-3.22 (m, 5H), 4 .19 (s, 1H), 4.45 (s, 1H), 5.71 (s, 1H), 6.46 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8 .1 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H) 7.38 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H).
MS (ESI): m / z 515 [M + Na] ^< +>.

(Synthesis Example 14)
(6,7-dihydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) -2,2,2-trichloroethane-1- Synthesis of ON (compound 26)

  Compound 17 (123 mg, 0.33 mmol) was dissolved in dichloromethane (5 mL), trichloroacetic anhydride (TCAA) (180 μL, 0.99 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours, and then saturated sodium hydrogen carbonate was added to the reaction solution. An aqueous solution was added. The mixture was extracted three times with chloroform, and the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform) to give the title compound 26 (95%) as a white oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-1.82 (m, 2H), 2.35-2.85 (m, 3H), 2.95-3.45 (m, 3H), 3.71 (s, 3H), 4.40-4.50 (m, 1H), 5.15 (s, 1H), 5.64 (s, 1H), 6.58-6.70 (m, 2H), 7.00-7.10 (m, 1H), 7.11-7.20 (m, 1H), 7.28-7.35 (m, 1H), 7.35-7.40 ( m, 1H), 8.40-8.63 (m, 1H).
MS (ESI): m / z 541 [M + Na] ^< +>.

(Synthesis Example 15)
17- (2,2,2-trichloroethyl) -6,7-didehydro-4,5α-epoxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 27) Synthesis of

  The title compound 27 (33%) was obtained as a white oil from the compound 26 in the same manner as in the synthesis method of the compound 8 described in Synthesis Example 3 and Step 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.78-1.85 (m, 1H), 2.52 (dt, J = 5.2, 12.7 Hz, 1H), 2.61 (d, J = 15.7 Hz, 1H), 2.86 (dt, J = 3.2, 12.1 Hz, 1H), 2.95 (d, J = 15.7 Hz, 1H), 3.02-3.15 ( m, 3H), 3.37 (d, J = 14.9 Hz, 1H), 3.50 (d, J = 3.9 Hz, 1H), 3.54 (d, J = 15.0 Hz, 1H), 3.75 (s, 3H), 4.54 (s, 1H), 5.72 (s, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H) ), 7. 40 (d, J = 7.9 Hz, 1H), 8.41 (s, 1H).
MS (ESI): m / z 505 [M + H] ^< +>.

(Synthesis Example 16)
Synthesis of 17- (3,3,3-trichloroethyl) -6,7-didehydro-4,5α-epoxyindolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 28)

  The title compound 28 (26%) was obtained as a white oil from the compound 27 in the same manner as in the synthesis of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.76-1.82 (m, 1H), 2.53 (dt, J = 5.2, 12.7 Hz, 1H), 2.62 (d, 15 .7 Hz, 1H), 2.87 (dt, J = 3.4, 12.1 Hz, 1H), 2.62 (d, J = 15.7 Hz, 1H), 3.02-3.15 (m, 3H), 3.38 (d, J = 14.9 Hz, 1H), 3.50 (d, J = 3.1 Hz, 1H), 3.55 (d, J = 15.0 Hz, 1H), 4. 61 (s, 1H), 5.34 (s, 1H), 5.74 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8. 1 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 8.2 Hz, 1H), 7.27 (d, J = 9.1 Hz, 1H), 7.4 (D, J = 7.9Hz, 1H), 8.23 (s, 1H).
MS (ESI): m / z 513 [M + Na] ^< +>.

(Synthesis Example 17)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2-hydroxyethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 29)

  The title compound 29 (78%) was obtained as a white solid substance from the crude product of compound 17 by the same method as the synthesis method of compound 18 described in Synthesis Example 7 and Step 3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.65-1.80 (m, 1H), 2.25-2.37 (m, 2H), 2.52-2.73 (m, 3H), 2.61 (d, J = 15.2 Hz, 1H), 2.85 (dd, J = 6.3, 16.6 Hz, 1H), 2.89 (d, J = 16.3 Hz, 1H), 3 .14 (d, J = 18.5 Hz, 1H), 3.15 (d, J = 6.3 Hz, 1H), 3.71-3.60 (m, 2H), 3.73 (s, 3H) , 5.62 (s, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 7.01 (t, J = 7. 2 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 8,55 (s IH), 2 protons (OHX2) not observed.
MS (ESI): m / z 441 [M + Na] ^< +>.

(Synthesis Example 18)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2-hydroxyethyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 30)

  The title compound 30 (22%) was obtained as a white oil from the compound 29 in the same manner as in the synthesis of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.69-1.73 (m, 1H), 2.25-2.42 (m, 2H), 2.55-2.74 (m, 3H), 2.59 (d, J = 14.8 Hz, 1H), 2.80 (d, J = 15.7 Hz, 1H), 2.84 (dd, J = 6.4, 18.7 Hz, 1H), 3 .13 (d, J = 7.0 Hz, 1H), 3.17 (d, J = 19.0 Hz, 1H), 3.58-3.72 (m, 2H), 5.58 (s, 1H) 6.53 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.90-6.98 (m, 1H), 7.03-7. 10 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 3 protons (OHX3 ) Observation not.
MS (ESI): m / z 427 [M + Na] ^< +>.

(Synthesis Example 19)
Synthesis of (E) -7-benzylidene-4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3,14β-dihydroxymorphinan-6-one (Compound 32)

<< Step 1 >> Synthesis of 4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3,14β-dihydroxymorphinan-6-one (Compound 32)

  48% hydrobromic acid (10 mL) was added to compound 3 (151 mg, 0.35 mmol) and refluxed for 1 hour. Under ice cooling, 25% ammonia was added to the reaction solution to adjust pH = 9. After adding purified water and extracting three times with chloroform, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, hexane: ethyl acetate = 3: 1) to give the title compound 31 (47 mg, 36%) as a white amorphous.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.55-1.68 (m, 1H), 1.91 (ddd, J = 2.9, 5.0, 13.4 Hz, 1H), 2.32 (Dt, J = 3.0, 14.5 Hz, 1H), 2.45-2.59 (m, 2H), 2.72-2.82 (m, 2H), 2.90-3.20 ( m, 5H), 4.70-4.80 (m, 2H), 6.61 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 2 protons (OHX2) Not observed.
MS (ESI): m / z 392 [M + Na] ^< +>.

<< Step 2 >> Synthesis of (E) -7-benzylidene-4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3,14β-dihydroxymorphinan-6-one (Compound 32)

Compound 31 (52.6 mg, 0.14 mmol) was dissolved in toluene (5 mL) and DMF (1 mL), benzoic acid (45.8 mg, 0.38 mmol), benzaldehyde (0.036 mL, 0.36 mmol), and N , N-diisopropylethylamine (0.13 mL, 0.75 mmol) was added and stirred at 140 ^° C. for 24 hours. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC (hexane: ethyl acetate = 130: 104) to give the title compound 32 (28.5 mg, 44%) as a white oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.63-1.73 (m, 1H), 2.30-2.38 (m, 1H), 2.43 (dt, J = 5.5, 12) .7 Hz, 1H), 2.67 (dt, J = 3.5, 12.0 Hz, 1H), 2.73-2.80 (m, 1H), 2.84-2.94 (m, 1H) , 2.99-3.15 (m, 3H), 3.07 (d, J = 18.4 Hz, 1H), 3.10 (d, J = 18.1 Hz, 1H), 4.40 (d, J = 2.0 Hz, 1H), 4.71 (s, 1H), 6.02 (s, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 7.28-7.40 (m, 5H), 7.66 (d, J = 2.6 Hz, 1H).
MS (ESI): m / z 480 [M + Na] ^< +>.

(Synthesis Example 20)
Synthesis of (E) -17-benzyl-7-benzylidene-4,5α-epoxy-14β-hydroxy-3-methoxymorphinan-6-one (compound 35)

<< Step 1 >> Synthesis of 17-benzyl-4,5α-epoxy-6,6-ethylenedioxy-3-methoxymorphinan-14β-ol (Compound 33)

  The title compound 33 (744 mg, 91%) was obtained as a white amorphous form from the compound 1 by the same method as the synthesis method of the compound 18 described in Synthesis Example 7 and Step 3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.38-1.60 (m, 4H), 2.15-2.29 (m, 3H), 2.43-2.50 (m, 1H), 2.62 (dd, J = 5.7, 18.1 Hz, 1H), 2.88 (d, J = 5.5 Hz, 1H), 3.19 (d, J = 18.3 Hz, 1H), 3 .65 (s, 2H), 3.74-3.82 (m, 1H), 3.87 (s, 3H), 3.85-3.93 (m, 1H), 4.02 (q, J = 6.6, 13.2 Hz, 1H), 4.19 (ddd, J = 5.5, 6.9, 12.6 Hz, 1H), 4.57 (s, 1H), 4.90-5. 15 (brs, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 7.22-7.38 (m, 5H).
MS (ESI): m / z 436 [M + H] ^< +>.

<< Step 2 >> (E) Synthesis of 17-benzyl-7-benzylidene-4,5α-epoxy-14β-hydroxy-3-methoxymorphinan-6-one (Compound 35)

  A crude product of compound 34 was obtained from compound 33 in the same manner as the synthesis method of compound 4 described in Synthesis Example 1 and Step 2. The obtained crude product of compound 34 was used in the next reaction without purification.

  From the crude product of compound 34, the title compound 35 (103.8 mg, two-stage yield 73%) is obtained as a white oily substance by the same method as the synthesis method of the compound 32 described in Synthesis Example 19 and Step 2. It was.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.62-1.70 (m, 1H), 2.27-2.42 (m, 3H), 2.54-2.60 (m, 1H), 2.71 (dd, J = 6.5, 18.6 Hz, 1H), 2.93 (d, J = 15.5 Hz, 1H), 3.00 (d, J = 6.4 Hz, 1H), 3 .33 (d, J = 18.7 Hz, 1H), 3.67 (s, 2H), 3.88 (s, 3H), 4.67 (s, 1H), 6.71 (d, J = 8 .2 Hz, 1 H), 6.75 (d, J = 8.2 Hz, 1 H), 7.22-7.38 (m, 10 H), 7.63-7.68, m, 1 H), 1 proton ( OH) Not observed.
MS (ESI): m / z 480 [M + H] ⁺ .

(Synthesis Example 21)
Synthesis of (E) -17-benzyl-7-benzylidene-4,5α-epoxy-3,14β-dihydroxymorphinan-6-one (Compound 36)

  The title compound 36 (23%) was obtained as a white oil from the compound 35 in the same manner as in the synthesis of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-1.70 (m, 1H), 2.28-2.42 (m, 3H), 2.55-2.63 (m, 1H), 2.70 (dd, J = 6.1, 18.5 Hz, 1H), 2.94 (d, J = 15.5 Hz, 1H), 3.00 (d, J = 6.1 Hz, 1H), 3 .31 (d, J = 18.6 Hz, 1H), 3.67 (s, 2H), 4, 69 (s, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.76 (D, J = 8.2 Hz, 1H), 7.20-7.40 (m, 10H), 7.60-7.68 (m, 1H), 2 protons (OHX2) not observed.
MS (ESI): m / z 466 [M + H] ^< +>.

(Synthesis Example 22)
Synthesis of 6,7-didehydro-4,5α-epoxy-17- (2,2,2-trifluoroethyl) benzofuro [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 37)

  Compound 31 (56.3 mg, 0.15 mmol) was dissolved in ethanol (5 mL), and O-phenylhydroxylamine hydrochloride (44.4 mg, 0.31 mmol) and methanesulfonic acid (0.045 mL, 0.46 mmol) were added. In addition, the mixture was stirred at 90 ° C. for 9 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC (chloroform: methanol = 200: 10) to give the title compound 37 (30.2 mg, 39%) as a white oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.78-1.83 (m, 1H), 2.47 (dt, J = 5.4, 12.7 Hz, 1H), 2.54-2.61 (M, 1H), 2.67 (dt, J = 3.5, 12.0 Hz, 1H), 2.75-2.82 (m, 1H), 2.84 (d, J = 16.0 Hz, 1H), 2.95-3.19 (m, 2H), 3.10 (d, J = 18.5 Hz, 1H), 3.03 (d, J = 6.3 Hz, 1H), 3.22 ( d, J = 6.0 Hz, 1H), 4.45 (d, J = 1.7 Hz, 1H), 5.15 (s, 1H), 5.64 (s, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 7.15-7.20 (m, 1H), 7.25-7.30 (m, 1H) , 7.38 (d, = 7.7Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H).
MS (ESI): m / z 466 [M + Na] ^< +>.

(Synthesis Example 23)
Synthesis of 17-benzyl-6,7-didehydro-4,5α-epoxy-3-methoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 38)

  The title compound 38 (39%) was obtained as a white oil from the compound 34 by a method similar to the method for synthesizing the compound 37 described in Synthesis Example 22.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.79-1.85 (m, 1H), 2.23-2.42 (m, 2H), 2.52-2.63 (m, 2H), 2.74 (d, J = 16.0 Hz, 1H), 2.82 (dd, J = 6.5, 18.6 Hz, 1H), 3.13 (d, J = 6.4 Hz, 1H), 3 .33 (d, J = 18.6 Hz, 1H), 3.70 (s, 2H), 3.78 (s, 3H), 5.61 (s, 1H), 6.64 (d, J = 8 .3 Hz, 1 H), 6.67 (d, 8.2 Hz, 1 H), 7.10-7.15 (m, 1 H), 7.20-7.50 (m, 9 H).
MS (ESI): m / z 466 [M + H] ^< +>.

(Synthesis Example 24)
Synthesis of 17-benzyl-6,7-didehydro-4,5α-epoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 39)

  The title compound 39 (52%) was obtained as a white oil from the compound 38 in the same manner as in the synthesis of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.72-1.85 (m, 1H), 2.31-2.43 (m, 2H), 2.50-2.65 (m, 2H), 2.74 (d, J = 16.0 Hz, 1H), 2.79 (dd, J = 6.5, 18.5 Hz, 1H), 3.12 (d, J = 6.4 Hz, 1H), 3 .30 (d, J = 18.6 Hz, 1H), 3.69 (dd, J = 13.1, 18.1 Hz, 2H), 4.40-4.90 (brs, 1H), 5.61 ( s.1H), 6.57 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 7.10-7.18 (m, 1H), 7. 20-7.44 (m, 8H), 1 proton (OH) not observed.
MS (ESI): m / z 452 [M + H] ^< +>.

(Synthesis Example 25)
Synthesis of (6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) (cyclopropyl) methanone (compound 40)

  The title compound 40 (quantitative) was obtained as a white oil from the compound 17 in the same manner as in the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.70-0.90 (m, 2H), 0.90-1.20 (m, 2H), 1.60-2.00 (m, 2H), 2.25-3.18 (m, 5H), 3.20-3.50 (m, 1H), 3.76 (s, 3H), 4.05-4.20 (m, 0.65H), 4.48-4.60 (m, 0.35H), 4.67-4.78 (m, 0.35H), 5.24 (d, J = 6.3 Hz, 0.65H), 5.62 (S, 0.35), 5.67 (s, 0.65H), 6.63 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 7 .05 (t, J = 7.4, 14.5 Hz, 1H), 7.17 (t, J = 7.7, 14.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H) ), 7.41 (d, J = 7.9 Hz, 1H), 8.25-8.50 (m, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 465 [M + H] ^< +>.

(Synthesis Example 26)
Synthesis of (6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) (cyclopropyl) methanone (Compound 41)

  The title compound 41 (92%) was obtained as a white amorphous form from the compound 40 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 0.70-0.91 (m, 3H), 0.91-1.05 (m, 1H), 1.67 (dd, J = 2.9, 12.8 Hz, 0.5 H), 1.73 (dd, J = 2.9, 12.8 Hz, 0.5 H), 1.92-2.05 (m, 0.5 H), 2.05-2 .18 (m, 0.5H), 2.41 (dt, J = 5.2, 12.7 Hz, 0.5H), 2.55 (dt, J = 4.8, 12.5 Hz, 0.5H) ), 2.60-3.05 (m, 3H), 2.76 (dt, J = 4.0, 13.6 Hz, 0.5H), 3.18-3.40 (m, 1H), 3 .47 (dd, J = 6.6, 18.4 Hz, 0.5H), 4.22 (dd, J = 4.8, 13.8 Hz, 0.5H), 4, 46 (dd, J = 4 .9, 13.6 Hz, 0 .5H), 4.78 (d, J = 6.5 Hz, 0, 5H), 5.09 (d, J = 6.6 Hz, 0.5H), 5.61 (s, 0.5H), 5 .62 (s, 0.5H), 6.50-6.67 (m, 2H), 6.90-7.00 (m, 1H), 7.02-7.13 (m, 1H), 7 .31 (dd, J = 3.7, 8.7 Hz, 1H), 7.38 (dd, J = 4.6, 7.8 Hz, 1H), 3 protons (OHX2, NH) not observed.
MS (ESI): m / z 451 [M + Na] ^< +>.

(Synthesis Example 27)
(6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) (pyridin-3-yl) methanone (compound 42 )

  The title compounds 42 and 43 were obtained as a white oil from the compound 17 (200 mg, 0.53 mmol) by the same method as the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1. A mixture of compounds 42 and 43 was dissolved in methanol (2 mL), triethylamine (72 μL, 0.52 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Citric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (40-100 chloroform: ammonia methanol = 100: 2) to give the title compound 42 (164 mg, 2-step yield 64%) as a white oily substance.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.42-1.80 (m, 1H), 2.54 (dt, J = 5.2, 13.0 Hz, 0.6H), 2.30− 2.71 (m, 2H), 2.89 (dt, J = 4.4, 13.4 Hz, 0.4H), 2.92-3.18 (m, 1.6H), 3.18-3 .50 (m, 1.4H), 3.66 (d, J = 7.2 Hz, 3H), 3.62-3.80 (m, 0.4H), 4.05 (d, J = 6. 4 Hz, 0.6 H), 4.55 (dd, J = 5.2, 13.6 Hz, 0.6 H), 5.23 (d, J = 6.6 Hz, 0.4 H), 5.60-5 .68 (m, 1H), 6.58-6.75 (m, 2H), 6.85-7.00 (m, 1H), 7.01-7.14 (m, 1H), 7.20 -7.58 (m, 3H), 7.8 0-8.03 (m, 1H), 8.55-8.75 (m, 2H), 2 protons (OH, NH) not observed.
MS (ESI): m / z 480 [M + H] ⁺ .

(Synthesis Example 28)
(6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) (pyridin-3-yl) methanone (compound 44) Composition

  The title compound 44 (32%) was obtained as a white amorphous form from the compound 42 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, Pyridine-d ₅ ): δ 1.74-1.82 (m, 0.33H), 1.87-1.95 (m, 0.67H), 2.82 (d, J = 15.6 Hz, 0.67H), 2.90-3.10 (m, 2H), 2.96 (d, J = 15.6 Hz, 0.33H), 3.18 (dt, J = 3. 5, 13.5 Hz, 0.67H), 3.20-3.29 (m, 1H), 3.30-3.40 (m, 0.67H), 3.46 (dt, J = 3.5 , 13.5 Hz, 0.33H), 3.54-3.63 (m, 0.33H), 3.68-3.78 (m, 0.33H), 4.53 (d, J = 6. 2 Hz, 0.67H), 5.01-5.10 (m, 0.67H), 5.85-5.90 (m, 0.33H), 5.94 (s, 0.67H), 6. 10 (s, 0.33H), 6.82 (d, J = 8.0 Hz, 1H), 7.10-7.69 (m, 6H), 7.95-8.00 (m, 0.33H) ), 8.22-8.27 (m, 0.67H), 8.66-8.84 (m, 1H), 9.13-9.17 (m, 0.33H), 9.34-9 .38 (m, 0.67H), 11.5-11.8 (m, 1H), 12.4-12.6 (m, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 488 [M + Na] ^< +>.

(Synthesis Example 29)
Synthesis of 6,7-didehydro-4,5α-epoxy-17-((1-fluorocyclopropyl) methyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 48)

<< Step 1 >> 3-((tert-Butyldimethylsilyl) oxy) -6,7-didehydro-4,5α-epoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 46) Synthesis of

  Portoghese PS, et al., Opioid agonist and antagonist activities of morphindoles related to naltrindole, J. Med. Chem., 35, 4325-4329, 1992. Compound 45 (92.8 mg, 0. 258 mmol) is dissolved in N, N-dimethylformamide (DMF) (1.5 mL), and tert-butyldimethylchlorosilane (116 mg, 0.77 mmol) and imidazole (105 mg, 1.55 mmol) in DMF (0.5 mL) are dissolved. And stirred at room temperature for 4 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform: methanol = 100: 6-100: 14) to give the title compound 46 (111 mg, 91%) as a white amorphous.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.00-0.02 (s, 3H), 0.03-0.05 (s, 3H), 0.87-0.90 (s, 9H), 1.63-1.75 (m, 1H), 2.34 (dt, J = 5.4, 12.5 Hz, 1H), 2.60 (d, J = 15.7 Hz, 1H), 2.72 -2.90 (m, 2H), 2.83 (d, J = 15.8 Hz, 1H), 3.08 (d, J = 18.3 Hz, 1H), 3.25 (d, J = 6. 4 Hz, 1H), 3.33 (dd, J = 6.6, 18.4 Hz, 1H), 4.23 (s, 1H), 5.55 (s, 1H), 6.52 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.97-7.08 (m, 1H), 7.10-7.19 (m, 1H), 7. 28 (d, J = 8 .2 Hz, 1 H), 7.39 (d, J = 7.9 Hz, 1 H), 8.39 (s, 1 H), 1 proton (NH) not observed.
MS (ESI): m / z 475 [M + H] ^< +>.

<< Step 2 >> (3-((tert-butyldimethylsilyl) oxy) -6,7-didehydro-4,5α-epoxy-14β-hydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17- Yl) ((1-fluorocyclopropyl) methyl) methanone (Compound 47)

  The title compound 47 (80%) was obtained as a white amorphous form from the compound 46 in the same manner as in the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.01-0.10 (m, 6H), 0.81-0.95 (m, 9H), 1.15-1.50 (m, 4H), 1.70-1.80 (m, 1H), 2.30-3.50 (m, 7H), 4.17-4.50 (m, 1H), 4.70-4.80 (m, 0 .4H), 5.00-5.11 (m, 0.6H), 5.48-5.64 (m, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.62. (D, J = 8.1 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 8.10-8.30 (m, 1H).
MS (ESI): m / z 583 [M + Na] ^< +>.

<< Step 3 >> 6,7-didehydro-4,5α-epoxy-17-((1-fluorocyclopropyl) methyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 48) )

Compound 47 (63.1 mg, 0.11 mmol) was dissolved in THF (3 mL), a 1.0 M THF solution of borane-THF complex (0.71 mL, 0.68 mmol) was added, and the mixture was refluxed for 1 hour. After allowing to cool, 2M hydrochloric acid (1.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC (hexane: ethyl acetate = 100: 100) to give the title compound 48 (25.2 mg, 2-step yield 52%) as a white oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.59-0.71 (m, 2H), 1.08-1.18 (m, 2H), 1.70-1.78 (m, 1H), 2.36-2.48 (m, 2H), 2.65 (d, J = 15.6 Hz, 2H), 2.69 (d, J = 6.5 Hz, 1H), 2.77-3.02 (M, 3H), 2.93 (d, J = 15.8 Hz, 1H), 3.13 (d, J = 18.6 Hz, 1H), 3.36 (d, J = 6.3 Hz, 1H) , 5.74 (s, 1H), 6.43 (d, J = 8.1 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 7.00 (t, J = 7. 4 Hz, 1 H), 7.10 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 8.39 (s, H), is not 1 proton (OH) observed.
MS (ESI): m / z 433 [M + H] ^< +>.

(Synthesis Example 30)
6,7-didehydro-4,5α-epoxy-17-((1- (trifluoromethyl) cyclopropyl) methyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (compound 50 )

<< Step 1 >> (3-((tert-Butyldimethylsilyl) oxy) -6,7-didehydro-4,5α-epoxy-14β-hydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17- Yl) (1- (trifluoromethyl) cyclopropyl) methanone (Compound 49)

  The title compound 49 (79%) was obtained as a white oil from the compound 46 in the same manner as in the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.00-0.05 (m, 6H), 0.85-0.90 (m, 9H), 1.15-1.40 (m, 3H), 1.63-1.90 (m, 2H), 2.20-3.40 (m, 7H), 3.50-3.68 (m, 1H), 4.10-4.30 (m, 0 .5H), 5.00-5.20 (m, 0.5H), 5.53 (s, 1H), 6.54 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.32-7.40 (m, 1H), 8.15-8.35 (m, 1H).
MS (ESI): m / z 633 [M + Na] ^< +>.

<< Step 3 >> 6,7-didehydro-4,5α-epoxy-17-((1- (trifluoromethyl) cyclopropyl) methyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β- Synthesis of diol (compound 50)

  The title compound 50 (2-step yield: 71%) was obtained as a white oil from the compound 49 in the same manner as in the synthesis of the compound 48 described in Synthesis Example 29, Step 3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.55-0.70 (m, 2H), 1.02-1.15 (m, 2H), 1.73 (d, J = 11.6 Hz, 1H ), 2.20-2.31 (m, 1H), 2.38 (dd, J = 4.8, 12.6 Hz, 1H), 2.45 (d, J = 13.7 Hz, 1H), 2 .62 (d, J = 15.7 Hz, 1H), 2.70-3.09 (m, 3H), 2.83 (dd, J = 6.4, 18.5 Hz, 1H), 2.93 ( d, J = 16.2 Hz, 1H), 3.21 (d, J = 6.1 Hz, 1H), 4.82 (s, 1H), 5.76 (s, 1H), 5.90 (s, 1H), 6.42 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 7 .11 (t, = 7.6Hz, 1H), 7.23 (d, J = 8.2Hz, 1H), 7.40 (d, J = 7.8Hz, 1H), 8.36 (s, 1H).
MS (ESI): m / z 483 [M + H] ^< +>.

(Synthesis Example 31)
Synthesis of ((E) -7-benzylidene-4,5α-epoxy-14β-hydroxy-3-methoxy-6-oxomorphinan-17-yl) (cyclopropyl) methanone (Compound 52)

<< Step 1 >> Synthesis of (E) -7-benzylidene-4,5α-epoxy-14β-hydroxy-3-methoxymorphinan-6-one (Compound 51)

  The title compound 51 (60%) was obtained as a white oil from the compound 16 in the same manner as in the synthesis of the compound 32 described in Synthesis Example 19 and Step 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-1.68 (m, 1H), 2.30-2.44 (m, 2H), 2.80-2.94 (m, 2H), 2.99 (d, J = 16.6 Hz, 1H), 3.10-3.18 (m, 2H), 3.26-3.34 (m, 1H), 3.88 (s, 3H), 4.59 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 7.20-7.40 (m, 5H) ), 7.64 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 412 [M + Na] ^< +>.

<< Step 2 >> Synthesis of ((E) -7-benzylidene-4,5α-epoxy-14β-hydroxy-3-methoxy-6-oxomorphinan-17-yl) (cyclopropyl) methanone (Compound 52)

  The title compound 52 (80%) was obtained as a white amorphous form from the compound 51 by a method similar to the method for synthesizing the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.60-1.00 (m, 4H), 1.50-1.68 (m, 1H), 1.68-1.95 (m, 1H), 2.30-2.60 (m, 2H), 2.80-3.40 (m, 3H), 3.89 (s, 3H), 4.00-4.16 (m, 0.65H), 4.35-4.48 (m, 0.35H), 4.50-4.62 (m, 0.35H), 4.68 (s, 1H), 5.02 (d, 0.65H), 6.70 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 7.20-7.40 (m, 5H), 7.66 (s, 1H) ).
MS (ESI): m / z 480 [M + Na] ^< +>.

(Synthesis Example 32)
Synthesis of ((E) -7-benzylidene-4,5α-epoxy-3,14β-dihydroxy-6-oxomorphinan-17-yl) (cyclopropyl) methanone (Compound 53)

  The title compound 53 (51%) was obtained as a yellow amorphous compound from the compound 52 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 0.60-1.00 (m, 4H), 1.48-1.62 (m, 1H), 1.90-2.10 (m, 1H) , 2.38 (dt, J = 5.4, 12.8 Hz, 0.5H), 2.44-2.60 (m, 1.5H), 2.74 (dt, J = 4.0, 13 .5 Hz, 0.5 H), 2.85 (d, J = 18.6 Hz, 0.5 H), 3.02 (d, J = 18.4 Hz, 0.5 H), 3.02-3.15 ( m, 1H), 3.16-3.28 (m, 1H), 3.39 (dd, J = 6.6, 18.6 Hz, 0.5H), 4.21 (dd, J = 4.9). , 14.0 Hz, 0.5 H), 4.42 (dd, J = 5.1, 13.8 Hz, 0.5 H), 4.63 (d, J = 5.4 Hz, 1 H), 4.67 ( d, J = 6.4 Hz, 0.5H), 4.94 (d, J = 6.5 Hz, 0.5H), 6.62-6.75 (m, 2H), 7.28-7.40 (m, 5H), 7. 62 (dd, J = 2.3, 12.3 Hz, 1H), 2 protons (OHX2) not observed.
MS (ESI): m / z 466 [M + Na] ^< +>.

(Synthesis Example 33)
Synthesis of (6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-17-yl) (cyclopropyl) methanone (compound 55)

<< Step 1 >> Synthesis of 6,7-didehydro-4,5α-epoxy-3-methoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 54)

  The title compound 54 (57%) was obtained as a brown amorphous form from the compound 16 in the same manner as in the synthesis method of the compound 37 described in Synthesis Example 22.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70-1.88 (m, 1H), 2.36 (dt, J = 7.2, 12.6 Hz, 1H), 2.59 (dd, J = 1.5, 16.0 Hz, 1H), 2.75-2.81 (m, 1H), 2.79 (d, J = 15.7 Hz, 1H), 2.87 (dt, J = 3. 5, 12.2 Hz, 1 H), 3.09 (d, J = 17.5 Hz, 1 H), 3.22-3.28 (m, 2 H), 3.79 (s, 3 H), 5.59 ( s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 7.2, 11.1 Hz) , 1H), 7.20-7.28 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 2 protons ( OH, N H) Not observed.
MS (ESI): m / z 376 [M + H] ^< +>.

<< Step 2 >> (6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-17-yl) (cyclopropyl) methanone (compound 55)

  The title compound 55 (quantitative) was obtained as a white amorphous form from the compound 54 by a method similar to the method for synthesizing the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.70-1.18 (m, 4H), 1.70-1.90 (m, 2H), 2.50-3.50 (m, 7H), 3.80 (s, 3H), 4.02-4.18 (m, 0.7H), 4.45-4.59 (m, 0.3H), 4.69-4.75 (m, 0 .3H), 5.22 (d, J = 6.3 Hz, 0.7H), 5.55-5.68 (m, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6 .70 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 7.4, 14.9 Hz, 1H), 7.21-7.35 (m, 1H), 7.39 ( d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H).
MS (ESI): m / z 466 [M + Na] ^< +>.

(Synthesis Example 34)
(6,7-didehydro-4,5α-epoxy-3,14β-dihydroxy-3-methoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-17-yl) (cyclopropyl) methanone (Compound 56) Synthesis of

  The title compound 56 (51%) was obtained as a white amorphous form from the compound 55 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 0.70-1.00 (m, 4H), 1.60-1.75 (m, 1H), 1.90-2.12 (m, 1H) , 2.40 (dt, J = 5.2, 12.8 Hz, 0.5H), 2.48-2.88 (m, 3H), 2.71 (dt, J = 3.9, 13.6 Hz) , 0.5H), 3.00 (d, J = 18.5 Hz, 0.5H), 3.14 (dt, J = 3.6, 13.6 Hz, 0.5H), 3.25-3. 38 (m, 0.5 H), 3.46 (dd, J = 6.6, 18.5 Hz, 0.5 H), 4.18 (dd, J = 4.7, 13.8 Hz, 0.5 H) 4.44 (dd, J = 4.9, 13.7 Hz, 0.5H), 4.80 (d, J = 6.6 Hz, 0.5H), 5.10 (d, J = 6.6 Hz). , 0.5H), 5.5 5 (s, 0.5H), 5.56 (s, 0.5H), 6.55-6.70 (m, 2H), 7.10-7.20 (m, 1H), 7.20- 7.30 (m, 1H), 7.41 (dd, J = 6.4, 11.5 Hz, 2H), 2 protons (OHX2) not observed.
MS (ESI): m / z 452 [M + Na] ^< +>.

(Synthesis Example 35)
Synthesis of (6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) (phenyl) methanone (Compound 57)

  The title compound 57 (quantitative) was obtained as a white amorphous form from the compound 17 in the same manner as in the synthesis method of the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.52-1.65 (m, 0.6H), 1.74-1.85 (m, 0.4H), 2.40-2.60 (m 1.4H), 2.65-2.75 (m, 1H), 2.85-3.00 (m, 1H), 3.09 (d, J = 8.6 Hz, 1H), 3.15. -3.30 (m, 1H), 3.42 (dd, J = 6.6, 18.6 Hz, 0.6H), 3.58-3.69 (m, 0.6H), 3.72 ( s, 3H), 4.23-4.32 (m, 0.4H), 4.60-4.71 (m, 0.4H), 5.34 (d, J = 10.0 Hz, 0.6H) ), 5.57 (s, 0.4H), 5.64 (s, 0.6H), 6.57-6.70 (m, 2H), 6.98-7.08 (m, 1H), 7.10-7.20 (m, 1H), 7. 21-7.60 (m, 7H), 8.47 (s, 0.6H), 8.57 (s, 0.4H), 1 proton (OH) not observed.
MS (ESI): m / z 501 [M + Na] ^< +>.

(Synthesis Example 36)
Synthesis of (6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) (phenyl) methanone (Compound 58)

  The title compound 58 (62%) was obtained as a white amorphous form from the compound 57 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.50-1.60 (m, 0.5H), 1.70-1.80 (m, 0.5H), 2.40-2.73 (M, 2.5H), 2.85-3.16 (m, 2.5H), 3.21 (dd, J = 6.5, 18.3 Hz, 0.5H), 3.43 (dd , J = 6.8, 18.6 Hz, 0.5H), 3.53 (dd, J = 4.6, 13.9 Hz, 0.5H), 4.18 (d, J = 6.6 Hz, 0) .5H), 4.58 (dd, J = 5.0, 13.7 Hz, 0.5H), 5.23 (d, J = 6.6 Hz, 0.5H), 5.63 (s, 1H) 6.50-6.62 (m, 2H), 6.83-7.00 (m, 1H). 7.02-7.10 (m, 1H), 7.22-7.36 (m, 2H), 7.38-7.60 (m, 5H), 3 protons (OHX2, NH) not observed.
MS (ESI): m / z 487 [M + Na] ^< +>.

(Synthesis Example 37)
Synthesis of (6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) ethane-1-one (Compound 59)

  Compound 17 (103 mg, 0.28 mmol) was dissolved in dichloromethane (6 mL), triethylamine (0.11 mL, 0.83 mmol) and acetic anhydride (80 μL, 0.83 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Half stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (40-100 μm, chloroform: ammonia saturated methanol = 50: 1) to obtain the title compound 59 (114 mg, quantitative).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.71-1.81 (m, 1H), 2.13 (s, 1.8H), 2.24 (s, 1.2H), 2.34 ( dt, J = 5.3, 12.9 Hz, 0.4H), 2.54 (dt, J = 5.2, 12.7 Hz, 0.6H), 2.62-2.75 (m, 2H) 2.8.2.98 (m, 2H), 3.04 (d, J = 18.4 Hz, 0.4 H), 3.23 (dt, J = 3.6, 13.4 Hz, 0.6 H) ), 3.32 (dd, J = 6.8, 18.7 Hz, 0.6H), 3.40 (dd, J = 6.9, 18.4 Hz, 0.4H), 3.67 (dd, J = 4.7, 13.9 Hz, 0.6H), 3.75 (s, 3H), 4.26 (d, J = 6.6 Hz, 0.4H), 4.60 (dd, J = 4 .9, 10.4 Hz, 0.4H), 5.26 (d, J = 6.6 Hz, 0.6H), 5.60 (s, 0.4H), 5.66 (s, 0.6H), 6.62 (d, J = 8.3 Hz, 0.6H), 6.63 (d, J = 8.2 Hz, 0.4H), 6.66 (d, J = 8.3 Hz, 0.6H), 6.67 (d , J = 8.3 Hz, 0.4H), 7.03-7.09 (m, 1H), 7.14-7.21 (m, 1H), 7.31 (d, J = 8.0 Hz, 0.6H), 7.33 (d, J = 8.0 Hz, 0.4H), 7.41 (d, J = 7.8 Hz, 1H), 8.43 (brs, 0.6H), 8. 52 (brs, 0.4H).
MS (ESI): m / z 439 [M + Na] ^< +>.

(Synthesis Example 38)
Synthesis of (6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) ethane-1-one (Compound 60)

  The title compound 60 (23%) was obtained from the compound 59 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.57-1.67 (m, 1H), 2.09 (s, 1.5H), 2.22 (s, 1.5H), 2.38 (Dt, J = 5.2, 12.8 Hz, 0.5H), 2.45 (dt, J = 5.3, 12.8 Hz, 0.5H), 2.47-2.73 (m, 1 .5H), 2.80 (d, J = 18.5 Hz, 0.5H), 2.83-2.92 (m, 1H), 2.94 (d, J = 18.5 Hz, 0.5H) , 3.09 (dt, J = 3.8, 13.4 Hz, 0.5H), 3.24-3.33 (m, 0.5H), 3.39 (dd, J = 6.7, 18 .5 Hz, 0.5 H), 3.66 (dd, J = 4.9, 13.9 Hz, 0.5 H), 4.30 (d, J = 6.5 Hz, 0.5 H), 4.48 ( dd, J = 4.9, 13. 7 Hz, 0.5 H), 5.09 (d, J = 6.5 Hz, 0.5 H), 5.60 (s, 1 H), 6.55 (d, J = 8.1 Hz, 0.5 H), 6.56 (d, J = 8.1 Hz, 0.5H), 6.60 (d, J = 8.1 Hz, 0.5H), 6.61 (d, J = 8.1 Hz, 0.5H) 6.94 (t, J = 7.1 Hz, 0.5H), 6.95 (t, J = 7.1H, 0.5H), 7.07 (t, J = 7.1H, 0.5H) ), 7.08 (t, J = 7.2 Hz, 0.5H), 7.31 (d, J = 8.2 Hz, 0.5H), 7.32 (d, J = 8.1 Hz, 0. 2). 5H), 7.37 (d, J = 7.8 Hz, 0.5H), 7.38 (d, J = 7.8 Hz, 0.5H), 3 protons (OHX2, NH) not observed.
MS (ESI): m / z 425 [M + Na] ^< +>.

(Synthesis Example 39)
(6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxyindolo [2 ', 3': 6,7] morphinan-17-yl) -2,2,2-trifluoroethane- Synthesis of 1-one (Compound 61)

  The title compound 61 (75%) was obtained from the compound 17 in the same manner as in the synthesis method of the compound 2 described in Synthesis Example 1 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.77 (dd, J = 2.1, 12.7 Hz, 0.7 H), 1.83 (dd, J = 3.0, 12.9 Hz, 0.8). 3H), 2.19 (s, 0.3H), 2.20 (s, 0.7H), 2.49 (dt, J = 5.4, 13.0 Hz, 0.3H), 2.59 ( dt, J = 5.0, 12.8 Hz, 0.7 H), 2.71 (d, J = 16.1 Hz, 0.7 H), 2.73 (d, J = 15.8 Hz, 0.3 H) , 2.85 (d, J = 16.1 Hz, 0.7H), 2.87-2.97 (m, 0.3 H), 2.88 (d, J = 15.8 Hz, 0.3 H), 3.02 (d, J = 18.9 Hz, 0.7 H), 3.11 (d, J = 18.7 Hz, 0.3 H), 3.28-3.36 (m, 0.7 H), 3 .41 (dd, J = 7.0, 18.9 Hz, 0.7 H), 3.45 (dd, J = 6.5, 18.7 Hz, 0.3 H), 3.75 (s, 3 H), 3.89 (brd, J = 11.7 Hz, 0.7 H), 4.38 (d, J = 6.5 Hz, 0.3 H), 4.89 (dd, J = 5.3, 13.9 Hz, 0.3 H), 5 .15 (d, J = 7.0 Hz, 0.7H), 5.61 (s, 0.3H), 5.64 (s, 0.7H), 6.64-6.52 (m, 2H) 7.04-7.11 (m, 1H), 7.17-7.23 (m, 1H), 7.19-7.35 (m, 1H), 7.37-7.42 (m, 1H), 8.39 (s, 0.7H), 8.44 (s, 0.3H).

(Synthesis Example 40)
(6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) -2,2,2-trifluoroethane-1- Synthesis of ON (compound 62)

  The title compound 62 (85%) was obtained from the compound 61 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.72-1.82 (m, 1H), 2.42-2.70 (m, 2H), 2.88-3.12 (m, 2. 34H), 3.26-3.38 (m, 0.66H), 3.40-3.52 (m, 1H), 3.89 (brd, J = 13.8 Hz, 0.66H), 4. 35 (d, J = 6.5 Hz, 0.34H), 4.38-4.46 (m, 0.34H), 5.06 (d, J = 6.7 Hz, 0.66H), 5.62 (S, 0.34H), 5.64 (s, 0.66H), 6.56-6.64 (m, 2H) 6.95 (t, J = 7.5 Hz, 1H), 7.08 ( t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 3 protons (OHX2, NH) are observed. Z.
MS (ESI): m / z 457 [M + H] ^< +>.

(Synthesis Example 41)
(6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) -2-phenylethane-1-one (Compound 64) Synthesis of

  Compound 17 (100 mg, 0.27 mmol) was dissolved in THF (5 mL), diisopropylethylamine (93 μL, 0.54 mmol) and phenylacetyl chloride (72 μL, 0.54 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Half stirred. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product of compound 63 was used in the next reaction without purification. The title compound 64 (98 mg, 2-step yield 76%) was obtained from the crude product of the compound 63 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.51-1.59 (m, 0.55H), 1.26-1.69 (m, 0.45H), 2.27-2.47 ( m, 1H), 2.50-2.75 (m, 1.9H), 2.81 (dd, J = 5.4, 18.6 Hz, 0.55H), 2.89 (d, J = 15 .8 Hz, 1H), 2.98-3.11 (m, 1H), 3.29-3.38 (m, 0.55H), 3.53-3.88 (m, 2.1H), 4 .09 (dd, J = 1.7, 15.2 Hz, 0.45H), 4.42 (d, J = 6.4 Hz, 0.45H), 4.48-4.57 (m, 0.45H) ), 5.17 (brd, J = 4.5 Hz, 0.55H), 5.56 (s, 0.55H), 5.60 (s, 0.45H), 6.43 (d, J = 8) 1 Hz, 0. 45H), 6.50-6.60 (m, 1.55H), 6.91-6.98 (m, 1H), 7.04-7.12 (m, 1H), 7.17-7. 41 (m, 7H), 3 protons (OHX2, NH) not observed.
MS (ESI): m / z 501 [M + Na] ^< +>.

(Synthesis Example 42)
(6,7-didehydro-4,5α-epoxy-3,14β-dihydroxyindolo [2 ′, 3 ′: 6,7] morphinan-17-yl) -3-phenylpropan-1-one (Compound 66) Synthesis of

  The title compound 66 (2 step yield: 65%) was obtained from the compound 17 in the same manner as in the synthesis method of the compound 64 described in Synthesis Example 41.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.60-1.70 (m, 1H), 2.35-2.49 (m, 1H), 2.57-2.82 (m, 3. 55H), 2.82-3.07 (m, 4.45H), 3.26-3.37 (m, 1H), 3.72-3.83 (m, 0.55H), 4.36 ( d, J = 6.2 Hz, 0.45H), 4.53 (dd, J = 4.6, 13.7 Hz, 0.45H), 5.13 (d, J = 6.5 Hz, 0.55H) , 5.59 (s, 1H), 6.49-6.55 (m, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 7.05-7.11 (m, 1H), 7.12-7.33 (m, 6H), 7.35-7.40 (m, 1H), 3 protons (OHX2, NH) observation not.
MS (ESI): m / z 493 [M + H] ^< +>.

(Synthesis Example 43)
Synthesis of 4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3-methoxy-5′-nitroindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 67)

  Compound 4 (1.14 g, 2.97 mmol) was dissolved in acetic acid (20 mL), and 4-nitrophenylhydrazine hydrochloride (846 mg, 4.46 mmol) and methanesulfonic acid (0.58 mL, 8.92 mmol) were added. After stirring at room temperature for 2 hours, the mixture was stirred at 70 degrees for 2 hours. After cooling, the mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with chloroform. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (40-100 μm, chloroform) and recrystallized from chloroform / ether to give the title compound 67 (629 mg, 42%) as a brown amorphous substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.80-1.90 (m, 1H), 2.48 (dt, J = 5.4, 12.5 Hz, 1H), 2.62 (d, J = 15.8 Hz, 1H), 2.70 (dt, J = 3.4, 11.9 Hz, 1H), 2.82 (dd, J = 4.8, 11.5 Hz, 1H), 2.96 ( d, J = 15.8 Hz, 1H), 3.00-3.21 (m, 4H), 3.27 (d, J = 6.7 Hz, 1H), 3.78 (s, 3H), 4. 46 (s, 1H), 5.65 (s, 1H), 6.68-6.75 (m, 2H), 7.20 (d, J = 9.1 Hz, 1H), 7.88-8. 01 (m, 1H), 8.28-8.38 (m, 1H), 8.74 (s, 1H).
MS (ESI): m / z 502 [M + H] ⁺ .

(Synthesis Example 44)
5′-Amino-4,5α-epoxy-17- (2,2,2-trifluoroethyl) -3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 68) Synthesis of

  Copper acetate monohydrate (159.6 mg, 0.88 mmol) was dissolved in ethanol (6 mL), and sodium borohydride (474.8 mg, 12.6 mmol) was added under ice cooling, followed by stirring for 5 minutes. did. A solution of compound 67 (629 mg, 1.25 mmol) in THF (5 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (40-100 μm, chloroform: ammonia saturated methanol = 100: 2) to obtain the title compound 68 (494 mg, 83%) as a brown amorphous substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.74-1.83 (m, 1H), 2.42 (dt, J = 5.4, 12.6 Hz, 1H), 2.53 (d, J = 15.4 Hz, 1H), 2.64 (dt, J = 3.5, 12.8 Hz, 1H), 2.75 (dd, J = 4.9, 11.5 Hz, 1H), 2.80 ( d, J = 15.6 Hz, 1H), 2.95-3.18 (m, 4H), 3.20 (d, J = 5.4 Hz, 1H), 3.75 (s, 3H), 4 20-4.35 (brs, 1H), 5.62 (s, 1H), 6.50-6.70 (m, 4H), 7.04 (d, J = 8.5 Hz, 1H), 8 .14 (s, 1H), 2 protons (NH ₂ ) not observed.
MS (ESI): m / z 472 [M + H] ^< +>.

(Synthesis Example 45)
Synthesis of 5′-amino-4,5α-epoxy-17- (2,2,2-trifluoroethyl) indolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 69)

  The title compound 69 (45%) was obtained as a white amorphous form from the compound 68 by the same method as the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.65-1.75 (m, 1H), 2.40 (dt, J = 5.7, 15.6 Hz, 1H), 2.47-2 .55 (m, 1H), 2.62-2.78 (m, 3H), 3.01 (dd, J = 6.2, 18.6 Hz, 1H), 3.10-3.2 (m, 2H), 3.14 (d, J = 18.6 Hz, 1H), 3.25-3.40 (m, 1H), 5.55 (s, 1H), 6.54 (d, J = 8. 2 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.67 (dd, J = 2.2, 8.6 Hz, 1H), 6.78 (d, J = 1.6 Hz) , 1H), 7.11 (d, J = 7.9Hz, 1H), 5 protons (OHX2, NH, NH ₂₎ not observed.
MS (ESI): m / z 458 [M + H] ^< +>.

(Synthesis Example 46)
Synthesis of 17-benzyl-4,5α-epoxy-3-methoxy-5′-nitroindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (compound 70)

  The title compound 70 (69%) was obtained from the compound 34 in the same manner as in the synthesis method of the compound 67 described in Synthesis Example 43.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.75-1.88 (m, 1H), 2.30-2.45 (m, 2H), 2.55-2.70 (m, 2H), 2.87 (d, J = 18.9 Hz, 1H), 2.89 (dd, J = 6.7, 12.2 Hz, 1H), 3.20 (d, J = 6.4 Hz, 1H), 3 .36 (d, J = 18.7 Hz, 1H), 3.73 (s, 2H), 3.77 (s, 3H), 5.64 (s, 1H), 6.70 (d, J = 8 .3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 7.28-7.42 (m, 5H), 7 .94 (dd, J = 2, 2, 9.0 Hz, 1H), 8.25 (d, J = 2, 2 Hz, 1H), 8.82 (s, 1), 1 proton (OH) is observed. Z.
MS (ESI): m / z 510 [M + H] ⁺ .

(Synthesis Example 47)
Synthesis of 5′-amino-17-benzyl-4,5α-epoxy-3-methoxyindolo [2 ′, 3 ′: 6,7] morphinan-14β-ol (Compound 71)

  The title compound 71 (69%) was obtained from the compound 70 in the same manner as in the synthesis method of the compound 68 described in Synthesis Example 44.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70-1.82 (m, 1H), 2.35-2.42 (m, 2H), 2.49-2.64 (m, 2H), 2.73 (d, J = 15.7 Hz, 1H), 2.84 (dd, J = 6.5, 18.5 Hz, 1H), 3.14 (d, J = 6.4 Hz, 1H), 3 .32 (d, J = 18.5 Hz, 1H), 3.70 (s, 2H), 3.76 (s, 3H), 4.60-5.00 (brs, 1H), 5.62 (s) , 1H), 6.56-6.68 (m, 4H), 7.07 (d, J = 8.5 Hz, 1H), 7.27-7.40 (m, 5H), 7.99 (s) , 1H), 2 protons (NH ₂ ) not observed.
MS (ESI): m / z 480 [M + H] ⁺ .

(Synthesis Example 48)
Synthesis of 5′-amino-17-benzyl-4,5α-epoxyindolo [2 ′, 3 ′: 6,7] morphinan-3,14β-diol (Compound 72)

  The title compound 72 (30%) was obtained as a white amorphous form from the compound 71 by a method similar to the method for synthesizing the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.63-1.78 (m, 1H), 2.27-2.44 (m, 2H), 2.49 (d, J = 15.7 Hz, 1H), 2.60-2.62 (m, 1H), 2.61 (d, J = 15.8 Hz, 1H), 2.71-2.85 (m, 1H), 3.07 (d, J = 6.4 Hz, 1H), 3.27-3.39 (m, 1H), 3.71 (s, 2H), 5.54 (s, 1H), 6.51-6.60 (m, 2H), 6.61-6.68 (m, 1H), 6.70-6.79 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.20-7. 41 (m, 5H), 5 protons (OHX2, NH, NH ₂₎ not observed.
MS (ESI): m / z 466 [M + H] ^< +>.

(Synthesis Example 49)
((E) -7-benzylidene-4,5α-epoxy-14β-hydroxy-3-methoxy-6-oxomorphinan-17-yl) (phenyl) methanone (Compound 73)

  The title compound 73 (73%) was obtained as a white amorphous form from the compound 51 by a method similar to the method for synthesizing the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.40-1.50 (m, 0.8H), 1.50-1.63 (m, 0.2H), 2.20-2.60 (m , 2H), 3.00-3.40 (m, 4.2H), 3.51-3.70 (m, 0.8H), 3.88 (s, 3H), 4.40-4.58. (M, 0.2H), 4.68 (s, 1H), 5.17 (d, J = 5.7 Hz, 0.8H), 6.60-6.82 (m, 2H), 7.18 -7.50 (m, 9H), 7.61-7.78 (m, 1H), 7.85-7.97 (m, 1H), 1 proton (OH) not observed.
MS (ESI): m / z 516 [M + Na] ^< +>.

(Synthesis Example 50)
((E) -7-benzylidene-4,5α-epoxy-3,14β-dihydroxy-6-oxomorphinan-17-yl) (phenyl) methanone (Compound 74)

  The title compound 74 (50%) was obtained as a white amorphous form from the compound 73 in the same manner as the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.35-1.47 (m, 0.6H), 1.55-1.70 (m, 0.4H), 2.35-2.60 ( m, 2H), 2.76 (d, J = 16.2 Hz, 0.6H), 2.93 (dt, J = 3.8, 13.5 Hz, 0.4H), 3.02-3.25. (M, 2.6H), 3.38 (dd, J = 6.7, 18.8 Hz, 0.4H), 3.54 (dd, J = 4.9, 14.1 Hz, 0.6H), 4.06 (d, J = 4.6 Hz, 0.4H), 4.55 (dd, J = 5.9, 13.8 Hz, 0.4H), 4.61-4.65 (m, 1H) 5.11 (d, J = 6.5 Hz, 0.6H), 6.62-6.78 (m, 2H), 7.20-7.55 (m, 10H), 7.58-7. 70 (m, 1H), 2 proto (OHX2) not observed.
MS (ESI): m / z 502 [M + Na] ^< +>.

(Synthesis Example 51)
Synthesis of (6,7-didehydro-4,5α-epoxy-14β-hydroxy-3-methoxybenzofuro [2 ′, 3 ′: 6,7] morphinan-17-yl) (phenyl) methanone (Compound 75)

  The title compound 75 (76%) was obtained as a white amorphous form from the compound 54 by a method similar to the method for synthesizing the compound 7 described in Synthesis Example 3 and Step 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.55-1.90 (m, 1H), 3.25-3.95 (m, 3H), 3.00-3.30 (m, 3H), 3.41 (dd, J = 7.3, 19.7 Hz, 0.7H), 3.58-3.70 (m, 0.7H), 3.78-3.90 (m, 0.3H) , 3.79 (s, 3H), 4.25-4.38 (m, 0.3H), 4.55-4.62 (m, 0.3H), 5.32 (d, J = 6. 5Hz, 0.7H), 5.51 (s, 0.3H), 5.60 (s, 0.7H), 6.59-6.70 (m, 2H), 7.10-7.70 ( m, 9H).
MS (ESI): m / z 480 [M + H] ⁺ .

(Synthesis Example 52)
Synthesis of (6,7-didehydro-4,5α-epoxy-3,14β-dihydroxybenzofuro [2 ′, 3 ′: 6,7] morphinan-17-yl) (phenyl) methanone (compound 76)

  The title compound 76 (82%) was obtained as a white amorphous form from the compound 75 in the same manner as in the synthesis method of the compound 6 described in Synthesis Example 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.54 (d, J = 11.8 Hz, 0.7 H), 1.60-1.75 (m, 0.3 H), 2.05-2.70 (M, 2H), 2.72-2.90 (m, 1H), 3.04 (d, J = 18.5 Hz, 1H), 3.09-3.23 (m, 1H), 3.52 (Dd, J = 6.5, 18.6 Hz, 0.7H), 3.44 (s, 1H), 3.50-3.64 (m, 0.7H), 3.65-3.75 ( m, 0.3H), 4.20-4.32 (m, 0.3H), 4.45-4.60 (m, 0.3H), 5, 27 (d, J = 6.3 Hz, 0 .7H), 5.44 (s, 0.3H), 5.55 (s, 0.7H), 5.72-5.98 (brs, 1H), 6.45-6.60 (m, 1H) ), 6.61-6.70 (m 1H), 7.00-7.63 (m, 9H).
MS (ESI): m / z 466 [M + H] ^< +>.

The structures of the compounds of Synthesis Examples 1 to 18, 25 to 30, and 35 to 48 are summarized in Table 1. The compounds of Synthesis Examples 1 to 18 and 25 to 30 were compounds in which R ²¹ and R ³³ are groups shown in Table 1 below in the compound represented by the following formula (6). In Table 1, “cPr” represents a cyclopropyl group, “Py” represents a pyridyl group, and “Ph” represents a phenyl group.

The structures of the compounds of Synthesis Examples 19 to 21, 31, 32, 49, and 50 are summarized in Table 2. The compounds of Synthesis Examples 19 to 21, 31, and 32 were compounds in which R ²² and R ³³ were groups shown in Table 2 below in the compound represented by the following formula (7). In Table 2, “cPr” represents a cyclopropyl group, and “Ph” represents a phenyl group.

The structures of the compounds of Synthesis Examples 22 to 24, 33, 34, 51, and 52 are summarized in Table 3. The compounds of Synthesis Examples 22 to 24, ^33, and ³⁴ were compounds in which R ²³ and R ³³ are groups shown in Table 3 below in the compound represented by the following formula (8). In Table 2, “cPr” represents a cyclopropyl group, and “Ph” represents a phenyl group.

<Experimental example 2>
[[ ³⁵ S] GTPγS binding assay]
Synthesis examples 2, 4, 6, 8, 19, 21, ²² , 24, 26, 28, ^{32, 34} , 36, by [ ³⁵ S] GTPγS binding assay using CHO cells expressing human δ opioid receptor The inverse agonist activity of 50 and 52 compounds was examined. As a control, ICI-174864 (Tocris), which is known to be an inverse agonist of the opioid δ receptor, was used.

The results of the compounds of Synthesis Examples 2, 4, 6, and 8 are shown in Table 4 and FIG. 1A. In the figure, the lower the value of the vertical axis of the graph and the smaller the value of _Emax shown in Table 4, the higher the inverse agonist activity. In Table 4, EC ₅₀ means 50% effect concentration, E _max means the maximum value of effect, and so on.

  The results of the compounds of Synthesis Examples 19 and 21 are shown in Table 5 and FIG. 1B.

  The results of the compounds of Synthesis Examples 22 and 24 are shown in Table 6 and FIG. 1C.

  The results of the compounds of Synthesis Examples 26, 28, 32 and 34 are shown in Table 7 and FIG. 1D.

  The results of the compounds of Synthesis Examples 36, 50 and 52 are shown in Table 8 and FIG. 1E.

  No inverse agonist activity of the opioid δ receptor was observed in the compounds of Synthesis Examples 11, 13, 16, 18, 29, 30, 38, 40, 41, and 42.

<Experimental example 3>
[Animal experimentation]
Restraint stress was applied to the mice, and the learning function was examined by administering the compound of Synthesis Example 24.

  The restraint stress was applied by confining the mouse in a 50 mL polypropylene tube with an air hole for 2 hours per day for 5 consecutive days. After 24 hours from the final restraint, the learning and memory function was tested by a Y-shaped maze test. The compound of Synthesis Example 24 was intraperitoneally administered at a dose of 0.6 mg / kg or 2 mg / kg 60 minutes before the Y-shaped maze test. In addition, naltolindole (NTI), an antagonist of opioid δ receptor, was subcutaneously administered at a dose of 1 mg / kg or 3 mg / kg 15 minutes before administration of the compound of Synthesis Example 24.

  The experimental results are shown in FIG. In the graph of FIG. 2, a lower bar in the graph indicates that the learning function has been reduced. In FIG. 2, “*” means that there is a significant difference when the risk rate is less than 5%, and “**” means that there is a significant difference when the risk rate is less than 1%. As a result, a decrease in learning function was induced by restraint stress load, and the decrease in learning function was significantly improved by administration of the compound of Synthesis Example 24, that is, a memory improvement effect was shown.

  The effect of the compound of Synthesis Example 24 was antagonized by administration of an opioid δ receptor antagonist (NTI). This result indicates that the memory improvement effect is a phenomenon mediated by the opioid δ receptor.

<Experimental example 4>
The same experiment as in Experiment 3 was performed using the compound of Synthesis Example 26. The experimental results are shown in FIG. In the graph of FIG. 3, the lower bar of the graph indicates that the learning function is reduced. In FIG. 3, “*” means that there is a significant difference when the risk rate is less than 5%, “**” means that there is a significant difference when the risk rate is less than 1%, and “ns” indicates that there is a significant difference. Means no. As a result, a decrease in the learning function was induced by the restraint stress load, and the administration of the compound of Synthesis Example 26 significantly improved the decrease in the learning function, that is, an effect of improving memory.

  The effect of the compound of Synthesis Example 26 was antagonized by administration of an opioid δ receptor antagonist (NTI). This result indicates that the memory improvement effect is a phenomenon mediated by the opioid δ receptor.

  ADVANTAGE OF THE INVENTION According to this invention, the novel use of the inverse agonist of an opioid delta receptor can be provided. In addition, novel compounds can be provided.

Claims (5)

  A memory improving agent comprising, as an active ingredient, a compound that is an inverse agonist of an opioid δ receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof. The memory improving agent according to claim 1, wherein the inverse agonist is a compound represented by the following formula (1).

[In the formula (1), R ¹ is an optionally substituted alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms, and a cycloalkenylalkyl group having 5 to 7 carbon atoms. An aryl group having 6 to 12 carbon atoms, a heteroaryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an alkenyl group having 4 to 7 carbon atoms, an allyl group, and furan-2 having 1 to 5 carbon atoms. -Ylalkyl group, thiophen-2-ylalkyl group having 1 to 5 carbon atoms, halogenated alkyl group having 1 to 6 carbon atoms, alkylcarbonyl group having 1 to 6 carbon atoms, cycloalkylcarbonyl group having 1 to 6 carbon atoms , An arylcarbonyl group having 7 to 13 carbon atoms, a heteroarylcarbonyl group having 6 to 12 carbon atoms, an arylalkylcarbonyl group having 6 to 12 carbon atoms, and a heteroarylalkylcarbon having 6 to 12 carbon atoms R ² and R ³ each independently represent a hydrogen atom, a hydroxy group, an alkanoloxy group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms. Group, an arylcarbonyloxy group having 7 to 13 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, and X represents the following formula (2)

[In Formula (2), R ⁴ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 7 to 13 carbon atoms, and R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom. , Fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, isothiocyanato group, trifluoromethyl group, trifluoromethoxy group, cyano group, phenyl group, amino group, alkyl group having 1 to 5 carbon atoms, carbon number 1 ˜5 alkoxy group, C 1-3 hydroxyalkyl group, C 3-7 cycloalkyl group, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ (where m Is an integer of 0 to 3, R ⁸ represents an alkyl group having 1 to 5 carbon atoms), SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ or (CH ₂ ) _n NR ⁹ R ¹⁰ (where n is 0 An integer of ~ 3, R ⁹ And R ¹⁰ each independently represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a cycloalkylalkyl group having 4 to 6 carbon atoms), or R ⁷ is the same as defined above, and R ⁵ And R ⁶ (1) an alkylene group having 3 to 6 carbon atoms (provided that the hydrogen in the alkylene portion is R ¹¹ (R ¹¹ is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, alkanoyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon _{^{atoms, SR 8, SOR 8, SO}} 2 R 8, (CH 2) m CO 2 R 8, SO 2 NR 9 R 10, CONR 9 R ¹⁰ , (CH ₂ ) _n NR ⁹ R ¹⁰ (where m, n, R ⁸ , R ⁹ and R ¹⁰ are the same as defined above)), and the alkylene group is a benzene ring Bonded to adjacent carbons to form a ring Or (2) -S = TU = V- (S, T, U and V are nitrogen atoms or CH (however, hydrogen atoms are R ¹² (R ¹² is fluorine atom, chlorine atom, bromine) Atom, iodine atom, nitro group, isothiocyanato group, trifluoromethyl group, trifluoromethoxy group, cyano group, phenyl group, alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, 1 to 3 carbon atoms Hydroxyalkyl group, SR ⁸ , SOR ⁸ , SO ₂ R ⁸ , (CH ₂ ) _m CO ₂ R ⁸ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ or (CH ₂ ) _n NR ⁹ R ¹⁰ (provided that m, n, R ⁸ , R ⁹ and R ¹⁰ are the same as defined above. )) And may be substituted with the adjacent carbon of the benzene ring to form a ring. ). ] Or the following formula (3)

[In Formula (3), R ¹³ and R ¹⁴ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, an amino group, an alkyl group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms. Or R ¹³ and R ¹⁴ together represent a benzo group. ] Or the following formula (4)

[In the formula (4), R ⁵ , R ⁶ and R ⁷ are the same as defined above. ]. ] R ¹ may be any substituted benzyl group, heteroarylmethyl group, fluoroalkyl group having 1 to 6 carbon atoms, cycloalkylcarbonyl group having 1 to 6 carbon atoms, aryl having 7 to 13 carbon atoms The memory improving agent according to claim 1 or 2, which is a carbonyl group or a heteroarylcarbonyl group having 6 to 12 carbon atoms.   A memory improving composition comprising the memory improving agent according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. A compound represented by the following formula (5), a pharmaceutically acceptable salt thereof, or a solvate thereof.

[In Formula (5), R ^1b is an optionally substituted alkylcarbonyl group having 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 1 to 6 carbon atoms, and an arylcarbonyl group having 7 to 13 carbon atoms. Represents a heteroarylcarbonyl group having 6 to 12 carbon atoms, an arylalkylcarbonyl group having 6 to 12 carbon atoms, a heteroarylalkylcarbonyl group having 6 to 12 carbon atoms, an alkenylcarbonyl group having 1 to 6 carbon atoms, R ^2b , R ^3b and X ^b are the same as the definitions of R ² , R ³ and X in the formula (1), respectively. ]

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