JP2015180605A - Morphinan derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide morphinan derivatives having opioid δ receptor agonist activity.SOLUTION: The present invention provides morphinan derivatives represented by general formula (B) in the figure.

Description

The present invention relates to a morphinan derivative having an opioid δ receptor agonistic action.

Three types of opioid receptors, μ, δ, and κ, are known, and morphine that exhibits a strong affinity for μ receptors has long been used as an analgesic. Although the analgesic action of morphine is powerful, it is known to cause adverse events such as dependence formation, respiratory depression, and constipation through the μ receptor.
On the other hand, δ receptors also have analgesic effects, but δ receptor agonists are known not to participate in adverse events seen in morphine.
Therefore, it is considered that an agonist selective for the δ receptor may be an analgesic superior to morphine, and research on its creation has been actively conducted. However, no δ receptor agonist has yet been approved as a therapeutic or prophylactic agent.
In Patent Document 1, the following formula (A),

It is described that the compound represented by the formula has an opioid δ receptor agonistic action.

On the other hand, Non-Patent Document 1 includes the following formula (B) by the present inventors:

The compound represented by the formula (1) has been reported, but this compound had higher affinity for the μ receptor than the δ receptor.
Further, when the compound represented by the above formula (B) is compared with the morphinan derivative represented by the general formula (I) described later, there is a difference in chemical structure in that the constituent elements of the ring in both compounds are different. That is, in the compound represented by the above formula (B), the 5-membered ring portion containing nitrogen has hydroxy, but the latter does not have this.
In the compound represented by the above formula (B), the hydroxy group is not a simple substituent but forms a special partial structure called a hemiaminal structure (the carbon atom to which the hydroxy group is bonded is a 5-membered ring). It is also connected to the nitrogen atom of The fact that the hemiaminal structure is a special partial structure is also clear from the fact that the compound of the present invention can finally be synthesized from the compound represented by the above formula (B) or an analog thereof through multiple steps. (Refer to the manufacturing method (1) described later: Six steps are required to synthesize the compound (g) of the present invention from the analog (a) of the compound represented by the formula (B)).

WO 2008/001859

Tetrahedron, 2011, 67, 6682

  An object of the present invention is to provide a morphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof, and an analgesic containing these as an active ingredient.

  That is, the present invention provides the following general formula (I),

(Wherein R ¹ is hydrogen, C _1-6 alkyl, C _6-10 aryl, C _2-6 alkenyl, cycloalkylalkyl (the number of carbon atoms in the cycloalkyl moiety is 3-6, the number of carbon atoms in the alkylene moiety) 1-5.), Aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), C _3-6 cycloalkyl or heteroarylalkyl (heteroaryl is N, 1 to 4 heteroatoms selected from O and S are included as ring constituent atoms, and the alkylene moiety has 1 to 5 carbon atoms.)
R ² contains hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, heteroaryl (1-4 heteroatoms selected from N, O and S as ring members. ), Aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), heteroarylalkyl (heteroaryl is selected from 1 to 4 selected from N, O and S) A hetero atom is included as a ring constituent atom, the alkylene moiety has 1 to 5 carbon atoms, and a cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms. _{), C 2-6} alkenyl, the number of carbon atoms is 6-10 arylalkenyl (the aryl moiety, 2-6 carbon atoms alkenyl moiety.), heteroarylalkenyl (heteroar- Includes 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkenyl moiety has 2 to 6 carbon atoms), cycloalkylalkenyl (the number of carbon atoms in the cycloalkyl moiety) Is 3-6, the number of carbon atoms in the alkenyl moiety is 2-6.), C _4-6 cycloalkenyl, cycloalkenylalkyl (the number of carbon atoms in the cycloalkenyl moiety is 4-6, the number of carbon atoms in the alkylene moiety is 1-5.), Or cycloalkenylalkenyl (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms),
R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen, hydroxy, halogen, cyano, carbamoyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyloxy, nitro, amino, C _{1 -8 represents} alkylamino, aralkylamino (aryl moiety has 6 to 10 carbon atoms, alkylene moiety has 1 to 5 carbon atoms) or acylamino (acyl moiety has 2 to 6 carbon atoms);
R ⁶ and R ⁷ are the same or different and each represents hydrogen, fluorine or hydroxy,
R ⁸ and R ⁹ are the same or different and represent hydrogen, fluorine or hydroxy, or R ⁸ and R ⁹ together represent ═O,
X represents O or CH _2,
Y represents C═O, C═S, SO ₂ , C (═O) O, C (═O) NR ¹⁰ , C (═S) NR ¹⁰ or a bond, where R ¹⁰ is hydrogen, C _1-6 alkyl, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), heteroarylalkyl (heteroaryl is selected from N, O and S 1 Containing 4 heteroatoms as ring-constituting atoms, 1 to 5 carbon atoms in the alkylene moiety, cycloalkylalkyl (3 to 6 carbon atoms in the cycloalkyl moiety, and carbon atoms in the alkylene moiety being 1-5.).
However, the alkylene part and cycloalkyl part of C1-6 alkyl of R < ¹ _> and R < ² _> , cycloalkyl alkyl (the carbon number of the cycloalkyl part is 3-6, and the carbon number of the alkylene part is 1-5). , As well as aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) has 1 to 6 halogen atoms, hydroxy, C _1-6 alkoxy, C _{6 And} substituted with at least one substituent selected from _-10 aryloxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, carboxyl and alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1-6). Well,
The aryl and aralkyl ^{R 1} (carbon atoms of the aryl moiety is 6 to 10, carbon atoms is 1 to 5. The alkylene portion) aryl moiety of the ^{R 2} aryl, heteroaryl (N, O and S 1 to 4 heteroatoms selected from as a ring-constituting atom), an aryl moiety of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), Heteroaryl alkyl (wherein heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkylene moiety has 1 to 5 carbon atoms), The aryl moiety has 6 to 10 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms.) The aryl moiety and heteroarylalkenyl (heteroaryl N, containing from 1 to 4 heteroatom selected from O and S as a ring-constituting atom, the heteroaryl portion of the carbon atoms 2-6.) Alkenyl ^moiety, R 3, ^{R 4} and ^{R 5} C The aryl part of _6-10 aryloxy and the aryl part of aralkylamino are: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl ), Carbamoyl, alkylcarbamoyl (the alkyl part has 1 to 6 carbon atoms), dialkylcarbamoyl (the alkyl part has 1 to 6 carbon atoms), halogen, nitro, cyano, 1 to 3 halogens substituted _{C 1-6} alkyl, 1-3 halogen substituted _{C 1-6} alkoxy, phenyl, heteroaryl (N, O Containing from 1 to 4 heteroatoms selected from finely S as a ring-constituting atom.), Phenoxy, phenylalkyl (number of carbon atoms of alkyl is 1 to 3.), It is selected from methylenedioxy and ^NR 11 ^{R 12} Wherein R ¹¹ and R ¹² are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, or alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1-6), or R ¹¹ and R ¹² together with the N atom to which they are attached, further N, O, A 4- to 7-membered ring which may contain a heteroatom selected from S may be formed;
Furthermore, the alkylene part of R ¹ and R ² aralkyl (the aryl part has 6 to 10 carbon atoms and the alkylene part has 1 to 5 carbon atoms) was substituted with phenyl or 1 to 3 halogens. It may be substituted with at least one substituent selected from C _1-6 alkyl. )
Or a pharmacologically acceptable acid addition salt thereof.

The present invention also relates to a medicament comprising the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof.
The present invention also relates to a pharmaceutical composition containing, as an active ingredient, the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof.
The present invention also relates to an analgesic containing the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
Furthermore, the present invention relates to a method for treating pain, which comprises administering an effective amount of the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof.

Next, the present invention will be described in more detail.
Of the morphinan derivatives represented by the above general formula (I) or pharmacologically acceptable acid addition salts thereof, the following are preferable.
(1)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10. The morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, wherein the alkylene moiety has 1 to 5 carbon atoms in the alkylene moiety.
(2)
Wherein R ¹ is C _2-6 alkyl substituted with hydroxy, C _1-6 alkyl substituted with _1-6 halogens or C _2-6 alkyl substituted with C _1-6 alkoxy; A morphinan derivative represented by I) or a pharmacologically acceptable acid addition salt thereof.
(3)
The morphinan derivative represented by the above general formula (I), wherein Y is C═O, C (═O) O, C (═O) NR ¹⁰ or a bond, or the morphinan described in the above (1) or (2) A derivative or a pharmacologically acceptable acid addition salt thereof.
(4)
Y is a bond, R ² is C _1-6 alkyl, C _6-10 aryl, heteroaryl (including 1 to 4 heteroatoms selected from N, O and S as ring members), aralkyl (The aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms.) Or heteroarylalkyl (heteroaryl represents 1 to 4 heteroatoms selected from N, O and S). The morphinan derivative represented by the above general formula (I), which is included as a ring-constituting atom and has 1 to 5 carbon atoms in the alkylene moiety, or the morphinan derivative described in (1) or (2) above or a pharmacology thereof Acceptable acid addition salts.
(5)
Y is a bond, R ² is C _1-6 alkyl, aralkyl (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms) or heteroarylalkyl (heteroaryl is N , A morphinan derivative represented by the above general formula (I), which contains 1 to 4 heteroatoms selected from O and S as ring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atoms, or The morphinan derivative according to the above (1) or (2) or a pharmacologically acceptable acid addition salt thereof.
(6)
The morphinan derivative represented by the above general formula (I), wherein X is CH ₂ , the morphinan derivative described in the above (1) to (5), or a pharmaceutically acceptable acid addition salt thereof.
(7)
Among R ³ and R ⁴ , one is hydroxy and the other is hydrogen, the morphinan derivative represented by the above general formula (I), the morphinan derivative described in the above (1) to (6) or pharmacologically thereof Acceptable acid addition salt.
(8)
R ³ is halogen, cyano, carbamoyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, amino or acylamino (acyl moiety has 2 to 6 carbon atoms), R ⁴ is hydrogen or hydroxy, and R ⁵ is The morphinan derivative represented by the above general formula (I) which is hydrogen, or the morphinan derivative described in the above (1) to (6) or a pharmacologically acceptable acid addition salt thereof.

(9)
The morphinan derivative represented by the above general formula (I), wherein R ³ is hydroxy or carbamoyl, and R ⁴ and R ⁵ are hydrogen, or the morphinan derivative described in (1) to (6) above or a pharmacologically acceptable salt thereof Acid addition salts.

(10)
The morphinan derivative represented by the above general formula (I), wherein R ³ , R ⁴ and R ⁵ are all hydrogen, or the morphinan derivative described in (1) to (6) above or a pharmacologically acceptable acid addition thereof salt.

(11)
R ⁶ , R ⁷ , R ⁸ and R ⁹ are all hydrogen, the morphinan derivative represented by the above general formula (I), the morphinan derivatives described in the above (1) to (10) or pharmacologically acceptable thereof Acid addition salts.

In this patent,
C _1-6 alkyl includes methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, neopentyl, hexyl and the like.
C _1-6 alkyl substituted with 1 to 3 halogens includes 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl or 3,3,3-trimethyl. Examples include fluoropropyl.
Examples of C _2-6 alkenyl include 2-propenyl and 3-methyl-2-butenyl.
Cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) is substituted with C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl Methyl, ethyl and the like.
Examples of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) include a benzyl group or a phenethyl group.
C _3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
C _6-10 aryl includes phenyl or naphthyl.
Examples of heteroaryl (including 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms) include pyridyl, furyl, imidazolyl, pyrimidinyl, pyrazinyl, and thiazolyl.
Heteroarylalkyl (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkylene moiety has 1 to 5 carbon atoms). Yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, (furan-2-yl) methyl, (furan-3-yl) methyl, (imidazol-2-yl) methyl, Examples include imidazol-4-yl) methyl, (imidazol-5-yl) methyl, (thiazol-2-yl) methyl, (thiazol-4-yl) methyl, and (thiazol-5-yl) methyl.
As arylalkenyl (the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkenyl moiety is 2 to 6), 2-propenyl or 3-methyl-2-butenyl substituted with phenyl or naphthyl, etc. Is mentioned.
Heteroarylalkenyl (heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkenyl moiety has 2 to 6 carbon atoms) as pyridyl, furyl, imidazolyl or Examples include 2-propenyl or 3-methyl-2-butenyl substituted with thiazolyl and the like.
Cycloalkylalkenyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms) substituted with C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl 2-propenyl or 3-methyl-2-butenyl etc. which were made.
Examples of C _4-6 cycloalkenyl include cyclobutenyl and cyclopentenyl.
Examples of cycloalkenylalkyl (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) include methyl and ethyl substituted with cyclobutenyl or cyclopentenyl.
Cycloalkenylalkenyl (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms) is 2-propenyl or 3-methyl-2 substituted with cyclobutenyl, cyclopentenyl, or the like. -Butenyl.
_{Examples of} C _1-3 alkyl include methyl and ethyl.
Examples of C _2-6 alkyl substituted with hydroxy include 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and the like.
_{Examples of} C _2-6 alkyl substituted with C _1-6 alkoxy include 2-methoxyethyl and the like.
Examples of C _1-6 alkanoyl include acetyl and propionyl.
C _1-6 alkoxy includes methoxy, ethoxy, propoxy and the like.
Examples of C _1-6 alkanoyloxy include acetoxy and the like.
Examples of alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety is 1 to 6) include methoxycarbonyl and ethoxycarbonyl.
Examples of the halogen include fluorine, chlorine, bromine and the like.
Examples of C _1-6 alkoxy substituted with 1 to 3 halogens include fluoromethoxy and trifluoromethoxy.
Examples of phenylalkyl (the number of carbon atoms in the alkylene moiety is 1 to 3) include benzyl and the like.
_{Examples of} C _6-10 aryloxy include phenoxy.
_{Examples of} C _1-8 alkylamino include methylamino and ethylamino.
Examples of aralkylamino (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) include benzylamino and the like.
Examples of acylamino (acyl moiety having 2 to 6 carbon atoms) include acetylamino and the like.
Examples of alkylcarbamoyl (wherein the alkyl moiety has 1 to 6 carbon atoms) include ethylcarbamoyl and the like.
Examples of the dialkylcarbamoyl (the alkyl moiety has 1 to 6 carbon atoms) include diethylcarbamoyl and the like.
In addition, R ¹¹ , R ¹² and N atom are combined, and a 4- to 7-membered ring which may contain a hetero atom selected from N, O and S includes a piperidine ring, a piperazine ring or a morpholine ring. Can be mentioned.
In the morphinan derivative represented by the above general formula (I), pharmacologically acceptable acid addition salts include hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, camphorsulfonate, and the like. Examples include salts with organic acids or inorganic acids.
The morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof includes cis, trans isomers, racemates, optically active substances, and the like.
These hydrates and solvates are also included in the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof.

Next, a method for producing the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof will be described below.

(I) A morphinan derivative represented by the above general formula (I), wherein R ¹ = cyclopropylmethyl, Y = bond, R ³ = C _1-6 alkoxy or hydroxy, R ⁴ , R ⁵ , R ⁶ , R ^{When 7} , R ⁸ , R ⁹ = hydrogen:

(In the formula, R ³⁰ represents C _1-6 alkoxy, and X and R ² are the same as described above.)

Compound (b) can be synthesized by reducing compound (a) in the first step with a borane-THF complex or the like in a solvent such as tetrahydrofuran (THF). The starting material (a) can be synthesized by a known method (Tetrahedron, 2011, 67, 6682, etc.) and a method analogous thereto.

Compound (c) is synthesized by reacting the second step compound (b) with bromobenzene in a solvent such as pyridine in the presence of a catalyst such as copper powder and a base such as potassium carbonate.

Third Step Compound (d) is synthesized by birch reduction of compound (c). The reaction is performed using, for example, sodium silica gel stage I and ethylenediamine as reagents in a solvent such as THF.

Fourth step Compound (e) can be obtained by catalytic reduction of compound (d) using palladium-carbon as a catalyst.

In the fifth step compound (e), an oxidizing agent such as iodosobenzene acts in a solvent such as acetonitrile, dimethylformamide (DMF), dichloromethane or chloroform in the presence or absence of an additive such as trimethylsilyl cyanide or potassium cyanide. Inventive compound (f) can be obtained.

Sixth Step The compound (g) of the present invention in which R ^{3 in the} general formula (I) is C _1-6 alkoxy is obtained by N-alkylation or N-arylation reaction of the compound (f). When R ² is alkyl or aralkyl, an alkylation reaction with alkyl halide or halogenated aralkyl is used in the presence of a base such as sodium hydride. When R ² is aryl, a cross-coupling reaction with an aryl halide is used. In this case, palladium catalyst such as palladium acetate, tris (dibenzylideneacetone) dipalladium, tetrakistriphenylphosphine palladium, and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 1,1′- The reaction is carried out using a phosphorus ligand such as bis (diphenylphosphino) ferrocene or 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.

Seventh Step A compound (h) of the present invention wherein R ^{3 in the} general formula (I) is hydroxy is obtained by reacting compound (g) with boron tribromide or the like in dichloromethane, or compound (g) in DMF. In the presence of a base such as potassium t-butoxide in the presence of an alkanethiol such as 1-dodecanethiol.

(II) A morphinan derivative represented by the above general formula (I), wherein R ¹ = cyclopropylmethyl, Y = bond, R ³ = hydrogen, R ⁴ = hydroxy, R ⁵ , R ⁶ , R ⁷ , R ⁸ , When R ⁹ = hydrogen:

(In the formula, R ² and X are the same as above.)

First Step Conversion from compound (i) to compound (j) is performed by tetrazolylation of the hydroxy group using 5-chloro-1phenyl-1H-tetrazole. Compound (i) can be synthesized by a known method (Tetrahedron, 2011, 67, 6682, etc.) and a method analogous thereto.

Second Step The compound (k) can be obtained by catalytic reduction of the compound (j) using palladium-carbon as a catalyst.

The third step and thereafter The compound (l) of the present invention is prepared by the method (first, fourth, fifth and sixth steps) described in (I) above following a known rearrangement reaction (Tetrahedron, 2011, 67, 6682, etc.). ) And methods equivalent thereto.


(III) in morphinan derivative represented by the general formula (I), other than ^{R 1} = cyclopropylmethyl ^{R 1, R 3, R 4} = hydrogen or _{C 1-6} ^{alkoxy, R 5, R 6, R} 7 , R ⁸ , R ⁹ = hydrogen, Y = bonded hand:

(In the formula, R ^1a represents R ¹ other than cyclopropylmethyl, R ³¹ and R ⁴¹ are different and represent hydrogen or C _1-6 alkoxy, and X and R ² are the same as above.)

First step Starting from compound (g-1) synthesized by the method described in the above production method (I) or (II), or a method analogous thereto, the compound ( m) is synthesized.

(Method A)
De-N-alkylation method consisting of reaction with chloroformate and subsequent decarbamate reaction (Bioorg. Med. Chem. Lett., 2010, 20, 6302, etc.).
(Method B)
A method using diethyl azodicarboxylate (Synthetic Communications, 1995, 25, 829, etc.).

Second Step Conversion from the compound (m) to the invention compound (n) can be carried out by a normal N-alkylation reaction or reductive amination reaction.

(IV) A morphinan derivative represented by the above general formula (I), wherein R ³ , R ⁴ = hydrogen or C _1-6 alkoxy, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ = hydrogen, Y = CO , C (= O) O or C (= O) NR ¹⁰ :

(Wherein R ³¹ and R ⁴¹ are different and represent hydrogen or C _1-6 alkoxy; Y ¹ represents C (═O), C (═O) O or C (═O) NR ¹⁰ ; ¹ , R ² , R ¹⁰ and X are the same as above.)

The compound (p) of the present invention in which Y ¹ is C (═O), C (═O) O or C (═O) NR ¹⁰ is converted to the compound (o) in the presence of a base such as triethylamine or sodium hydride. They can be synthesized by reacting compound (q-1), (q-2) or (q-3), respectively. The starting material compound (o) is synthesized by the method described in the above production methods (I) and (III) or a method analogous thereto.


(V) A morphinan derivative represented by the above general formula (I), wherein R ⁴ is a hydrogen atom, R ³ = C _1-6 alkanooxy, hydrogen, cyano, CONH ₂ , amino or acylamino, R ⁵ , R ⁶ , When R ⁷ , R ⁸ , R ⁹ = hydrogen:

Said compound is each synthesize | combined by the method according to either of the methods illustrated to the following reaction schemes, or those.

In the case of R ³ = C _1-6 alkanooxy:

(In the formula, R ³² represents C _1-6 alkanooxy, and R ¹ , R ² , X and Y are the same as above.)

Inventive compound (s) is synthesized using acid chloride or acid anhydride as acylating agent in a solvent such as pyridine. The compound (r) is synthesized by the method described in the above (I), (III) and (IV) and a method analogous thereto.


When R ³ = hydrogen:

(Wherein R ¹ , R ² , X and Y are the same as above)

The conversion from the first step compound (r) to the compound (t) is synthesized by trifluoromethanesulfonylation of a hydroxy group using N-phenylbis (trifluoromethanesulfonimide) or trifluoromethanesulfonic anhydride or the like.

Second Step Invention Compound (u) can be obtained by a reduction reaction of compound (t) under a palladium catalyst (such as the method described in Tetrahedron Letters, 2010, 51, 2359.).

(3) When R ³ = cyano, CONH ₂ :

(Wherein R ¹ , R ² , X and Y are the same as above)

As shown in the above scheme, the inventive compound (w) is obtained in two steps from the compound (t) (first step: introduction of a cyano group under a palladium catalyst, second step: conversion of the cyano group to a first amide). It is synthesized through. In the second step, instead of the method described in the above scheme, a normal hydrolysis reaction may be used.

(4) When R ³ = amino, acylamino:

(In the formula, R ³³ represents C _1-6 acylamino, and R ¹ , R ² , X and Y are the same as described above.)

As shown in the above scheme, the inventive compound (z) is prepared in three steps from the compound (t) (first step: cross-coupling reaction between triflate (t) and benzophenone imine under a palladium catalyst, second step: imine ( x) hydrolysis, third step: acylation to an amino group with acid chloride or the like).

Other compounds included in the general formula (I) can also be produced by a combination of the above synthesis methods and the methods described in Examples below.

Next, pharmacological experiment results will be described.
As described in Table 1 of Example 6 below, the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is an excellent δ receptor in an opioid receptor function test. It became clear that it had an agonistic action.
Therefore, the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is used for pain treatment in diseases accompanied by acute pain and chronic pain, rheumatoid arthritis, osteoarthritis, bone tumor, etc. It can be used as a prophylactic and therapeutic agent for cancer pain accompanied by severe pain, diabetic neuropathic pain, postherpetic neuralgia, visceral pain and the like.
In addition, the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has anxiety such as depression, panic disorder, anxiety disorder, and stress disorder (PTSD, acute stress disorder). As a therapeutic agent for accompanying psychiatric disorders, it can be used as a prophylactic and therapeutic agent for urinary incontinence, myocardial ischemia, hypertension, Parkinson's disease and other motor dysfunctions.

The morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can be administered to humans by an appropriate administration method such as oral administration or parenteral administration. It can also be used in combination with other analgesics.
For formulation, it can be produced into a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
For these preparations, for example, in the case of tablets, usual excipients, disintegrants, binders, lubricants, pigments and the like are used. Here, as the excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca), etc., as the lubricant, magnesium stearate, Examples of binders include talc and the like, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for preparing injections.
In general, for adults, the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, which is an active ingredient, is 0.1 μg to 1 g / in. Day, preferably 0.001 to 200 mg / day. In oral administration, 1 μg to 10 g / day, preferably 0.01 to 2000 mg / day, but may be increased or decreased depending on age, symptoms and the like.
Next, although a reference example and an example are given and the present invention is explained still in detail, the present invention is not limited to these.
(Reference Example 1)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H- Synthesis of 6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-11-ol (2)

Under an argon atmosphere, (1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-14- (cyclopropylmethyl) -3a, 11-dihydroxy-10-methoxy-1,3,3a, 4,5, 6,7,11c-octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one [compound 1: Tetrahedron, 2011, 67, 6682 Compound] (10.1 g, 20 mmol) was dissolved in tetrahydrofuran (THF) (100 mL), borane-THF complex / THF solution (1.0 mol / L, 100 mL, 100 mmol) was added, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, 6M hydrochloric acid (200 mL) was added, and the mixture was refluxed for 1 hr. The reaction solution was adjusted to pH 11 with potassium carbonate and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 2 (8.84 g, 94%) as a white amorphous.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.02-0.16 (m, 2H), 0.42-0.70 (m, 3H), 0.90-1.02 (m, 1H), 1.37-1.47 (m, 1H), 1.51 (dd, J = 7.6, 14.8 Hz, 1H), 1.66-1.89 (m, 2H), 1.97-2 .12 (m, 2H), 2.22 (dd, J = 7.2, 12.8 Hz, 1H), 2.55 (dd, J = 5.6, 12.8 Hz, 1H), 2.56- 2.68 (m, 1H), 2.81-2.93 (m, 2H), 3.05 (d, J = 18.4 Hz, 1H), 3.31 (dd, J = 6.8, 10 .8 Hz, 1H), 3.46-3.59 (m, 2H), 3.60 (d, J = 6.4 Hz, 1H), 3.74 (d, J = 13.6 Hz, 1H), 3 .75 (d, J = 3.6 Hz, 1H), 3.79 (s, 3H) 4.91-4.98 (m, 1H), 6.25 (brs, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 7.11-7.31 (m, 5H).

(Reference Example 2)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-11-phenoxy-2,3,3a, 4,5,6,7,11c- Synthesis of octahydro-1H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indole (3)

Compound 2 (8.84 g, 19 mmol) was dissolved in pyridine (100 mL) under an argon atmosphere, bromobenzene (98.5 mL, 94 mmol), potassium carbonate (7.76 g, 56 mmol), copper powder (1.19 g, 19 mmol). ) Was added and refluxed for 16 hours. Bromobenzene (4.92 g, 47 mmol), potassium carbonate (7.76 g, 56 mmol) and copper powder (1.19 g, 19 mmol) were added to the reaction solution, and the mixture was further refluxed for 24 hours. The reaction solution was filtered through Celite, poured into distilled water, and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography to give the title compound 3 (10.1 g, 98%) as a black oil.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.00-0.16 (m, 2H), 0.40-0.78 (m, 3H), 0.86-1.02 (m, 1H), 1.04-1.14 (m, 1H), 1.41-1.53 (m, 1H), 1.68-1.93 (m, 3H), 2.06 (dt, J = 3.0) , 12.3 Hz, 1H), 2.23 (dd, J = 7.2, 12.3 Hz, 1H), 2.49-2.61 (m, 2H), 2.86 (dd, J = 2. 4, 10.8 Hz, 1 H), 2.83-2.99 (m, 1 H), 3.11 (d, J = 18.6 Hz, 1 H), 3.15 (dd, J = 6.3, 11 .1 Hz, 1 H), 3.22 (dd, J = 6.0, 7.5 Hz, 1 H), 3.53-3.63 (m, 2 H), 3.66 (d, J = 13.5 Hz, 1H), 3.67 ( 3H), 3.75 (d, J = 13.5 Hz, 1H), 4.77-4.86 (m, 1H), 6.76 (d, J = 7.8 Hz, 2H), 6.80. (D, J = 8.4 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 7.16-7.32 ( m, 7H).

(Reference Example 3)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H- Synthesis of 6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indole (4)

Under an argon atmosphere, compound 3 (90.7 mg, 0.17 mmol) was dissolved in THF (2 mL), ethylenediamine (333 μL, 6.2 mmol) was added, and sodium silica gel (stage I) (900 mg) was added 5 times per hour. The mixture was stirred at room temperature for 5 hours while adding in portions. The reaction solution was poured into distilled water under ice cooling, and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 4 (68.2 mg, 90%) as a colorless oil.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.00-0.16 (m, 2H), 0.41-0.59 (m, 3H), 0.87-1.03 (m, 1H), 1.13-1.30 (m, 1H), 1.51 (dd, J = 6.9, 15.0 Hz, 1H), 1.62-1.84 (m, 2H), 2.00-2 .16 (m, 2H), 2.23 (dd, J = 7.2, 12.3 Hz, 1H), 2.54-2.67 (m, 1H), 2.55 (dd, J = 5. 4, 12.6 Hz, 1H), 2.73-2.87 (m, 2H), 2.97-3.07 (m, 1H), 3.07 (d, J = 18.6 Hz, 1H), 3.30 (dd, J = 6.9, 10.8 Hz, 1H), 3.47 (t, J = 6.6 Hz, 1H), 3.62 (d, J = 6.9 Hz, 1H), 3 .66 (d, J = 13.5 Hz, 1H), 3.75 (s, 3H), 3.78 (d, J = 13.5 Hz, 1H), 4.93-5.02 (m, 1H), 6.66-6. 74 (m, 2H), 6.88-7.07 (m, 1H), 7.17-7.34 (m, 5H).

(Reference Example 4)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H-6,11b- Synthesis of (Iminoethano) -1,5a-epoxynaphtho [1,2-e] indole (5)

Compound 4 (1.83 g, 4.0 mmol) was dissolved in ethanol (20 mL), 10% palladium-carbon (1.12 g) was added, and the mixture was stirred at 40 ° C. for 15 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated. The resulting crude product was purified by silica gel column chromatography to give the title compound 5 (1.27 g, 86%) as a yellow oil.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.02-0.16 (m, 2H), 0.42-0.60 (m, 2H), 0.80-1.11 (m, 3H), 1.20-1.35 (m, 1H), 1.76 (dd, J = 4.8, 10.8 Hz, 2H), 1.96 (brs, 1H), 2.00-2.20 ( m, 2H), 2.25 (dd, J = 7.2, 12.3 Hz, 1H), 2.55-2.70 (m, 1H), 2.56 (dd, J = 5.4, 12) .3 Hz, 1 H), 2.74-2.93 (m, 2 H), 3.08 (d, J = 18.3 Hz, 1 H), 3.22 (dd, J = 2.4, 12.6 Hz, 1H), 3.38 (dd, J = 6.3, 12.6 Hz, 1H), 3.56-3.68 (m, 2H), 3.79 (s, 3H), 4.97 (dt, J = 2.1 6.3Hz, 1H), 6.66-6.77 (m, 2H), 6.99-7.08 (m, 1H).

(1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c-octahydro-2H-6 11b- (Iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (7)

(1) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -14- (cyclopropylmethyl) -10-methoxy-1,3,3a, 4,5,6,7,11c-octahydro-2H Synthesis of -6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (6)

Under an argon atmosphere, Compound 5 (147 mg, 0.40 mmol) was dissolved in dichloromethane (4 mL), iodosobenzene (440 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. A 10% aqueous sodium thiosulfate solution (12 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 minutes. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC to give the title compound 6 (82.7 mg, 54%) as a white amorphous.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.17 (m, 2H), 0.42-0.58 (m, 2H), 0.77-0.99 (m, 2H), 1.16 (dd, J = 6.8, 14.8 Hz, 1H), 1.27 (d, J = 10.4 Hz, 1H), 1.72-1.92 (m, 2H), 1.99 (Dt, J = 5.2, 12.8 Hz, 1H), 2.08-2.24 (m, 1H), 2.22 (dd, J = 7.6, 12.0 Hz, 1H), 2. 58-2.73 (m, 2H), 2.88 (dd, J = 6.4, 18.4 Hz, 1H), 3.11 (d, J = 18.0 Hz, 1H), 3.20 (dd , J = 6.4, 7.6 Hz, 1H), 3.75 (d, J = 6.0 Hz, 1H), 3.79 (s, 3H), 3.94 (dd, J = 4.8, 7.6 Hz, 1 H), 4.54 (d, J = 5.6 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.74 (dd, J = 2.8, 8.4 Hz, 1H) ), 7.08 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H).

(2) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c-octahydro-2H Synthesis of -6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (7)

Compound 6 (117 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL) under an argon atmosphere, and boron tribromide-dichloromethane solution (1.00 mol / L, 1.5 mL, 1.5 mmol) was added under ice cooling. Stir at room temperature for 1 hour. Thereafter, 25% aqueous ammonia (5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Distilled water was added, extracted three times with chloroform, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative TLC to give the title compound 7 (78.7 mg, 70%) as a colorless oil. Further, this compound was treated with a 15% hydrogen chloride / methanol solution to obtain a hydrochloride.

Compound 7 (free base) ¹ H NMR (CD ₃ OD, 300 MHz): δ 0.08-0.24 (m, 2H), 0.45-0.64 (m, 2H), 0.83-0. 98 (m, 2H), 1.07-1.20 (m, 1H), 1.22-1.32 (m, 1H), 1.66-1.99 (m, 3H), 2.18 ( dt, J = 3.3, 12.3 Hz, 1H), 2.33 (dd, J = 7.2, 12.6 Hz, 1H), 2.46-2.60 (m, 2H), 2.93. (Dd, J = 6.3, 18.6 Hz, 1H), 3.12 (d, J = 18.6 Hz, 1H), 3.20-3.36 (m, 1H), 3.71 (d, J = 6.0 Hz, 1H), 3.94 (dd, J = 4.2, 7.8 Hz, 1H), 4.43 (d, J = 5.7 Hz, 1H), 6.60-6.68. (M, 2H , 7.02 (d, J = 8.1Hz, 1H).

(1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c-octahydro- 2H-6,11b- (Iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (9)

(1) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-1,3,3a, 4,5,6,7,11c Synthesis of octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (8)

Under an argon atmosphere, compound 6 (237 mg, 0.62 mmol) was dissolved in THF (5 mL), benzyl bromide (297 μL, 2.5 mmol) and 60% sodium hydride (124 mg, 3.1 mmol) were added, and at room temperature. Stir for 19 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 8 (221 mg, 75%) as a white amorphous.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.17 (m, 2H), 0.42-0.60 (m, 2H), 0.63-0.77 (m, 1H), 0.82-1.04 (m, 1H), 1.18-1.33 (m, 2H), 1.66-1.83 (m, 2H), 2.01 (dt, J = 5.2) , 12.8 Hz, 1H), 2.07-2.37 (m, 2H), 2.58-2.73 (m, 2H), 2.81-2.96 (m, 1H), 3.02 -3.22 (m, 1H), 3.07 (dd, J = 6.0, 7.6 Hz, 1H), 3.65-3.83 (m, 2H), 3.75 (s, 3H) , 3.94 (d, J = 15.2 Hz, 1H), 4.71 (d, J = 16.0 Hz, 1H), 4.93 (d, J = 15.2 Hz, 1H), 6.55 ( d, J = 2.8 Hz, 1 H), 6.71 (dd, J = 2.8, 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.19-7.42 (m, 5H).

(2) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c Synthesis of Octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (9)

According to the method described in Example 1 (2), using 8 (19.5 mg, 0.041 mmol) obtained in (1) above, the title compound 9 (7.5 mg, 40%) and its hydrochloric acid as colorless oil were obtained. Salt was obtained.

Compound 9 (free base) ¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06-0.19 (m, 2H), 0.41-0.58 (m, 2H), 0.66-1.03 (M, 2H), 1.17-1.34 (m, 2H), 1.63-1.78 (m, 2H), 1.96 (dt, J = 5.1, 12.9 Hz, 1H) 2.14-2.45 (m, 2H), 2.61-2.77 (m, 2H), 2.81-2.96 (m, 1H), 2.98-3.23 (m, 2H), 3.68-3.83 (m, 2H), 3.95 (d, J = 14.7 Hz, 1H), 4.65 (d, J = 5.7 Hz, 1H), 4.89 ( d, J = 15.0 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 6.97 (d , J = 8.4 z, 1H), 7.16-7.35 (m, 5H)

(1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-9-chloro-14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7, 11c-octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (10) and (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S ) -3-Benzyl-11-chloro-14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c-octahydro-2H-6,11b- (iminoethano)- Synthesis of 1,5a-epoxynaphtho [1,2-e] indol-2-one (11)

Under an argon atmosphere, compound 9 (37.4 mg, 0.082 mmol) is dissolved in acetonitrile (2 mL), 2M hydrochloric acid (2 mL) and iodosobenzene (18.0 mg, 0.082 mmol) are added, and the mixture is stirred at room temperature for 30 minutes. did. Saturated aqueous sodium hydrogen carbonate solution (10 mL) and 10% aqueous sodium thiosulfate solution (10 mL) were added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by preparative TLC to give the title compound 10 (14.2 mg, 35%) and the title compound 11 (9.4 mg, 23%) as colorless oils, respectively. Furthermore, each was made into hydrochloride.

Compound 10 (free base) ¹ H NMR (CDCl ₃ , 400 MHz): δ 0.04-0.18 (m, 2H), 0.43-0.58 (m, 2H), 0.66-1.02 (M, 2H), 1.16-1.36 (m, 2H), 1.56-1.82 (m, 2H), 1.99 (dt, J = 5.2, 12.8 Hz, 1H) 2.10-2.40 (m, 2H), 2.60-2.77 (m, 2H), 2.87 (dd, J = 5.2, 18.4 Hz, 1H), 3.01- 3.21 (m, 1H), 3.05 (t, J = 6.8 Hz, 1H), 3.68-3.82 (m, 2H), 3.95 (d, J = 14.8 Hz, 1H ), 4.68 (d, J = 5.6 Hz, 1H), 4.90 (d, J = 14.8 Hz, 1H), 6.75 (s, 1H), 7.12 (s, 1H), 7.18 7.38 (m, 5H)

Compound 11 (free base) ¹ H NMR (CDCl ₃ , 400 MHz): δ 0.02-0.18 (m, 2H), 0.42-0.59 (m, 2H), 0.63-0.78 (M, 1H), 0.82-1.02 (m, 1H), 1.22-1.37 (m, 1H), 1.52 (d, J = 12.0 Hz, 1H), 1.68 -1.80 (m, 2H), 1.98 (dt, J = 5.2, 13.2 Hz, 1H), 2.02-2.37 (m, 2H), 2.57-2.76 ( m, 2H), 2.91-3.17 (m, 2H), 3.62-3.78 (m, 2H), 3.89 (dd, J = 4.0, 8.0 Hz, 1H), 4.06 (d, J = 15.2 Hz, 1H), 4.68 (d, J = 6.0 Hz, 1H), 4.82 (d, J = 14.8 Hz, 1H), 6.89 (d , J = 8 4Hz, 1H), 6.97 (d, J = 8.4Hz, 1H), 7.20-7.37 (m, 5H)

(1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -1,3,3a, 4,5,6,7,11c-octahydro-2H-6 11b- (Iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (13)

(1) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -2-oxo-1,3,3a, 4,5,6,7,11c Synthesis of Octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-10-yl trifluoromethanesulfonate (12)

Under an argon atmosphere, compound 9 (77.3 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (DMF) (2 mL), and N-phenylbis (trifluoromethanesulfonimide) (71.5 mg, 0.20 mmol). ), Potassium carbonate (41.5 mg, 0.30 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC to give the title compound 16 (58.4 mg, 59%) as a white amorphous.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.05-0.18 (m, 2H), 0.44-0.62 (m, 3H), 0.84-1.03 (m, 1H), 1.17-1.35 (m, 2H), 1.67 (dd, J = 7.6, 16.0 Hz, 1H), 1.82 (ddd, J = 7.2, 12.8, 16. 0 Hz, 1H), 1.99-2.17 (m, 2H), 2.30 (dd, J = 7.6, 12.4 Hz, 1H), 2.64 (dd, J = 4.8, 12 .0Hz, 1H), 2.72 (d, J = 8.0Hz, 1H), 2.97 (dd, J = 6.4, 14.8Hz, 1H), 3.11 (dd, J = 6. 0, 7.6 Hz, 1 H), 3.21 (d, J = 18.4 Hz, 1 H), 3.70-3.81 (m, 2 H), 4.00 (d, J = 14.8 Hz, 1 H) ), 4 .73 (d, J = 5.6 Hz, 1H), 4.89 (d, J = 15.2 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 2.8, 8.4 Hz, 1H), 7.21-7.38 (m, 6H).

(2) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-benzyl-14- (cyclopropylmethyl) -1,3,3a, 4,5,6,7,11c-octahydro-2H Synthesis of -6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (13)

Under an argon atmosphere, 12 (29.4 mg, 0.05 mmol) was dissolved in DMF (1 mL), and palladium (II) acetate (2.3 mg, 0.01 mmol), 1,3-bis (diphenylphosphino) propane ( 4.1 mg, 0.01 mmol) and triethylsilane (24.0 μL, 0.15 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC to give the title compound 13 (15.0 mg, 68%) and its hydrochloride salt as a colorless oil.

Compound 13 (free base) ¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.19 (m, 2H), 0.43-0.69 (m, 3H), 0.89-1.05 (M, 1H), 1.17-1.35 (m, 2H), 1.63-1.85 (m, 2H), 2.02 (dt, J = 5.2, 12.8 Hz, 1H) , 2.06-2.39 (m, 2H), 2.57-2.76 (m, 2H), 2.89-3.02 (m, 1H), 3.10-3.27 (m, 1H), 3.11 (dd, J = 6.0, 7.6 Hz, 1H), 3.70-3.83 (m, 2H), 3.93 (d, J = 15.2 Hz, 1H), 4.73 (d, J = 5.6 Hz, 1H), 4.94 (d, J = 15.2 Hz, 1H), 6.99-7.07 (m, 1H), 7.08-7.19 (M, 3H , 7.20-7.36 (m, 5H).

(Reference Example 5)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H- Synthesis of 6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indol-11-ol (15)

According to the method described in Reference Example 1, (1S, 3aS, 5aS, 6R, 11bS, 11cS) -3-benzyl-14- (cyclopropylmethyl) -3a, 11-dihydroxy-10-methoxy-1,3,3a 4,5,6,7,11c-octahydro-2H-6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indol-2-one [Compound 14: Tetrahedron, 2011, 67, The compound described in 6682] was used to obtain the title compound 15.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.14 (m, 2H), 0.40-0.50 (m, 2H), 0.66-0.86 (m, 2H), 1.08-1.15 (m, 1H), 1.20-1.35 (m, 2H), 1.49-1.75 (m, 3H), 1.84-2.05 (m, 2H) ), 2.30 (d, J = 5.9 Hz, 2H), 2.49-2.59 (m, 1H), 2.60-2.70 (m, 1H), 2.87-3.00 (M, 3H), 3.01-3.15 (m, 2H), 3.20-3.31 (m, 1H), 3.32-3.45 (m, 1H), 3.60-3 .80 (m, 2H), 3.84 (s, 3H), 5.63 (br s, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 8.3Hz, 1H), 7.16- .40 (m, 5H).

(Reference Example 6)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-11-phenoxy-2,3,3a, 4,5,6,7,11c- Synthesis of octahydro-1H-6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indole (16)

The title compound 16 was obtained from the compound 15 according to the method described in Reference Example 2.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.15 (m, 2H), 0.40-0.51 (m, 2H), 0.70-0.85 (m, 2H), 0.96-1.11 (m, 2H), 1.12-1.25 (m, 1H), 1.55-1.78 (m, 3H), 1.99 (dt, J = 3.4) , 12.2 Hz, 1H), 2.29 (d, J = 5.9 Hz, 2H), 2.46 (dd, J = 3.9, 11.2 Hz, 1H), 2.58-2.80 ( m, 3H), 2.90-3.24 (m, 6H), 3.55-3.75 (m, 2H), 3.67 (s, 3H), 6.73-6.85 (m, 3H), 6.95 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 7.15-7.34 (m, 7H).

(Reference Example 7)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H- Synthesis of 6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indole (17)

The title compound 17 was obtained from the compound 16 according to the method described in Reference Example 3.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.04-0.15 (m, 2H), 0.40-0.52 (m, 2H), 0.57-0.70 (m, 1H), 0.75-0.85 (m, 1H), 1.05-1.19 (m, 2H), 1.23-1.33 (m, 1H), 1.46-1.71 (m, 3H) ), 1.92-2.04 (m, 2H), 2.25-2.40 (m, 2H), 2.50-2.65 (m, 2H), 2.81-3.05 (m) , 4H), 3.06-3.18 (m, 2H), 3.22-3.30 (m, 1H), 3.66 (d, J = 13.7 Hz, 1H), 3.73 (d , J = 13.7 Hz, 1H), 3.75 (s, 3H), 6.65 (dd, J = 2.9, 8.3 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 7.01 (d, J = .3Hz, 1H), 7.18-7.34 (m, 5H).

(Reference Example 8)
(1S, 3aR, 5aS, 6R, 11bR, 11cS) -14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H-6,11b- Synthesis of (Iminoethano) -1,5a-methanonaphtho [1,2-e] indole (18)

The title compound 18 was obtained from the compound 17 according to the method described in Reference Example 4.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.06-0.14 (m, 2H), 0.44-0.52 (m, 2H), 0.75-0.86 (m, 1H), 0.98-1.10 (m, 3H), 1.15 (d, J = 8.8 Hz, 1H), 1.34-1.45 (m, 1H), 1.60-1.72 (m , 1H), 1.86-2.06 (m, 3H), 2.26-2.36 (m, 2H), 2.52-2.60 (m, 1H), 2.70-2.76. (M, 1H), 2.78-3.00 (m, 4H), 3.08 (d, J = 5.9 Hz, 1H), 3.10-3.25 (m, 1H), 3.30 (Dd, J = 7.8, 11.2 Hz, 1H), 3.50-3.58 (m, 1H), 3.77 (s, 3H), 6.66 (dd, J = 2.4) 8.3 Hz, 1 H), 6.73 (d J = 2.4Hz, 1H), 7.02 (d, J = 8.3Hz, 1H).

(1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c-octahydro- 2H-6,11b- (Iminoethano) -1,5a-methanonaphtho [1,2-e] indol-2-one (21)

(1) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -14- (cyclopropylmethyl) -10-methoxy-1,3,3a, 4,5,6,7,11c-octahydro-2H Synthesis of -6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indol-2-one (19)

According to the method described in Example 1 (1), Compound 18 (36.4 mg, 0.10 mmol) was used to give the title compound 19 (10.4 mg, 27%) as a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.17 (m, 2H), 0.41-0.57 (m, 2H), 0.77-0.92 (m, 2H), 0.99 (dd, J = 7.2, 14.8 Hz, 1H), 1.11-1.21 (m, 1H), 1.46-1.60 (m, 2H), 1.71 (dd , J = 8.4, 15.2 Hz, 1H), 1.80 (dt, J = 5.2, 12.8 Hz, 1H), 1.96-2.07 (m, 1H), 2.22- 2.41 (m, 2H), 2.53-2.66 (m, 1H), 2.85-3.02 (m, 3H), 3.12-3.25 (m, 2H), 3. 38 (t, J = 12.4 Hz, 1H), 3.78 (s, 3H), 3.91 (dd, J = 4.8, 8.0 Hz, 1H), 5.99 (m, 1H), 6.61 (d, J = 2 .4 Hz, 1H), 6.70 (dd, J = 2.8, 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H).

(2) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -10-methoxy-1,3,3a, 4,5,6,7,11c Synthesis of octahydro-2H-6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indol-2-one (20)

According to the method described in Example 2 (1), Compound 19 (31.0 mg, 0.082 mmol) was used to give the title compound 20 (21.2 mg, 55%) as a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.03-0.18 (m, 2H), 0.42-0.54 (m, 2H), 0.57-0.71 (m, 1H), 0.76-0.92 (m, 1H), 1.07-1.28 (m, 2H), 1.32-1.47 (m, 1H), 1.53-1.72 (m, 2H) ), 1.76-1.91 (m, 1H), 1.94-2.08 (m, 1H), 2.18-2.43 (m, 2H), 2.53-2.68 (m) , 1H), 2.93 (br s, 2H), 3.01 (t, J = 8.0 Hz, 1H), 3.12-3.27 (m, 1H), 3.13 (t, J = 9.6 Hz, 1H), 3.36-3.51 (m, 1H), 3.63-3.77 (m, 1H), 3.72 (s, 3H), 3.88 (d, J = 15.2 Hz, 1 H), 4.93 d, J = 15.2 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 2.4, 8.4 Hz, 1H), 7.04 (d , J = 8.4 Hz, 1H), 7.17-7.38 (m, 5H).

(3) (1S, 3aR, 5aS, 6R, 11bR, 11cS, 12S) -3-Benzyl-14- (cyclopropylmethyl) -10-hydroxy-1,3,3a, 4,5,6,7,11c -Synthesis of octahydro-2H-6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indol-2-one (21)

According to the method described in Example 1 (2), using 20 (21.2 mg, 0.045 mmol) obtained in (1) above, the title compound 21 (16.3 mg, 79%) and its hydrochloric acid as colorless oil were obtained. Salt was obtained.
Compound 21 (free base) ¹ H NMR (CDCl ₃ , 400 MHz): δ 0.04-0.18 (m, 2H), 0.41-0.54 (m, 2H), 0.63-0.92 (M, 2H), 1.06-1.42 (m, 4H), 1.57 (d, J = 13.2 Hz, 1H), 1.65 (dd, J = 8.0, 14.8 Hz, 1H), 1.66-1.84 (m, 1H), 1.93-2.07 (m, 1H), 2.17-2.42 (m, 2H), 2.52-2.64 ( m, 1H), 2.83-2.96 (m, 2H), 3.05-3.23 (m, 1H), 3.10 (dt, J = 2.0, 5.6 Hz, 1H), 3.41 (t, J = 12.0 Hz, 1H), 3.72 (dd, J = 5.2, 8.4 Hz, 1H), 3.85 (d, J = 15.2 Hz, 1H), 4 .88 ( , J = 15.2 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 2.4, 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.16-7.34 (m, 5H).

Opioid Receptor Function Test The functional activity of the compounds of the present invention against μ, δ and κ opioid receptors was examined.
Method: Lance Ultra cAMP kit (Perkin Elmer) was used and carried out according to a predetermined method. In the evaluation of agonist activity, each opioid receptor (δ, μ and κ) -expressing CHO cell and test compound were each assay buffer (1 × HBSS, 1M HEPES, pH 7.4, 250 mM IBMX (in the presence of 10 μM forskolin). The reaction was allowed to proceed in Isobutylmethylxanthine), 7.5% BSA) for 30 minutes. Subsequently, the cAMP detection reagent in the kit was added, and after 1 hour, time-resolved fluorescence measurement was performed using an EnVision plate reader (Perkin Elmer). A dose response curve of the test compound was obtained from the fluorescence value at 665 nm, and EC ₅₀ value and E _max value were calculated. The E _max value was determined by the ratio of the maximum response of the test compound when the maximum response of each control drug (δ: SNC80, μ: DAMGO, κ: U-69593) was 100%.
(2) Results Table 1 shows the results.

SNC80:
(+)-4-[(αR) -α-((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzyl] -N, N-diethylbenzamide

DAMGO:
^{[D-Ala 2, N-} MePhe 4, Gly-ol] enkephalin

U-69593:
(+)-(5α, 7α, 8β) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzeneacetamide

N. C. : EC ₅₀ value was not calculated because the maximum response was not reached at the highest concentration (10 μM).
^a : Since the maximum reaction was not reached at the maximum concentration, the reaction rate at the maximum concentration was shown as a reference value.

1) Hydrochloride was used.

As shown in Table 1, it was confirmed that the compound of the present invention has a strong agonist activity for the opioid δ receptor.

Claims (16)

The following general formula (I),

(Wherein R ¹ is hydrogen, C _1-6 alkyl, C _6-10 aryl, C _2-6 alkenyl, cycloalkylalkyl (the number of carbon atoms in the cycloalkyl moiety is 3-6, the number of carbon atoms in the alkylene moiety) 1-5.), Aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), C _3-6 cycloalkyl or heteroarylalkyl (heteroaryl is N, 1 to 4 heteroatoms selected from O and S are included as ring constituent atoms, and the alkylene moiety has 1 to 5 carbon atoms.)
R ² contains hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, heteroaryl (1-4 heteroatoms selected from N, O and S as ring members. ), Aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), heteroarylalkyl (heteroaryl is selected from 1 to 4 selected from N, O and S) A hetero atom is included as a ring-constituting atom, and the alkylene moiety has 1 to 5 carbon atoms.), Cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms. _{), C 2-6} alkenyl, the number of carbon atoms is 6-10 arylalkenyl (the aryl moiety, 2-6 carbon atoms alkenyl moiety.), heteroarylalkenyl (heteroar- Includes 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkenyl moiety has 2 to 6 carbon atoms), cycloalkylalkenyl (the number of carbon atoms in the cycloalkyl moiety) Is 3-6, the number of carbon atoms in the alkenyl moiety is 2-6.), C _4-6 cycloalkenyl, cycloalkenylalkyl (the number of carbon atoms in the cycloalkenyl moiety is 4-6, the number of carbon atoms in the alkylene moiety is 1-5.), Or cycloalkenylalkenyl (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms),
R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen, hydroxy, halogen, cyano, carbamoyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyloxy, nitro, amino, C _{1 -8 represents} alkylamino, aralkylamino (aryl moiety has 6 to 10 carbon atoms, alkylene moiety has 1 to 5 carbon atoms) or acylamino (acyl moiety has 2 to 6 carbon atoms);
R ⁶ and R ⁷ are the same or different and each represents hydrogen, fluorine or hydroxy,
R ⁸ and R ⁹ are the same or different and represent hydrogen, fluorine or hydroxy, or R ⁸ and R ⁹ together represent ═O,
X represents O or CH _2,
Y represents C═O, C═S, SO ₂ , C (═O) O, C (═O) NR ¹⁰ , C (═S) NR ¹⁰ or a bond, where R ¹⁰ is hydrogen, C _1-6 alkyl, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), heteroarylalkyl (heteroaryl is selected from N, O and S 1 Containing 4 heteroatoms as ring-constituting atoms, 1 to 5 carbon atoms in the alkylene moiety, cycloalkylalkyl (3 to 6 carbon atoms in the cycloalkyl moiety, and carbon atoms in the alkylene moiety being 1-5.).
However, the alkylene part and cycloalkyl part of C1-6 alkyl of R < ¹ _> and R < ² _> , cycloalkyl alkyl (the carbon number of the cycloalkyl part is 3-6, and the carbon number of the alkylene part is 1-5). , As well as aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) has 1 to 6 halogen atoms, hydroxy, C _1-6 alkoxy, C _{6 And} substituted with at least one substituent selected from _-10 aryloxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, carboxyl and alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1-6). Well,
The aryl and aralkyl ^{R 1} (carbon atoms of the aryl moiety is 6 to 10, carbon atoms is 1 to 5. The alkylene portion) aryl moiety of the ^{R 2} aryl, heteroaryl (N, O and S 1 to 4 heteroatoms selected from as a ring-constituting atom), an aryl moiety of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), Heteroaryl alkyl (wherein heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkylene moiety has 1 to 5 carbon atoms), The aryl moiety has 6 to 10 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms.) The aryl moiety and heteroarylalkenyl (heteroaryl N, containing from 1 to 4 heteroatom selected from O and S as a ring-constituting atom, the heteroaryl portion of the carbon atoms 2-6.) Alkenyl ^moiety, R 3, ^{R 4} and ^{R 5} C The aryl moiety of _6-10 aryloxy and the aryl moiety of aralkylamino are C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1-6. ), Carbamoyl, alkylcarbamoyl (the alkyl part has 1 to 6 carbon atoms), dialkylcarbamoyl (the alkyl part has 1 to 6 carbon atoms), halogen, nitro, cyano, 1 to 3 halogens substituted _{C 1-6} alkyl, 1-3 halogen substituted _{C 1-6} alkoxy, phenyl, heteroaryl (N, O Containing from 1 to 4 heteroatoms selected from finely S as a ring-constituting atom.), Phenoxy, phenylalkyl (number of carbon atoms of alkyl is 1 to 3.), It is selected from methylenedioxy and ^NR 11 ^{R 12} Wherein R ¹¹ and R ¹² are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, or alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1-6), or R ¹¹ and R ¹² together with the N atom to which they are attached, further N, O, A 4- to 7-membered ring which may contain a heteroatom selected from S may be formed;
Furthermore, the alkylene part of R ¹ and R ² aralkyl (the aryl part has 6 to 10 carbon atoms and the alkylene part has 1 to 5 carbon atoms) was substituted with phenyl or 1 to 3 halogens. It may be substituted with at least one substituent selected from C _1-6 alkyl. )
Or a pharmacologically acceptable acid addition salt thereof. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10. The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, wherein the alkylene moiety has 1 to 5 carbon atoms in the alkylene moiety. 2. R ¹ is C _2-6 alkyl substituted with hydroxy, C _1-6 alkyl substituted with _1-6 halogens or C _2-6 alkyl substituted with C _1-6 alkoxy. Or a pharmacologically acceptable acid addition salt thereof. The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, wherein Y is C═O, C (═O) O, C (═O) NR ¹⁰ or a bond. Y is a bond, R ² is C _1-6 alkyl, C _6-10 aryl, heteroaryl (including 1 to 4 heteroatoms selected from N, O and S as ring members), aralkyl (The aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms.) Or heteroarylalkyl (heteroaryl represents 1 to 4 heteroatoms selected from N, O and S). The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, wherein the morphinan derivative is contained as a ring-constituting atom, and the alkylene moiety has 1 to 5 carbon atoms. Y is a bond, R ² is C _1-6 alkyl, aralkyl (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms) or heteroarylalkyl (heteroaryl is N The morphinan derivative or a pharmacological thereof according to claim 1, wherein 1 to 4 heteroatoms selected from, O and S are included as ring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atoms. Acceptable acid addition salts. X is a morphinan derivative or a pharmacologically acceptable acid addition salts of the claims 1-6, wherein is CH _2. The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, wherein one of R ³ and R ⁴ is hydroxy and the other is hydrogen. R ³ is halogen, cyano, carbamoyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, amino or acylamino (acyl moiety has 2 to 6 carbon atoms), R ⁴ is hydrogen or hydroxy, and R ⁵ is The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, which is hydrogen. The morphinan derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein R ³ is hydroxy or carbamoyl, and R ⁴ and R ⁵ are hydrogen. R ³ , R ⁴ and R ⁵ are all hydrogen, The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1. R ⁶ , R ⁷ , R ⁸ and R ⁹ are all hydrogen, The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1.   A medicament comprising the morphinan derivative according to any one of claims 1 to 12 or a pharmacologically acceptable acid addition salt thereof.   A pharmaceutical composition comprising the morphinan derivative according to any one of claims 1 to 12 or a pharmacologically acceptable acid addition salt thereof as an active ingredient.   An analgesic comprising the morphinan derivative according to any one of claims 1 to 12 or a pharmacologically acceptable acid addition salt thereof as an active ingredient.   A method for treating pain, comprising administering an effective amount of the morphinan derivative according to any one of claims 1 to 12 or a pharmacologically acceptable acid addition salt thereof.