JP2014073964A - Morphinan derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide morphinan derivatives having opioid δ receptor agonist action.SOLUTION: Provided are morphinan derivatives represented by the specified general formula (I) or pharmacologically acceptable acid addition salts thereof. The morphinan derivatives are used as analgesics. (In the formula, R, Rand Rrepresent hydrogen or the like; Rand Rtogether form an oxygen-containing ring or the like; X represents oxygen or the like; and A and B represent C=O or the like.)

Description

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

Three subtypes of μ, δ, and κ are known for opioid receptors, 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.
Non-Patent Document 1 includes the following formula (B) by the present inventors:

However, when the present inventors investigated the affinity of each compound for each opioid receptor, the affinity for the μ receptor was higher than that for the δ receptor. It was confirmed.
As a compound similar in structure to the morphinan derivative represented by the following general formula (I), the following general formula (C),

The compound represented by this is described in Patent Document 2.
However, the compound of the general formula (C) is crosslinked between the 14-position and the 6-position, whereas the morphinan derivative represented by the general formula (I) described later is crosslinked between the 14-position and the 5-position. In the compound of formula (C), the N atom of the side chain amide group does not form a ring. Furthermore, the compound of formula (C) is a kappa receptor agonist.

WO 2008/001859 JP 2009-196933 A

Proceedings of the 28th Medicinal Chemistry Symposium 1P-73, p212, 2009

  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 relates to a morphinan derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof.

(In the formula, ^{R 1} is _{hydrogen, C 1-6} alkyl, 1-3 _{C 1-6} alkyl substituted with _{halogen, C 2-6} alkenyl, the number of carbon atoms of the cycloalkyl alkyl (cycloalkyl moiety is 3 -6, the alkylene moiety has 1 to 3 carbon atoms), or aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 3 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 3 carbon atoms), heteroarylalkyl (heteroaryl is selected from 1 to 4 carbon atoms selected from N, O and S) A hetero atom is included as a ring-constituting atom, the alkylene moiety has 1 to 3 carbon atoms, and a cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 3 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 1-3), or cycloalkenylalkenyl (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms),
R ³ and R ⁴ together form —O— (CHR ⁶ ) _m —O— or —O— (CHR ⁶ ) _m —NR ⁷ —.
Here, R ⁶ represents hydrogen or C _1-3 alkyl, R ⁷ represents hydrogen, C _1-6 alkyl, or C _1-6 alkanoyl, and m represents 1, 2 or 3.
R ⁵ represents hydrogen, hydroxy, C _1-6 alkoxy or C _1-6 alkanoyloxy,
X represents O or CH _2,
A represents CH ₂ or C═O,
B represents C = O or a bond.
However, when A is C = O, B is a bond.
Also, the aryl part of R ¹ aralkyl, the aryl part of R ² , heteroaryl, the aryl part of aralkyl, the heteroaryl part of heteroarylalkyl, the aryl part of arylalkenyl and the heteroaryl part of heteroarylalkenyl are C _1-6. Alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the alkoxy moiety has 1 to 6 carbon atoms), halogen, nitro, cyano, C substituted with 1 to 3 halogens _1-6 alkyl, 1-3 halogen substituted _{C 1-6} alkoxy, phenyl, phenoxy, phenylalkyl (number of carbon atoms in the alkyl is 1 to 3.), selected from methylenedioxy and ^NR 8 ^{R 9} Optionally substituted with at least one substituent, wherein R ⁸ and R ⁹ 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 in the alkoxy moiety is 1-6) Or a R ⁴ and R ⁹ together with the N atom to which they are attached may further contain a heteroatom selected from N, O, S May form,
C _1-6 alkyl of R ² is C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1). To 6)) and may be substituted with at least one substituent selected from halogen. )

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)
A morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, wherein A is C = O and B is a bond.
(2)
The morphinan derivative represented by the above general formula (I), wherein X is O, the morphinan derivative described in the above (1), or a pharmaceutically acceptable acid addition salt thereof.
(3)
The morphinan derivative represented by the above general formula (I) or the morphinan derivative described in the above (1) or (2), wherein R ³ and R ⁴ are combined to form —O— (CHR ⁶ ) _m —O—. Or a pharmacologically acceptable acid addition salt thereof.
(4)
The morphinan derivative according to the above (3), wherein R ⁶ is hydrogen, or a pharmacologically acceptable acid addition salt thereof.
(5)
The morphinan derivative represented by the above general formula (I), wherein R ⁵ is hydrogen or hydroxy, the morphinan derivative described in the above (1) to (4), or a pharmaceutically acceptable acid addition salt thereof.

In the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof,
C _1-6 alkyl includes methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, neopentyl, hexyl and the like.
Examples of C _1-6 alkyl substituted with 1 to 3 halogens include chloromethyl, fluoromethyl, 2-fluoroethyl, and trifluoromethyl.
Examples of C _2-6 alkenyl include 2-propenyl and 3-methyl-2-butenyl.
Cycloalkylalkyl (wherein the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 3 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 3 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 and thiazolyl.
Heteroarylalkyl (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring atoms, and the alkylene moiety has 1 to 3 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 3 carbon atoms) include methyl and ethyl substituted with cyclobutenyl, cyclopentenyl and the like.
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 _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 alkyl has 1 to 3 carbon atoms) include benzyl and the like.
_{Examples of} C _6-10 aryloxy include phenoxy.
In addition, R ⁸ , R ⁹ and N atom may be 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. Is 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) In the morphinan derivative represented by the above general formula (I), R ¹ = cyclopropylmethyl, X═O, A═CO, B = bond, R ³ and R ⁴ together form —O When — (CHR ⁶ ) m—O—, R ⁵ = hydrogen or C _1-6 alkoxy:

(In the formula, Hal represents halogen, R ⁵⁰ represents hydrogen or C _1-6 alkoxy, and R ² , R ⁶ and m are the same as above.)

(1) Synthesis of Compound (c) Compound (a) in a solvent such as tetrahydrofuran (THF) or N, N-dimethylformamide (DMF) in the presence or absence of a base such as n-butyllithium or sodium hydride ) Is reacted with an amine represented by compound (b) to obtain compound (c). Amine (b) can also be used as a reagent and solvent. Compound (a) can be synthesized by a known method (Bioorg. Med. Chem. Lett., 2010, 20, 121, etc.) and a method analogous thereto.

(2) Synthesis of Compound (e) Compound (e) can be synthesized by one of the following two methods.

Method A:
Compound (e) can be obtained by reacting compound (c) with a base such as potassium t-butoxide or sodium hydride in a solvent such as t-butanol, cyclopentyl methyl ether, DMF, or dimethyl sulfoxide. The reaction is carried out at room temperature to the reflux temperature of the solvent used, and a temperature of 80 ° C. or higher is preferred. Moreover, as a solvent, cyclopentyl methyl ether and t-butanol are preferable.

Method B:
A compound such as sodium hydride is allowed to act on compound (c) at the reflux temperature in THF to induce compound (d), and then this compound is dissolved in a solvent such as t-butanol or cyclopentyl methyl ether at 80 ° C. or higher. The compound (e) can be obtained by allowing a base such as potassium t-butoxide or sodium hydride to act at a temperature of

(3) Synthesis of Compound (g) of the Present Invention In a solvent such as THF or DMF, the compound (e) is reacted with a halide represented by the compound (f) in the presence of a base such as sodium hydride or potassium carbonate. The compound (g) of the present invention can be obtained. The reaction is preferably carried out under high dilution conditions.

(II) In the morphinan derivative represented by the above general formula (I), R ¹ = cyclopropylmethyl, X═O, A═CO, B = bond, R ³ and R ⁴ together form —O When-(CHR ⁶ ) mO—, R ⁵ = hydroxy or C _1-6 alkanooxy:

(In the formula, R ⁵¹ represents C _1-6 alkanooxy, and R ² , R ⁶ and m are the same as above.)

The compound (h) of the present invention in which R ⁵ is a hydroxyl group in the morphinan derivative represented by the general formula (I) is compounded with the compound (g) of the present invention in which R ⁵⁰ is C _1-6 alkoxy in a solvent such as dichloromethane. It can be synthesized by reacting boron tribromide or the like. In general formula (I) compound of the present invention R ⁵ is a C _1-6 Arukanookishi in (i) can be synthesized by reacting an acylating agent of the present invention the compound (h).

In morphinan derivative represented by formula (III) above general formula (I), ^R 1 other than ^{R 1} = cyclopropylmethyl, X = O, A = CO , B = bond, ^{R 3} and ^{R 4} together turned by ^{-O- (CHR 6) m-O-} , when the ^{R 5} = hydrogen or _{C 1-6} alkoxy:

The above compounds can be synthesized by any one of methods C to E.

(Method C)

(In the formula, R ⁵⁰ represents hydrogen or C _1-6 alkoxy, and R ² , R ⁶ and m are the same as above.)

(1) First Step Conversion from compound (e) to compound (j) is carried out using a known de-N-alkylation method (Bioorg. Med. Chem. Lett., 2010, 20, 6302, etc.). Can do.

(2) Second Step Conversion from compound (j) to compound (k) can be carried out by a normal N-alkylation reaction or reductive amination reaction.

(3) Third Step and Fourth Step The compound (m) of the present invention can be synthesized by the method shown in the synthesis step of the compound (g) of the present invention in the above production method (I). Moreover, this invention compound (n) is compoundable by the method shown by the synthetic | combination process of this invention compound (h) in the said manufacturing method (II).

(Method D)

(In the formula, R ⁵⁰ represents hydrogen or C _1-6 alkoxy, and R ² , R ⁶ and m are the same as above.)

(1) First Step The compound (o) of the present invention is produced by the method (reaction with chloroformate, followed by decarbamate) shown in the synthesis step of compound (j) in the above production method (Method C of III). Can be synthesized from the compound (g) of the present invention.
(2) Second Step Conversion from the compound (o) of the present invention to the compound (m) of the present invention can be carried out by a normal N-alkylation reaction or reductive amination reaction.

(E method)

(Wherein R ⁵⁰ represents hydrogen or C _1-6 alkoxy, and R ² is the same as above.)

(1) First Step Compound (p) can be synthesized by the method shown in the synthesis step of compounds (j) and (k) in the above production method (Method C of III).
(2) Second Step Compound (k) can be synthesized by the method shown in the synthesis step from compound (d) to compound (e) in the above production method (I). The third step is as already described.

(IV) In the morphinan derivative represented by the above general formula (I), X═O, A═CO, B = bond, R ⁵ ═OH, R ³ and R ⁴ together form —O— ( _{^{CHR 6) m -N (R 7}} ) - for:

(Wherein R ⁵² represents C _1-6 alkoxy, and R ¹ , R ² , R ⁶ , R ⁷ and m are the same as above)

The compound (r) of the present invention can be synthesized by reacting the compound (q) of the present invention with boron tribromide and then treating the resulting product with an amine represented by R ⁷ NH ₂ .

(V) A morphinan derivative represented by the above general formula (I), wherein X = O, A = CH ₂ , and B = a bond

(Wherein R ¹ , R ² , R ⁵ , R ⁶ and m are the same as above)

Inventive compound (t) can be synthesized by reducing inventive compound (s) with diborane or the like.

(VI) In the case where X = O, A = CH ₂ and B = CO in the morphinan derivative represented by the above general formula (I)

(Wherein R ¹ , R ² , R ⁵ , R ⁶ and m are the same as above)

The compound (v) of the present invention can be synthesized by debenzylation reaction of the compound (u) of the present invention. The compound (w) of the present invention can be synthesized by a usual acylation reaction for the compound (v) of the present invention.

Other morphinan derivatives represented by the above general formula (I) can also be synthesized using the synthesis methods described above, the methods described in the examples below, and other known methods.

Next, pharmacological experiment results will be described.
As described in Example 44 below, the morphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has high affinity for the opioid δ receptor and is excellent. It became clear to have a δ receptor 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, and hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of 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)
(5R, 6S, 6′R, 9R, 13S, 14S) -N-benzyl-17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-3-methoxy-6 -Synthesis of methylmorphinan-6'-carboxamide (2a)

Under an argon atmosphere, benzylamine (4.4 mL, 40 mmol) is dissolved in THF (100 mL), and after cooling to −78 ° C., an n-butyllithium / hexane solution (1.65 mol / L, 24.2 mL, 40 mmol) is slowly added. And stirred for 15 minutes. Then (5R, 6S, 6′R, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-3-methoxy-6-methylmorphinan -6'-ethyl carboxylate [1a: Bioorg. Med. Chem. Lett. A compound described in 2010, 20, 121] (4.42 g, 10 mmol) in THF (50 mL) was added dropwise over 15 minutes, and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution 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 obtained crude product was purified by silica gel column chromatography to obtain the title compound 2a (4.97 g, 99%) as a white amorphous.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.05-0.22 (m, 2H), 0.43-0.62 (m, 2H), 0.83-0.95 (m, 1H), 1.2-1.36 (m, 1H), 1.41-1.66 (m, 3H), 2.12 (dt, J = 3.6, 12.0 Hz, 1H), 2.20-2 .43 (m, 4H), 2.53-2.71 (m, 2H), 3.04 (d, J = 18.6 Hz, 1H), 3.10 (d, J = 5.4 Hz, 1H) 3.68 (s, 1H), 3.85 (s, 3H), 4.31-4.46 (m, 2H), 4.75 (s, 1H), 5.15 (brs, 1H) 6.37-6.53 (m, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 7.12-7. 34 (m, 5H).

(Reference Example 2)
(5R, 6S, 6'S, 9R, 13S, 14S) -N-benzyl-17- (cyclopropylmethyl) -4,5-epoxy-6,6'-epoxy-14-hydroxy-3-methoxy-6 -Synthesis of methylmorphinan-6'-carboxamide (2b)

Under an argon atmosphere, benzylamine (4.4 mL, 40 mmol) is dissolved in THF (100 mL), and after cooling to −78 ° C., an n-butyllithium / hexane solution (1.65 mol / L, 24.2 mL, 40 mmol) is slowly added. And stirred for 15 minutes. 5R, 6S, 6 ′S, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-3-methoxy-6-methylmorphinan 6'-ethyl carboxylate [Compound 1b: Bioorg. Med. Chem. Lett. A compound described in 2010, 20, 121] (4.42 g, 10 mmol) in THF (50 mL) was added dropwise over 15 minutes, and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution 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 obtained crude product was purified by silica gel column chromatography and recrystallized from ethyl acetate to obtain the title compound 2b (4.01 g, 80%) as white crystals.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06-0.22 (m, 2H), 0.44-0.60 (m, 2H), 0.74-0.94 (m, 1H), 1.14 (dt, J = 3.6, 14.4 Hz, 1H), 1.44-1.62 (m, 3H), 2.08-2.30 (m, 2H), 2.30-2 .42 (m, 2H), 2.44-2.70 (m, 3H), 3.04 (d, J = 18.6 Hz, 1H), 3.09 (d, J = 6.0 Hz, 1H) 3.28 (s, 1H), 3.49 (s, 3H), 4.24 (dd, J = 4.2, 15.0 Hz, 1H), 4.75 (s, 1H), 4.87. (Dd, J = 5.1, 15.0 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 7.17 ( s, 1H), 7. 2-7.41 (m, 5H).

(Reference Example 3)
(5R, 6S, 7S, 9R, 13S, 14S) -N-benzyl-17- (cyclopropylmethyl) -4,5-epoxy-6-hydroxy-3-methoxy-8-oxa-6,14-ethanomorphinan- Synthesis of 7-carboxamide (3)

Under an argon atmosphere, 60% sodium hydride (2.54 g, 64 mmol) was washed with anhydrous hexane, suspended in THF (50 mL), and the compound 2a (2.54 g, 5.1 mmol) obtained in Reference Example 1 was suspended. A THF (50 mL) solution was added and stirred for 30 minutes under reflux. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution 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 3 (2.11 g, 83%) as a white amorphous.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.05-0.18 (m, 2H), 0.42-0.64 (m, 2H), 0.79-1.06 (m, 2H), 1.31-1.53 (m, 2H), 1.66-1.91 (m, 2H), 2.12 (dd, J = 8.1, 12.6 Hz, 1H), 2.18- 2.35 (m, 2H), 2.41 (dt, J = 3.6, 12.6 Hz, 1H), 2.66-2.82 (m, 2H), 3.20 (d, J = 18) .3 Hz, 1 H), 3.54 (d, J = 6.6 Hz, 1 H), 3.89 (s, 3 H), 4.28 (d, J = 2.4 Hz, 1 H), 4.46 (dd , J = 5.7, 14.7 Hz, 1H), 4.54 (d, J = 1.5 Hz, 1H), 4.59 (dd, J = 6.6, 14.7 Hz, 1H), 5 .49 (br s, 1 ), 6.53 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 7.23-7.38 (m, 5H), 7.51-7 .73 (m, 1H).

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

Under an argon atmosphere, 60% sodium hydride (4.31 g, 110 mmol) was washed with anhydrous hexane, suspended in cyclopentyl methyl ether (30 mL), and compound 2a (4.32 g, 8.6 mmol) obtained in Reference Example 1 was obtained. ) In cyclopentyl methyl ether (20 mL) was added and stirred under reflux for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution 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 obtained crude product was recrystallized from methanol to give the title compound 4 (3.51 g, 81%) as white crystals.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.02-0.14 (m, 2H), 0.40-0.58 (m, 2H), 0.87-1.00 (m, 2H), 1.32-1.42 (m, 3H), 1.63 (dd, J = 7.8, 4.4 Hz, 1H), 1.91 (dt, J = 4.8, 12.6 Hz, 1H) 2.10 (dt, J = 3.0, 12.3 Hz, 1H), 2.25 (dd, J = 7.5, 2.6 Hz, 1H), 2.63 (dt, J = 3.6) , 11.4 Hz, 2H), 2.86 (dd, J = 6.3, 18.6 Hz, 1H), 3.09 (d, J = 18.6 Hz, 1H), 3.30 (d, J = 5.7 Hz, 1H), 3.68 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 4.40 (d, J = 14.7 Hz, 1H), 4.51 (D, J = 1 4.7 Hz, 1H), 4.72 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H) ), 7.13-7.30 (m, 3H), 7.41 (d, J = 6.9 Hz, 2H).

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

Under an argon atmosphere, Compound 2b (101 mg, 0.20 mmol) obtained in Reference Example 2 was dissolved in t-butyl alcohol (2 mL), potassium t-butoxide (224 mg, 2.0 mmol) was added, and the mixture was refluxed for 1 hour. . Under ice-cooling, the reaction mixture was acidified with 2M aqueous hydrochloric acid, and chloroform and potassium carbonate were added to adjust the aqueous layer to pH = 11. Distilled water was added 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 4 (89.4 mg, 89%) as a colorless oil.

Example 1
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7- (cyclopropylmethyl) -1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano- Of 4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (5) Composition

Under an argon atmosphere, Compound 4 (25.1 mg, 0.050 mmol) obtained in Reference Example 4 was dissolved in DMF (100 mL), potassium carbonate (2.07 g, 15 mmol), dibromomethane (520 μL, 7.2 mmol). And stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, azeotroped with toluene, poured into a saturated aqueous sodium hydrogen carbonate solution, 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 preparative TLC to give the title compound 5 (7.6 mg, 30%) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.06-0.19 (m, 2H), 0.44-0.63 (m, 2H), 0.90-1.12 (m, 2H), 1 27-1.41 (m, 2H), 1.46-1.65 (m, 2H), 1.93 (dt, J = 5.4, 12.9 Hz, 1H), 2.22-2. 40 (m, 2H), 2.68-2.86 (m, 3H), 3.18-3.35 (m, 1H), 3.51 (d, J = 6.0 Hz, 1H), 3. 73-3.81 (m, 1H), 3.83 (s, 3H), 4.35 (d, J = 14.7 Hz, 1H), 4.46 (d, J = 14.7 Hz, 1H), 4.75 (d, J = 6.0 Hz, 1H), 4.81 (d, J = 7.2 Hz, 1H), 5.74 (d, J = 7.2 Hz, 1H), 6.82 (d , J = 8.4 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 7.16-7.30 (m, 3H), 7.34-7.44 (m, 2H).

(Example 2)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7- (cyclopropylmethyl) -1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano- Of 4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (6) Composition

Compound 5 (103 mg, 0.20 mmol) obtained in Example 1 was dissolved in dichloromethane (7 mL) under an argon atmosphere, and boron tribromide-dichloromethane solution (1.00 mol / L, 1.0 mL) was cooled with ice. 1.0 mmol) and stirred at room temperature for 30 minutes. Thereafter, a saturated aqueous potassium carbonate solution (7 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Further, 12M aqueous ammonia (7 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 silica gel column chromatography to obtain the title compound 6 (89.4 mg, 85%) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.03-0.20 (m, 2H), 0.41-0.62 (m, 2H), 0.86-1.16 (m, 2H), 1.21-1.72 (m, 4H), 1.89 (dt, J = 5.4, 12.9 Hz, 1H), 2.20-2.40 (m, 2H), 2.58-2 .83 (m, 3H), 3.23 (d, J = 18.3 Hz, 1H), 3.46 (d, J = 5.7 Hz, 1H), 3.74 (d, J = 6.0 Hz, 1H), 4.36 (d, J = 14.7 Hz, 1H), 4.47 (d, J = 15.0 Hz, 1H), 4.72 (d, J = 6.0 Hz, 1H), 4. 86 (d, J = 7.5 Hz, 1H), 5.78 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1 ), 7.13-7.29 (m, 3H), 7.38 (d, J = 6.9Hz, 2H).

(Example 3)
(4bR, 8R, 8aS, 9aS, 11aR, 11bR) -11-benzyl-7- (cyclopropylmethyl) -1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano- 4,8-methano-9,14-dioxa-7,11,12-triazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (7) Composition

Compound 5 (154 mg, 0.30 mmol) obtained in Example 1 was dissolved in dichloromethane (10 mL) under an argon atmosphere, and boron tribromide-dichloromethane solution (1.00 mol / L, 1.5 mL) was cooled with ice. 1.5 mmol) and stirred at room temperature for 30 minutes. Thereafter, 6M aqueous ammonia (10 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Distilled water (10 mL) was added, 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 obtain Compound 6 (58.0 mg, 39%) and the title compound 7 (64.7 mg, 43%) as a colorless oil.

Compound 7:
¹ H NMR (300 MHz, CDCl 3): δ 0.02-0.14 (m, 2H), 0.41-0.59 (m, 2H), 0.85-1.02 (m, 1H), 1 .06.-1.19 (m, 1H), 1, 23-1.74 (m, 4H), 1.80-1.97 (m, 1H), 2.17-2.32 (m, 2H) 2.59 (dd, J = 5.4, 12.6 Hz, 1H), 2.61-2.78 (m, 2H), 3.18 (d, J = 18.6 Hz, 1H), 3. 45 (d, J = 6.0 Hz, 1H), 3.68 (d, J = 6.0 Hz, 1H), 4.33-4.48 (m, 2H), 4.63 (d, J = 7 .5 Hz, 1H), 4.89 (d, J = 6.0 Hz, 1H), 5.60 (d, J = 7.2 Hz, 1H), 6.72-6.81 (m, 2H), 7 .09-7.26 (m 3H), 7.37 (d, J = 7.2Hz, 2H).

Example 4
(4bR, 8R, 8aS, 9aS, 11aR, 11bR) -11-benzyl-7- (cyclopropylmethyl) -1-hydroxy-12-methyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-Ethano-4,8-methano-9,14-dioxa-7,11,12-triazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one Synthesis of (8)

Compound 5 (83.4 mg, 0.16 mmol) obtained in Example 1 was dissolved in dichloromethane (3 mL) under an argon atmosphere, and boron tribromide / dichloromethane solution (1.00 mol / L, 0) was cooled with ice. .9 mL, 0.9 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, 33% methylamine / ethanol solution (3 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and distilled water was added. The mixture was extracted 3 times with chloroform, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by preparative TLC to obtain Compound 6 (41.5 mg, 51%) and the title compound 8 (29.4 mg, 35%) as a colorless oil.

Compound 8:
¹ H NMR (300 MHz, CDCl 3): δ 0.08-0.18 (m, 2H), 0.45-0.64 (m, 2H), 0.83-0.97 (m, 1H), 1 .16 (dd, J = 4.2, 14.1 Hz, 1H), 1.23-1.76 (m, 4H), 1.94 (dt, J = 5.4, 12.9 Hz, 1H), 2.15 (dd, J = 8.1, 12.6 Hz, 1H), 2.27 (dt, J = 3.6, 12.3 Hz, 1H), 2.61 (dd, J = 4.8, 12.3 Hz, 1 H), 2.67-2.84 (m, 2 H), 3.19 (s, 3 H), 3.20 (d, J = 18.3 Hz, 1 H), 3.43 (d, J = 6.6 Hz, 1H), 3.77 (d, J = 6.0 Hz, 1H), 4.35 (d, J = 15.6 Hz, 1H), 4.55 (d, J = 15.9 Hz) , 1H 4.60 (d, J = 7.5 Hz, 1H), 5.26 (d, J = 6.3 Hz, 1H), 5.60 (d, J = 7.2 Hz, 1H), 6.76. (D, J = 8.4 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 7.08-7.25 (m, 3H), 7.36 (d, J = 7. 5Hz, 2H).

(Reference Example 6)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-3a, 11-dihydroxy-10-methoxy-1,3,3a, 4,5,6,7,11c-octahydro-2H-6 Synthesis of 11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (9)

Under an argon atmosphere, Compound 4 (787 mg, 1.6 mmol) obtained in Reference Example 4 was dissolved in 1,1,2,2-tetrachloroethane (30 mL), and potassium carbonate (865 mg, 6.3 mmol), chloroformate 2,2,2-Trichloroethyl (630 μL, 4.7 mmol) was added and stirred at 150 ° C. for 5 hours. The reaction solution was poured into distilled water and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. Excess reagent was removed from the resulting crude product by silica gel column chromatography. The obtained crude product was dissolved in acetic acid (30 mL), zinc (3.1 g, 47 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered through Celite, concentrated and azeotroped with toluene. Then, distilled water was added and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain the title compound 9 (563 mg, 80%) as a white solid.

¹ H NMR (300 MHz, CDCl 3): δ 0.88-1.03 (m, 1H), 1.22-1.44 (m, 3H), 1.46-1.66 (m, 2H), 2 .53-2.76 (m, 2H), 3.05 (d, J = 18.0 Hz, 1H), 3.25-3.45 (m, 3H), 3.83 (s, 3H), 4 .37 (d, J = 14.7 Hz, 1H), 4.57 (d, J = 14.7 Hz, 1H), 4.64 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 7.14-7.29 (m, 3H), 7.41 (d, J = 6.6 Hz, 2H) ).

(Reference Example 7)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-14- (cyclopentylmethyl) -3a, 11-dihydroxy-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 (10d)

Under an argon atmosphere, compound 9 (224 mg, 0.50 mmol) obtained in Reference Example 6 was dissolved in 1,2-dichloroethane (30 mL), and cyclopentanecarbaldehyde (213 μL, 2.0 mmol), acetic acid (240 μL, 4 0.0 mmol) was added and stirred at room temperature for 1 hour. To the reaction solution was added 12M aqueous ammonia under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Distilled water was added, 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 10d (258 mg, 97%) as a white amorphous.

¹ H NMR (300 MHz, CDCl 3): δ 0.82-0.97 (m, 1H), 1.13 to 1.62 (m, 10H), 1.66 to 1.80 (m, 2H), 1 .87 (dt, J = 5.1, 12.6 Hz, 1H), 1.91-2.09 (m, 1H), 2.16 (dt, J = 3.3, 12.6 Hz, 1H) 2.41-2.54 (m, 3H), 2.91 (dd, J = 6.3, 18.3 Hz, 1H), 3.11 (d, J = 18.3 Hz, 1H), 3. 28 (d, J = 6.0 Hz, 1H), 3.35 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 4.38 (d, J = 14.7 Hz, 1H), 4.55 (d, J = 14.7 Hz, 1H), 4.68 (d, J = 6.0 Hz, 1H), 6.685 (d, J = 8.4 Hz, 1H), 6. 694 (d , J = 8.4 Hz, 1H), 7.14-7.29 (m, 3H), 7.36-7.44 (m, 2H).

(Reference Example 8-11)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-3a, 11-dihydroxy-10-methoxy-14-methyl-1,3,3a, 4,5,6,7,11c-octahydro- 2H-6,11b- (Iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (10a), (1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl- 14-ethyl-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 (10b), (1S, 3aS, 5aS, 6R, 11bR, 11cR) -3,14-dibenzyl-3a, 11-dihydroxy-10- Toxi-1,3,3a, 4,5,6,7,11c-octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (10f) ), And (1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-3a, 11-dihydroxy-10-methoxy-14- (2-phenethyl) -1,3,3a, 4,5,6 , 7,11c-Octahydro-2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (10 g)

According to the method of Reference Example 7, paraformaldehyde, acetaldehyde, benzaldehyde, and 2-phenylacetaldehyde were used instead of cyclopentanecarbaldehyde, and the title compounds 10a (quantitative), 10b (99%), 10f (91%), And 10 g (74%) were obtained.

Compound 10a:
¹ H NMR (300 MHz, CDCl 3): δ 0.84-1.02 (m, 1H), 1.31-1.47 (m, 3H), 1.55-1.66 (m, 1H), 1 .87 (dt, J = 5.1, 12.6 Hz, 1H), 2.13 (dt, J = 3.3, 12.3 Hz, 1H), 2.34-2.49 (m, 1H), 2.38 (s, 3H), 2.86 (dd, J = 6.3, 18.6 Hz, 1H), 3.17 (d, J = 18.9 Hz, 1H), 3.23 (d, J = 6.0 Hz, 1H), 3.30 (d, J = 6.0 Hz, 1H), 3.82 (s, 3H), 4.38 (d, J = 14.4 Hz, 1H), 4.49. (D, J = 14.7 Hz, 1H), 4.67 (d, J = 6.0 Hz, 1H), 6.64-6.74 (m, 2H), 7.12-7.26 (m, 3H), 7. 0 (d, J = 6.6Hz, 2H).

Compound 10b:
¹ H NMR (300 MHz, CDCl 3): δ 0.84-1.02 (m, 1H), 1.09 (t, J = 7.2 Hz, 3H), 1.32-1.47 (m, 3H) 1.56-1.76 (m, 1H), 1.89 (dt, J = 5.1, 12.3 Hz, 1H), 2.10 (dt, J = 3.3, 12.3 Hz, 1H) ), 2.46-2.68 (m, 3H), 2.85 (dd, J = 6.3, 18.6 Hz, 1H), 3.13 (d, J = 18.6 Hz, 1H), 3 .30 (d, J = 6.0 Hz, 1H), 3.40 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 4.39 (d, J = 14.7 Hz, 1H), 4.50 (d, J = 14.7 Hz, 1H), 4.70 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6. 70 (d J = 8.4Hz, 1H), 7.13-7.27 (m, 3H), 7.37-7.44 (m, 2H).

Compound 10f:
¹ H NMR (300 MHz, CDCl 3): δ 0.82-0.98 (m, 1H), 1.25-1.42 (m, 3H), 1.48-1.60 (m, 1H), 1 .90 (dt, J = 5.4, 12.6 Hz, 1H), 2.25 (dt, J = 3.3, 12.3 Hz, 1H), 2.45 (dt, J = 4.5, 12 .6 Hz, 1H), 2.92 (dt, J = 6.6, 18.6 Hz, 1H), 3.19 (d, J = 18.6 Hz, 1H), 3.30 (d, J = 6. 0 Hz, 1H), 3.34 (d, J = 6.3 Hz, 1H), 3.74 (s, 2H), 3.84 (s, 3H), 4.38 (d, J = 14.7 Hz, 1H), 4.56 (d, J = 14.7 Hz, 1H), 4.73 (d, J = 5.7 Hz, 1H), 6.71 (s, 2H), 7.13-7.34 ( m, 6 ), 7.35-7.44 (m, 4H).

Compound 10g:
¹ H NMR (300 MHz, CDCl 3): δ 0.84-1.00 (m, 1H), 1.33-1.49 (m, 3H), 1.62 (dd, J = 7.8, 14. 4 Hz, 1H), 1.92 (dt, J = 5.1, 12.6 Hz, 1H), 2.19 (dt, J = 3.3, 12.3 Hz, 1H), 2.60 (dd, J = 4.2, 12.3 Hz, 1H), 2.68-2.86 (m, 4H), 2.91 (dd, J = 6.3, 18.6 Hz, 1H), 3.16 (d , J = 18.6 Hz, 1H), 3.32 (d, J = 6.0 Hz, 1H), 3.45 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 4 .41 (d, J = 14.7 Hz, 1H), 4.51 (d, J = 14.7 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 6.64-6. 75 ( , 2H), 7.14-7.32 (m, 8H), 7.38-7.45 (m, 2H).

(Reference Example 12)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -14-allyl-3-benzyl-3a, 11-dihydroxy-10-methoxy-1,3,3a, 4,5,6,7,11c-octahydro- Synthesis of 2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (10e)

Under an argon atmosphere, Compound 9 (224 mg, 0.50 mmol) obtained in Reference Example 6 was dissolved in DMF (5 mL), sodium bicarbonate (84.0 mg, 1.0 mmol), allyl bromide (64.9 μL, 0.75 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was 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 obtain the title compound 10e (225 mg, 92%) as a white amorphous.

¹ H NMR (300 MHz, CDCl 3): δ 0.83-1.00 (m, 1H), 1.31-1.46 (m, 3H), 1.54-1.66 (m, 1H), 1 .89 (dt, J = 5.1, 12.6 Hz, 1H), 2.12 (dt, J = 3.3, 12.3 Hz, 1H), 2.53 (dd, J = 5.2, 12 .3 Hz, 1H), 2.85 (dd, J = 6.3, 18.6 Hz, 1H), 3.07-3.27 (m, 3H), 3.30 (d, J = 6.0 Hz, 1H), 3.39 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 4.40 (d, J = 14.4 Hz, 1H), 4.50 (d, J = 14.7 Hz, 1H), 4.72 (d, J = 5.7 Hz, 1H), 5.11 (dd, J = 1.5, 10.2 Hz, 1H), 5.18 (d, J = 1.5, 7.4 Hz, 1H), 5.84-6.00 (m, 1H), 6.66-6.74 (m, 2H), 7.14-7.29 (m, 3H), 7.37- 7.44 (m, 2H).

(Reference Example 13)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-3a, 11-dihydroxy-14-isobutyl-10-methoxy-1,3,3a, 4,5,6,7,11c-octahydro- Synthesis of 2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (10c)

According to the method of Reference Example 12, isobutyl bromide was used instead of allyl bromide to obtain the title compound 10c (48%).

¹ H NMR (300 MHz, CDCl 3): δ 0.82-0.98 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H), 1.24-1.41 (m, 3H), 1.50-1.80 (m, 2H), 1.86 (dt, J = 5.1, 12.6 Hz, 1H), 2. 15-2.49 (m, 4H), 2.95 (dd, J = 6.0, 18.3 Hz, 1H), 3.12 (d, J = 18.6 Hz, 1H), 3.24-3 .32 (m, 1H), 3.30 (d, J = 5.4 Hz, 1H), 3.83 (s, 3H), 4.36 (d, J = 14.7 Hz, 1H), 4.58 (D, J = 14.7 Hz, 1H), 4.66 (d, J = 5.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.4Hz, 1H), 7.14-7.27 (m, 3H), 7.36-7.43 (m, 2H).

(Example 5)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7- (cyclopentylmethyl) -1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4 , 8-Methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11d)

Under an argon atmosphere, bromochloromethane (6.67 mL, 100 mmol) was dissolved in DMF (200 mL), and potassium carbonate (27.6 g, 200 mmol) was added and stirred. Thereafter, a DMF (10 mL) solution of the compound 10d (106 mg, 0.2 mmol) obtained in Reference Example 7 at room temperature was added in 5 portions every 12 hours (2 mL × 5), and the mixture was further stirred for 12 hours. The reaction solution was 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 preparative TLC and white amorphous to obtain the title compound 11d (106 mg, 98%).

¹ H NMR (300 MHz, CDCl 3): δ 0.94-1.07 (m, 1H), 1.15-1.83 (m, 12H), 1.87 (dt, J = 5.4, 12. 9 Hz, 1H), 2.04 (sept, J = 7.5 Hz, 1H), 2.28-2.59 (m, 4H), 2.80 (dd, J = 6.6, 18.6 Hz, 1H) ), 3.28 (d, J = 18.6 Hz, 1H), 3.39 (d, J = 6.0 Hz, 1H), 3.48 (d, J = 6.0 Hz, 1H), 3.82 (S, 3H), 4.33 (d, J = 14.7 Hz, 1H), 4.51 (d, J = 14.7 Hz, 1H), 4.69 (d, J = 6.0 Hz, 1H) , 4.80 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.93 ( , J = 8.4Hz, 1H), 7.14-7.31 (m, 3H), 7.33-7.42 (m, 2H).

(Example 6-11)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7-methyl-1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8- Methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11a), (4bR, 8R , 8aS, 9aS, 11aS, 11bR) -11-benzyl-7-ethyl-1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9, 12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11b), (4bR, 8R 8aS, 9aS, 11aS, 11bR) -11-benzyl-7-isobutyl-1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9,12 , 14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11c), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7-allyl-11-benzyl-1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa -7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11e), (4bR, 8R, 8aS, aS, 11aS, 11bR) -7,11-dibenzyl-1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa -7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11f), and (4bR, 8R, 8aS, 9aS, 11aS, 11bR ) -11-benzyl-1-methoxy-7- (2-phenethyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9,12,14- Synthesis of trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (11g)

According to the method of Example 5, compound 10a obtained in Reference Example 8, compound 10b obtained in Reference Example 9, compound 10c obtained in Reference Example 13, compound obtained in Reference Example 12 instead of compound 10d 10e, compound 10f obtained in Reference Example 10 and compound 10g obtained in Reference Example 11 were used to give the title compounds 11a (84%), 11b (69%), 11c (79%), 11e (87%) , 11f (86%), and 11 g (98%).

Compound 11a:
¹ H NMR (300 MHz, CDCl 3): δ 1.06 (dd, J = 5.7, 14.1 Hz, 1H), 1.27-1.42 (m, 2H), 1.46-1.64 ( m, 2H), 1.90 (dt, J = 5.7, 12.9 Hz, 1H), 2.27 (dt, J = 3.6, 12.3 Hz, 1H), 2.41 (s, 3H) ), 2.50 (dd, J = 5.1, 12.3 Hz, 1H), 2.74 (dd, J = 6.3, 18.6 Hz, 1H), 3.26 (d, J = 6. 0 Hz, 1H), 3.33 (d, J = 18.3 Hz, 1H), 3.50 (d, J = 6.0 Hz, 1H), 3.83 (s, 3H), 4.36 (d, J = 14.4 Hz, 1 H), 4.43 (d, J = 14.4 Hz, 1 H), 4.72 (d, J = 6.0 Hz, 1 H), 4.82 (d, J = 7.2 Hz) , H), 5.74 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7. 16-7.29 (m, 3H), 7.39 (d, J = 6.6 Hz, 2H).

Compound 11b:
¹ H NMR (300 MHz, CDCl 3): δ 1.05 (dd, J = 5.7, 14.1 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.24-1. 66 (m, 4H), 1.90 (dt, J = 5.7, 12.9 Hz, 1H), 2.30 (dt, J = 3.3, 12.6 Hz, 1H), 2.51-2 .69 (m, 3H), 2.75 (dd, J = 6.3, 18.9 Hz, 1H), 3.31 (d, J = 18.9 Hz, 1H), 3.45 (d, J = 6.0 Hz, 1H), 3.50 (d, J = 6.3 Hz, 1H), 3.83 (s, 3H), 4.35 (d, J = 14.4 Hz, 1H), 4.45 ( d, J = 14.7 Hz, 1H), 4.73 (d, J = 6.3 Hz, 1H), 4.81 (d, J = 7.2 Hz, 1H), 5.74 (d, J = 7) .5H , 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.15-7.29 (m, 3H), 7.36 -7.42 (m, 2H).

Compound 11c:
¹ H NMR (300 MHz, CDCl 3): δ 0.90 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H), 0.94-1.04 (m, 1H), 1.17-1.57 (m, 4H), 1.61-1.78 (m, 1H), 1.87 (dt, J = 6.0, 12.6 Hz, 1H), 2. 22-2.52 (m, 4H), 2.82 (dd, J = 6.3, 18.6 Hz, 1H), 3.18-3.32 (m, 2H), 3.48 (d, J = 6.0 Hz, 1H), 3.82 (s, 3H), 4.32 (d, J = 14.7 Hz, 1H), 4.53 (d, J = 14.7 Hz, 1H), 4.68. (D, J = 6.0 Hz, 1H), 4.80 (d, J = 7.2 Hz, 1H), 5.73 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 8.7Hz, 1 ), 6.93 (d, J = 8.4Hz, 1H), 7.15-7.29 (m, 3H), 7.34-7.41 (m, 2H).

Compound 11e:
¹ H NMR (300 MHz, CDCl 3): δ 0.98-1.10 (m, 1H), 1.23-1.63 (m, 4H), 1.90 (dt, J = 5.7, 12. 9 Hz, 1H), 2.31 (dt, J = 3.3, 12.6 Hz, 1H), 2.57 (dd, J = 4.8, 12.6 Hz, 1H), 2.73 (dd, J = 6.3, 18.6 Hz, 1H), 3.17 (dd, J = 7.5, 13.5 Hz, 1H), 3.22-3.36 (m, 2H), 3.42 (d, J = 6.0 Hz, 1H), 3.50 (d, J = 6.0 Hz, 1H), 3.83 (s, 3H), 4.35 (d, J = 14.7 Hz, 1H), 4. 45 (d, J = 14.4 Hz, 1H), 4.73 (d, J = 6.6 Hz, 1H), 4.81 (d, J = 6.9 Hz, 1H), 5.14 (d, J = 10 2 Hz, 1H), 5.21 (dd, J = 1.5, 17.4 Hz, 1H), 5.74 (d, J = 7.2 Hz, 1H), 5.86-6.02 (m, 1H) ), 6.83 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.14-7.30 (m, 3H), 7.35-7. .44 (m, 2H).

Compound 11f:
¹ H NMR (300 MHz, CDCl 3): δ 0.94-1.06 (m, 1H), 1.21-1.56 (m, 4H), 1.92 (dt, J = 6.3, 12. 6 Hz, 1H), 2.37-2.59 (m, 2H), 2.80 (dd, J = 6.3, 18.6 Hz, 1H), 3.34 (d, J = 18.9 Hz, 1H) ), 3.36 (d, J = 6.3 Hz, 1H), 3.51 (d, J = 6.0 Hz, 1H), 3.71-3.91 (m, 2H), 3.83 (s) 3H), 4.34 (d, J = 14.7 Hz, 1H), 4.51 (d, J = 14.7 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 4 .80 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 z, 1H), 7.14-7.47 (m, 10H).

Compound 11g:
¹ H NMR (300 MHz, CDCl 3): δ 0.99-1.11 (m, 1H), 1.22-1.64 (m, 4H), 1.92 (dt, J = 5.4, 12. 9 Hz, 1H), 2.30-2.47 (m, 1H), 2.66 (dd, J = 4.8, 12.6 Hz, 1H), 2.72-2.93 (m, 5H), 3.34 (d, J = 18.3 Hz, 1H), 3.45-3.54 (m, 2H), 3.83 (s, 3H), 4.36 (d, J = 14.4 Hz, 1H) ), 4.46 (d, J = 14.4 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 4.81 (d, J = 7.5 Hz, 1H), 5.74. (D, J = 7.2 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 7.14-7.33 ( m, 8H) 7.35-7.42 (m, 2H).

(Examples 12-18)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7-methyl-1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8- Methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12a), (4bR, 8R , 8aS, 9aS, 11aS, 11bR) -11-benzyl-7-ethyl-1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9, 12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12b), (4bR, R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-1-hydroxy-7-isobutyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9 , 12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12c), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7- (cyclopentylmethyl) -1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9, 12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12d) (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7-allyl-11-benzyl-1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8- Methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12e), (4bR, 8R , 8aS, 9aS, 11aS, 11bR) -7,11-dibenzyl-1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9,12, 14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12f), and (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-1-hydroxy-7- (2-phenethyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8 Synthesis of methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (12 g)

According to the method of Example 2, compound 11a obtained in Example 6 instead of compound 5, compound 11b obtained in Example 7, compound 11c obtained in Example 8, compound obtained in Example 5 11d, compound 11e obtained in Example 9, compound 11f obtained in Example 10, and compound 11g obtained in Example 11 were used to give the title compounds 12a (76%), 12b (74%), 12c (92%), 12d (81%), 12e (89%), 12f (95%), and 12 g (89%) were obtained.

Compound 12a:
¹ H NMR (300 MHz, CDCl 3): δ 1.02-1.16 (m, 1H), 1.33 (br d, J = 12.0 Hz, 1H), 1.39-1.71 (m, 3H) ), 1.87 (dt, J = 5.4, 12.6 Hz, 1H), 2.20-2.37 (m, 1H), 2.41 (s, 3H), 2.50 (dd, J = 4.8, 14.7 Hz, 1H), 2.75 (dd, J = 6.3, 18.6 Hz, 1H), 3.21-3.36 (m, 2H), 3.46 (d, J = 6.0 Hz, 1H), 4.37 (d, J = 14.7 Hz, 1H), 4.44 (d, J = 14.7 Hz, 1H), 4.70 (d, J = 6.0 Hz) , 1H), 4.87 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.5 Hz, 1H), 6.81-6.90 (m, 2H), 7.15. -7. 31 (m, 3H), 7.38 (d, J = 6.9 Hz, 2H).

Compound 12b:
¹ H NMR (300 MHz, CDCl 3): δ 1.02-1.16 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H), 1.29 (br d, J = 13.5 Hz) , 1H), 1.38-1.71 (m, 3H), 1.87 (dt, J = 5.4, 12.6 Hz, 1H), 2.29-2.34 (m, 1H), 2 49-2.74 (m, 3H), 2.74 (dd, J = 6.3, 18.3 Hz, 1H), 3.25 (d, J = 18.6 Hz, 1H), 3.40- 3.49 (m, 2H), 4.37 (d, J = 14.7 Hz, 1H), 4.45 (d, J = 14.7 Hz, 1H), 4.73 (d, J = 6.0 Hz) , 1H), 4.86 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 6.84-6.90 (m, 2H), 7.14 -7. 9 (m, 3H), 7.38 (d, J = 6.6Hz, 2H).

Compound 12c:
¹ H NMR (300 MHz, CDCl 3): δ 0.89 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.97-1.12 (m, 1H), 1.14-1.24 (m, 1H), 1.35-1.77 (m, 4H), 1.84 (dt, J = 6.0, 12.6 Hz, 1H), 2. 22-2.52 (m, 4H), 2.81 (dd, J = 6.3, 18.3 Hz, 1H), 3.22 (d, J = 18.3 Hz, 1H), 3.29 (d , J = 6.0 Hz, 1H), 3.43 (d, J = 6.0 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 4.51 (d, J = 15. 0 Hz, 1H), 4.69 (d, J = 6.0 Hz, 1H), 4.85 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 6.85 d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 7.15-7.29 (m, 3H), 7.34-7.42 (m, 2H) ).

Compound 12d:
¹ H NMR (300 MHz, CDCl 3): δ 0.98-1.11 (m, 1H), 1.13-1.29 (m, 3H), 1.36-1.67 (m, 7H), 1 .68-1.84 (m, 2H), 1.87 (dd, J = 5.4, 12.9 Hz, 1H), 2.02 (sept, J = 7.5 Hz, 1H), 2.26 2.60 (m, 4H), 2.79 (dd, J = 6.6, 18.6 Hz, 1H), 3.25 (d, J = 18.3 Hz, 1H), 3.39 (d, J = 6.3 Hz, 1H), 3.44 (d, J = 6.0 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 4.49 (d, J = 14.7 Hz, 1H), 4.70 (d, J = 6.0 Hz, 1H), 4.85 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 6. 85 d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.15-7.29 (m, 3H), 7.33-7.41 (m, 2H) ).

Compound 12e:
¹ H NMR (300 MHz, CDCl 3): δ 1.01-1.14 (m, 1H), 1.22-1.35 (m, 1H), 1.38-1.69 (m, 3H), 1 .87 (dt, J = 5.4, 12.9 Hz, 1H), 2.30 (dt, J = 3.3, 12.3 Hz, 1H), 2.51-2.62 (m, 1H), 2.73 (dd, J = 6.6, 18.6 Hz, 1H), 3.10-3.32 (m, 3H), 3.42 (d, J = 6.0 Hz, 1H), 3.46 (D, J = 6.0 Hz, 1H), 4.37 (d, J = 14.7 Hz, 1H), 4.45 (d, J = 14.7 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 4.86 (d, J = 7.2 Hz, 1H), 5.13 (d, J = 10.2 Hz, 1H), 5.21 (dd, J = 1.2, 17 .4Hz 1H), 5.78 (d, J = 7.2 Hz, 1H), 5.83-6.00 (m, 1H), 6.867 (d, J = 8.4 Hz, 1H), 6.874 ( d, J = 8.4 Hz, 1H), 7.16-7.28 (m, 3H), 7.34-7.42 (m, 2H).

Compound 12f:
¹ H NMR (300 MHz, CDCl 3): δ 0.97-1.12 (m, 1H), 1.24 (brd, J = 11.4 Hz, 1H), 1.36-1.61 (m, 3H) , 1.87 (dt, J = 6.0, 12.6 Hz, 1H), 2.33-2.56 (m, 2H), 2.78 (dd, J = 6.6, 18.9 Hz, 1H) ), 3.23-3.38 (m, 2H), 3.45 (d, J = 6.0 Hz, 1H), 3.74 (d, J = 14.1 Hz, 1H), 3.78 (d , J = 14.1 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 4.48 (d, J = 14.7 Hz, 1H), 4.74 (d, J = 6. 0 Hz, 1H), 4.84 (d, J = 7.5 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), .90 (d, J = 8.4Hz, 1H), 7.14-7.44 (m, 10H).

Compound 12g:
¹ H NMR (300 MHz, CDCl 3): δ 1.01-1.16 (m, 1H), 1.22-1.35 (m, 1H), 1.39-1.71 (m, 3H), 1 .88 (dt, J = 5.4, 12.9 Hz, 1H), 2.27-2.44 (m, 1H), 2.63 (dd, J = 4.8, 12.3 Hz, 1H), 2.69-2.87 (m, 5H), 3.28 (d, J = 18.6 Hz, 1H), 3.47 (d, J = 5.7 Hz, 2H), 4.37 (d, J = 14.7 Hz, 1H), 4.46 (d, J = 14.7 Hz, 1H), 4.75 (d, J = 6.0 Hz, 1H), 4.87 (d, J = 7.2 Hz, 1H), 5.78 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4, 1H), 7. 14-7.30 m, 8H), 7.36-7.41 (m, 2H).

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

According to the method of Reference Example 4, instead of compound 2a, compound 13 (5R, 6S, 6′R, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6-hydroxy-3- Methoxy-N-phenyl-8-oxa-6,14-ethanomorphinan-7-carboxamide: Bioorg. Med. Chem. Lett. The compound described in 2010, 20, 121) was used to obtain the title compound 14 (72%).

¹ H NMR (300 MHz, CDCl 3): δ 0.06-0.22 (m, 2H), 0.43-0.67 (m, 2H), 0.84-1.02 (m, 1.75H) 1.42-2.40 (m, 7.25H), 2.58-2.86 (m, 2.25H), 2.95 (dd, J = 6.6, 18.3 Hz, 0.75H) ), 3.09-3.19 (m, 1H), 3.50 (d, J = 5.7 Hz, 0.75H), 3.76 (d, J = 6.6 Hz, 1H), 3.79. (S, 0.75H), 3.84 (s, 2.25H), 4.08 (d, J = 5.7 Hz, 0.25H), 4.83 (d, J = 6.6 Hz, 0.8). 75H), 5.23 (d, J = 6.0 Hz, 0.25H), 6.63 (d, J = 8.4 Hz, 0.25H), 6.67 (d, J = 8.4 Hz, 0) .25H) 6.72 (s, 1.5H), 7.08-7.16 (m, 0.25H), 7.24-7.42 (m, 4.25H), 7.55-7.61 (m , 0.5H), 8.73 (s, 0.25H),

(Example 19)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-methoxy-11-phenyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano- Of 4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (15) Composition

According to the method of Example 5, using Compound 14 obtained in Reference Example 14 instead of Compound 10d, the title compound 15 (73%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.05-0.20 (m, 2H), 0.42-0.62 (m, 2H), 0.82-1.03 (m, 1H), 1 11-1.44 (m, 3H), 1.66-1.85 (m, 2H), 1.98 (dt, J = 5.4, 12.9 Hz, 1H), 2.23-2. 41 (m, 2H), 2.72 (dd, J = 5.4, 12.6 Hz, 2H), 2.82 (dd, J = 6.6, 18.6 Hz, 1H), 3.28 (d , J = 18.6 Hz, 1H), 3.68 (d, J = 6.0 HZ, 1H), 3.80 (d, J = 6.9 HZ, 1H), 3.81 (s, 3H), 4 .68 (d, J = 7.2 Hz, 1H), 4.85 (d, J = 6.0 Hz, 1H), 5.73 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.4Hz 1H), 6.96 (d, J = 8.4Hz, 1H), 7.24-7.41 (m, 5H).

(Example 20)
4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-hydroxy-11-phenyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4 , 8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (16)

According to the method of Example 2, the compound 15 obtained in Example 19 was used instead of the compound 5, and the title compound 16 (89%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.06-0.18 (m, 2H), 0.44-0.60 (m, 2H), 0.87-1.01 (m, 1H), 1 .13-1.27 (m, 1H), 1.29-1.49 (m, 2H), 1.70-1.84 (m, 2H), 1.96 (dt, J = 5.4) 12.9 Hz, 1H), 2.24-2.40 (m, 2H), 2.62-2.77 (m, 2H), 2.82 (dd, J = 6.6, 18.6 Hz, 1H ), 3.25 (d, J = 18.3 Hz, 1H), 3.63 (d, J = 5.7 Hz, 1H), 3.80 (d, J = 6.0 Hz, 1H), 4.71 (D, J = 7.2 Hz, 1H), 4.84 (d, J = 6.0 Hz, 1H), 5.75 (d, J = 7.5 Hz, 1H), 6.82-6.91 ( m, 2H), 7. 5-7.40 (m, 5H).

(Reference Example 15)
(5R, 6S, 6′R, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-3-methoxy-6-methylmorphinane-6 Synthesis of '-carboxamide (17)

Under an argon atmosphere, compound 1a (2.0 g, 4.8 mmol) was dissolved in ethanol (60 mL), 12 M aqueous ammonia (20 mL) was added, and the mixture was stirred at room temperature for 3 days. Thereafter, 12M aqueous ammonia (20 mL) was added, and the mixture was stirred at room temperature for 2 days. The reaction 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, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 17 (1.36 g, 73%) as a white amorphous.

¹ H NMR (300 MHz, CDCl 3): δ 0.09-0.20 (m, 2H), 0.47-0.61 (m, 2H), 0.77-0.92 (m, 1H), 1 .39 (td, J = 3.6, 14.4 Hz, 1H), 1.43-1.71 (m, 3H), 2.13 (dt, J = 3.6, 12.0 Hz, 1H), 2.22-2.44 (m, 4H), 2.57-2.71 (m, 2H), 3.06 (d, J = 18.9 Hz, 1H), 3.11 (d, J = 6 .0Hz, 1H), 3.61 (s, 1H), 3.87 (s, 3H), 4.73 (s, 1H), 5.72 (brd, J = 2.7 Hz, 1H), 6 .12 (brd, J = 3.3 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H).

(Reference Example 16)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -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 and (4R, 4aR, 10R, 10aS, 12S) -13- (cyclopropylmethyl) -5 , 6-Dihydroxy-3-oxo-1,2,3,4,9,10-hexahydro-10,4a- (iminoethano) -10a, 4- (epoxymethano) phenanthrene-12-carboxamide (18) Synthesis of

According to the method of Reference Example 5, using Compound 17 obtained in Reference Example 15 instead of Compound 2b, the title equilibrium mixture 18 (quantitative) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.00-0.14 (m, 2H), 0.37-0.60 (m, 2H), 0.81-0.96 (m, 1H), 1 .07-1.27 (m, 1H), 1.47-2.18 (m, 6H), 2.26 (dd, J = 7.2, 12.6 Hz, 1H), 2.51-2. 72 (m, 2H), 2.77 (dd, J = 6.3, 18.6 Hz, 0.1H), 2.92 (dd, J = 6.3, 18.6 Hz, 0.9H), 3 .10 (d, J = 18.6 Hz, 1H), 3.48 (d, J = 5.4 Hz, 0.9H), 3.69 (d, J = 6.0 Hz, 1H), 3.81 ( s, 3H), 4.01 (d, J = 5.7 Hz, 0.1H), 4.65 (d, J = 5.7 Hz, 0.9H), 5.09 (d, J = 5.7 Hz) , 0.1H), 5. 4 (br s, 1.9H), 6.56-6.76 (m, 2H), 6.96 (br s, 0.2H), 7.17 (br s, 0.9H).

(Example 21)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8 Synthesis of methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (19)

According to the method of Example 5, the title compound 19 (93%) was obtained using the equilibrium mixture 18 obtained in Reference Example 16 instead of the compound 10d.

¹ H NMR (300 MHz, CDCl 3): δ 0.04-0.19 (m, 2H), 0.41-0.60 (m, 2H), 0.86-1.02 (m, 1H), 1 17-1.41 (m, 2H), 1.47-1.84 (m, 3H), 1.89 (dt, J = 5.7, 12.9 Hz, 1H), 2.16-2. 48 (m, 2H), 2.61-2.89 (m, 3H), 3.28 (d, J = 18.6 Hz, 1H), 3.54 (d, J = 5.7 Hz, 1H), 3.78 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 4.68 (d, J = 6.0 Hz, 1H), 4.77 (d, J = 7.2 Hz) , 1H), 5.68 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 7 .41 (s, 1H).

(Example 22)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-methoxy-11- (2-phenethyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a-Ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one Synthesis of (20a)

Under an argon atmosphere, compound 19 (118 mg, 0.28 mmol) obtained in Example 21 was dissolved in DMF (3 mL), 60% sodium hydride (55.7 mg, 1.4 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, (2-bromoethyl) benzene (381 μL, 2.8 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was poured into distilled water under ice-cooling, and extracted twice with a mixed solvent of chloroform / ethanol and twice 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 20a (122 mg, 83%) as a colorless oil.

¹ H NMR (300 MHz, CDCl 3): δ 0.04-0.17 (m, 2H), 0.42-0.60 (m, 2H), 0.86-1.04 (m, 1H), 1 .18 (dd, J = 6.6, 14.4 Hz, 1H), 1.27-1.73 (m, 4H), 1.93 (dt, J = 5.4, 13.2 Hz, 1H), 2.18-2.37 (m, 2H), 2.60-3.15 (m, 6H), 3.27 (d, J = 17.4 Hz, 1H), 3.49 (d, J = 6 .0Hz, 1H), 3.52-3.66 (m, 1H), 3.75 (d, J = 5.4 Hz, 1H), 3.85 (s, 3H), 4.74 (d, J = 6.0 Hz, 1H), 4.79 (d, J = 7.2 Hz, 1H), 5.70 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.96 d, J = 8.7Hz, 1H), 7.14-7.33 (m, 5H).

(Examples 23-26)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -11-isobutyl-1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano- 4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (20b), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11- (cyclohexylmethyl) -7- (cyclopropylmethyl) -1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-Etano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pen Len-10 (11H) -one (20c), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-allyl-7- (cyclopropylmethyl) -1-methoxy-5,6,7,8, 9a, 11b-Hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] Pentalen-10 (11H) -one (20d) and (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-methoxy-11-methyl-5,6,7,8 , 9a, 11b-Hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta 1,2,3-gh] pentalene -10 (11H) - Synthesis of on (20e)

According to the method of Example 22, using isobutyl bromide, bromomethylcyclohexane, allyl bromide, and methyl iodide instead of (2-bromoethyl) benzene, the title compounds 20b (76%), 20c (71%), 20d (87%) and 20e (86%) were obtained.

Compound 20b:
¹ H NMR (300 MHz, CDCl 3): δ 0.06-0.14 (m, 2H), 0.44-0.58 (m, 2H), 0.82-1.00 (m, 1H), 0 .87 (d, J = 6.9, 3H), 0.91 (d, J = 6.9 Hz, 3H), 1.18-1.47 (m, 3H), 1.51-1.74 ( m, 2H), 1.93 (dt, J = 5.7, 12.9 Hz, 1H), 2.03-2.33 (m, 3H), 2.55-2.84 (m, 4H), 3.20-3.32 (m, 2H), 3.47 (d, J = 6.0 Hz, 1H), 3.73 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H ), 4.74 (d, J = 6.3 Hz, 1H), 4.76 (d, J = 7.2 Hz, 1H), 5.68 (d, J = 7.2 Hz, 1H), 6.85. (D, J = 8.4 Hz, 1 ), 6.96 (d, J = 8.4Hz, 1H).

Compound 20c:
¹ H NMR (300 MHz, CDCl 3): δ 0.02-0.16 (m, 2H), 0.42-0.58 (m, 2H), 0.78-1.01 (m, 3H), 1 .04-1.48 (m, 6H), 1.51-2.00 (m, 9H), 2.17-2.33 (m, 2H), 2.54-2.73 (m, 3H) , 2.76 (dd, J = 6.6, 18.9 Hz, 1H), 3.24 (d, J = 18.9 Hz, 1H), 3.27 (dd, J = 7.2, 12.9 Hz) , 1H), 3.46 (d, J = 6.3 Hz, 1H), 3.73 (d, J = 6.3 Hz, 1H), 3.85 (s, 3H), 4.69-4.80 (M, 2H), 5.69 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H) .

Compound 20d:
¹ H NMR (300 MHz, CDCl 3): δ 0.04-0.16 (m, 2H), 0.42 to 0.60 (m, 2H), 0.87 to 1.02 (m, 1H), 1 24-1.49 (m, 3H), 1.52-1.74 (m, 2H), 1.92 (dt, J = 5.4, 12.9 Hz, 1H), 2.18-2. 35 (m, 2H), 2.68 (dd, J = 5.1, 12.3 Hz, 2H), 2.78 (dd, J = 6.6, 18.6 Hz, 1H), 3.25 (d , J = 18.3 Hz, 1H), 3.48 (d, J = 6.0 Hz, 1H), 3.70-3.94 (m, 3H), 3.85 (s, 3H), 4.72. (D, J = 6.0 Hz, 1H), 4.80 (d, J = 7.2 Hz, 1H), 5.09 (dd, J = 1.5, 10.5 Hz, 1H), 5.21 ( dd, J = 1 5, 17.4 Hz, 1H), 5.72 (d, J = 7.5 Hz, 1H), 5.84-5.99 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H) ), 6.96 (d, J = 8.4 Hz, 1H).

Compound 20e:
¹ H NMR (300 MHz, CDCl 3): δ 0.05-0.15 (m, 2H), 0.44-0.59 (m, 2H), 0.86-1.01 (m, 1H), 1 .22-1.46 (m, 3H), 1.50-1.75 (m, 2H), 1.92 (dt, J = 5.4, 12.9 Hz, 1H), 2.22-2. 34 (m, 2H), 2.62-2.86 (m, 3H), 2.76 (s, 3H), 3.26 (d, J = 18.6 Hz, 1H), 3.46 (d, J = 6.0 Hz, 1H), 3.73 (d, J = 6.3, 1H), 3.85 (s, 3H), 4.71 (d, J = 6.3 Hz, 1H), 4. 80 (d, J = 7.2 Hz, 1H), 5.72 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1 H).

(Examples 27-31)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-hydroxy-11- (2-phenethyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a-Ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (21a), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-hydroxy-11-isobutyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-Etano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] penta -10 (11H) -one (21b), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11- (cyclohexylmethyl) -7- (cyclopropylmethyl) -1-hydroxy-5,6 7,8,9a, 11b-Hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2, 3-gh] pentalen-10 (11H) -one (21c), (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-allyl-7- (cyclopropylmethyl) -1-hydroxy-5,6, 7,8,9a, 11b-Hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5 Cycloocta [1,2,3-gh] pentalen-10 (11H) -one (21d) or (4bR, 8R, 8aS, 9aS, 11aS, 11bR) -7- (cyclopropylmethyl) -1-hydroxy-11 -Methyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5 Synthesis of cycloocta [1,2,3-gh] pentalen-10 (11H) -one (21e)

According to the method of Example 2, instead of Compound 5, Compound 20a obtained in Example 22, Compound 20b obtained in Example 23, Compound 20c obtained in Example 24, obtained in Example 25 Using compound 20d and compound 20e obtained in Example 26, the title compounds 21a (61%), 21b (78%), 21c (91%), 21d (23%) and 21e (27%) were obtained. It was.

Compound 21a:
¹ H NMR (300 MHz, CDCl 3): δ 0.05-0.19 (m, 2H), 0.41-0.61 (m, 2H), 0.82-1.03 (m, 1H), 1 12-1.36 (m, 2H), 1.46-1.80 (m, 3H), 1.91 (dt, J = 5.4, 12.9 Hz, 1H), 2.20-2. 39 (m, 2H), 2.58-3.18 (m, 6H), 3.25 (d, J = 18.6 Hz, 1H), 3.45 (d, J = 6.0 Hz, 1H), 3.54-3.68 (m, 1H), 3.75 (d, J = 6.0, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.87 (d, J = 7.2 Hz, 1H), 5.78 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 7.13-7. 2 (m, 5H).

Compound 21b:
¹ H NMR (300 MHz, CDCl 3): δ 0.06-0.18 (m, 2H), 0.43-0.59 (m, 2H), 0.80-1.02 (m, 1H), 0 .88 (d, J = 6.9, 3H), 0.90 (d, J = 6.9 Hz, 3H), 1.20-1.36 (m, 2H), 1.46-1.81 ( m, 3H), 1.91 (dt, J = 5.4, 13.2 Hz, 1H), 2.03-2.40 (m, 3H), 2.57-2.87 (m, 4H), 3.16-3.35 (m, 2H), 3.43 (d, J = 6.0 Hz, 1H), 3.74 (d, J = 5.4 Hz, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.84 (d, J = 7.2 Hz, 1H), 5.76 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.92 (d, J 8.4Hz, 1H).

Compound 21c:
¹ H NMR (300 MHz, CDCl 3): δ 0.02-0.17 (m, 2H), 0.39-0.60 (m, 2H), 0.73-1.35 (m, 8H), 1 .43-1.98 (m, 10H), 2.18-2.38 (m, 2H), 2.56-2.87 (m, 4H), 3.12-3.34 (m, 2H) 3.42 (d, J = 6.0 Hz, 1H), 3.74 (d, J = 6.0 Hz, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.84 ( d, J = 6.9 Hz, 1H), 5.76 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8) .4Hz, 1H).

Compound 21d:
¹ H NMR (300 MHz, CD3OD): δ 0.18-0.32 (m, 2H), 0.48-0.73 (m, 2H), 0.86-1.04 (m, 1H), 1 .25-1.63 (m, 4H), 1.73-1.99 (m, 2H), 2.49-2.78 (m, 4H), 2.97 (dd, J = 6.3) 18.9 Hz, 1H), 3.32 (d, J = 18.9 Hz, 1H), 3.50 (d, J = 6.0 Hz, 1H), 3.71-3.95 (m, 3H), 4.66 (d, J = 6.0 Hz, 1H), 4.89 (d, J = 7.5 Hz, 1H), 5.10 (dd, J = 1.5, 10.2 Hz, 1H), 5 .22 (dd, J = 1.5, 17.4 Hz, 1H), 5.70 (d, J = 7.5 Hz, 1H), 5.79-5.95 (m, 1H), 6.84 ( d, J = 8.4 z, 1H), 6.93 (d, J = 8.4Hz, 1H).

Compound 21e:
¹ H NMR (300 MHz, CDCl 3): δ 0.07-0.17 (m, 2H), 0.44-0.60 (m, 2H), 0.84-1.02 (m, 1H), 1 .22-1.38 (m, 2H), 1.44-1.82 (m, 3H), 1.90 (dt, J = 5.7, 12.9 Hz, 1H), 2.22-2. 38 (m, 2H), 2.60-2.87 (m, 3H), 2.77 (s, 3H), 3.25 (d, J = 18.0 Hz, 1H), 3.42 (d, J = 5.7 Hz, 1H), 3.74 (d, J = 6.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 1H), 4.88 (d, J = 7.2 Hz) , 1H), 5.79 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H).

(Reference Example 17)
(5R, 6S, 7S, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6-hydroxy-3-methoxy-8-oxa-6,14-ethanomorphinan-7-carboxamide ( 22) Synthesis

According to the method of Reference Example 3, using Compound 17 obtained in Reference Example 15 instead of Compound 2a, the title compound 22 (83%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.07-0.21 (m, 2H), 0.46-0.67 (m, 2H), 0.82-1.13 (m, 2H), 1 41-1.59 (m, 2H), 1.67-1.91 (m, 2H), 2.10 (dd, J = 8.1, 12.6 Hz, 1H), 2.19-2. 38 (m, 2H), 2.43 (dt, J = 3.6, 12.6 Hz, 1H), 2.71 (dd, J = 4.8, 12.0 Hz, 1H), 2.81 (dd , J = 4.8, 12.6 Hz, 1H), 3.22 (d, J = 18.3 Hz, 1H), 3.59 (d, J = 6.9 Hz, 1H), 3.89 (s, 3H), 4.24 (d, J = 2.4 Hz, 1H), 4.53 (d, J = 1.2 Hz, 1H), 5.25 (s, 1H), 6.30 (d, J = 3.6 Hz, 1 ), 6.56 (d, J = 8.1Hz, 1H), 6.73 (d, J = 8.1Hz, 1H), 7.24 (d, J = 3.6Hz, 1H).

(Reference Example 18)
Synthesis of (5R, 6S, 7S, 9R, 13S, 14S) -4,5-epoxy-6-hydroxy-3-methoxy-8-oxa-6,14-ethanonormorphinan-7-carboxamide (23)

According to the method of Reference Example 6, using Compound 22 obtained in Reference Example 17 instead of Compound 4, the title compound 23 (86%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.82-0.97 (m, 1H), 1.59-2.02 (m, 5H), 2.80-3.04 (m, 3H), 3 .15 (d, J = 18.6 Hz, 1H), 3.29 (d, J = 7.2 Hz, 1H), 3.61 (br s, 1H), 3.88 (s, 3H), 4. 37 (d, J = 1.8 Hz, 1H), 4.59 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1 H).

(Example 32)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-methoxy-7-methyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9, Synthesis of 12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (25)

Compound 23 (383 mg, 1.1 mmol) obtained in Reference Example 18 was dissolved in 1,2-dichloroethane (20 mL), paraformaldehyde (320 mg, 11 mmol) and acetic acid (489 μL, 8.5 mmol) were added, and 1 at room temperature was added. Stir for hours. To the reaction solution was added 12M aqueous ammonia under ice-cooling and stirred at room temperature for 30 minutes, and then distilled water was added to the reaction solution and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained white solid crude product was suspended in t-butyl alcohol (10 mL), potassium t-butoxide (1.20 g, 11 mmol) was added, and the mixture was stirred under reflux for 7 hours. The reaction mixture was acidified with 2M aqueous hydrochloric acid under ice cooling, and chloroform and potassium carbonate were added to adjust the aqueous layer to pH = 11. Distilled water was added and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain an equilibrium mixture (218 mg, 55%) as a white amorphous. This equilibrium mixture was used in place of compound 10d and the title compound 25 (23%) was obtained according to the method of Example 4.

¹ H NMR (300 MHz, CDCl 3): δ 1.20-1.39 (m, 2H), 1.46-1.79 (m, 3H), 1.87 (dd, J = 5.7, 12. 9 Hz, 1H), 2.27 (dt, J = 3.3, 12.6 Hz, 1H), 2.41 (s, 3H), 2.51 (dd, J = 4.8, 12.0 Hz, 1H) ), 2.83 (dd, J = 6.3, 18.6 Hz, 1H), 3.28 (d, J = 6.3 Hz, 1H), 3.35 (d, J = 18.6 Hz, 1H) , 3.52 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 4.63 (d, J = 6.0 Hz, 1H), 4.77 (d, J = 7. 2 Hz, 1H), 5.68 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.63 s, 1H).

(Examples 33 and 34)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-methoxy-7-methyl-11- (4-methylbenzyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano -4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (26a) And (1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-methoxy-7-methyl-11- (pyridin-4-ylmethyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a -Etano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalene-10 (11H - Synthesis of on (26b)

According to the method of Example 22, using Compound 25 obtained in Example 32 instead of Compound 19, p-methylbenzyl chloride and 4- (bromomethyl) pyridine · hydrogen bromide instead of (2-bromoethyl) benzene The acid salt was used to give the title compounds 26a (46%) and 26b (13%).

Compound 26a:
¹ H NMR (300 MHz, CDCl 3): δ 1.01-1.12 (m, 1H), 1.24-1.41 (m, 2H), 1.45-1.64 (m, 2H), 1 .90 (dt, J = 5.7, 12.9 Hz, 1H), 2.20-2.34 (m, 1H), 2.28 (s, 3H), 2.42 (s, 3H), 2 .50 (dd, J = 4.8, 12.0 Hz, 1H), 2.74 (dd, J = 6.3, 18.6 Hz, 1H), 3.27 (d, J = 6.3 Hz, 1H) ), 3.33 (d, J = 18.6 Hz, 1H), 3.48 (d, J = 6.0 Hz, 1H), 3.83 (s, 3H), 4.32 (d, J = 14) .4 Hz, 1 H), 4.40 (d, J = 14.7 Hz, 1 H), 4.71 (d, J = 6.0 Hz, 1 H), 4.81 (d, J = 7.2 Hz, 1 H) 5.7 (D, J = 7.2Hz, 1H), 6.83 (d, J = 8.4Hz, 1H), 6.96 (d, J = 8.4Hz, 1H), 7.05. (D, J = 7.8 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H).

Compound 26b:
¹ H NMR (300 MHz, CDCl 3): δ 1.12 (dd, J = 6.3, 14.7 Hz, 1H), 1.33-1.73 (m, 4H), 1.92 (dd, J = 5.7, 12.9 Hz, 1H), 2.22-2.36 (m, 1H), 2.43 (s, 3H), 2.52 (dd, J = 5.1, 12.3 Hz, 1H) ), 2.77 (dd, J = 6.3, 18.6 Hz, 1H), 3.30 (d, J = 6.3 Hz, 1H), 3.36 (d, J = 18.6 Hz, 1H) 3.56 (d, J = 5.7 Hz, 1H), 3.84 (s, 3H), 4.25 (d, J = 15.0 Hz, 1H), 4.44 (d, J = 15. 3 Hz, 1 H), 4.76 (d, J = 6.0 Hz, 1 H), 4.80 (d, J = 7.5 Hz, 1 H), 5.70 (d, J = 7.5 Hz, 1 H), 6). 5 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 5.7 Hz, 2H), 8.51 (d, J = 6.3 Hz, 2H).

(Examples 35 and 36)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-hydroxy-7-methyl-11- (4-methylbenzyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano -4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (27a) Or (1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-hydroxy-7-methyl-11- (pyridin-4-ylmethyl) -5,6,7,8,9a, 11b-hexahydro-8a, 11a -Etano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalene-10 (1 H) - Synthesis of on (27b)

According to the method of Example 2, using Compound 26a obtained in Example 33 and Compound 26b obtained in Example 34 instead of Compound 5, the title compounds 27a (82%) and 27b (48%) were obtained. It was.

Compound 27a:
¹ H NMR (300 MHz, CDCl 3): δ 1.02-1.16 (m, 1H), 1.32 (br d, J = 14.4 Hz, 1H), 1.38-1.71 (m, 3H) ), 1.88 (dt, J = 5.7, 12.9 Hz, 1H), 2.20-2.34 (m, 1H), 2.28 (s, 3H), 2.42 (s, 3H) ), 2.50 (dd, J = 4.5, 12.3 Hz, 1H), 2.75 (dd, J = 6.3, 18.9 Hz, 1H), 3.24-3.36 (m, 2H), 3.44 (d, J = 6.0 Hz, 1H), 4.32 (d, J = 14.7 Hz, 1H), 4.42 (d, J = 14.7 Hz, 1H), 4. 70 (d, J = 5.7 Hz, 1H), 4.88 (d, J = 7.2 Hz, 1H), 5.79 (d, J = 7.2 Hz, 1H), 6.80-6.91 (M, H), 7.05. (D, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H).

Compound 27b:
¹ H NMR (300 MHz, CDCl 3): δ 1.14-1.30 (m, 1H), 1.37 (dd, J = 2.4, 13.5 Hz, 1H), 1.50-1.83 ( m, 3H), 1.92 (dt, J = 5.7, 12.6 Hz, 1H), 2.22-2.35 (m, 1H), 2.43 (s, 3H), 2.48-. 2.57 (m, 1H), 2.79 (dd, J = 6.6, 18.6 Hz, 1H), 3.27-3.39 (m, 2H), 3.54 (d, J = 5 .7 Hz, 1 H), 4.16 (d, J = 15.3 Hz, 1 H), 4.59 (d, J = 15.6 Hz, 1 H), 4.80 (d, J = 6.0 Hz, 1 H) , 4.82 (d, J = 7.8 Hz, 1H), 5.52 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.93 ( d, J = 8 4Hz, 1H), 7.29 (d, J = 6.0Hz, 2H), 8.52 (d, J = 5.4Hz, 2H).

(Reference Examples 19 and 20)
(5R, 6S, 6′R, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-6-methylmorphinane-6′-carboxylic acid Ethyl (29a) and (5R, 6S, 6 ′S, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-6-methylmorphinan Synthesis of ethyl 6'-carboxylate (29b)

Under an argon atmosphere, 60% sodium hydride (40 mg, 1.0 mmol) was suspended in THF (1 mL), cooled to −78 ° C., ethyl chloroacetate (1.07 mL, 1.0 mmol), compound 28 [(5R, 9R, 13S, 14S) -17- (cyclopropylmethyl) -4,5-epoxy-14-hydroxymorphinan-6-one: compound described in Heterocycles 1994, 38,877] (65.1 mg, 0.2 mmol ) In THF (1 mL) was added and stirred at room temperature for 12 hours. The reaction solution was poured into distilled water under ice cooling 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 preparative TLC and the title compounds 29a (47.9 mg, 58%) and 29b (20.8 mg, 25%) as colorless oils.

Compound 29a:
¹ H NMR (300 MHz, CDCl 3): δ 0.06-0.21 (m, 2H), 0.48-0.61 (m, 2H), 0.78-0.96 (m, 1H), 1 .27 (t, J = 7.2 Hz, 3H), 1.41-1.73 (m, 4H), 2.07-2.39 (m, 3H), 2.39 (d, J = 6. 6 Hz, 2H), 2.61-2.74 (m, 2H), 3.09 (d, J = 18.6 Hz, 1H), 3.14 (d, J = 5.7 Hz, 1H), 3. 60 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.70 (s, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.66 ( d, J = 7.5 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H).

Compound 29b:
¹ H NMR (300 MHz, CDCl 3): δ 0.10-0.19 (m, 2H), 0.48-0.61 (m, 2H), 0.78-0.92 (m, 1H), 1 .23-1.77 (m, 4H), 1.38 (t, J = 7.2 Hz, 3H), 1.91 (ddd, J = 6.3, 7.8, 14.1 Hz, 1H), 2.12-2.26 (m, 2H), 2.37 (d, J = 6.6 Hz, 2H), 2.60-2.72 (m, 2H), 3.11 (d, J = 18 .3 Hz, 1 H), 3.15 (d, J = 6.0 Hz, 1 H), 3.34 (s, 1 H), 4.37-4.49 (m, 2 H), 4.71 (s, 1 H) ), 6.62 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H).

(Reference Example 21)
(5R, 6S, 6′R, 9R, 13S, 14S) -N-benzyl-17- (cyclopropylmethyl) -4,5-epoxy-6,6′-epoxy-14-hydroxy-6-methylmorphinan-6 Synthesis of '-carboxamide (30)

According to the method of Reference Example 1, the compound 29a obtained in Reference Example 19 was used instead of Compound 1a to obtain the title compound 30 (66%).

¹ H NMR (300 MHz, CDCl 3): δ 0.08-0.18 (m, 2H), 0.48-0.60 (m, 2H), 0.77-0.92 (m, 1H), 1 .26 (td, J = 3.6, 14.4 Hz, 1H), 1.41-1.66 (m, 3H), 2.11 (dt, J = 3.9, 12.0 Hz, 1H), 2.22-2.42 (m, 4H), 2.57-2.72 (m, 2H), 3.02-3.16 (m, 2H), 3.64 (s, 1H), 4. 38 (dd, J = 5.7, 14.4 Hz, 1H), 4.41 (dd, J = 6.0, 14.4 Hz, 1H), 4.70 (s, 1H), 5.16 (br s, 1H), 6.39 (t, J = 6.0 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 7.08 (t, = 7.8Hz, 1H), 7.14-7.32 (m, 5H).

(Reference Example 22)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-14- (cyclopropylmethyl) -3a, 11-dihydroxy-1,3,3a, 4,5,6,7,11c-octahydro- Synthesis of 2H-6,11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (31)

According to the method of Reference Example 5, the compound 30 obtained in Reference Example 21 was used instead of the compound 2b to give the title compound 31 (46%).

¹ H NMR (300 MHz, CDCl 3): δ 0.00-0.10 (m, 2H), 0.34-0.47 (m, 2H), 0.66-0.81 (m, 2H), 0 .98-1.16 (m, 2H), 1.19-1.29 (m, 1H), 1.47-1.60 (m, 1H), 1.63-1.77 (m, 1H) , 1.83-1.96 (m, 1H), 2.27 (d, J = 6.3 Hz, 2H), 2.86-2.96 (m, 2H), 3.22-3.42 ( m, 3H), 4.21 (d, J = 15.3 Hz, 1H), 4.38 (d, J = 15.3 Hz, 1H), 4.43 (d, J = 5.4 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 7.12-7 .37 (m, 5H).

(Reference Example 23)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-3a, 11-dihydroxy-1,3,3a, 4,5,6,7,11c-octahydro-2H-6,11b- (iminoethano ) -1,5a-epoxynaphtho [1,2-e] indol-2-one (32)

According to the method of Reference Example 6, using Compound 31 obtained in Reference Example 22 instead of Compound 4, the title compound 32 (42%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.72-0.87 (m, 1H), 0.97-1.26 (m, 3H), 1.42-1.58 (m, 2H), 2 .24-2.38 (m, 1H), 2.46-2.57 (m, 1H), 2.79 (d, J = 18.3 Hz, 1H), 3.22 (d, J = 6. 9 Hz, 1H), 3.28-3.47 (m, 2H), 4.14 (d, J = 15.0 Hz, 1H), 4.39 (d, J = 15.0 Hz, 1H), 4. 50 (d, J = 5.7 Hz, 1H), 6.53-6.65 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 7.12-7.37 (m , 5H).

(Reference Example 24)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -3-benzyl-3a, 11-dihydroxy-14-methyl-1,3,3a, 4,5,6,7,11c-octahydro-2H-6 Synthesis of 11b- (iminoethano) -1,5a-epoxynaphtho [1,2-e] indol-2-one (33)

According to the method of Reference Example 7, using Compound 32 obtained in Reference Example 23 instead of Compound 9, the title compound 33 (76%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.68-0.82 (m, 1H), 1.01-1.18 (m, 2H), 1.22-1.33 (m, 1H), 1 .50-1.62 (m, 1H), 1.66-1.78 (m, 1H), 1.86-1.97 (m, 1H), 2.19-2.31 (m, 1H) , 2.21 (s, 3H), 2.83-3.11 (m, 3H), 3.40 (d, J = 5.4 Hz, 1H), 4.13 (d, J = 15.3 Hz, 1H), 4.40 (d, J = 15.3 Hz, 1H), 4.43 (d, J = 5.7 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6. 60 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 7.16-7.37 (m, 5H).

(Example 37)
(4bR, 8R, 8aS, 9aS, 11aS, 11bR) -11-benzyl-7-methyl-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4,8-methano-9, Synthesis of 12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (34)

According to the method of Example 5, using Compound 33 obtained in Reference Example 24 instead of Compound 10d, the title compound 34 (quantitative) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 1.02-1.13 (m, 1H), 1.20-1.40 (m, 2H), 1.48-1.66 (m, 2H), 1 .91 (dt, J = 5.7, 12.9 Hz, 1H), 2.26 (dt, J = 5.7, 12.3 Hz, 1H), 2.44 (s, 3H), 2.52 ( dd, J = 4.8, 12.3 Hz, 1H), 2.82 (dd, J = 6.3, 18.9 Hz, 1H), 3.31 (d, J = 6.0 Hz, 1H), 3 .40 (d, J = 18.9 Hz, 1H), 3.48 (d, J = 6.0 Hz, 1H), 4.37 (d, J = 14.4 Hz, 1H), 4.40 (d, J = 14.7 Hz, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 5.71 (d, J = 7.2 Hz) , 1 ), 6.84 (dd, J = 0.9, 7.8 Hz, 1H), 7.03 (dd, J = 0.9, 7.8 Hz, 1H), 7.16-7.30 (m, 4H), 7.35-7.43 (m, 2H).

(Reference Example 25)
(5R, 6R, 7S, 9R, 13S, 14R) -N-benzyl-17- (cyclopropylmethyl) -4,5-epoxy-6-hydroxy-3-methoxy-6, 14-ethenomorphinan-7-carboxamide ( 36) Synthesis

Compound 35 [5R, 6R, 7S, 9R, 13S, 14R) -N-benzyl-17- (cyclopropylmethyl) -4,5-epoxy-3,6-dimethoxy-6, 14-ethenomorphinan- under argon atmosphere 7-Carboxamide: Bioorg. Med. Chem. 2004, 12, 4133] (402 mg, 0.83 mmol) was dissolved in DMF (10 mL), and potassium carbonate (276 mg, 2.0 mmol) and methyl iodide (61.9 μL, 1.0 mmol) were added. The mixture was stirred for 24 hours at room temperature in the dark. Thereafter, methyl iodide (20.6 μL, 0.33 mmol) was added and stirred for 6 hours. The reaction solution was poured into distilled water, extracted three times with ethyl acetate, the organic layers were combined, washed twice with distilled water, 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 36 (379 mg, 92%) as a white amorphous.

¹ H NMR (300 MHz, CDCl 3): δ 0.06-0.21 (m, 2H), 0.43-0.57 (m, 2H), 0.76-0.90 (m, 1H), 1 .65 (dd, J = 6.0, 12.9 Hz, 1H), 1.83 (dd, J = 2.4, 13.2 Hz, 1H), 2.00 (dt, J = 5.7, 12 .6 Hz, 1H), 2.27-2.48 (m, 4H), 2.57 (dd, J = 6.0, 9.6 Hz, 1H), 2.71 (dd, J = 4.8, 12.0 Hz, 1H), 3.03-3.17 (m, 2H), 3.56 (d, J = 6.6 Hz, 1H), 3.69-3.88 (m, 1H), 3. 81 (s, 3H), 4.33 (d, J = 1.2 Hz, 1H), 4.43 (d, J = 5.7 Hz, 1H), 5.47 (d, J = 8.7 Hz, 1H) ), 5.76 d, J = 8.7 Hz, 1H), 6.46-6.56 (m, 2H), 6.62 (d, J = 8.1 Hz, 1H), 7.19-7.35 (m, 5H) ).

(Reference Example 26)
Synthesis of N-benzyl-17- (cyclopropylmethyl) -4,5α-epoxy-6β-hydroxy-3-methoxy-6α, 14α-ethanomorphin-7α-carboxamide (37)

Compound 36 (99.7 mg, 0.20 mmol) obtained in Reference Example 25 was dissolved in methanol (15 mL) in bomben roll, 10% palladium-activated carbon (21.3 mg, 0.020 mmol) was added, and a hydrogen atmosphere ( The mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was filtered through celite and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 37 (89.6 mg, 90%) as a colorless oil.

¹ H NMR (300 MHz, CDCl 3): δ 0.05-0.14 (m, 2H), 0.42-0.53 (m, 2H), 0.59-0.86 (m, 2H), 1 .22-1.37 (m, 2H), 1.63-1.74 (m, 1H), 2.01-2.40 (m, 6H), 2.46-2.69 (m, 3H) , 2.87 (ddd, J = 3.9, 11.4, 13.5 Hz, 1H), 3.00 (d, J = 18.3 Hz, 1H), 3.11 (d, J = 6.3 Hz) , 1H), 3.88 (s, 3H), 4.25 (d, J = 2.1 Hz, 1H), 4.49 (d, J = 5.7 Hz, 2H), 6.53 (br t, J = 5.7 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 7.21-7.34 (m, 5H) ).

(Reference Example 27)
(1S, 3aS, 5aS, 6R, 11bS, 11cS) -3-benzyl-14- (cyclopropylmethyl) -3a, 11-dihydroxy-10-methoxy-1,3,3a, 4,5,6,7, Synthesis of 11c-octahydro-2H-6,11b- (iminoethano) -1,5a-methanonaphtho [1,2-e] indol-2-one (38)

According to the method of Reference Example 4, using Compound 37 obtained in Reference Example 26 instead of Compound 2a, the title compound 38 (77%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.02-0.18 (m, 2H), 0.37-0.56 (m, 2H), 0.71-1.07 (m, 3H), 1 20-1.64 (m, 4H), 1.73 (dt, J = 4.8, 12.6 Hz, 1H), 1.88-2.03 (m, 1H), 2.18-2. 39 (m, 2H), 2.50-2.67 (m, 1H), 2.92 (d, J = 2.7 Hz, 2H), 3.08-3.23 (m, 2H), 3. 27-3.44 (m, 2H), 3.82 (s, 3H), 4.36 (d, J = 15.0 Hz, 1H), 4.51 (d, J = 15.0 Hz, 1H), 6.66 (s, 2H), 7.13-7.29 (m, 3H), 7.39 (d, J = 6.9 Hz, 2H).

(Example 38)
(4bS, 8R, 8aS, 9aS, 11aS, 11bS) -11-benzyl-7- (cyclopentylmethyl) -1-methoxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano-4 Of 1,8-methano-12,14-dioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (39)

According to the method of Example 4, using Compound 38 obtained in Reference Example 27 instead of Compound 10d, the title compound 39 (60%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.04-0.17 (m, 2H), 0.39-0.54 (m, 2H), 0.72-0.89 (m, 1H), 0 .91-1.59 (m, 6H), 1.73 (dt, J = 5.7, 12.9 Hz, 1H), 2.13 (dt, J = 3.6, 12.3 Hz, 1H), 2.23-2.41 (m, 2H), 2.59 (dd, J = 5.1, 12.0 Hz, 1H), 2.78 (dd, J = 6.0, 18.6 Hz, 1H) , 3.07 (d, J = 18.6 Hz, 1H), 3.06-3.23 (m, 2H), 3.34-3.49 (m, 1H), 3.52 (d, J = 7.5 Hz, 1 H), 3.81 (s, 3 H), 4.29 (d, J = 15.0 Hz, 1 H), 4.51 (d, J = 15.0 Hz, 1 H), 4.76 ( d, J = .9 Hz, 1H), 5.69 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H) , 7.12-7.30 (m, 3H), 7.37 (d, J = 6.9 Hz, 2H).

(Example 39)
(4bS, 8R, 8aS, 9aS, 11aS, 11bS) -11-benzyl-7- (cyclopropylmethyl) -1-hydroxy-5,6,7,8,9a, 11b-hexahydro-8a, 11a-ethano- Synthesis of 4,8-methano-12,14-dioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalen-10 (11H) -one (40)

According to the method of Example 2, using Compound 39 obtained in Example 38 instead of Compound 5, the title compound 40 (34%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 0.03-0.13 (m, 2H), 0.40-0.53 (m, 2H), 0.71-0.88 (m, 1H), 0 .95-1.19 (m, 3H), 1.42-1.65 (m, 3H), 1.72 (dt, J = 5.4, 12.9 Hz, 1H), 2.11 (dt, J = 3.6, 12.3 Hz, 1H), 2.32-2.40 (m, 2H), 2.58 (dd, J = 5.1, 12.0 Hz, 1H), 2.72-2 .84 (m, 1H), 3.04 (d, J = 18.3 Hz, 1H), 3.11-3.26 (m, 2H), 3.34-3.49 (m, 2H), 4 .32 (d, J = 15.0 Hz, 1H), 4.49 (d, J = 15.0 Hz, 1H), 4.81 (d, J = 7.2 Hz, 1H), 5.72 (d, J = 6.9H , 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 7.14-7.31 (m, 3H), 7.37 (D, J = 7.2 Hz, 2H).

(Examples 40 and 41)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-methoxy-7- (cyclopropylmethyl) -11- (4-trifluoromethoxybenzyl) -5,6,7,8,9a, 11b-hexahydro -8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalene-10 (11H ) -One (41a) and (1S, 3aS, 5aS, 6R, 11bR, 11cR) -11- (4-chlorobenzyl) -1-methoxy-7- (cyclopropylmethyl) -5,6,7,8, 9a, 11b-Hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta 1,2,3-gh] pentalene -10 (11H) - Synthesis of on (41b)

According to the method of Example 22, p-trifluoromethoxybenzyl bromide and p-chlorobenzyl chloride were used in place of (2-bromoethyl) benzene to obtain 41a (52%) and 41b (71%).

Compound 41a:
¹ H NMR (300 MHz, CDCl 3): δ 0.04-0.16 (m, 2H), 0.41-0.60 (m, 2H), 0.86-1.02 (m, 1H), 1 .10 (dt, J = 6.3, 14.4 Hz, 1H), 1.23-1.72 (m, 4H), 1.92 (dt, J = 5.7, 12.9 Hz, 1H), 2.17-2.34 (m, 2H), 2.60-2.83 (m, 3H), 3.25 (d, J = 18.6 Hz, 1H), 3.52 (d, J = 6 .0 Hz, 1H), 3.75 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 4.33 (d, J = 14.7 Hz, 1H), 4.40 (d , J = 14.7 Hz, 1H), 4.75 (d, J = 6.3 Hz, 1H), 4.82 (d, J = 7.5 Hz, 1H), 5.74 (d, J = 7. 2Hz, 1H) 6.84 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 7.06-7.16 (m, 2H), 7.39-7.50 (M, 2H).

Compound 41b:
¹ H NMR (300 MHz, CDCl 3): δ 0.03-0.18 (m, 2H), 0.41-0.62 (m, 2H), 0.83-1.02 (m, 1H), 1 .07 (dd, J = 6.6, 14.4 Hz, 1H), 1.22-1.70 (m, 4H), 1.91 (dt, J = 5.4, 12.9 Hz, 1H), 2.16-2.37 (m, 2H), 2.60-2.83 (m, 3H), 3.25 (d, J = 18.6 Hz, 1H), 3.50 (d, J = 6) .0Hz, 1H), 3.74 (d, J = 6.3 Hz, 1H), 3.84 (s, 3H), 4.34 (s, 2H), 4.74 (d, J = 6.0 Hz) , 1H), 4.81 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6 .95 (d, J = .4Hz, 1H), 7.18-7.26 (m, 2H), 7.30-7.38 (m, 2H).

(Examples 42 and 43)
(1S, 3aS, 5aS, 6R, 11bR, 11cR) -1-hydroxy-7- (cyclopropylmethyl) -11- (4-trifluoromethoxybenzyl) -5,6,7,8,9a, 11b-hexahydro -8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cycloocta [1,2,3-gh] pentalene-10 (11H ) -One (42a) and (1S, 3aS, 5aS, 6R, 11bR, 11cR) -11- (4-chlorobenzyl) -1-hydroxy-7- (cyclopropylmethyl) -5,6,7,8, 9a, 11b-Hexahydro-8a, 11a-ethano-4,8-methano-9,12,14-trioxa-7,11-diazabenzo [a] benzo [4,5] cyclo Data [1,2,3-gh] pentalene -10 (11H) - one Synthesis of (42b)

According to the method of Example 2, instead of Compound 5, using Compound 41a obtained in Example 40 and Compound 41b obtained in Example 41, the title compounds 42a (73%) and 42b (78%) were obtained. It was.

Compound 42a:
¹ H NMR (300 MHz, CDCl 3): δ 0.03-0.16 (m, 2H), 0.40-0.60 (m, 2H), 0.84-1.00 (m, 1H), 1 .06.-1.37 (m, 2H), 1.4-1.78 (m, 3H), 1.90 (dt, J = 5.4, 12.9 Hz, 1H), 2.16-2. 35 (m, 2H), 2.54-2.84 (m, 3H), 3.22 (d, J = 18.0 Hz, 1H), 3.48 (d, J = 5.7 Hz, 1H), 3.74 (d, J = 5.7 Hz, 1H), 4.34 (d, J = 14.7 Hz, 1H), 4.42 (d, J = 14.7 Hz, 1H), 4.75 (d , J = 6.0 Hz, 1H), 4.88 (d, J = 7.5 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 6.81-6.92 (m, 2H), 7.1 (D, J = 8.1Hz, 2H), 7.48 (d, J = 8.7Hz, 2H).

Compound 42b:
¹ H NMR (300 MHz, CDCl 3): δ 0.05-0.17 (m, 2H), 0.42-0.59 (m, 2H), 0.83-1.02 (m, 1H), 1 .04-1.18 (m, 1H), 1.22-1.76 (m, 4H), 1.90 (dt, J = 5.4, 12.9 Hz, 1H), 2.18-2. 38 (m, 2H), 2.59-2.85 (m, 3H), 3.23 (d, J = 18.3 Hz, 1H), 3.46 (d, J = 6.0 Hz, 1H), 3.75 (d, J = 5.7 Hz, 1H), 4.28-4.43 (m, 2H), 4.74 (d, J = 6.0 Hz, 1H), 4.86 (d, J = 7.2 Hz, 1H), 5.76 (d, J = 7.2 Hz, 1H), 6.82-6.91 (m, 2H), 7.18-7.26 (m, 2H), 7 .30-7.37 (m 2H).

(Example 44)
(1) Opioid receptor binding test
The binding affinity of the compounds of the present invention for μ, δ and κ opioid receptors was examined.
Method: Mouse cerebrum and guinea pig cerebellar membrane fraction were prepared according to the previous report (J. Biol. Chem. 2001 276: 15409-15414.). [ ³ H] DAMGO (μ opioid receptor), [ ³ H] DPDPE (δ opioid receptor), [ ³ H] U69,593 (κ opioid receptor) were used as radioligands for each opioid receptor. The murine cerebral membrane fraction was used for the assay of μ and δ receptors, and the guinea pig cerebellar membrane fraction was used for the assay of κ receptor. For non-specific binding, μ: DAMGO, δ: DPDPE, and κ: U69,593 were each used at 1 μM. Each receptor membrane fraction is reacted with the radioligand and various concentrations of the sample for a predetermined time. After the B / F separation, the amount of radioactivity remaining on the filter is measured with a liquid scintillation counter, and the binding inhibition rate of the test compound ( IC ₅₀ value) was calculated. The Ki value was calculated from the obtained IC ₅₀ value using the following formula.
Ki = IC ₅₀ / (1 + L / Kd)
L: Concentration of radioligand used Kd: Kd value of radioligand

Further, the δ-receptor selectivity in the opioid receptor was determined by calculating the ratio (μ / δ or κ / δ) between the Ki value for μ or κ and the Ki value for δ.

DAMGO:
[D-Ala ² , N-MePhe ⁴ , Gly-Ol] enkephalin
DPDPE:
[D-Pen ² , D-Pen ⁵ ] enkephalin

1) Camphor sulfonate was used.

As shown in Table 1, the compounds of the present invention showed specific affinity for the opioid δ receptor.
(2) Opioid δ receptor function test
The functional activity of the compound of the present invention against the δ opioid receptor was examined.
Method: Lance Ultra cAMP kit (Perkin Elmer) was used and carried out according to a predetermined method. Human δ receptor-expressing CHO cells and specimens were incubated in the presence of 10 μM forskolin in assay buffer (1 × HBSS, 1M HEPES, pH 7.4, 250 mM IBMX (Isobutymethylxanthine), 7.5% BSA) for 30 minutes. The cAMP detection reagent in the kit was added, and after 1 hour, time-resolved fluorescence measurement was performed with an EnVision plate reader (Perkin Elmer). A dose response curve of the specimen 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 specimen when the maximum response of the control drug DPDPE was 100%.

1) Camphor sulfonate was used.

As shown in Table 2, it was confirmed that the compound of the present invention has a strong agonist activity for the opioid δ receptor.


(3) Analgesic action (acetic acid rising method)

ICR male mice were used as 8 mice per group. 20 minutes after subcutaneous administration of the test substance, a 0.6% acetic acid aqueous solution (0.1 mL / 10 g body weight) was intraperitoneally administered, and the number of rising that developed within 20 minutes from 5 minutes later was counted.
In this experiment, the camphor sulfonate salt of the compound (12e) described in Example 16 exhibited a significant rising number-reducing action when subcutaneously administered at 10 mg / kg, and was confirmed to have analgesic activity.

Claims (10)

The following general formula (I),

(In the formula, ^{R 1} is _{hydrogen, C 1-6} alkyl, 1-3 _{C 1-6} alkyl substituted with _{halogen, C 2-6} alkenyl, the number of carbon atoms of the cycloalkyl alkyl (cycloalkyl moiety is 3 -6, the alkylene moiety has 1 to 3 carbon atoms), or aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 3 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 3 carbon atoms), heteroarylalkyl (heteroaryl is selected from 1 to 4 carbon atoms selected from N, O and S) A hetero atom is included as a ring-constituting atom, the alkylene moiety has 1 to 3 carbon atoms, and a cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 3 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 1-3), or cycloalkenylalkenyl (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms),
R ³ and R ⁴ together form —O— (CHR ⁶ ) _m —O— or —O— (CHR ⁶ ) _m —NR ⁷ —.
Here, R ⁶ represents hydrogen or C _1-3 alkyl, R ⁷ represents hydrogen, C _1-6 alkyl, or C _1-6 alkanoyl, and m represents 1, 2 or 3.
R ⁵ represents hydrogen, hydroxy, C _1-6 alkoxy or C _1-6 alkanoyloxy,
X represents O or CH _2,
A represents CH ₂ or C═O,
B represents C = O or a bond.
However, when A is C = O, B is a bond.
Also, the aryl part of R ¹ aralkyl, the aryl part of R ² , heteroaryl, the aryl part of aralkyl, the heteroaryl part of heteroarylalkyl, the aryl part of arylalkenyl and the heteroaryl part of heteroarylalkenyl are C _1-6. Alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the alkoxy moiety has 1 to 6 carbon atoms), halogen, nitro, cyano, C substituted with 1 to 3 halogens _1-6 alkyl, 1-3 halogen substituted _{C 1-6} alkoxy, phenyl, phenoxy, phenylalkyl (number of carbon atoms in the alkyl is 1 to 3.), selected from methylenedioxy and ^NR 8 ^{R 9} Optionally substituted with at least one substituent, wherein R ⁸ and R ⁹ 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 in the alkoxy moiety is 1-6) Or a R ⁴ and R ⁹ together with the N atom to which they are attached may further contain a heteroatom selected from N, O, S May form,
C _1-6 alkyl of R ² is C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the number of carbon atoms of the alkoxy moiety is 1). To 6)) and may be substituted with at least one substituent selected from halogen. )
Or a pharmacologically acceptable acid addition salt thereof.   The morphinan derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein A is C = O and B is a bond. 3. The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1 or 2, wherein X is O. The morphinan derivative or the pharmaceutically acceptable acid thereof according to any one of claims 1 to ^3, wherein R ³ and R ⁴ are combined to form -O- (CHR ⁶ ) _m -O-. Addition salt. The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 4, wherein R ⁶ is hydrogen. Morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to any one of claims 1 to 5 R ⁵ is hydrogen or hydroxy.   A medicament comprising the morphinan derivative according to any one of claims 1 to 6 or a pharmacologically acceptable acid addition salt thereof.   The pharmaceutical composition which contains the morphinan derivative of any one of Claims 1-6, or its pharmacologically acceptable acid addition salt as an active ingredient.   An analgesic comprising the morphinan derivative according to any one of claims 1 to 6 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 6 or a pharmacologically acceptable acid addition salt thereof.