JP2009051749A - 6,14-epoxymorphinan derivative and pharmaceutical use thereof - Google Patents

Abstract

【効果】本発明の新規化合物及びその薬理学的に許容される酸付加塩は、高いオピオイドκ受容体への選択的結合性を有し、オピオイドκ受容体に関連する様々な疾患、症状、特に疼痛の治療または予防に有用である。
【選択図】なし[PROBLEMS] To provide a novel pharmaceutical useful for the prevention or treatment of various diseases and symptoms related to opioid κ receptor, particularly pain.
The present invention provides a 6,14-epoxymorphinan derivative represented by the following or a pharmacologically acceptable acid addition salt thereof, and a medicament containing the compound as an active ingredient.

[Effect] The novel compound of the present invention and a pharmacologically acceptable acid addition salt thereof have a high selective binding property to opioid κ receptor, and various diseases, symptoms, It is particularly useful for the treatment or prevention of pain.
[Selection figure] None

Description

  The present invention relates to novel 6,14-epoxymorphinan derivatives and their use as medicaments.

  Three types of opioid receptors (μ, δ, and κ) have been identified as membrane proteins to which morphine and the like, which have been used as analgesics since ancient times, bind. It has been reported that opioid receptors are involved in various pharmacological actions including analgesic action, and ligands (agonists and antagonists) of the receptors can be used as therapeutic agents for various diseases and symptoms. In addition, if a ligand that selectively binds to each type of opioid receptor is used, side effects caused by other types of receptors may be reduced, and a more useful drug can be obtained. Among these, opioid κ receptor ligands are expected as drugs without side effects (for example, drug dependence, respiratory depression, etc.) possessed by μ receptor agonists such as morphine.

By the way, the following compounds are known as 6,14-epoxymorphinan compounds in which the 6th and 14th positions of the morphinan skeleton are bridged by oxygen atoms.
(1) 6,14-epoxymorphinan compound disclosed as a synthetic intermediate (Patent Document 1).

 (2) 6,14-epoxymorphinan compounds disclosed as opioid ligands (Non-patent Documents 1 and 2).

 (3) 6,14-epoxymorphinan compound 1 disclosed together with opioid binding properties and analgesic activity, and compound 2 shown as a future synthesis plan (Non-patent Document 3).

  However, Patent Document 1 and Non-Patent Documents 1 and 2 do not disclose a compound having a side chain at the 6-position as in the present compound. Non-patent document 3 suggests that the novel compound of the present application has opioid κ receptor selective binding compared to the compound disclosed therein and can be a more useful drug. Not in.

International Publication WO02 / 080918 Portoghese P.S.et.al., J.Org.Chem., 55, 2957-2959, 1990. Nelson W.L.et.al., J. Heterocyclic Chem., 31, 1509-1511, 1994. Toru Nemoto, Kitasato University Graduate School, Master's Thesis, 2006.

  The present invention relates to a 6,14-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof useful for the prevention or treatment of various diseases and symptoms related to opioid κ receptor, and the compound as an active ingredient It aims at providing the medicine contained as.

  As a result of intensive studies to achieve the above object, a compound having a specific substituent at a specific position of the 6,14-epoxymorphinan structure is unexpectedly compared with the known compound described in Non-Patent Document 3. The present invention was completed by finding that it has high selective binding to opioid κ receptors.

  That is, the present invention relates to the general formula (I)

[Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 4 to 9 carbon atoms, cycloalkenyl alkyl having 6 to 9 carbon atoms, aryl having 6 to 12 carbon atoms, or 7 to 13 carbon atoms. Aralkyl, alkenyl having 3 to 7 carbon atoms, furanyl, furanylalkyl (the alkyl part has 1 to 5 carbon atoms), thienyl, thienylalkyl (the alkyl part having 1 to 5 carbon atoms), pyridyl, or pyridylalkyl ( The alkyl part represents 1 to 5 carbon atoms;
R ² and R ³ are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons. Representation;
R ⁴ represents hydrogen or alkyl having 1 to 5 carbons;
X represents —C (═O) — or —SO ₂ —;
R ⁵ is aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, furanyl, furanyl alkyl (the alkyl part has 1 to 5 carbon atoms), furanyl alkenyl (the alkenyl part has 1 to 5 carbon atoms) ), Thienyl, thienylalkyl (the alkyl part has 1 to 5 carbon atoms), thienylalkenyl (the alkenyl part has 1 to 5 carbon atoms), pyridyl, pyridylalkyl (the alkyl part has 1 to 5 carbon atoms), pyridylalkenyl (The alkenyl moiety has 1 to 5 carbon atoms), camphor, —NR ⁶ ₂ (wherein R ⁶ represents hydrogen or alkyl having 1 to 5 carbon atoms, and each R ⁶ may be the same or different). Representation;
The aryl moiety, heteroaryl moiety, and cycloalkyl moiety included in the substituents shown above are fluoro, chloro, bromo, nitro, hydroxy, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, and carbon numbers Optionally substituted with one or more substituents R ⁷ selected from the group consisting of 1 to 5 thioalkoxy and alkanoyloxy having 1 to 5 carbons;
Provided that when R ¹ is cyclopropylmethyl, R ³ and R ⁴ are hydrogen, X is —C (═O) —, and R ⁵ is phenyl or benzyl, the phenyl or benzyl group is one or more substituents R ⁷ Must be replaced with Or a pharmacologically acceptable acid addition salt thereof. The present invention also provides a medicament, particularly an analgesic, containing the 6,14-epoxymorphinan derivative of the present invention or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

  The present invention provides novel compounds. The novel compounds of the present invention and pharmacologically acceptable acid addition salts thereof are useful for the treatment or prevention of various diseases and conditions related to opioid κ receptors, particularly pain.

  As described above, the present invention provides a 6,14-epoxymorphinan derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, and a medicament containing the compound as an active ingredient. provide. General formula (I) includes (+) isomer, (−) isomer and (±) isomer. In the general formula (I), the alkyl moiety contained in each of the following substituents includes straight and branched chains.

Among the compounds represented by the general formula (I), R ³ is preferably hydrogen.

R ¹ is preferably alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 4 to 9 carbon atoms, or aralkyl having 7 to 13 carbon atoms, and particularly preferably isobutyl, cyclopropylmethyl, or benzyl.

R ² is preferably hydrogen, hydroxy, or alkoxy having 1 to 5 carbon atoms, and among them, hydroxy is preferable.

R ⁴ is preferably hydrogen or methyl, and particularly preferably hydrogen.

R ⁵ includes aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, furanylalkyl (the carbon number of the alkyl part is 1 to 5), furanylalkenyl (the carbon number of the alkenyl part is 1 to 5) , Camphor, or —NR ⁶ ₂ (both R ⁶ are both alkyl having 1 to 5 carbon atoms, and preferably both are methyl), among which phenyl, hydroxyphenyl, benzyl, phenethyl, camphor, or dimethylamino are preferable. .

The aryl moiety, heteroaryl moiety, and cycloalkyl moiety included in the substituents shown above are fluoro, chloro, bromo, nitro, hydroxy, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, and carbon numbers It may be substituted with one or more substituents R ⁷ selected from the group consisting of 1 to 5 thioalkoxy and alkanoyloxy having 1 to 5 carbon atoms.

However, in the general formula (I), when R ¹ is cyclopropylmethyl, R ³ and R ⁴ are hydrogen, X is —C (═O) —, and R ⁵ is phenyl or benzyl, the phenyl or benzyl group is Must be substituted with one or more substituents R ⁷ .

  Pharmacologically preferred acid addition salts include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates and other inorganic acid salts, acetates, lactates, citrates, Organic carboxylates such as oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, methanesulfonate, ethanesulfonate Organic sulfonates such as benzene sulfonate, p-toluene sulfonate, camphor sulfonate, etc., among which hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonic acid A salt, p-toluenesulfonate, camphor-sulfonate and the like are preferably used, but are not limited thereto.

  Specific examples of the compound represented by formula (I) according to the present invention are shown in Table 1.

Of the compounds of the general formula (I), R ¹ is benzyl, R ² is hydroxy, R ³ and R ⁴ are hydrogen, X is —C (═O) —, and R ⁵ is 4-hydroxyphenyl Compound

Named N-[(17-benzyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -4-hydroxybenzamide.

  The 6,14-epoxymorphinan derivative represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof can be specifically produced by the method of Scheme 1. “Ms” represents a mesyl group.

That is, according to the following steps:
(a) Hydroxymethyl compound (II) obtained by the method described in Nagase H. et.al., Tetrahedron Lett., 2007, 48 (14), 2547-2553. [However, R ¹ , R ² , R ³ is the same as defined above in formula (I).
(b) Azide the compound represented by the general formula (III) [wherein R ¹ , R ² , R ³ are the same as defined in the general formula (I) above].
(c) A compound represented by general formula (IV) [wherein R ¹ , R ² and R ³ are the same as defined in general formula (I) above] is reduced.
(d) a compound represented by the general formula (V) [wherein R ¹ , R ² , R ³ are the same as defined in the general formula (I) above], a compound represented by the general formula (VI) [ However, R ⁵ and X are the same as defined in the general formula (I), and Y is a leaving group such as halogen, hydroxy, and acyloxy] to form an amide or sulfonamid.
(e) a compound represented by the general formula (Ia) [wherein R ¹ , R ² , R ³ , R ⁵ , X are the same as defined in the general formula (I)]; The alkyl halide is represented by reacting [wherein R ⁴ is the same as defined in the general formula (I) and Z is a halogen] to be alkylated.

  Specifically, each step can be performed by the following method.

  The mesylation step (a) can be performed by reacting the hydroxymethyl compound (II) with methanesulfonyl halide in the presence of a base. The methanesulfonyl halide is preferably used in an amount of 1 to 10 equivalents, particularly preferably 1 to 5 equivalents, based on the hydroxymethyl compound (II). When the produced mesyl form (III) is unstable, good results may be obtained by carrying out azidation in the next step without purification. As the base to be used, an organic base such as pyridine, dimethylaminopyridine, triethylamine, N, N-diisopropylethylamine is preferably used, and pyridine is particularly preferable. As the reaction solvent, a base that is liquid at room temperature such as pyridine is used as a solvent, or a halogen solvent such as dichloromethane or chloroform, or a hydrocarbon solvent such as benzene or toluene is preferably used, but pyridine is also used as a base / solvent. The method is preferably used. The reaction temperature can be -78 ° C to 50 ° C, more preferably -30 ° C to 30 ° C. The reaction time can be 0.5 to 30 hours, and more preferably 1 to 10 hours. Although the substrate concentration is not particularly limited, it can be usually carried out at 1 mmol / L to 1 mol / L.

  The azidation step (b) can be performed by reacting the mesyl body (III) with a metal azide in a solvent. As the metal azide, sodium azide, potassium azide and the like are preferably used, and sodium azide is particularly preferable. The metal azide is preferably used in an amount of 1 to 30 equivalents, more preferably 1 to 20 equivalents, relative to the mesyl body (III). As the reaction solvent, aprotic polar solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), ether solvents such as tetrahydrofuran (THF) and dioxane, and halogen solvents such as dichloromethane, chloroform and dichloroethane are preferably used. However, aprotic polar solvents, especially DMSO, are preferably used. The reaction temperature can be 0 to 200 ° C, and more preferably 50 to 150 ° C. The reaction time can be 0.5 to 30 hours, and more preferably 1 to 10 hours. Although the substrate concentration is not particularly limited, it can be usually carried out at 1 mmol / L to 1 mol / L.

  The reduction step (c) can be performed on the azide (IV) under hydrogenation conditions in the presence of a metal catalyst and optionally an acid. The type of metal catalyst to be used is not particularly limited. For example, palladium hydroxide, platinum oxide, and palladium / carbon are preferably used, and palladium / carbon provides a sufficiently satisfactory result. The catalyst is used in an amount of 1 to 50 w%, particularly preferably 5 to 30 w%. When the acid is allowed to coexist, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids such as acetic acid and tartaric acid, and organic sulfonic acids such as methanesulfonic acid and camphorsulfonic acid can be used. Particularly favorable results are obtained with camphorsulfonic acid. The acid is used in an amount of 1 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the azide (IV). As the reaction solvent, alcohol solvents such as methanol, ethanol and propanol, and hydrocarbon solvents such as benzene and toluene are preferably used. Alcohol solvents, particularly methanol, are preferably used. The reaction temperature, reaction time, and substrate concentration are appropriately selected and are not particularly limited, but the reaction is usually carried out at 0-100 ° C, more preferably 10-50 ° C, for 0.1-24 hours, preferably 0.5-15 hours. The target compound can be obtained in good yield at a concentration of 1 mmol / L to 1 mol / L.

  The amidation or sulfonamidation step of (d) is carried out in the presence of a base or a condensing agent in the presence of a base or a condensing agent, and a carboxylic acid, carboxylic acid halide, carboxylic acid anhydride, sulfonic acid halide, etc. Can be performed. The amidation or sulfonamidation agent can be used in an amount of 0.5 to 50 equivalents relative to the amino form (V), preferably 1 to 20 equivalents, and 1 to 10 equivalents in particular gives good results. It is done. Solvents include aprotic polar solvents such as DMF, dimethylacetamide, DMSO, ether solvents such as diethyl ether, THF, DME, dioxane, hydrocarbon solvents such as benzene, toluene, xylene, dichloromethane, chloroform, 1, Halogen solvents such as 2-dichloroethane, alcohol solvents such as methanol, ethanol, propanol and butanol, and acidic solvents such as acetic acid and propionic acid can be used, among which DMF, toluene and acetic acid are preferably used. As the base to coexist as necessary, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine can be used. Triethylamine, pyridine, potassium carbonate and sodium carbonate are preferably used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to the substrate. The reaction temperature can usually be in the range of -20 to 200 ° C, and satisfactory results are preferably obtained in the range of 0 to 150 ° C. The reaction time is appropriately selected according to conditions such as the reaction temperature, but satisfactory results are usually obtained in about 30 minutes to 30 hours. The concentration of the substrate in the reaction system is not particularly limited, but usually about 1 mmol / L to 1 mol / L is preferable.

  The alkylation step (e) can be performed by reacting the secondary amide or sulfonamide (Ia) with an alkyl halide in the presence of a base. Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, metal hydrides such as sodium hydride and potassium hydride, metal alkoxides such as sodium ethoxide and potassium t-butoxide, triethylamine, Organic bases such as diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to the substrate. Solvents include aprotic polar solvents such as DMF, dimethylacetamide, DMSO, ether solvents such as diethyl ether, THF, DME, dioxane, hydrocarbon solvents such as benzene, toluene, dichloromethane, chloroform, 1,2- A halogen-based solvent such as dichloroethane can be used, among which DMF and THF are preferably used. Satisfactory results are obtained when the reaction temperature is usually from -20 to 200 ° C, preferably from -10 to 150 ° C. The reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 30 minutes to 100 hours. The concentration of the substrate in the reaction system is not particularly limited, but usually 1 mmol / L to 1 mol / L is preferable.

  Treatment of diseases related to opioid κ receptors by selective binding of 6,14-epoxymorphinan derivatives represented by general formula (I) or pharmaceutically acceptable acid addition salts thereof to opioid κ receptors It is useful as a prophylactic agent, for example, by a receptor binding assay using guinea pig brain homogenate described in the examples, and that the compound has an analgesic effect by an acetic acid rising test described in the examples. Can be confirmed.

  When the medicament according to the present invention is used clinically, the drug may be a free base or a salt thereof itself, and an excipient, a stabilizer, a preservative, a buffer, a solubilizer, an emulsifier, a diluent, Additives such as tonicity agents may be appropriately mixed. Moreover, the said chemical | medical agent can be manufactured by a normal method, using these pharmaceutical carriers suitably. The dosage form includes oral preparations such as tablets, capsules, granules, powders, and syrups, parenteral preparations such as injections, suppositories, and liquids, or topical administration such as ointments, creams, and patches. Can be mentioned.

  The medicament according to the present invention desirably contains 0.00001 to 90% by weight, more preferably 0.0001 to 70% by weight of the above active ingredient. The amount used is appropriately selected according to symptoms, age, body weight, administration method, etc., and is not particularly limited, but the daily active ingredient amount for adults is 0.1 μg to 1 g for injections and 1 μg for oral agents. -10 g, each can be administered once or in several divided doses.

  The medicament according to the present invention can be used for prevention or treatment of various diseases or symptoms related to opioid κ receptors. Here, the “disease or symptom related to opioid κ receptor” refers to a disease or symptom in which binding of a ligand to the opioid κ receptor is involved in the expression of the symptom. More specifically, it refers to a disease in which the onset of symptoms is promoted by binding of a ligand to an opioid κ receptor, or a disease in which the onset of symptoms is suppressed by the binding. As described in the Examples below, the compounds of the present invention have selective binding to opioid κ receptors. Therefore, for example, in the case of a disease in which the onset of symptoms is promoted by binding of a ligand to an opioid κ receptor, when the drug of the present invention is administered to a patient, the ligand and the compound of the present invention compete in the patient. As a result, the compound of the present invention acts antagonistically on the receptor-ligand binding, and as a result, the symptoms of the disease can be improved. In this case, the compounds of the invention act as antagonists. In addition, for example, in the case of a disease whose symptoms are suppressed by the binding of a ligand to an opioid κ receptor, the compound of the present invention binds to the opioid κ receptor in the patient when the medicament of the present invention is administered to the patient. So it can alleviate the symptoms. In this case, the compounds of the invention act as agonists. The disease or symptom related to such opioid κ receptor is not particularly limited. For example, in addition to pain, cough, pruritus, ischemic brain disease, drug dependence, WO 05/015242 is related to opioid κ receptor. And the like described as diseases to be treated. Among these diseases, as shown in Example 53, the therapeutic effect on pain has been confirmed, and the medicament of the present invention can be used for the prevention or treatment of pain.

Hereinafter, the present invention will be specifically described with reference to examples. These are given for illustrative purposes only, and should not be taken as limiting in any way. In addition, the symbol in chemical formula represents the following meaning, respectively.
Ms: Mesyl group
ⁿ Pr: Normal propyl group
tBoc: tert-butoxylcarbonyl group

Reference example 1
Synthesis of (17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methylmethanesulfonate (3)

  (Nagase H. et.al., Tetrahedron Lett., 2007, 48 (14), 2547-2553.) (17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorph) obtained by a known method Nan-6α-yl) methanol (700 mg, 1.97 mmol) is dissolved in pyridine (4 ml), ice-cooled under argon, methanesulfonyl chloride (0.46 ml, 5.97 mmol) is added, and the mixture is stirred for 2.5 hours. A small amount of water was added to the liquid and concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue to adjust the pH to 9, followed by extraction with chloroform three times. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product of the title compound (790 mg) as a white amorphous product. Since it was unstable, it proceeded to the next reaction without purification.

Reference example 2
Synthesis of 6α-azidomethyl-17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan (4)

The crude product 3 (790 mg) obtained in Reference Example 1 was dissolved in anhydrous DMSO (4 ml), sodium azide (700 mg, 10.8 mmol) was added, and the mixture was stirred at 110 ° C. under argon. After 5 hours, the reaction solution was concentrated and extracted three times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (50 g; chloroform / methanol 50 / 1-15 / 1) to give the title compound (628 mg, 84%, 2 steps) as an orange oil.
IR (neat): 2100 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.17 (2H, m), 0.42-0.58 (2H, m), 0.93 (1H, m), 1,24 (1H, dt, J = 12.5, 2.0 Hz), 1.45 (1H, dt, J = 13.0, 6.0 Hz), 1.54-1.94 (5H, m), 2.14 (1H, dt, J = 2.0, 12.5 Hz), 2.28 (1H, dt, J = 12.5, 4.5 Hz), 2.42 (1H, dd, J = 7.0, 12.5 Hz), 2.57 (1H, dd, J = 6.0, 12.5 Hz), 2.65 (1H, ddd, J = 2.0, 4.5, 12.5 Hz), 2.66 ( 1H, dd, J = 5.5, 18.0 Hz), 3.12 (1H, d, J = 18.0 Hz), 3.66 (1H, d, J = 5.5 Hz), 3.67 (1H, d, J = 13.0 Hz), 3.74 ( 1H, d, J = 13.0 Hz), 3.78 (3H, s), 6.57 (1H, d, J = 2.5 Hz), 6.70 (1H, dd, J = 2.5, 8.5 Hz), 7.02 (1H, d, J = 8.5 Hz)
MS (FAB) m / z = 381 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₂ H ₂₉ NO ₂ [M + H] ⁺ : 381.2291; Found 381.2290

Reference example 3
Synthesis of (17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methanamine (5)

  Compound 4 (630 mg, 1.66 mmol) obtained in Reference Example 2 and camphorsulfonic acid (962 mg, 4.14 mmol) were dissolved in methanol (10 ml), 10% palladium (300 mg, 1.32 mmol) was added, Stir at room temperature under hydrogen atmosphere. After 12 hours, the reaction solution was filtered and concentrated. 1N NaOH water was added to adjust to pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (541 mg) of the title compound as a clear oil. Since it was unstable, it proceeded to the next reaction without purification.

Reference example 4
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] benzamide (6)

Crude product 5 (250 mg) obtained in Reference Example 3 was dissolved in pyridine (2.0 ml), benzoic anhydride (208 mg, 0.918 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere. After 3 hours, the reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to adjust pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The resulting crude product was purified by silica gel column chromatography (50 g; chloroform / methanol 50/1 to 25/1) to give the free form of the title compound (221 mg, 63%, 2 steps) as a white amorphous product. Obtained.
IR (neat): 1651 cm ^-1
1 H NMR (300 MHz, CDCl3): δ 0.04-0.20 (2H, m), 0.40-0.62 (2H, m), 0.98 (1H, m), 1,27 (1H, dt, J = 13.0, 2.0 Hz ), 1.47 (1H, m), 1.53-2.16 (6H, m), 2.25 (1H, dt, J = 4.5, 13.0 Hz), 2.37 (1H, dd, J = 7.0, 12.5 Hz), 2.54-2.68 ( 3H, m), 3.14 (1H, d, J = 18.0 Hz), 3.72 (1H, d, J = 5.5 Hz), 3.77 (3H, s), 3.88-4.02 (2H, m), 6.58 (1H, d , J = 2.5 Hz), 6.69 (1H, dd, J = 2.5, 8.0 Hz), 6.84 (1H, t, J = 6.0 Hz), 7.00 (1H, d, J = 8.0 Hz), 7.39-7.56 (3H , m), 7.80-7.89 (2H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2639

Reference Example 5
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] benzamide hydrochloride (1)

Compound 6 (110 mg, 0.240 mmol) obtained in Reference Example 4 was dissolved in DMF (4 ml) and potassium t-butoxide (240 mg, 2.14 mmol) and 1-propanethiol (0.33 ml, 3.65 mmol) were added under argon. ) Was added and stirred at 150 ° C. After 12 hours, the reaction solution was concentrated, and 1N HCl was added to the residue to pH = 9, followed by extraction with chloroform three times. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as a brown oil. The resulting crude product was purified by silica gel column chromatography (11 g; chloroform / methanol 50 / 1-15 / 1) to give the title compound free form (71 mg, 67%) as a clear oil. .
IR (neat): 1645 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.18 (2H, m), 0.42-0.60 (2H, m), 0.93 (1H, m), 1,28 (1H, dt, J = 12.5, 2.0 Hz), 1.37 (1H, m), 1.51-1.90 (5H, m), 2.09 (1H, dt, J = 2.0, 12.5 Hz), 2.23 (1H, dt, J = 4.5, 12.5 Hz), 2.34 (1H , dd, J = 7.0, 12.5 Hz), 2.52-2.62 (3H, m), 3.10 (1H, d, J = 18.0 Hz), 3.70 (1H, d, J = 5.5 Hz), 3.85-4.02 (2H, m), 6.61 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz), 6.89 (1H, t, J = 6.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 7.40-7.56 (3H, m), 7.81-7.88 (2H, m)
MS (FAB) m / z = 445 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₃ N ₂ O ₃ [M + H] ⁺ : 445.2491; Found 445.2504

The obtained free form was converted into a hydrochloric acid salt in methanol to obtain the title compound (54 mg, 76%) as a white powder.
mp 181-185 ° C (dec).
Anal.Calcd for C ₂₈ H ₃₂ N ₂ O ₃・ HCl ・ 4 / 5H ₂ O: C, 67.88; H, 7.04; N, 5.65. Found: C, 67.85; H, 7.16; N, 5.46.

Reference Example 6
Synthesis of 2-phenyl-N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] acetamide hydrochloride (2)

Using the amino compound 5 obtained in Reference Example 3, in the same manner as in Reference Examples 4 and 5, using THF and triethylamine in place of pyridine and phenylacetyl chloride in place of benzoic anhydride, the free form of the title compound (54%, 3 steps) and then salified to obtain the desired product.
IR (neat): 1652 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.18 (2H, m), 0.43-0.60 (2H, m), 0.90 (1H, m), 1,10 (1H, dt, J = 12.5, 2.0 Hz), 1.26 (1H, m), 1.51-1.90 (5H, m), 2.09 (1H, dt, J = 2.0, 12.5 Hz), 2.23 (1H, dt, J = 4.5, 12.5 Hz), 2.34 (1H , dd, J = 7.0, 12.5 Hz), 2.52-2.62 (3H, m), 3.10 (1H, d, J = 18.0 Hz), 3.70 (1H, d, J = 5.5 Hz), 3.85-4.02 (2H, m), 6.61 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz), 6.89 (1H, t, J = 6.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 7.40-7.56 (3H, m), 7.81-7.88 (2H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2649
Hydrochloride
mp 172-172 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₄ N ₂ O ₃ HCl0.7H ₂ O: C, 68.61; H, 7.23; N, 5.52. Found: C, 68.52; H, 7.31; N, 5.37.

Reference Example 7
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] formamide (7)

  Formic acid (1.4 ml) was added to acetic anhydride (3.75 ml) and reacted at 50 ° C. for 20 minutes under argon. The mixture was ice-cooled, and the amino compound 5 (700 mg) obtained in Reference Example 3 was dissolved in this solution and stirred at an ice-cooling temperature in an argon atmosphere. After 1.5 hours, the reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (751 mg) of the title compound as a clear oil. This was subjected to the next reaction without purification.

Reference Example 8
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] -N-methylformamide (8)

Compound 7 (71.3 mg, 0.18 mmol) obtained in Reference Example 7 was dissolved in THF (2.0 ml), NaH (80 mg, 18.3 mmol) was added, and methyl iodide (0.1 ml, 0.66 mmol) was added and stirred. After 30 minutes, the reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to adjust pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The obtained crude product was purified by silica gel column chromatography (11 g; chloroform / methanol 50/1 to 20/1) to obtain the title compound (36%, 3steps) as a white amorphous.
IR (neat): 1668 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.19 (2H, m), 0.42-0.59 (2H, m), 0.89 (1H, m), 1.16-1.92 (8H, m), 1.92-2.22 ( 2H, m), 2.40 (1H, m), 2.52-2.74 (4H, m), 3.02-3.24 (4H, m), 3.60-3.94 (5H, m), 6.52-6.59 (1H, m), 6.64- 6.72 (1H, m), 6.96-7.04 (1H, m), 8.12-8.18 (1H, m)
MS (FAB) m / z = 397 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₄ H ₃₃ N ₂ O ₃ [M + H] ⁺ : 397.2491; Found 397.2493

Reference Example 9
Synthesis of (17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) -N-methylmethanamine (9)

  Compound 8 (290 mg) obtained in Reference Example 8 was dissolved in 1 mol / L HCl (15.0 ml) and heated to reflux. After 4 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (232 mg) of the title compound as a clear oil. This was subjected to the next reaction without purification.

Examples 1-13
N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -trans-3-furanacrylamide hydrochloride (10), N-[(17-cyclopropylmethyl -6β, 14-Epoxy-3-hydroxymorphinan-6α-yl) methyl] -3-n-propylthiobenzamide hydrochloride (11), N-[(17-cyclopropylmethyl-6β, 14-epoxy-3 -Hydroxymorphinan-6α-yl) methyl] -4-methylbenzamide hydrochloride (12), N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -3-methylbenzamide hydrochloride (13), N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -2-methylbenzamide hydrochloride (14), N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -4-hydroxybenzamide hydrochloride (15 , N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -3-hydroxybenzamide hydrochloride (16), N-[(17-cyclopropylmethyl- 6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -2-hydroxybenzamide hydrochloride (17), 3-phenyl-N-[(17-cyclopropylmethyl-6β, 14-epoxy-3 -Hydroxymorphinan-6α-yl) methyl] propionamide hydrochloride (18), N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -1- Naphthoamide hydrochloride (19), N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -2-naphthamide hydrochloride (20), N-[(17 -Cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl]-(1S) -camphorsulfonamide hydrochloride (21), N-[(17- Black propyl methyl -6β, 14- epoxy-3-hydroxy mol chick down -6α- yl) methyl] - (1R) - Synthesis of camphor sulphonamide hydrochloride (22)

  Using amino compound 5 obtained in Reference Example 3, in the same manner as Reference Examples 4 and 5, THF and triethylamine were used instead of pyridine, and 3-trans-3- (3-furyl) was used instead of benzoic anhydride. Acryloyl chloride, 3-fluorobenzoic acid, 4-toluoyl chloride, 3-toluoyl chloride, 2-toluoyl chloride, 4-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 2-methoxybenzoyl chloride, hydrocinnamoyl chloride, Using 1-naphthoyl chloride, 2-naphthoyl chloride, (1S) -camphorsulfonyl chloride, (1R) -camphorsulfonyl chloride, compound 10 (37%, 3 steps), compound 11 (32%, 3 steps) , Compound 12 (54%, 3 steps), Compound 13 (40%, 3 steps), Compound 14 (37%, 3 steps), Compound 15 (52%, 3 steps), Compound 16 (67%, 3 steps) , Compound 17 (74%, 3 steps), Compound 18 (66%, 3 steps), Compound 19 (52%, 3 steps), Compound 20 (65%, 3 steps), Compound 21 (61%, 3 steps), and Compound 22 (69%, 3 steps) were obtained in free forms and converted into hydrochloric acid to give the title compound.

Compound 10
IR (neat): 1666, 1619 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.18 (2H, m), 0.43-0.60 (2H, m), 0.93 (1H, m), 1.26-1.40 (2H, m), 1.51-1.65 ( 2H, m), 2.04-2.28 (3H, m), 2.23 (1H, dt, J = 4.5, 12.5 Hz), 2.38 (1H, dd, J = 7.0, 12.5 Hz), 2.52-2.69 (3H, m) , 3.10 (1H, d, J = 18.0 Hz), 3.70 (1H, d, J = 5.5 Hz), 3.70 (1H, dd, J = 6.5, 15.0 Hz), 3.91 (1H, dd, J = 6.5, 15.0 Hz), 6.21 (1H, d, J = 15.0 Hz), 6.52 (1H, t, J = 6.5 Hz), 6.56 (1H, d, J = 2.0 Hz), 6.61 (1H, d, J = 2.5 Hz) , 6.67 (1H, dd, J = 2.5, 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.40 (1H, t, J = 2.0 Hz), 7.54 (1H, d, J = 15.0 Hz) , 7.60 (1H, s)
MS (FAB) m / z = 461 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 461.2440; Found 461.2441.
Hydrochloride
mp 198-201 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₂ N ₂ O ₄ HCl0.7H ₂ O: C, 65.99; H, 6.80; N, 5.50. Found: C, 66.30; H, 7.11; N, 5.39.

Compound 11
IR (neat): 1644 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.06-0.19 (2H, m), 0.43-0.60 (2H, m), 0.94 (1H, m), 1,10 (3H, dt, J = 7.5 Hz) , 1.20-1.42 (2H, m), 1.51-1.87 (4H, m), 1.68 (2H, tq, J = 7.5, 7.5 Hz), 2.09 (2H, m), 2.37 (1H, m), 2.52-2.70 (3H, m), 2.95 (2H, t, J = 7.5 Hz), 3.10 (1H, d, J = 18.0 Hz), 3.71 (1H, d, J = 5.5 Hz), 3.87 (1H, dd, 6.0, 15.0 Hz), 3.94 (1H, 6.0, 15.0 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz), 6.93 (1H, d, J = 8.0 Hz ), 6.95 (1H, t, J = 6.0 Hz), 7.28-7.83 (5H, m)
MS (FAB) m / z = 519 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₃₉ N ₂ O ₃ S [M + H] ⁺ : 519.2681; Found 519.2686
Hydrochloride
Anal. Calcd for C ₃₁ H ₃₈ N ₂ O ₃ SHClH ₂ O: C, 64.96; H, 7.21; N, 4.89. Found: C, 64.79; H, 7.01; N, 4.63

Compound 12
IR (neat): 1642 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.24 (2H, m), 0.44-0.62 (2H, m), 0.98 (1H, m), 1,27 (1H, dt, J = 12.5, 2.0 Hz), 1.37 (1H, m), 1.51-1.90 (5H, m), 2.00-2.34 (3H, m), 2.40 (3H, s), 2.52-2.75 (3H, m), 3.12 (1H, d, J = 18.0 Hz), 3.74 (1H, d, J = 5.5 Hz), 3.85-4.02 (2H, m), 6.62 (1H, d, J = 2.5 Hz), 6.67 (1H, dd, J = 2.5, 8.0 Hz), 6.88 (1H, m), 6.94 (1H, d, J = 8.0 Hz), 7.20-7.34 (2H, m), 7.70-7.86 (2H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2635.
Hydrochloride
mp 184-187 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₄ N ₂ O ₃ HClH ₂ O: C, 67.89; H, 7.27; N, 5.46. Found: C, 67.60; H, 7.26; N, 5.44

Compound 13
IR (neat): 1644 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.05-0.23 (2H, m), 0.44-0.62 (2H, m), 0.97 (1H, m), 1,27 (1H, dt, J = 12.5, 2.0 Hz), 1.34 (1H, m), 1.51-1.88 (5H, m), 2.00-2.34 (3H, m), 2.40 (3H, s), 2.52-2.74 (3H, m), 3.12 (1H, d, J = 18.0 Hz), 3.74 (1H, d, J = 5.5 Hz), 3.85-4.02 (2H, m), 6.62 (1H, d, J = 2.5 Hz), 6.67 (1H, dd, J = 2.5, 8.0 Hz), 6.90 (1H, m), 6.94 (1H, d, J = 8.0 Hz), 7.28-7.36 (2H, m), 7.58-7.74 (2H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2640
Hydrochloride
mp 176-180 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₄ N ₂ O ₃ HCl0.8H ₂ O: C, 68.37; H, 7.27; N, 5.50. Found: C, 68.31; H, 7.15; N, 5.35

Compound 14
IR (neat): 1645 cm-1
¹ H NMR (300 MHz, CDCl3): δ 0.02-0.22 (2H, m), 0.40-0.62 (2H, m), 0.92 (1H, m), 1,28 (1H, dt, J = 12.5, 2.0 Hz ), 1.40 (1H, m), 1.51-1.94 (5H, m), 2.00-2.40 (3H, m), 2.48 (3H, s), 2.51-2.73 (3H, m), 3.10 (1H, d, J = 18.0 Hz), 3.70 (1H, d, J = 5.5 Hz), 3.85-4.02 (2H, m), 6.48 (1H, m), 6.60 (1H, d, J = 2.5 Hz), 6.63 (1H, dd , J = 2.5, 8.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 7.17-7.48 (4H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2662.
Hydrochloride
mp 181-185 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₄ N ₂ O ₃ HCl 0.8H ₂ O: C, 68.37; H, 7.24; N, 5.50. Found: C, 68.48; H, 7.27; N, 5.43

Compound 15
IR (KBr): 1641 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 0.14-0.28 (2H, m), 0.48-0.68 (2H, m), 0.93 (1H, m), 1,18 (1H, m), 1.47-1.67 (3H, m), 1.72-1.92 (3H, m), 2.12-2.28 (2H, m), 2.45 (1H, dd, J = 7.0, 12.5 Hz), 2.57 (1H, m), 2.61 (1H, dd , J = 6.0, 12.5 Hz), 2.65 (1H, dd, J = 5.5, 18.0 Hz), 3.14 (1H, d, J = 18.0 Hz), 3.71 (1H, d, J = 5.5 Hz), 3.66 (1H , d, J = 14.5 Hz), 4.00 (1H, d, J = 14.5 Hz), 6.48 (1H, d, J = 2.5 Hz), 6.57 (1H, dd, J = 2.5, 8.0 Hz), 6.80-6.88 (2H, m), 6.94 (1H, d, J = 8.0 Hz), 7.75-7.84 (2H, m)
MS (FAB) m / z = 461 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 461.2440; Found 461.2456
Hydrochloride
mp 215-220 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₂ N ₂ O ₄ HClH2O: C, 65.30; H, 6.85; N, 5.44. Found: C, 65.07; H, 6.87; N, 5.35

Compound 16
IR (KBr): 1640 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 0.13-0.30 (2H, m), 0.48-0.66 (2H, m), 0.93 (1H, m), 1,20 (1H, m), 1.47-1.69 (3H, m), 1.72-1.94 (3H, m), 2.11-2.30 (2H, m), 2.44 (1H, dd, J = 7.0, 12.5 Hz), 2.56 (1H, m), 2.59 (1H, dd , J = 6.0, 12.5 Hz), 2.65 (1H, dd, J = 5.5, 18.0 Hz), 3.14 (1H, d, J = 18.0 Hz), 3.67 (1H, d, J = 14.5 Hz), 3.70 (1H , d, J = 5.5 Hz), 4.00 (1H, d, J = 14.5 Hz), 6.48 (1H, d, J = 2.5 Hz), 6.58 (1H, dd, J = 2.5, 8.0 Hz), 6.93 (1H , d, J = 8.0 Hz), 6.96 (1H, m), 7.24-7.38 (3H, m)
MS (FAB) m / z = 461 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 461.2440; Found 461.2447.
Hydrochloride
mp 202-208 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₂ N ₂ O ₄ HClH ₂ O: C, 65.30; H, 6.85; N, 5.44. Found: C, 65.41; H, 6.82; N, 5.30

Compound 17
IR (KBr): 1642 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 0.16-0.30 (2H, m), 0.48-0.70 (2H, m), 0.95 (1H, m), 1,22 (1H, dt, 13.0, 2.0) , 1.49-1.72 (3H, m), 1.72-1.94 (3H, m), 2.18-2.34 (2H, m), 2.57 (1H, dd, J = 7.0, 12.5 Hz), 2.61 (1H, m), 2.64 (1H, dd, J = 6.0, 12.5 Hz), 2.74 (1H, dd, J = 5.5, 18.0 Hz), 3.15 (1H, d, J = 18.0 Hz), 3.76 (1H, d, J = 14.5 Hz) , 3.77 (1H, d, J = 5.5 Hz), 3.99 (1H, d, J = 14.5 Hz), 6.50 (1H, d, J = 2.5 Hz), 6.59 (1H, dd, J = 2.5, 8.0 Hz) , 6.82-6.93 (3H, m), 6.95 (1H, d, J = 8.0 Hz), 7.89 (1H, m)
MS (FAB) m / z = 461 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 461.2440; Found 461.2436
Hydrochloride
mp 198-202 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₂ N ₂ O ₄ HCl1.25H ₂ O: C, 64.73; H, 6.89; N, 5.39. Found: C, 64.63; H, 6.74; N, 5.31

Compound 18
IR (neat): 1658 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.20 (2H, m), 0.43-0.60 (2H, m), 0.92 (1H, m), 1,18 (1H, dt, J = 12.5, 2.0 Hz), 1.18-1.34 (2H, m), 1.38-1.78 (5H, m), 2.09 (2H, m), 2.36 (1H, dd, J = 7.0, 12.5 Hz), 2.52-2.62 (4H, m) , 2.90-3.06 (2H, m), 3.10 (1H, d, J = 18.0 Hz), 3.57 (1H, dd, J = 6.0, 14.0 Hz), 3.66 (1H, d, J = 5.5 Hz), 3.76 ( 1H, dd, J = 6.0, 14.0 Hz), 6.28 (1H, t, J = 6.0 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 7.14-7.31 (5H, m)
MS (FAB) m / z = 473 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₀ H ₃₇ N ₂ O ₃ [M + H] ⁺ : 473.2804; Found 473.2811
Hydrochloride
mp 160-164 ° C (dec).
Anal. Calcd for C ₃₀ H ₃₆ N ₂ O ₃ HCl1.33H ₂ O: C, 67.59; H, 7.50; N, 5.25. Found: C, 67.43; H, 7.28; N, 5.17

Compound 19
IR (neat): 1645 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.06-0.22 (2H, m), 0.41-0.60 (2H, m), 0.84 (1H, m), 1,20 (1H, dt, J = 12.5, 2.0 Hz), 1.52-1.84 (4H, m), 1.95 (1H, d, J = 12.0 Hz), 1.97 (1H, dd, J = 2.5, 12.0 Hz), 2.19 (1H, dt, J = 4.5, 12.5 Hz ), 2.39 (1H, dd, J = 7.0, 12.5 Hz), 2.47 (1H, m), 2.48 (1H, dd, J = 6.0, 12.5 Hz), 2.64 (1H, dd, J = 5.5, 18.0 Hz) , 3.12 (1H, d, J = 18.0 Hz), 3.65 (1H, d, J = 5.5 Hz), 3.76 (1H, d, J = 14.0 Hz), 4.12 (1H, d, J = 14.0 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5, 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.50-7.64 (3H, m), 7.70 (1H, m), 7.90-8.06 (3H, m), 8.25 (1H, m)
MS (FAB) m / z = 495 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₂ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 495.2648; Found 495.2646
Hydrochloride
mp 191-194 ° C (dec).
Anal. Calcd for C ₃₂ H ₃₄ N ₂ O ₃ HCl 1.2H ₂ O: C, 69.54; H, 6.82; N, 5.07. Found: C, 69.54; H, 6.62; N, 5.14

Compound 20
IR (neat): 1644 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.11-0.26 (2H, m), 0.46-0.65 (2H, m), 0.93 (1H, m), 1,18 (1H, dt, J = 12.5, 2.0 Hz), 1.50-1.83 (4H, m), 1.89 (1H, dd, J = 2.5, 12.0 Hz), 1.91 (1H, d, J = 12.0 Hz), 2.17 (1H, dt, J = 2.0, 12.5 Hz ), 2.24 (1H, dt, J = 4.5, 12.5 Hz), 2.42 (1H, dd, J = 7.0, 12.5 Hz), 2.54 (1H, m), 2.59 (1H, dd, J = 6.0, 12.5 Hz) , 2.66 (1H, dd, J = 5.5, 18.0 Hz), 3.14 (1H, d, J = 18.0 Hz), 3.71 (1H, d, J = 5.5 Hz), 3.77 (1H, d, J = 14.0 Hz) , 4.07 (1H, d, J = 14.0 Hz), 6.50 (1H, d, J = 2.5 Hz), 6.58 (1H, dd, J = 2.5, 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz) , 7.52-7.64 (4H, m), 7.90-8.04 (2H, m), 8.46 (1H, m)
MS (FAB) m / z = 495 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₂ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 495.2648; Found 495.2652
Hydrochloride
mp 185-190 ° C (dec).
Anal. Calcd for C ₃₂ H ₃₄ N ₂ O ₃ HClH ₂ O: C, 69.99; H, 6.79; N, 5.10. Found: C, 70.23; H, 6.74; N, 5.18

Compound 21
IR (neat): 1742 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.22 (2H, m), 0.42-0.60 (2H, m), 0.91 (1H, m), 0.91 (3H, s), 1.06 (3H, s) , 1,26 (1H, dt, J = 12.5, 2.0 Hz), 1.38-1.52 (2H, m), 1.60 (1H, m), 1.68-2.18 (9H, m), 2.26 (1H, dt, J = 4.5, 12.5 Hz), 2.28-2.46 (3H, m), 2.48-2.68 (3H, m), 2.96 (1H, d, J = 15.0 Hz), 3.10 (1H, m), 3.46 (1H, d, J = 15.0 Hz), 3.46 (1H, d, J = 14.5 Hz), 3.57 (1H, d, J = 5.5 Hz), 3.57 (1H, d, J = 14.5 Hz), 6.54 (1H, d, J = 2.5 Hz), 6.67 (1H, dd, J = 2.5, 8.0 Hz), 6.96 (1H, d, J = 8.0 Hz)
MS (FAB) m / z = 555 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₄₃ N ₂ O ₅ S [M + H] ⁺ : 555.2893; Found 555.2886
Hydrochloride
mp 190-194 ° C (dec).
Anal. Calcd for C ₃₁ H ₄₂ N ₂ O ₅ SHCl0.5H2O: C, 62.03; H, 7.39; N, 4.67. Found: C, 62.05; H, 7.29; N, 4.58

Compound 22
IR (neat): 1741 cm ^-1
1 H NMR (300 MHz, CDCl3): δ 0.04-0.20 (2H, m), 0.42-0.60 (2H, m), 0.91 (1H, m), 0.91 (3H, s), 1.08 (3H, s), 1,26 (1H, dt, J = 12.5, 2.0 Hz), 1.36-1.52 (2H, m), 1.60 (1H, m), 1.70-2.16 (9H, m), 2.24 (1H, dt, J = 4.5 , 12.5 Hz), 2.30-2.46 (3H, m), 2.48-2.68 (3H, m), 2.95 (1H, d, J = 15.0 Hz), 3.10 (1H, d, 18.0 Hz), 3.53 (1H, d , J = 15.0 Hz), 3.55 (1H, dd, J = 6.0, 14.5 Hz), 3.63 (1H, d, J = 5.5 Hz), 3.65 (1H, dd, J = 6.0, 14.5 Hz), 5.34 (1H , t, J = 6.0 Hz), 6.53 (1H, d, J = 2.5 Hz), 6.63 (1H, dd, J = 2.5, 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz)
MS (FAB) m / z = 555 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₄₃ N ₂ O ₅ S [M + H] ⁺ : 555.2893; Found 555.2882
Hydrochloride
mp 197-201 ° C (dec).
Anal. Calcd for C ₃₁ H ₄₂ N ₂ O ₅ SHCl0.5H ₂ O: C, 62.03; H, 7.39; N, 4.67. Found: C, 62.17; H, 7.39; N, 4.69

Example 14
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] -N-methylbenzamide (23)

Compound 6 (81 mg, 0.18 mmol) obtained in Reference Example 4 was dissolved in THF (2.0 ml), NaH (80 mg, 18.3 mmol) was added, and methyl iodide (0.1 ml, 0.1 ml, under ice cooling under argon) was added. 0.66 mmol) was added and stirred. After 30 minutes, the reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to adjust pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The obtained crude product was purified by silica gel column chromatography (11 g; chloroform / methanol 50/1 to 20/1) to obtain the title compound (64 mg, 77%) as a white amorphous.
IR (neat): 1620 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.19 (2H, m), 0.40-0.60 (2H, m), 0.91 (1H, m), 1,25 (1H, dt, J = 12.5, 2.0 Hz), 1.46-1.82 (5H, m), 1.86-2.03 (2H, m), 2.06-2.30 (2H, m), 2.32-2.78 (3H, m), 3.20 (3H, s), 3.26 (1H, d, J = 18.0 Hz), 3.66 (1H, m), 3.78 (3H, m), 3.90 (1H, d, J = 14.5 Hz), 4.21 (1H, d, J = 14.5 Hz), 6.60 (1H, d, J = 2.5 Hz), 6.70 (1H, dd, J = 2.5, 8.5 Hz), 7.01 (1H, d, J = 8.5 Hz), 7.34-7.50 (5H, m)
MS (FAB) m / z = 473 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₀ H ₃₇ N ₂ O ₃ [M + H] ⁺ : 473.2804; Found 473.2803

Example 15
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -N-methylbenzamide hydrochloride (24)

From the compound 23 obtained in Example 14, a free form of the title compound was obtained as a transparent oil in a yield of 84% in the same manner as in the method of Reference Example 5.
IR (neat): 1621 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.19 (2H, m), 0.40-0.60 (2H, m), 0.92 (1H, m), 1,10 (1H, dt, J = 12.5, 2.0 Hz), 1.26 (1H, m), 1.39-1.56 (2H, m), 1.57-1.77 (3H, m), 1.90 (1H, dt, J = 4.5, 13.0 Hz), 2.06 (1H, dt, J = 13.0, 2.0 Hz), 2.32-2.62 (4H, m), 3.06 (1H, d, J = 18.0 Hz), 3.54-3.64 (3H, m), 3.56 (1H, dd, J = 6.5, 14.5 Hz), 3.77 (1H, dd, 6.5, 14.5 Hz), 6.21 (1H, t, 6.5 Hz), 6.53 (1H, d, J = 2.0 Hz), 6.63 (1H, dd, J = 2.0, 8.0 Hz), 6.92 ( 1H, d, J = 8.0 Hz), 7.20-7.38 (5H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2633

The title compound was obtained by converting into hydrochloride according to a conventional method.
mp 177-183 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₄ N ₂ O ₃ HCl 1.2H ₂ O: C, 67.51; H, 7.51; N, 5.36. Found: C, 67.36; H, 7.31; N, 5.28

Examples 16-17
2-Phenyl-N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -N-methylacetamide hydrochloride (25), N-[(17-cyclo Synthesis of Propylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -N-methyl-2-methylbenzamide hydrochloride (26)

  Using Compound 9 obtained in Reference Example 9 and according to the methods of Reference Examples 4 and 5, in Reference Example 4, the room temperature was ice-cooled, THF and triethylamine were used instead of pyridine, and benzoic anhydride was used instead. Using phenylacetyl chloride and 2-toluoyl chloride, free forms of compound 25 (35%, 3 steps) and compound 26 (42%, 3 steps) were obtained, and the title compound was obtained as the hydrochloride.

Compound 25
IR (neat): 1624 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.19 (2H, m), 0.40-0.59 (2H, m), 0.90 (1H, m), 1,03 (1H, dt, J = 12.5, 2.0 Hz), 1.12-1.27 (1H, m), 1.33-1.49 (2H, m), 1.50-1.68 (3H, m), 1.74 (1H, m), 1.90 (1H, dt, J = 4.5, 13.0 Hz) , 2.06 (1H, m), 2.32-2.72 (4H, m), 3.10 (1H, d, J = 18.0 Hz), 3.18 (3H, s), 3.62 (1H, m), 3.67 (1H, d, J = 14.5 Hz), 3.75-3.83 (2H, m), 4.02 (1H, d, J = 14.5 Hz), 6.53 (1H, d, J = 2.5 Hz), 6.64 (1H, dd, J = 2.5, 8.5 Hz ), 6.90 (1H, d, J = 8.5 Hz), 7.18-7.38 (5H, m)
MS (FAB) m / z = 473 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₀ H ₃₇ N ₂ O ₃ [M + H] ⁺ : 473.2804; Found 473.2813
Hydrochloride
mp 157-160 ° C (dec).
Anal. Calcd for C ₃₀ H ₃₆ N ₂ O ₃ HCl 1.6H ₂ O: C, 66.99; H, 7.53; N, 5.21. Found: C, 66.93; H, 7.44; N, 5.13

Compound 26
IR (neat): 1613 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.05-0.22 (2H, m), 0.42-0.61 (2H, m), 0.94 (1H, m), 1.13-1.32 (2H, m), 1.36-1.49 ( 1H, m), 1.49-1.77 (4H, m), 1.77-1.96 (2H, m), 2.20 (1H, dt, J = 2.0, 12.0 Hz), 2.38 (3H, s), 2.52-2.79 (3H, m), 3.18 (3H, s), 3.20 (1H, d, J = 18.0 Hz), 3.73 (1H, d, J = 5.5 Hz), 3.98 (1H, d, J = 14.5 Hz), 4.08 (1H, d, J = 14.5 Hz), 6.58 (1H, d, J = 2.5 Hz), 6.64 (1H, dd, J = 2.5, 8.5 Hz), 6.92 (1H, d, J = 8.5 Hz), 7.12-7.38 ( 4H, m)
MS (FAB) m / z = 473 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₀ H ₃₇ N ₂ O ₃ [M + H] +: 473.2804; Found 473.2823
Hydrochloride
mp 170-174 ° C (dec).
Anal. Calcd for C ₃₀ H ₃₆ N ₂ O ₃ HCl1.1H ₂ O: C, 68.13; H, 7.47; N, 5.30. Found: C, 68.01; H, 7.35; N, 5.18

Reference Example 10
Synthesis of 6α-azidomethyl-6β, 14-epoxy-3-methoxymorphinan (27)

Compound 4 (2.68 g) obtained in Reference Example 2 was dissolved in 1,1,2,2-tetrachloroethane (25 ml), 1-chloroethyl chloroformate (3.8 ml, 35.2 mmol) was added, and argon was added. Stir at 100 ° C. After 2.5 hours, the reaction solution was concentrated, dissolved by adding MeOH (20 ml), and then heated to reflux. After 2 hours, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with aqueous sodium bicarbonate solution, twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as a brown oil. The obtained crude product was purified by silica gel column chromatography (50 g; chloroform / methanol 33/1 to 20/1) to obtain the title compound (1.38 g, 60%) as an orange oil.
IR (neat): 2101 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1,23 (1H, dt, J = 12.5, 2.0 Hz), 1.40-1.76 (4H, m), 1.85 (1H, d, J = 12.0 Hz), 1.90 (1H, dd, J = 2.0, 12.0 Hz), 2.04 (1H, dt, J = 4.5, 12.5 Hz), 2.55 (1H, m), 2.66 (1H, ddd, J = 2.0, 4.5, 12.5 Hz), 3.01 (1H, d, J = 18.0 Hz), 3.15 (1H, dd, J = 5.5, 18.0 Hz), 3.48 (1H, d, J = 5.5 Hz), 3.57 (1H, d, J = 13.0 Hz), 3.72 (1H, d, J = 13.0 Hz), 3.78 (3H, s), 6.56 (1H, d, J = 2.5 Hz), 6.72 (1H, dd, J = 2.5, 8.5 Hz), 7.06 (1H, d , J = 8.5 Hz)
MS (FAB) m / z = 327 [M + H] ⁺
HRMS (FAB) Calcd for C ₁₈ H ₂₃ N ₄ O ₂ [M + H] ⁺ : 327.1821; Found 327.1831

Reference Example 11
Synthesis of 6α-azidomethyl-6β, 14-epoxy-3-methoxy-17-methylmorphinan (28)

Compound 27 (1.3 g, 3.98 mmol) obtained in Reference Example 10 was dissolved in 2N acetic acid (150 ml), sodium acetate (1.6 g, 19.9 mmol), 37% aqueous formaldehyde solution (1.6 ml) was added, and argon atmosphere was added. And stirred at room temperature. After 3 h, sodium borohydride (1.5 g, 39.8 mmol) was added under ice-cooling, and after stirring for 5 minutes, an aqueous ammonia solution was added to adjust the pH to 10, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (1.28 g) as a colorless oil. The obtained crude product was recrystallized from ethanol to give the title compound (0.90 g, 66%) as white crystals.
IR (KBr): 2091 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1,28 (1H, dt, J = 12.5, 2.0 Hz), 1.40-1.78 (4H, m), 1.84-1.94 (2H, m), 2.15 (1H, dt, J = 2.0, 12.5 Hz), 2.26 (1H, dt, J = 4.0, 12.5 Hz), 2.42 (1H, m), 2.44 (3H, s), 2.64 (1H, dd, J = 5.5, 18.0 Hz ), 3.20 (1H, d, J = 18.0 Hz), 3.30 (1H, d, J = 5.5 Hz), 3.70 (1H, d, J = 13.0 Hz), 3.71 (1H, d, J = 13.0 Hz), 3.78 (3H, s), 6.57 (1H, d, J = 2.5 Hz), 6.70 (1H, dd, J = 2.5, 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz)
MS (FAB) m / z = 341 [M + H] ⁺
HRMS (FAB) Calcd for C ₁₉ H ₂₅ N ₄ O ₂ [M + H] ⁺ : 341.1978; Found 341.1992

Example 18
Synthesis of N-[(6β, 14-epoxy-3-hydroxy-17-methyl-morphinan-6α-yl) methyl] benzamide (29) hydrochloride

From the compound 28 obtained in Reference Example 11, a free form (57%, 3 steps) of the title compound was obtained as a white amorphous in the same manner as in Reference Examples 3, 4, and 5.
IR (neat): 1621 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1,29 (1H, dt, J = 12.5, 2.0 Hz), 1.37 (1H, m), 1.50-1.92 (6H, m), 2.12-2.32 (2H, m), 2.50 (3H, s), 2.66 (1H, dd, J = 5.5, 18.0 Hz), 3.22 (1H, d, J = 18.0 Hz), 3.34 (1H, d, J = 5.5 Hz), 3.92 ( 1H, dd, J = 6.5, 14.5 Hz), 3.96 (1H, dd, 6.5, 14.5 Hz), 6.60 (1H, d, J = 2.0 Hz), 6.68 (1H, dd, J = 2.0, 8.0 Hz), 6.94 (1H, m), 6.96 (1H, d, J = 8.0 Hz), 7.40-7.56 (3H, m), 7.80-7.92 (2H, m)
MS (FAB) m / z = 405 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₅ H ₂₉ N ₂ O ₃ [M + H] ⁺ : 405.2178; Found 405.2166

The obtained free form was converted to hydrochloric acid to give the title compound.
mp 181-185 ° C (dec).
Anal.Calcd for C ₂₅ H ₂₈ N ₂ O ₃ HCl 0.9H ₂ O: C, 65.71; H, 6.85; N, 6.11. Found: C, 65.77; H, 6.84; N, 5.99

Reference Example 12
Synthesis of (17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methanamine (30)

  Compound 5 (160 mg, 0.45 mmol) obtained in Reference Example 3 was dissolved in DMF (4 ml). Under argon, potassium t-butoxide (336 mg, 3.0 mmol) and 1-propanethiol (0.38 ml, 4.23 mmol) ) Was added and stirred at 150 ° C. After 6 hours, the reaction solution was concentrated, and 1N HCl was added to the residue to adjust pH = 9, followed by extraction three times with (chloroform: 2-propanol = 3: 2). The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product of the title compound (202 mg) as a brown oil.

Example 19
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -3-fluorobenzamide hydrochloride (31)

  From the crude product 30 obtained in Reference Example 12 (199 mg), according to Reference Example 4, the room temperature was cooled with ice, THF and triethylamine were used instead of pyridine, and 3-fluorobenzoyl chloride was used instead of benzoic anhydride. Was used to give the 3-position benzoyl compound (130 mg, 49%, 2 steps) of the title compound as a white amorphous substance.

This (100 mg) was dissolved in THF (2 ml), 4N NaOH (1 ml) was added, and the mixture was stirred at room temperature under an argon atmosphere. After 4 hours, 2N HCl was added to the reaction solution to adjust to pH = 9, followed by extraction with chloroform three times. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The obtained crude product was purified by silica gel column chromatography (20 g; chloroform / methanol 100/2 to 33/1) to obtain a free form (62 mg, 78%) of the title compound as a white amorphous substance.
IR (neat): 1649 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.18 (2H, m), 0.41-0.60 (2H, m), 0.91 (1H, m), 1.26 (1H, dt, 13.0, 2.0 Hz), 1.36 (1H, m), 1.50-1.86 (5H, m), 2.10 (1H, dt, J = 2.0, 12.5 Hz), 2.21 (1H, dt, J = 4.5, 12.5 Hz), 2.36 (1H, dd, J = 7.0, 12.5 Hz), 2.50-2.68 (3H, m), 3.10 (1H, d, J = 18.0 Hz), 3.71 (1H, d, J = 5.5 Hz), 3.81 (1H, dd, J = 6.5, 14.5 Hz), 3.96 (1H, dd, 6.5, 14.5 Hz), 6.58 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.95 (1H, t, J = 6.0 Hz), 7.19 (1H, m), 7.39 (1H, m), 7.55-7.66 (2H, m)
MS (FAB) m / z = 445 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₂ FN ₂ O ₃ [M + H] ⁺ : 463.2397; Found 463.2388

The obtained free form was converted into a hydrochloric acid salt to give the title compound.
mp 181-185 ° C (dec).
Anal.Calcd for C ₂₈ H ₃₁ FN ₂ O ₃ 2HCl0.67H ₂ O: C, 61.43; H, 6.32; N, 5.12. Found: C, 61.57; H, 6.24; N, 4.88

Example 20
Synthesis of N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -4-nitrobenzamide hydrochloride (32)

From the crude product 30 obtained in Reference Example 12, in the same manner as in Example 19, using 4-nitrobenzoyl chloride instead of 3-fluorobenzoyl chloride, the free form of the title compound (18%, 3 steps) Got.
IR (neat): 1651 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.04-0.20 (2H, m), 0.42-0.60 (2H, m), 0.91 (1H, m), 1,18-1.32 (2H, m), 1.44 ( 1H, m), 1.53-1.90 (5H, m), 2.11 (1H, dt, J = 2.0, 12.5 Hz), 2.20 (1H, dt, J = 4.5, 12.5 Hz), 2.37 (1H, dd, J = 7.0, 12.5 Hz), 2.50-2.70 (3H, m), 3.12 (1H, d, J = 18.0 Hz), 3.74 (1H, d, J = 5.5 Hz), 3.80 (1H, dd, J = 6.5, 14.5 Hz), 4.06 (1H, dd, 6.5, 14.5 Hz), 6.54 (1H, d, J = 2.5 Hz), 6.63 (1H, dd, J = 2.5, 8.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 8.00-8.10 (2H, m), 8.21-8.29 (2H, m)
MS (FAB) m / z = 490 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₂ N ₃ O ₅ [M + H] ⁺ : 490.2342; Found 490.2327

This was converted to hydrochloric acid to give the title compound.
mp 200-205 ° C (dec).
Anal.Calcd for C ₂₈ H ₃₁ N ₃ O ₅ 2HCl0.33H ₂ O: C, 59.30; H, 6.15; N, 7.32. Found: C, 59.47; H, 5.97; N, 6.94

Reference Example 13
Synthesis of (6β, 14-epoxy-17-isobutyl-3-methoxymorphinan-6α-yl) methanamine (33)

  Compound 4 (1.09 g, 2.87 mmol) obtained in Reference Example 2 and camphorsulfonic acid (4.0 g, 17.2 mmol) are dissolved in methanol (15 ml), platinum oxide (546 mg, 2.4 mmol) is added, and hydrogen is added. Stir at room temperature under atmosphere. After 96 hours, the reaction solution was filtered and concentrated. 1N NaOH water was added to adjust to pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (937 mg) of the title compound as a clear oil. Since it was unstable, it proceeded to the next reaction without purification.

Example 21
Synthesis of N-[(6β, 14-epoxy-3-hydroxy-17-isobutylmorphinan-6α-yl) methyl] benzamide hydrochloride (34)

The free form (23%, 3 steps) of the title compound was obtained from Compound 33 obtained in Reference Example 13 in the same manner as Reference Examples 4 and 5.
IR (neat): 1644 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.93 (6H, d, 6.0 Hz), 1,23 (2H, m), 1.37 (1H, m), 1.48-1.90 (7H, m), 2.15 (1H , m), 2.24-2.50 (2H, m), 2.61 (1H, m), 3.13 (1H, d, J = 18.0 Hz), 3.32 (1H, d, J = 5.5 Hz), 3.87 (1H, dd, J = 6.0, 14.5 Hz), 3.99 (1H, dd, J = 6.0, 14.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz), 6.94 ( 1H, t, J = 6.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.40-7.56 (3H, m), 7.81-7.92 (2H, m)
MS (FAB) m / z = 447 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 447.2491; Found 447.2663

This was hydrochlorinated to give the title compound.
mp 184-188 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₄ N ₂ O ₃ HCl1.33H ₂ O: C, 66.32; H, 7.49; N, 5.52. Found: C, 66.52; H, 7.21; N, 5.28

Example 22
Synthesis of N-[(6β, 14-epoxy-3-hydroxy-17-isobutylmorphinan-6α-yl) methyl] -N-methylbenzamide hydrochloride (35)

The free form (22%, 3 steps) of the title compound was obtained from compound 33 obtained in Reference Example 13 in the same manner as in Reference Examples 4, 6, and 5.
IR (neat): 1614 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.90 (6H, d, 6.0 Hz), 1,23 (2H, m), 1.35 (1H, m), 1.41-1.90 (7H, m), 2.17 (1H , m), 2.24-2.48 (2H, m), 2.67 (1H, m), 3.10 (1H, d, J = 18.0 Hz), 3.23 (3H, s), 3.27 (1H, d, J = 5.5 Hz) , 3.67 (1H, d, J = 14.5 Hz), 4.38 (1H, d, J = 14.5 Hz), 6.58 (1H, d, J = 2.5 Hz), 6.66 (1H, dd, J = 2.5, 8.0 Hz) , 6.94 (1H, d, J = 8.0 Hz), 7.37-7.52 (5H, m)
MS (FAB) m / z = 447 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₇ N ₂ O ₃ [M + H] ⁺ : 461.2804; Found 461.2811

This was converted to hydrochloric acid to give the title compound.
mp 178-182 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₆ N ₂ O ₃ 1.5HCl0.8H ₂ O: C, 65.75; H, 7.44; N, 5.29. Found: C, 65.68; H, 7.30; N, 5.25

Examples 23-26
N-[(6β, 14-epoxy-3-hydroxy-17-isobutylmorphinan-6α-yl) methyl] -trans-3-furanacrylamide hydrochloride (36), N-[(6β, 14-epoxy-3 -Hydroxy-17-isobutylmorphinan-6α-yl) methyl] -4-hydroxybenzamide hydrochloride (37), N-[(6β, 14-epoxy-3-hydroxy-17-isobutylmorphinan-6α-yl) Of methyl] -3-hydroxybenzamide hydrochloride (38), N-[(6β, 14-epoxy-3-hydroxy-17-isobutylmorphinan-6α-yl) methyl] -2-hydroxybenzamide hydrochloride (39) Composition

  From Compound 33 obtained in Reference Example 13, according to Reference Examples 4 and 5, in Reference Example 4, the room temperature was cooled with ice, THF and triethylamine were used instead of pyridine, and 3-trans- Compound 36 (22%, 3 steps), Compound 37 (26%, 3 steps) using 3- (3-furyl) acryloyl chloride, 4-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 2-methoxybenzoyl chloride Compound 38 (35%, 3 steps) and Compound 39 (46%, 3 steps) were obtained in free form, and each was converted to hydrochloric acid to give the title compound.

Compound 36
IR (neat): 1665, 1619 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.92 (6H, d), 1.19-1.36 (2H, m), 1.44-1.65 (2H, m), 1.65-1.88 (4H, m), 2.04-2.50 ( 5H, m), 2.60 (1H, dd, J = 5.5, 18.0 Hz), 3.13 (1H, d, J = 18.0 Hz), 3.32 (1H, d, J = 5.5 Hz), 3.74 (1H, dd, J = 6.5, 15.0 Hz), 3.89 (1H, dd, J = 6.5, 15.0 Hz), 6.20 (1H, d, J = 15.0 Hz), 6.48 (1H, t, J = 6.5 Hz), 6.55 (1H, d , J = 2.0 Hz), 6.63 (1H, d, J = 2.5 Hz), 6.69 (1H, dd, J = 2.5, 8.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.40 (1H, t , J = 2.0 Hz), 7.54 (1H, d, J = 15.0 Hz), 7.60 (1H, s)
MS (FAB) m / z = 463 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₅ N ₂ O ₄ [M + H] ⁺ : 463.2597; Found 463.2594
Hydrochloride
mp 200-206 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₄ N ₂ O ₄ HCl 1.2H ₂ O: C, 64.59; H, 7.24; N, 5.38. Found: C, 64.67; H, 7.37; N, 5.18

Compound 37
IR (KBr): 1637 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 0.96 (3H, d), 0.98 (3H, d), 1.18 (1H, dt, J = 12.5, 2.0 Hz), 1.47-1.65 (3H, m), 1.70-1.92 (4H, m), 2.12-2.32 (2H, m), 2.27 (1H, dd, J = 7.0, 12.5 Hz), 2.39 (1H, dt, J = 4.5, 12.5 Hz), 2.45 (1H, dd, J = 6.5, 12.5 Hz), 2.63 (1H, dd, J = 5.5, 18.0 Hz), 3.14 (1H, d, J = 18.0 Hz), 3.36 (1H, d, J = 5.5 Hz), 3.62 ( 1H, d, J = 14.5 Hz), 4.03 (1H, d, J = 14.5 Hz), 6.48 (1H, d, J = 2.5 Hz), 6.57 (1H, dd, J = 2.5, 8.0 Hz), 6.82- 6.88 (2H, m), 6.93 (1H, d, J = 8.0 Hz), 7.75-7.82 (2H, m)
MS (FAB) m / z = 463 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₅ N ₂ O ₄ [M + H] ⁺ : 463.2597; Found 463.2591
Hydrochloride
mp 203-208 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₄ N ₂ O ₄ HCl1.33H ₂ O: C, 64.29; H, 7.26; N, 5.36. Found: C, 64.33; H, 7.03; N, 5.28

Compound 38
IR (KBr): 1640 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 0.95 (3H, d), 0.97 (3H, d), 1.17 (1H, dt, J = 12.5, 2.0 Hz), 1.45-1.66 (3H, m), 1.68-1.90 (4H, m), 2.10-2.32 (2H, m), 2.24 (1H, dd, J = 7.5, 12.5 Hz), 2.37 (1H, dt, J = 4.5, 12.5 Hz), 2.43 (1H, dd, J = 6.5, 12.5 Hz), 2.61 (1H, dd, J = 5.5, 18.0 Hz), 3.13 (1H, d, J = 18.0 Hz), 3.34 (1H, d, J = 5.5 Hz), 3.62 ( 1H, d, J = 14.5 Hz), 4.03 (1H, d, J = 14.5 Hz), 6.48 (1H, d, J = 2.5 Hz), 6.58 (1H, dd, J = 2.5, 8.0 Hz), 6.93 ( 1H, d, J = 8.0 Hz), 6.96 (1H, m), 7.24-7.37 (3H, m)
MS (FAB) m / z = 463 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₅ N ₂ O ₄ [M + H] ⁺ : 463.2597; Found 463.2597
Hydrochloride
mp 182-186 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₄ N ₂ O ₄ HCl 0.8H ₂ O: C, 65.50; H, 7.18; N, 5.46. Found: C, 65.50; H, 7.15; N, 5.43

Compound 39
IR (KBr): 1639 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 0.97 (3H, d), 0.99 (3H, d), 1.19 (1H, dt, J = 12.5, 2.0 Hz), 1.49-1.70 (3H, m), 1.71-1.94 (4H, m), 2.18-2.32 (2H, m), 2.24 (1H, dd, J = 7.5, 12.5 Hz), 2.27 (1H, dt, J = 4.5, 12.5 Hz), 2.45 (1H, m), 2.57 (1H, dd, J = 6.5, 12.5 Hz), 2.75 (1H, dd, J = 5.5, 18.0 Hz), 3.16 (1H, d, J = 18.0 Hz), 3.48 (1H, d, J = 5.5 Hz), 3.73 (1H, d, J = 14.5 Hz), 4.03 (1H, d, J = 14.5 Hz), 6.50 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5 , 8.0 Hz), 6.86-6.95 (2H, m), 6.96 (1H, d, J = 8.0 Hz), 7.38 (1H, m), 7.87 (1H, m)
MS (FAB) m / z = 461 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₈ H ₃₅ N ₂ O ₄ [M + H] ⁺ : 463.2597; Found 463.2586.
Hydrochloride
mp 180-185 ° C (dec).
Anal. Calcd for C ₂₈ H ₃₄ N ₂ O ₄ HCl0.67H ₂ O: C, 65.81; H, 7.17; N, 5.48. Found: C, 65.79; H, 7.18; N, 5.37

Reference Example 14
Synthesis of t-butyl N-[(17-cyclopropylmethyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] carbamate (40)

The amino compound 5 (1.32 g) obtained in Reference Example 3 was dissolved in pyridine (8.0 ml), di-t-butyl dicarbonate (2.6 ml, 11.2 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere. After 3 hours, a small amount of water was added to the reaction solution, and the mixture was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to adjust to pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The obtained crude product was purified by silica gel column chromatography (50 g; chloroform / methanol 50/1) to obtain the title compound (1.13 g, 61%, 2 steps) as a white amorphous.
IR (neat): 1712 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 0.03-0.20 (2H, m), 0.40-0.60 (2H, m), 0.94 (1H, m), 1,26 (1H, dt, J = 13.0, 2.0 Hz), 1.38 (1H, m), 1.45 (9H, s), 1.50-1.92 (5H, m), 2.06 (1H, dt, J = 2.0, 12.5 Hz), 2.23 (1H, dt, J = 4.5, 13.0 Hz), 2.31 (1H, dd, J = 7.0, 12.5 Hz), 2.48-2.68 (3H, m), 3.11 (1H, d, J = 18.0 Hz), 3.54 (1H, dd, J = 6.5, 13.5 Hz), 3.59 (1H, dd, J = 6.5, 13.5 Hz), 3.68 (1H, d, J = 5.5 Hz), 3.77 (3H, s), 5.12 (1H, t, J = 6.5 Hz), 6.57 ( 1H, d, J = 2.5 Hz), 6.68 (1H, dd, J = 2.5, 8.0 Hz), 7.00 (1H, d, J = 8.0 Hz)
MS (FAB) m / z = 455 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₇ H ₃₉ N ₂ O ₄ [M + H] ⁺ : 455.2910; Found 455.2901.

Reference Example 15
Synthesis of t-butyl N-[(6β, 14-epoxy-3-methoxy-17-trichloroethoxycarbonylmorphinan-6α-yl) methyl] carbamate (41)

Compound 40 (1.0 g) obtained in Reference Example 14 was dissolved in dichloromethane (30.0 ml), and proton sponge (1.04 g, 4.84 mmol) and 2,2,2-trichloroethoxycarbonyl chloride (2.6 ml, 11.2 mmol) were dissolved. In addition, the mixture was stirred at room temperature under an argon atmosphere. After 2 hours, 1N HCl was added to the reaction solution, and extracted three times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The obtained crude product was purified by silica gel column chromatography (30 g; chloroform) to give the title compound (1.22 g, 96%) as a white amorphous product.
IR (neat): 1784, 1713 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1.20-1.40 (2H, m), 1.48 (9H, s), 1.54-1.92 (4H, m), 2.12 (1H, dt, J = 4.5, 13.0 Hz) , 2.66-3.02 (2H, m), 2.93 (1H, d, J = 18.0 Hz), 3.22 (1H, dd, J = 5.5, 18.0 Hz), 3.54 (1H, dd, J = 5.5, 13.5 Hz), 3.59 (1H, m), 3.80 (3H, s), 3.91 (1H, m), 4.50-5.13 (4H, m), 6.60 (1H, d, J = 2.5 Hz), 6.68 (1H, m), 7.03 (1H, m)
MS (FAB) m / z = 597 [M + Na] ⁺
HRMS (FAB) Calcd for C ₂₆ H ₃₃ Cl ₃ N ₂ O ₆ [M + Na] ⁺ : 597.1302; Found 597.1331

Reference Example 16
Synthesis of t-butyl N-[(6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] carbamate (41)

  Compound 41 (1.22 g) obtained in Example 15 was dissolved in acetic acid (8 ml), zinc (555 mg, 8.48 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere. After 6 hours, the reaction solution was filtered, concentrated, aqueous ammonia was added to pH = 9, and the mixture was extracted 3 times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (921 mg) of the title compound as a clear oil.

Reference Example 17
Synthesis of t-butyl N-[(17-benzyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methyl] carbamate (43)

The crude product 42 (920 mg) obtained in Reference Example 16 was dissolved in DMF (10 ml), potassium carbonate (1.59 g, 11.5 mmol) and benzyl bromide (0.81 ml, 6.9 mmol) were added, and under an argon atmosphere, Stir at room temperature. After 40 minutes, the reaction solution was concentrated and extracted three times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product as an oil. The obtained crude product was purified by silica gel column chromatography (30 g; chloroform) to give the title compound (884 mg, 85%, 2steps) as a white amorphous product.
IR (neat): 1712 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1,23 (1H, dt, J = 13.0, 2.0 Hz), 1.37 (1H, m), 1.47 (9H, s), 1.48-1.91 (5H, m) , 2.14-2.32 (2H, m), 2.48 (1H, ddd, J = 2.0, 4.5, 12.0 Hz), 2.64 (1H, dd, J = 5.5, 18.0 Hz), 3.26 (1H, d, J = 18.0 Hz) ), 3.35 (1H, d, J = 5.5 Hz), 3.54 (1H, dd, J = 6.5, 13.5 Hz), 3.64 (1H, dd, J = 6.5, 13.5 Hz), 3.76 (1H, d, J = 5.5 Hz), 3.78 (3H, s), 3.85 (1H, d, J = 13.5 Hz), 5.15 (1H, t, J = 6.5 Hz), 6.58 (1H, d, J = 2.5 Hz), 6.71 (1H , dd, J = 2.5, 8.0 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.22-7.45 (5H, m)
MS (FAB) m / z = 491 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₀ H ₃₉ N ₂ O ₄ [M + H] ⁺ : 491.2910; Found 491.2917.

Reference Example 18
Synthesis of (17-benzyl-6β, 14-epoxy-3-methoxymorphinan-6α-yl) methanamine (44)

  Compound 43 (890 mg) obtained in Reference Example 17 was dissolved in methanol (8 ml), 1N HCl (4 ml) was added, and the mixture was stirred at 60 ° C. under an argon atmosphere. After 8 hours, the reaction mixture was concentrated, adjusted to pH = 9 with aqueous sodium hydrogen carbonate solution, and extracted three times with chloroform. The chloroform layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to give a crude product (721 mg) of the title compound as a clear oil.

Examples 27-30
N-[(17-benzyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] benzamide hydrochloride (45), N-[(17-benzyl-6β, 14-epoxy-3-hydroxy Morphinan-6α-yl) methyl] -4-hydroxybenzamide hydrochloride (46), N-[(17-benzyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -3-hydroxy Synthesis of benzamide hydrochloride (47), N-[(17-benzyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] -2-hydroxybenzamide hydrochloride (48)

  Compound 45 (33%, 3 steps) was obtained from the roughly purified product 44 obtained in Reference Example 18 in the same manner as in Reference Examples 4 and 5. In Reference Example 4, the room temperature was kept under ice cooling to replace pyridine. Compound 46 (47%, 3 steps), Compound 47 (43%, 3 steps) using 4-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 2-methoxybenzoyl chloride instead of benzoic anhydride using THF and triethylamine steps), a free form of compound 48 (59%, 3 steps). Each was chlorinated to give the title compound.

Compound 45
IR (neat): 1644 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1,18 (1H, dt, J = 12.5, 2.0 Hz), 1.26-1.82 (6H, m), 2.04-2.25 (2H, m), 2.40 (1H, m), 2.55 (1H, dd, J = 5.5, 18.0 Hz), 3.16 (1H, d, J = 18.0 Hz), 3.28 (1H, d, J = 5.5 Hz), 3.62-3.74 (2H, m), 3.82 (1H, dd, J = 6.5, 14.0 Hz), 3.92 (1H, dd, J = 6.5, 14.0 Hz), 6.53 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5, 8.0 Hz), 6.82 (1H, t, 6.5 Hz), 6.92 (1H, d, J = 8.0 Hz), 7.17-7.49 (8H, m), 7.72-7.85 (2H, m)
MS (FAB) m / z = 481 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₃₃ N ₂ O ₃ [M + H] ⁺ : 481.2491; Found 481.2474
Hydrochloride
mp 186-192 ° C (dec).
Anal. Calcd for C ₃₁ H ₃₂ N ₂ O ₃ HCl1.4H ₂ O: C, 68.66; H, 6.65; N, 5.17. Found: C, 68.51; H, 6.55; N, 5.19

Compound 46
IR (KBr): 1640 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 1,10-1.24 (2H, m), 1.36-1.60 (3H, m), 1.71 (1H, m), 1.78-1.91 (2H, m), 2.22 (1H, dt, J = 4.5, 13.0 Hz), 2.30 (1H, dt, J = 2.0, 12.0 Hz), 2.48 (1H, m), 2.57 (1H, dd, J = 5.5, 18.0 Hz), 3.24 ( 1H, d, J = 5.5 Hz), 3.28 (1H, d, J = 18.0 Hz), 3.64 (1H, d, J = 14.0 Hz), 3.74 (1H, d, J = 13.5 Hz), 3.78 (1H, d, J = 13.5 Hz), 4.03 (1H, d, J = 14.0 Hz), 6.50 (1H, d, J = 2.5 Hz), 6.59 (1H, dd, J = 2.5, 8.0 Hz), 6.94-7.02 ( 2H, m), 6.97 (1H, d, J = 8.0 Hz), 7.21-7.38 (6H, m), 7.38-7.46 (2H, m)
MS (FAB) m / z = 497 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 497.2440; Found 497.2456
Hydrochloride
mp 177-181 ° C (dec).
Anal.Calcd for C ₃₁ H ₃₂ N ₂ O ₄ HCl0.8H ₂ O: C, 68.01; H, 6.37; N, 5.12. Found: C, 67.87; H, 6.38; N, 5.03

Compound 47
IR (KBr): 1638 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 1,14-1.32 (2H, m), 1.38-1.64 (3H, m), 1.70 (1H, m), 1.80-1.89 (2H, m), 2.21 (1H, dt, J = 4.5, 13.0 Hz), 2.29 (1H, dt, J = 2.0, 12.0 Hz), 2.48 (1H, m), 2.57 (1H, dd, J = 5.5, 18.0 Hz), 3.25 ( 1H, d, J = 5.5 Hz), 3.27 (1H, d, J = 18.0 Hz), 3.63 (1H, d, J = 14.0 Hz), 3.75 (1H, d, J = 13.5 Hz), 3.79 (1H, d, J = 13.5 Hz), 4.02 (1H, d, J = 14.0 Hz), 6.49 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5, 8.0 Hz), 6.82-6.90 ( 2H, m), 6.97 (1H, d, J = 8.0 Hz), 7.21-7.45 (5H, m), 7.74-7.84 (2H, m)
MS (FAB) m / z = 497 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 497.2440; Found 497.2462
Hydrochloride
mp 190-195 ℃ (dec)

Compound 48
IR (KBr): 1639 cm ^-1
1 H NMR (300 MHz, CD ₃ OD): δ 1,14-1.23 (2H, m), 1.40-1.66 (3H, m), 1.72 (1H, m), 1.82-1.91 (2H, m), 2.25 (1H, dt, J = 4.5, 13.0 Hz), 2.33 (1H, dt, J = 2.0, 12.0 Hz), 2.47 (1H, m), 2.62 (1H, dd, J = 5.5, 18.0 Hz), 3.26 ( 1H, d, J = 18.0 Hz), 3.28 (1H, d, J = 5.5 Hz), 3.73 (1H, d, J = 14.0 Hz), 3.78 (1H, d, J = 13.5 Hz), 3.82 (1H, d, J = 13.5 Hz), 4.03 (1H, d, J = 14.0 Hz), 6.49 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5, 8.0 Hz), 6.88-6.95 ( 2H, m), 6.98 (1H, d, J = 8.0 Hz), 7.21-7.46 (6H, m), 7.88 (1H, m)
MS (FAB) m / z = 497 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₁ H ₃₃ N ₂ O ₄ [M + H] ⁺ : 497.2440; Found 497.2444
Hydrochloride
mp 182-187 ° C (dec).
Anal. Calcd for C ₃₁ H ₃₂ N ₂ O ₄ HCl0.67H ₂ O: C, 68.31; H, 6.35; N, 5.14. Found: C, 68.38; H, 6.41; N, 5.18

Examples 31-32
N-[(6β, 14-epoxy-3-hydroxy-17-phenethylmorphinan-6α-yl) methyl] benzamide hydrochloride (49), N-[(17-cyclobutylmethyl-6β, 14-epoxy-3 Of -Hydroxy-6α-yl) methyl] benzamide hydrochloride (50)

  From the roughly purified product 42 obtained in Reference Example 16, compound 49 (36%) was obtained by using phenethyl bromide and cyclobutylmethyl bromide instead of benzyl bromide in Reference Example 17 in the same manner as in Reference Examples 17, 18, 4, and 5. 5steps), and a free form of Compound 50 (32%, 5steps) was obtained. These were converted to hydrochloric acid to give the title compound.

Compound 49
IR (neat): 1644 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ1,20-1.42 (2H, m), 1.50-1.90 (5H, m), 2.12-2.32 (2H, m), 2.58 (1H, m), 2.64 (1H , dd, J = 5.5, 18.0 Hz), 2.70-2.94 (4H, m), 3.20 (1H, d, J = 18.0 Hz), 3.52 (1H, d, J = 5.5 Hz), 3.92 (1H, dd, J = 6.5, 14.0 Hz), 3.96 (1H, dd, J = 6.5, 14.0 Hz), 6.64 (1H, d, J = 2.5 Hz), 6.70 (1H, dd, J = 2.5, 8.0 Hz), 6.96 ( 1H, d, J = 8.0 Hz), 6.98 (1H, t, 6.5 Hz), 7.14-7.32 (5H, m), 7.39-7.56 (3H, m), 7.82-7.91 (2H, m)
MS (FAB) m / z = 481 [M + H] ⁺
HRMS (FAB) Calcd for C ₃₂ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 495.2648; Found 495.2653
Hydrochloride
mp 183-187 ° C (dec).
Anal. Calcd for C ₃₂ H ₃₄ N ₂ O ₃ HClH ₂ O: C, 69.99; H, 6.79; N, 5.10. Found: C, 70.09; H, 6.74; N, 5.13

Compound 50
IR (neat): 1645 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ1,16-1.36 (2H, m), 1.44-1.92 (9H, m), 1.94-2.24 (4H, m), 2.38 (1H, m), 2.54 (1H , dd, J = 5.5, 18.0 Hz), 2.54-2.64 (3H, m), 3.18 (1H, d, J = 18.0 Hz), 3.31 (1H, d, J = 5.5 Hz), 3.83 (1H, dd, J = 6.5, 14.0 Hz), 3.93 (1H, dd, J = 6.5, 14.0 Hz), 6.60 (1H, d, J = 2.5 Hz), 6.68 (1H, dd, J = 2.5, 8.0 Hz), 6.94 ( 1H, d, J = 8.0 Hz), 6.95 (1H, t, 6.5 Hz), 7.37-7.54 (3H, m), 7.80-7.88 (2H, m)
MS (FAB) m / z = 459 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₉ H ₃₅ N ₂ O ₃ [M + H] ⁺ : 459.2648; Found 459.2651
Hydrochloride
mp 188-193 ° C (dec).
Anal. Calcd for C ₂₉ H ₃₄ N ₂ O ₃ 1.5HCl0.6H ₂ O: C, 66.49; H, 7.11; N, 5.33. Found: C, 66.76; H, 6.98; N, 5.07

Example 51
Synthesis of 1,1-dimethyl-3-[(17-cyclopropylmethyl-6β, 14-epoxy-3-hydroxymorphinan-6α-yl) methyl] urea (51)

Compound 43 obtained in Reference Example 17 was reacted with dimethylamine in the same manner as in Reference Example 4, and demethylated in the same manner as in Reference Example 5 to obtain the title compound (53%). Pharmacological evaluation was performed with hydrochloride.
IR (NaCl): 1632 cm ^-1
1 H NMR (300 MHz, CDCl ₃ ): δ 1,14-1.32 (2H, m), 1.44 (1H, dt, J = 12.5, 2.0 Hz), 1.56 (1H, m), 1.64-1.82 (3H, m), 2.16 (1H, dt, J = 4.5, 12.5 Hz), 2.24 (1H, dt, J = 2.0, 12.0 Hz), 2.46 (1H, m), 2.58 (1H, dd, J = 5.5, 18.0 Hz) ), 2.96 (6H, s), 3.23 (1H, d, J = 18.0 Hz), 3.30 (1H, d, J = 5.5 Hz), 3.63-3.82 (4H, m), 5.10 (1H, t, J = 5.5 Hz), 6.68 (1H, dd, J = 2.5, 8.0 Hz), 6.71 (1H, d, J = 2.5 Hz), 6.96 (1H, d, J = 8.0 Hz), 7.18-7.42 (5H, m)
MS (FAB) m / z = 448 [M + H] ⁺
HRMS (FAB) Calcd for C ₂₇ H ₃₄ N ₃ O ₃ [M + H] ⁺ : 448.2600; Found 448.2614

Example 52
Receptor binding test using guinea pig brain homogenate After homogenizing guinea pig forebrain and cerebellum with ice-cold buffer (50 mM Tris-HCl, pH 7.4), centrifuge (12,000 xg, 20 minutes, 4 ° C), and Abandoned Qing. This operation was repeated three times, and the resulting precipitate was resuspended in a buffer to obtain a membrane specimen.

Membrane specimen (0.2-0.6 mg / tube) in polypropylene tube, radioligand (μ receptor: 0.5 nM [ ³ H] -DAMGO, δ receptor: 0.1 nM [ ³ H] -NTI, κ receptor: 0.5 nM [ ³ H] -U69593), the test compound was added and incubated at 25 ° C. for 120 minutes. After completion of the reaction, the solution was quickly suction filtered through a GF / B filter (Whatman) immersed in 0.1% polyethyleneimine for at least 2 hours, and washed with ice-cold buffer (5 times 3 mL). The filter was transferred to a vial, 5 mL of scintillation cocktail was added, and the radioactivity (dpm) in the vial was measured with a liquid scintillation counter (manufactured by Packard).

Specific binding (SB) is calculated by subtracting non-specific binding (NSB) obtained by adding an excess of non-radioactive ligand for each receptor from the total binding (TB) (TB-NSB), for various tests. SB in the presence of compound was expressed as a percentage of control SB. The concentration (IC ₅₀ ) of the test compound that inhibits the specific binding by the radioligand by 50% was calculated by a spreadsheet software Microsoft Excel (manufactured by Microsoft) (2-point linear regression with 50% sandwiched). Subsequently, the inhibition constant Ki was calculated by the following formula, and the ratio of the Ki value of the μ receptor and the κ receptor was determined.
Ki = IC ₅₀ / (1+ [L *] / Kd) L *: Radioligand concentration, Kd: Dissociation constant μ: [ ³ H] DAMGO [L *]: 0.5 nM, Kd: 0.54 nM
κ: [ ³ H] U-69,593 [L *]: 0.5 nM, Kd: 0.87 nM

  As a result, it was revealed that compounds 16, 17, 18, 21, 34, 38, 39, 45, 46, 47, 48, 51 have selective binding to the opioid κ receptor, and opioid κ. It has been shown to be useful as a therapeutic or prophylactic agent for diseases and symptoms related to receptors.

Example 53
Analgesic evaluation by mouse acetic acid rising test
Using ddY male mice, the administration solvent or test compound was administered subcutaneously at a dose volume of 0.1 (mL / 10 g body weight). 15 minutes later, a 0.6% (v / v) acetic acid solution was administered intraperitoneally at a dose volume of 0.1 (mL / 10 g body weight), and after 10 minutes, a rising reaction (curving the body, The number of occurrences of twisting behavior was measured, and this number was used as an index of pain. The amount of the test compound at which the number of rising reactions in the group administered with the solvent of the test compound was 50% was taken as ED _50, and the analgesic activity was evaluated based on that value. Note that physiological saline or 10% DMSO was used as a test compound administration solvent.

  As shown in Table 3, it was found that compounds 45, 46, 48 and 51 have an acetic acid rising effect and can be expected as useful opioid κ selective analgesics in combination with Example 52.

Claims (6)

Formula (I)

[Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 4 to 9 carbon atoms, cycloalkenyl alkyl having 6 to 9 carbon atoms, aryl having 6 to 12 carbon atoms, or 7 to 13 carbon atoms. Aralkyl, alkenyl having 3 to 7 carbon atoms, furanyl, furanylalkyl (the alkyl part has 1 to 5 carbon atoms), thienyl, thienylalkyl (the alkyl part having 1 to 5 carbon atoms), pyridyl, or pyridylalkyl ( The alkyl part represents 1 to 5 carbon atoms;
R ² and R ³ are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons. Representation;
R ⁴ represents hydrogen or alkyl having 1 to 5 carbons;
X represents —C (═O) — or —SO ₂ —;
R ⁵ is aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, furanyl, furanyl alkyl (the alkyl part has 1 to 5 carbon atoms), furanyl alkenyl (the alkenyl part has 1 to 5 carbon atoms) ), Thienyl, thienylalkyl (the alkyl part has 1 to 5 carbon atoms), thienylalkenyl (the alkenyl part has 1 to 5 carbon atoms), pyridyl, pyridylalkyl (the alkyl part has 1 to 5 carbon atoms), pyridylalkenyl (The alkenyl moiety has 1 to 5 carbon atoms), camphor, or —NR ⁶ ₂ (wherein R ⁶ represents hydrogen or alkyl having 1 to 5 carbon atoms, and each R ⁶ may be the same or different). Represents;
The aryl moiety, heteroaryl moiety, and cycloalkyl moiety included in the substituents shown above are fluoro, chloro, bromo, nitro, hydroxy, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, carbon Optionally substituted with one or more substituents R ⁷ selected from the group consisting of thioalkoxy having 1 to 5 and alkanoyloxy having 1 to 5 carbons;
Provided that when R ¹ is cyclopropylmethyl, R ³ and R ⁴ are hydrogen, X is —C (═O) —, and R ⁵ is phenyl or benzyl, the phenyl or benzyl group is one or more substituents R ⁷ Must be replaced with Or a pharmacologically acceptable acid addition salt thereof. 6. The 6,14-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, wherein R ³ in formula (I) is hydrogen. In General Formula (I), R ¹ is alkyl having 1 to 5 carbons, cycloalkyl alkyl having 4 to 9 carbons, or aralkyl having 7 to 13 carbons, and R ² is hydrogen, hydroxy, or carbon An alkoxy group having 1 to 5 carbon atoms, R ⁴ is hydrogen or methyl, R ⁵ is an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, and a furanylalkyl (the carbon number of the alkyl moiety is 1 5), furanyl alkenyl (the carbon number of the alkenyl moiety is 1 to 5), camphor, or —NR ⁶ ₂ (wherein R ⁶ is both alkyl having 1 to 5 carbon atoms), 14-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof. In the general formula (I), R ¹ is isobutyl, cyclopropylmethyl, or benzyl, R ² is hydroxy, R ⁴ is hydrogen, and R ⁵ is phenyl, hydroxyphenyl, benzyl, phenethyl. 4. The 6,14-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 3, which is camphor, or dimethylamino.   5. A pharmaceutical comprising the 6,14-epoxymorphinan derivative according to any one of claims 1 to 4 or a pharmacologically acceptable acid addition salt thereof as an active ingredient.   5. A preventive or therapeutic agent for pain comprising the 6,14-epoxymorphinan derivative according to any one of claims 1 to 4 or a pharmacologically acceptable acid addition salt thereof as an active ingredient.