JPWO2016152953A1 - Morphinan derivatives and their pharmaceutical use - Google Patents

Abstract

The present invention has peripheral type selective opioid kappa receptor agonist, side effects such as drug dependence and respiratory depression based on opioid μ receptor action, and central opioid kappa receptor action The object is to provide an analgesic with reduced side effects such as sedation and discomfort. The present invention provides a medicament containing, as an active ingredient, a morphinan derivative represented by the following formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof.

Description

  The present invention relates to a morphinan derivative and a pharmaceutical use thereof.

  Opioid receptors are seven transmembrane receptors coupled to GTP-binding proteins, and are classified into three subtypes: μ receptors, δ receptors, and κ receptors.

  Opioid μ receptor agonists represented by morphine and fentanyl have a strong analgesic action and are currently widely used as analgesics in clinical settings. However, on the other hand, these opioid μ receptor agonists are also known to have side effects such as drug dependence and respiratory depression, and the development of analgesics that do not have such side effects is desired.

Selective opioid κ receptor agonists were expected to be powerful analgesics without the side effects of opioid μ receptor agonists such as drug dependence and respiratory depression. However, because selective opioid κ receptor agonists are difficult to separate from their analgesic effects and side effects such as sedation and discomfort, selective opioid κ receptor agonists are currently used as analgesics. Is not used. The only selective opioid κ receptor agonist used as a medicine, nalfrafin hydrochloride represented by the following formula (Patent Document 1) is used as a therapeutic drug for intractable pruritus associated with renal dialysis or liver injury. It is used.

  Opioid kappa receptors are present throughout the body, such as in the brain, in the spinal cord, in the center and periphery of the primary sensory afferents, and on immune cells. In recent years, it has been shown that opioid κ receptors present in the periphery are not related to side effects such as sedation and discomfort, and exert an analgesic action by activation thereof (Non-patent Documents 1 and 2). Therefore, even if it is an opioid κ receptor agonist, if it is a peripheral selective opioid κ receptor agonist with a high degree of central migration, it will be an analgesic with reduced side effects such as sedation and discomfort. You can expect as you get.

  Currently, as a peripheral selective opioid κ receptor agonist, non-morphinan derivative asimadrine (Patent Document 2), peptide CR-845 (Patent Document 3), and the like are known.

  On the other hand, 10α-hydroxy-nalfurafine is known as a morphinan derivative (Non-patent Document 3).

International Publication No. 1993/015081 Japanese Patent No. 3210771 International Publication No. 2008/057608

Riviere et al., British Journal of Pharmacology, 2004, vol. 141, p. 1331-1334 Hughes et al., The Open Medicinal Chemistry Journal, 2013, Vol. 7, p. 16-22 Horikiri et al., Chemical Pharmaceutical Bulletin, 2004, Vol. 52, p. 664-669

  However, it is not known at all that 10α-hydroxy-nalfurafine has a kappa receptor agonist or a peripheral opioid κ receptor agonist. In addition, no morphinan derivatives having peripheral type selective opioid κ receptor agonist activity are known.

  The present invention has peripheral type selective opioid κ receptor agonist, and is based on side effects such as drug dependence and respiratory depression based on opioid μ receptor agonist, and central opioid κ receptor agonist The object is to provide an analgesic with reduced side effects such as sedation and discomfort.

  As a result of intensive studies to achieve the above object, the present inventors have found a morphinan derivative having peripheral type selective opioid κ receptor agonist or a pharmacologically acceptable acid addition salt thereof, Furthermore, these have been found to be useful as analgesics based on their action, and the present invention has been completed.

That is, the present invention provides a morphinan derivative represented by the following formula (I) or a pharmacologically acceptable acid addition salt thereof.

The present invention also provides a medicament, particularly an analgesic, containing a morphinan derivative represented by the following formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

  The above formula (I), which is an active ingredient of the morphinan derivative represented by the above formula (I) or a pharmacologically acceptable acid addition salt thereof or the medicament of the present invention, particularly an analgesic, of the present invention. Alternatively, since the morphinan derivative represented by the formula (II) or a pharmacologically acceptable acid addition salt thereof has peripheral type selective opioid κ receptor agonist activity, drug dependence based on opioid μ receptor agonist activity It can be used as a medicine, particularly an analgesic, in which side effects such as sedation and discomfort based on vasoactivity, respiratory depression, and central opioid κ receptor agonist activity are reduced.

The morphinan derivative of the present invention is characterized by being represented by the following formula (I).

A morphinan derivative which is an active ingredient of the medicament of the present invention, particularly an analgesic, is characterized by being represented by the following formula (I) or formula (II).

  Examples of the pharmacologically acceptable acid addition salt of the morphinan derivative represented by the above formula (I) or formula (II) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodic acid. Inorganic acid salts such as salt or phosphate, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoic acid Examples include organic carboxylates such as salts or phthalates, or organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Hydrochloride, hydrobromide, phosphate, tartrate or methanesulfonate are preferred, and hydrochloride, tartrate or methanesulfonate are more preferred.

  The morphinan derivative represented by the above formula (I) or formula (II) can be produced by an appropriate method based on characteristics derived from the basic skeleton and the type of substituent. The starting materials and reagents used for this production can generally be purchased. Moreover, the synthesis method of the starting material used in Reference Example 7 is disclosed in JP-A-2014-62069.

  Examples of the acid used for the chlorination reaction of the morphinan derivative represented by the above formula (I) or formula (II) include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, or phosphoric acid. , Acetic acid, lactic acid, citric acid, oxalic acid, glutaric acid, malic acid, tartaric acid, fumaric acid, mandelic acid, maleic acid, benzoic acid, phthalic acid and other organic carboxylic acids or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid , Organic sulfonic acids such as p-toluenesulfonic acid or camphorsulfonic acid.

  The chlorination reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such solvents include aliphatic alcohols such as methanol, ethanol or isopropanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether, N, N-dimethylformamide or N-methyl. Amides such as pyrrolidone, sulfoxides such as dimethyl sulfoxide, aliphatic nitriles such as acetonitrile or propionitrile, ketones such as acetone or 2-butanone, esters such as methyl acetate, ethyl acetate or n-butyl acetate, or Water etc. are mentioned, You may use these mixed solvents.

  Since the morphinan derivative represented by the above formula (I) or formula (II) and a pharmacologically acceptable acid addition salt thereof have peripheral type opioid κ receptor agonist activity, opioid μ receptor operation It can be used as a medicine, particularly an analgesic, in which side effects such as drug dependence and respiratory depression based on sex and sedation and discomfort based on central opioid κ receptor agonists are reduced.

Selective opioid κ receptor agonist means that the ratio of μ receptor agonist to κ receptor agonist (μ receptor agonist / κ receptor agonist ratio) is 100 times or more. The morphinan derivative represented by the above formula (I) or formula (II) and a pharmacologically acceptable acid addition salt thereof have selective κ receptor agonist activity, for example, human opioid κ receptor and It can be evaluated by measuring the operability of these receptors (for example, the inhibitory effect on Forskolin-induced cAMP production) using cells stably expressing human opioid μ receptors. If the EC ₅₀ (κ) value relative to the EC ₅₀ (μ) value (EC ₅₀ (μ) value / EC ₅₀ (κ) value) is 100 times or more, it can be said that it has selective opioid κ receptor agonist activity.

  The peripheral type means that the ratio of the central drug concentration to the peripheral drug concentration after drug administration (central concentration / peripheral concentration) is 0.2 or less. The peripheral form of the morphinan derivative represented by the above formula (I) or formula (II) and its pharmacologically acceptable acid addition salt is, for example, a plasma concentration after intravenous administration to mice. It can be evaluated by measuring the brain concentration. If the ratio of brain concentration to plasma concentration (brain concentration / plasma concentration ratio) is 0.2 or less, it can be said to be a peripheral type.

  The excellent analgesic action of the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof can be evaluated using an appropriate animal model. Suitable animal models for evaluating analgesic action include, for example, mouse acetate rising model (Academic Press, 1977, Chapter 6, p. 83-99), rat formalin test (Pain, 1992, Vol. 51). , P. 5-17), rat carrageenin-induced inflammation model (Japan Journal of Pharmacology, 1970, 20, 337-348), rat hot plate test for acute pain (Journal of Pharmacology and Experimental Thermal, 1975, Vol. 192, pp. 497-505), or tail flick test (Journal of Pharmaceutical Sciences, 1962, No. Volume 1, p.185-186), and the like.

  A medicament containing the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof as an active ingredient is a mammal (eg, mouse, rat, hamster, rabbit, Cats, dogs, cows, sheep, monkeys or humans), especially when administered to humans, it exhibits excellent analgesic activity.

  As a dosage form of the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof, the morphinan derivative represented by the above formula (I) or formula (II) Alternatively, the pharmacologically acceptable acid addition salt thereof can be administered orally or parenterally as it is or with a pharmaceutically acceptable carrier.

  As a dosage form when orally administering a medicament containing the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof, for example, tablets (sugar-coated tablets and (Including film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions or suspensions, and dosage forms for parenteral administration Examples include injections, infusions, drops, and suppositories. Also, combined with an appropriate base (for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester) It is also effective to make a sustained-release preparation.

  The preparation of the above dosage form can be prepared according to a known production method generally used in the pharmaceutical field. In this case, excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents and / or emulsifiers and the like generally used in the pharmaceutical field are included as necessary. Can be manufactured.

  The above tablet can be prepared by adding an excipient, a binder, a disintegrant and / or a lubricant, and the pill and the above granule can be prepared by adding an excipient, a binder. It can be carried out by containing an agent and / or a disintegrant. The above powder and capsules are prepared with excipients, the syrup is prepared with sweeteners, and the emulsion or suspension is prepared with surfactants, suspensions. It can be carried out by containing an agent and / or an emulsifier.

  Examples of the excipient include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate or calcium sulfate.

  Examples of the binder include starch paste, gum arabic solution, gelatin solution, tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.

  Examples of the disintegrant include starch or calcium carbonate.

  Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.

  Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.

  Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.

  Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.

  Examples of the emulsifier include gum arabic, tragacanth, gelatin, and polysorbate 80.

  Furthermore, in the case of preparing a medicament containing the morphinan derivative represented by the above formula (I) or formula (II) or a pharmaceutically acceptable acid addition salt thereof in the above dosage form, Commonly used colorants, preservatives, fragrances, flavoring agents, stabilizers and / or thickeners can be added.

  The daily dose of the pharmaceutical containing the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof depends on the patient's condition, body weight, and type of compound. Depending on the route of administration, etc., for example, when administered orally, it is preferably administered in the range of 0.01 mg to 1000 mg in the case of an adult (body weight of about 60 kg), divided into 1 to 3 times, parenteral administration In the case of an injection, it is preferably administered by intravenous injection in the range of 0.001 mg to 100 mg per kg body weight.

  EXAMPLES Hereinafter, although a reference example and an Example are shown and this invention is explained in full detail, this invention is not limited to these.

  The solvent name in parentheses shown in the NMR data indicates the solvent used for the measurement.

  The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus manufactured by JEOL. The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), m ( Multiple lines), br (wide), or a combination thereof. The IR spectrum was measured using FT / IR-410 manufactured by JASCO Corporation, and the ESI-MS spectrum was measured using Micromass ZQ2K manufactured by Waters or 1200LC / MSD manufactured by Agilent Technology. All solvents were commercially available. For flash chromatography, YFLC W-prep2XY manufactured by Yamazen Co., Ltd. was used.

  Water used in Reference Examples and Examples means distilled water.

ナロキソン塩酸塩二水和物（１０ｇ、２５ｍｍｏｌ）の水（１００ｍＬ）溶液に、炭酸水素ナトリウム（４．２ｇ、５０ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液をクロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、ナロキソン（フリー体）を得た。得られたナロキソン（フリー体）のＮ，Ｎ−ジメチルホルムアミド（４０ｍＬ）溶液に、炭酸カリウム（１０ｇ、７５ｍｍｏｌ）、ベンジルブロミド（３．３ｍＬ、２８ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−３−アリル−９−（ベンジルオキシ）−４ａ−ヒドロキシ−２，３，４，４ａ，５，６−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７（７ａＨ）−オン（８．２ｇ、２工程収率７６％）を得た。
¹H NMR (400 MHz, CDCl₃): δ1.53-1.69 (m, 2H), 1.83-1.91 (m, 1H), 2.09-2.18 (m, 1H), 2.27-2.34 (m, 1H), 2.34-2.44 (m, 1H), 2.52-2.62 (m, 2H), 2.97-3.08 (m, 2H), 3.08 (d, J = 18.4 Hz, 1H), 3.15 (d, J = 6.4 Hz, 2H), 4.69 (s, 1H), 5.04 (brs, 1H), 5.19 (d, J = 10.4 Hz, 1H), 5.21 (d, J = 12.0 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.29 (d, J = 12.0 Hz, 1H), 5.82 (ddt, J = 10.4, 17.2, 6.4Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.35 (q, J = 7.2 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H).Reference Example 1 (4R, 4aS, 7aR, 12bS) -3-allyl-9- (benzyloxy) -4a-hydroxy-2,3,4,4a, 5,6-hexahydro-1H-4,12- Synthesis of methanobenzofuro [3,2-e] isoquinolin-7 (7aH) -one:

Sodium hydrogen carbonate (4.2 g, 50 mmol) was added to a solution of naloxone hydrochloride dihydrate (10 g, 25 mmol) in water (100 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain naloxone (free form). To a solution of the obtained naloxone (free form) in N, N-dimethylformamide (40 mL), potassium carbonate (10 g, 75 mmol) and benzyl bromide (3.3 mL, 28 mmol) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, (4R, 4aS, 7aR, 12bS) -3-allyl-9- (benzyloxy) -4a-hydroxy-2,3,4, 4a, 5,6-hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7 (7aH) -one (8.2 g, 76% yield over 2 steps) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.53-1.69 (m, 2H), 1.83-1.91 (m, 1H), 2.09-2.18 (m, 1H), 2.27-2.34 (m, 1H), 2.34 -2.44 (m, 1H), 2.52-2.62 (m, 2H), 2.97-3.08 (m, 2H), 3.08 (d, J = 18.4 Hz, 1H), 3.15 (d, J = 6.4 Hz, 2H), 4.69 (s, 1H), 5.04 (brs, 1H), 5.19 (d, J = 10.4 Hz, 1H), 5.21 (d, J = 12.0 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.29 (d, J = 12.0 Hz, 1H), 5.82 (ddt, J = 10.4, 17.2, 6.4Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H ), 7.29 (d, J = 7.2 Hz, 1H), 7.35 (q, J = 7.2 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H).

（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−３−アリル−９−（ベンジルオキシ）−４ａ−ヒドロキシ−２，３，４，４ａ，５，６−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７（７ａＨ）−オン（８．２ｇ、２５ｍｍｏｌ）のアセトニトリル（２５０ｍＬ）と水（５０ｍＬ）との混合溶液に、トリス（トリフェニルフォスフィン）ロジウム（Ｉ）クロリド（２．３ｇ、２．５ｍｍｏｌ）を加え、アルゴン雰囲気下、８０℃で１０時間撹拌した。反応液を室温まで冷却し、減圧濃縮した。残渣に飽和食塩水、酢酸エチルを加え、不溶物を濾別し、濾液を酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製し、（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−９−（ベンジルオキシ）−４ａ−ヒドロキシ−２，３，４，４ａ，５，６−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７（７ａＨ）−オン（３．５ｇ、２工程収率３９％）を得た。
¹H NMR (400 MHz , CDCl₃): δ1.58-1.70 (2H, m), 2.00-2.11 (1H, m), 2.27-2.35 (1H, m), 2.56-2.67 (1H, m), 2.73-2.82 (1H, m), 2.99-3.16 (3H, m), 3.29 (1H, d, J = 18.8 Hz), 3.66-3.78 (1H, m), 4.75 (1H, s), 5.21 (1H, d, J = 12.0 Hz), 5.28 (1H, d, J = 12.0 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.77 (1H, d, J = 8.0 Hz), 7.29 (1H, d, J = 7.6 Hz), 7.35 (2H, dd, J = 7.2, 7.6 Hz), 7.44 (2H, d, J = 7.2 Hz).Reference Example 2 (4R, 4aS, 7aR, 12bS) -9- (benzyloxy) -4a-hydroxy-2,3,4,4a, 5,6-hexahydro-1H-4,12-methanobenzofuro [3 Synthesis of 2-e] isoquinolin-7 (7aH) -one:

(4R, 4aS, 7aR, 12bS) -3-allyl-9- (benzyloxy) -4a-hydroxy-2,3,4,4a, 5,6-hexahydro-1H-4,12-methanobenzofuro [3,2 -E] To a mixed solution of isoquinolin-7 (7aH) -one (8.2 g, 25 mmol) in acetonitrile (250 mL) and water (50 mL) was added tris (triphenylphosphine) rhodium (I) chloride (2.3 g). 2.5 mmol), and the mixture was stirred at 80 ° C. for 10 hours under an argon atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. To the residue were added saturated brine and ethyl acetate, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to give (4R, 4aS, 7aR, 12bS) -9. -(Benzyloxy) -4a-hydroxy-2,3,4,4a, 5,6-hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7 (7aH) -one (3.5 g) 2 step yield 39%) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.58-1.70 (2H, m), 2.00-2.11 (1H, m), 2.27-2.35 (1H, m), 2.56-2.67 (1H, m), 2.73 -2.82 (1H, m), 2.99-3.16 (3H, m), 3.29 (1H, d, J = 18.8 Hz), 3.66-3.78 (1H, m), 4.75 (1H, s), 5.21 (1H, d , J = 12.0 Hz), 5.28 (1H, d, J = 12.0 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.77 (1H, d, J = 8.0 Hz), 7.29 (1H, d, J = 7.6 Hz), 7.35 (2H, dd, J = 7.2, 7.6 Hz), 7.44 (2H, d, J = 7.2 Hz).

（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−９−（ベンジルオキシ）−４ａ−ヒドロキシ−２，３，４，４ａ，５，６−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７（７ａＨ）−オン（２．９ｇ、７．６ｍｍｏｌ）、１−ヒドロキシ−１−シクロプロパンカルボン酸（０．７７ｇ、７．６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（６．０ｍＬ）溶液に、ジイソプロピルエチルアミン（１．６ｍＬ、９．１ｍｍｏｌ）、１−［ビス（ジメチルアミノ）メチレン］−１Ｈ−１，２，３−トリアゾロ［４，５−ｂ］ピリジニウム−３−オキシドヘキサフルオロホスフェイト（３．２ｇ、８．３ｍｍｏｌ）を加え、アルゴン雰囲気下、室温で１８時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を１Ｎ塩酸、０．１Ｎ塩酸、飽和重曹水、飽和食塩水の順で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／酢酸エチル＝１０／１）で精製し、（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−９−（ベンジルオキシ）−４ａ−ヒドロキシ−３−（１−ヒドロキシシクロプロパンカルボニル）−２，３，４，４ａ，５，６−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７（７ａＨ）−オン（２．６ｇ、４６％収率）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.80-1.30 (4H, m), 1.59-1.66 (1H, m), 1.70-1.80 (1H, m), 1.90-1.98 (1H, m), 1.90-1.98 (1H, m), 2.28-2.36 (1H, m), 2.50-2.70 (1H, m), 2.81-2.96 (1H, m), 2.96-3.09 (1H, m), 3.09-3.20 (1H, m), 3.85-4.00 (1H, m), 4.30-4.60 (1H, m), 4.71 (1H, s), 4.90 (1H, d, J = 6.0 Hz), 5.23 (1H, d, J = 12.0 Hz), 5.31 (1H, d, J = 12.0 Hz), 6.61 (1H, d, J = 8.0 Hz), 6.78 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 7.2 Hz), 7.36 (1H, dd, J = 7.2, 7.6 Hz), 7.46 (2H, d, J = 7.6 Hz).
LC/MS (ESI): m/z 462 ([M+H]⁺)(Reference Example 3) (4R, 4aS, 7aR, 12bS) -9- (benzyloxy) -4a-hydroxy-3- (1-hydroxycyclopropanecarbonyl) -2,3,4,4a, 5,6-hexahydro Synthesis of -1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7 (7aH) -one:

(4R, 4aS, 7aR, 12bS) -9- (Benzyloxy) -4a-hydroxy-2,3,4,4a, 5,6-hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline To a solution of -7 (7aH) -one (2.9 g, 7.6 mmol), 1-hydroxy-1-cyclopropanecarboxylic acid (0.77 g, 7.6 mmol) in N, N-dimethylformamide (6.0 mL) , Diisopropylethylamine (1.6 mL, 9.1 mmol), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate ( 3.2 g, 8.3 mmol) was added, and the mixture was stirred at room temperature for 18 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (eluent: chloroform / (4R, 4aS, 7aR, 12bS) -9- (benzyloxy) -4a-hydroxy-3- (1-hydroxycyclopropanecarbonyl) -2,3,4,4a , 5,6-hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7 (7aH) -one (2.6 g, 46% yield) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.80-1.30 (4H, m), 1.59-1.66 (1H, m), 1.70-1.80 (1H, m), 1.90-1.98 (1H, m), 1.90 -1.98 (1H, m), 2.28-2.36 (1H, m), 2.50-2.70 (1H, m), 2.81-2.96 (1H, m), 2.96-3.09 (1H, m), 3.09-3.20 (1H, m), 3.85-4.00 (1H, m), 4.30-4.60 (1H, m), 4.71 (1H, s), 4.90 (1H, d, J = 6.0 Hz), 5.23 (1H, d, J = 12.0 Hz ), 5.31 (1H, d, J = 12.0 Hz), 6.61 (1H, d, J = 8.0 Hz), 6.78 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 7.2 Hz), 7.36 (1H, dd, J = 7.2, 7.6 Hz), 7.46 (2H, d, J = 7.6 Hz).
LC / MS (ESI): m / z 462 ([M + H] ⁺ )

（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−９−（ベンジルオキシ）−４ａ−ヒドロキシ−３−（１−ヒドロキシシクロプロパンカルボニル）−２，３，４，４ａ，５，６−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７（７ａＨ）−オン（３．７ｇ、８．０ｍｍｏｌ）、安息香酸 （０．９７ｇ、８．０ｍｍｏｌ）のベンゼン（１００ｍＬ）溶液に、ベンジルメチルアミン（２．１ｍＬ、１６ｍｍｏｌ）を加え、液溜め部にＭＳ４Ａを詰めたＤｅａｎ−Ｓｔａｒｋ還流器を付け、１２０℃で１７時間加熱還流させた。反応液を室温まで冷却し、シアノ水素化ホウ素ナトリウム（０．６５ｇ、１０ｍｍｏｌ）のメタノール（１４ｍＬ）溶液を加え、室温で０．５時間撹拌した。反応液に水、飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製し、（（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−７−（ベンジル（メチル）アミノ）−９−（ベンジルオキシ）−４ａ−ヒドロキシ−４，４ａ，５，６，７，７ａ−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−３（２Ｈ）−イル）（１−ヒドロシクロプロピル）メタノン（２．５ｇ、収率５５％）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.60-1.35 (4H, m), 1.35-1.60 (3H, m), 1.60-1.75 (1H, m), 1.84-2.02 (1H, m), 2.30 (3H, s), 2.30-2.55 (1H, m), 2.60-2.68 (1H, m), 2.68-3.02 (2H, m), 3.02-3.30 (1H, m), 3.60-3.90 (2H, m), 4.20-4.45 (1H, m), 4.65-5.00 (2H, m), 5.10-5.24 (2H, m), 6.57 (1H, d, J = 8.0 Hz), 6.80 (1H, d, J = 8.0 Hz), 7.15-7.40 (8H, m), 7.44 (2H, d, J = 6.4 Hz).
LC/MS (ESI): m/z 567 ([M+H]⁺)Reference Example 4 ((4R, 4aS, 7aR, 12bS) -7- (benzyl (methyl) amino) -9- (benzyloxy) -4a-hydroxy-4,4a, 5,6,7,7a-hexahydro Synthesis of -1H-4,12-methanobenzofuro [3,2-e] isoquinolin-3 (2H) -yl) (1-hydrocyclopropyl) methanone:

(4R, 4aS, 7aR, 12bS) -9- (benzyloxy) -4a-hydroxy-3- (1-hydroxycyclopropanecarbonyl) -2,3,4,4a, 5,6-hexahydro-1H-4, To a solution of 12-methanobenzofuro [3,2-e] isoquinolin-7 (7aH) -one (3.7 g, 8.0 mmol), benzoic acid (0.97 g, 8.0 mmol) in benzene (100 mL), benzylmethylamine (2.1 mL, 16 mmol) was added, and a Dean-Stark reflux vessel packed with MS4A was attached to the liquid reservoir, and the mixture was heated to reflux at 120 ° C. for 17 hours. The reaction mixture was cooled to room temperature, a solution of sodium cyanoborohydride (0.65 g, 10 mmol) in methanol (14 mL) was added, and the mixture was stirred at room temperature for 0.5 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) ((4R, 4aS, 7aR, 12bS) -7- (benzyl (methyl) amino) -9- (benzyloxy) -4a-hydroxy-4,4a, 5,6,7,7a-hexahydro-1H-4,12-methanobenzofuro [ 3,2-e] isoquinolin-3 (2H) -yl) (1-hydrocyclopropyl) methanone (2.5 g, 55% yield) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.60-1.35 (4H, m), 1.35-1.60 (3H, m), 1.60-1.75 (1H, m), 1.84-2.02 (1H, m), 2.30 (3H, s), 2.30-2.55 (1H, m), 2.60-2.68 (1H, m), 2.68-3.02 (2H, m), 3.02-3.30 (1H, m), 3.60-3.90 (2H, m) , 4.20-4.45 (1H, m), 4.65-5.00 (2H, m), 5.10-5.24 (2H, m), 6.57 (1H, d, J = 8.0 Hz), 6.80 (1H, d, J = 8.0 Hz ), 7.15-7.40 (8H, m), 7.44 (2H, d, J = 6.4 Hz).
LC / MS (ESI): m / z 567 ([M + H] ⁺ )

水素化アルミニウムリチウム（０．６７ｇ、１８ｍｍｏｌ）のテトラヒドロフラン（７５ｍＬ）懸濁液に、（（４Ｒ，４ａＳ，７ａＲ，１２ｂＳ）−７−（ベンジル（メチル）アミノ）−９−（ベンジルオキシ）−４ａ−ヒドロキシ−４，４ａ，５，６，７，７ａ−ヘキサヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−３（２Ｈ）−イル）（１−ヒドロシクロプロピル）メタノン（２．５ｇ、４．４ｍｍｏｌ）のテトラヒドロフラン（７５ｍＬ）溶液を加え、２時間加熱還流させた。氷冷下、反応液に水（０．７ｍＬ）、２０％水酸化ナトリウム水溶液（０．７ｍＬ）、水 （２．０ｍＬ）を順に加えた。不溶物はセライトを通して濾別し、濾液を減圧濃縮し、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム）で精製し、（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−７−（ベンジル（メチル）アミノ）−９−（ベンジルオキシ）−３−（（１−ヒドロキシシクロプロピル）メチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ−オール（２．０ｇ、収率８２％）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.43-0.48 (2H, m), 0.82-0.87 (2H, m), 1.30-1.70 (4H, m), 1.95-2.08 (1H, m), 2.15-2.32 (2H, m), 2.35 (3H, s), 2.53 (1H, d, J = 12.8 Hz), 2.60-2.70 (2H, m), 2.75 (1H, d, J = 12.8 Hz), 2.72-2.82 (1H, m), 2.97-3.08 (2H, m), 3.72 (1H, d, J = 13.6 Hz), 3.81 (1H, d, J = 13.6 Hz), 4.77 (1H, d, J = 7.6 Hz), 5.20 (2H, s), 6.53 (1H, d, J = 8.0 Hz), 6.74 (1H, d, J = 8.0 Hz), 7.15-7.50 (10H, m).
LC/MS (ESI): m/z 553 ([M+H]⁺)Reference Example 5 (4R, 4aS, 7R, 7aR, 12bS) -7- (benzyl (methyl) amino) -9- (benzyloxy) -3-((1-hydroxycyclopropyl) methyl) -2,3 , 4,4a, 5,6,7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-4a-ol:

To a suspension of lithium aluminum hydride (0.67 g, 18 mmol) in tetrahydrofuran (75 mL) was added ((4R, 4aS, 7aR, 12bS) -7- (benzyl (methyl) amino) -9- (benzyloxy) -4a. -Hydroxy-4,4a, 5,6,7,7a-hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-3 (2H) -yl) (1-hydrocyclopropyl) methanone (2 0.5 g, 4.4 mmol) in tetrahydrofuran (75 mL) was added and heated to reflux for 2 hours. Under ice cooling, water (0.7 mL), 20% aqueous sodium hydroxide solution (0.7 mL), and water (2.0 mL) were added to the reaction solution in this order. Insoluble matter was filtered off through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by amine silica gel column chromatography (eluent: chloroform) to give (4R, 4aS, 7R, 7aR, 12bS) -7. -(Benzyl (methyl) amino) -9- (benzyloxy) -3-((1-hydroxycyclopropyl) methyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-4 , 12-methanobenzofuro [3,2-e] isoquinolin-4a-ol (2.0 g, yield 82%) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.43-0.48 (2H, m), 0.82-0.87 (2H, m), 1.30-1.70 (4H, m), 1.95-2.08 (1H, m), 2.15 -2.32 (2H, m), 2.35 (3H, s), 2.53 (1H, d, J = 12.8 Hz), 2.60-2.70 (2H, m), 2.75 (1H, d, J = 12.8 Hz), 2.72- 2.82 (1H, m), 2.97-3.08 (2H, m), 3.72 (1H, d, J = 13.6 Hz), 3.81 (1H, d, J = 13.6 Hz), 4.77 (1H, d, J = 7.6 Hz ), 5.20 (2H, s), 6.53 (1H, d, J = 8.0 Hz), 6.74 (1H, d, J = 8.0 Hz), 7.15-7.50 (10H, m).
LC / MS (ESI): m / z 553 ([M + H] ⁺ )

（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−７−（ベンジル（メチル）アミノ）−９−（ベンジルオキシ）−３−（（１−ヒドロキシシクロプロピル）メチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ−オール（２．０ｇ、３．６ｍｍｏｌ）のメタノール（２００ｍＬ）溶液に、フタル酸（１．２ｇ、７．２ｍｍｏｌ）、１０％パラジウム／カーボン（約５０％含水、１．５ｇ）を加え、水素雰囲気下、室温で１６．５時間撹拌した。不溶物はセライトを通して濾別し、濾液を減圧濃縮し、得られた粗生成物（３．０ｇ）をそのまま次工程に用いた。Reference Example 6 (4R, 4aS, 7R, 7aR, 12bS) -3-((1-hydroxycyclopropyl) methyl) -7- (methylamino) -2,3,4,4a, 5,6,7 , 7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9-diol:

(4R, 4aS, 7R, 7aR, 12bS) -7- (benzyl (methyl) amino) -9- (benzyloxy) -3-((1-hydroxycyclopropyl) methyl) -2,3,4,4a, To a solution of 5,6,7,7a-octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-4a-ol (2.0 g, 3.6 mmol) in methanol (200 mL), phthalic acid (1 0.2 g, 7.2 mmol), 10% palladium / carbon (about 50% water content, 1.5 g) was added, and the mixture was stirred at room temperature for 16.5 hours under a hydrogen atmosphere. The insoluble material was filtered off through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product (3.0 g) was directly used in the next step.

参考例６で得られた粗成生物（２．６ｇ）のテトラヒドロフラン（３５ｍＬ）溶液に、重曹（１．５ｇ、１５ｍｍｏｌ）の水（２０ｍＬ）溶液を加えた。（Ｅ）−３−（フラン−３−イル）アクリロイルクロリド（０．５７ｇ、３．６ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液を加え、アルゴン雰囲気下、室温で０．５時間撹拌した。反応液に２Ｎ水酸化ナトリウム水溶液（５．５ｍＬ）、メタノール（１３ｍＬ）を加え、室温で０．５時間撹拌した。反応液に飽和重曹水、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製し、（Ｅ）−Ｎ−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−４ａ，９−ジヒドロキシ−３−（（１−ヒドロキシシクロプロピル）メチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）−３−（フラン−３−イル）−Ｎ−メチルアクリルアミド（以下、実施例１の化合物）（１．３ｇ、２工程収率７８％）を得た。
¹H NMR (400 MHz, DMSO-d₆): δ0.27-0.42 (2H, m), 0.48-0.53 (2H, m), 1.15-1.53 (4H, m), 1.90-2.35 (4H, m), 2.45-2.60(1.35H, m), 2.65-2.80 (2H, m), 2.85-3.00 (1.65H, m), 2.86 (1.95H, s), 3.09 (1.05H, s), 3.52-3.67 (0.65H, m), 4.10-4.25 (0.35H, m), 4.63 (0.65H, d, J = 7.6 Hz), 4.72 (0.35H, d, J = 7.6 Hz), 5.12 (0.35H, s), 5.15 (0.65H, s), 5.25 (1H, s), 6.41 (0.65H, d, J = 15.6 Hz), 6.51 (0.35H, d, J = 8.0 Hz), 6.57 (0.35H, d, J = 8.0 Hz), 6.58 (0.65H, d, J = 8.0 Hz), 6.65 (0.65H, d, J = 8.0 Hz), 6.71 (0.65H, d, J = 8.0 Hz), 6.90 (0.35H, d, J = 14.8 Hz), 7.00 (0.35H, s), 7.21 (0.65H, d, J = 15.6 Hz), 7.36 (0.35H, d, J =14.8 Hz), 7.66 (0.65H, s), 7.72 (0.35H, s), 7.92 (0.65H, s), 8.03 (0.35H, s), 8.98 (0.35H, brs), 9.39 (0.65H, brs).
LC/MS (ESI): m/z 493 ([M+H]⁺)Example 1 (E) -N-((4R, 4aS, 7R, 7aR, 12bS) -4a, 9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -2,3,4,4a , 5,6,7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) -3- (furan-3-yl) -N-methylacrylamide:

A solution of sodium bicarbonate (1.5 g, 15 mmol) in water (20 mL) was added to a solution of the crude product (2.6 g) obtained in Reference Example 6 in tetrahydrofuran (35 mL). A solution of (E) -3- (furan-3-yl) acryloyl chloride (0.57 g, 3.6 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 0.5 hr under an argon atmosphere. A 2N aqueous sodium hydroxide solution (5.5 mL) and methanol (13 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hr. Saturated aqueous sodium hydrogen carbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by amine silica gel column chromatography (eluent: chloroform / methanol = 10/1), (E) -N-((4R, 4aS, 7R, 7aR, 12bS) -4a, 9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -2,3,4,4a, 5,6,7,7a -Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) -3- (furan-3-yl) -N-methylacrylamide (hereinafter the compound of Example 1) (1. 3 g, 2-step yield 78%).
¹ H NMR (400 MHz, DMSO-d ₆ ): δ0.27-0.42 (2H, m), 0.48-0.53 (2H, m), 1.15-1.53 (4H, m), 1.90-2.35 (4H, m) , 2.45-2.60 (1.35H, m), 2.65-2.80 (2H, m), 2.85-3.00 (1.65H, m), 2.86 (1.95H, s), 3.09 (1.05H, s), 3.52-3.67 ( 0.65H, m), 4.10-4.25 (0.35H, m), 4.63 (0.65H, d, J = 7.6 Hz), 4.72 (0.35H, d, J = 7.6 Hz), 5.12 (0.35H, s), 5.15 (0.65H, s), 5.25 (1H, s), 6.41 (0.65H, d, J = 15.6 Hz), 6.51 (0.35H, d, J = 8.0 Hz), 6.57 (0.35H, d, J = 8.0 Hz), 6.58 (0.65H, d, J = 8.0 Hz), 6.65 (0.65H, d, J = 8.0 Hz), 6.71 (0.65H, d, J = 8.0 Hz), 6.90 (0.35H, d, J = 14.8 Hz), 7.00 (0.35H, s), 7.21 (0.65H, d, J = 15.6 Hz), 7.36 (0.35H, d, J = 14.8 Hz), 7.66 (0.65H, s), 7.72 ( 0.35H, s), 7.92 (0.65H, s), 8.03 (0.35H, s), 8.98 (0.35H, brs), 9.39 (0.65H, brs).
LC / MS (ESI): m / z 493 ([M + H] ⁺ )

実施例1の化合物（１．１ｇ、２．３ｍｍｏｌ）の水（７５ｍＬ）溶液に、氷冷下、１Ｎ塩酸（２．５ｍＬ、２．５ｍｍｏｌ）を加え、１時間撹拌した。反応液を凍結乾燥し、（Ｅ）−Ｎ−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−４ａ，９−ジヒドロキシ−３−（（１−ヒドロキシシクロプロピル）メチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）−３−（フラン−３−イル）−Ｎ−メチルアクリルアミド塩酸塩（以下、実施例２の化合物）（１．２ｇ、収率１００％）を得た。
¹H NMR (400 MHz, DMSO-d₆): δ0.66-0.90 (4H, m), 1.22-1.55 (3H, m), 1.70-1.80 (1H, m), 2.03-2.24 (1H, m), 2.45-2.69 (3H, m), 2.92 (1.8H, s), 3.00-3.22 (2H, m), 3.16 (1.2H, s), 3.22-3.53 (2H, m), 3.53-3.65 (0.6H, m), 3.97-4.06 (1H, m), 4.14-4.26 (0.4H, m), 4.85 (0.6H, sd, J = 8.0 Hz), 4.92 (0.4H, d, J = 8.0 Hz), 6.18 (1H, s), 6.36 (0.6H, d, J = 15.6 Hz), 6.50 (0.4H, s), 6.59 (0.6H, s), 6.62 (0.6H, s), 6.64 (0.4H, d, J = 8.0 Hz), 6.71 (0.4H, d, J = 8.0 Hz), 6.71 (0.6H, d, J = 8.0 Hz), 6.85 (0.6H, d, J = 8.0 Hz), 6.90 (0.4H, d, J = 15.0 Hz), 7.00 (0.4H, s), 7.22 (0.6H, d, J = 15.6 Hz), 7.37 (0.4H, d, J = 15.0 Hz), 7.66 (0.6H, s), 7.72 (0.4H, s), 7.92 (0.6H, s), 8.03 (0.4H, s), 8.43 (1H, brs), 9.29 (0.4H, s), 9.69 (0.6H, s).
LC/MS (ESI): m/z 493 ([M+H]⁺)Example 2 (E) -N-((4R, 4aS, 7R, 7aR, 12bS) -4a, 9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -2,3,4,4a , 5,6,7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) -3- (furan-3-yl) -N-methylacrylamide hydrochloride :

To a solution of the compound of Example 1 (1.1 g, 2.3 mmol) in water (75 mL) was added 1N hydrochloric acid (2.5 mL, 2.5 mmol) under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was freeze-dried and (E) -N-((4R, 4aS, 7R, 7aR, 12bS) -4a, 9-dihydroxy-3-((1-hydroxycyclopropyl) methyl) -2,3,4 , 4a, 5,6,7,7a-octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) -3- (furan-3-yl) -N-methylacrylamide hydrochloride (Hereinafter, the compound of Example 2) (1.2 g, yield 100%) was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ0.66-0.90 (4H, m), 1.22-1.55 (3H, m), 1.70-1.80 (1H, m), 2.03-2.24 (1H, m) , 2.45-2.69 (3H, m), 2.92 (1.8H, s), 3.00-3.22 (2H, m), 3.16 (1.2H, s), 3.22-3.53 (2H, m), 3.53-3.65 (0.6H , m), 3.97-4.06 (1H, m), 4.14-4.26 (0.4H, m), 4.85 (0.6H, sd, J = 8.0 Hz), 4.92 (0.4H, d, J = 8.0 Hz), 6.18 (1H, s), 6.36 (0.6H, d, J = 15.6 Hz), 6.50 (0.4H, s), 6.59 (0.6H, s), 6.62 (0.6H, s), 6.64 (0.4H, d, J = 8.0 Hz), 6.71 (0.4H, d, J = 8.0 Hz), 6.71 (0.6H, d, J = 8.0 Hz), 6.85 (0.6H, d, J = 8.0 Hz), 6.90 (0.4H, d, J = 15.0 Hz), 7.00 (0.4H, s), 7.22 (0.6H, d, J = 15.6 Hz), 7.37 (0.4H, d, J = 15.0 Hz), 7.66 (0.6H, s), 7.72 (0.4H, s), 7.92 (0.6H, s), 8.03 (0.4H, s), 8.43 (1H, brs), 9.29 (0.4H, s), 9.69 (0.6H, s).
LC / MS (ESI): m / z 493 ([M + H] ⁺ )

２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−３−（シクロプロピルメチル）−４ａ，９−ジヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（特開２０１４−６２０６９号公報）（５．０ｇ、１１ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（８５ｍＬ）溶液に、炭酸カリウム（３．２ｇ、２３ｍｍｏｌ）、ベンジルブロミド（２．５ｍＬ、２１ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、粗成生物にメタノールを加え、スラリー濾過し、２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−９−（ベンジルオキシ）−３−（シクロプロピルメチル）−４ａ−ヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（５．８ｇ、収率９８％）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.13 (2H, m), 0.54 (2H, m), 0.86 (1H, m), 1.52 (3H, m), 1.71 (1H, m), 2.12 (1H, dt, J = 12.0, 4.0 Hz), 2.36 (3H, m), 2.65 (2H, m), 2.79 (1H, dq, J = 13.2, 2.4 Hz), 3.06 (1H, d, J = 18.4 Hz), 3.11 (1H, d, J = 5.2 Hz), 4.16 (1H, ddd, J = 13.2, 8.4, 4.8 Hz), 5.09 (1H, d, J = 12.0 Hz), 5.19 (1H, d, J = 12.0 Hz), 5.27 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.33 (2H, t, J = 7.6 Hz), 7.43 (2H, d, J = 7.6 Hz), 7.72 (2H, m), 7.84 (2H, m).Reference Example 7 2-((4R, 4aS, 7R, 7aR, 12bS) -9- (benzyloxy) -3- (cyclopropylmethyl) -4a-hydroxy-2,3,4,4a, 5,6 , 7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) isoindoline-1,3-dione:

2-((4R, 4aS, 7R, 7aR, 12bS) -3- (cyclopropylmethyl) -4a, 9-dihydroxy-2,3,4,4a, 5,6,7,7a-octahydro-1H-4 , 12-methanobenzofuro [3,2-e] isoquinolin-7-yl) isoindoline-1,3-dione (Japanese Patent Laid-Open No. 2014-62069) (5.0 g, 11 mmol) of N, N-dimethylformamide (85 mL) ) To the solution were added potassium carbonate (3.2 g, 23 mmol) and benzyl bromide (2.5 mL, 21 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Methanol was added to the crude product, and the slurry was filtered. 2-((4R, 4aS, 7R, 7aR, 12bS) -9- (benzyloxy) -3- (cyclopropylmethyl) -4a-hydroxy-2,3,4,4a, 5,6,7,7a-octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl ) Isoindoline-1,3-dione (5.8 g, 98% yield) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.13 (2H, m), 0.54 (2H, m), 0.86 (1H, m), 1.52 (3H, m), 1.71 (1H, m), 2.12 ( 1H, dt, J = 12.0, 4.0 Hz), 2.36 (3H, m), 2.65 (2H, m), 2.79 (1H, dq, J = 13.2, 2.4 Hz), 3.06 (1H, d, J = 18.4 Hz ), 3.11 (1H, d, J = 5.2 Hz), 4.16 (1H, ddd, J = 13.2, 8.4, 4.8 Hz), 5.09 (1H, d, J = 12.0 Hz), 5.19 (1H, d, J = 12.0 Hz), 5.27 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 7.26 (1H, t, J = 7.6 Hz) ), 7.33 (2H, t, J = 7.6 Hz), 7.43 (2H, d, J = 7.6 Hz), 7.72 (2H, m), 7.84 (2H, m).

２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ）−９−（ベンジルオキシ）−３−（シクロプロピルメチル）−４ａ−ヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（２．０ｇ、３．６ｍｍｏｌ）のアセトニトリル（１９０ｍＬ）と水（１０ｍＬ）との混合溶液に、ヘキサニトラトセリウム（ＩＶ）酸アンモニウム（７．７ｇ、１４ｍｍｏｌ）、重曹（４．７ｇ、５６ｍｍｏｌ）、セライト（６．２ｇ）を加え、室温で２０時間撹拌した。反応液に飽和重曹水、酢酸エチルを加え、不溶物はセライトを通して濾別し、濾液を酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１／２）にて精製し、２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−９−（ベンジルオキシ）−３−（シクロプロピルメチル）−４ａ，１３−ジヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（５６０ｍｇ、収率２７％）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.12-0.24 (2H, m), 0.53-0.60 (2H, m), 0.91 (1H, m), 1.44-1.55 (2H, m), 1.66 (1H, m), 1.80-1.90 (2H, m), 2.02 (1H, td, J = 11.6, 4.5 Hz), 2.36 (1H, td, J = 12.6, 5.4 Hz), 2.49 (1H, dd, J = 12.8, 6.7 Hz), 2.56 (1H, dd, J = 12.8, 6.7 Hz), 2.65 (3H, dd, J = 12.1, 5.0 Hz), 2.78 (1H, qd, J = 12.9, 4.6 Hz), 3.16 (1H, s), 4.07-4.11 (1H, m), 4.99 (1H, d, J = 4.4 Hz), 5.18 (2H, dd, J = 33.9, 12.0 Hz), 5.30 (1H, d, J = 8.3 Hz), 6.88 (1H, d, J = 8.3 Hz), 6.92 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 6.8 Hz), 7.34 (2H, t, J = 6.8 Hz), 7.43 (2H, d, J = 6.8 Hz), 7.71 (2H, dd, J = 5.5, 3.0 Hz), 7.84 (2H, dd, J = 5.5, 3.0 Hz).Reference Example 8 2-((4R, 4aS, 7R, 7aR, 12bS, 13S) -9- (benzyloxy) -3- (cyclopropylmethyl) -4a, 13-dihydroxy-2,3,4,4a , 5,6,7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) isoindoline-1,3-dione:

2-((4R, 4aS, 7R, 7aR, 12bS) -9- (benzyloxy) -3- (cyclopropylmethyl) -4a-hydroxy-2,3,4,4a, 5,6,7,7a- Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) isoindoline-1,3-dione (2.0 g, 3.6 mmol) in acetonitrile (190 mL) and water (10 mL) To the mixed solution was added ammonium hexanitratocerium (IV) acid (7.7 g, 14 mmol), sodium bicarbonate (4.7 g, 56 mmol), and celite (6.2 g), and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, insolubles were filtered off through celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2) to give 2-((4R, 4aS , 7R, 7aR, 12bS, 13S) -9- (benzyloxy) -3- (cyclopropylmethyl) -4a, 13-dihydroxy-2,3,4,4a, 5,6,7,7a-octahydro-1H -4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) isoindoline-1,3-dione (560 mg, 27% yield) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.12-0.24 (2H, m), 0.53-0.60 (2H, m), 0.91 (1H, m), 1.44-1.55 (2H, m), 1.66 (1H , m), 1.80-1.90 (2H, m), 2.02 (1H, td, J = 11.6, 4.5 Hz), 2.36 (1H, td, J = 12.6, 5.4 Hz), 2.49 (1H, dd, J = 12.8 , 6.7 Hz), 2.56 (1H, dd, J = 12.8, 6.7 Hz), 2.65 (3H, dd, J = 12.1, 5.0 Hz), 2.78 (1H, qd, J = 12.9, 4.6 Hz), 3.16 (1H , s), 4.07-4.11 (1H, m), 4.99 (1H, d, J = 4.4 Hz), 5.18 (2H, dd, J = 33.9, 12.0 Hz), 5.30 (1H, d, J = 8.3 Hz) , 6.88 (1H, d, J = 8.3 Hz), 6.92 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 6.8 Hz), 7.34 (2H, t, J = 6.8 Hz), 7.43 (2H, d, J = 6.8 Hz), 7.71 (2H, dd, J = 5.5, 3.0 Hz), 7.84 (2H, dd, J = 5.5, 3.0 Hz).

２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−９−（ベンジルオキシ）−３−（シクロプロピルメチル）−４ａ，１３−ジヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（４５０ｍｇ、０．７７ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液に、１０％パラジウム／カーボン（約５０％含水、２２０ｍｇ）、ギ酸（３．０ｍＬ）を加え、室温で１９時間撹拌した。不溶物はセライトを通して濾別、濾液を飽和重曹水で洗浄した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−３−（シクロプロピルメチル）−４ａ，９，１３−トリヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２，−メタノベンゾフロ［３，２，−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（３７０ｍｇ、収率９９％）を得た。
¹H NMR (400 MHz, DMSO-d₆): δ0.20-0.34 (2H, m), 0.44-0.55 (2H, m), 0.88-0.96 (1H, m), 0.88-0.98 (1H, m), 1.22-1.29 (1H, m), 1.35-1.44 (1H, m), 1.48-1.55 (1H, m), 1.76-1.95 (2H, m), 2.13-2.24 (1H, m), 2.37 (1H, dd, J = 12.7, 6.8 Hz), 2.42-2.62 (1H, m), 3.17 (2H, d, J = 5.1 Hz), 3.88 (1H, m), 4.82 (2H, d, J = 4.6 Hz), 5.04 (1H, d, J = 8.3 Hz), 5.24 (1H, d, J = 4.6 Hz), 6.69 (1H, d, J = 8.0 Hz), 6.84 (1H, d, J = 8.0 Hz), 7.86-7.91 (4H, m), 9.21 (1H, s).Reference Example 9 2-((4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -4a, 9,13-trihydroxy-2,3,4,4a, 5,6 , 7,7a-Octahydro-1H-4,12, -methanobenzofuro [3,2, -e] isoquinolin-7-yl) isoindoline-1,3-dione:

2-((4R, 4aS, 7R, 7aR, 12bS, 13S) -9- (benzyloxy) -3- (cyclopropylmethyl) -4a, 13-dihydroxy-2,3,4,4a, 5,6 To a solution of 7,7a-octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) isoindoline-1,3-dione (450 mg, 0.77 mmol) in tetrahydrofuran (15 mL) was added 10 % Palladium / carbon (containing about 50% water, 220 mg) and formic acid (3.0 mL) were added, and the mixture was stirred at room temperature for 19 hours. The insoluble material was filtered off through celite, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and 2-((4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -4a, 9,13-trihydroxy-2,3, 4,4a, 5,6,7,7a-Octahydro-1H-4,12, -methanobenzofuro [3,2, -e] isoquinolin-7-yl) isoindoline-1,3-dione (370 mg, yield 99) %).
¹ H NMR (400 MHz, DMSO-d ₆ ): δ0.20-0.34 (2H, m), 0.44-0.55 (2H, m), 0.88-0.96 (1H, m), 0.88-0.98 (1H, m) , 1.22-1.29 (1H, m), 1.35-1.44 (1H, m), 1.48-1.55 (1H, m), 1.76-1.95 (2H, m), 2.13-2.24 (1H, m), 2.37 (1H, dd, J = 12.7, 6.8 Hz), 2.42-2.62 (1H, m), 3.17 (2H, d, J = 5.1 Hz), 3.88 (1H, m), 4.82 (2H, d, J = 4.6 Hz), 5.04 (1H, d, J = 8.3 Hz), 5.24 (1H, d, J = 4.6 Hz), 6.69 (1H, d, J = 8.0 Hz), 6.84 (1H, d, J = 8.0 Hz), 7.86- 7.91 (4H, m), 9.21 (1H, s).

２−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−３−（シクロプロピルメチル）−４ａ，９，１３−トリヒドロキシ−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２，−メタノベンゾフロ［３，２，−ｅ］イソキノリン−７−イル）イソインドリン−１，３−ジオン（１３０ｍｇ、０．２２ｍｍｏｌ）のエタノール（１．０ｍＬ）溶液に、ヒドラジン一水和物（３３ｍｇ、０．６６ｍｍｏｌ）を加え、７０℃で３時間撹拌した。反応液を減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝１０／１）で精製し、（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−７−アミノ−３−（シクロプロピルメチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ，９，１３−トリオール（９３ｍｇ、収率９４％）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.11-0.22 (2H, m), 0.54-0.59 (2H, m), 0.86-0.92 (1H, m), 1.59-1.71 (10H, m), 1.99-2.20 (2H, m), 2.41-2.63 (4H, m), 3.09 (1H, s), 4.24 (1H, d, J = 7.6 Hz), 4.93 (1H, s), 6.77-6.85 (2H, m).Reference Example 10 (4R, 4aS, 7R, 7aR, 12bS, 13S) -7-amino-3- (cyclopropylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H Synthesis of -4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol:

2-((4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -4a, 9,13-trihydroxy-2,3,4,4a, 5,6,7,7a- To a solution of octahydro-1H-4,12, -methanobenzofuro [3,2, -e] isoquinolin-7-yl) isoindoline-1,3-dione (130 mg, 0.22 mmol) in ethanol (1.0 mL), hydrazine Monohydrate (33 mg, 0.66 mmol) was added and stirred at 70 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to give (4R, 4aS, 7R, 7aR, 12bS, 13S) -7-. Amino-3- (cyclopropylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13- Triol (93 mg, 94% yield) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.11-0.22 (2H, m), 0.54-0.59 (2H, m), 0.86-0.92 (1H, m), 1.59-1.71 (10H, m), 1.99 -2.20 (2H, m), 2.41-2.63 (4H, m), 3.09 (1H, s), 4.24 (1H, d, J = 7.6 Hz), 4.93 (1H, s), 6.77-6.85 (2H, m ).

（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−７−アミノ−３−（シクロプロピルメチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ，９，１３−トリオール（９３ｍｇ、０．２ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、ベンズアルデヒド（２１μＬ）、水素化トリアセトキシホウ素化ナトリウム（１４０ｍｇ、０．６５ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液にホルマリン（５０μＬ、０．６９ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１／２）で精製し、（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−７−（ベンジル（メチル）アミノ）−３−（シクロプロピルメチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ，９，１３−トリオール（５６ｍｇ、収率４９％）を得た。
¹H NMR (400 MHz, CDCl₃): δ0.12-0.22 (2H, m), 0.53-0.61 (2H, m), 0.85-0.95 (1H, m), 1.47-1.74 (5H, m), 1.97-2.07 (2H, m), 2.19-2.26 (8H, m), 3.10 (1H, m), 3.69-3.82 (2H, m), 4.77 (1H, d, J = 8.0 Hz), 4.93 (1H, s), 5.23 (2H, s), 6.84 (2H, s), 7.16-7.45 (7H, m).Reference Example 11 (4R, 4aS, 7R, 7aR, 12bS, 13S) -7- (Benzyl (methyl) amino) -3- (cyclopropylmethyl) -2,3,4,4a, 5,6,7 , 7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol:

(4R, 4aS, 7R, 7aR, 12bS, 13S) -7-amino-3- (cyclopropylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-4,12- To a solution of methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol (93 mg, 0.2 mmol) in dichloromethane (1 mL), benzaldehyde (21 μL), sodium triacetoxyborohydride (140 mg, 0.65 mmol). ) And stirred at room temperature for 1 hour. Formalin (50 μL, 0.69 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2) and (4R, 4aS, 7R, 7aR). , 12bS, 13S) -7- (benzyl (methyl) amino) -3- (cyclopropylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-4,12-methanobenzofuro [ 3,2-e] isoquinoline-4a, 9,13-triol (56 mg, 49% yield) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.12-0.22 (2H, m), 0.53-0.61 (2H, m), 0.85-0.95 (1H, m), 1.47-1.74 (5H, m), 1.97 -2.07 (2H, m), 2.19-2.26 (8H, m), 3.10 (1H, m), 3.69-3.82 (2H, m), 4.77 (1H, d, J = 8.0 Hz), 4.93 (1H, s ), 5.23 (2H, s), 6.84 (2H, s), 7.16-7.45 (7H, m).

（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−７−（ベンジル（メチル）アミノ）−３−（シクロプロピルメチル）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ，９，１３−トリオール（５６ｍｇ、０．１ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、１０％塩酸メタノール溶液（０．２ｍＬ）、１０％パラジウム／カーボン（約５０％含水、８ｍｇ）を加え、水素雰囲気下、室温で１６時間撹拌した。不溶物はセライトを通して濾別し、濾液を減圧濃縮し、（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−３−（シクロプロピルメチル）−７−（メチルアミノ）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ，９，１３−トリオール（５２ｍｇ、収率１００％）を得た。
¹H NMR (400 MHz, CD₃OD): δ0.55-0.62 (2H, m), 0.76-0.90 (2H, m), 1.18-1.24 (1H, m), 1.63-1.66 (1H, m), 1.84-2.11 (4H, m), 2.56-2.67 (2H, m), 2.89 (3H, s), 2.95-3.12 (3H, m), 3.34 (3H, s), 3.43-3.51 (1H, m), 3.88 (1H, s), 5.29 (1H, s), 6.88 (1H, d, J = 8.4 Hz), 7.04 (1H, d, J = 8.4 Hz).Reference Example 12 (4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -7- (methylamino) -2,3,4,4a, 5,6,7,7a- Synthesis of octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol

(4R, 4aS, 7R, 7aR, 12bS, 13S) -7- (Benzyl (methyl) amino) -3- (cyclopropylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro- 1H-4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol (56 mg, 0.1 mmol) in methanol (1 mL) solution in 10% hydrochloric acid in methanol (0.2 mL), 10 % Palladium / carbon (containing about 50% water, 8 mg) was added, and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure, and (4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -7- (methylamino) -2,3,4, 4a, 5,6,7,7a-Octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol (52 mg, 100% yield) was obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ0.55-0.62 (2H, m), 0.76-0.90 (2H, m), 1.18-1.24 (1H, m), 1.63-1.66 (1H, m), 1.84-2.11 (4H, m), 2.56-2.67 (2H, m), 2.89 (3H, s), 2.95-3.12 (3H, m), 3.34 (3H, s), 3.43-3.51 (1H, m), 3.88 (1H, s), 5.29 (1H, s), 6.88 (1H, d, J = 8.4 Hz), 7.04 (1H, d, J = 8.4 Hz).

（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−３−（シクロプロピルメチル）−７−（メチルアミノ）−２，３，４，４ａ，５，６，７，７ａ−オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−４ａ，９，１３−トリオール（５２ｍｇ、０．１２ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、１−［ビス（ジメチルアミノ）メチレン］−１Ｈ−１，２，３−トリアゾロ［４，５−ｂ］ピリジニウム−３−オキシドヘキサフルオロホスフェイト（９７ｍｇ、０．２５ｍｍｏｌ）、トリエチルアミン（４９ｍｇ、０．４８ｍｍｏｌ）、トランス−３−フランアクリル酸（３１ｍｇ、０．２３ｍｍｏｌ）を加え、室温で３時間撹拌した。反応液にメタノール（１ｍＬ）、１Ｎ水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温で１８時間撹拌した。反応液に酢酸エチル、飽和塩化アンモニウム水溶液、３５%アンモニア水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、減圧濃縮し、粗生成物に酢酸エチルを加え、スラリー濾過し、（Ｅ）−Ｎ−（（４Ｒ，４ａＳ，７Ｒ，７ａＲ，１２ｂＳ，１３Ｓ）−３−（シクロプロピルメチル）−４ａ，９，１３−トリヒドロキシ−２，３，４，４ａ，５，６，７，７ａ，オクタヒドロ−１Ｈ−４，１２−メタノベンゾフロ［３，２−ｅ］イソキノリン−７−イル）−３−（フラン−３−イル）−Ｎ−メチルアクリルアミド（以下、実施例３の化合物）（２２ｍｇ、収率４４％）を得た。
¹H NMR (400 MHz, DMSO-d₆): δ0.09-0.23 (2H, m), 0.45-0.53 (2H, m), 0.87-0.96 (1H, m), 1.18-1.35 (2H, m), 1.41-1.50 (1H, m), 1.70-1.96 (2H, m), 2.00-2.23 (2H, m), 2.32-2.40 (1H, m), 2.50-2.62 (2H, m), 2.84 (2H, s), 2.92 (1H, s), 3.08 (1H, s), 3.58 (0.66H, br), 4.20 (0.33H, br), 4.63 (0.66H, d, J = 8.0 Hz), 4.71-4.82 (2H, m), 5.20 (0.34H, d, J = 4.6 Hz), 5.25 (0.66H, d, J = 4.6 Hz), 6.41 (0.66H, d, J = 15.4 Hz), 6.65 (1H, m), 6.78-6.91 (2H, m), 6.99 (0.34H, s), 7.21 (0.66H, d, J = 15.4 Hz), 7.37 (0.34H, d, J = 15.4 Hz), 7.67 (0.66H, s), 7.71 (0.34H, s), 7.92 (0.66H, s), 8.02 (0.34H, s), 9.17 (0.34H, s), 9.61 (0.66H, s).Example 3 (E) -N-((4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -4a, 9,13-trihydroxy-2,3,4,4a , 5,6,7,7a, octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl) -3- (furan-3-yl) -N-methylacrylamide:

(4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclopropylmethyl) -7- (methylamino) -2,3,4,4a, 5,6,7,7a-octahydro-1H-4 , 12-methanobenzofuro [3,2-e] isoquinoline-4a, 9,13-triol (52 mg, 0.12 mmol) in dichloromethane (1 mL) to 1- [bis (dimethylamino) methylene] -1H-1, 2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (97 mg, 0.25 mmol), triethylamine (49 mg, 0.48 mmol), trans-3-furanacrylic acid (31 mg, 0. 23 mmol) was added and stirred at room temperature for 3 hours. Methanol (1 mL) and 1N aqueous sodium hydroxide solution (0.5 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate, saturated aqueous ammonium chloride solution and 35% aqueous ammonia were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the crude product, the slurry was filtered, and (E) -N-((4R, 4aS, 7R, 7aR, 12bS, 13S) -3- (cyclo Propylmethyl) -4a, 9,13-trihydroxy-2,3,4,4a, 5,6,7,7a, octahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-7-yl ) -3- (furan-3-yl) -N-methylacrylamide (hereinafter, the compound of Example 3) (22 mg, 44% yield) was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ0.09-0.23 (2H, m), 0.45-0.53 (2H, m), 0.87-0.96 (1H, m), 1.18-1.35 (2H, m) , 1.41-1.50 (1H, m), 1.70-1.96 (2H, m), 2.00-2.23 (2H, m), 2.32-2.40 (1H, m), 2.50-2.62 (2H, m), 2.84 (2H, s), 2.92 (1H, s), 3.08 (1H, s), 3.58 (0.66H, br), 4.20 (0.33H, br), 4.63 (0.66H, d, J = 8.0 Hz), 4.71-4.82 ( 2H, m), 5.20 (0.34H, d, J = 4.6 Hz), 5.25 (0.66H, d, J = 4.6 Hz), 6.41 (0.66H, d, J = 15.4 Hz), 6.65 (1H, m) , 6.78-6.91 (2H, m), 6.99 (0.34H, s), 7.21 (0.66H, d, J = 15.4 Hz), 7.37 (0.34H, d, J = 15.4 Hz), 7.67 (0.66H, s ), 7.71 (0.34H, s), 7.92 (0.66H, s), 8.02 (0.34H, s), 9.17 (0.34H, s), 9.61 (0.66H, s).

(Example 4) Human opioid κ receptor and μ receptor agonist test:
Using cells stably expressing human opioid κ receptor or human opioid μ receptor, the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof is human. Opioid κ receptor and μ receptor operability was evaluated.

  A modified human opioid kappa receptor gene whose base sequence is optimized to increase the expression level using GeneOptimizer (registered trademark; Takara Bio Inc.) is introduced into HEK-293 cells, and human opioid kappa receptor is stabilized according to a standard method. Expression cells were generated.

  A human opioid μ receptor gene was introduced into CHO-dhfr (−) cells, and human opioid μ receptor stably expressing cells were prepared according to a conventional method.

Human opioid κ receptor stably expressing cells are cultured with DMEM containing 10% FBS and 50 μg / mL Hygromycin B, and human opioid μ receptor stably expressing cells are cultured with MEM-α containing 10% FBS and 500 μg / mL G418. It was used as a liquid and maintained in culture in a 37 ° C., 5% CO ₂ incubator.

  The human opioid receptor operability of the test substance was evaluated using the above human opioid receptor stably expressing cells as an index of the inhibitory effect on Forskolin-induced cAMP production. For the measurement of cAMP production, AlphaScreen (registered trademark) cAMP Detection Kit (PerkinElmer) was used.

  As a stimulation buffer, an HBSS buffer (pH 7.4) (hereinafter referred to as SB) containing 0.5 mmol / L IBMX, 5 mmol / L HEPES, and 0.1% BSA was prepared at the time of use. In addition, a HEPES buffer (pH 7.4) (hereinafter referred to as L / DB) containing 0.1% BSA and 0.3% Tween-20 (registered trademark) was prepared as a Lysis / Detection buffer. A 1 U / 5 μL anti-cAMP antibody acceptor bead solution was prepared using SB, and an SA donor bead / biotinylated cAMP detection mix was prepared using L / DB. The SA donor beads / biotinylated cAMP detection mix was incubated for about 60 minutes at room temperature under light-shielding conditions after preparation.

  Each test substance and Forskolin were dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) and then diluted with SB to prepare a test substance / Forskolin mixed solution. The final concentration of Forskolin in the reaction system was 10 μmol / L, and the final concentration of DMSO was 0.4% or less.

The above human opioid receptor stable expression cells (human opioid kappa receptor stable expression cells or human opioid μ receptor stable expression cells) were suspended in PBS (−), and the number of living cells was determined. The cells were transferred to a tube and centrifuged for 5 minutes (room temperature, about 470 × g) to obtain a cell pellet. Anti-cAMP antibody acceptor bead solution was added to the cell pellet to prepare 1 × 10 ⁶ cells / mL cell / anti-cAMP antibody acceptor beads.

  5 μL of the test substance / Forskolin mixed solution was added to the plate (384 well). In addition, a well to which 5 μL of SB containing 10 μmol / L Forskolin was added was provided as a “test substance non-added well”. 5 μL of cell / anti-cAMP antibody acceptor beads was added to each well.

  In addition, in order to prepare a cAMP calibration curve, 5 μL of a cAMP standard solution obtained by serially diluting the 50 μmol / L cAMP standard solution attached to the kit with SB and 5 μL of an anti-cAMP antibody acceptor bead solution were added. .

  After incubating the plate for 30 minutes at 37 ° C. under light-shielded conditions, 15 μL of SA donor beads / biotinylated cAMP detection mix was added to all wells. The plate was allowed to stand for 120 minutes at room temperature and in the dark, and then the AlphaScreen (registered trademark) signal (cps: count per sec) of each well was measured using EnVision (PerkinElmaer).

  Each test substance was evaluated at a common ratio of 10 and N = 2 for each concentration. The cAMP calibration curve was created using GraphPad Prism, and the cAMP concentration in each well was calculated from the created calibration curve.

The cAMP concentration of the test substance non-added well was defined as 0% inhibition. In the human opioid κ receptor agonist test, c-AMP concentration when U-69593 (Sigma, # U103) (final concentration 10 μmol / L) showing human opioid κ receptor agonist was added instead of the test substance. Was controlled to 100%. In the human opioid μ receptor agonist test, the cAMP concentration when DAMGO (Sigma, # E7384) (final concentration 10 μmol / L) showing human opioid μ receptor agonist activity was added instead of the test substance was controlled at 100 %. The inhibition rate (%) for Forskolin-induced cAMP production of each test substance was determined, and the EC _{50 of} each test substance was calculated by two-point regression sandwiching the inhibition rate of 50%.

Table 1 shows the EC ₅₀ value of each test substance.

  As is clear from the results in Table 1, the compound of Example 2 and the compound of Example 3 showed potent human opioid κ receptor agonist activity. On the other hand, the compound of Example 2 and the compound of Example 3 showed extremely weak human opioid μ receptor agonist activity. Therefore, the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof has been shown to have selective opioid κ receptor agonist activity, It can be a powerful analgesic with reduced side effects of opioid μ receptor agonists such as respiratory depression.

(Example 5) Brain migration confirmation test in mice:
Measurement of plasma concentration and brain concentration after intravenous administration of the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof to a mouse, Sex was evaluated. Nalfurafine hydrochloride (International Publication No. 1993/015081) was similarly evaluated as a comparative compound.

  In the experiment, a 7-week-old Crl: CD1 (ICR) -type or Crlj: CD1 (ICR) -type male mouse (Nippon Charles River Co., Ltd.) was allowed to freely ingest solid feed (Oriental Yeast Co., Ltd.) and tap water. )It was used.

  The test substance was administered to the mouse once intravenously at a dose of 1 mg / kg. The administration solutions of the compound of Example 2, the compound of Example 3 and the comparative compound were physiological saline, DMSO / Tween 80 / distilled water mixture (1: 1: 8), DMSO / hydroxypropyl-β-cyclodextrin, respectively. (Hereinafter referred to as HP-β-CD) / distilled water mixed solution (1: 8: 11). Intravenous administration of the administration liquid was carried out in the tail vein with a volume of 5 mL / kg using a syringe needle and syringe without anesthesia.

  Fifteen minutes after intravenous administration, blood was collected from the hind vena cava or heart of mice under isoflurane anesthesia. Each test substance was administered to 3 mice. In addition, after finishing blood collection, the mouse was exsanguinated and euthanized, and then the brain was removed. Furthermore, blood and brain were collected from mice not administered the test substance.

  The collected blood was centrifuged at 4 ° C. and 15,000 rpm for 10 minutes (Hitachi Koki CT15RE) to separate plasma, and the obtained plasma was stored at −30 ° C. until the preparation of the sample for analysis. In addition, the collected brain is added with 2 to 3 times the brain weight of distilled water, and the tissue is ground until it becomes uniform (Biomedical Science, Shake Master Neo). The obtained brain homogenized solution is used as an analytical sample. Stored at −30 ° C. until preparation. The plasma and brain homogenized solution obtained from the mice administered with the test substance are called mouse plasma sample and mouse brain sample, respectively, and the plasma and brain homogenized solution obtained from the mouse not administered with the test substance are respectively blank plasma. This is called a blank brain.

  To 50 μL of mouse plasma sample or mouse plasma sample appropriately diluted with blank plasma, 5-20 μL of internal standard solution and 100-200 μL of methanol, acetonitrile or methanol / acetonitrile mixture (1: 1) were added, stirred, Cooled at 4 ° C. for 10 minutes. Also, add 50 to 20 μL of an internal standard solution and 100 to 200 μL of methanol, acetonitrile or methanol / acetonitrile mixed solution (1: 1) to 50 μL of a mouse brain sample or a mouse brain sample appropriately diluted with a blank brain, and stir. And cooled at 4 ° C. for 10 minutes. A calibration curve sample was prepared by treating a blank plasma and a blank brain to which a standard curve standard solution was added in the same manner.

  Each sample after cooling was centrifuged at 3,000 rpm at 4 ° C. for 10 minutes (Hitachi Koki Himac CF7D2), and the supernatant was added onto a 0.66 μm filter plate (Corning), and further 5 ° C. at 4 ° C. and 2,000 rpm. Centrifugal filtration (Hitachi Koki Himac CF7D2) was performed for a minute, and distilled water (0 to 100 μL) was added to the obtained filtrate to prepare a sample for analysis.

  The obtained analytical sample was subjected to LC / MS / MS analysis. The analysis was performed under the conditions shown in Table 2 or a method according thereto.

  From the results of LC / MS / MS analysis, a calibration curve was created using Analyst 1.5 or 1.6 (Applied Biosystems), and the concentration of the test substance in the sample for analysis was calculated. For each test substance, the plasma concentration (ng / mL) and brain concentration (ng / g tissue) (average value ± standard deviation, N = 3) of the administered test substance were calculated. Further, the brain concentration / plasma concentration ratio (Kp, brain) of each test substance was calculated.

  The results are shown in Table 3. Table 3 shows the brain concentration (ng / g tissue), plasma concentration (ng / mL) and brain concentration / plasma concentration ratio (Kp, brain) 15 minutes after administration of each test substance. .

  The brain concentration / plasma concentration ratio of the compound of Example 2 and the compound of Example 3 was 0.2 or less. Therefore, it was shown that the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof is a peripheral type.

(Example 6) Effect on nociceptive pain:
Using a mouse acetate rising model that can evaluate nociceptive pain, the analgesic action of the morphinan derivative represented by the above formula (I) or (II) or a pharmacologically acceptable acid addition salt thereof was evaluated.

  In the experiment, 5 to 6-week-old ddY male mice (Japan SLC Co., Ltd.) that were allowed to freely ingest solid feed (Oriental Yeast Co., Ltd.) and tap water were used.

  The compound of Example 2 was dissolved in 20% HP-β-CD containing 5% DMSO, and the compound of Example 3 was dissolved in 20% HP-β-CD to prepare an administration solution for each test substance. The prepared test substance administration solution was administered to mice in the tail vein at a volume of 5 mL / kg. A solvent corresponding to each test substance was similarly administered as a control to form a “solvent group”.

  Immediately after administration of the test substance, a 0.6% acetic acid solution was intraperitoneally administered to the mouse (10 mL / kg) to induce a rising reaction (behavior to stretch or warp the body). Rising reactions that occurred 10 minutes after administration of the 0.6% acetic acid solution were counted, and the number of times was used as an index of pain.

The average value of the number of rising reactions in the solvent group was taken as 100%, and the dose of the test substance that suppressed the rising reaction by 50% was shown as the 50% effective dose (ED ₅₀ ). For calculation of ED ₅₀ , GraphPad Prism ver. 5.04 (GraphPad) was used.

  The results are shown in Table 4.

The ED ₅₀ values of the compound of Example 2 and the compound of Example 3 were <1 mg / kg, indicating excellent analgesic activity. Therefore, it has been clarified that the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof exhibits an excellent analgesic action.

  Since the morphinan derivative represented by the above formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof has peripheral opioid κ receptor agonist activity, opioid μ receptor operation It can be used as an analgesic with reduced side effects such as drug dependence and respiratory depression based on sex and sedation and discomfort based on central opioid kappa receptor agonism.

Claims (3)

A morphinan derivative represented by the following formula (I) or a pharmacologically acceptable acid addition salt thereof:

A pharmaceutical comprising a morphinan derivative represented by the following formula (I) or formula (II) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

  An analgesic comprising the morphinan derivative according to claim 2 or a pharmacologically acceptable acid addition salt thereof as an active ingredient.