JP2023028184A - Morphinan derivative and pharmaceutical use thereof - Google Patents

Abstract

To provide an agent for treating, improving or preventing various diseases associated with an opioid κ receptor including a pain, having the ability to bind the opioid κ receptor and reduced side effect.SOLUTION: The present invention provides a morphinan derivative represented by the following formula or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to morphinan derivatives having opioid κ-receptor binding properties and pharmaceutical uses thereof.

Opioid receptors are classified into three types: mu receptors, delta receptors, and kappa receptors. Opioid μ receptor agonists represented by morphine and fentanyl have long been used as analgesics. However, since it causes serious side effects such as drug dependence and respiratory depression, it is desired to develop an analgesic without these side effects.

It has been reported that opioid κ receptor agonists have an analgesic effect similar to opioid μ agonists, but are not involved in the serious side effects seen with opioid μ agonists (Non-Patent Document 1). Therefore, opioid κ receptor agonists are expected to be safer therapeutic agents than opioid μ receptor agonists.

To date, many kappa receptor agonists are known. For example, Patent Document 1 reports a compound represented by general formula (A). This compound is said to have opioid kappa receptor selective binding and analgesic activity. However, its analgesic activity was not satisfactory.

κ receptor agonists are known to have side effects such as sedation and drug aversion. Although many of the kappa receptor agonists known to date have analgesic effects, there is a lack of sufficient divergence between the dose that produces analgesic effect and the dose that produces side effects. None have been approved. In fact, nalfurafine hydrochloride (Patent Document 2) shown in (B) below is the only κ receptor agonist on the market and is used as an antipruritic, but side effects occur frequently at analgesic doses. could not be used clinically as an analgesic.

In other words, a κ agonist with a sufficient gap between the dose at which an analgesic effect is exhibited and the dose at which side effects are exhibited can be an excellent therapeutic drug.

By the way, Patent Document 3 discloses that the compound represented by the general formula (C) has opioid ε receptor activity and analgesic action.

However, it is neither described nor suggested that these compounds contain opioid kappa agonists with well-isolated side effects.

Japanese Patent Application Laid-Open No. 2009-196933 WO 93/015081 WO 98/043978

Millan, Trends in Pharmacological Sciences, 1990, Vol. 11, p. 70-76

An object of the present invention is to provide a medicament effective in treating, improving, or preventing various diseases and symptoms associated with the κ opioid receptor, in which side effects such as sedative effects and drug aversive effects are suppressed.

Under such circumstances, the present inventors conducted intensive studies and found that a specific morphinan derivative has an opioid κ receptor binding property and achieves a high separation of side effects. The invention of (7) has been completed.
(1) A morphinan derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[In the formula, R ¹ represents a cycloalkylalkyl having 4 to 7 carbon atoms,
R ² represents hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms,
R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms,
R ⁴ represents alkyl having 1 to 5 carbon atoms,
Ar represents phenyl, pyridyl, furanyl or thiophenyl (which may be substituted with halogen, alkyl having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms). ]
(2) The morphinan derivative according to (1) or a pharmaceutically acceptable salt thereof, represented by the following general formula (Ia).

[In the formula, R ¹ represents a cycloalkylalkyl having 4 to 7 carbon atoms,
R ² represents hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms,
R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms,
R ⁴ represents alkyl having 1 to 5 carbon atoms,
Ar represents phenyl, pyridyl, furanyl or thiophenyl (which may be substituted with halogen, alkyl having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms). ]

(3) (4R,4aS,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6,7 ,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide, or a morphinan derivative according to (1) or a pharmaceutically acceptable salt thereof.

(4) (4R,4aS,6R,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6 ,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide, or a morphinan derivative according to (2) or a pharmaceutically acceptable salt thereof.

(5) A medicament acting on the opioid κ receptor, containing as an active ingredient the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof.
(6) Cardiovascular disorders, gastrointestinal disorders, hematological disorders, and respiratory disorders containing the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof as an active ingredient. , liver disease, nervous system disorder, urinary system disorder, pain, cough, pruritus, ischemic brain disease and drug dependence. .
(7) The therapeutic agent, ameliorating agent or preventive agent according to (6), wherein the disease associated with the opioid κ receptor is pain.

A compound of the present invention or a pharmaceutically acceptable salt thereof can treat, ameliorate or prevent diseases associated with the kappa opioid receptor.

Figure 2 shows good separation of analgesia (acetic acid writhing test) and sedation (rotarod test) by the compounds of the invention.

The present invention features a morphinan derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

Among the morphinan derivatives represented by the general formula (I), pharmaceutically acceptable salts thereof, and solvates thereof, the following are preferred.

R ¹ represents cycloalkylalkyl having 4 to 7 carbon atoms, preferably cycloalkylalkyl having 4 to 5 carbon atoms, particularly preferably cyclopropylmethyl.

R ² represents hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms, preferably hydroxy or alkoxy having 1 to 3 carbon atoms, particularly preferably hydroxy or methoxy.

R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms, preferably hydrogen or methyl.

R ⁴ represents alkyl having 1 to 5 carbon atoms, preferably methyl, ethyl or propyl, particularly preferably methyl.

Ar represents phenyl, pyridyl, furanyl or thiophenyl (which may be substituted with halogen, alkyl having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms), preferably phenyl or pyridyl, particularly phenyl is preferred.

In the morphinan derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt preferably includes an acid addition salt. Examples of the acid addition salt include (I ) salts with mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, (b) salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid, or (c) methane Examples thereof include salts with sulfonic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

The morphinan derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof can also exist as a hydrate or solvate. Accordingly, the compounds of the present invention include all crystal forms and hydrates or solvates thereof.

Preferred solvates are pharmacologically acceptable solvates. A pharmacologically acceptable solvate may be either a hydrate or a non-hydrate. Solvents constituting solvates include, for example, water, alcoholic solvents such as methanol, ethanol or n-propanol, N,N-dimethylformamide (hereinafter, DMF) or dimethylsulfoxide (hereinafter, DMSO), and acetonitrile. be done.

The morphinan derivative represented by the above general formula (I) has optical isomers, and includes not only single isomers but also racemates and diastereomeric mixtures.

Among the compounds represented by the above general formula (I), (4R,4aS,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1 ,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide, especially (4R,4aS,6R ,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6,7,7a-octahydro-4a, 7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (compound 10 of Example 4) is preferred.

Another aspect of the present invention provides use of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating, ameliorating or preventing a disease associated with the κ opioid receptor.

Furthermore, as another aspect, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for producing a therapeutic agent, ameliorating agent or preventive agent for a disease associated with the kappa opioid receptor provide the use of

Furthermore, in another aspect, in a method for treating, ameliorating or preventing a disease associated with the κ opioid receptor, the above-described A method is provided comprising administering a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

The morphinan derivative represented by the above general formula (I) can be produced by an appropriate method based on the characteristics derived from its basic skeleton and types of substituents. The starting materials and reagents used for the production of these compounds can be generally purchased, or can be produced by known methods or methods based thereon.

The morphinan derivatives represented by the above general formula (I) and the intermediates and starting materials used for their production can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, crystallization or chromatography.

When the morphinan derivative represented by the above general formula (I) contains optical isomers or stereoisomers, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.

The morphinan derivative represented by the above general formula (I) can be obtained, for example, by the method described in scheme 1 or 2 below.

(Step 1-1)
Amide derivative (b) in Scheme 1 is prepared according to H. Nagase, Tetrahedron. 65, 2009, 4808-4813, by hydrolyzing an ester derivative (a) obtained by a known method, followed by amidation.

Hydrolysis can be carried out under acidic or basic conditions, but acidic conditions are preferred. As the acid to be used, hydrochloric acid, sulfuric acid, phosphoric acid, or the like can be used, and hydrochloric acid is preferably used as the solvent. Hydrochloric acid is preferably 1 to 12N, more preferably 4 to 8N. The reaction temperature is preferably 0°C to 110°C, more preferably 50°C to 100°C. The reaction time is appropriately selected according to conditions such as the reaction temperature, and is preferably 0.25 to 30 hours, more preferably 0.5 to 5 hours.

Amidation includes aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, monoglyme or diglyme; halogenation such as methylene chloride, chloroform or carbon tetrachloride; Hydrocarbons: alcohols such as methanol or ethanol; aliphatic hydrocarbons such as pentane, hexane, heptane or ligroin; N,N-dimethylaminopyridine, trimethylamine, triethylamine in an aprotic polar solvent such as DMF or DMSO , tributylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine or procaine; inorganic bases such as potassium carbonate or lithium carbonate. Amine (g) was converted to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(benzotriazole-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4 Using a condensing agent such as -(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate, from 0°C to under reflux, preferably 0°C. Compound (b) can be synthesized by reacting at ~50°C for 1 to 12 hours, more preferably 1 to 5 hours.

(Step 1-2)
Compound (b) can be converted to compound (c) by a general demethylation reaction of phenolic methyl ether. Specifically, (1) a method using boron tribromide or (2) a method using an alkylthiol under basic conditions can be used.

In method (1), the amount of boron tribromide used is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents. The reaction solvent is preferably a halogen solvent such as dichloromethane, chloroform or 1,2-dichloroethane, more preferably dichloromethane. The reaction temperature is preferably -70°C to 50°C, more preferably -50°C to 40°C. The reaction time is preferably 10 minutes to 10 hours, more preferably 30 minutes to 5 hours.

In method (2), alkylthiols such as ethanethiol, propanethiol or butanethiol are preferred as the reactant, and propanethiol is more preferred. The amount of the reactant used is preferably 1 to 20 equivalents, more preferably 1 to 7 equivalents. Potassium tert-butoxide, sodium hydride, potassium hydride, or the like is preferable as the base, and potassium tert-butoxide is more preferable. The amount of base used is preferably 1-20 equivalents, with 1-7 equivalents giving satisfactory results. The reaction solvent is preferably an aprotic polar solvent such as DMF or dimethylacetamide, or an ether solvent such as tetrahydrofuran (hereinafter THF) or dimethyl ether (hereinafter DME), more preferably DMF which is an aprotic solvent. The reaction temperature is preferably 50°C to 200°C, more preferably 80°C to 150°C. The reaction time is preferably 1 hour to 15 hours, more preferably 2 hours to 8 hours.

(Step 2-1)
Raw material (d) and 2-chloroacrylonitrile to benzene, aromatic hydrocarbons such as toluene or xylene; ethers such as diethyl ether, THF, dioxane, monoglyme or diglyme; alcohols such as methanol or ethanol; pentane, hexane, Aliphatic hydrocarbons such as heptane or ligroin; after reacting in an aprotic polar solvent such as DMF or DMSO at 80 to 190° C. for 3 to 24 hours, or in a sealed tube, using a microwave synthesizer. After reacting with irradiation, compound (e) can be synthesized by hydrolysis. The hydrolysis reaction can be carried out using a known acid or base, but a base is preferred. For example, ethers such as THF or dioxane; 1 to 5 equivalents of an inorganic basic aqueous solution such as an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide is added, and the mixture is reacted for 1 to 24 hours under heating under reflux.

The starting material (d) can be synthesized by a generally known method. For example, J. Chem. Soc. C, 1966, 617; Chem. Soc. C, 1969, 2569; Chem. Soc. Perkin Trans. I, 1994, 911 can be synthesized.

(Step 2-2)
In the subsequent reduction step, compound (e) is treated with a metal catalyst such as nickel (Raney nickel, etc.) in a solvent such as ethers such as diethyl ether, THF, dioxane, monoglyme or diglyme; alcohols such as methanol or ethanol. , in the presence of palladium (palladium-activated carbon (Pd/C), Pearlman's catalyst: Pd(OH) ₂ etc.) or platinum (Adams catalyst (PtO ₂ ) etc.) at room temperature to under reflux with heating. Compound (f) can be synthesized by reacting for 1 to 24 hours.

(Step 2-3)
Tf etherification is carried out by adding ethers such as diethyl ether, THF, dioxane, monoglyme or diglyme to compound (f) under an inert gas atmosphere; , a base such as potassium bis(trimethylsilyl)amide or lithium diisopropylamide; trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine , an organic base such as cyclohexylamine or procaine; trifluoromethanesulfonic anhydride or N-phenyl-bis(trifluoromethanesulfonimide) or the like in the presence of an inorganic base such as potassium carbonate or lithium carbonate at -78 ° C. to room temperature for 30 Compound (g) can be synthesized by reacting for minutes to 5 hours.

(Step 2-4)
The coupling reaction can be performed using a metal such as palladium as a catalyst. In an inert gas atmosphere, the compound (g) is treated with ethers such as diethyl ether, THF, dioxane, monoglyme or diglyme; aromatic hydrocarbons such as benzene, toluene or xylene. A zerovalent palladium catalyst or a divalent palladium catalyst such as palladium acetate, (dichlorobis(tri-o-tolylphosphine))palladium, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis[ phosphine ligands such as 2-(diphenylphosphino)phenyl]ether or (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and trimethylamine, triethylamine, tributylamine, pyridine, N , N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine or an organic base such as procaine; 2,4,6-trichlorophenylformate in the presence of an inorganic base such as potassium carbonate or lithium carbonate. The compound (h) can be synthesized by reacting at 0° C. to under reflux with heating for 1 to 24 hours.

(Step 2-5)
Ester-amide exchange using the obtained active ester (h) can be carried out by reacting the corresponding primary amine in the presence of a base. The amount of the amine derivative used for transamidation is preferably 1 to 10 equivalents, more preferably 3 to 7 equivalents, relative to the active ester (h). The reaction solvent is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include THF, 1,4-dioxane, ethylene glycol, DME, dimethoxyethane, and the like. Ether solvents, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic solvents such as DMF or DMSO, ketone solvents such as acetone or methyl ethyl ketone, or acetonitrile Alternatively, a nitrile solvent such as propionitrile may be used, but THF is preferred. As the base to be used, triethylamine, N,N-diisopropylethylamine, pyridine, dimethylaminopyridine or a combination thereof is used, and a combination of triethylamine and dimethylaminopyridine is preferred. Although the amount of the base is selected as appropriate, 0.001 to 2 equivalents, more preferably 0.05 to 0.5 equivalents of dimethylaminopyridine are used in 1 to 20 equivalents, more preferably 1 to 10 equivalents of triethylamine. It can be carried out. The reaction temperature is preferably 0°C to 200°C, more preferably 30°C to 70°C. The reaction time is appropriately selected according to conditions such as the reaction temperature, preferably 0.5 to 30 hours, more preferably 1 to 5 hours.

(Step 2-6)
In the subsequent reduction step, compound (i) is treated with a metal catalyst such as nickel (Raney nickel, etc.) in a solvent such as diethyl ether, THF, dioxane, ethers such as monoglyme or diglyme; alcohols such as methanol or ethanol. Or the presence of palladium (palladium-activated carbon (Pd/C), Pearlman's catalyst (Pd(OH) ₂ ), palladium-fibroin, palladium-ethylenediamine, etc.), platinum (Adams catalyst (PtO ₂ ), etc.) However, it is particularly preferred to use palladium-fibroin. Although the reaction can be carried out at room temperature to under reflux with heating, room temperature to 70°C is preferred. The reaction takes 1 to 24 hours, more preferably 5 to 18 hours to synthesize compound (j).

(Step 2-7)
Alkylation of amides can be carried out by reacting an alkyl halide or an alkyl tosylate in the presence of a base. As the base to be used, sodium hydride, potassium hydride, sodium, sodium t-butoxy, or the like can be used, and sodium hydride is preferably used. As the alkylating agent, an alkyl iodide or an alkyl bromide can be used, and it is particularly preferable to use an alkyl iodide. The reaction solvent is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include THF, 1,4-dioxane, ethylene glycol, DME, dimethoxyethane, and the like. Ether solvents, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile but THF is preferred. The reaction temperature is -20°C to heating reflux temperature, preferably 0°C to 50°C. The compound (k) can be obtained in a reaction time of 0.5 to 24 hours, preferably 1 to 18 hours.

(Step 2-8)
Compound (k) can be converted to compound (l) by a general demethylation reaction of phenolic methyl ether. Specifically, (1) a method using boron tribromide or (2) a method using an alkylthiol under basic conditions can be used.

In method (1), the amount of boron tribromide used is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents. The reaction solvent is preferably a halogen solvent such as dichloromethane, chloroform or 1,2-dichloroethane, more preferably dichloromethane. The reaction temperature is preferably -70°C to 50°C, more preferably -50°C to 40°C. The reaction time is preferably 10 minutes to 10 hours, more preferably 30 minutes to 5 hours.

In method (2), alkylthiols such as ethanethiol, propanethiol or butanethiol are preferred as the reactant, and propanethiol is more preferred. The amount of the reactant used is preferably 1 to 20 equivalents, more preferably 1 to 7 equivalents. Potassium tert-butoxide, sodium hydride, potassium hydride, or the like is preferable as the base, and potassium tert-butoxide is more preferable. The amount of base used is preferably 1 to 20 equivalents, more preferably 1 to 7 equivalents. The reaction solvent is preferably an aprotic polar solvent such as DMF or dimethylacetamide or an ether solvent such as THF, more preferably DMF which is an aprotic solvent. The reaction temperature is preferably 50°C to 200°C, more preferably 80°C to 150°C. The reaction time is preferably 1 to 15 hours, more preferably 2 to 8 hours.

The compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof can be used as a therapeutic agent, ameliorating agent or preventive agent for diseases associated with opioid κ receptors. The diseases associated with the opioid κ receptor are not limited to those listed below, but include, for example, cardiovascular disorders, digestive system diseases, blood system diseases, respiratory system diseases, liver diseases, neurological diseases, system disorders, urinary system disorders, pain, cough, pruritus, ischemic brain disease or drug dependence.

As used herein, a therapeutic agent for a disease associated with the κ opioid receptor means a drug administered to a patient for the purpose of treating a disease associated with the κ opioid receptor. An ameliorating agent for κ opioid receptor-related diseases means a drug administered to a patient for the purpose of ameliorating a κ opioid receptor-related disease. In addition, a prophylactic agent for a disease associated with the κ opioid receptor means a drug administered to a patient for the purpose of preventing a disease associated with the κ opioid receptor.

The fact that the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is effective for treating, ameliorating or preventing a disease associated with the κ opioid receptor is confirmed by, for example, Animal models of related diseases can be used to evaluate the ameliorating effect on characteristic symptoms of diseases related to opioid κ receptors as an index. For example, evaluation of analgesic activity, which is a disease associated with the kappa opioid receptor, is performed in the mouse acetic acid writhing model (Academic Press, 1977, Chapter 6, pp. 83-99), the rat formalin test (Pain, 1992, 51 vol., p.5-17), rat carrageenan-induced inflammation model (Japanese Journal of Pharmacology, 1970, vol.20, pp.337-348), cancer pain model (European Journal of Pharmacology, 2002, 441 vol., pp. 185-191) the rat hot plate test (Journal of Pharmacology and Experimental Therapeutics, 1975, vol. 192, pp. 497-505) or the tail flick test (Journal of Pharmaceutical Sciences, 1962) for acute pain. , Vol. 51, p.185-186), etc. can be used.

The compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is an opioid for mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.). It can be used as a therapeutic agent, ameliorating agent or preventive agent for diseases associated with κ receptors.

When the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is clinically used as a therapeutic agent, ameliorating agent or preventive agent for diseases associated with the opioid κ receptor, the general formula The compound represented by (I) or a pharmaceutically acceptable salt thereof may be used as it is, for example, excipients, capsule shells, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents Additives such as agents, tonicity agents, disintegrants, lubricants, coating agents, plasticizers and coloring agents are appropriately mixed as pharmacologically acceptable carriers to form a pharmacologically acceptable carrier. It may be provided as a pharmaceutical composition containing A pharmaceutical composition containing a pharmaceutically acceptable carrier can be administered orally or parenterally.

Examples of the above excipients include D-mannitol, erythritol, lactose, macrogol, and the like. Examples of the capsule shell include gelatin or succinated gelatin. Examples of the stabilizer include sodium thiosulfate hydrate and the like. Examples of the disintegrant include crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and the like. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, and the like. Examples of the coating agent include hydroxypropylmethylcellulose, polyvinyl alcohol, and the like. Examples of the plasticizer include concentrated glycerin, macrogol 400, and the like. Examples of the coloring agent include titanium oxide, iron sesquioxide, yellow iron sesquioxide, and talc.

In addition, the therapeutic agent, ameliorating agent or preventive agent for diseases associated with the opioid κ receptor can be produced by a conventional method using the above carrier as appropriate. A pharmaceutical composition containing a compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier can also be produced in the same manner.

When the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is orally administered as a therapeutic agent, ameliorating agent or preventive agent for a disease associated with the κ opioid receptor, the dosage form includes: Examples include tablets, capsules, orally disintegrating agents, powders or granules, and parenteral administration includes intravenous rapid infusion, intravenous continuous infusion, intramuscular injection, subcutaneous injection, intradermal injection, and inhalation. agents, suppositories, ointments, creams, patches and the like. Alternatively, it may be a known long-acting preparation.

The content of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof in the therapeutic agent, ameliorating agent or preventive agent for diseases associated with the opioid κ receptor is not particularly limited, but one It can be prepared to contain 0.01 μg to 100 mg per dose. In addition, the dose can be appropriately selected according to the patient's symptoms, age, sex, body weight, administration method, etc. Generally, the compound represented by the general formula (I) or its pharmacological The acceptable amount of the salt is preferably 0.01 μg to 20 mg, more preferably 0.1 μg to 10 mg, even more preferably 0.1 μg to 100 μg, and each can be administered once or divided into several doses.

The therapeutic agent, ameliorating agent, or preventive agent for diseases associated with κ opioid receptors described above is used to supplement or enhance the therapeutic effect, ameliorating effect, or preventive effect, or to reduce the dosage of κ opioid receptor-related diseases. can be administered in combination with one or more other agents used for the treatment, prevention, reduction or suppression of symptoms of A drug to be combined may be a low-molecular-weight compound, or may be a high-molecular-weight protein, polypeptide, antibody, vaccine, or the like. In this case, the drugs to be combined can be administered simultaneously or with a time lag. As for the method of combination, each drug may be used in combination, and a combination drug is also possible. The doses of the drugs to be combined can be appropriately selected based on the doses used clinically. In addition, the compounding ratio of the therapeutic agent, ameliorating agent or preventive agent for the above-mentioned opioid κ receptor-related diseases and the drug to be combined is determined by the administration subject, the age of the administration subject, the body weight, the symptoms, the administration time, the dosage form, or the administration method. etc., can be selected as appropriate.

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited by these.

As for the compounds used in the synthesis of the compounds of the examples and not described in the synthesis method, the commercially available compounds were used. Solvent names shown in the NMR data indicate solvents used for measurement. Also, 400 MHz NMR spectra were measured using a high-resolution Fourier transform nuclear magnetic resonance spectrometer JNM-ECS 400 (JEOL). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (singlet), d (doublet), t (triplet), m (multiplet), br ( wide). ESI-MS spectra were measured using JMS-T100LP (JEOL). Elemental analysis was performed using a microcoder JM10 (J-SCIENCE LAB). Silica gel used was PSQ60B-CHROMATOREX (manufactured by Fuji Silysia Chemical Ltd.), and preparative TLC used Silica gel 60 F254 (0.25 mm, 0.5 mm) (manufactured by Merck Ltd.).

(Reference example 1)
(4R,4aR,7S,7aR,12bS)-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a,7-ethano-4,12- Synthesis of methanobenzofuro[3,2-e]isoquinolin-14-one (hereinafter compound 1):

(4R,7aR,12bS)-3-(Cyclopropylmethyl)-7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline (J. C, 1966, 617, J. Chem. Soc. C, 1969, 2569 and J. Chem. Soc. Perkin Trans. I, 1994, 911) (2.0 g, 5. 63 mmol) in 1,2-dichloroethane (10 mL) was placed in a vial for microwave reaction, 2-chloroacrylonitrile (4.5 mL, 56.6 mmol) was added, and three sealed vials were prepared. Each was irradiated with microwaves in a microwave synthesizer and reacted under conditions of 180° C. and 10 bar for 30 minutes. After cooling, the contents of the three vials were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25-50% ethyl acetate/hexane). The obtained 2-chloroacrylonitrile adduct was dissolved in ethanol (144 mL), 1M aqueous sodium hydroxide solution (36 mL) was added, and the mixture was heated under reflux for 3 hours. After allowing to cool, water (200 mL) was added, and the mixture was extracted twice with diethyl ether. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (25-50% ethyl acetate/hexane) to obtain compound 1 (2.5 g, 44%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.77-0.91 (m , 1H), 1.87 (dd, J = 2.8, 12.8Hz, 1H), 2.07 (ddd, J = 5.4, 12.8, 12.8Hz, 1H), 2.17 ( d, J = 18.8 Hz, 1 H), 2.32-2.55 (m, 4 H), 2.77 (dd, J = 5.4, 11.9 Hz, 1 H), 3.17 (d, J = 18.3Hz, 1H), 3.32 (d, J = 18.8Hz, 1H), 3.63 (s, 3H), 3.65 (d, J = 6.9Hz, 1H), 3.83 (s, 3H), 4.68 (d, J = 1.4Hz, 1H), 5.70 (d, J = 8.7Hz, 1H), 5.88-5.93 (m, 1H), 6 .57 (d, J=7.8 Hz, 1 H), 6.66 (d, J=7.8 Hz, 1 H).

(Reference example 2)
(4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a,7-ethano-4,12- Synthesis of methanobenzofuro[3,2-e]isoquinolin-6(5H)-one (hereinafter compound 2):

Compound 1 (2.43 g, 6.18 mmol) was dissolved in ethanol (100 mL) and 5% palladium-activated carbon (2.01 g) was added. In a hydrogen atmosphere, the mixture was stirred at 60°C for 12 hours, allowed to cool, and then filtered through celite. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (100 mL) was added to the residue, and the mixture was extracted twice with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol, filtered, and purified by recrystallization to obtain Compound 2 (2.25 g, 92%) as colorless plate crystals (melting point: 164-165°C).

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.16 (m, 2H), 0.43-0.56 (m, 2H), 0.73-0.86 (m , 1H), 1.01 (dddd, J = 3.2, 3.2, 12.8, 12.8 Hz, 1H), 1.26 (ddd, J = 6.0, 12.8, 12.8 Hz , 1H), 1.49-1.61 (m, 1H), 1.68 (dd, J = 3.7, 13.3 Hz, 1H), 1.76 (ddd, J = 6.0, 12. 8, 12.8Hz, 1H), 2.01 (ddd, J = 5.8, 12.8, 12.8Hz, 1H), 2.22 (d, J = 19.7Hz, 1H), 2.29 -2.42 (m, 4H), 2.70 (dd, J = 5.8, 11.9Hz, 1H), 3.07 (d, J = 18.3Hz, 1H), 3.13 (d, J = 6.4 Hz, 1H), 3.46-3.55 (m, 1H), 3.53 (s, 3H), 3.89 (s, 3H), 4.60 (s, 1H), 6 .63 (d, J=8.2 Hz, 1 H), 6.76 (d, J=8.2 Hz, 1 H).

(Reference example 3)
(4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a,7-ethano-4,12- Synthesis of methanobenzofuro[3,2-e]isoquinolin-6-yl trifluoromethanesulfonate (hereinafter compound 3)

Under an argon atmosphere, 11% KHMDS toluene solution (5.5 mL, 2.75 mmol) was added to anhydrous THF (4 mL) and cooled to -78°C. A solution of compound 2 (885 mg, 2.24 mmol) in anhydrous THF (4 mL) and a solution of N-phenyl-bis(trifluoromethanesulfonimide) (1.1 g, 3.36 mmol) in anhydrous THF (2 mL) were sequentially added, and the mixture was stirred for 1 hour. Stirred. A saturated aqueous sodium hydrogencarbonate solution (5 mL) was added, and the temperature was raised to room temperature. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (15-25% diethyl ether/hexane) to give compound 3 (1.17 g, 99%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.20 (m, 2H), 0.46-0.61 (m, 2H), 0.76 (ddd, J=2 .8, 9.6, 12.8 Hz, 1 H), 0.80-0.92 (m, 1 H), 1.03 (ddd, J = 5.6, 12.4, 12.4 Hz, 1 H), 1.43 (dddd, J = 2.4, 2.4, 12.4, 12.4 Hz, 1H), 1.65 (dd, J = 2.4, 13.3 Hz, 1H), 1.79 ( ddd, J = 5.6, 9.6, 12.4Hz, 1H), 1.91 (ddd, J = 5.6, 12.8, 12.8Hz, 1H), 2.26-2.45 ( m, 4H), 2.62 (dd, J = 5.6, 12.0Hz, 1H), 3.09 (d, J = 18.3Hz, 1H), 3.42 (d, J = 6.4Hz , 1H), 3.58 (s, 3H), 3.90 (s, 3H), 4.62 (d, J = 2.4 Hz, 1H), 6.54 (s, 1H), 6.61 ( d, J=8.2 Hz, 1 H), 6.76 (d, J=8.2 Hz, 1 H).

(Reference example 4)
2,4,6-trichlorophenyl(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a, Synthesis of 7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxylate (hereinafter compound 4)

Compound 3 (1.07 g, 2.03 mmol) was dissolved in toluene (15 mL), 2,4,6-trichlorophenyl formate (564 mg, 2.50 mmol), palladium acetate (46 mg, 0.205 mmol) and 4, 5-bis(diphenylphosphino)-9,9-dimethylxanthene (234 mg, 0.404 mmol) was added. Triethylamine (0.34 mL) was slowly added dropwise under an argon atmosphere, and the mixture was stirred at room temperature for 10 hours. A saturated aqueous sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate three times. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain compound 4 (1.1 g, 90%) as a colorless amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.09-0.21 (m, 2H), 0.47-0.62 (m, 2H), 0.74-0.84 (m , 1H), 0.85-0.96 (m, 1H), 0.98 (ddd, J = 5.5, 12.8, 12.8Hz, 1H), 1.43-1.54 (m, 1H), 1.66-1.76 (m, 2H), 1.81 (ddd, J = 5.5, 12.8, 12.8Hz, 1H), 2.28-2.51 (m, 4H ), 2.63 (dd, J = 4.6, 11.9 Hz, 1 H), 3.12 (d, J = 18.3 Hz, 1 H), 3.51 (d, J = 6.9 Hz, 1 H) , 3.56 (s, 3H), 3.90 (s, 3H), 4.65 (d, J=1.4 Hz, 1 H), 6.63 (d, J=8.0 Hz, 1 H), 6 .77 (d, J = 8.0Hz, 1H), 7.40 (s, 2H), 8.07 (s, 1H)

(Reference example 5)
(4R,4aS,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a,7-ethano- Synthesis of 4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (hereinafter compound 5)

Compound 4 (31.7 mg, 0.0525 mmol) was dissolved in THF (2 mL), benzylamine (13 μL, 0.119 mmol), triethylamine (19 μL, 0.136 mmol) and N,N-dimethyl-4-aminopyridine ( 1.0 mg, 0.0082 mmol) was added and stirred at 50°C for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (28% aqueous ammonia:methanol:chloroform=1:9:400). Compound 5 (20 mg, 74%) was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.08-0.18 (m, 2H), 0.46-0.58 (m, 2H), 0.67-0.77 (m , 1H), 0.85-0.98 (m, 2H), 1.26 (dddd, J = 2.3, 2.3, 11.9, 11.9Hz, 1H), 1.59 (dd, J = 2.3, 12.8Hz, 1H), 1.72-1.90 (m, 2H), 2.25-2.44 (m, 4H), 2.60 (dd, J = 5.0 , 11.9 Hz, 1 H), 3.08 (d, J = 18.3 Hz, 1 H), 3.46 (d, J = 6.4 Hz, 1 H), 3.49 (s, 3 H), 3.89 (s, 3H), 4.47 (d, J=2.3Hz, 1H), 4.53 (dd, J=5.5, 14.7Hz, 1H), 4.60 (dd, J=5. 5, 14.7Hz, 1H), 6.61 (d, J = 8.0Hz, 1H), 6.75 (d, J = 8.0Hz, 1H), 7.25-7.39 (m, 5H ), 7.85(s, 1H), 8.12(br t, J=5.5Hz, 1H).

(Reference example 6)
(4R,4aS,6R,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro- 4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (hereinafter, compound 6)

Compound 5 (0.252 g, 0.492 mmol) obtained by the method of Reference Example 5 was dissolved in ethanol (20 mL), and 2.5% palladium-fibroin (0.423 g) was added. The mixture was heated and stirred at 50° C. for 14 hours in a hydrogen atmosphere, allowed to cool, and filtered through a cotton plug. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (7.0 mL) was added, and the mixture was extracted with chloroform (50 mL, 30 mL, 20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (5-10% acetone/hexane) to give compound 6 (0.250 g, 99%) as a colorless amorphous material.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H), 0.42-0.52 (m, 2H), 0.75-0.91 (m , 2H), 1.14 (ddd, J = 5.8, 12.5.12.5 Hz, 1H), 1.20-1.31 (m, 1H), 1.44-1.52 (m, 1H), 1.61 (dd, J = 1.5, 13.3Hz, 1H), 1.72 (ddd, J = 6.2, 12.5, 12.5Hz, 1H), 2.18-2 .33 (m, 4H) 2.64-2.76 (m, 3H), 3.00 (d, J = 13.7Hz, 1H), 3.03 (d, J = 1.8Hz, 1H), 3.35 (ddd, J=4.6, 4.6, 13.7 Hz, 1H), 3.44 (s, 3H), 3.87 (s, 3H), 4.42 (ddd, J=5 .5, 14.9Hz, 1H), 4.60 (dd, J = 5.5, 14.9Hz, 1H), 4.91 (d, J = 2.3Hz, 1H), 6.56 (d, J = 8.0Hz, 1H), 6.70 (d, J = 8.0Hz, 1H), 6.87 (t, J = 5.5Hz, 1H), 7.23-7.31 (m, 1H) ), 7.32-7.37 (m, 4H).
HRMS-ESI (m/z): [M+H] ⁺ calcd for C ₃₂ H ₃₉ N ₂ O ₄ : 515.2910, found: 515.2899.

(Example 1)
(4R,4aS,6S,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-N-methyl-1,2,3,4,5,6,7, 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (hereinafter, compound 7)

Ethyl (4R,4aS,6S,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)- which is an ester obtained by the method described in Patent Document (International Publication No. 98/043978) 7,9-dimethoxy-N-methyl-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6- Carboxylate (0.158 g, 0.349 mmol) was dissolved in 6M hydrochloric acid aqueous solution (10 mL), heated with stirring at 90° C. for 2 hours, and the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DMF (10 mL) and treated with N-methylbenzylamine (0.102 mL, 0.698 mmol), N,N-diisopropylethylamine (0.182 mL, 1.05 mmol) and 1-[bis(dimethyl Amino)methylene]-1H-1,2,3-triazolo[4,5-b]]pyridinium 3-oxide hexafluorophosphate (0.201 g, 0.558 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution (10.0 mL) and purified water (30 mL), and extracted with a 1:1 mixed solution of hexane and ethyl acetate (100 mL, 60 L, 30 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (10-15% acetone/hexanes) to give compound 7 (0.161 g, 87%) as an orange amorphous material.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.05-0.14 (m, 2H), 0.42-0.54 (m, 2H), 0.71-0.88 (m , 2H), 1.25-1.33 (m, 2H), 1.43-1.74 (m, 2H), 2.00-2.14 (m, 2H), 2.19-2.38 (m, 4H), 2.50-2.73 (m, 1H), 2.81-2.88 (m, 2H), 2.94-3.06 (m, 4H), 3.10-3 .14 (m, 1H), 3.40 (s, 1.2H), 3.43 (s, 1.8H), 3.87 (s, 1.2H), 3.88 (s, 1.8H) ), 4.27-4.34 (m, 14.9Hz, 1H), 4.38-4.40 (m, 1H), 4.96-5.14 (m, 1H), 6.54-6 .58 (m, 1H), 6.69-6.73 (m, 1H), 7.21-7.35 (m, 5H).
HRMS-ESI (m/z): [M+H] ⁺ calcd for C ₃₃ H ₄₁ N ₂ O ₄ : 529.3066, found: 529.3069.

(Example 2)
(4R,4aS,6S,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6,7, 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (hereinafter, compound 8)

Compound 7 obtained in Example 1 (0.159 g, 0.301 mmol) was dissolved in dichloromethane (6 mL), and stirred at -20°C while adding 1.0 M boron tribromide in dichloromethane (1.82 mL, 1 .82 mmol) was added. After stirring at −20° C. for 3.0 hours, 28% aqueous ammonia solution (3.0 mL) was added under ice-cooling, and the mixture was further stirred at room temperature for 1 hour. After that, a saturated aqueous sodium hydrogencarbonate solution (10 mL) and chloroform (5 mL) were added, and the mixture was extracted with chloroform (50, 30, 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (methanol:chloroform=1:20) to obtain the free form of compound 8 (128.6 mg, 85%) as a colorless amorphous substance. This free form was dissolved in ethyl acetate, and 1M hydrogen chloride--diethyl ether solution was added under ice-cooling. After adding diethyl ether at room temperature and stirring for 30 minutes, the resulting white precipitate was collected by filtration to obtain the hydrochloride of compound 8.

(free body)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.04-0.18 (m, 2H), 0.41-0.55 (m, 2H), 0.63-0.85 (m , 2H), 1.17-1.41 (m, 2H), 1.57-1.75 (m, 2H), 1.76-1.93 (m, 0.6H), 1.91-2 .07 (m, 0.4H), 2.15-2.40 (m, 4H), 2.50-2.69 (m, 1H), 2.83-3.10 (m7H), 4.00 -4.12 (m, 1H), 4.20-4.34 (m, 1H), 4.49-4.50 (m, 2H), 6.48-6.56 (m, 1H), 6 .68-6.74 (m, 1H), 7.17-7.35 (m, 5H).
No two hydroxyl hydrogens were observed.
HRMS-ESI (m/z): [M+H] ⁺ calcd for C ₃₁ H ₃₇ N ₂ O ₄ : 501.2753, found: 501.2737.
(hydrochloride)
Elemental analysis calcd _{for C31H34N2O4.HCl.1.1H2O :} C, 66.86; _H , 7.10; _N , 5.03. found C, 67.05,; H, 7.38; N, 5.10.

(Example 3)
(4R,4aS,6R,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-N-methyl-1,2,3,4,5,6,7, 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (hereinafter, compound 9)

Under an argon atmosphere, sodium hydride (55% in oil, 70.5 mg, 1.56 mmol) was suspended in anhydrous THF (5.0 mL) and ice-cooled to give compound 6 (0.250 g, 0.468 mmol) in anhydrous form. A THF (10.0 mL) solution was added. After that, under light shielding, iodomethane (32.0 μL, 0.515 mmol) was added, and the mixture was returned to room temperature and stirred for 13 hours. A saturated aqueous ammonium chloride solution (6.0 mL) was slowly added to the reaction mixture under ice-cooling, followed by purified water (7.0 mL), followed by extraction with chloroform (40 mL, 30 mL, and 20 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (5-10% acetone/hexane) to give compound 9 (0.187 g, 73%) as a colorless amorphous material.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.06-0.13 (m, 2H). 0.42-0.52 (m, 2H), 0.75-0.91 (m, 2H), 1.10-1.26 (m, 2H), 1.44-. 180 (m, 3H), 2.18-2.33 (m, 4H), 2.63-2.72 (m, 1H), 2.92-3.10 (m, 7H), 3.16- 3.23 (m, 0.5H), 3.32-3.36 (m, 0.5H), 3.45 (s, 3H), 3.86 (s, 1.2H), 3.87 ( s, 1.8H), 4.33-4.41 (m, 1H), 4.93-5.10 (m, 1H), 5.45 (s, 1H) 6.50-6.58 (m , 1H), 6.65-6.71 (m, 1H), 7.23-7.31 (m, 1H), 7.32-7.37 (m, 4H).
HRMS-ESI (m/z): [M+H] ⁺ calcd for C ₃₃ H ₄₁ N ₂ O ₄ : 529.3066, found: 529.3051.

(Example 4)
(4R,4aS,6R,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6,7, 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide (hereinafter, compound 10)

Compound 9 (0.183 g, 0.347 mmol) was dissolved in dichloromethane (7 mL), and 1.0 M boron tribromide in dichloromethane (2.10 mL, 2.10 mmol) was added while stirring at -20°C. After stirring at −20° C. for 4 hours, 28% aqueous ammonia solution (3.5 mL) was added under ice-cooling, and the mixture was further stirred at room temperature for 1 hour. Then, saturated aqueous sodium hydrogencarbonate solution (15 mL) and chloroform (7 mL) were added, and extracted with chloroform (50 mL, 40 mL, 30 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-5% methanol/chloroform) to obtain compound 10 free form (0.135 g, 77%) as a colorless amorphous substance. This free form was dissolved in ethyl acetate, and a 1M hydrogen chloride-diethyl ether solution was added under ice-cooling. After adding diethyl ether at room temperature and stirring for 30 minutes, the resulting white precipitate was collected by filtration to obtain a hydrochloride of compound 10.

(free body)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.02-0.18 (m, 2H), 0.41-0.52 (m, 2H), 0.70-0.90 (m , 2H), 1.17-1.41 (m, 2H), 1.02-1.33 (m, 2H), 1.45-1.63 (m, 2H), 1.64-1.89 (m, 1H), 2.18-2.38 (m, 4H), 2.50-2.70 (m, 1H), 2.77-3.05 (m, 6H), 2.09-3 .28 (m, 1H), 4.31 (bs, 1H), 4.40-4.80 (m, 2H), 5.75-5.76 (d, J=6.9Hz, 1H), 6 .46-6.54 (m, 1H), 6.66-6.74 (m, 1H), 7.17-7.35 (m, 5H).
HRMS-ESI (m/z): [M+H] ⁺ calcd for C ₃₁ H ₃₇ N ₂ O ₄ : 501.2753, found: 501.2768.
(hydrochloride)
Elemental analysis calcd _{for C31H34N2O4.HCl.1.4H2O} : C, _66.22 ; _H , 7.13; _N , 4.98. found C, 66.19,; H, 7.12; N, 4.91.

(Test Example 1) Human Opioid κ Receptor Binding Test Cell membrane fractions in the receptor binding test were collected from HEK293 cells stably expressing opioid receptors. In the experiment, [3H]U-69593 (κ opioid receptor ligand) adjusted to a final concentration of 2 nM was added to the cell membrane fraction of the corresponding receptor, and compound 8 and compound 10 (both 10 ^{− 15} to 10 ^-6 M) was added and incubated. The receptor binding affinity (Ki value) of the test compound was calculated based on the change in radioactivity obtained from the competitive displacement reaction between the radioligand and the test compound occurring on the receptor.

Ki value Compound 8 122 pM
Compound 10 115 pM

(Test Example 2) Analgesic action (acetic acid writhing test)
ICR male mice (25-30 g) acclimated to the laboratory environment were transferred to acrylic open field cages for measurement and acclimated for 10 minutes. After acclimation, a sample compound or saline was administered subcutaneously at a dose of 10 mL/kg body weight of the mice and returned to the cage for measurement. Thirty minutes after compound administration, each mouse was intraperitoneally treated with 0.6% acetic acid aqueous solution at a dose per mouse body weight. Ten minutes after administration of the aqueous acetic acid solution, the number of writhing reactions induced in the mice was counted for 10 minutes, and the number of writhing reactions was compared with that of the control group (physiological saline-administered group) to evaluate the analgesic effect of the test compound.

Analgesic ED ₅₀ value Compound 8 1.29 μg/kg
Compound 10 3.32 μg/kg

(Test Example 3) Sedative effect (rotarod test)
Before starting the experiment, ICR male mice were repeatedly trained to walk on the rotating shaft of the rotarod apparatus with breaks so that they could walk at 5 rpm for 120 seconds, 6 rpm for 180 seconds, and 8 rpm for 300 seconds. Mice that repeatedly fell from the rotating shaft more than 20 times under constant speed training were discarded before the experiment. After sufficient rest for 2-3 hours, mice that had achieved locomotion training received compound 8 (100-3000 μg/kg), compound 10 (300-30000 μg/kg) or saline at 10 mL/kg of mouse body weight. Dosages were administered subcutaneously. In the rotarod test, the number of times the mice fell from the rotary shaft and the residence time until the first fall were measured at 8 rpm for 300 seconds at 30-minute intervals after administration, and evaluated up to 120 minutes after drug treatment.

FIG. 1 shows the evaluation results of the analgesic action and sedative action of Compounds 8 and 10. Compound 8 showed a dose-dependent increase in the total number of falls, but its ED ₅₀ value was 531 μg/kg, which is 400 times greater than the analgesic ED ₅₀ value of 1.29 μg/kg determined in Test Example 2. There was a gap of Compound 10 did not show any increase in the number of falls within the tested range, and the difference was 9000 times or more. These results demonstrate that compounds 8 and 10 have significantly weaker side effects than nalfurafine.

The morphinan derivative or pharmaceutically acceptable salt thereof of the present invention binds to the κ opioid receptor and has significantly reduced side effects. It is useful in the pharmaceutical field as a prophylactic agent.

Claims (7)

A morphinan derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[In the formula, R ¹ represents a cycloalkylalkyl having 4 to 7 carbon atoms,
R ² represents hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms,
R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms,
R ⁴ represents alkyl having 1 to 5 carbon atoms,
Ar represents phenyl, pyridyl, furanyl or thiophenyl (which may be substituted with halogen, alkyl having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms). ] The morphinan derivative or a pharmaceutically acceptable salt thereof according to claim 1, represented by the following general formula (Ia).

[In the formula, R ¹ represents a cycloalkylalkyl having 4 to 7 carbon atoms,
R ² represents hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms,
R ³ represents hydrogen or alkyl having 1 to 5 carbon atoms,
R ⁴ represents alkyl having 1 to 5 carbon atoms,
Ar represents phenyl, pyridyl, furanyl or thiophenyl (which may be substituted with halogen, alkyl having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms)] (4R,4aS,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6,7,7a- The morphinan derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide. (4R,4aS,6R,7R,7aR,12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dihydroxy-N-methyl-1,2,3,4,5,6,7, The morphinan derivative or a pharmaceutically acceptable salt thereof according to claim 2, which is 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide. A medicament acting on the opioid κ receptor, containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient. Cardiovascular disorders, digestive system diseases, blood system diseases, respiratory system diseases, liver diseases, containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient An agent for treating, improving or preventing a disease associated with the κ opioid receptor selected from the group consisting of diseases, nervous system disorders, urinary system disorders, pain, cough, pruritus, ischemic brain disease and drug dependence. 7. The therapeutic agent, ameliorating agent or preventive agent according to claim 6, wherein the disease associated with the opioid κ receptor is pain.

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