WO2001074819A1

WO2001074819A1 - Analgesics containing morphinan n-oxide derivatives as the active ingredient

Info

Publication number: WO2001074819A1
Application number: PCT/JP2001/002847
Authority: WO
Inventors: Hiroshi Nagase; Toru Miyamoto; Kuniaki Kawamura; Takashi Endoh
Original assignee: Toray Industries, Inc.
Priority date: 2000-04-03
Filing date: 2001-04-02
Publication date: 2001-10-11

Abstract

Analgesics containing as the active ingredient morphinan N-oxide derivatives of the general formula (I) or pharmacologically acceptable acid addition salts thereof [wherein R?1, R2, R3, R4, R5¿, and A are each as defined in the description]. The derivatives and the salts exhibit potent analgesic activity and are reduced in side effects.

Description

Description: Analgesic containing morphinan-N-oxide derivative as active ingredient

The present invention relates to an analgesic containing a morphinan-N-year-old oxide derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient. Background art

Morphine has long been known as a powerful analgesic having a morphinan skeleton, and is still widely used today. However, this drug has serious side effects that cause clinical problems such as dependence formation, respiratory depression, smooth muscle motility inhibition (constipation), etc. Requires management. Therefore, there is a long-awaited need for safe and powerful analgesics without any narcotic properties.

The existence of opioid receptors as receptors involved in central analgesia has been clarified, and it is known that they can be further classified into three types, δ and κ (W. R. Μ artin, C. G. E ades, J. A. T hompson, R. E. Hupier. And P. E. Gilbert, J. Pharmacol. E. xp. Ther, 1976, 197, 517. , J. A. H. Lord, A. A Waterfield, J. Hughesand HW Kosterlitz, Nature, 1977, 2667, 499.5)). Also, sigma receptors, which are thought to exhibit mental effects, are known. Among them, agonist, which has an affinity for the κ1 receptor, has strong analgesic activity. —Dependency formation, respiratory depression, smooth muscle motility inhibition seen in the receptor agonist morphine, etc. It is not reported to cause any serious clinical side effects such as effects. In addition, the kappa-receptor agonist does not show cross-resistance with morphine and the like; u-receptor agonist. Analgesics without such side effects are considered to be highly useful for pain relief in postoperative pain patients and cancer pain patients. The lack of cross-resistance also indicates that it is effective for patients who have become resistant to analgesics such as morphine. However, existing κ-receptor agonists represented by the U—50488H system are also compatible with σ receptors, which are said to be involved in mental effects such as hallucinations and obsessions. And no successful analgesics (Brian. R. de. Costa, Wayre. D. Bowen, eta1, J, Med. Chem. 1989, 32) , 1 9 9 6) ₀

Recently, κ-receptor agonists that have no affinity for σ receptors, which are involved in mental effects such as hallucinations and obsessions, have been reported (Japanese Patent Application No. 5-509616). It is known that body agonist generally has a strong diuretic effect as another side effect. This side effect is not always acceptable when considered for a wide range of pain applications. In addition, a morphinan Ν-salt derivative (W098Z2230) has been reported as Κ-agonist. Nothing is disclosed.

That is, an object of the present invention is to provide an analgesic having strong analgesic activity and reduced side effects. Disclosure of the invention

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the tertiary amine moiety in the morphinan structure of the morphinan-based obioid / receptor-selective agonist can be converted into a oxo group by oxidizing it. The present inventors have found that the analgesic activity is maintained as compared with before the oxidization, but the diuretic effect as a side effect is attenuated, and the present invention has been completed. That is, the present invention provides a compound represented by the general formula (I):

[In the formula,… represents a double bond or a single bond, and R ′ represents an alkyl having 1 to 5 carbons, Represents cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, and aryl, and R ² is hydrogen, hydroxy, or ni. Toro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, and R ³ is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or carbon R ⁴ represents hydrogen, linear or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms, and A represents 1 to 6 carbon atoms. Alkylene, one CH = CH— or —C≡C—, wherein R ⁵ is the following basic skeleton:

An organic group represented by

An organic group having any one of the following (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy, hydroxy, fluorine, fluorine, chlorine, bromine, iodine, nitro, having 1 to 5 carbons) Or cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, or methylenedioxy, which may be substituted with at least one or more substituents. And a pharmacologically acceptable acid addition salt thereof as an active ingredient. The present invention also provides a method for reducing pain, which comprises administering a drug containing, as an active ingredient, a morphinan-N-oxide derivative represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof. About the method. Further, the present invention relates to the use of a morphinan-N-year-old oxide derivative represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for the production of chain collic. BEST MODE FOR CARRYING OUT THE INVENTION

In the formula, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aralkyl having 7 to 13 carbons, and 4 to 7 carbons. Alkenyl and aryl are preferred, especially methyl, ethyl, propyl, butyl, isoptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl, trans-1-butenyl, 2- — Methyl-2-butenyl and aryl are preferred. More preferred are methyl, ethyl, propyl, butyl, isoptyl, cyclopropylmethyl, benzyl, phenethyl and aryl.

Hydrogen as R ^2, human Dorokishi, nitro, § Se butoxy, main butoxy, methyl, E chill, propyl are preferred, especially hydrogen, arsenate Dorokishi, Asetokishi, main butoxy virtuous preferable.

R ³ is preferably hydrogen, hydroxy, acetate, or methoxy.

R ⁴ is preferably hydrogen, straight-chain or branched alkyl having 0.1 to 5 carbon atoms, or phenyl, particularly straight-chain or branched alkyl having 1 to 5 carbon atoms, particularly methyl, ethyl, propyl, isopropyl, butyl, Isobutyl is preferred.

A is preferably an alkylene having 1 to 6 carbon atoms, one CH = CH-, one CO-C-I, particularly preferably one CH-CH-, one C-C-I.

R ⁵ has the following basic skeleton:

An organic group represented by

An organic group having any of the following (although alkyl having 1 to 5 carbons, At least one selected from the group consisting of alkoxy, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanate, trifluoromethyl, trifluoromethoxy, and methylenedioxy. Which may be substituted by one or more substituents), particularly phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-cyclophenyl, 2-phenyl. Fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-brophenyl, 2-ditrophenyl, 3-ditrophenyl, 412-trophenyl , 2 — trifluoromethylphenyl, 3 — trifluoromethylphenyl, 4 Trifluoromethylphenyl, 2 — Trifluoromethoxyphenyl, 3 — Trifluoromethoxyphenyl, 4-Trifluoromethoxyphenyl, 2 —Methylphenyl, 3 —Methylphenyl, 4-Methylphenyl, 2 — Preference is given to methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-furanyl, 3-furanyl, cyclopentyl and cyclohexyl, but of course not limited to these.

— Among the compounds represented by the general formula (I), ¹ is an alkyl having 1 to 5 carbons, a cycloalkylalkyl having 4 to 7 carbons, a cycloalkenylalkyl having 5 to 7 carbons, and a compound having 7 to 7 carbons. R 3 is aralkyl having 3 to 7 carbon atoms, alkenyl or aryl having 4 to 7 carbon atoms, R ² is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, R ³ Is the same as defined above, R ⁴ is hydrogen or straight or branched alkyl having 1 to 5 carbon atoms, A is the same as defined above, and R ⁵ is the following basic skeleton:

Organic group represented by R ⁵ An organic group having any of the following (provided that the alkyl has 1 to 5 carbons, the alkoxy has 1 to 5 carbons, the alkanoyloxy, the hydroxy, the hydroxy, the fluorine, the chlorine, the bromine, the iodine, the nitrogen, A compound which may be substituted with at least one substituent selected from the group consisting of cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

Among them, R ¹ is methyl, ethyl, propyl, butyl, isopropyl, cyclopropylmethyl, aryl, benzyl or phenethyl, and R ² and R ³ are each independently hydrogen, hydroxy, acetyl or methoxy. R ⁴ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl, A is —CH = CH—, or 1 C≡C 1, and R ⁵ is the following basic skeleton:

Organic group having any of the organic groups represented by R ⁵ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoloxy, hydroxy having 1 to 5 carbons, fluorine, chlorine) , Bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, methylenedioxy, which may be substituted by at least one or more substituents).

Pharmacologically preferred acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, acetate, lactate, and guanate. Organic carboxylate, methanesulfonate, such as oxalate, daltartrate, lingate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, etc. Organic sulfonates such as ethanesulfonate, benzenesulfonate, ρ-toluenesulfonate, camphorsulfonate and the like, among which hydrochloride, hydrobromide, phosphate, tartaric acid Salts, methanesulfonates, maleates and the like are preferred, but of course are not limited to these.

The compound of the present invention represented by the general formula (本) can be specifically obtained by the method shown in W〇98 / 232,900. In general, as shown in Chart 1, 17 represented by the general formula (II) (where R ¹ , R ² , ³ , R ⁵ , ^Re and A are the same as the definition of the general formula (I)) Oxidation of tertiary amines with organic peracids such as m-peroxybenzoic acid, performic acid, peracetic acid, perbenzoic acid, trifluoroperacetic acid, permaleic acid and perphthalic acid However, the present invention is not limited to these.

Char 1

(Π) (D

The 17-position tertiary amine (II) used for this oxidation can be produced according to the method described in Japanese Patent No. 25255552. There are a number of oxidants that can be used to convert the tertiary amide (ン) at the 7-position to the tertiary amide N-oxidized form (I). m-Black perbenzoic acid is convenient because it generally reacts quickly to produce N-yearly-oxide. However, other organic peracids such as formic acid, peracetic acid, perbenzoic acid, trifluoroperacetic acid, permaleic acid and perphthalic acid may be used. Alternatively, the tertiary amine is dissolved in an acid, for example formic acid, acetic acid or trifluoroacetic acid, and aqueous hydrogen peroxide at a concentration of 3% to 50%, preferably 30% to 50%. May be added to generate an oxidizing agent in the reaction system. Solvents include porogen solvents such as methylene chloride, chloroform, or 1,2-dichloroethane, or aromatic solvents such as benzene or toluene, or ether solvents such as getyl ether or Tetrahydrofuran or an alcohol-based solvent such as methanol, ethanol, propanol, or tertiary butyl may be used as a reaction medium, or, when an oxidizing agent is formed in the reaction system, the acid. May be used as a reaction medium if desired.

Instead of using an organic peracid as described above, a peroxide such as hydrogen peroxide may be used. Good. Aqueous hydrogen peroxide may be used alone at a concentration of 3% to 50%, or it may be used in a solvent as in the examples above. Other oxidizing agents that may be used include ozone, tertiary butyl hydroperoxide, and cumene hydroperoxide.

Generally, the oxidizing agent is used at a temperature of from 0 ° C. to the boiling point of the solvent, more particularly from room temperature to the boiling point of the solvent, for a few minutes to 3 days, more particularly 1 hour to 24 hours. The peroxide may be used in a ratio of 1 equivalent of the peroxide to 1 equivalent of the tertiary amine, or for example, an excess of 10% to 100% or more excess peroxide is used. You may. If excess peroxide is present at the end of the reaction (it is very easily detected by iodine / starch paper), an inorganic reducing agent such as sodium bisulfite or sodium sulfite is used. It can be treated by adding a metal catalyst such as 5% platinum or palladium supported on carbon or alumina, or an organic reducing agent such as dimethyl sulfide.

Other oxidizing agents that can be used in the production of tertiary aminoxides include ozone in solvents (eg, clog form, methylene chloride, freon or methanol), ozone adsorbed on silica gel, and optionally catalysts such as Peroxide in the presence of a vanadium compound, for example, peroxide in the third butyl group.

When cost is important, for example when producing on an industrial scale, the preferred reactant is 30% to 50% aqueous hydrogen peroxide using tertiary butanol as a solvent. For example, several kg of a morphinan derivative (general formula (II)) can be obtained by reacting it with 50% aqueous hydrogen peroxide in boiling No. 3 solvent for 2.5 hours to obtain a morphinan-N-oxide derivative. (General formula (I)) can be oxidized.

The compound of the present invention represented by the general formula (I) was found to have a strong analgesic action as opioid κ-agonist as a result of pharmacological tests in vitro and in vivo, and is expected to be a useful analgesic. It became clear what we could do. Furthermore, it was found that the compound of the present invention separated the analgesic action from the diuretic action, suggesting the possibility as an analgesic with reduced side effects.

The analgesic of the present invention can be administered to mammals (eg, mice, rats, hamsters, egrets, It is effective in reducing pain in cats, dogs, dogs, dogs, sheep, monkeys, humans, etc .; cancer pain, postoperative pain, neuropathic pain (eg, trauma, pain from radiation or pharmacotherapy, Neuralgia, tension spasm, erythromelalgia, gray myelitis pain, glossopharyngeal neuralgia, cow sargi, reflex sympathetic atrophy and central pain, thalamic pain, phantom limb pain, painful diabetic It applies to neuropathy, alcoholic neuropathic pain, pain in AIDS-infected patients, pain in multiple sclerosis, arthritis pain, etc.), arodinia, shingles pain, postherpetic neuralgia, etc.

When clinically using the analgesic of the present invention, morphinan-N-xyloxide itself or a salt thereof may be used, and excipients such as a stabilizer, a buffer, a diluent, an isotonic agent, and a preservative may be appropriately used. You may mix. Examples of the administration form include oral preparations such as injections, tablets, capsules, granules, powders, and syrups, and enteral administration using suppositories; or topical administration using ointments, creams, and patches. Can be mentioned. The analgesic and sedative according to the present invention preferably contain 1 to 90% by weight, more preferably 30 to 70% by weight of the above active ingredient. The amount to be used is appropriately selected according to the symptoms, age, body weight, administration method, etc. For adults, the amount of active ingredient per day for injections is from 0,000 lmg per day: L g. In the case of a drug, the dose is 0.005 mg to 10 g, and each can be administered once or in several divided doses. In addition, various adjuvants for the purpose of enhancing the therapeutic effect on pain can be contained. Furthermore, it can be used in combination with known drugs that can be used for treating pain, and there is no particular limitation on the concomitant drug, but specific examples include 'obiooid agonists, Anti-inflammatory drugs, antidepressants, anxiolytics, anticonvulsants, local anesthetics, α2-adrenergic agonists, anti-coline teratase drugs, NMDA receptor antagonists, calcium channel blockers Pharmaceuticals, serotonin receptor antagonists, GA receptor receptor function promoters, bradykinin receptor antagonists, neurokinin antagonists, and the like. More specifically, morphine, fenyu neil, pentazocine, buprenorphine, diclofenac, amitriptyline, imimiramin, desibramin, fluoxetine, carbamazepine, diazepam, guiapentin, valproic acid, carbamazepine, lidocaine, Clonidine, phentolamine, prazosin, neostigmine, ketamine, ifenprodil, dextromethorphan, mexitylene, ketanseri , Sarpogrelate hydrochloride, benzodiazepine, barbilate, tramadol and the like. It can also be used in combination with various herbal medicines that can be used in pain clinic practice, and can also be used in combination with therapeutic drugs for various diseases that cause pain. In addition, it can be used in combination with nerve block therapy, acupuncture, phototherapy, and epidural stimulation therapy used for the treatment of pain.

Hereinafter, the present invention will be described more specifically with reference to examples.

[Example】

Example 1. Obioid activity test using a guinea pig ileum extirpated sample

Hartley male guinea pigs were used. After exterminating the guinea pig, the ileum was excised, the inside of the tube was washed with a nutrient solution, and only the longitudinal muscle was detached. Meet, Krebes-Henselei t solution was kept in the longitudinal muscle in 3 7 (Glucose llmM NaCI 135fflM; KC1 .8mM; CaCl 2 3.4mM; Η 2 Ρ0 4 1.2mM; NaHCOa 8.3mM;; MgS04 2.5mM) It was suspended in a Magnus tube ventilated with 5% carbon dioxide and 95% oxygen. Electrical stimulation was performed at 0.5 IHz for 0.5 ms via the upper and lower ring-shaped platinum electrodes. Tissue contraction was recorded on a polygraph using the Isometric ί ranceducer.

Compounds I to _______________ Synthesized according to the method described in WO98 / 232900 were used as test drugs.

Naloxone, an antagonist, or n 0 r, a kappa antagonist, in the presence or absence of 'Β ΝI, add the test drug cumulatively to a concentration that suppresses 50% of sample contraction due to electrical stimulation. IC ₅ each. Values were calculated. The Ke value was calculated from the difference in potency in the presence and absence of the antagonist by the following formula.

Ke = [added with antagonist concentration] / (IC _5. Ratio one 1)

IC _5. IC ₅ of the presence ratio == antagonists. / I c ₅ antagonists absence time.

Table 1 shows the evaluation results of the compounds of the present invention. Taking the ratio of Ke value () and Ke value (κ) of compounds 丄 to A, Ke () / Ke (K) = 84 to 、, and the compound of the present invention is an agonist selective for κ receptor. It was shown that there is. Evidence-based pipoid activity test using guinea pig ileum exudates e (nM)

1 C ₅ ο (π) naloxone nor BN 1

Compound C5nM) 丄 1.06 0.02-

4.09 28.7 0.09

1.55 29.5 0.19

11- 3 75.1 0.89

Two

Four

Two

Example 2 Obioid activity test using a mouse vas deferred specimen

Male ddY mice were used for the experiment. 37U This kept the Krebes-HenseleU solution (NaCl 20.7nM; KC1 5.9mM; CaCl 2 2.5raM; NaHaPO .. I.2mM; NaHC0 3 15.5m; Glucose The vas deferens isolated from animals were suspended in Magnus tubes filled with 11.5raM) and aerated with 5! ¾ carbon dioxide and 95! ¾ oxygen. The electrical stimulation was performed at 0.1 Hz and 1.0 ms through the upper and lower ring-shaped platinum electrodes. Tissue contraction was recorded on a polygraph using an IsoDicic ansducer.

^ In the presence or absence of naloxone, an antagonist, NTI, a delta antagonist, or n0r-BNI, a kappa antagonist, the test drug to a concentration that suppresses contraction of the specimen by 50% by electrical stimulation Were added cumulatively, each with an IC ₅ . Values were calculated. Ke value was calculated from the difference in potency between the presence and absence of the antagonist by the following formula. -

Ke = [concentration of added antagonist] / (ICs. Ratio 1 1) _

ic _s . Ratio - antagonists exist at the time of the ic _s. ₅ of Neno antagonist non-existent at the time. value

Table 2 shows the evaluation results of the compounds of the present invention. Ke () / Ke (/ c) = 18∼∞, Ke ((), Ke (κ), Ke (δ), Ke (κ)) 6) / K e (/ i) = 15-∞, indicating that the compound of the present invention is a selective agonist for the κ receptor.

Table 2.Obioid activity test using mouse vasectomy specimens

Ke (n)

Q (πΜ) naloxone NTi norSNl

Compound (30πΜ) (10n) (10nH) 丄 2.14 30.48 0.040

1.80 50 11 0.67

0.59 5.9 5.0 0.33.

_4 4. 6 20 0.26 Example 3. Analgesic activity test by acetic acid writhing method

Five-week-old ddY mice were used for the experiment. A 0.6% acetic acid aqueous solution was intraperitoneally administered at 0.1 lffll / 10 g body weight, and the number of ligating reactions that occurred within 10 minutes from 10 minutes after administration was evaluated using the index as an index. The test drug was administered subcutaneously on the back 15 'minutes before acetic acid administration. Table 3 shows some of the results. As a comparative example, the results of a compound that is a 17-amino form of compounds I to A, ϋ-50488, which is a representative K-receptor agonist, and morphine, which is a -receptor agonist, are also shown. Was. In this test, Compound II,! _,! _ And Α showed strong analgesic activity against chemical stimulation.

Table 3砟酸Analgesic test compound ED ₅ by Lai managing _((.mg / kg) Compound ED ₅ 0 (mg / kg)丄0.0057

0. 0031 0.; 0011

3 0.016 7_ 0.0070

0. 0051 8_

Morphine Q.55

U-50488H 1.16

Five

7 8

Morphine υ-50488Ε Example 4. Evaluation of diuretic effect

7-8-week-old male Wistar rats were used in a water-free condition one hour before the start of the experiment. The lower abdomen of the rat was slightly stimulated to excrete urine accumulated in the bladder, and then the drug was subcutaneously administered. 30 minutes later, 20 ffll / kg of physiological saline was orally administered by gavage. Immediately after drug administration, animals were placed in metabolic cages (2 animals / "1 cage") and urinary output was measured 5 hours after loading with physiological saline. A dose of 5 ml per 100 g body weight was expressed as 5 ml ED.

The separation ratio between the analgesic activity and the diuretic activity was expressed by the following equation. Therefore, the higher the value, the more the analgesic effect and diuretic effect are separated. Segregation = diuretic ED5m I Roh acetic acid writhing analgesic activity ED ₅ 0

Table 4 shows some of the results. In addition, as a specific example, 17-amino The results for ~ J_, which is a body, and U-50488Η, which is a typical receptor agonist, are also shown. From the result of the separation ratio of diuretic action / analgesic action, the compounds exchange ~! Compared with _ (17-amino form), the corresponding Ν-type oxide form (compounds 丄 ~) has a more separated diuretic effect from analgesic effect, and reduces diuretic effect as a side effect. There was found.

Table 4 Diuretic activity and separation ratio between analgesic and diuretic effects

INDUSTRIAL APPLICABILITY As a result of in vitro and in vivo activity tests, the compound of the present invention was found to have strong analgesic activity, and it was clear that it could be expected as a useful analgesic. Furthermore, it was suggested that the compound of the present invention may be a potent analgesic with reduced diuretic effect.

Claims

The scope of the claims

1. General formula (I)

0)

[Wherein, 2 represents a double bond or a single bond, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenyl alkyl having 5 to 7 carbons, 7 carbons Represents an aralkyl of 1 to 13; an alkenyl of 4 to 7 carbons; an aryl of ² to 7 carbon atoms; R ² represents hydrogen, hydroxy, nitro, alkanoloxy of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, 1 carbon atom R ³ represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms, and R ⁴ represents hydrogen, a straight chain having 1 to 5 carbon atoms. Represents a chain or branched alkyl, or an aryl having 6 to 12 carbons, A represents an alkylene having 1 to 6 carbons, —CH—CH— or 1 C≡C 1, and R ^s represents Basic skeleton of:

An organic group represented by Or an organic group having any of the following (provided that the alkyl has 1 to 5 carbons, the alkoxy has 1 to 5 carbons, the alkanoyloxy, the hydroxy has 1 to 5 carbons, fluorine, chlorine, bromine, iodine, nitro) , Cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, methylenedioxy, which may be substituted with at least one or more substituents. An analgesic comprising as an active ingredient a morphinan-N-oxide derivative represented by the formula: or a pharmaceutically acceptable acid addition salt thereof.

2. In the general formula (I), R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aralkyl having 7 to 13 carbons, R ² is alkenyl or aryl having 4 to 7 carbons, R ² is hydrogen, hydroxy, alkanoloxy having 1 to 5 carbons, alkoxy having 1 to 5 carbons; ³ is the same as defined in claim 1; Wherein: R ⁴ is hydrogen or linear or branched alkyl having 1 to 5 carbon atoms, A is the same as defined in claim 1, and: R ⁵ is the following basic skeleton:

, 0,

T: CH, O

(CH2), 1 = 0—5

(CH ₂ ) L M CH ₂ ) _n m, n> 0

m + n <5

Yes represented by R ⁵ «

An organic group having any of the following formulas (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy, hydroxy, fluorine, fluorine, chlorine, bromine, iodine, nitro, The analgesic according to claim 1, which is substituted with at least one substituent selected from the group consisting of cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy).

3. — In formula (I), R 'is methyl, ethyl, propyl, butyl, or izob Chill, Sik b cyclopropylmethyl, Ariru, benzyl or phenethyl der Ri, R - and R ³ are each independently hydrogen, arsenate Dorokishi, Ri Ah in § Se butoxy or main butoxy, R ⁴ is methyl, Echiru, propyl , Isopropyl, butyl or isobutyl, wherein A is —CH = CH— or 1 C≡C 1, and R ⁵ is the following basic skeleton:

An organic group having any of the organic groups represented by (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoloxy, hydroxy having 1 to 5 carbons, fluorine, chlorine, bromine, iodine 3. The analgesic according to claim 2, which is substituted with at least one substituent selected from the group consisting of nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

4. An effective amount of general formula (I) for reducing pain

[Wherein, 2 represents a double bond or a single bond, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenyl alkyl having 5 to 7 carbons, carbon number Represents an aralkyl having 7 to 13 carbon atoms, an alkenyl having 4 to 7 carbon atoms, or an aryl, wherein ^Ra is hydrogen, hydroxy, nitro, an alkanoloxy having 1 to 5 carbon atoms, an alkoxy having 1 to 5 carbon atoms, Represents an alkyl having 1 to 5 carbons, and ^Ra is hydrogen, hydroxy, alkanoloxy having 1 to 5 carbons, or an alkyl having 1 to 5 carbons. Represents alkoxy, R ⁴ represents hydrogen, linear or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms, A represents alkylene having 1 to 6 carbon atoms, 1 CH = CH— or C 1 C 1, where R ⁵ is the following basic skeleton:

, 0,

(CH ₂ ), T: CH, O

1 = 0—5

(CH2) _m , / (CH ₂ ) _n m, n≥ 0

an organic group having any of the organic groups represented by m + n <5 (however, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkanoloxy group having 1 to 5 carbon atoms, hydroxy, fluorine, Chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, methylenedioxy, which may be substituted with at least one or more substituents). ] The method for alleviating pain, which comprises administering a morphinan-N one-year-old oxide derivative represented by the following formula or a pharmacologically acceptable acid addition salt thereof.

5. In the general formula '(I), R ¹ is an alkyl having 1 to 5 carbons, a cycloalkylalkyl having 4 to 7 carbons, a cycloalkenylalkyl having 5 to 7 carbons, and a cycloalkyl having 7 to 13 carbons. Ararukiru, alkenyl or Ariru from 4 carbon atoms 7, R ² is hydrogen, arsenate Dorokishi, 5 alk Noiruokishi from 1 carbon atoms, Ri Oh alkoxy having 1 to 5 carbon atoms, defined R ³ is according to claim 4 R ⁴ is hydrogen or a straight or branched alkyl having 1 to 5 carbon atoms, A is the same as defined in claim 4, and R ⁵ is the following basic skeleton:

An organic group having any of the following »represented by R ⁵ (alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoloxy, hydroxy having 1 to 5 carbons, fluorine, chlorine, bromine 5. The method according to claim 4, which is substituted by at least one substituent selected from the group consisting of, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy. .

6. In the general formula (I), R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, pendyl or phenethyl, and R ² and R ³ are each independently hydrogen, R ⁴ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl, A is —CH—CH—, or 1 C≡C 1, and R ⁵ is Skeleton ：

0,

An organic group having any of the organic groups represented by R ⁵ (alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy, hydroxy having 1 to 5 carbons, fluorine, chlorine, bromine , Iodine, nitro, cyano, isothiocyanate, trifluoromethyl, trifluoromethoxy and methylenedioxy, which may be substituted by at least one or more g-substituents). The described method.

7. General formula (I)

(D

[Wherein, 2 represents a double bond or a single bond, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenyl alkyl having 5 to 7 carbons, 7 carbons Represents 1 to 13 aralkyl, 4 to 7 carbon atoms, alkenyl and aryl, and R ² is hydrogen, hydroxy, nitro, 1 to 5 carbon atoms alkanoloxy, 1 to 5 carbon atoms alkoxy, 1 carbon atoms R ³ represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbons, or alkoxy having 1 to 5 carbons, and R ⁴ represents hydrogen, a straight chain having 1 to 5 carbons. Represents a chain or branched alkyl, or an aryl having 6 to 12 carbons, A represents an alkylene having 1 to 6 carbons, one CH = CH— or one C≡C—, and R ⁵ represents Basic skeleton:

An organic group having any of the following »represented by R ⁵ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoloxy, hydroxy, hydroxy, fluorine, chlorine, bromine having 1 to 5 carbon atoms) , Iodine, nitro, cyano, isothiocyanato, trifluoromethyl, tri Fluoromethoxy and methylenedioxy, which may be substituted with at least one or more substituents). Use of a morphinan-N-oxide derivative represented by〗 or a pharmacologically acceptable acid addition salt thereof for producing an analgesic.

8. —In the general formula (I), R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aralkyl having 7 to 13 carbons, alkenyl or Ariru from 4 carbon atoms 7, R ² is hydrogen, arsenate Dorokishi, alk Noi Ruo alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, R ³ is the definition of claim 1 R ⁴ is hydrogen or straight or branched alkyl having 1 to 5 carbon atoms, A is the same as defined in claim 7, and R ⁵ is the following basic skeleton:

m, n> 0

An organic group having any of the groups represented by R ⁵ (alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy, hydroxy having 1 to 5 carbons, fluorine, chlorine, bromine, 8. The use according to claim 7, which is substituted by at least one substituent selected from the group consisting of iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

. 9 In the general formula (I), methyl R ¹ is Echiru, propyl, heptyl, Lee Su Wu chill, consequent Ropuro Pirumechiru ', Ariru, benzyl or phenethyl der Ri, R ² and ^{R: |.} Are each independently Hydrogen, hydroxy, acetate or methoxy, and R is methyl, ethyl, propyl, isopropyl, butyl or isobutyl. Ri, A gar CH = CH-, or a C ® C- der Ri, R ^s is the following basic skeleton:

, 0,

An organic group having any of the organic groups represented by (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy, hydroxy having 1 to 5 carbons, fluorine, chlorine, bromine, iodine 9. Nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy, which may be substituted with at least one or more substituents.