WO2001014382A1

WO2001014382A1 - Analgesics containing as the active ingredient quaternary ammonium salt derivatives of morphinan

Info

Publication number: WO2001014382A1
Application number: PCT/JP2000/005626
Authority: WO
Inventors: Hiroshi Nagase; Tohru Miyamoto; Kuniaki Kawamura; Takashi Endoh; Hiroshi Sekiyama
Original assignee: Toray Industries, Inc.
Priority date: 1999-08-23
Filing date: 2000-08-23
Publication date: 2001-03-01

Abstract

Analgesics exerting an excellent analgesic effect and containing as the active ingredient quaternary ammonium salt derivatives of morphinan including the compound represented by formula (2).

Description

Specification

Analgesic containing morphinan quaternary ammonium salt derivative as active ingredient

Technical field

The present invention relates to an analgesic containing a morphinan quaternary ammonium salt derivative 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), vomiting, and nausea. Use requires strict control. Therefore, there is a strong need for safe analgesics that are non-narcotic.

Ovioid receptors have been identified as receptors involved in central analgesia, and are known to be classified into three types;, S and κ (WR Art in, CG Eades, JA Thompson, RE Huppler. And PE Gilbert, J. Pharmao. Exp. Ther, 1976, 197, 517., JAH Lord, AA Waterfield, J. Hughes and

HW Koster litz, Nature, 1977, 267, 495.). Also, sigma receptors, which are thought to exhibit mental effects, are known. Among them, agonists with affinity for one receptor have strong analgesic activity, and cause clinical problems such as dependence formation, respiratory depression, and smooth muscle motility, which are observed in morphine, which is one receptor agonist. No serious side effects are reported. Furthermore, the / c-receptor agonist does not show cross-resistance to one receptor agonist such as morphine. Analgesics without such side effects are considered to be highly useful for pain relief in postoperative pain patients and cancer pain patients. In addition, lack of cross-resistance indicates that it is also effective for patients who can tolerate analgesics such as morphine. However, the existing receptor agonists represented by the U-504 488-series have high affinity for the receptors that are said to be involved in mental effects such as hallucinations and obsessions, and are analgesics. There has been no example of successful development as (Brian. R. de. Costa, Wayre. D. Bowen, et al., J, Med. Chem. 1989, 32, 1996). In addition, κ agonists are generally known to have a strong central diuretic effect and sedation, and this side effect is not always acceptable when considering adaptation to a wide range of pain. Conventionally, it has been generally thought that an opioid analgesic acts on a central ovioid receptor to produce an analgesic effect and a central side effect (Reisine. T. and

Pasternak, G..Opioid analgesics and antagonists.In; JG Hardman, A. Goodman G ii I man LE Linb i rd (Eds.), Goodman and Gi i I man's The Pharmacoloical Bas is of Therapeutics, New (York, cGraw-Hi II, 1996, 521-555) ₀ However, it has recently been reported that opioid receptors are also present in the peripheral nervous system (Ghr i stoph Stein, Alexander assour idis). , Pain. 1997, 71, 119., TL Yaksh, Brain Res., 1988, 458, 319-324., A. Barber., Et al, Br. J. Pharmaco 1.1994, 113, 1317., C. Stein, et al, Med., 1995, 332, 1685-1690 to N. Eng). Therefore, peripherally acting Λ: -agonist, which suppresses central nervous system transfer, is considered to be a useful analgesic with reduced central side effects.

Known examples of peripherally acting -agonist include hydroxypyrrolidine acetate-based EMD-60400, EMD-61753, piperazine acetate-based GR_94893, and phenoxyacetic acid-acetoamide-based ICI-20448 ( A. Barber., Et al Br. J. Pharmaco 1.1994, 111, 843., A. Barber., Et al,

Br. J. Pharmacol. 1994, 113, 1317., H. Rogers, et.a I, Br.

1992, 106, 783., J. S. Shaw., Et al, Br. J. Pharmacol. 1989, 96, 986.). Furthermore, a morphinan compound having an / obioid agonistic effect (Patent No. 2525552) and a morphinan quaternary ammonium salt derivative (WO 98/23290) have been reported, but no peripheral action of these compounds has been disclosed. Absent.

Disclosure of the invention

An object of the present invention is to provide, as an analgesic, a peripheral receptor agonist that has a morphinan skeleton, does not exhibit severe morphine-like side effects, does not exhibit cross-resistance with morphine, etc., and further has reduced central side effects. It is to be.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a tertiary amine moiety in a morphinan structure of a morphinan-based obioid κ receptor-selective agonist has a quaternary ammonium salt obtained by quaternary ammonium chloride. The morphinan quaternary ammonium salt derivative shown in (I) is an excellent analgesic with peripheral action and reduced central side effects. We found that we got to complete the present invention

That is, the present invention provides a compound represented by the general formula (I):

(I)

(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, cycloalkenylalkyl having 5 to 7 carbons, 7 carbons Represents an aralkyl having 1 to 13 carbon atoms, an alkenyl or an aryl having 4 to 7 carbon atoms, and R ² is hydrogen, hydroxy, nitro, an alkanoloxy having 1 to 5 carbon atoms, an alkoxy having 1 to 5 carbon atoms or an alkoxy having 1 to 5 carbon atoms. 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 linear or branched alkyl having 1 to 5 carbon atoms. Represents a aryl or aryl having 6 to 12 carbon atoms, A represents an alkylene having 1 to 6 carbon atoms, one CH = CH— or one C≡C—, and R ⁵ represents the following basic skeleton:

'Q,

An organic group having any of the following (however, 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, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy R ⁶ is an alkyl or aryl having 1 to 5 carbon atoms, and X— represents a pharmacologically acceptable counter ion thereof. And a morphinan quaternary ammonium salt derivative represented by the formula:

As specifically described in the Examples below, as a result of in vitro and in vivo activity tests, the compounds of the present invention have potent analgesic activity as peripheral κ-obioid agonists, and further reduce side effects. It can be expected as a useful analgesic.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the inhibitory effect of Compound I on hyperalgesia tested in Example 6.

BEST MODE FOR CARRYING OUT THE INVENTION

In the morphinan quaternary ammonium salt derivative represented by 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 carbon atoms, alkenyl and carbon atoms having 4 to 7 carbon atoms are preferred, and methyl, ethyl, propyl, butyl, isoptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl are particularly preferred. , Benzyl, phenethyl, trans-1-butenyl, 2-methyl-2-butenyl and aryl are preferred. More preferred are methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, benzyl, phenethyl, and aryl.

As R ² , hydrogen, hydroxy, acetyl, methoxy, methyl, ethyl, and propyl are preferable, and hydrogen, hydroxy, acetoxy, and methoxy are particularly preferable.

R ³ is preferably hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms, and particularly preferably hydrogen, hydroxy, acetoxy and methoxy. R ⁴ is preferably hydrogen, straight-chain or branched alkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms, and particularly straight-chain or branched alkyl having 1 to 5 carbon atoms, particularly methyl, ethyl, propyl , Isopropyl, butyl, and isobutyl are preferred.

A is preferably an alkylene having 1 to 6 carbon atoms, one CH = CH-, one C≡C-I, particularly preferably one CH-CH-, one C3-C-.

R ⁵ has the following basic skeleton:

Organic groups having 1 to 5 carbon atoms (alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanolyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, Trifluoromethyl, trifluoromethoxy, and methylenedioxy, and may be substituted with at least one substituent selected from the group consisting of methylenedioxy), and more preferably the following basic skeleton:

Organic groups having 1 to 5 carbon atoms (alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, triflu Or a substituent of at least one substituent selected from the group consisting of trifluoromethyl, trifluoromethoxy, and methylenedioxy). In particular, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2 —Bromophenyl, 3-Bromophenyl, 4-Bromophenyl, 2-Nitrophenyl, 3-Nitrophenyl, 4-Trophenyl, 2-Trifluor La

Romethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3_trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl Methylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, Preferred are, but not limited to, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3-furanyl, 2-furanyl, 3-phenyl, 2-phenyl, cyclopentyl, cyclohexyl . In addition, the organic group of R ⁵ may be bonded to A at any position of the above basic skeleton (of course, those which cannot be chemically considered are excluded). Further, as described in the chemical formulas showing the R ^5, In these formulas, Q is indicates ◦ or S, T represents CH or O, I 0-5 number, m and n are each Is independently a number greater than or equal to 0, and the sum of m and π is less than or equal to 5.

As R ⁶ , alkyl and aryl having 1 to 5 carbon atoms are preferable, and methyl is particularly preferable.

The pharmacologically preferable counter ion X— is preferably an iodide ion, a bromide ion, a chloride ion, a methanesulfonate ion, or the like, but is not of course limited to these.

Among the morphinan quaternary ammonium salt derivatives represented by 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, carbon R ⁷ is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbons, alkoxy having 1 to 5 carbons, R is aralkyl having 7 to 13 carbons, alkenyl or aryl having 4 to 7 carbons, R ³ is the same as defined in claim 1, R ⁴ is hydrogen or a linear or branched alkyl having 1 to 5 carbons, A is an alkylene having 1 to 6 carbons, one CH = CH-, or I C3

C— and R ⁵ is the following basic skeleton:

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 alkanoloxy has 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, Isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy, which may be substituted with at least one or more substituents), R ⁶ is methyl or aryl, and X— is iodide. Those which are ions, bromide ions, chloride ions, and methanesulfonate ions are preferred.

More preferably, R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, and R ² and R ³ are each independently hydrogen, hydroxy, acetoxy or methoxy. R ^{4 is} methyl, ethyl, propyl, isopropyl, butyl or isobutyl, A is one CH = CH— or one C≡C one, and R 5 is the following basic skeleton:

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 alkanoloxy has 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, R ⁶ may be substituted with at least one substituent selected from the group consisting of isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy, R ⁶ is methyl, and X— is a chloride ion. It is a morphinan quaternary ammonium salt derivative that is a bromide ion, a chloride ion, and a methanesulfonate ion.

The compound of the general formula (I) of the present invention can be specifically obtained by the method described in WO98 / 232,900. As generally shown in chart 1, the general formula ^{(II) (R \ R 2} , R 3, RR

⁵ and A are the same as defined above) and can be obtained by quaternary ammonium salification of the 17-position tertiary amine represented by the formula (1) with an alkylating agent such as an alkyl halide or a methanesulfonic acid ester.

(II) (I) The 17-position tertiary amine of the general formula (II) used for this alkylation is described in Japanese Patent No. 25

It can be obtained by the production method of No. 17 There are many alkylating agents that can be used to convert tertiary amines to quaternary ammonium salts. Methyl iodide, propyl iodide, propyl iodide, butyl iodide, aryl iodide, methyl methanesulfonate, and dimethyl sulfate are convenient because they react relatively quickly to form quaternary ammonium salts. However, other alkylating agents such as methyl bromide, butyl bromide, propyl bromide, butyl bromide, aryl bromide, methyl chloride, chlorinated propyl chloride, propyl chloride, butyl chloride or aryl chloride may be used. . Examples of the solvent include halogen solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, aprotic polar solvents such as dimethylformamide and acetonitrile, methanol, and the like. Alcohol solvents such as ethanol, propanol, and tert-butanol, or acetone and the like may be used alone or in combination as a reaction medium.

Generally, quaternary ammonium chloride is used at a temperature of 0 ° C to the boiling point of the solvent, more preferably <room temperature to the boiling point of the solvent, for 1 day to 14 days, more preferably 1 day to 10 days. Alternatively, perform at normal pressure. The alkylating agent may be used in a ratio of 1 equivalent to 1 equivalent of the tertiary amine, or an excess of 0.1 equivalent to 5.0 equivalents or more may be used. In addition, as a base, hydrogen carbonate Sodium hydrogen, potassium carbonate, and sodium carbonate may be used in a ratio of 1 equivalent to 1 equivalent of the tertiary amine, or an excess of 0.1 equivalent to 5.0 equivalent or more base may be used. .

—It was revealed that the morphinan quaternary ammonium salt derivative represented by the general formula (I) is a peripherally acting / obioid agonist and can be expected as a useful analgesic with reduced side effects.

The analgesic of the present invention may have various pains, such as hyperalgesia, arodinia, visceral pain, cancer pain, postoperative pain, angina pain, myofascial pain, fibrotic pain, abdominal migraine, sympathetic nerve dependence. Pain, Sympathetic Independent Pain, Root Pain, Neuropathic Pain, Postherpetic Neuralgia, Kausalgi, Phantom Limb Pain, Sudden Induced Pain, Reflex Sympathetic Atrophy, Afferent Nerve Blocking Pain, etc. Effective for treatment.

When the analgesic of the present invention is used clinically, excipients such as a stabilizer, a buffer, a diluent, an isotonic agent, a preservative and the like may be appropriately mixed. Examples of the administration form include oral preparations such as injections, tablets, capsules, granules, powders, syrups and the like, enteral administrations using suppositories, topical administrations using ointments, creams, patches and the like. . For ophthalmic use, it can also be prepared as eye drops or eye ointment. The analgesic of the present invention desirably contains the active ingredient in an amount of 1 to 90% by weight, more preferably 30 to 70% by weight. The amount to be used is appropriately selected according to the symptoms, age, body weight, administration method, etc.In the case of an injection for an adult, the active ingredient amount is 0.001 mg to 1 g per day, In the case of an oral preparation, 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 enhancing the therapeutic effect on various pains can be included. Further, it can be used in combination with a drug that can be used for treating known pain, and the drug used in combination is not particularly limited. Analgesics, anti-inflammatory drugs, antidepressants, anxiolytics, anticonvulsants, local anesthetics, sympathomimetics, NMDA receptor antagonists, calcium channel blockers, serotonin receptor antagonists, GABA receptor function promotion Drugs and the like can be mentioned. More specifically, morphine, buprenorphine, pentazocine, butorphanol, fentanyl, tramadol, pethidine, reporfano Aspirin, diclofenac, indomethacin, amitriptyline, imipramine, desibramin, fluoxetine, carbamazepine, diazepam, gear bapentin, valproic acid, lidocaine, clodidine, phentolamine, brazocin, ketamine, mefentrozil, defenstril, chyfenprozil, defenstril. Tanceline, sarpogrelate hydrochloride, benzodiazepine, barbilate, and the like. In addition, drugs that act on receptors such as nicotine receptor, vanilloid receptor, cannabinoid receptor, neurokinin receptor, and bradykinin receptor, which are considered to be effective for treating pain, can be used in combination. Furthermore, it can be used in combination with antiviral agents such as Ashiku-guchi Building and Funsik-guchi Building to treat pain caused by viral infection. In addition, silver spike point (S i I ver sp i ke po int (SSP)) therapy used for the treatment of pain, transcutaneous electrical nerve stimulation (TENS), nerve block therapy, bile therapy, phototherapy, hard therapy It is also possible to treat in combination with extramembrane conduction stimulation therapy.

Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to the following examples.

Reference example 1

17-cyclopropylmethyl-3,14) 8-dihydroxy-14,5-epoxy17-methyl-6 / S— (N-methyl-trans-3- (3-furyl) acrylamide) morphinamide Iodide salt

1 7-cyclopropylmethyl-3,14-dihydroxy-1,4,1-hydroxy-1- (N-methyl-trans-3- (3-furyl) acrylamide) mol 2.0699 g (4.3 mmol) of hinane, 60 m of ethyl acetate and 6 ml of methanol and 1.3 ml of methyl iodide were added to a sealed vessel, and the mixture was stirred at 100 ° C. for 4 days under a sealed tube. 60 ml of methanol was added to the reaction solution, and the precipitated solid was dissolved and concentrated. 400 ml of distilled water was added to the obtained residue. The aqueous solution was washed with black-mouthed form (100 ml × 7), the aqueous layer was concentrated, and the obtained residue was recrystallized from ethyl acetate-methanol, and the obtained crystal was dissolved in distilled water (500 ml). After washing this aqueous solution with chloroform (100 ml X3), the aqueous layer was concentrated, and the obtained residue was recrystallized three times with methanol to obtain 102 mg of the title compound.

mp 202.40-207.9 ° C (decomposition)

NMR (500MHz, DMSO-d6)

δ 0.38 (1H, m), 0.60 (1H, m), 0.70 (1H, m), 0.78 (1H, m), 1.23 (1.4H, m), 1.32 (0.6H, m), 1.40--1.62 (2H , M), 1.73 (1H, m), 1.97-2.22 (1H, m), 2, 63 (1H, m), 2.75 (1H, m), 2, 84-2.95 (1 H, m), 2.87 ( 1.8H, s), 3.02-3.20 (1H, m), 3.10 (1.2H, s), 3.22-3.35 (1H, m), 3.44-3.70 (1.6H, m), 3.58 (3H, s), 3 , 85 (2H, m), 4.18 (0.4H, m), 4.80 (0.6H, d, J = 7.8 Hz), 4.88 (0.4H, d, J = 8.3 Hz), 5.86 (0, 4H, br s ), 5.93 (0.6H, br s), 6.36 (0.6H, d, J = 15.6Hz), 6.63 (0.6H, s), 6.71 (1H, s), 6.77 (0.4H, d, J = 8.3Hz) ), 6.84 (0.6H, d, J = 7.8Hz), 6.89 (0.4H, d, J = 15.1Hz), 6.99 (0.4H, s), 7.23 (0.6H, d, J = 15.6Hz), 7.36 (0.4H, d, J = 15, 1Hz), 7.66 (0.6H, s), 7.72 (0.4H, s), 7.92 (0.6H, s), 8.03 (0.4H, s), 9.33 (0.4H, s), 9.72 (0.6H, s).

IR (KBr)

v 3460, 1649, 1595, 1454, 1410, 1321, 1158, 1139, 596 cnT ¹ .

Mass (FAB)

m / z 491 (M + H) +.

Elemental analysis value C 29 H 3 5 N 205 I 1

Calculated: C, 55.51; H, 5.78; N, 4.46; I, 20.22.

Found: C, 55.50; H, 5.86; N, 4.45; I, 20.23.

Reference example 2

17-Cyclopropylmethyl-3,14 ^ -dihydroxy_4,5 α-epoxy 17-Methyl-6β- (Ν-methyl-13-methoxycinnamamide) morph 1Z nanium iodide salt

17-cyclopropylmethyl-1,3,14 S-dihydroxy-1,4 α-epoxy-163- (Ν-methyl-13-methoxycinnamamide) morphinan 2.0014 g (3.9 mmol), tetrahydrofuran 40 m 1.3 ml of methyl iodide was added to the sealed vessel, and the mixture was stirred at 100 ° C for 8 days under a sealed tube. 60 ml of methanol was added to the reaction solution, and the precipitated solid was dissolved and concentrated. The obtained residue was dissolved in 120 ml of a chloroform-methanol mixture, and extracted with 200 ml of distilled water × 3. The residue obtained by concentrating the aqueous layer was recrystallized four times with methanol-distilled water to obtain 295 mg of the title compound.

mp 176.0-183.0 ° C (decomposition)

NMR (600MHz, DMS0-d6)

δ 0.37 (1Η, m), 0.60 (1Η, m), 0.70 (1H, m), 0.77 (1H, m), 1.23 (1.4H, m), 1.35 (0.6H, m), 1.43-1.63 (2H , m), 1.74 (1H, m), 2.02-2.22 (1H, m), 2.62 (1 H, m), 2, 75 (1 H, m), 2.83-2.96 (1H, m), 2.90 (1.8 H, s), 3.04- 3.19 (1 H, m), 3.15 (1.2H, s), 3.23-3.35 (1H, m), 3.50 (0.6H, s), 3.53 (0.4H, s), 3.59 (3H, s), 3.68 (0.6H, m), 3.78 (1.8H, s), 3.80 (1.2H, s), 3.85 (2H, m), 4.21 (0.4H, m), 4.82 (0.6H , d, J = 7.9Hz), 4.89 (0.4H, d, J = 8.2Hz), 5.87 (0.4H, br s), 5.94 (0.6H, br s),

6.63 (0.6H, d, J = 15.0Hz), 6, 72 (0.8H, s), 6.76 (0.6H, d, J = 8.2Hz), 6.81 (0.6H, d, J = 8.2Hz), 6.92 (0.6H, dd, J = 8.2 and 2.1Hz), 6.96 (0, 4H, dd, J = 8.2 and 2.1Hz), 7.00 (0, 6H, m), 7.09 (0.6H, d, J = 7.6Hz ), 7.17 (0.4H, d, J = 15.3Hz), 7.24-

7.30 (2H, m), 7.33 (0.4H, t, J = 7.9Hz), 7.42 (0.4H, d, J = 15.3Hz), 9.35 (0.4H, s), 9.63 (0.6H, s). IR (KBr)

v 3410, 1642, 1595, 1491, 1460, 1410, 1321, 1274, 857, 793 cm— ^1. Mass (FAB)

m / z 531 (M ⁺ H) +.

Elemental analysis value C 32 H 39 N 205 '1 1

Calculated: C, 57.89; H, 6.01; N, 4.22; I, 19.11.

Observed values: C, 57.80; H, 5.86; N, 4.22; I, 19.14. Example 1 Opioid activity test using guinea pig ileum extract

Hartley male guinea pigs were used. After eradication of the guinea pig, the ileum was removed, the inside of the tube was washed with a nutrient solution, and only the longitudinal muscle was exfoliated. The longitudinal muscle was kept at 37 ° C Krebes- Hense leit solution (NaC I 135mM; KCI 4.8mM; CaCI 2 3.4mM; KH 2 P0 4 1.2mM; NaHC0 3 8.3m; MgS0 4 2.5m; glucose 11 mM) And suspended in a Magnus tube ventilated with 5% carbon dioxide and 95% oxygen. The electrical stimulation was performed at 0.1 Hz for 0.5 ms via the upper and lower ring-shaped platinum electrodes. Tissue contraction is determined by using Isomeric tranceducer ¾C.

Presence or absence of naloxone or K antagonist is an antagonist nor BN I, the shrinkage of the specimen due to electrical stimulation study drug was cumulatively added to 50% inhibition concentrations, each IC _5. 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 = [concentration of added antagonist] Z (I 〇 ₅₀ ratio_1)

I 〇 ₅₀ ratio = illustrating a part of the evaluation results of the compounds of the present invention to I c _{5 ()} Bruno I c ₅₀ Table 1 antagonist absence at the time of antagonist present. As a result, when the ratio of Ke value () and Ke value (κ) is calculated, Ke (Ai) / Ke («r) = 182 to 556, and the compound of the present invention is selective for / receptor. Agonist. 00/05626

14- Table 1 Obioid activity test using guinea pig ileum extract

Example 2 Opioid activity test using mouse vas deferred specimen

Male dd Y mice were used for the experiment. Krebes-Henseleit solution maintained at 37 ° C (NaCI 120.7n; KCI 5.9mM; CaCI 2 2.5m; NaH 2 P0 4 1.2mM; NaHCO 3 15.5m; glucose 11.5 mM) meet, 5% carbon dioxide, 95 The vas deferens removed from the animals were suspended in Magnus tubes ventilated with% oxygen. The electrical stimulation was performed at 0.1 Hz and 1.0 mS via upper and lower ring-shaped platinum electrodes. Tissue contraction was recorded on a polygraph using an Isometric transducer.

In the presence or absence of naloxone, an antagonist, or NT I, an S antagonist, or nor BN I, an antagonist, the test drug is cumulatively increased to a concentration that suppresses 50% of contraction of the specimen by electrical stimulation. And the IC ₅₀ value was calculated for each. The 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] no (I 〇 ₅₀ ratio -1)

I 〇 ₅₀ ratio = illustrating a part of the evaluation results of the compounds of the present invention to I c ₅₀ value Table 2 I 〇 ₅₀ values antagonist absence at the time of antagonist present. As a result, when the ratio of Ke value (L, Ke value (κ) and Ke value (S), Ke value (/ c)) is taken, Ke () / Ke (/ c) = 83-222, K e (<5) / K e (/ c) = 56 to 66, indicating that the compound of the present invention is a selective agonist for the / receptor.

Table 2 Obioid activity test using mouse vas deferens

Example 3 Analgesic activity test by acetic acid writhing method Five week old dd 丫 mice were used for the experiments. A 0.6% aqueous acetic acid solution was intraperitoneally administered at 0.1 ml Z10 _g body weight, and the number of writhing reactions occurring 10 minutes after the administration and 10 minutes after the 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. Table 3 also shows the results of U-50488H, a representative κ-receptor agonist, and morphine, a single receptor agonist, as comparative examples. In this test, compound 1, 2 ED ₅₀ are each passing Li shown in Table 3, compound丄, showed strong analgesic activity to chemical stimuli.

Table 3 Analgesic test by acetic acid writhing

Example 4 Evaluation of Diuretic Effect

Seven- to eight-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 rats was slightly <irritated to excrete urine accumulated in the bladder, and then the drug was subcutaneously administered. Thirty minutes later, 2 OmI _kg of physiological saline was orally administered by gavage. Immediately after drug administration, animals were placed in metabolic cages (one cage per two animals), and urine output was measured 5 hours after loading with saline. The drug efficacy was expressed as the ED 5mI at a dose of 5mI per 100g of rat body weight, with the urination volume 5 hours after saline loading.

The separation ratio between analgesic activity and diuretic activity was calculated by the following equation. Separation ratio = diuretic ED5mI / acetic acid rising analgesic activity ED50 Some of the results are shown in Table 4. As a comparative example, the results of U-50488H, which is a representative K-receptor agonist, are also shown. From the results of the separation ratio of diuretic / analgesic effects, Compound II showed diminished diuretic effects on analgesic effects as compared to U-50488H, a central kappa agonist. This suggested that Compound I may be a potential analgesic with reduced diuretic effects, a central side effect. Table 4 Separation ratio of diuretic activity and analgesic effect from diuretic effect

Example 5 Sedation activity by mouse rotating basket test

dd Y male mice were used. The test drug or vehicle was administered subcutaneously, and 30 minutes later, the animals were placed in a rotating basket, and the cumulative number of rotations per hour was measured. The decrease in the number of rotations was regarded as the sedative effect of the drug. When the number of rotations in the solvent-administered group was set to 100%, the dose of the test drug that suppressed it to 50% was sedation ED ₅ . Value. The separation ratio between the analgesic activity and the sedative activity was calculated by the following equation. Separation ratio = sedation ED _ς 0 Z Rising analgesic activity of acetic acid ED ₅₀ Some of the results are shown in Table 5. As a comparative example, the results of U-50488Η, which is a typical κ-receptor agonist, are also shown. Sedative effect From the results of the segregation ratio of the analgesic effect, Compound II had a reduced sedative effect on the analgesic effect as compared with the central agonist U-50488H. This suggested that Compound I could be a potential analgesic with reduced central side effects.

Table 5 Sedative activity and separation ratio between analgesic and sedative effects

Example 6 Evaluation of peripheral analgesic activity using a rat burn model

The analgesic effect of Compound I was evaluated using the Dirig et al. System (DM Drig et al. J. Neurosc, Methods 1997, 76, 183), which measures peripheral analgesic activity. Specifically, burns were created by applying radiant heat (55-56 ° C) to the surface of the bottom of the right hind limb of a mature male rat under Halotane inhalation anesthesia for 10 seconds. Twenty-four hours later, rats with a difference in response latency to radiant heat of their right and left feet of 1.5 seconds or longer were used as judged to be hyperalgesic. Next, compound 1 (0.48 g) dissolved in physiological saline was added to 20 It was administered to the right hind footpad in a volume of μI. Peripheral analgesic activity of Compound I was evaluated by subtracting the time required to raise the normal left hind limb from the time required to raise the right hind limb on a hot plate (56 ° C). Measurements were taken every 15 minutes for up to 2 hours. As a result, 0.48 g of Compound I significantly suppressed hyperalgesia from 30 minutes to 75 minutes after administration (FIG. 1).

In this experiment, even when the dose of Compound I was increased to 4 Og, no diuretic effect considered to exhibit a centrally mediated effect was observed.

Claims

The scope of the claims

(I)

(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, cycloalkenylalkyl having 5 to 7 carbons, 7 carbons Represents an aralkyl having 1 to 13 carbon atoms, an alkenyl or an aryl having 4 to 7 carbon atoms, and R ² is hydrogen, hydroxy, nitro, an alkanoloxy having 1 to 5 carbon atoms, an alkoxy having 1 to 5 carbon atoms or an alkoxy having 1 to 5 carbon atoms. 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 linear or branched alkyl having 1 to 5 carbon atoms. Represents a aryl or aryl having 6 to 12 carbon atoms, A represents an alkylene having 1 to 6 carbon atoms, _CH = CH—, or 1 C≡C 1, and R ⁵ represents the following basic skeleton:

Organic group having any of IS (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano R ⁶ may be substituted with at least one substituent selected from the group consisting of isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy, and R ⁶ is alkyl or aryl having 1 to 5 carbon atoms. And X— represents a pharmacologically acceptable counter ion. An analgesic containing a morphinan quaternary ammonium salt derivative represented by the formula:

2. In the 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, carbon R ² is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, and R ³ is the same as defined in claim 1; Wherein R ⁴ is hydrogen or a straight 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:

T: CH or 0

(CH ₂ ), 1: 0 to 5

[Me CH ₂ ) _n

T m, n> 0

T

m + n <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 alkanoloxy has 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, Isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy, which may be substituted with at least one or more substituents), R ⁶ is methyl or aryl, and X— is iodine. The analgesic according to claim 1, which is a chloride ion, a bromide ion, a chloride ion or a methanesulfonate ion.

3 in. The formula (I), methyl R ¹ is Echiru, propyl, heptyl, isobutanol chill, cyclopropylmethyl, Ariru, benzyl or phenethyl, R ² And R ³ are each independently hydrogen, hydroxy, acetate or methoxy, R ⁴ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl, and A is one CH = CH— or one C≡C And R ⁵ is the following basic skeleton:

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 alkanoloxy has 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, R ⁶ may be substituted with at least one substituent selected from the group consisting of isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy, R ⁶ is methyl, and X— is a chloride ion. The analgesic according to claim 1, which is bromide ion, chloride ion or methanesulfonate ion.

4. Use of the morphinan quaternary ammonium salt derivative according to any one of claims 1 to 3 for producing an analgesic.