JP2000302761A - Morphan derivative and its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound comprising a specific morphan derivative and useful as an activation modifier of glycine receptor. SOLUTION: This compound is represented by formula I [R1 is H, a (substituted)lower alkyl or the like; and R2 is H, a (substituted)lower alkyl or a (substituted)alkenyl], e.g. 2-methyl-2-azabicyclo[3.3.1]nonane. The compound of formula I can be obtained by method, etc., reacting 2-azabicyclo[3.3.1]-nonane of formula II with formalin, etc., in a polar solvent such as methanol. The compound of formula I can be used as medicines in the forms of various agents by formulating it with a convention vehicle. The dose of the compound is 0.1-1,000 mg/kg. The compound is extremely useful as a therapeutic medicine for various nervous diseases and a central nervous system acting medicine such as anesthetic medicine or antitussive medicine and extremely useful also as pharmacological tool for carrying out functional analysis of glycine receptor.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a glycine receptor which enhances or suppresses the activation of a receptor (glycine receptor) to which the inhibitory neurotransmitter glycine specifically containing a morphane derivative or a salt thereof is bound. It relates to a body activation regulator. More specifically, the glycine receptor activation enhancer of the present invention is useful as a therapeutic or anesthetic for seizures, epileptic seizures, and the glycine receptor activation inhibitor of the present invention is a non-ketotic high glycine It is useful as a therapeutic agent for blood, an antitussive or a central stimulant. The glycine receptor activation regulator of the present invention is also useful as a pharmacological tool for analyzing the function of a glycine receptor. The present invention also relates to a pharmaceutical composition comprising a morphane derivative represented by the general formula (1) or a salt thereof. Furthermore, the present invention relates to a novel compound comprising a morphane derivative represented by the general formula (2) or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Glycine is a major inhibitory neurotransmitter in the central nervous system, is widely distributed in the medulla and spinal cord, and is another inhibitory neurotransmitter, γ-aminobutyric acid (GAB).
This is in contrast to A), which is distributed in the upper center. Regarding the GABA receptor and the GABAergic neurotransmission mechanism, the binding that is modified on the GABA receptor-ion channel complex (hereinafter abbreviated as GABA receptor) by an anxiolytic, an anesthetic, an anticonvulsant or a sleeping pill. The existence of the site was revealed (Annu. Rev. Neurosci., 17,
569-602, 1994), and pharmaceuticals targeting GABA receptors are being vigorously developed. GABA
Receptors have been recognized for their importance in maintaining the function of the psychiatric nervous system, and their physiological roles and pharmacological significance, including their regulatory mechanisms, are being steadily elucidated. On the other hand, as a drug that modifies the function of the glycine receptor, only a small number of drugs such as the known glycine receptor antagonist strychnine have been found. As a result, not only the pharmacological significance of the glycine receptor has not been elucidated, but also many points remain unknown even in the physiological role.

[0003] Regarding the function and structure of the glycine receptor,
In addition to the results of research on electrophysiological properties by the patch clamp method (Nature, 277, 234-236; Nature, 305, 805-80
8, 1983; J. Physiol. (Lond.), 385, 243-286, 1987;
J. Physiol. (Lond.), 435, 303-331, 1991), the molecular structure of the glycine receptor was deduced by the introduction of molecular biological techniques (J. Physiol. (Paris), 88, 243-248, 1994; Cur
r. Opin. Neurobiol., 5, 318-323, 1995), the entity of the glycine receptor as a functional molecule is being grasped more accurately. Based on these findings, the relationship between glycine receptors and neurological disorders has recently been elucidated clinically.For example, mice lacking glycine receptors exhibit seizure symptoms (Nature, 298, 655-657). , 1982), familial
It has been reported that the etiology of startledisease is due to mutations in the gene encoding the glycine receptor
(J. Biol. Chem., 269, 18739-18742, 1994 ,; Trends N
eurosci., 18, 80-82, 1995). Since all neurological disorders are attributable to glycine receptor dysfunction in networks of the central nervous system, drugs that can enhance glycine receptor activation will strengthen the few glycine receptors that function normally in vivo. It is expected that activation will restore the original function of the network of the central nervous system and reduce or treat the symptoms of neurological diseases.

As another glycine receptor-related neurological disease, a fatal inborn error of metabolism called non-ketotic hyperglycinemia has been reported (The Metaboli).
c Basis of Inherited Disease, McGraw-Hill, New Yor
k, pp. 743-753, 1989). Non-ketotic hyperglycinemia is a disease characterized by elevated levels of glycine in cerebrospinal fluid and blood due to deficiency of glycine-cleaving enzymes, and causing severe neuropathy due to excessive activation of glycine receptors. Conventionally, drugs that suppress glycine receptor activation have been expected as drugs that reduce neurotoxicity caused by glycine, and clinical cases in which the above-mentioned strychnine has been applied as a therapeutic drug for this disease have been reported (Helv .
Paediat. Acta, 32, 517-525, 1977; Pediatrics, 63,
369-373,1979; Helv.paediat.Acta., 34, 589-599, 1
979). However, large doses of strychnine exhibit extremely high systemic toxicity, and even when administered in small doses, they are extremely difficult to treat clinically because of their toxic symptoms and accumulation. Therefore, development of a highly safe activation inhibitor instead of strychnine has been desired.

[0005] Furthermore, recently, the relationship between the glycine receptor and the mechanism of the central nervous system acting drug has been reported and attracted attention. First, it has been shown that the known volatile general anesthetic enfuran recognizes certain amino acid residues of the glycine receptor and enhances receptor activation (Na
ture, 389, 385-389, 1997). Conventionally, the mechanism of action of anesthetics has been considered to be a non-selective effect that affects the fluidity of nerve cell membranes. It is a result suggesting that it acts on highly likely targets. Therefore, drugs that enhance glycine receptor activation are expected to be candidate drugs for anesthetics. Secondly,
Inhibition of glycine receptor activation has been reported as a common mechanism of many central antitussives, including dextromethorphan (Br. J. Pharmacol., 120, 6).
90-694, 1997; Meth. Find. Exp. Clin. Pharmacol., 2
0,125-132, 1998). Antitussives are drugs developed to relieve or control morbid cough that often accompanies respiratory illness and other conditions, and many narcotic and non-narcotic central antitussives are currently used as drugs. It is widely used. However, despite the fact that the former has a strong antitussive effect, its narcotic nature limits its use, and the latter is not sufficient in terms of its antitussive effect. From this fact, there is a strong demand for the development of an ideal antitussive having few side effects and sufficient efficacy, and it is expected that a glycine receptor activation inhibitor will be a candidate drug for an antitussive with certainty of success. I have.

[0006] In addition, drugs developed as pharmaceuticals are also used as pharmacological tools, and are used to analyze the regulatory mechanisms of various receptors or ion channels. On the other hand, for the glycine receptor, the above-mentioned strychnine and the like have only been widely used. Therefore, an agent that regulates glycine receptor activation is expected to be a useful pharmacological tool for understanding the regulatory mechanism or physiological role of the receptor.

As morphane derivatives, pentacyclic morphylin and immunosuppressant FR901483 are known, and various morphane derivatives have been reported in synthetic studies of such compounds. For example, N. Yamazaki, et al., J. Org. Chem., 62, 8280-8
281 (1997) discloses a method for synthesizing 1-lower alkyl-morphan derivatives and the like.

[0008]

As described above, the fact that the glycine receptor is involved in neurological diseases and that existing drugs have a mechanism of regulating the function of the glycine receptor are known as new glycine receptors in drug development. As a promising target, the development of drugs with new mechanisms is expected. Furthermore, if a drug that modifies the function of the glycine receptor can be developed, a completely new treatment for various neurological diseases can be provided. Accordingly, the present invention provides a morphane derivative useful as a novel glycine receptor activation regulator.

[0009]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found that morphane derivatives or salts thereof, particularly morphane derivatives represented by the general formula (1) (2-azabicyclo) [3.3.1] Nonane derivative) or a salt thereof was found for the first time to enhance or suppress the activation of glycine receptor, and the present invention has been completed.

That is, the present invention relates to a glycine receptor activation regulator comprising a morphane derivative or a salt thereof. Further, the present invention provides the following general formula (1)

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(Wherein R ₁ is hydrogen, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an araliphatic group which may have a substituent, or R 1 ₂ represents an alkylene group which may have a substituent capable of forming a ring together with an adjacent atom together with R ₂ , and R ₂ represents hydrogen, a lower alkyl group which may have a substituent, or a substituent. And a salt thereof, and a pharmaceutically acceptable carrier. More specifically, the present invention relates to a glycine receptor activation regulator comprising a morphane derivative represented by the general formula (1) or a salt thereof.

Further, the present invention provides the following general formula (2)

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(Wherein R ₁ is hydrogen, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an araliphatic group which may have a substituent, or R 1 ₂ represents an alkylene group which may have a substituent capable of forming a ring together with an adjacent atom together with R ₂ , and R ₂ represents hydrogen, a lower alkyl group which may have a substituent, or a substituent. In the case where R ₁ is a hydrogen atom, R ₂ is not a hydrogen atom or an unsubstituted lower alkyl group, but is a lower alkyl group, alkenyl group or araliphatic of R ₁ and R _2. The substituent in the group is not a hydroxyl group, and
When R ₁ is an alkylene group, it is not a propylene group. )
And a salt thereof, and a pharmaceutical composition comprising the same.

Further, the present invention relates to the use of the morphane derivative represented by the above general formulas (1) and (2) or a salt thereof for the production of a glycine receptor activation regulator or a central nervous system drug. . The present invention also relates to a method for treating or preventing a central nervous system disease, which comprises administering an effective amount of the morphane derivative represented by the general formulas (1) and (2) or a salt thereof.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The lower alkyl group in the general formulas (1) and (2) of the present invention has 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 7 carbon atoms.
And alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. As the alkenyl group, one or two or more linear or branched C-C unsaturated bonds having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 7 carbon atoms. Have
For example, an allyl group, a 3-methylallyl group, a 3,3-dimethylallyl group and the like can be mentioned. As the araliphatic group, 1 to 5, preferably 1 to 5,
A group consisting of two or more aromatic rings, such as a benzyl group, a phenethyl group and an α-naphthylmethyl group, with a benzyl group being preferred. Also, R ₂
Examples of the alkylene group which can form a ring together with an adjacent atom together with a carbon atom have 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 7 carbon atoms. A nitrogen atom adjacent to R ₁ and a carbon atom adjacent to R ₂ to form a ring having a size of four or more members. Preferred alkylene groups include, for example, a propylene group and a butylene group.

In the general formulas (1) and (2) of the present invention, the lower alkyl group, alkenyl group, araliphatic group and alkylene group may be appropriately substituted. Such substituents are not particularly limited as long as they do not impair the glycine receptor activation regulating action of the present invention. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. And the like, in addition to the above-mentioned lower alkyl groups and alkenyl groups, etc., as well as lower alkoxy groups comprising the above-mentioned lower alkyl groups such as halogen atoms, hydroxyl groups, methoxy groups and ethoxy groups.

Further, the morphane derivative as a glycine receptor activation regulator of the present invention is not limited to the compound represented by the above-mentioned general formula (1) or (2). There is no particular limitation as long as it is a morphane derivative having a function as an activation regulator. It is an object of the present invention to provide a novel glycine receptor activation regulator of the present invention. More specifically, the present invention provides a morphine derivative or a salt thereof having a glycine receptor activation regulating action. Therefore, the glycine receptor activation modifier of the present invention is limited to the morphane derivative represented by the general formula (1) or (2) or a salt thereof. Morphine derivatives having a glycine receptor activation regulating action or salts thereof.

The morphane derivative of the present invention, more specifically, the morphane derivative represented by the above general formulas (1) and (2), can be substituted with a salt if necessary, or the resulting salt can be converted into a free base. You can also. Examples of the salt of the present invention include mineral salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, and succinic acid. And organic acid salts such as tartaric acid, malic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Further, the morphane derivative of the present invention can be a solvate such as a hydrate, if necessary. Preferred embodiments of the morphane derivative of the present invention are specifically exemplified in the following Examples and the like, but the present invention is not limited to these specific examples.

The morphane derivative of the present invention, more specifically, the morphane derivative represented by the general formulas (1) and (2), is a hydrogen atom at the 2-position nitrogen atom of 2-azabicyclo [3.3.1] nonane. Can be produced by various methods such as substitution. For example, it can be produced by a method represented by the following reaction formula.

[0020]

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That is, in step 1, 2-azabicyclo [3.3.1] nonane represented by the general formula (3) is reacted with formalin, acetaldehyde or allyl bromide in a polar solvent such as methanol or dimethoxyethane. Thus, the above general formula (1) according to the present invention
Can be obtained. Further, the compound of the present invention or a salt thereof is described in J. Org. Chem., 62, 8280-8281,
(1997).

The glycine receptor activation regulator of the present invention is useful as a central nervous system drug, more specifically, a central nervous system drug involving a glycine receptor. It is useful as a body activation enhancer as a therapeutic agent for seizures and seizures or as an anesthetic, and as a glycine receptor activation inhibitor, a therapeutic agent for non-ketotic hyperglycinemia, an antitussive or a central stimulant Useful as The glycine receptor activation regulator of the present invention is also useful as a pharmacological tool for analyzing the function of glycine receptor.

The morphane derivative of the present invention or a salt thereof,
More specifically, a medicament containing a morphane derivative represented by the above general formula (1) or (2) or a salt thereof as an active ingredient,
In general, they can be combined with conventional excipients to take the form of various pharmaceutically acceptable drugs. When the morphane derivative or a salt thereof of the present invention is used as a glycine receptor activation enhancer or activation inhibitor, it can be administered in any of oral or parenteral dosage forms. For example,
Oral administration forms include capsules, tablets, syrups, granules, fine granules, powders and the like. Parenteral administration forms include cataplasms, ointments, gels, creams, gel creams, lotions, liniments, aerosols, plasters, suppositories, eye drops, nasal drops,
Examples include external preparations such as oral preparations and poultices, and injections. The above-mentioned preparation for oral or parenteral administration can be prepared based on a known base and a known formulation.
For example, 1) Comprehensive technology for new formulation development system-bases and additives, date of issue: July 12, 1985, date of issue: R & D
Planning, 2) Today's external preparation for skin, date of issue: 198
May 15, 1st (1st edition), issuance office; Nanzando, 3) 11th edition Japanese Pharmacopoeia commentary, publication date: July 1, 1986
8th, Issued by: Hirokawa Shoten, 4) Pharmaceuticals I / II-Pharmacology / Pharmaceutics, Issued in 1988, Issued by: Japan Federation of Industrial Technology, 5) Related documents before the filing application, patent disclosure, Each known document such as a magazine can be mentioned.

The specific formulation will be described in more detail. For oral preparations, for example, the morphane derivative of the present invention or a salt thereof and an organic acid (for example, citric acid, ascorbic acid, fumaric acid, tartaric acid, succinic acid, malic acid,
A pharmaceutical composition or an additive which is appropriately blended with an adipic acid) or an antacid (eg, sodium hydrogen carbonate, calcium hydrogen phosphate, magnesium aluminate metasilicate, magnesium hydroxide, synthetic hydrotalcite, etc.). Microcapsules may be added by a known method, or a binder, a lubricant, a disintegrant, an excipient, a disintegration rate adjusting agent, a plasticizer, and a colorant, as required for the pharmaceutical composition. , Flavoring agents, etc., tablets, granules,
It can be made into tablets such as fine granules. In addition, these preparations are further used as sustained-release film agents, such as water-insoluble polymers such as ethyl cellulose, aminoalkyl methacrylate copolymer, polyvinyl acetate, and polyethylene; cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate. Carboxymethyl ethyl cellulose, styrene acrylic copolymer, methacrylic acid copolymer,
Enteric polymers such as maleic anhydride polymers and ceramics;
Paraffin wax such as paraffin and microcrystalline wax; higher alcohol such as stearyl alcohol and cetanol; glycerin fatty acid ester, hardened oil,
By treating with a fatty acid ester such as carnauba wax or beeswax, a long-lasting preparation can be obtained. Syrup preparations include sugar sweeteners such as sucrose and fructose; sugar alcohol-based sweeteners such as sorbitol and maltitol; non-saccharide natural sweeteners such as stevia extract and glycyrrhizin; saccharin, aspartame, etc. Prepared by blending with a synthetic or semi-synthetic sweetener.
In addition, cyclodextrins and the like can be added as other excipients.

As described above, as oral preparations, capsules, tablets, granules,
Fine granule and syrup formulations can be formulated. Next, the eye drops will be described. As the aqueous base for eye drops, commonly used additives such as an isotonic agent, a buffer and a preservative are appropriately blended. For example, as the tonicity agent, sodium chloride, potassium chloride, polyhydric alcohol, saccharides and the like, as the buffering agent, sodium borate,
Sodium citrate, sodium monohydrogen phosphate, sodium dihydrogen phosphate and the like, and preservatives include benzethonium hydrochloride, benzalkonium hydrochloride, chlorobutanol and the like. In addition, a stabilizer such as glycerin or polysoribate 80 and a pH adjuster are blended as required. Further, by appropriately prescribing various bases such as an ointment base, a gel base, and a suspension base to the components of the above-mentioned eye drops, the ophthalmic ointment, the gelling agent, the ophthalmic suspension, etc. An agent can be prepared. The morphane derivative of the present invention used in an aqueous ophthalmic solution is preferable in formulating because the form of an inorganic salt or an organic acid salt is easily dissolved in water.

Next, the injection will be described. The morphane derivative of the present invention used in an injection is preferably in a water-soluble form, and is particularly preferably used in a state of an inorganic salt or an organic salt. Examples of the base for injection include solvents and / or solubilizers such as glycols such as propylene glycol and glycerin; poly (oxyethylene) -poly (oxypropylene) polymer, glycerin formal, benzyl alcohol, and butane Polyoxyalkylenes such as diols; soybean oil, cottonseed oil, rapeseed oil,
Vegetable oils such as saffron oil; triglycerides of medium-chain fatty acids having 8 to 12 carbon atoms (for example, caprylic acid, capric acid, lauric acid, etc.) usually abbreviated as MCT;
And mono- or diglycerides of fatty acids (e.g., caproic acid, capric acid, myristic acid, palmitic acid, linoleic acid, and stearic acid). Cholesterol, tocopherol, albumin, polysaccharides, sodium bisulfite, etc. as stabilizers; benzyl alcohol, etc. as preservatives; phospholipids, such as egg yolk phospholipids, soybean phospholipids, phosphatidyl choline, polyoxygens as emulsifiers Alkylene polymer (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight in the range of 1,000 to 20,000), hydrogenated castor oil polyoxyethylene- (40) -ether, and hydrogenated castor oil polyoxyethylene And non-ionic surfactants such as-(20) -ether. In addition, if necessary, a tonicity agent (for example, glycerin, sorbitol,
Polyhydric alcohols such as xylitol, glucose, monosaccharides such as fructose, disaccharides such as maltose, L-alanine,
L-valine, amino acids such as glycine, etc.), emulsifiers (eg, stearic acid, palmitic acid, linoleic acid,
Linolenic acid or salts thereof, phosphatidylethanol, phosphatidylserine and the like can be mentioned. Aqueous or milky injections can be prepared by appropriately combining and formulating these various bases.

Next, the plaster will be described. Bases for plasters are known polymer bases (for example, acrylic compositions which are copolymers with vinyl monomers such as methacrylates, acrylonitrile, vinyl acetate, vinyl propionate, etc .; silicone resins; Isopropylene; polyisobutylene rubber; natural rubber; acrylic rubber;
Butadiene-styrene block copolymer; styrene-isoprene-styrene block copolymer, etc.), fats and oils or higher fatty acids (eg, almond oil, olive oil, camellia oil, persic oil, peanut oil, oleic acid, liquid paraffin, polybutene, etc.) And a tackifier (for example, rosin, rosin-modified maleic acid, hydrogenated rosin ester, etc.) and an anti-rash agent. If necessary, other additives (for example, dl-camphor, 1-menthol, thymol, nonylate vanillylamide, pepper tincture, peppermint oil, peppermint oil, etc.) are added to the base, and then the morphane derivative of the present invention or The salt is compounded, and further, an ultraviolet absorber or an antioxidant is appropriately compounded, if necessary, and this is stretched or non-stretchable support (for example, polypropylene, polyester, polyvinylidene chloride, polyacryl, Polyurethane, rayon,
A plaster can be obtained by spreading and applying on a release coating on cotton, an ethylene-vinyl acetate copolymer, a nonwoven fabric, a nonwoven paper, etc.).

Next, the poultice will be described. Compress base,
For example, pressure-sensitive adhesives (eg, synthetic water-soluble polymers such as sodium polyacrylate, polyacrylic acid, poval, polyvinylpyrrolidone, polyethylene oxide, and polyvinyl methacrylate; natural products such as gum arabic, starch, and gelatin; methylcellulose, hydroxypropylcellulose , Alginic acid, sodium alginate, ammonium alginate, sodium carboxymethylcellulose), wetting agents (eg, urea, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), fillers (eg, carion, zinc oxide, talc,
Titanium, pentonite, epoxy resins, organic acids (citric acid, tartaric acid, maleic acid, succinic acid, etc.), calcium, aluminum, etc., water, solubilizers (eg, propylene carbonate, crotamiton, diisopropyl adipate, etc.), adhesive Imparting agents (eg, rosin, ester gum, polybutene, polyacrylate), anti-rash agents (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, glycyrrhizic acid, dexamethasone, betamethasone, fluocinolone acetonide), and others (For example, l-menthol, camphor, nonylate vanillylamide, thymol, capsicum extract, peppermint oil, etc.), and the morphane derivative of the present invention or a salt thereof is added thereto. Or as needed acid resistant Agent can be obtained poultice by appropriately blended.

When molding as an ointment, the ointment base is selected from known or commonly used ones. For example, higher fatty acids or esters thereof (for example, adipic acid, myristic acid, Palmitic acid, stearic acid, oleic acid, adipate,
Myristate, palmitate, hexyl laurate, ethyl isooctanoate, etc., waxes (eg, spermaceti, beeswax, celsin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphate, higher alcohols) For example, cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (eg, dimethyl polycycloxane, methylphenyl polysiloxane, glycol methyl polysiloxane, silicone glycol polymer, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum) , Purified lanolin, liquid paraffin, etc.), water, humectants (eg, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), anti-rash agents, and other additives (eg, l-menthol, Or mint oil, etc.) The morphane derivative of the present invention or a salt thereof is appropriately blended and formulated with these bases, whereby a formulation for transdermal, oral mucosa and rectal mucosa can be obtained. it can.

Next, the gel agent will be described. The gel base is selected from various known or commonly used bases. For example, a lower alcohol (eg, ethanol, isopropyl alcohol, etc.), water, a gelling agent (eg, carboxyvinyl polymer, hydroxyethyl cellulose,
Ethyl cellulose, carboxyethyl cellulose, propylene glycol alginate, etc.), neutralizing agents (eg, triethanolamine, diisopropanolamine, sodium hydroxide, etc.), surfactants (eg, sorbitan sesquioleate, sorbitan trioleate,
Sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene phenyl ether, polyoxyethylene lauryl ether, etc., rash preventives, and other additives (eg, l-menthol,
Camphor, peppermint oil and the like). By appropriately compounding the morphane derivative of the present invention or a salt thereof with these bases, a preparation for transdermal, oral mucosa and rectal mucosa can be obtained.

Next, the cream will be described. The cream is selected from various known or commonly used bases, and includes, for example, higher fatty acid esters (eg, diester myristic acid, hexyl palmitate, diethyl sebacate, hexyl laurate, cetyl isooctanoate), lower grades Alcohols (eg, ethanol, isopropanol, etc.), hydrocarbons (eg, liquid paraffin, squalene, etc.), polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, Cetanol, 2-octyldecanol, etc.), emulsifiers (eg, polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, etc.), preservatives (eg, paraoxybenzoic acid ester), anti-rash agents, Other additives (e.g., l-menthol, camphor, peppermint oil, etc.). A cream can be obtained by adding the morphane derivative of the present invention or a salt thereof to each of the above-mentioned bases, and further appropriately adding an ultraviolet absorber or an antioxidant as necessary.

Gel creams having properties intermediate between creams and gels include gelling agents (eg, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, etc.) And a neutralizing agent (e.g., diisopropanolamine, triethanolamine, sodium hydroxide, etc.), and a pH value of 4 to 8,
Preferably, it can be obtained by adjusting to 5 to 6.5. It should be noted that a formulation for transdermal, oral mucosa and rectal mucosa can be obtained by appropriately blending the morphane derivative or a salt thereof of the present invention with a base in a cream or gel cream.

Next, the liniment will be described. The liniment in the present invention includes alcohols (for example, monohydric alcohols such as ethanol, propanol and isopropanol, polyhydric alcohols such as polyethylene glycol, propylene glycol and butylene glycol),
Water, a fatty acid ester (eg, adipic acid, sebacic acid, myristic acid, etc.), a surfactant (eg, polyoxyethylene alkyl ether), and the morphane derivative or a salt thereof according to the present invention; Alternatively, a cream can be obtained by appropriately mixing an antioxidant as needed. In the liniment of the present invention, if necessary, a neutralizing agent for adjusting pH, a viscosity imparting agent such as cetyl cellulose, carboxyvinyl alcohol, or hydroxypropyl cellulose, a rash preventive, or other additives (for example, l) Menthol, camphor, peppermint oil, pepper extract, vanillyl amide nonylate, thymol, crotamiton, propylene carbonate, diisopropyl adipate, etc.).

Next, suppositories will be described. The suppository base is appropriately selected from, for example, synthetic oil bases such as cocoa butter, hydrogenated peanut oil, and hydrogenated coconut oil, and water-soluble bases such as polyethylene glycols, monolen, twine, and pluronic. . Next, nasal drops will be described. The aqueous base can be prepared by adding the morphane derivative of the present invention or a salt thereof to water, a buffer (eg, sorensen buffer (Ergeb. Physiol., 12, 393, 1912), a Clark-Lubs buffer (J). . Bact., 2, 109, 191, 191
7), Macll-vaine buffer (J. Biol. C)
hem., 49, 183, 1921), Michaelis buffer (Die Wasserstollionen Komzentralion, p. 186, 191).
4), Koithoff buffer (Bio-Chem. Z., 17)
9, 410, 1926)) or dissolved, suspended or emulsified in an aqueous solution. Oily suspending agents are
The morphane derivative of the present invention or a salt thereof is added to an oily base (for example, sesame oil, olive oil, corn oil, soybean oil,
It is formulated by suspending or emulsifying in cottonseed oil, peanut oil, lanolin, petrolatum, paraffin, silicone oil, and medium-chain fatty acids or their glycerin or alcohol esters. Semi-solid preparations (ointments, gels, creams) are formulated by using the above-mentioned ointments, gels and cream bases. Also,
In the case of liquid preparations, it is particularly desirable to place such liquid preparations in nasal drops containers, spray containers and similar containers suitable for intranasal application, and to drip or spray into the nasal passages.

Next, the aerosol is formulated by using a base component such as liquefied natural gas, dimethyl ether, carbon dioxide, and CFC as a propellant and an excipient. Finally, as the oral adhesive, hydroxypropyl cellulose, acrylic acid copolymer, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, maleic anhydride-methylvinyl ether copolymer, chitosan, Chitosan derivative, vinyl acetate copolymer,
Agar, hydrophilic polymer such as gelatin, antibacterial agent, softener,
Surfactants, crosslinking agents, neutralizing / buffering agents, extenders, coloring agents,
An adhesive tablet or a film-like adhesive patch can be formed by appropriately blending and formulating the base components of the flavoring agent and other excipients, and blending it with the morphane derivative of the present invention or a salt thereof.

The morphane derivative of the present invention or a salt thereof,
More specifically, the dose of the morphane derivative represented by the general formula (1) or a salt thereof depends on the condition and specific symptoms of the patient, but is usually 0.1 to 1000 mg / k.
g is administered once or twice a day. The morphane derivative or its salt of the present invention, more specifically, the morphane derivative or its salt represented by the general formula (1) or (2) can control and regulate the activation of a glycine receptor. It can be used as a therapeutic agent for neurological diseases, a central nervous system acting drug such as an anesthetic or an antitussive. Further, the morphane derivative of the present invention or a salt thereof,
It acts specifically on the glycine receptor and is useful as a drug with few side effects. Furthermore, since the morphane derivative or a salt thereof of the present invention can specifically regulate the activation of glycine receptor, it is extremely useful as a pharmacological tool for analyzing the function of glycine receptor. .

[0037]

The present invention will be described below with reference to examples.
The present invention is not limited to these examples.

Embodiment 1

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2-Methyl-2-azabicyclo [3.3.
1] Nonane 2-azabicyclo [3.3.1] nonane hydrochloride (10
0 mg, 0.62 mmol) in methanol (2 m
L) in 35% formalin aqueous solution (1 mL) and 10%
Palladium activated carbon (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution is subjected to suction filtration,
The filtrate was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate (10 mL) was added, and the mixture was extracted with chloroform (3 × 20 mL). After the extract was dried (MgSO ₄ ), the solvent was distilled off, and the obtained residue was subjected to silica gel chromatography (chloroform-methanol-triethylamine 100:
The oily substance obtained by purification in 9: 1) was dissolved in a 5% methanol solution of hydrogen chloride (20 mL), and concentrated under reduced pressure to obtain crude crystals of hydrochloride (98 mg, 90%), which were purified from chloroform-hexane. The crystals were recrystallized to give 2-methyl-2-azabicyclo [3.3.1] nonane hydrochloride as yellow needles.

Melting point: 147-152 ° C.¹ 1 H NMR spectrum: (500 MHz, CDC
l₃) Δ; 1.36-1.39 (1H, m), 1.54-1.71 (6H, m), 1.
83-1.89 (2H, m), 2.00-2.17 (2H, m), 2.42 (3H, s),
2.78-2.82 (2H, m), 2.88 (1H, td, J = 12.4,5.1Hz).¹³ C NMR spectrum: (125 MHz, CDCl
₃) Δ; 22.2 (CH₂), 24.6 (CH₂), 25.2 (CH), 30.5
(CH₂), 30.7 (CH₂), 34.7 (CH ₂), 43.3 (CH₃), 51.5 (CH
₂), 53.3 (CH). Electron impact mass spectrum: m / s (relative intensit
y); 139 (M⁺-HCl, 32), 96 (100).

Embodiment 2

Embedded image

2-ethyl-2-azabicyclo [3.3.
1] Nonane 2-azabicyclo [3.3.1] nonane (100 mg,
0.62 mmol) in a methanol solution (2 mL).
A 0% acetaldehyde solution (5 mL) and 10% palladium activated carbon (100 mg) were added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was subjected to suction filtration, and the filtrate was concentrated under reduced pressure. Saturated sodium hydrogen carbonate solution (10 mL) in the residue
And extracted with chloroform (3 × 20 mL). After the extract is dried (MgSO ₄ ), the solvent is distilled off, and the residue obtained is subjected to silica gel calamagraphy (chloroform-
Purification with methanol-triethylamine (100: 9: 1) gave 2-ethyl-2-azabicyclo [3.3.1] nonane (68 mg, 72%) as a colorless oil.

[0043]¹1 H NMR spectrum: (400 MH
z, CDCl₃) Δ; 1.12 (3H, t, J = 7.2Hz), 1.30-1.4
1 (1H, m), 1.52-1.79 (6H, m), 1.83-1.95 (2H, m), 2.00-2.1
3 (2H, m), 2.63 (2H, q, J = 7.2Hz), 2.79 (1H, td, J = 12.2,5.2
Hz), 2.89-3.01 (2H, m).¹³ C NMR spectrum: (100 MHz, CDCl
₃) Δ; 12.4 (CH₃), 22.2 (CH₂), 25.1 (CH₂), 25.8
(CH), 30.4 (CH₂), 30.9 (CH ₂), 34.4 (CH₂), 49.3 (C
H₂), 49.6 (CH₂), 50.4 (CH). Electron impact mass spectrum: m / s (relative intensit
y); 153 (M⁺, 17), 138 (13), 110 (100).

Embodiment 3

Embedded image

2-Allyl-2-azabicyclo [3.3.
1] Nonane 2-azabicyclo [3.3.1] nonane (100 mg,
0.62 mmol) in dimethoxyethane (6.5 m
L) to allyl bromide (105 mg, 0.87 mmol)
l) and potassium carbonate (94 mg, 0.68 mmol)
l) was added and the mixture was heated under reflux for 3.5 hours. Ether (10 mL) was added to the reaction mixture, and after filtration, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (chloroform-methanol-triethylamine 100: 9: 1).
And purified with 2-allyl-2-azabicyclo [3.3.
1] Nonane (52 mg, 51%) was obtained as a colorless oil.

[0046]¹1 H NMR spectrum: (400 MH
z, CDCl₃) Δ; 1.27-1.37 (1H, m), 1.55-2.07 (1
0H, m), 2.78-2.81 (2H, m), 2.87 (1H, quint, J = 3.2Hz), 3.1
7 (1H, qdt, J = 13.3,6.5,1.2Hz), 5.08 (1H, dddd, J = 9.9,
2.0, 1.0, 1.0Hz), 5.19 (1H, dq, J = 17.0, 1.6Hz), 5.89 (1
(H, dddd, J = 17.0, 9.9, 6.5, 6.5Hz).¹³ C NMR spectrum: (100 MHz, CDCl
₃) Δ; 22.4 (CH₂), 25.3 (CH₂), 25.8 (CH), 30.7 (C
H₂), 31.0 (CH₂), 34.9 (CH ₂), 49.6 (CH₂), 50.9 (CH),
 59.5 (CH₂), 116.9 (CH₂), 136.5 (CH). Electron impact mass spectrum: m / s (relative intensit
y) 165 (M⁺, 11), 122 (100).

Example 4 1-Ethyl-2-azabicyclo [3.3.1] nonane A method for producing 1-ethyl-2-azabicyclo [3.3.1] nonane is described in J. Org. Chem., 62. , 8280-8281,
(1997), according to the method for producing 1-lower alkyl-morphane.

Example 5 1-Propyl-2-azabicyclo [3.3.1] nonane A method for producing 1-propyl-2-azabicyclo [3.3.1] nonane is described in J. Org. Chem., 62. , 8280-828
1, (1997).

[0049] The preparation method of Example 6 5- azatricyclo [6.3.1.0 ^{1, 5]} dodecane 5- azatricyclo [6.3.1.0 ^{1, 5]} dodecane, J. Org. Chem. , 62, 8280-828
1, (1997).

Example 7 2-{[1-allyl- (2-propenyl) -2-azabicyclo [3.3.1] non-2-yl] methyl} phenol 2-{[1-allyl- (2- A method for producing (propenyl) -2-azabicyclo [3.3.1] non-2-yl] methyl} phenol is described in J. Org. Chem., 62, 8280-8.
281, (1997).

Test Example 1 In order to confirm the superior glycine receptor-modifying action of the derivative of the present invention, the effects of a series of morphane derivatives on glycine-induced ion current in guinea pig arc bundle nucleus single neurons were evaluated. . Table 1 shows the chemical structures of the compounds performed.

(1) Experimental method The isolation of a single neuron was performed according to the method of Kay et al. (J. Neurosc.
i. Meth., 16, 227-238, 1986). Hart
A light guinea pig (7 to 10 days old) was lightly anesthetized with ethyl ether, and then blood was removed, the head was decapitated, and the medulla was rapidly removed. Then, using a micro slicer, a thickness of 400
μm slice sections were prepared. After incubating the obtained slice section at 37 ° C. for 30 minutes, the arc bundle nucleus region was punched out under a stereoscopic microscope. This punched-out sample was placed in a trypsin solution under 100% oxygen pressure, 37
The enzyme treatment was performed at 30 ° C. for 30 to 60 minutes. A piece of tissue treated with the enzyme was mechanically dispersed to obtain a single neuron.
The measurement of the ionic current activated by glycine was performed in the whole cell mode of the patch clamp method, and the obtained ionic current was plotted on a pen recorder. The test compound was administered by a Y-tube method in which the external solution around the cells could be replaced with a drug solution within 2 ms (Neurosci. Lett., 103,
56-63, 1989). The effect of the test compound was examined at a concentration of 1 mM. However, 30 for compound 7 having high fat solubility.
It was studied at a concentration of 0 μM. All data are mean ±
Expressed as standard error.

(2) Results The results of the effects of the seven morphane derivatives on the glycine-induced current are shown in Table 1.

[0054]

[Table 1]

Table 1 shows that in a solitary nucleus single neuron,
FIG. 9 summarizes the effects of morphane derivatives on ionic currents induced by 30 μM glycine.

The morphine derivative has a weak effect on the glycine-induced current (compound of Example 1) and a compound showing an inhibitory effect (compound of Example 4 and Example 7).
No. 3), and those exhibiting further enhancing action (compound of Example 2, compound of Example 3, compound of Example 5 and compound of Example 6). Above all, the compound of Example 2 showing the glycine-induced current enhancing action and the compound of Example 7 showing the inhibitory action were further studied. The compound of Example 2 reversibly enhances the glycine evoked current in the range of 10 μM to 1 mM, while the compound of Example 2 has no effect on the GABA evoked current at a concentration of 1 mM and the compound of Example 2 The concentration-dependent and specificity of the potentiating effect of was observed (see FIG. 1). The compound of Example 7 inhibited glycine-induced current in a concentration-dependent and reversible manner in the range of 10 to 300 µM (see Fig. 2).

Next, formulation examples of the morphane derivative or its salt of the present invention, more specifically, a preparation prepared using the morphane derivative or its salt represented by the general formula (1) will be described. In addition, this formulation example is only an example,
Various formulations can be made according to known methods.

Formulation 1 An aqueous injection is prepared according to the following formulation. Compound of Example 2 (Na salt) 1.0 g Benzyl alcohol 2.0 g Nicotinamide 3.0 g Propylene glycol 40.0 g Distilled water 100 ml

Formulation Formulation 2 The following formulation formulas a fat emulsion for injection. Compound of Example 4 (Na salt) 1.0 g Japanese soybean oil 21.0 g Purified soybean phospholipid 2.5 g Glycerin 5.0 g Distilled water 175 ml

Formulation Formulation 3 A tablet is prepared according to the following formulation (total amount 100
weight%). Compound of Example 2 24.0% by weight Microcrystalline cellulose 21.0% by weight Lactose 54.0% by weight Magnesium stearate 1.0% by weight

Formulation Formulation 4 A tablet is prepared according to the following formulation (total amount 100
weight%). Compound of Example 3 26.0% by weight Microcrystalline cellulose 21.0% by weight Lactose 42.0% by weight Crospovidone 10.0% by weight Magnesium stearate 1.0% by weight The tablets are composed of Eudragit E, ethyl alcohol, water and After spray coating the coating agent composed of talc according to a conventional method, a coating agent composed of Eudragit S, ethyl alcohol, water, talc and polyethylene glycol 6000 was spray-coated according to a conventional method to prepare a large intestine disintegrating preparation. .

Formulation Formulation 5 Tablets are prepared according to the following formulation (total amount 100
weight%). Compound of Example 7 25.0% by weight Fumaric acid 10.0% by weight Calcium hydrogen phosphate 40.0% by weight Lactose 24.0% by weight Talc 1.0% by weight This tablet contains ethyl cellulose, polyvinylpyrrolidone K30, talc and A coating solution composed of ethyl alcohol was spray-coated according to a conventional method to prepare a sustained-release tablet.

Formulation 6 Suppositories are prepared according to the following formulation (total amount 100
weight%). Compound of Example 4 5.0% by weight Polyethylene glycol 6.0% by weight bleached beeswax 10.0% by weight Sorbitan sesquioleate 4.49% by weight Medium-chain fatty acid triglyceride 74.5% by weight Dibutylhydroxytoluene 0.01% by weight

Formulation 7 A suppository is prepared according to the following formulation (total amount 100
weight%). Compound of Example 6 5.0% by weight Polyethylene glycol 400 10.0% by weight Polyethylene glycol 1,000 27.0% by weight Polyethylene glycol 6,000 43.5% by weight Propylene glycol Suitable amount

Formulation 8 An ointment is prepared according to the following formulation:
0% by weight). Compound of Example 2 5.0% by weight Propylene glycol 6.5% by weight Isopropyl myristate 5.5% by weight White petrolatum 83.0% by weight

Formulation 9 An ointment is prepared according to the following formulation:
0% by weight). Compound of Example 5.0 5.0% by weight Isopropyl myristate 12.0% by weight White petrolatum 75.0% by weight Whale wax 5.0% by weight Polyoxyethylene lauryl ether sodium phosphate 3.0% by weight

Formulation Formulation 10 A liniment is prepared according to the following formulation (total amount: 100% by weight). Compound of Example 2 3.0% by weight Ethanol 38.0% by weight 2-Hydroxy-4-methoxybenzophenone 0.5% by weight Propylene glycol 13.0% by weight Methylcellulose 0.8% by weight Ethyl sebacate 3.0% by weight Purified water appropriate amount Sodium hydroxide 0.07% by weight

Formulation 11 A liniment is prepared according to the following formulation (total amount: 100% by weight). Compound of Example 7 3.0% by weight Carboxymethylcellulose 0.1% by weight Purified water appropriate amount Polyethylene glycol 7.0% by weight

Formulation 12 A gel is prepared according to the following formulation (total amount 10).
0% by weight). Compound of Example 2 3.0% by weight Diisopropyl adipate 3.0% by weight Ethanol 38.5% by weight Carboxyvinyl polymer 2.0% by weight Purified water Proper amount Hydroxypropyl cellulose 2.0% by weight Propylene glycol 17.0% by weight Di 2.5% by weight of isopropanolamine

Formulation Formulation 13 A gel cream is prepared according to the following formulation (total amount: 100% by weight). Compound of Example 7 3.0% by weight Isopropyl myristate 11.0% by weight Ethanol 6.0% by weight Carboxyvinyl polymer 1.5% by weight Purified water Appropriate amount Polyoxyethylene (55) monostearate 1.0% by weight Coconut palm Oil fatty acid diethanolamide 4.0% by weight

Formulation 14 A cream is prepared according to the following formulation (total amount 100% by weight). Compound of Example 2 5.0% by weight Cetyl alcohol 12.0% by weight Stearyl alcohol 2.5% by weight Glycerol monostearate 6.0% by weight 1,3-butylene glycol 13.0% by weight Purified water

Formulation Formulation 15 A compress is prepared according to the following formulation (total amount: 10).
0% by weight). Compound of Example 2 3.0% by weight Gelatin 6.0% by weight Aluminum silicate 11.0% by weight Polyvinyl alcohol 4.5% by weight Purified water qs Glycerin 28.0% by weight Carboxymethylcellulose 3.0% by weight

Formulation 16 A plaster is prepared according to the following formulation:
0% by weight). Compound of Example 6 3.0% by weight Styrene-isoprene-styrene block copolymer 24.5% by weight (Califlex TR1107, manufactured by Shell Chemical Co., Ltd.) Liquid paraffin 43.5% by weight Hydrogenated rosin ester 29.0% by weight

Formulation 17 A nasal drop is prepared according to the following formulation.
0% by weight). Compound of Example 7 10 mg Propylene glycol 20 mg Appropriate amount of distilled water (total amount is 100 ml)

[0075]

As described above, the morphane derivative of the present invention or a salt thereof, more specifically, the above-mentioned general formula (1)
Alternatively, since the morphane derivative or salt thereof represented by (2) can enhance or suppress the activation of glycine receptor, it is extremely useful as a therapeutic agent for various neurological diseases, a central nervous system drug such as an anesthetic or an antitussive. Further, the present invention is extremely useful as a pharmacological tool for analyzing the function of a glycine receptor.

[Brief description of the drawings]

FIG. 1 shows Example 2 in which the potentiating effect was the strongest.
FIG. 4 shows the effect of the compound of Example 1 on the ionic current induced by 30 μM of glycine and 30 μM of GABA.

FIG. 2 shows Example 7 in which the inhibitory effect was the strongest.
FIG. 4 shows the effect of the compound of Example 1 on ionic current induced by 30 μM of glycine.

────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] May 9, 2000 (200.5.9)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0024

[Correction method] Change

[Correction contents]

Specific formulation will be described in more detail. For oral preparations, for example, the morphane derivative of the present invention or a salt thereof and an organic acid (for example, citric acid, ascorbic acid, fumaric acid, tartaric acid, succinic acid, malic acid, adipic acid, etc.) or an antacid (for example, carbonic acid) Pharmaceutical composition appropriately mixed with sodium hydrogen, calcium hydrogen phosphate, magnesium metasilicate aluminate, magnesium hydroxide, synthetic hydrotalcite, or the like, or microcapsules obtained by adding an additive thereto, by a known method. Or a binder, a lubricant, a disintegrant, an excipient, a disintegration rate adjusting agent as required for the pharmaceutical composition,
By adding a plasticizer, a coloring agent, a flavoring agent, and the like, tablets, granules, fine granules and the like can be formed by a conventional method. In addition, these preparations are further used as a sustained-release film agent, such as water-insoluble polymers such as ethyl cellulose, aminoalkyl methacrylate copolymer, polyvinyl acetate, and polyethylene; cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate. Carboxymethyl ethyl cellulose,
Enteric polymers such as styrene acrylic copolymer, methacrylic acid copolymer, maleic anhydride polymer, and shellac ; paraffin wax such as paraffin and microcrystalline wax; higher alcohols such as stearyl alcohol and cetanol; glycerin fatty acid ester; , Carnauba wax, beeswax, and other fatty acid esters to give a long-lasting preparation. Syrup preparations include sugar sweeteners such as sucrose and fructose; sugar alcohol-based sweeteners such as sorbitol and maltitol; non-saccharide natural sweeteners such as stevia extract and glycyrrhizin; saccharin, aspartame, etc. Prepared by blending with a synthetic or semi-synthetic sweetener. In addition, cyclodextrins and the like can be added as other excipients.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/08 A61P 25/08 25/26 25/26 43/00 111 43/00 111 C07D 471/08 C07D 471/08 (72) Inventor Hidenao Fukushima 1-25-11 Kannondai, Tsukuba-shi, Ibaraki Hisamitsu Pharmaceutical Co., Ltd.Tsukuba Research Laboratories F-term (reference) CB14 MA04 NA14 ZA02 ZA06 ZA62 ZC41

Claims (5)

[Claims] 1. The following general formula (1): (Wherein R ₁ is hydrogen, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an araliphatic group which may have a substituent, or R ₂ together with Represents an alkylene group which may have a substituent capable of forming a ring together with an adjacent atom, wherein R ₂ is hydrogen, a lower alkyl group which may have a substituent, or A morphane derivative represented by the formula: or a salt thereof. 2. A glycine receptor activation regulator comprising a morphane derivative or a salt thereof as an active ingredient. 3. The morphane derivative or a salt thereof,
The glycine receptor activation regulator according to claim 2, which is the morphane derivative or a salt thereof according to claim 1. 4. The glycine receptor activation regulator according to claim 2, which is a glycine receptor activity enhancer or inhibitor. 5. The following general formula (2): (Wherein R ₁ is hydrogen, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an araliphatic group which may have a substituent, or R ₂ together with Represents an alkylene group which may have a substituent capable of forming a ring together with an adjacent atom, wherein R ₂ is hydrogen, a lower alkyl group which may have a substituent, or represents an alkenyl group. However, if R ₁ is a hydrogen atom R ₂ is not hydrogen atom or an unsubstituted lower alkyl group, R ₁ and R ₂
The substituent in the lower alkyl group, alkenyl group or araliphatic group is not a hydroxyl group, and when R ₁ is an alkylene group, it is not a propylene group. ) Or a salt thereof.