JP2000086517A - Allodynia medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject treating or preventing medicine useful in treating or preventing allodynia by adding a specific compound having a benzene ring as an active ingredient. SOLUTION: This allodynia medicine contains a compound of formula I the group of formula II is a group of formula III [(e) is 3-5; (p) is 0-4] or the like; R1 is H or a 1-4C alkyl; R2 is a group of formula IV (R3 is H, a 1-8C alkyl or the like; R4 is a 1-8C alkyl, phenyl or the like) or the like}, for example, (E)-[5-[-2-[1-phenyl-1-(3-pyridyl)methylideneaminoxy]ethyl]-7,8- dihydroxynaphthalen-1-yloxy]acetic acid, or their non-toxic salts as an active ingredient. The medicine is preferably administered at a dose of 1 μg to 100 mg (as the active ingredient) for ran adult once to several times a day, when orally administered. The medicine is useful in treating and/or preventing allodynia, for example, a pain caused by the damage of a peripheral nerve or a pain caused by the damage of the central nerve.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic and prophylactic agent for allodynia. More specifically, the present invention relates to a therapeutic agent and a prophylactic agent for allodynia, comprising a compound represented by the following general formula (I) and a nontoxic salt thereof as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Pain is a life-sustaining alert response to external noxious stimuli and pathological conditions in the body,
The pain itself has two sides: it can cause harmful conditions to the body. Under physiological conditions, pain is a result of a noxious stimulus applied to the living body, and the released and released pain-inducing substance responds to peripheral nociceptors and is transmitted as a pain signal, which is a warning response for the living body . Nociceptors have thin myelinated A
There are high-threshold mechanoreceptors that transmit pain to the central nervous system using delta fibers as primary afferent fibers, and polymodal receptors through unmyelinated C fibers. High-threshold mechanoreceptors respond only when the mechanical stimulus reaches a noxious level or higher. Polymodal receptors respond not only to mechanical stimuli but also to thermal and chemical stimuli. Nociceptors increase their activity depending on the intensity of the noxious stimulus. On the other hand, under pathological conditions such as inflammation and tissue damage of peripheral tissues, pain-killing and sensitizing substances produced and released continuously activate nociceptors in the periphery, causing heat, mechanical and chemical Lowers the threshold for noxious stimuli, such as substances, to cause a hyperalgesic response.

[0003] Non-noxious stimuli, such as touch and pressure, are transmitted from peripheral non-nociceptors to the central nervous system via thick, myelinated Aβ fibers, but do not cause pain under physiological conditions. However, in pathological situations, light tactile stimuli and cold sensations cause pain. This state is called allodynia. Allodynia is caused by pain due to peripheral nerve injury, such as causalgia, reflex sympathetic dystrophy,
Pain due to central nervous injury, such as phantom limb pain, postherpetic neuralgia, thalamic pain, pain after spinal cord injury, or pain from diabetic neuropathy or neuroinvasive cancer.

Although the mechanism of inducing allodynia is unknown, it has recently been found that prostaglandin (PG) administered intrathecally for the first time as a physiologically active substance induces allodynia together with a hyperalgesic response [ Pa
in, 50 , 223-9 (1992)]. For example, intrathecal administration of PGE ₂ induces allodynia with non-noxious tactile stimuli as well as hyperalgesic response to noxious thermal stimuli. Intrathecal administration of PGF _2α does not induce a hyperalgesic response but induces allodynia. On the other hand, PG
D ₂ causes pain hypersensitivity reaction, but allodynia does not cause. It has further been suggested that PGD ₂ may be present as an endogenous inhibitor of allodynia induced by non-noxious tactile stimuli. Also, PG
Neither allodynia nor hyperalgesia occurs with administration of I ₂ or TXA ₂ . Thus, various facts have been revealed about the relationship between PGs and allodynia,
Not fully understood.

On the other hand, the compound represented by the general formula (I) used in the present invention has a PGI ₂ receptor agonistic action and prevents thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcer, hypertension and the like. Or that it is useful for treatment,
Compounds disclosed in JP-A-25074 and JP-A-8-87811. However, the specification does not describe that PGI ₂ is related to pain, and of course does not describe allodynia. Furthermore, there is no description or suggestion that the compound represented by the general formula (I) can be used as a therapeutic agent for allodynia.

[0006]

OBJECTS OF THE INVENTION The present inventors have conducted intensive studies to find compounds that can be used for the treatment and / or prevention of allodynia. As a result, they have found that the compound represented by the general formula (I) achieves the object. Thus, the present invention has been completed.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a therapeutic agent for allodynia and / or
Or regarding prophylactic agents. More specifically, general formula (I)

Embedded image

[0008]

Embedded image (In the formula, e represents an integer of 3 to 5, p represents an integer of 0 or 1 to 4, q represents an integer of 0 or 1 to 2, and s represents an integer of 0 or 1 to 3), and R ¹ Is a hydrogen atom or C1
Represents an alkyl group of 4 to 4, wherein R ² is

Embedded image

(Wherein R ³ is (i) a hydrogen atom, (ii) C1
To 8 alkyl groups, (iii) phenyl group or C4 to 7
(Iv) a monocyclic heterocyclic ring containing one 4 to 7 membered nitrogen atom, (v) a phenyl group or C4 to
A C1-4 alkyl group substituted by a cycloalkyl group of 7, or (vi) a C1-4 alkyl group substituted by a monocyclic hetero ring containing one 4- to 7-membered nitrogen atom, R ⁴ is (i) C1-8 alkyl group, (ii) a cycloalkyl group of a phenyl group or a C4~7, (iii) 4
A monocyclic heterocycle containing one to seven membered nitrogen atoms, (iv)
A C1-4 alkyl group substituted by a phenyl group or a C4-7 cycloalkyl group, or (v) 4-7
Represents C1~4 alkyl groups wherein the nitrogen atom is substituted with one heterocyclic monocyclic containing membered, R ⁵ is a hydrogen atom, C1
And R ⁶ represents (i) a C1-15 alkyl group, (ii) benzene, C4
Or a C1-8 alkyl group substituted by one or two substituents selected from a cycloalkyl group of 1 to 7 or a monocyclic hetero ring containing one 4 to 7-membered nitrogen atom, or (iii)
Represents a C10-15 condensed three ring. ). However,

Embedded image Is the above (iii) or (iv),-(CH ₂ )
_p -, and = CH- (CH _{2) s} - is linked to the position of the ring a or b, all of the ring in R ^2, R ³ and R ^6,
It may be substituted with 1 to 3 substituents selected from a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom, a nitro group, and a trihalomethyl group. ) Or a non-toxic salt thereof as an active ingredient.

[0010] In the general formula (I), the alkyl group C1~4 wherein R ¹ represents a methyl, ethyl, propyl, butyl and isomeric groups thereof. In the general formula (I), R ⁵
Represents a C1-6 alkyl group represented by methyl, ethyl,
Propyl, butyl, pentyl, hexyl and isomers thereof. In the general formula (I), R ³ , R ⁴ and R
^The C1-8 alkyl group represented by ⁶ is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof. In the general formula (I), the C1-15 alkyl group represented by R ⁶ is
Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and isomers thereof. In the general formula (I),
The cycloalkyl group C4~7 which R ^3, R ⁴ and R ⁶ represent, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl group. In the general formula (I), R ³ ,
The monocyclic heterocyclic ring containing one 4- to 7-membered nitrogen atom represented by R ⁴ and R ⁶ includes azeto, azole, pyridine,
An azepine ring and a ring in which some or all of these rings are saturated. C10-1 represented by R ⁶ in the general formula (I)
The condensed tricyclic ring of 5 is an indacene, fluorene, anthracene, dibenzocycloheptene ring or a ring in which some or all of these rings are saturated.

Among the compounds used in the present invention, preferred are those wherein R ² is

Embedded image (Wherein all symbols have the same meanings as described above). More preferably, R ² is

[0012]

Embedded image Wherein R ³ is (iii) a phenyl group or a C4-7 cycloalkyl group, (iv) a monocyclic heterocycle containing one 4 to 7-membered nitrogen atom, (v) a phenyl group or C4-7 Or (vi) a C1-4 alkyl group substituted by a single-ring heterocyclic ring containing one 4 to 7-membered nitrogen atom,

R ⁴ is (ii) a phenyl group or a C4-7 cycloalkyl group, (iii) a monocyclic hetero ring containing one 4-7 membered nitrogen atom, (iv) a phenyl group or a C4-7
A compound which is a C1-4 alkyl group substituted by a cycloalkyl group of 7, or (v) a C1-4 alkyl group substituted by a monocyclic heterocycle containing one 4-7 membered nitrogen atom It is.

Specifically, compound 1: (E)-[5-
[2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid, and compound 2: (Z)-[5- [2- [1-phenyl-1-
(3-pyridyl) methylideneaminooxy] ethyl]-
7,8-dihydronaphthalen-1-yloxy] acetic acid.

[0015]

[Salt] The compound used in the present invention represented by the general formula (I) is converted into a corresponding salt by a known method. Non-toxic, water-soluble salts are preferred. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine) Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine and the like. Further, the compound represented by the general formula (I) can be converted to a hydrate by a known method.

[0016]

[Method for producing compound according to the present invention] The method for producing the compound represented by formula (I) is disclosed in JP-A-6-25074 or JP-A-6-87811. For example, (E)
-[5- [2- [1-Phenyl-1- (3-pyridyl)
[Methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid (compound 1) is described as Example 2 (f) in JP-A-6-87811. Also, (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy]
Acetic acid (Compound 2) is described in Example 2 (g) herein.

[0017]

EXAMPLES The following experiments proved that the compounds of the formula (I) can be used for the treatment and / or prevention of allodynia. [Pharmacological experiment] (1) Inhibitory effect of allodynia by intrathecal administration Under no anaesthesia, 27 lumps between the 5th and 6th lumbar spinal cords of male ddY-mouse
Using a stainless steel gauge needle (0.33 mm, od),
GF _2α (1 μg / body) and various concentrations of compound 1 ((E)-[5- [2- [1-phenyl-1- (3
-Pyridyl) methylideneaminooxy] ethyl] -7,
8-dihydronaphthalen-1-yloxy] acetic acid) was administered intrathecally. Every 5 minutes after administration of the drug, the tail of the mouse was tactilely stimulated with a brush from the flank and observed for 15 minutes, and the allodynia response after 15 minutes was represented by a score. The score is 0 for no change, 1 for crying response, fleeing from the brush trying to apply the tactile stimulus, 2 for violently crying due to tactile stimulus, and 100% for all subjects with a score of 2. displayed. The result is shown in FIG. As shown in FIG. 1, Compound 1 significantly suppressed allodynia.

(2) Inhibitory effect of oral administration on allodynia Male ddY-mice were given various concentrations of ((E)
-[5- [2- [1-Phenyl-1- (3-pyridyl)
[Methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid (compound 1) was orally administered. One hour later, PGF _2α (1 μg / body) was intrathecally administered between the fifth and sixth lumbar spinal cords of the mice using a 27-gauge stainless steel needle (0.33 mm, od). PGF _{2 alpha} every 5 minutes to administer, and tactile stimulation with a brush tail from the flank of the mice were observed for 15 minutes, showing the reaction of allodynia after 15 minutes score. The score is 0 for no change, and escapes from the brush trying to apply a tactile stimulus.
The response of singing is indicated by 1, the response of violently escaping by tactile stimulation and escaping vigorously is indicated by 2, and 100% when all subjects have a score of 2. The result is shown in FIG. FIG.
As shown in Table 1, Compound 1 significantly suppressed allodynia.

[0019]

[Toxicity] The toxicity of the compound used in the present invention was sufficiently low, and it was confirmed that the compound was sufficiently safe for use as a pharmaceutical. For example, compound 1 ((E)-[5-
The acute toxicity value of [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid is 250 mg / kg orally when administered orally. That was all.

[0020]

[Application to pharmaceutical products] The compound represented by the general formula (I)
Useful for treating and / or preventing allodynia.
For example, pain due to peripheral nerve injury, such as causalgia, reflex sympathetic dystrophy, and pain due to central nerve injury, such as phantom limb pain, postherpetic neuralgia,
It is useful for the treatment and / or prevention of thalamic pain, pain after spinal cord injury, and allodynia associated with diabetic neuropathy or pain from neuroinvasive cancer.

In order to use the compound represented by the formula (I) or a non-toxic salt thereof for the above purpose, it is usually administered systemically or locally, in an oral or parenteral form. The use of a prodrug has advantages such as elimination of irritation, improved absorption, and improved stability.

[0022] The dose is determined by the age, body weight, symptoms, therapeutic effect,
Depending on the administration method, treatment time, etc., it is usually orally administered once to several times a day in the range of 1 μg to 100 mg per adult per person, or 0.1 μg per time per adult. Parenteral administration (preferably intravenous administration) once to several times a day in the range of 1 to 10 mg, or continuous intravenous administration in the range of 1 hour to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or administration outside the range may be necessary. When administering the compound according to the present invention, it is used as a solid composition, a liquid composition and other compositions for oral administration, an injection, an external preparation, a suppository and the like for parenteral administration.

[0023] Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, mannitol,
It is mixed with glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The composition may comprise, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a solubilizing agent such as glutamic acid or aspartic acid. May be contained. The tablet or pill may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylcellulose phthalate, or may be coated with two or more layers, if necessary. . Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.
The composition contains, in addition to the inert diluent, a stabilizing agent such as sodium bisulfite to render it isotonic and an isotonic agent such as sodium chloride, sodium citrate or citric acid. You may. Methods for producing sprays are described, for example, in U.S. Patent Nos. 2,868,691 and 3,093.
It is described in detail in the specification of 5,355.

The injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (registered trademark) and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the manufacture of sterile solid compositions which are sterilized or dissolved in sterile distilled water for injection or other solvents before use. Other compositions for parenteral administration include one or more active substances and are formulated as external solutions, ointments, liniments, suppositories for rectal administration and vaginal administration in a conventional manner. Pessaries etc. are included.

Formulation Example 1 The following components are mixed by a conventional method, and then tableted to give 1
One hundred tablets containing 5 mg of the active ingredient in tablets were obtained. (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid 500 mg carboxymethylcellulose calcium ……… 200mg ・ Magnesium stearate ……… 100mg ・ Microcrystalline cellulose ………… 9.2g

Formulation Example 2 After the following components are mixed by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 10 ml portions, freeze-dried by a conventional method, and contains 2 mg of the active ingredient in one ampule. 100 ampoules were obtained. (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid 200 mg mannitol ………… 50g ・ Distilled water …………… 1000ml

[Brief description of the drawings]

FIG. 1. Compound 1 ((E)-[5-
The graph which shows the inhibitory effect of [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid against _PGF2α- induced allodynia.

FIG. 2. Oral administration of compound 1 ((E)-[5- [2
-[1-Phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene-
1 is a graph showing the inhibitory effect of 1-yloxy] acetic acid) on PGF _2α- induced allodynia.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C055 AA01 BA01 CA02 CA06 CA30 CB08 DA01 4C086 AA01 AA02 BC05 BC06 BC07 BC16 BC17 BC21 BC31 MA01 MA04 NA14 ZA08 ZC54

Claims (3)

[Claims] 1. A compound of the general formula (I) Embedded image (In the formula, e represents an integer of 3 to 5, p represents an integer of 0 or 1 to 4, q represents an integer of 0 or 1 to 2, and s represents an integer of 0 or 1 to 3), and R ¹ Is a hydrogen atom or C1
R ² represents an alkyl group represented by the formula: (In the group, R ³ represents (i) a hydrogen atom, (ii) a C1-8 alkyl group, (iii) a phenyl group or a C4-7 cycloalkyl group, and (iv) a 4- to 7-membered nitrogen atom. A monocyclic heterocyclic ring, (v) a C1-4 alkyl group substituted by a phenyl group or a C4-7 cycloalkyl group, or (vi) a monocyclic ring containing one 4- to 7-membered nitrogen atom to represent C1~4 alkyl group substituted by heterocycle, R ⁴
Are (i) a C1-8 alkyl group, (ii) a phenyl group or a C4-7 cycloalkyl group, (iii) a monocyclic heterocycle containing one 4- to 7-membered nitrogen atom, (iv) phenyl Or a C1-4 alkyl group substituted by a C4-7 cycloalkyl group, or (v) a C1-4 alkyl substituted by a monocyclic heterocycle containing one 4-7 membered nitrogen atom. R ⁵ represents a hydrogen atom, a C1-6 alkyl group or a phenyl group, and R ⁶ represents (i) C1
C1 substituted with one or two substituents selected from an alkyl group of 5; (ii) benzene, a C4-7 cycloalkyl group, or a monocyclic heterocycle containing one 4- to 7-membered nitrogen atom. And (iii) a C10-15 condensed tricyclic ring. ). However, Is the above (iii) or (iv),-(CH ₂ )
_p -, and = CH- (CH _{2) s} - is linked to the position of the ring a or b, all of the ring in R ^2, R ³ and R ^6,
It may be substituted with 1 to 3 substituents selected from a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom, a nitro group, and a trihalomethyl group. Or a non-toxic salt thereof as an active ingredient. 2. A pain caused by peripheral nerve injury, a pain caused by central nerve injury, a diabetic neuropathy or a nerve infiltration containing the compound according to claim 1 or a non-toxic salt thereof as an active ingredient. A therapeutic or prophylactic agent for allodynia that is accompanied by pain caused by sex cancer. 3. The compound according to claim 1, wherein the compound is (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid. Or (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy]
The therapeutic or preventive agent for allodynia according to claim 1, which is [ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid.