JP2001097945A - Sulfonamide derivative and allodynia medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an allodynia-treating and/or preventing medicine containing a sulfonamide derivative of formula (W), its ester, its non-toxic salt, or its cyclodextrin clathrate compound as an active ingredient, and to provide the new sulfonamide derivative. SOLUTION: The sulfonamide derivative of formula (W) is useful for treating and/or preventing allodynia (for example, causalgia or reflex sympathetic dystrophy) caused by peripheral nerve injury, allodynia [for example, phantom limb pain, neuralgia after herpes zoster (pain after herpes), thalamic pain or pain after vertebra damage], or allodynia caused by diabetic central nerve injury or neroinfiltrating cancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic and / or prophylactic agent for allodynia. More specifically, the present invention relates to a therapeutic and / or prophylactic agent for allodynia containing, as an active ingredient, a sulfonamide derivative represented by the following formula (W), an ester thereof, a nontoxic salt thereof, and a cyclodextrin inclusion compound thereof. The present invention also relates to a novel compound, a sulfonamide derivative represented by the following formula (WA), their esters, their non-toxic salts, and their cyclodextrin inclusion compounds.

[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 the dual nature of causing harmful conditions to the body. Under physiological conditions, pain is a result of a nociceptive stimulus applied to the body, and the released and released pain-inducing substance responds to peripheral nociceptors, is transmitted as a pain signal, and warns the living body.

Nociceptors include high-threshold mechanoreceptors that transmit pain to the central nervous system using thin myelinated Aδ fibers as primary afferent fibers, and polymodal receptors via 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. Its activity increases in an intensity-dependent manner against noxious stimuli. 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.

[0004] Non-noxious stimuli, such as touch and compression, 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 may include pain due to peripheral nerve injury (eg, causalgia, reflex sympathetic dystrophy), pain due to central nerve injury (eg, phantom limb pain,
It is associated with postherpetic neuralgia (postherpetic pain), thalamic pain, pain after spinal cord injury), and diabetic neuropathy and pain from neuroinvasive cancer.

Although the mechanism of inducing allodynia has not been fully elucidated, recently, prostaglandin (PG) administered intrathecally for the first time as a bioactive substance induces allodynia together with a hyperalgesic response. (Pain, 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. In the intrathecal PGF _{2 alpha,} but hyperalgesia is not caused, allodynia is induced. On the other hand, PGD ₂ causes a hyperalgesic response, but not allodynia. Furthermore, PGD
_It has also been suggested that 2 may be present as an endogenous inhibitor of allodynia induced by non-noxious tactile stimuli. In addition, administration of PGI ₂ or TXA ₂ produces neither allodynia nor hyperalgesia. Thus, PG
Various facts about the relationship between species and allodynia have been revealed, but they have not been clarified yet.

However, from the above, it is clear that 1) normal pain, 2) hyperalgesia, and 3) allodynia are symptoms that should be considered separately. It is also clear that the effectiveness of these pains can only be ascertained by examining each compound, as each mechanism is different. As described above, PGE ₂ is generally known to be a pain-causing substance associated with inflammation. Among the PGE ₂ receptors, the subtype EP1 is considered to be involved in the onset of pain, and the EP1 antagonist is considered to be useful as an analgesic for ordinary pain.

[0007] Also, a compound named ONO-NT-012 has been reported to be effective against allodynia, and it has been reported that the EP1 receptor is involved in the onset of its action (British Journal of Pharmacology). , 115 ,
73-76 (1995)).

[0008] On the other hand, it is described in the claims of EP 312,906.
The listed compounds are represented by formulas (I) and (II) below.
The invention compounds. The compounds of this application are
XA _TwoUseful as an antagonist, inflammation, hypertension, thrombosis,
Stroke, asthma, myocardial infarction, angina, cerebral infarction, acute cardiac death
Is useful as a prophylactic and / or therapeutic agent for
However, this application shows the formulas (I) and (II)
The compounds to be used are not specifically described.

The compounds described in the claims of EP 878,465 include the compounds of the present invention represented by the following formulas (III) and (IV). Although the compounds of this application are EP1 agonists or antagonists and are disclosed to be useful as therapeutic agents for antipyretic, analgesic, or pollakiuria, this application discloses compounds of formulas (III) and (IV) Is not specifically described.

[0010] Further, Example 3 of EP 608,847 specification
(D) and 3 (a) describe the compounds represented by formulas (V) and (VI) according to the present invention described below. This application states that these compounds are useful as PGE ₂ antagonists or agonists because they bind to the PGE ₂ receptor and show an antagonistic or agonistic effect, It is disclosed that it has a gastrointestinal peristaltic movement inhibitory and sleep-inducing action, and that the agonist has uterine contraction, a gastrointestinal peristaltic movement promotion, gastric acid secretion suppression, and blood pressure lowering action.

Further, in the specification of EP 226,346, a compound represented by the formula (VI) according to the present invention, which will be described later as compound number Ih-ba (2St-5Z), is described. It discloses that it is useful as a TXA ₂ antagonist, inhibits platelet aggregation and vasoconstriction, and is useful as an antithrombotic agent and an antivasoconstrictor.

[0012]

[Object of the Invention] The present inventors screened various compounds in order to find a compound having a strong antiallodynic effect, and found that a compound having a bicyclo skeleton was useful. When the binding affinities of these compounds to the EP1 receptor were examined, the binding affinities were weak, and no correlation was observed between the antiallodynia effect and the EP1 antagonist activity. Therefore, it was considered that the expression of the antiallodynic action of these compounds was not caused by the EP1 antagonistic action.

[0013] In addition, when the structures of the compounds were compared with respect to the results obtained in the present screening, some of the compounds had similar structures but some were effective against allodynia, while others were ineffective. I couldn't find it. The present inventors have found that, as will be described later, compounds that are very similar in structure are both effective for allodynia and ineffective. Also,
It does not correlate with the generally expected binding activity to various PG receptors and TX receptors, suggesting that there is a high possibility that new unknown target molecules (such as receptors) are involved. . The present inventors have found that only specific compounds are effective for allodynia, and have completed the present invention.

[0014]

DISCLOSURE OF THE INVENTION That is, the present invention provides a compound of the formula (W)

Embedded image (Each symbol in the formula represents the following (1), (2) or (3)
Represents a combination of: (1) ring Y is

Embedded image Where X is

Embedded image And Z is

Embedded image And (R) n represents 2-iodo, 2-fluoro or 3,4-difluoro; (2) ring Y is

Embedded image Where X is

Embedded image And Z is

Embedded image And (R) n represents 2,5-difluoro; (3) ring Y is

Embedded image Where X is

Embedded image And Z is

Embedded image And (R) n represents 4-methoxy or hydrogen. The present invention relates to a therapeutic and / or prophylactic agent for allodynia comprising as an active ingredient one or more compounds selected from the sulfonamide derivatives, esters, non-toxic salts thereof, and cyclodextrin clathrates thereof. Specific examples of the sulfonamide derivative represented by the above formula (W) include the following formulas (I) to (VI)

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image and

Embedded image The compound shown by these is mentioned. Hereinafter, the “compound of the present invention” means a sulfonamide derivative represented by the above formula (W), an ester thereof, a non-toxic salt thereof, or a cyclodextrin inclusion compound thereof.

The formula (W-A)

Embedded image (The symbols in the formula represent a combination of the following (1) or (2): (1) When ring Y ^A is

Embedded image And X ^A is

Embedded image And Z ^A is

Embedded image And (R ^A ) n ^A represents 2-iodo, 2-fluoro or 3,4-difluoro; (2) ring Y is

Embedded image And X ^A is

Embedded image And Z ^A is

Embedded image And (R ^A ) n ^A represents 2,5-difluoro. )
The sulfonamide derivative, its ester, its non-toxic salt, or its cyclodextrin inclusion compound represented by is included in the description of the claims of the above-mentioned patent publication, but is specifically described in the specification. These compounds are not included in the present invention, and these compounds are also included in the present invention.

[0016]

[Ester] The sulfonamide derivative represented by the formula (W) can be converted into an ester by a known method. The ester form is useful because stability and absorbability are increased. Preferably, an alkyl ester,
More preferably, it is a C1-4 alkyl ester.

[0017]

[Salt] The sulfonamide derivative represented by the formula (W) is converted into a corresponding salt by a known method. Salt is non-toxic,
Water-soluble ones 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 sulfonamide derivative represented by the formula (W), its ester, and its non-toxic salt can be converted into a hydrate by a known method.

[0018]

[Inclusion compound] The sulfonamide derivative represented by the formula (W), an ester thereof, and a non-toxic salt thereof are obtained by using α-, β-, or γ-cyclodextrin, or a mixture thereof using GB 1,351,238 or It can be converted to a cyclodextrin inclusion compound by using the method described in GB 1,419,221. Conversion to a cyclodextrin clathrate compound is convenient for use as a drug because it increases stability and increases water solubility.

[0019]

[Production method of the compound of the present invention]
06, EP 608,847, EP 878,465 or EP 226,346
Can be produced by the method described in the specification. Moreover, it can also be manufactured by the methods described in Reference Examples and Examples described later.

[0020]

[Pharmacological activity] The following experiments confirmed that the compound of the present invention can be used for the treatment and / or prevention of allodynia, and that other compounds having a similar structure are not effective.

[Pharmacological experiment] (1) Inhibitory effect of allodynia by intrathecal administration of PGE ₂ Male ddY mice weighing 22 ± 2 g were used in groups of 5 to 6 mice. Under no anaesthesia, 27 between the 5th and 6th lumbar spinal cords of mice
Using a stainless steel gauge needle (0.33 mm, od)
PGE ₂ (10 ng / body) and compound (10n
g / body) (5 μL) was administered intrathecally.
Five minutes after the administration of the drug, the tail of the mouse from the flank was tactilely stimulated with a brush and observed, and allodynia was evaluated by a score. The score was 0: no change, 1: escaped from the brush trying to apply the tactile stimulus, cried, 2: escaped vigorously by the tactile stimulus, cried violently, and allodynia occurred when all subjects scored 2. Rate was 100%. For example, when the score 0 is 1, the score 1 is 3 and the score 2 is 2 out of 6 cases, the allodynia expression rate is as follows.

(Equation 1)

[0022] (2) as PGF _{2 alpha} intrathecal allodynia suppression medication by the administration, with a mixture of PGF _{2 alpha} (1 [mu] g / body) and compound (100 ng / body), except that was performed evaluated after 15 minutes Was performed in the same manner as in (1).

[0023]

[Table 1]

[0024]

Embedded image

[0025]

Embedded image

[0026]

[Table 2]

[0027]

Embedded image

[0028]

Embedded image

[0029]

[Table 3]

[0030]

Embedded image

[0031]

Embedded image

As shown in Tables 1, 2 and 3, the compounds of the present invention strongly suppressed allodynia. On the other hand, Comparative Compounds 1 to 6 having similar structures had no effect at all.
Specific considerations are described below.

In Table 1, it is apparent that bicyclo [2.2.1]
In the heptane skeleton, an o-halogen-substituted compound in the phenyl moiety appears to be effective, but in the same skeleton, Comparative Compound 1 in which o-halogen is chlorine has no effect. Further, even in the case of an o-iodine-substituted phenyl compound, there is no effect if the stereochemistry of the bicyclo [2.2.1] heptane skeleton portion is different.

In Table 2, a compound having a bicyclo [2.2.1] heptane skeleton which is not effective in Table 1 is effective in the case of a disubstituted compound (Compound (IV)). However, Comparative Compound 4 in which only the substitution position was changed is invalid. Compound (III) in which the stereochemistry of the bicyclo [2.2.1] heptane skeleton of Comparative Compound 4 is changed is effective. Further, although the substitution position is slightly different, Comparative Compound 3, which is a disubstituted chlorine compound, is ineffective. These results show that it is not easy to predict the activity of the comparative compound and the compound of the present invention from stereochemistry.

In Table 3, compounds having a bicyclo [3.1.1] heptane skeleton have activity (Compounds (V) and (VI)) with or without a substituent on the phenyl moiety, but have If methylene is inserted between the phenyl group and the phenyl group, it has no activity. Further, the compound having a bicyclo [2.2.1] heptane skeleton which was effective in the aforementioned compound (IV) and a combination of unsubstituted phenyl which was effective in the compound (VI) are ineffective.

From these facts, it can be seen that there is no correlation between the ring structure, the substituent and the antiallodynic effect.
Further, no correlation was observed between the EP1 binding activity of the comparative compound and the compound of the present invention and the anti-allodynia effect.

[0037]

[Toxicity] The toxicity of the compound of the present invention is sufficiently low.
It was confirmed to be safe enough for use as a pharmaceutical. For example, the maximum tolerated dose of the compound represented by the formula (I), (IV) or (VI) is 2000 mg / k for oral administration to rats.
g Animal weight or higher.

[0038]

[Application to pharmaceutical products] The compounds of the present invention are useful for treating and / or preventing allodynia. For example, allodynia due to peripheral nerve injury (eg, causalgia, reflex sympathetic dystrophy), allodynia due to central nerve injury (eg, phantom limb pain, postherpetic neuralgia (postherpetic pain), thalamic pain, spinal cord injury Later pain) as well as for the treatment and / or prevention of allodynia caused by diabetic neuropathy or neuroinvasive cancer.

In order to use the sulfonamide derivatives represented by the formula (W), their non-toxic salts, their esters, and cyclodextrin inclusion compounds for the above-mentioned purposes, they are usually used systemically or locally, orally or parenterally. It is administered in the form of Forming a non-toxic salt, ester, or cyclodextrin clathrate has advantages such as reduced irritation, improved absorption, and improved stability.

The dosage 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 of 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.

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 3,095,3.
No. 55 describes it in detail.

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. Pat. Nos. 2,868,691 and 3,095,
It is described in detail in the specification of '355. 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 further comprise preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizing agents (eg, glutamic acid,
Adjuvants such as 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:
Topical solutions, ointments, liniments, suppositories for rectal administration, and pessaries for vaginal administration, which contain one or more active substances and are formulated in a conventional manner, are included.

[0045]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in parentheses shown in the chromatographic separation and in TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume. NM
The solvent in parentheses shown at R indicates the solvent used for the measurement.

Reference Example 1 Sodium o-iodobenzenesulfonate

Embedded image O-Aminobenzenesulfonic acid (10 g) suspended in water (65 ml) was stirred at room temperature, and sodium carbonate (3.06 g) was added thereto. Sodium nitrite (4.2 g) was added little by little to the reaction mixture, and the mixture was stirred at 0 ° C for 20 minutes.
The reaction was poured into a mixture of concentrated hydrochloric acid (10 ml) and ice (50 g) and stirred. Here potassium iodide (10.5
A solution of g) in water (10 ml) was slowly added dropwise. The reaction solution was stirred at 0 ° C. to 100 ° C. for 1.5 hours, and then concentrated to remove water. The obtained solid was collected by filtration to give the title compound (9.78 g) as a tan powder. NMR (DMSO-d ₆ ): δ 7.93 (dd, J = 8.0, 1.5 Hz, 1H),
7.88 (dd, J = 7.5, 1.5Hz, 1H), 7.34 (dt, J = 8.0, 1.5
Hz, 1H), 7.00 (dt, J = 7.5, 1.5 Hz, 1H).

Reference Example 2 o-Iodobenzenesulfonic acid chloride

Embedded image Under an argon stream, the sodium salt (5
A solution of g) in DMF (30 ml) was stirred, and thionyl chloride (2.6 ml) was added dropwise thereto, followed by stirring at 0 ° C. for 1 hour.
After completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with water and once with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated, and then subjected to silica gel column chromatography (ethyl acetate / hexane = 1/5).
The title compound (3.41 g) was obtained as a pale orange solid. NMR (CDCl ₃ ): δ 8.25 (dd, J = 8.0, 1.5 Hz, 1H),
8.21 (dd, J = 8.0, 1.0 Hz, 1H), 7.59 (dt, J = 8.0, 1.0
Hz, 1H), 7.35 (dt, J = 8.0, 1.5 Hz, 1H); TLC: R
f 0.33 (ethyl acetate / hexane = 1/10).

Example 1 6-[(1S, 2S, 3S, 4R) -3- (2-iodophenylsulfonylaminomethyl) bicyclo [2.
2.1] Heptan-2-yl] -5Z-methylhexenoate

Embedded image

6-[(1S, 2S, 3S, 4R) -3-
A solution of methyl (t-butoxycarbonylaminomethyl) bicyclo [2.2.1] heptane-2-yl] -5Z-hexenoate (100 mg) in methanol (2 ml) was stirred at room temperature, and a 4N hydrochloric acid-dioxane solution (1 ml) was used. ) Was added and stirred at room temperature for 16 hours. After the reaction, concentrate.
The amine hydrochloride was obtained. Under an argon stream, the amine hydrochloride was dissolved in methylene chloride (3 ml), and triethylamine (0.1 ml) was added.
-Iodophenylsulfonyl chloride (112 mg)
Was added and stirred at 0 ° C. for 1 hour. After completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. Water and 1N organic layer
Washed twice with hydrochloric acid and once with saturated saline. The extract was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (ethyl acetate / hexane = 1/5 → 1/1) to give the title compound (139 mg) as a colorless oil. NMR (CDCl ₃ ): δ 8.16 (dd, J = 8.0, 1.5 Hz, 1H),
8.07 (dd, J = 8.0, 1.0 Hz, 1H), 7.51 (dt, J = 8.0, 1.0
Hz, 1H), 7.21 (dt, J = 8.0, 1.5 Hz, 1H), 5.45-5.15
(m, 3H), 3.66 (s, 3H), 2.69 (t, J = 6.5 Hz, 2H), 2.3
0 (t, J = 7.5 Hz, 2H), 2.20 (m, 1H), 2.15-2.00 (m, 4
H), 1.80-1.00 (m, 9H); TLC: Rf 0.46 (ethyl acetate / hexane = 1 /
3).

Example 2 6-[(1S, 2S, 3S, 4R) -3- (2-iodophenylsulfonylaminomethyl) bicyclo [2.
2.1] Heptan-2-yl] -5Z-hexenoic acid (compound represented by formula (I))

Embedded image

The methyl ester prepared in Example 1 (13
9 mg) in methanol (3 ml) and stirring at room temperature, a 2N aqueous sodium hydroxide solution (1 m
l) was added and stirred for 3 hours. After completion of the reaction, 1N hydrochloric acid was added, and the reaction solution was extracted three times with ethyl acetate. The organic layer was washed twice with water and 1N hydrochloric acid and once with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated and concentrated to give the title compound (12
8 mg) as a colorless oil. NMR (200 MHz, CDCl ₃ ): δ 8.16 (dd, J = 8.0, 1.5H
z, 1H), 8.07 (dd, J = 8.0, 1.0Hz, 1H), 7.51 (dt, J =
8.0, 1.0Hz, 1H), 7.22 (dt, J = 8.0, 1.5Hz, 1H), 5.45
5.20 (m, 3H), 2.69 (t, J = 6.5Hz, 2H), 2.36 (t, J = 7.
5Hz, 2H), 2.30-1.90 (m, 5H), 1.80-1.00 (m, 9H); TLC: Rf 0.53 (ethyl acetate / hexane / acetic acid = 7
/ 12/1).

Examples 2 (a) to 2 (e) The following compounds were obtained by the same operations as in Reference Examples 1, 2 and 3, and Examples 1 and 2.

Example 2 (a) 6-[(1S, 2S, 3S, 4R) -3- (2-fluorophenylsulfonylaminomethyl) bicyclo [2.
2.1] Heptan-2-yl] -5Z-hexenoic acid (compound represented by formula (II))

Embedded image NMR (300 MHz, CDCl ₃ ): δ 7.89 (1H, dt, J = 1.5,
7.8Hz), 7.62-7.52 (1H, m), 7.34-7.16 (2H, m), 5.44-
5.28 (2H, m), 4.91 (1H, t, J = 5.7Hz), 2.93-2.70 (2
H, m), 2.36 (2H, t, J = 7.8Hz), 2.30-1.88 (6H, m),
1.82-1.64 (2H, m), 1.62-1.42 (2H, m), 1.42-1.02 (4
H, m); TLC: Rf 0.52 (chloroform: methanol = 9:
1).

Example 2 (b) 6-[(1S, 2S, 3S, 4R) -3- (3,4-difluorophenylsulfonylaminomethyl) bicyclo [2.2.1] heptane-2-yl]- 5Z-hexenoic acid (compound represented by formula (III))

Embedded image NMR (300 MHz, CDCl ₃ ): δ 7.74-7.60 (m, 2H), 7.3
7-7.27 (m, 1H), 5.45-5.29 (m, 2H), 5.07 (t, J = 6.3
Hz, 1H), 3.00-2.88 (m, 1H), 2.74-2.64 (m, 1H), 2.5
0-2.20 (m, 4H), 2.14-1.06 (m, 12H); TLC: Rf 0.31 (hexane: ethyl acetate = 2:
1).

Example 2 (c) 6-[(1R, 2S, 3S, 4S) -3- (2,5-difluorophenylsulfonylaminomethyl) bicyclo [2.2.1] heptane-2-yl]- 5Z-hexenoic acid (compound represented by formula (IV))

Embedded image NMR (200 MHz, CDCl ₃ ): δ 7.62 (m, 1H), 7.22 (m,
2H), 5.22 (m, 2H), 4.83 (m, 1H), 3.04 (m, 2H), 2.
35 (t, J = 7.6 Hz, 2H), 2.20 (m, 1H), 2.10 (m, 2H),
1.89 (m, 1H), 1.0-1.8 (m, 10H); TLC: Rf 0.39 (chloroform / methanol = 9 /
1).

Example 2 (d) 7-[(1S, 2S, 3S, 5R) -3- (4-methoxybenzenesulfonylamino) -6,6-dimethylbicyclo [3.1.1] heptane-2- Yl] -5Z-heptenoic acid (compound represented by formula (V))

Embedded image NMR (CDCl ₃ ): δ 7.82 (2H, dt), 6.96 (2H, dt),
5.38 (2H, m), 5.00 (1H, br), 3.85 (3H, s), 3.58 (1
H, m), 2.40-1.40 (14H, m), 1.16 (3H, s), 0.93 (3H,
s), 0.76 (1H, d); TLC: Rf 0.50 (methanol / methylene chloride = 1 /
10).

Example 2 (e) 7-[(1S, 2S, 3S, 5R) -3-benzenesulfonylamino-6,6-dimethylbicyclo [3.1.
1] Heptan-2-yl] -5Z-heptenoic acid (formula (V
Compounds represented by I))

Embedded image NMR (CDCl ₃ ): δ 7.92 (2H, m), 7.55 (3H, m), 5.
34 (3H, m), 3.66 (1H, m), 2.40-1.44 (14H, m), 1.16
(3H, s), 0.94 (3H, s), 0.79 (1H, d); TLC: Rf 0.50 (methanol / methylene chloride = 1 /
10).

Synthesis of Comparative Compound The following comparative compound was obtained in the same manner as in Reference Examples 1, 2 and 3, and Examples 1 and 2.

Comparative Compound 1 6-[(1S, 2S, 3S, 4R) -3- (2-chlorophenylsulfonylaminomethyl) bicyclo [2.
2.1] Heptan-2-yl] -5Z-hexenoic acid

Embedded image NMR (200 MHz, CDCl ₃ ): δ 8.12-8.04 (1H, m), 7.5
6-7.49 (2H, m), 7.49-7.37 (1H, m), 5.50-5.30 (2H, m
m), 5.09 (1H, t, J = 6.0Hz), 2.78-2.68 (2H, m), 2.35
(2H, t, J = 7.4Hz), 2.30-1.95 (5H, m), 1.85-1.00 (9
H, m); TLC: Rf 0.27 (n-hexane / ethyl acetate / acetic acid = 3/1 / 0.04).

Comparative compound 2 6-[(1R, 2S, 3S, 4S) -3- (2-Iodophenylsulfonylaminomethyl) bicyclo [2.
2.1] Heptan-2-yl] -5Z-hexenoic acid

Embedded image NMR (200 MHz, CDCl ₃ ): δ 8.13 (dd, J = 7.6, 1.6 H
z, 1H), 8.07 (m, 1H), 7.52 (m, 1H), 5.22 (m, 2H),
5.07 (m, 1H), 7.20 (dd, J = 7.6, 1.6 Hz, 1H), 5.22
(m, 2H), 5.09 (m, 1H), 2.98 (m, 1H), 2.78 (m, 1H),
2.34 (t, J = 7.2 Hz, 2H), 2.18 (m, 1H), 2.10 (m, 2
H), 1.88 (m, 1H), 1.65 (m, 4H), 1.43 (m, 2H), 1.08-
1.30 (m, 6H); TLC: Rf 0.44 (chloroform / methanol = 9 /
1).

Comparative compound 3 6-[(1S, 2S, 3S, 4R) -3- (2,6-dichlorophenylsulfonylaminomethyl) bicyclo [2.2.1] heptane-2-yl] -5Z-hexenoic acid

Embedded image NMR (300 MHz, CDCl ₃ ): δ 7.50-7.45 (m, 2H), 7.3
8-7.32 (m, 1H), 5.47-5.28 (m, 3H), 2.94-2.77 (m, 2
H), 2.37 (t, J = 7.5 Hz, 2H), 2.30-2.20 (m, 1H), 2.2
0-2.04 (m, 3H), 2.03-1.97 (m, 1H), 1.80-1.64 (m, 2
H), 1.60-1.44 (m, 2H), 1.44-1.00 (m, 5H); TLC: Rf 0.36 (chloroform / methanol = 9 /
1).

Comparative compound 4 6-[(1R, 2S, 3S, 4S) -3- (3,4-difluorophenylsulfonylaminomethyl) bicyclo [2.2.1] heptane-2-yl] -5Z-hexene acid

Embedded image NMR (200 MHz, CDCl ₃ ): δ 7.70 (m, 2H), 7.33 (m,
1H), 5.22 (m, 2H), 4.74 (m, 1H), 2.94 (m, 2H), 2.
37 (t, J = 7.8 Hz, 2H), 2.17 (m, 1H), 2.10 (m, 2H),
1.89 (m, 1H), 1.0-1.8 (m, 10H); TLC: Rf 0.41 (chloroform / methanol = 9 /
1).

Comparative compound 57 7-[(1S, 2S, 3S, 5R) -3-benzylsulfonylamino-6,6-dimethylbicyclo [3.1.
1] Heptan-2-yl] -5Z-heptenoic acid

Embedded image NMR (CDCl ₃ ): δ 7.40 (5H, m), 5.42 (2H, m), 4.
86 (1H, d), 4.28 (2H, d), 3.74 (1H, br), 1.22 (3H,
s), 1.00 (3H, s), 0.80 (1H, d); TLC: Rf 0.50 (methanol / methylene chloride = 1 /
10).

Comparative compound 6 6-[(1R, 2S, 3S, 4S) -3-phenylsulfonylaminobicyclo [2.2.1] heptane-2-
Yl] -5Z-heptenoic acid

Embedded image NMR (CDCl ₃ ): δ 7.81-7.91 (2H, m), 7.42-7.61
(3H, m), 5.29 (2H, m), 2.99 (1H, m), 2.34 (2H, t),
0.82-2.22 (17H, m).

Formulation Example 1 The following components were mixed by a conventional method, and then compressed into tablets.
One hundred tablets containing 5 mg of the active ingredient in tablets were obtained. 6-[(1S, 2S, 3S, 4R) -3- (2-iodophenylsulfonylaminomethyl) bicyclo [2.2.1] heptan-2-yl] -5Z-hexenoic acid・ 500mg ・ Carboxymethylcellulose calcium ・ ・ ・ ・ ・ ・ ・ 200mg ・ Magnesium stearate ・ ・ ・ ・ ・ ・ ・ 100mg ・ Microcrystalline cellulose ・ ・ ・ ・ 9.2g

Formulation Example 2 After mixing the following components 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. 6-[(1S, 2S, 3S, 4R) -3- (2-iodophenylsulfonylaminomethyl) bicyclo [2.2.1] heptan-2-yl] -5Z-hexenoic acid・ 200mg ・ Mannit ・ ・ ・ ・ ・ ・ ・ 50g ・ Distilled water ・ ・ ・ ・ 1000ml

Continued on the front page (72) Inventor Atsushi Nagana 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka Prefecture Inside the Minase Research Laboratory, Ono Pharmaceutical Co., Ltd. (72) Takayuki Maruyama 3-1-1, Sakurai, Shimamoto-cho, Mishima-gun, Osaka No. 1 Ono Pharmaceutical Co., Ltd. Minase Research Laboratory F-term (reference) 4C206 AA01 AA02 AA03 JA13 KA01 KA11 KA20 MA01 MA04 ZA08 ZA21 ZC12 4H006 AA01 AA03 AB21

Claims (3)

[Claims] (1) Formula (W) (Each symbol in the formula represents the following (1), (2) or (3)
(1) Ring Y is And X represents Wherein Z is And (R) n represents 2-iod, 2-fluoro or 3,4-difluoro; (2) ring Y is And X represents And Z is And (R) n represents 2,5-difluoro;
(3) When ring Y is And X represents Wherein Z is And (R) n represents 4-methoxy or hydrogen. ) A therapeutic and / or prophylactic agent for allodynia comprising, as an active ingredient, one or more compounds selected from sulfonamide derivatives, esters, non-toxic salts thereof, and cyclodextrin inclusion compounds thereof. 2. The method according to claim 1, wherein the pain is allodynia caused by peripheral nerve injury, allodynia caused by central nerve injury, or allodynia caused by diabetic neuropathy or neuroinvasive cancer. Or prophylactic agents. 3. A compound of the formula (WA) (The symbols in the formula represent a combination of the following (1) or (2): (1) Ring Y ^A is Wherein X ^A is And Z ^A is And (R ^A ) n ^A represents 2-iodo, 2-fluoro or 3,4-difluoro; (2) ring Y is Wherein X ^A is And Z ^A is And (R ^A ) n ^A represents 2,5-difluoro. )
Or a sulfonamide derivative thereof, an ester thereof, a non-toxic salt thereof, or a cyclodextrin inclusion compound thereof.