JP2011201818A - Potential-dependent cation channel inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent potential-dependent cation channel inhibitor.SOLUTION: The potential-dependent cation channel inhibitor comprises a phthalide analog represented by formula (1) [wherein, ring A is a saturated, partially unsaturated or completely unsaturated six-membered ring; X is C=CH-R(Ris 1-12C alkyl), CRR(Ris 1-12C alkyl; Ris a hydrogen atom or 1-5C alkyl); Rand Rare each, same or different, a hydrogen atom or hydroxy] as an active ingredient.

Description

  The present invention relates to a voltage-gated cation channel inhibitor.

  In recent years, there has been an increase in hypersensitivity such as allergies due to an increase in external stimulating substances such as chemical substances and house dust caused by changes in the living environment, as well as the odors of the living environment, including the body odor and various living odors at home. Daily discomfort resulting from irritability, such as an increased tendency to dislike, is a problem.

  Sensations can be classified into somatic sensations such as skin sensations and deep sensations, visceral sensations such as visceral pain, and special sensations such as vision, hearing, taste, and smell. Sensory information is received by peripheral sensory receptors such as various receptors on the skin, muscle spindle, retina, olfactory mucosa, taste buds, cochlear hair cells, etc., and after being converted into nerve impulses in sensory sensation It is transmitted to the center as an electrical signal.

  For example, pain sensations are triggered by nociceptive stimuli (temperature stimuli, chemical stimuli, mechanical stimuli) received at the free nerve endings of the skin. At the free nerve ending, there are ion channels that are sensitive to each stimulus, and when these stimuli are received, the ion channels are opened and the cation channels flow into the cell, resulting in voltage-dependent cations. The channel is activated and a nerve action potential (impulse) is generated (Non-patent Document 1). As stimuli that cause itching, physical stimuli such as mechanical stimuli, thermal stimuli, and electrical stimuli, and chemical stimuli such as pollutants are known. These stimuli release histamine mainly from mast cells in the dermis, and the released histamine binds to a receptor on the free nerve endings, causing calcium ion influx and ultimately generating a neural action potential. (Non-patent document 2).

  Similarly, in any other sensory development, information is ultimately transmitted to the center in the form of action potentials generated by activation of nerve cell voltage-gated cation channels. Voltage-gated cation channels are not only involved in the generation and conduction of these action potentials, but also in the release of neurotransmitters into synaptic clefts and neuromuscular terminals.

  Therefore, if the activation of the voltage-gated cation channel is inhibited, it is possible to stimulate the sense. Actually, methods for suppressing sensation using a voltage-gated cation channel inhibitor have been used in the medical field. For example, lidocaine (eg, kilosicaine®) used as a local anesthetic and antiarrhythmic agent is a voltage-gated sodium channel inhibitor. A voltage-dependent calcium channel inhibitor gabapentin (for example, gabapen (registered trademark), neurontin (registered trademark)) is used as an anticonvulsant or analgesic. Occasionally, inhibitors of voltage-gated calcium channels or sodium channels (for example, valapamil) have been reported to increase the skin's tolerance threshold against external attack and can be applied to skin hypersensitivity (Patent Document 1).

  Inhibiting the sensory nerve's voltage-gated cation channel not only provides a sensory suppression effect for medical purposes, but also improves quality of life by suppressing or adjusting the sensitive or unpleasant sensations that are felt daily There is a possibility that you can.

  By the way, phthalide analogues are widely used as dyes for heat-sensitive recording materials. Among these, pharmacological agents such as anti-inflammatory disorder treatment compounds (Patent Document 2) and oncogenic drug sensitivity-enhancing compounds (Patent Document 3). What has an effect | action is known. Moreover, the manufacturing method of such a phthalide analog is disclosed by patent documents 4 and 5, and nonpatent literature 3-6, for example.

  However, it is not known that phthalide analogs have a voltage-dependent channel inhibitory action.

JP-T-2002-505268 Special table 2008-542226 gazette Special table 2009-511436 gazette Japanese Patent Laid-Open No. 07-206843 Japanese Patent Laid-Open No. 04-077480

Tominaga Makoto, (2006), Experimental Medicine, vol.24, No.15: 54-59 Masahiko Toyoda, (2004), Sogo Clinical, Vo.53, No.5: 1629-1636 Li, Shaobai et al., Lanzhou Daxue Xuebao, Ziran Kexueban (1990), 26 (1), pp118-19 Ogawa, Y et al., Heterocycles, (1991), 32 (9), pp 1737-1744 Kobayashi, M et al., Chem pharm bull, (1987), 35 (4), pp 1427-1433 Cocker, W et al., Chemical Communications, (1965), 20, pp 479-80

  The present invention relates to a voltage-gated cation channel inhibitor that can be used for suppression or adjustment of sensation, or reduction of daily sensitive sensation or unpleasant sensation.

  As a result of searching for substances that can effectively inhibit a voltage-gated channel and can be used for suppression or regulation of sensation, the present inventors have found that a phthalide analog represented by the following formula is effective in inhibiting a voltage-gated channel. It was found that the effect was recognized.

  That is, the present invention relates to the following 1) to 5).

  1) The following formula (1)

[Ring A represents a saturated, partially unsaturated or completely unsaturated 6-membered ring, and X represents C═CH—R ¹ (wherein R ¹ represents an alkyl group having 1 to 12 carbon atoms) Or CR ² R ³ (wherein R ² represents an alkyl group having 1 to 12 carbon atoms, R ³ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), and R ⁴ and R ⁵ represent Each is the same or different and represents a hydrogen atom or a hydroxyl group. ] The voltage-dependent cation channel inhibitor which uses the phthalide analog represented by this as an active ingredient.

2) The voltage-gated cation channel inhibitor as described above, wherein R ¹ and R ² are linear alkyl groups having 3 to 8 carbon atoms.
3) The voltage-gated cation channel inhibitor as described above, wherein R ³ is a hydrogen atom.
4) The voltage-gated cation channel inhibitor as described above, wherein R ⁴ and R ⁵ are each a hydrogen atom or a hydroxyl group.
5) The voltage-dependent cation channel inhibitor as described above, wherein the phthalide analog is 3-butylphthalide, 3-octylphthalide, 3-butylidenephthalide, sedanolide, sencunolide H or sencunolide I.

  The voltage-gated cation channel inhibitor of the present invention is useful not only in the field of pharmaceuticals but also in the field of foods, cosmetics, household products, etc. by effectively suppressing or adjusting various sensations. Sensations or unpleasant sensations can be reduced.

The measurement experimental data of the voltage-dependent cation channel activity suppression ability by a test substance are shown. The inward current suppression rate of each phthalide analog is shown. The inward current suppression rate of each phthalide analog is shown. The correlation of a voltage-dependent cation channel inhibitory activity rate and a masking score is shown.

  Examples of the ring A include a benzene ring, a cyclohexadiene ring, a cyclohexene ring, and a cyclohexane ring. Among these, a benzene ring and a cyclohexene ring are preferable.

The alkyl group having 1 to 12 carbon atoms represented by R ¹ and R ² includes a straight chain or branched chain group, preferably an alkyl group having 1 to 10 carbon atoms, and further having 2 to 9 carbon atoms. Straight chain alkyl groups are preferred. Examples of the alkyl group represented by R ¹ and R ² include an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, an isopropyl group, an isobutyl group, and a sec-butyl group. , Tert-butyl group, isopentyl group, neopentyl group and the like.
Among these, a linear alkyl group is preferable, a linear alkyl group having 3 to 8 carbon atoms is more preferable, and a propyl group and a butyl group are more preferable.

Moreover, as a C1-C5 alkyl group shown by R < ³ >, a linear or branched thing is included. Examples of the alkyl group represented by R ³ include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group and tert-butyl group, isopentyl group and neopentyl group. Etc.
When R ³ is an alkyl group having 1 to 5 carbon atoms, preferably a linear alkyl group having 1 to 4 carbon atoms, more preferably a methyl group, R ² is an alkyl group having 1 to 8 carbon atoms. Of these, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl and isopentyl are preferred.
When R ³ is a hydrogen atom, R ² is preferably a linear alkyl group having 1 to 8 carbon atoms, more preferably a linear alkyl group having 3 to 8 carbon atoms, and a butyl group. Is preferred.
R ³ is preferably a hydrogen atom and a linear alkyl group having 1 to 4 carbon atoms, more preferably a hydrogen atom.

R ⁴ and R ⁵ are each preferably a hydrogen atom or each preferably a hydroxyl group. Further, the steric coordination of the hydroxyl group may be either α configuration or β configuration, but it is preferable that either one is α configuration and the other is β configuration.

  The compound represented by the above formula (1) includes an optical isomer, but any isomer or racemate may be used.

  Of the above formula (1), the following compounds 1 to 6, 8 and 9 are preferred, compounds 1 to 6 are more preferred, compounds 1 to 3 and 6 are still more preferred, in terms of potential-dependent channel inhibitory action, 1, 2 and 6 are even more preferred.

The compound represented by the above formula (1) can be produced mainly by known chemical synthesis (Patent Documents 4 to 5 and Non-Patent Documents 3 to 6). For example, as disclosed in Non-Patent Document 3, alkylidene phthalide (for example, Compound 2) can be obtained from phthalic anhydride, fatty acid anhydride, and NaOAc by a condensation reaction, and further, alkylidene phthalide is converted into Pd / C. Is used as a catalyst to obtain an alkyl phthalide (for example, Compound 1).
In addition, the compound represented by the above formula (1) may be a commercially available product or may be extracted / isolated from a plant.

1) In the case of formula (1) [ring A is a benzene ring, X is CR ² R ³ (where R ³ is a hydrogen atom) and R ⁴ and R ⁵ are hydrogen atoms], phthalic anhydride and fatty acid anhydride, NaOAc From the 3-alkylidene phthalide, a 3-alkylidene phthalide is synthesized and reduced using Pd / C as a catalyst (Non-patent Document 3).

2) In the case of formula (1) [ring A is a benzene ring, X is CR ² R ³ (where R ³ is an alkyl group) and R ⁴ and R ⁵ are hydrogen atoms], by phthalic anhydride and Grignard reagent, Or it can manufacture from an acylbenzoic acid and a Grignard reagent (patent document 4).

3) In the case of formula (1) [ring A is a benzene ring, X is C═CH—R ¹ and R ⁴ and R ⁵ are hydrogen atoms], it can be produced from phthalic anhydride, anhydrous fatty acid, NaOAc by a condensation reaction. Yes (Non-Patent Document 3).

4) In the case of formula (1) [ring A is a benzene ring, X is CR ² R ³ (where R ³ is a hydrogen atom) and R ⁴ and R ⁵ are hydroxyl groups), for example, 3-butyl-6,7 A methyl group is eliminated from dimethoxyphthalide with boron tribromide to produce 3-butyl-6,7-dihydroxyphthalide (Patent Document 5), which can be produced according to this.

5) In the case of formula (1) [ring A is a benzene ring, X is C═CH—R ¹ and R ⁴ and R ⁵ are hydroxyl groups], for example, 3-butylidene-6,7-dimethoxyphthalide to boron tribromide The methyl group can be eliminated by the above, and 3-butylidene-6,7-dihydroxyphthalide can be produced (Non-patent Document 4), and can be produced according to this.

6) In the case of formula (1) [ring A is a partially unsaturated 6-membered ring, X is C═CH—R ¹ and R ⁴ and R ⁵ are hydroxyl groups], for example, from ligustilide to m-chloroperbenzoic acid Sencunolide H (Compound 4a) can be produced by synthesizing a 6,7-epoxy compound and hydrolyzing with 6,7-epoxy compound with perchloric acid (Non-Patent Document 5). it can.

7) In the case of formula (1) [ring A is a partially unsaturated 6-membered ring, X is CR ² R ³ (where R ³ is a hydrogen atom) and R ⁴ and R ⁵ are hydroxyl groups), for example, sencunolide Senkyunolide J (compound 5a) can be produced by synthesizing a 6,7-epoxy compound from A with m-chloroperbenzoic acid and hydrolyzing the 6,7-epoxy compound with perchloric acid (Non-patent Document 5). So it can be manufactured according to this

8) In the case of formula (1) [ring A is a partially unsaturated 6-membered ring, X is CR ² R ³ (where R ³ is a hydrogen atom) and R ⁴ and R ⁵ are hydrogen atoms), for example, pentadione Ethyl 2-formylcyclohex-5-enoate was synthesized from ethyl acetate and acrolein, and then treated with Ethyl 2-formylcyclohex-5-enoate and BuMgBr to treat kunidylide and cnidylide with Al ₂ O ₃ to produce sedanolide (compound 6 ) Can be manufactured (Non-Patent Document 6), and can be manufactured according to this.

  The voltage-gated cation channel inhibitor according to the present invention may contain only one of the compounds of the present invention, or may contain two or more.

  As shown in the Examples below, the compound of the present invention suppresses the electrical activity generated by the voltage-gated cation channel of living body-derived receptor cells, in other words, can suppress the generation and transmission of nerve action potentials, That is, since it has a potential-dependent cation channel inhibitory action, it can be used to suppress or adjust various sensations of an organism. For example, inhibition of sodium or calcium channels in the skin peripheral nervous system can increase the skin tolerance threshold (Patent Document 1). As shown in the examples below, since the correlation between the voltage-dependent cation channel inhibition rate and the masking score (unpleasant odor) is recognized, the plant of the present invention or its extract is used for masking unpleasant odor. You can also.

  Here, the “skin tolerance threshold” exceeds the value of the skin against external stimuli, a sign of sensory failure, ie a more or less painful sensation in the skin area, eg stinging, tingling pain, itching or pruritus, It means the excitability threshold of the skin that causes a reaction with burns, warmth, discomfort, severe pain and / or redness or erythema.

  In addition, “external stimuli” include, for example, compounds having stimulating properties such as surfactants, preservatives, and fragrances, and the environment, food, wind, friction, shaving, soap, hard water with high calcium concentration, temperature change, yarn, etc. Means.

Here, the inhibition of the voltage-dependent cation channel in the present invention refers to inhibiting the inflow of ions from the voltage-dependent cation channel into the cell. Examples of the voltage-gated cation channel inhibited in the present invention include voltage-gated Na ⁺ channel, voltage-gated K ⁺ channel, and voltage-gated Ca ²⁺ channel. Among these, voltage-gated Ca ²⁺ channels can be further classified into L-, N, P-, Q-, R-, and T-type based on electrophysiological and pharmacological properties. Are both targets of the compounds of the present invention.

  In addition, the various sensations that are suppressed or adjusted include somatic sensations including tactile sensation, pressure sensation, warm sensation, cold sensation, pain sensation, and sensations from muscles, tendons, and joints; Visceral sensations including sensations and visceral pain; special sensations including vision, hearing, taste, olfaction and balance sensation; and other sensations (eg, pruritus, numbness, neuralgia, pain, other discomfort, etc.). Any of these sensations can be suppressed, reduced or improved by voltage-dependent cation inhibitors. These various sensations are often more sensitive to stimuli and exhibit unpleasant symptoms such as hypersensitivity, or hyperalgesia, allodynia, and hypersensitivity to the skin such as itching. If the voltage-gated cation channel is inhibited, it can be used for the prevention, amelioration, or treatment of symptoms caused by increased peripheral sensory nerve activity among these symptoms.

  Cutaneous hyperalgesia is a sensory abnormality in which the sensation of pain is enhanced and the stimulus that causes pain becomes stronger. Allodynia is a sensory abnormality that is recognized as pain even if the stimulus does not normally cause pain. That is, itching sensitivity is a sensory abnormality that feels itching even for stimuli that do not usually feel itching.

  Therefore, the compound of the present invention can be used as a voltage-dependent cation channel inhibitor, a hypersensitivity improving agent, and a masking agent (hereinafter, also referred to as “voltage-dependent cation channel inhibitor etc.”). It can be used to produce a cationic cation channel inhibitor or the like.

  Therefore, the voltage-gated cation channel inhibitor of the present invention is a drug, quasi-drug, cosmetic, house care product, food, functional food or feed for voltage-gated cation channel inhibition, hypersensitivity improvement or masking. It is useful as a raw material or a preparation for blending with these medicines and the like.

  Examples of pharmaceuticals, quasi drugs or other compositions containing the compound of the present invention include anesthetics, sedatives, analgesics, antitussives, anti-inflammatory agents, hypersensitivity and allergic reactions used in the medical or veterinary field. Drugs and quasi-drugs, such as anti-sensation agents such as excessive sensation, anti-itch, medicine for pain clinics, and olfactory depressant with aspiration and nasal nose used in nursing care and travel; anti-fungal agents, liquid-type clothing Antibacterial finishing agent, clothing detergent, clothing softener, clothing bleach, residential detergent, drain cleaner, bathroom cleaner, toilet cleaner, toilet deodorant cleaner, washing machine detergent, kitchen cleaner House care products such as detergents, dishwashing agents, deodorants, etc .; bathing agents and cosmetics that suppress skin hypersensitivity, toothpaste and mouthwash that suppress hypersensitivity, wet tissues, antiperspirants, wipes Etc. Medicare products, and the like.

  Examples of pharmaceuticals, quasi drugs or other compositions containing the compound of the present invention include anesthetics, sedatives, analgesics, antitussives, anti-inflammatory agents, hypersensitivity and allergic reactions used in the medical or veterinary field. Drugs and quasi-drugs, such as anti-sensation agents such as excessive sensation, anti-itch, medicine for pain clinics, and olfactory depressant with aspiration and nasal nose used in nursing care and travel; anti-fungal agents, liquid-type clothing Antibacterial finishing agent, clothing detergent, clothing softener, clothing bleach, residential detergent, drain cleaner, bathroom cleaner, toilet cleaner, toilet deodorant cleaner, washing machine detergent, kitchen cleaner House care products such as detergents, dishwashing agents, deodorants, etc .; bathing agents and cosmetics that suppress skin hypersensitivity, toothpaste and mouthwash that suppress hypersensitivity, wet tissues, antiperspirants, wipes Etc. Medicare products, and the like.

  The pharmaceutical and quasi-drug containing the compound of the present invention can be administered in any dosage form depending on the target sensation or the target or body part to be targeted. The target sensation is as described above, and examples of the target and body part to be targeted include living bodies and tissues, organs and cells derived from living bodies.

  Examples of the dosage form include oral administration and parenteral administration. Dosage forms for oral administration include solid dosage forms such as tablets, coated tablets, granules, powders, capsules, or liquid dosage forms such as elixirs, syrups and suspensions. Routes for parenteral administration include injection, infusion, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, etc., and dosage forms include tablets, capsules, liquids, powders, Granules, ointments, sprays, mists, creams, emulsions, gels, pastes, lotions, pops, plasters, sticks, sheets and the like.

  In the above preparation, the compound of the present invention may be used in combination with any other component, if necessary. Preferred other ingredients include pharmaceutically acceptable carriers. Specific examples of pharmaceutically acceptable carriers include excipients, binders, disintegrants, lubricants, diluents, osmotic pressure adjusting agents, pH adjusting agents, emulsifiers, preservatives, stabilizers, oxidation Inhibitors, colorants, ultraviolet absorbers, humectants, thickeners, brighteners, activity enhancers, flavoring agents, flavoring agents and the like can be mentioned. The voltage-gated cation channel inhibitor of the present invention is further used in combination with other known medicinal ingredients (for example, other ion channel inhibitors, sensory suppression or regulators, anti-inflammatory agents, fungicides, etc.). Also good.

  The compounding amount of the voltage-dependent cation channel inhibitor of the present invention in pharmaceuticals, quasi-drugs, other compositions and the like varies depending on the use form and purpose, but for example, when used for sensory suppression, it is usually 0.01. -50 mass%, preferably 0.1-10 mass%, more preferably 0.1-5 mass%.

  The food and feed containing the present invention include, for example, breads, noodles, confectionery, jelly, dairy products, frozen foods, instant foods, processed starch products, processed meat products, other processed foods, beverages and soups. Foods such as seafood, seasonings and dietary supplements; livestock feed for cattle, pigs, chickens, sheep, horses, etc., feed for small animals for rabbits, rats, mice, etc., tuna, eel, Thailand, hamachi, shrimp, etc. And feed for fish and shellfish used for food, and feed for pet food used for dogs, cats, small birds, squirrels and the like.

  In the above food and feed, the compound of the present invention may be used in combination with any other component, if necessary. Preferred other components include carriers that are acceptable in the food and feed fields. Specific examples of such acceptable carriers include solvents, softeners, fats and oils, emulsifiers, preservatives, fragrances, stabilizers, colorants, UV absorbers, antioxidants, humectants, thickeners, gelling. Agents, shape-preserving agents, pH adjusters, seasonings, preservatives, nutritional supplements and the like.

  The form of food and feed is not particularly limited, but in addition to liquid, semi-solid and solid forms, tablets, pills, capsules, liquids, syrups, powders and granules similar to those for oral administration It may be in the form of an agent or the like.

Moreover, although content of this invention compound in a foodstuff or feed changes with the usage forms, it is 0.001-50 mass% normally in dry matter conversion, 0.01-10 mass% is preferable, 0 More preferably, the content is 1 to 5% by mass.
When the compound of the present invention is used as a pharmaceutical or in combination with a pharmaceutical, the dosage may vary according to the patient's condition, body weight, sex, age or other factors, but the daily dose per adult for oral administration The dose of is usually preferably 0.001 to 100 g as the compound of the present invention. Moreover, although the said formulation can be administered according to arbitrary administration schedules, it is preferable to divide once to several times a day, and to administer continuously for several weeks to several months.

  Hereinafter, examples and test examples will be given to specifically describe the present invention, but the present invention is not limited to these examples.

[Phthalide analogues]
Compound 1a: 3-Butylphthalide [3-Butylphthalide: 3-Butylisobenzofuran-1 (3H) -one] S form (Production examples are described later)
Compound 1b: 3-Butylphthalide [3-Butylphthalide: 3-Butylisobenzofuran-1 (3H) -one] R form (Production example will be described later)
Compound 2: 3-Butylidenephthalide [3-Butylidenephthalide: 3-butylideneisobenzofuran-1 (3H) -one] (Purchased by: Wako Pure Chemical Industries, Ltd.)
Compound 3: 3-octylphthalide [3-Octylphthalide: 3-octylisobenzofuran-1 (3H) -one] S form (supplier: Kao)
Compound 4a: Senkyunolide H: (3Z, 6S) -3-butylidene 4,5,6,7-tetrahydro-6α, 7α-dihydroxyisobenzofuran-1 (3H) -one] (Production examples will be described later)
Compound 4b: Senkyunolide I: (3Z, 6S) -3-butylidene-4,5,6,7-tetrahydro-6α, 7β-dihydroxyisobenzofuran-1 (3H) -one] (Production examples will be described later)
Compound 5a: Senkyunolide J [rel-3α ^* -butyl-4,5,6,7-tetrahydro-6α ^* , 7β ^* -dihydroxy-1 (3H) -isobenzofuranone] (Production examples will be described later)
Compound 5b: Senkyunolide N [(3S) -4,5,6,7-tetrahydro-6α, 7β-dihydroxy-3β-butylisobenzofuran-1 (3H) -one] (Production examples will be described later)
Compound 6: sedanolide (neocnidilide) (Production examples are described later)
Compound 7: 3,3-dimethylphthalide (Production examples are described later)
Compound 8: 3-methyl-3-ethylphthalide (Production examples are described later)
Compound 9: 3-methyl-3-hexylphthalide (Production examples are described later)
Compound 10: 3,3-dibutylphthalide (Production examples are described later)
Compound 11: 3-methyl-3-octylphthalide (Production examples are described later)
Compound 12: 3,3-diisopentylphthalide (Production examples are described later)

Production Example 1: Production of Compounds 1a and 1b A mixture of 60 g of phthalic anhydride, 79.3 g of valeric anhydride, and 21 g of sodium acetate was heated at 170 ° C. for 7 hours, and after treatment, butylidenephthalide was obtained by distillation under reduced pressure. . This butylidene phthalide was dissolved in ethanol, 5% Pd / C (2 g, 5 wt%) was added, hydrogenated at a hydrogen pressure of 40 atm for 2 hours, and after filtration, 39.6 g of 3-butyl phthalide was obtained by distillation under reduced pressure. . The obtained 3-butylphthalide was optically resolved with an optical resolution column (Chiral Cell OB, hexane: isopropyl alcohol = 9: 1) to obtain S form (1a) and R form (1b).

¹ H NMR data (CDCl ₃ ) δ of the obtained Compound S form (1a): 0.87 (t, 3H, J = 6.8 Hz), 1.29-1.49 (m, 4H), 1.73 (m, 1H), 2.01 ( m, 1H), 7.42 (dd, 1H, J = 7.5, 1.0Hz), 7.49 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.64 (ddd, 1H, J = 7.5, 7.5, 1.0Hz) , 7.85 (dd, 1H, J = 7.5, 1.0 Hz) / [α] _D : −71
¹ H NMR data (CDCl ₃ ) δ of the obtained Compound R form (1b): 0.87 (t, 3H, J = 6.8 Hz), 1.29-1.49 (m, 4H), 1.73 (m, 1H), 2.01 ( m, 1H), 7.42 (dd, 1H, J = 7.5, 1.0Hz), 7.49 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.64 (ddd, 1H, J = 7.5, 7.5, 1.0Hz) , 7.85 (dd, 1H, J = 7.5, 1.0 Hz) / [α] _D : +71

Production Example 2: Production of compounds 4a, 4b, 5a and 5b 200 g of Cnidium officinale obtained from Shinwa Bussan Co., Ltd. was extracted with 2 L of 50 vol% ethanol for 2 weeks at room temperature to obtain 1.8 L of an extract. It was. The extract was concentrated with a rotary evaporator to obtain about 10 g of a solid. 10 g of solid matter was added to Yamazen Hi-Flash column (injection column: L size, main column 3 L size, A: hexane, B: ethyl acetate, 0% B → 100% B (400 min) → 100% B (500 min), 10 mL) / min, fractions of 100 mL each) were subjected to medium pressure silica gel chromatography to obtain about 1.5 g of a fraction containing dihydroxyphthalide (Fr. 11 and later, a fraction more polar than butylphthalide). A fraction containing 1.5 g of dihydroxyphthalide was subjected to ODS-HPLC fractionation (column: GL-Science, Inertsil-ODS, 10 × 250 mm, A: Water, B: MeOH, 15B% → 71% B (20 min) → 100% B (20.1min) → 100% B (35min) → 15% B (35.1min) → 15% B (45min), 10mL / min, 40 ℃, UV280nm, 14.0 ~ 21.5min in 0.5min steps (5 mL / Fr.), Sample; 1.5 g / 1.8 mL EtOH, 100 μL each, repeated 18 times in total). The impurity fatty acid was removed from each fraction with activated alumina, and the NMR spectrum was measured. From a comparison with literature values, a 1: 1 mixture of sencunolide J and N was found to be Fr. 5 (5 mg), Sencunolide I was Fr. 8-9 (10 mg), Sencunolide H is Fr. It was confirmed that it was separated into 10 to 11 (5 mg).

Fr. ¹³ C NMR data of 5 compounds (mixture of sencunolide J and N); (13.8, 13.8, 21.4, 21.8, 22.3, 22.4, 26.5, 26.7, 26.7, 27.0, 31.8, 31.8, 68.0, 68.6, 71.6, 71.9, 82.7 , 82.8, 126.2, 126.3, 165.6, 165.8, 172.4, 172.5 ppm)
Fr. ¹³ C NMR data of 8-9 compounds (sencunolide I); (13.8, 19.1, 22.2, 26.6, 28.1, 67.8, 71.8, 114.7, 125.0, 147.9, 153.1, 169.2 ppm)
Fr. ¹³ C NMR data of 10 to 11 compounds (sencunolide H); (13.8, 18.2, 22.3, 25.7, 28.1, 63.5, 67.1, 114.6, 125.2, 148.2, 153.2, 169.4 ppm)

Production Example 3 Production of Compound 6 (Sedanolide [Neocnidilide]) According to the reference (Agric. Biol. Chem., 51 (12), pp 3369-3373, 1987), (±) -1-hepten-3-ol and (S) -triene ester is synthesized from 2,4-pentadienoic acid and heated in toluene at 220 ° C for 24 hours using 4.4'-thiobis (2-tert-butyl-5-methylphenol) as a catalyst. Diels-Alder reaction was performed to obtain a cyclized product. Thereafter, the cyclized product was refluxed in tetrahydrofuran with 1,8-diazabicyclo [5.4.0] undec-7-ene for 24 hours, and the main product was separated from the reaction solution by TLC fractionation (developing solvent hexane: ethyl acetate = 7 : 3) Compound 6 (sedanolide [neocnidilide]) was obtained.
¹³ C NMR data of Compound 6; (13.7, 22.3, 26.7, 34.3, 81.3, 121.7, 125.5, 126.0, 128.9, 133.9, 150.0, 170.6 ppm)

Production Example 4: Production of Compounds 7 to 12 Synthesis of Compound 7 (3,3-dimethylphthalide) 20 mL of dry diethyl ether was added to 3.78 g (155 mmol) of dry metal magnesium in a 500 mL capacity four-necked flask under a nitrogen atmosphere. added. Methyl iodide (21.1 g, 148 mmol) in 20 mL of dry diethyl ether was added dropwise at room temperature over 30 minutes. After stirring at room temperature for 30 minutes, 10.0 g (67.5 mmol) of phthalic anhydride in 80 mL of dry THF was added over 40 minutes. It was dripped. The solution was stirred at 60 ° C. for 1.5 hours, 40 mL of concentrated hydrochloric acid was added at room temperature, and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was poured into 150 mL of water, the organic phase was separated, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was subjected to silica gel column chromatography, and hexane / ethyl acetate (20/3) was used as a developing solution to obtain 6.3 g (yield 57.5%) of 3,3-dimethylphthalide.

¹ H NMR data (CDCl ₃ ) δ of the obtained compound 7: 1.67 (s, 6H), 7.41 (dd, 1H, J = 7.5, 0.7 Hz), 7.51 (ddd, 1H, J = 7.5, 7.5, 0.7 Hz), 7.67 (ddd, 1H, J = 7.5, 7.5, 0.9 Hz), 7.87 (dd, 1H, J = 7.5, 0.9 Hz)

Synthesis of Compound 8 (3-methyl-3-ethylphthalide) 5 mL of dry THF was added to 0.34 g (14.0 mmol) of dry metal magnesium in a 100 mL 4-neck flask under a nitrogen atmosphere. 1.46 g (13.4 mmol) of ethyl bromide in 10 mL of dry THF at room temperature was added dropwise over 10 minutes, stirred at room temperature for 10 minutes, and then 1.0 g (6.09 mmol) of o-acetylbenzoic acid in 10 mL of dry THF was added. Dropped in minutes. The solution was stirred at 60 ° C. for 1.5 hours, 10 mL of concentrated hydrochloric acid was added at room temperature, and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was poured into 150 mL of water, the organic phase was separated, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was subjected to silica gel column chromatography, and hexane / ethyl acetate (3/1) was used as a developing solution to obtain 0.86 g (yield: 80.1%) of 3-methyl-3-ethylphthalide.

¹ H NMR data (CDCl ₃ ) δ of the obtained compound 8: 0.77 (dt, 3H, J = 7.4, 1.5 Hz), 1.65 (ds, 3H, J = 1.5 Hz), 1.83-2.19 (m, 2H), 7.38 (dd, 1H, J = 7.5, 0.8Hz), 7.52 (ddd, 1H, J = 7.5, 7.4, 0.8Hz), 7.68 (ddd, 1H, J = 7.5, 7.4, 1.1Hz), 7.88 (dd, 1H, J = 7.5, 0.8Hz)

Synthesis of Compound 9 (3-methyl-3-hexylphthalide) Under a nitrogen atmosphere, 20 mL of dry THF was added to 1.70 g (69.9 mmol) of dry metal magnesium in a 200 mL capacity four-necked flask. 11.1 g (67.0 mmol) of hexyl bromide in 20 mL of dry THF at room temperature was added dropwise over 10 minutes. After stirring for 10 minutes at room temperature, 5.0 g (30.5 mmol) of o-acetylbenzoic acid in 30 mL of dry THF was added. Dropped in minutes. The solution was stirred at 60 ° C. for 2 hours, 20 mL of concentrated hydrochloric acid was added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. The reaction solution was poured into 150 mL of water, the organic phase was separated, extracted with ethyl acetate, washed with saturated brine, and concentrated. Hexanol produced as a by-product was removed by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, hexane / ethyl acetate (30/1) was used as a developing solution, and 5-methyl-3-hexylphthalide was added to 5 .70 g (yield 80.4%) was obtained.

¹ H NMR data (CDCl ₃ ) δ of the obtained compound 9: 0.83 (t, 3H, J = 6.9 Hz), 1.19-1.33 (br, 8H), 1.64 (s, 3H), 1.74-2.11 (m, 2H), 7.37 (dd, 1H, J = 7.5, 1.0 Hz), 7.50 (ddd, 1H, J = 7.5, 7.5, 1.0 Hz), 7.67 (ddd, 1H, J = 7.5, 7.5, 1.0 Hz), 7.67 (ddd, 1H, J = 7.5, 7.5,1.0Hz), 7.87 (dd, 1H, J = 7.5, 1.0Hz)

Synthesis of Compound 10 (3,3-dibutylphthalide) 3.22 g (20 mmol) of nBuMgCl reagent was added dropwise to a THF solution of 1.48 g (10 mmol) of phthalic anhydride, and after acidification, the low boiling point component was distilled under reduced pressure. The residue was removed by silica gel column chromatography, and hexane / ethyl acetate (30/1) was used as a developing solution to obtain 1.48 g (yield 60.2%) of 3,3-dibutylphthalide.

¹ H NMR data (CDCl ₃ ) δ of the obtained compound 10: 0.85 (t, 6H, J = 6.8 Hz), 1.20-1.40 (br, 8H), 1.80-2.20 (m, 4H), 7.37 (dd, 1H, J = 7.5, 1.0Hz), 7.50 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.67 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.87 (dd, 1H, J = (7.5, 1.0Hz)

Synthesis of Compound 11 (3-methyl-3-octylphthalide) 5 mL of dry THF was added to 0.34 g (14.0 mmol) of dry metal magnesium in a 200 mL capacity four-necked flask under a nitrogen atmosphere. 2.59 g (13.4 mmol) of octyl bromide in 10 mL of dry THF at room temperature was added dropwise over 10 minutes. After stirring for 10 minutes at room temperature, 1.0 g (6.09 mmol) of o-acetylbenzoic acid in 10 mL of dry THF was added. Dropped in minutes. The solution was stirred at 60 ° C. for 1.5 hours, 10 mL of concentrated hydrochloric acid was added at room temperature, and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was poured into 150 mL of water, the organic phase was separated, extracted with ethyl acetate, washed with saturated brine, and concentrated. Octanol produced as a by-product was removed by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, hexane / ethyl acetate (30/1) was used as a developing solution, and 3-methyl-3-octylphthalide was 1 Obtained .32 g (yield 83.2%).

¹ H NMR data (CDCl ₃ ) δ of the obtained compound 11: 0.85 (t, 3H, J = 6.8 Hz), 1.20 (br, 12H), 1.64 (s, 3H), 1.74-2.09 (m, 2H) 7.37 (dd, 1H, J = 7.5, 1.0Hz), 7.50 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.67 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.87 (dd , 1H, J = 7.5, 1.0Hz)

Synthesis of Compound 12 (3,3-diisopentylphthalide) To a THF solution of 1.48 g (10 mmol) of phthalic anhydride, 3.86 g (22 mmol) of iPeMgCl reagent was dropped, and after acidification, the low boiling point component was reduced in pressure. The residue was removed by distillation, and silica gel column chromatography was used. Hexane / ethyl acetate (30/1) was used as a developing solution, and 1.86 g of 3,3-dibutylphthalide (yield 67.9%). )Obtained.

¹ H NMR data (CDCl ₃ ) δ of the obtained compound 12: 0.72 (m, 2H), 0.78 (d, 6H, J = 6.6 Hz), 0.80 (d, 6H, J = 6.6 Hz), 1.13 (m , 2H), 1.43 (m, 2H), 1.85 (m, 2H), 2.04 (m, 2H), 7.31 (dd, 1H, J = 7.5, 1.0Hz), 7.50 (ddd, 1H, J = 7.5, 7.5 , 1.0Hz), 7.65 (ddd, 1H, J = 7.5, 7.5, 1.0Hz), 7.86 (dd, 1H, J = 7.5, 1.0Hz)

Test Example 1: Voltage-dependent cation channel inhibitory effect confirmation test Isolation of olfactory cells Olfactory cells were isolated according to a method known from Kakarai Mori (Kurahashi et al., J. Physiol. (1989), 419: 177-192) and immersed in normal Ringer's solution. To briefly show the isolation method, a double piss is applied to a newt hibernated in ice water, the skull is cut open, and the olfactory mucosa is removed. The removed olfactory mucosa was incubated in a 0.1% collagenase solution at 37 ° C. for 5 minutes to wash away the collagenase, and the tissue was crushed with a glass pipette to isolate cells. As normal Ringer's solution, NaCl 110 mM, KCl 3.7 mM, CaCl ₂ 3 mM, MgCl ₂ 1 mM, glucose 15 mM, sodium pyruvate 1 mM, HEPES 10 mM, phenol red 0.001% (w / v), pH 7.4 ( Adjusted with NaOH).

2. Measurement of electrical activity [A. Setting] Membrane currents were measured after the isolated olfactory cells were fixed by whole cell recording (Kawai et al., J. Gen. Physiol. (1997), vol. 109: 265-272). The electrode was prepared using a borosilicate glass capillary (diameter 1.2 mm) with an electrode creation puller (P-97, SUTTER INSTRUMENT CO.) (Electrode resistance around 6.0 MΩ). The electrode solution and silver-silver chloride wire were inserted into the electrode, and the silver-silver chloride wire was connected to a patch clamp amplifier (EPC10, HEKA) to fix the membrane potential and stimulate depolarization.
As the solution in the electrode, CsCl 119 mM, HEPES 10 mM, CaCl ₂ 1 mM, EGTA 5 mM, phenol red 0.001% (w / v), pH 7.4 (adjusted with CsOH) were used.
The membrane current was recorded by a computer (IBM compatible machine) connected to a patch clamp amplifier (Sampling frequency, 1 kHz), and Patch Master software (HEKA) was used for measurement and analysis. A pressure control device was used for the addition (spraying) of the test substance.
The pressure control device is a device that decompresses compressed air sent from an air compressor to an arbitrary pressure by computer control, and sends the compressed air to a glass pipette tail filled with a test substance for a set time ( Ito et al., Physiological Journal of Japan, 1995, vol.57, 127-133).

  [B. Procedure] In order to investigate the influence of the test substance (butylphthalide) on the voltage-dependent cation channel activity, the membrane potential of the isolated olfactory cells was fixed at -90 mV, and the membrane potential was -20 mV for 20 milliseconds at 200 millisecond intervals. The peak intensity of the inward current generated immediately after depolarization (FIG. 1, | a | = [inward current value generated immediately after depolarization] − [baseline value]) was measured. A glass in which the test substance (2% solution / solvent: ethanol) is mixed in an amount of 20 or 5 μL per mL of normal Ringer solution while the depolarization stimulation is repeated, and is set so that the tip comes near the olfactory cell (10 μm) Added to olfactory cells by spraying through a pipette (tip diameter 1 μm) (650 milliseconds, pressures 100 kPa and 50 kPa), and accompanying inward current change (FIG. 1, | b | = [when peak intensity is most suppressed) Inward current value]-[baseline value]). This spraying was performed 5 times in succession. Further, the average value A of the inward current peak intensity (a) generated by depolarization immediately before the addition of the extract is calculated, and the average value B of the inward current peak intensity (b) generated by depolarization immediately after the addition of the extract is calculated. did.

  During the test, the olfactory receptor responds rarely with the addition of the test substance, and an inward current derived from the CNG channel is observed, but this case was excluded. This case is thought to be caused by the test substance acting as an agonist of the olfactory receptor on the olfactory cells used in the test. The CNG channel current can be easily distinguished from the voltage-dependent channel current due to its strength, peak shape, duration, and the like.

  This measurement was performed in the same manner using new olfactory cells, replacing butylphthalide with other phthalide analogs.

  [D. Results] In the following equations, “B: average value of inward current value (b) when peak intensity is most suppressed” and “A: inward current value generated immediately after depolarization immediately before addition of test substance (a ) "Inward current inhibition rate (%)" was calculated from the "average value", and based on this result, the ability to inhibit the electrical activity of the voltage-dependent cation channel by the addition of each test substance was evaluated. In addition, a component with a higher inward current suppression rate has a higher potential-dependent cation channel inhibition effect.

  Inward current suppression rate (%) = [1- (A / B)] × 100

  The inward current suppression rate of each phthalide analog is shown in FIGS.

Reference example: Correlation between voltage-dependent channel inhibitory action and masking effect As shown in FIG. 4 and Table 2, there is a correlation between the inward current inhibition rate (%) and the masking score, so there is a potential dependence. A component having a strong cation channel inhibitory action is useful as a masking material for unpleasant odors.

[Sensory evaluation test]
An olfactory masking test for sensory evaluation was performed on 20 panelists. As a malodorous substance, 1% isovaleric acid was used, and as a control, 1,8-cineole, which is known to have an effect of reducing olfactory sensitivity to malodor, was used.
2 μL of bad odor and 4 μL of the test solution of the evaluation compound having a concentration of 0.1% shown in Table 2 were soaked in separate cotton balls (diameter 1 cm) and volatilized at room temperature for 12 hours in separate 50 mL syringes. The isovaleric acid vaporized in the syringe and the evaluation compound were poured into a PP container (capacity 500 mL) with a lid and mixed.
In the evaluation, the paneler himself opened the lid of the PP container slightly, sniffed the smell in the container, and judged the masking strength against the smell of isovaleric acid.
The masking strength was evaluated by comparing the odor strength in the PP container into which only vaporized isovaleric acid was injected, and the following six levels of masking score. The results are shown in Table 2.

0: Not masked 1: Slight masking effect 2: Slight masking effect 3: Sufficient masking effect 4: Almost masked 5: Completely masked

Claims (5)

Following formula (1)

[Ring A represents a saturated, partially unsaturated or completely unsaturated 6-membered ring, and X represents C═CH—R ¹ (wherein R ¹ represents an alkyl group having 1 to 12 carbon atoms) Or CR ² R ³ (wherein R ² represents an alkyl group having 1 to 12 carbon atoms, R ³ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), and R ⁴ and R ⁵ represent Each is the same or different and represents a hydrogen atom or a hydroxyl group. ] The voltage-dependent cation channel inhibitor which uses the phthalide analog represented by this as an active ingredient. The voltage-gated cation channel inhibitor according to claim ^1, wherein R ¹ and R ² are linear alkyl groups having 3 to 8 carbon atoms. The voltage-gated cation channel inhibitor according to claim 1 or 2, wherein R ³ is a hydrogen atom. The voltage-dependent cation channel inhibitor according to any one of claims 1 to 3, wherein each of R ⁴ and R ⁵ is a hydrogen atom or a hydroxyl group.   The voltage-dependent cation channel inhibitor according to any one of claims 1 to 4, wherein the phthalide analog is 3-butylphthalide, 3-octylphthalide, 3-butylidenephthalide, sedanolide, sencunolide H, or sencunolide I. .

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