JP5294601B2 - TRPV4 receptor inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a TRPV4 receptor inhibitor which can mitigate or prevent pain caused by a nociceptive mechanical stimulus. <P>SOLUTION: The TRPV4 receptor inhibitor has a compound 1 represented by formula (1) as an active ingredient. The TRPV4 receptor inhibitor further comprises a compound 2 represented by formula (2). <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a TRPV4 receptor inhibitor containing a compound represented by formula (1) as an active ingredient.

  “Pain” is a very unpleasant sensation. Pain is broadly divided into physiological pain and patho-ecological pain, and pain caused by external stimuli such as mechanical stimulation, thermal stimulation, cold stimulation, and chemical stimulation (collectively referred to as noxious pain) The patho-ecological pain includes inflammatory pain, neuropathic pain, etc. (collectively referred to as chronic pain). Various types of pain act on different nociceptors in the living body, are converted into electrical stimulation by the nociceptors, are transmitted through nerves, and are perceived as “pain”.

  Because "pain" is uncomfortable, analgesic treatment is necessary, and various measures are taken. Although prevention is desired, improvement of lifestyle habits and appropriate exercise are only recommended.

In relieving and preventing this “pain”, it is necessary to appropriately cope with the cause. In particular, nociceptive mechanical stimulation is frequently encountered in daily life, and there is a need for drugs that can cope with it.
"Pain Physiology" Physiotherapy Chemistry 15,3 73-79 (2000) Mieko Kurosawa

  The main object of the present invention is to provide a TRPV4 receptor inhibitor capable of alleviating or preventing pain caused by noxious mechanical stimulation.

  Pain due to mechanical stimulation occurs through nociceptive receptors called TRPV4 receptors. As a result of intensive studies, the present inventors have found that Compound 1, which is known for its use as a non-steroidal anti-inflammatory agent, has a preventive effect against noxious mechanical stimulation. Inflammatory response pain is transmitted through prostanoid receptors and is different from the mechanical pain transmission pathway. It has been found for the first time that a compound represented by the following formula (1) (hereinafter sometimes referred to as compound 1) inhibits a TRPV4 receptor that transmits mechanical stimulation. Furthermore, the present inventors have found that when the compound represented by the following general formula (2) (hereinafter, sometimes referred to as compound 2) is used in combination with compound 1, this effect is further enhanced. The present invention has been completed as a result of further research based on such findings.

The present invention provides the following TRPV4 receptor inhibitors.
Item 1. A TRPV4 receptor inhibitor comprising a compound represented by the following formula (1) as an active ingredient.

Item 2. Furthermore, the TRPV4 receptor inhibitor of claim | item 1 containing at least 1 sort (s) of the compound represented by following General formula (2).

[In the formula (2), n represents 8 or 9, and m represents an integer of 17 to 19]
Item 3. Item 3. The TRPV4 receptor inhibitor according to Item 2, wherein the compound represented by the general formula (2) is contained in a total amount of 0.0005 to 4 parts by weight with respect to 1 part by weight of the compound represented by the formula (1).
Item 4. Item 4. The TRPV4 receptor inhibitor according to any one of Items 1 to 3, which is used for alleviating or preventing pain caused by mechanical stimulation.
Item 5. Item 5. An inhibitor of nociceptive pain comprising the TRPV4 receptor inhibitor according to any one of Items 1 to 4.
Item 6. Item 6. The inhibitor of nociceptive pain according to Item 5, wherein the content of the TRPV4 receptor inhibitor is 0.25 to 5% by weight in terms of the content of the compound represented by the formula (1).
Item 7. Item 7. The inhibitor of nociceptive pain according to Item 5 or 6, which is in the form of an external preparation for skin.

  According to the TRPV4 receptor inhibitor of the present invention, pain due to mechanical stimulation can be effectively suppressed.

  Furthermore, the TRPV4 receptor inhibitor of the present invention can be prepared in the form of a topical skin preparation in combination with various bases and the like, and is preferably used for pain relief (prevention) by mechanical stimulation more easily and effectively. can do.

  In addition, since the TRPV4 receptor inhibitor of the present invention has a rapid onset of effects, for example, for the purpose of preventing pain caused by mechanical stimulation such as a syringe needle by applying an appropriate amount to the skin in advance before injection or infusion. Can be used. Therefore, the TRPV4 receptor inhibitor of the present invention is useful for improving the quality of life (QOL) of patients who must be injected or infused daily.

(1) TRPV4 receptor inhibitor The TRPV4 receptor inhibitor of this invention contains the compound 1 represented by following formula (1) as an active ingredient.

  The above compound 1 has been conventionally used as a phenylacetic acid-based anti-inflammatory agent (prostanoid receptor inhibitor), but it has an inhibitory action on a TRPV4 receptor that transmits pain caused by mechanical stimulation for the first time by the present inventors. It was found.

  Compound 1 is commercially available from, for example, Wako Pure Chemical Industries, Ltd., Sumitomo Chemical Co., Ltd. and Shiono Chemical Co., Ltd.

  The compounding amount of Compound 1 in the TRPV4 receptor inhibitor of the present invention is about 0.25 to 5% by weight, preferably about 0.5 to 4% by weight, more preferably about 1 to 3.5% by weight.

  By further adding the compound 2 represented by the following general formula (2) to the compound 1, the inhibitory effect of the TRPV4 receptor of the present invention is enhanced.

[In the formula (2), n represents 8 or 9, and m represents 17 to 19]
In the present invention, n is preferably 8 or 9, and m is preferably 17. One type can be selected from these compounds and used alone, or two or more types may be combined.

  Compound 2 is a compound known to be able to reduce the sensitivity to thermal stimulation and chemical stimulation, and is commercially available from, for example, Nagaoka Jitsugyo Co., Ltd.

  When the compound 1 and the compound 2 are used in combination, the compounding ratio of the compound 2 is usually about 0.0005 to 4 parts by weight, preferably about 0.0003 to 0.46 parts by weight with respect to 1 part by weight of the compound 1, More preferably, it is about 0.0012 to 0.01 parts by weight.

  Other than the above, various components, aqueous components, oily components, moisturizing components, excipients, thickeners, antiseptics that are generally used in quasi drugs and pharmaceuticals as long as the effects of the present invention are not impaired. Agents, antioxidants, carriers, fragrances, colorants, drugs and the like may be used alone or in combination of two or more in combination with the TRPV4 receptor inhibitor of the present invention.

  The TRPV4 receptor inhibitor of the present invention thus obtained is useful as an inhibitor of nociceptive pain because it is excellent in the action of suppressing transmission of nociceptive mechanical stimulation by the TRPV4 receptor. As used herein, nociceptive pain means pain caused by a mechanical stimulus applied from outside the body (noxious mechanical stimulus) capable of substantially injuring or damaging tissue (for example, the above non-pain). (See Patent Document 1).

  Moreover, the inhibitor of the nociceptive pain can also be prepared in the form of a skin external preparation. As the dosage form of the external preparation for skin, various dosage forms can be prepared depending on its use, and examples thereof include ointments, lotions, gels, solutions, patches, aerosols and the like.

  The skin external preparation of the present invention contains an appropriate amount of a base or the like for obtaining a desired dosage form, such as, but not limited to, paraffin, petrolatum, squalane, paraffin, white wax, plastic base, Oil bases such as polyethylene glycol, macrogol, lauro macrogol, silicone oil, silicone, polysorbate, polyoxyethylene hydrogenated castor oil, olive oil, cottonseed oil, soybean oil, coconut oil; higher alcohols such as cetanol and stearyl alcohol; ethanol Lower alcohols such as isopropanol; polyhydric alcohols such as propylene glycol, dipropylene glycol, glycerin and 1,3-butylene glycol; carboxyvinyl polymer, polyvinyl alcohol, polyvinyl methyl ether, polyvinylpyrrolidone, poly Water-soluble polymers such as kyrylic acid and partially neutralized products thereof, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, pullulan, agar, gelatin, alginic acid and salts thereof, carrageenan, gums; fatty acids Ester (isopropyl myristate, sorbitan fatty acid ester, etc.), higher fatty acid salt emulsifier, highly purified egg yolk lecithin, soybean lecithin, purified soybean lecithin, white beeswax, propylene carbonate, egg yolk phospholipid, egg yolk oil, coconut oil fatty acid, sodium lauryl sulfate Other emulsifiers such as ionic and nonionic surfactants; pH adjusters such as phosphoric acid, acetic acid, hydrochloric acid, sodium hydroxide, kaolin, titanium oxide, talc, silicic acid Magnesium Rumin acid, magnesium stearate, aluminum stearate, iron oxide, zinc oxide, such as a powder component, such as starches, and the like.

  In addition, as a support (base fabric) for producing a patch, conventionally known ones can be used. For example, natural rubber; isoprene rubber, chloroprene rubber, butadiene rubber, nitrile rubber, styrene-butadiene rubber, ethylene -Synthetic rubber such as propylene rubber, acrylic rubber, urethane rubber, silicon rubber, fluoro rubber, polyethylene elastomer; heat of styrene thermoplastic elastomer, urethane thermoplastic elastomer, vinyl chloride thermoplastic elastomer, olefin thermoplastic elastomer, etc. Plastic elastomers; Polyesters such as polyethylene terephthalate; Thermoplastic synthetic resins such as polypropylene, polyacetal, polyurethane, polyvinyl chloride, polystyrene; Fabrics composed of synthetic fibers (nonwoven fabrics, woven fabrics, knitted fabrics); natural fibers Constructed fabric (non-woven, woven, knitted); and metal foils and the like.

  The external preparation for skin of the present invention can be prepared by mixing the above components according to a conventionally known method. Conditions such as temperature in preparation, order of addition of each component, mixing time, etc. are appropriately set based on technical common sense in the field according to physical or scientific properties of each component, concentration, stress of equipment, etc. It is not limited.

  Although the dosage of the nociceptive pain inhibitor (TRPV4 receptor inhibitor) of the present invention can be appropriately adjusted depending on the dosage form, symptoms, purpose, etc., the dosage of the preparation is usually 0.025 to 5.0 g / time. , Preferably 0.05 to 3.5 g / time, more preferably 0.1 to 2.0 g / time.

  Since the nociceptive pain inhibitor (TRPV4 receptor inhibitor) of the present invention can suppress the occurrence of pain due to mechanical stimulation such as cuts, stab wounds, bruises, injections, etc., it is used for mitigation or prevention of mechanical stimulation. be able to. The TRPV4 receptor inhibitor of the present invention can be applied for the purpose of suppressing (relaxing) pain after being injured such as a bruise in the same way as a normal analgesic, but it has the effect of suppressing the transmission of pain. Since the onset is fast, it is preferable to apply in advance before injection, drip, etc., for example.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Formulation Examples, but the present invention is not limited thereto.
<Test example>
After an acclimatization period of 1 week, 100 mg of the test substance was applied to the legs of Wistar rats (male: 5 weeks old) once a day. The Randall celite method was carried out 1 hour after the final application. The Randall Cerit method is as follows according to the method described in “A Method of measurement of analgetic activity on inflamed tissue”, Arch Int Pharamacodyn Ther. 1957 Sep 1; 111 (4) 409-19. RANDALL LO SELITTO JJ. Went to.

[Randal Celit Method]
In this test, a Randall Cerit tester (ANALGESY METER) was used. The Randall Cerit method is a method generally used for pain threshold measurement, and in this test example, it was used to evaluate the inhibitory action of pain due to mechanical stimulation of the composition shown in the following table. The test method is as follows.
(1) Mechanical stimulation was applied to the rat leg by a conventional method using pressure.
(2) The pressure causing reflex behavior due to pain was measured.
(3) The average value of 6 measured values was adopted.

  A numerical value A was calculated from the obtained average value based on the following formula.

Numerical value A = value at the time of administration of each test substance / value without drug treatment Here, if numerical value A is 1.5 or more, it is considered to be effective. This is because, when performing the test between the untreated group and the two groups for each group, it can be determined that there is a significant difference at a rejection rate of 5% if the above value is obtained. The results are shown in Table 1 below.

  Compound 1 is a component having the properties described above. Conventionally, the action which suppresses the pain accompanying inflammation by suppressing a prostanoid receptor is known. On the other hand, inflammatory pain and pain caused by mechanical stimulation are considered to have different transmission pathways (see, for example, “Types of Pain and Analgesics” Clinical and Research 84, 6 (20077.6)). From the above test examples, it was confirmed that Compound 1 acts suppressively on the TRPV4 receptor which transmits pain due to mechanical stimulation. In addition, since indomethacin shown in Comparative Examples 1 to 4 (the same component used as a prostanoid receptor inhibitor as in Compound 1) has no TRPV4 inhibitory effect, the TRPV4 receptor inhibitory action is a compound. 1 was shown to be specific. Furthermore, it was shown that addition of Compound 2, which is known to suppress pain caused by thermal stimulation or chemical stimulation, enhances the TRPV4 receptor inhibitory action of Compound 1.

  The effects of Examples 1 to 5 are comparable to lidocaine (numerical value A = 1.6), which is an anesthetic that suppresses nerve sodium channels and paralyzes pain, and exhibits an excellent pain suppressing effect equivalent to or higher than that. It was. In addition, the effect when the compounds 1 and 2 were used in combination was particularly excellent.

  Further, as is clear from Comparative Examples 3 and 4 using indomethacin, it was also shown that Compound 2 potentiates the TRPV4 receptor inhibitory action specifically for Compound 1.

The TRPV4 receptor is activated by mechanical stimulation among noxious stimuli. Therefore, suppressing the activation of this receptor can suppress the transmission of mechanical stimulation, and as a result, can suppress the pain caused by mechanical stimulation. The prescription example of the present invention is shown below. The unit of the blending amount of each component in the formulation example is g / 100 ml for the liquid, and g for the gel and the patch.

Claims (6)

The nociceptive pain preventive agent which uses the compound represented by following formula (1) as an active ingredient.

Furthermore, the nociceptive pain preventive agent of Claim 1 containing at least 1 sort (s) of the compound represented by following General formula (2).

[In the formula (2), n represents 8 or 9, and m represents an integer of 17 to 19] The nociceptive pain preventive agent according to claim 2, comprising 0.0005 to 4 parts by weight of the compound represented by the general formula (2) with respect to 1 part by weight of the compound represented by the formula (1). . Nociceptive pain preventive agent according to any one of claims 1 to 3 is the content of the compound is 0.25 to 5% by weight indicated in the previous following formula (1). The nociceptive pain preventive agent according to any one of claims 1 to 4 , which is in the form of an external preparation for skin. The preventive agent for nociceptive pain according to any one of claims 1 to 5, which is preliminarily administered to the site before mechanical stimulation.