JP2003128546A - Antipruritic drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antipruritic drug useful for remedy of pruritus of a disease accompanying various pruritus. SOLUTION: This antipruritic drug includes an opioid k receptor agonist compound expressed by general formula (IV) and a salt of its pharmacologically permissible acid adduct as an active ingredient. [R is two hydrogen or -O-(CH2 )3 -, X and Y are each independently H or Cl, Z is O or S (excludxng trans-2-(3, 4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-Acetamide). And the general formula (IV) includes a (+) isomer, a (-) isomer and (±) isomers].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an opioid κ receptor agonist compound which is useful for the treatment of pruritus in various itch-related diseases and an antipruritic agent containing the same.

[0002]

2. Description of the Related Art Pruritus is a sensation peculiar to skin,
It is often found in various skin diseases with inflammation, but some medical diseases (malignant tumor, diabetes, liver disease, renal failure, renal dialysis, gout, thyroid disease, blood disease, iron deficiency), pregnancy, and parasites It can be caused by an infection, and sometimes it can be drug- or psychogenic.

Since itching is a subjective sensation, it is difficult to quantitatively and objectively evaluate itching, and the mechanism of expression of itching has not been sufficiently clarified.

At present, histamine, substance P, bradykinin, proteinase, prostaglandin, opioid peptide and the like are known as stimulants that cause itching. Perception as pruritus is that these pruritus-stimulating substances act on the nerve endings (pruritic receptors) corresponding to multiple stimuli existing at the epidermis-dermis boundary, and the resulting impulses are in the order of spinal thalamus → thalamus → cerebral cortex. It is believed that it will occur upon reaching (Yoshiki Miyaji, Approach to the treatment of pruritus skin, p.22, 1996, Advanced Medicine Company).

Pruritus is a very unpleasant symptom for the patient himself, and in severe cases, it becomes a serious obstacle to daily life. To treat itching, first of all, it is necessary to treat dermatitis and underlying underlying diseases, but especially in the case of skin diseases, scratching worsens the symptoms. There is a need.

[0006] Scratching is the greatest exacerbation factor of dermatitis because it causes damage to the skin, impairs the barrier function of the skin, and increases the susceptibility to physical and chemical stimuli and bacterial infection. Become. In addition, since the skin epidermis becomes thin and weak, the nerve becomes irritable, and itching is more likely to be felt, and as a result, a repeated vicious cycle of repeated scratches is often caused.

[0007] For example, the time to feel itching and to scratch the skin during sleep is only 0.1% of the total sleep time in a healthy person, but it reaches an average of 24% in patients with severe atopic dermatitis. . If you sleep for 8 hours, you will be scratching your skin for about 2 hours, and it becomes clear that this scratching during sleep exacerbates atopic dermatitis and contributes to the formation of atopic eruption. Tekita (Nikkei Medical, July 10, 1996, p13).

As described above, it is considered that the treatment of pruritus itself directly leads to the fundamental treatment of the skin diseases accompanied by strong itching.

Specific skin diseases to be treated by pruritus include atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum. Deficiency, pruritus senile, insect bite, photosensitivity, urticaria, prurigo, herpes, impetigo, eczema, ringworm, lichen, psoriasis,
Examples include scabies and acne vulgaris. Further, as visceral diseases accompanied by pruritus, malignant tumor, diabetes, liver disease, renal failure, renal dialysis, and pregnancy are particularly problematic.

For the treatment of such pruritus, antihistamines, antiallergics and the like are mainly used as internal preparations, and as external preparations, antihistamines, external corticosteroid preparations, nonsteroidal anti-inflammatory agents and camphor are used. ,
Moisturizers such as menthol, phenol, salicylic acid, tar, crotamiton, capsaicin (urea, hirudoid,
Vaseline etc.) is used. However, in the case of an oral drug, side effects such as the time required for the onset of action, central nervous system depressant action (drowsiness, malaise), and damage to the digestive system have become problems. On the other hand, in the case of external preparations, the antipruritic effect is not sufficient, and especially in the case of external steroid preparations, side effects such as adrenal function decline and rebound during long-term use have become problems.

Regarding opioids and itch, it has been known that opioids have an analgesic action while also functioning as a chemical mediator of itch. It has been reported that endogenous opioid peptides such as β-endorphin and enkephalin cause pruritus (B. FjellerAct
a, Dermato-Venereol., 61 (suppl. 97), 1-34, 1981)
It became clear that pruritus was also induced as a side effect when morphine or an opioid compound was administered intradurally or intrathecally (JH Jaffe and WRMartin,
Goodman and Gilman's Pharmacological Basis of The
raputics, Macmillan, New York, 1985). On the other hand, the itch caused by intrathecal administration of morphine was suppressed by the morphine antagonist naloxone (J. Bernstein et al., J. Invest. Dermatol., 78 , 8).
2-83, 1982) and strong itching caused by elevation of endogenous opioid peptide in cholestasis patients with liver disorder were suppressed by the opioid antagonist nalmefene (JR Thornton and MS Losowsky, Br. Med. J.,
297 , 1501-1504, 1988) was also clarified, and it was concluded that opioid agonists have an itching effect and that antagonists have an antipruritic effect. Recently, it was also found that the serum β-endorphin concentration in children with atopic dermatitis was significantly higher than that in healthy children, and it was reported that opioid antagonists may be effective in itching of atopic dermatitis. (S. Georgala et a
L., J. Dermatol. Sci., 8 , 125-128, 1994).

As described above, it has been conventionally considered that opioid agonists cause itch and that antagonists thereof may be used as antipruritic agents. However, the application of opioid antagonists as an antipruritic has not been put into practical use so far.

[0013]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide an opioid kappa receptor agonist having an extremely fast and strong antipruritic action, which solves the above problems, and an antipruritic agent containing the same. is there.

[0014]

The present invention provides the following general formula (IV)

[0015]

[Chemical 2]

[In the formula, R is two hydrogens or -O-CH.
₂ CH ₂ CH ₂ - and is, X, Y is hydrogen or chlorine independently, Z is represents O or S (where trans-2- (3,4-dichlorophenyl) -N- methyl -N
-[2- (1-pyrrolidinyl) cyclohexyl] acetamide, except). Further, the general formula (IV) is a (+) form,
The antipruritic agent comprises an opioid κ receptor agonist compound represented by (-) form or (±) form] or a pharmacologically acceptable acid addition salt thereof as an active ingredient. Further, it is the above-mentioned antipruritic agent in which pruritus is associated with a skin disease or a visceral disease.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Opioid receptors include μ, δ,
It is known that there are γ- and κ-receptors, and an endogenous opioid peptide that selectively stimulates each has already been discovered. That is, β-endorphin and enkephalin identified as the aforementioned μ and δ receptor agonists, and dynorphin identified as the κ receptor agonist endogenous opioid peptide. However, the effects of κ receptor agonists, including dynorphin itself, on itching have not been clarified at all, and have been clarified for the first time by the present invention.

The kappa receptor agonist as used in the present invention is not restricted to its chemical structural specificity as long as it shows agonisticity to the opioid kappa receptor, but it is classified as a kappa receptor rather than a mu and delta receptor. High selectivity is preferred. Specifically, the general formula (IV)

[0019]

[Chemical 3]

[In the formula, R is two hydrogens or -O-CH.
₂ CH ₂ CH ₂ - and is, X and Y are hydrogen or chlorine, Z is represents O or S (where trans-2
-(3,4-Dichlorophenyl) -N-methyl-N-
[2- (1-pyrrolidinyl) cyclohexyl] acetamide, except). Further, the general formula (IV) is (+) form, (-)
Body, including (±) body] or a pharmaceutically acceptable acid addition salt thereof. These kappa receptor agonists can be used not only as one type but also as several types as active ingredients.

Specific skin diseases with pruritus to be treated include atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, Sebum deficiency, pruritus senile, insect bite, photosensitivity, urticaria, prurigo, herpes, impetigo, eczema, ringworm, lichen,
Examples include psoriasis, scabies and acne vulgaris. In addition, visceral diseases accompanied by pruritus include malignant tumor, diabetes, liver disease, renal failure, renal dialysis, and pruritus caused by pregnancy. Furthermore, it can be applied to itching due to diseases of ophthalmology and otolaryngology.

Among the compounds represented by the general formula (IV) of the present κ receptor agonist, trans-N-methyl-N- [2- (1
-Pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide, (5β, 7β, 8α) -3,4
-Dichloro-N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4,5] dec-8-yl] benzeneacetamide, (5β, 7β, 8α) -N-methyl-N -[7- (1-Pyrrolidinyl) -1-oxaspiro [4,5] dec-8-yl] benzo [b] furan-4-
Acetamide, (5β, 7β, 8α) -N-methyl-N-
[7- (1-pyrrolidinyl) -1-oxaspiro [4,
5] Dec-8-yl] benzeneacetamide is preferred.
The kappa receptor agonists represented by the general formula (IV) are J. Szmus.
zkoviczet al., J. Med. Chem., 25 , 1125 (1982), DC
Horwell et al., US PatentAppl. 558737 (1983), J.
Szmuszkovicz et al., Eur. Patent Appl. EP126612 (1
984), PR Halfpenny, DC Horwell et al., J. Med.
It can be manufactured according to the method shown in Chem., 33 , 286 (1990).

Among the above-mentioned κ receptor agonists, a compound represented by the general formula (IV)
As the pharmacologically preferable acid addition salt to the substance represented by the following, inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, acetate, lactic acid salt,
Citrate, oxalate, glutarate, malate,
Tartrate, fumarate, mandelate, maleate,
Organic carboxylic acid salts such as benzoate and phthalate, methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate, camphor sulfonate, etc. Of these, hydrochlorides, hydrobromides, phosphates, tartrates, methanesulfonates, etc. are preferred, but are not limited to these.

These κ receptor agonists have been purified to be used for pharmaceuticals, and have passed the necessary safety tests, and then, as they are or mixed with known pharmacologically acceptable acids, carriers, excipients and the like. The pharmaceutical composition can be administered orally or parenterally.

Tablets and capsules are also used as oral agents, but external agents are preferred for the treatment of skin diseases. As the external preparation, fats and oils (preferably vegetable oil, animal oil, 臘, fatty acid, fatty alcohol, mineral oil, turpentine oil, petrolatum, etc.), solvent (preferably water, ethanol, glycerin,
Propylene glycol, isopropyl alcohol, ether, etc.), preservative (preferably paraoxybenzoic acid ester, benzoic acid, salicylic acid, sorbic acid, benzalkonium, benzethonium, propylene glycol, chlorobutanol, benzyl alcohol, ethanol, etc.),
Stabilizer (preferably tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, sulfite,
Edetate disodium), anionic surfactant (preferably potassium soap, medicated soap, zinc undecylenate, calcium stearate, magnesium stearate, aluminum monostearate, calcium linoleate,
Sodium lauryl sulfate, etc., nonionic surfactant (preferably glyceryl monostearate, sorbitan fatty acid partial ester, sucrose fatty acid ester, polyoxyl stearate 40, macrogols, lauromacrogol, polyoxyethylene 160 polyoxy) Propylene 30 glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid partial esters, etc.), cationic surfactants (preferably benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, etc.), powders (preferably Zinc oxide, zinc white starch, kaolin, bismuth subnitrate, titanium oxide, titanium dioxide, sulfur, silicic acid anhydride, talc, etc., preservative (preferably paraoxybenzoic acid ester, sorbic acid, p-
Chloro-m-xylenol, Irgasan, hexachlorophen, etc.), emulsifier (preferably gum arabic powder, tragacanth powder, bentonite, sodium carboxymethylcellulose, methylcellulose etc.), wetting agent (preferably glycerin, propylene glycol, polyethylene glycol, 1,3) -Butylene glycol, sorbitol,
Sodium polypyrrolidone carboxylate, sodium lactate, sodium hyaluronate, chitin derivative, urea, amino acids, sugar amino acids, etc.) are mixed and used as a base to prepare ointments, creams, poultices, coatings, patches, etc. It can also be used as a liquid preparation for external use. It can also be prepared as an eye drop for ophthalmic use.

The content of the kappa receptor agonist in the pharmaceutical composition is not particularly limited, but it is usually 0.1 per oral dosage.
Myuji～1000mg, the external preparation is prepared so that the normal and 0.001ng ^{/ m 2} ~10mg ^/ m 2 per single application.

[0027]

EXAMPLES The present invention will be described more specifically below based on examples. However, the following examples are described only for the purpose of illustration, and are not limited to these in any sense.

EXAMPLE Male ddY mice were received from Japan SLC at the age of 4 weeks,
It was used at 5 weeks of age after preliminary breeding. On the day before the experiment, the rostral back of the mouse was hair-removed using a clipper. Each compound was dissolved in 10% DMSO. Compound 48/80 (100 μg / 100 μg / 100 mg / ml) was administered subcutaneously to the rostral dorsal region of mice with the test drug or solvent, and 30 minutes later.
site) was intradermally administered to the hair removal site at a dose of 50 μL. Immediately afterwards, observation cage (10 x 7 x 16 cm)
After that, the behavior for 30 minutes was photographed with a video camera in an unmanned environment. Play videotape and mouse in hind limb
The number of scratching behaviors near the compound 48/80 administration site was counted. The experiment was conducted with 8 to 10 animals per group.

The inhibition rate of scratching behavior by each test compound was calculated by the following formula. The action of reducing scratching behavior was used as an index of the antipruritic effect of the test compound.

Scratching behavior suppression rate (%) = {1- (A-
C) / (B−C)} × 100 A = average number of scratching behaviors of the test drug administration group B = average number of scratching behaviors of the group that was administered the solvent instead of the test drug C = administer the solvent instead of the pruritus The average number of scratching behaviors of the treated group was trans-N-methyl-N- [2-
(1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide hydrochloride 22 , (5β, 7
β, 8α) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4,5] dec-8-yl] benzo [b] furan-4-acetamide hydrochloride 23 was used. .

[0031]

[Chemical 4]

The results are summarized in Table 1. The compound used in the test showed an antipruritic effect at the dose used.

[0033]

[Table 1]

[0034]

The antipruritic agent of the present invention is characterized by containing an opioid κ receptor agonist as an active ingredient, and has various itch-related skin diseases such as atopic dermatitis, neurodermatitis and contact skin. Inflammation, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, pruritus senile, insect bite, photosensitivity, urticaria, prurigo, blisters, impetigo, eczema, ringworm. ,
It is useful for treating lichen, psoriasis, scabies, acne vulgaris and the like and visceral diseases accompanied by itching such as malignant tumor, diabetes, liver disease, renal failure, renal dialysis and pregnancy.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 17/00 A61P 17/00 17/04 17/04 17/06 17/06 17/08 17/08 17 / 16 17/16 25/00 25/00 25/02 101 25/02 101 31/10 31/10 33/00 33/00 35/00 35/00 37/08 37/08 43/00 111 43/00 111 C07D 307/94 C07D 307/94 // C07D 333/54 333/54 (72) Inventor Atsushi Kamei 391 Shibamachi, Kanazawa-ku, Yokohama, Kanagawa Marinecity Kanazawa Bunko C-504 (72) Kuniaki Kawamura, Kanagawa Prefecture 1-20-33 Tsunishi, Kamakura-shi I-1 F term (reference) 4C037 WA02 4C086 AA01 AA02 BC07 GA02 GA04 GA07 MA01 MA04 NA14 ZA01 ZA21 ZA75 ZA81 ZA89 ZB11 ZB13 ZB26 ZB35 ZC33 ZC35 ZC42

Claims (2)

[Claims] 1. The following general formula (IV): [Wherein, R represents two hydrogen or _-O-CH 2 _CH 2 CH
_2- , X and Y are independently hydrogen or chlorine,
Z represents O or S (provided that trans-2- (3,
4-dichlorophenyl) -N-methyl-N- [2- (1
-Pyrrolidinyl) cyclohexyl] acetamide)). Further, the general formula (IV) has a (+) form, a (−) form,
An antipruritic agent containing an opioid κ receptor agonist compound represented by (±) body or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 2. The antipruritic agent according to claim 1, wherein the pruritus is associated with a skin disease or a visceral disease.