JP2000247884A - Arachidonic acid-induced skin disease treatment - Google Patents

Abstract

(57) [Problem] To provide a novel drug having few side effects, which is useful for prevention and treatment of skin diseases induced by arachidonic acid. SOLUTION: The therapeutic agent for arachidonic acid-induced skin disease contains imiquimod or an acid addition salt or solvate thereof as an active ingredient. Since the therapeutic agent for arachidonic acid-induced skin disease of the present invention has an inhibitory effect on arachidonic acid-induced skin inflammatory response, various diseases caused by abnormally increased production of arachidonic acid metabolites, for example, psoriasis, ultraviolet dermatitis, mast cells Is useful as a novel therapeutic agent for skin diseases, which can treat or prevent arachidonic acid-induced skin diseases such as basal cell carcinoma and basal cell carcinoma in good and with few side effects.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to 1H-imidazo.
The present invention relates to a therapeutic agent for arachidonic acid-induced dermatosis comprising, as an active ingredient, a compound R837 [Imiquimod] having a [4,5-C] quinolin-4-amine structure. More specifically, the above-mentioned compounds satisfactorily cause diseases caused by enhanced production of arachidonic acid metabolites, that is, arachidonic acid-induced skin diseases such as psoriasis, ultraviolet dermatitis, mastocytosis, basal cell carcinoma or stabbing cell carcinoma, The present invention relates to a novel skin disease therapeutic agent which can be treated or prevented with few side effects.

[0002]

2. Description of the Related Art At present, it is considered that arachidonic acid metabolites are involved in various skin inflammatory diseases. Arachidonic acid metabolites refer to factors produced by the arachidonic acid metabolic pathway described below. The arachidonic acid metabolic pathway starts with the release of arachidonic acid normally stored in the phospholipid of the cell membrane into the cytoplasm by various stimuli due to the inflammatory reaction. There are two major systems for arachidonic acid metabolism, prostaglandins (PG) produced by cyclooxygenase enzymes, leukotrienes (LT) produced by lipoxygenase enzymes, and hydroxyeicosatetraenoic acid (12-HETE). Divided. These metabolites are mediators that trigger an inflammatory response. Vasodilator action of PG and leukotriene C,
Increased vascular permeability of D and E (LTC, LTD, LTE) induces a skin redness / edema reaction. In addition, leukotriene 5,12-dihydroxy compound (LTB ₄ ) enhances polynuclear leukocyte migration and forms subcorneal and intracorneal pustules characteristic of psoriasis and the like. From the above description, arachidonic acid metabolites include arachidonic acid and prostaglandins (P
_{G), LTB 4, LTC,} LTD, leukotrienes such as LTE (LT), means 12-HETE.

[0003] Psoriasis is a chronic disease that shows benign overgrowth of epidermal cells and infiltration of polymorphonuclear leukocytes into the epidermis. Increased PG, arachidonic acid and 12-HETE have been shown in the psoriatic rash (Hammerstrom, S. et al. Proc. Nat.
Acad. Sci. USA. 72 , 5130-5134 (1975)). Also, LT
When patches B ₄ to human skin, small abscesses in the skin seen in psoriasis skin疹部is formed (Camp, S. et al. J. Inve
st. Dermatol. 82 , 202-204 (1984)). From the above,
Psoriasis is thought to be associated with arachidonic acid metabolite abnormalities. Mastocytosis is a condition in which histamine and the like are released from mast cells proliferating in the skin, causing flushing of the skin and urticaria. These histamines are considered to be mainly due to histamine, so antihistamines are used.However, when PG synthesis inhibitors are administered alone to patients whose symptoms do not improve, marked improvement may be observed (Main , R.
A. et al. Br. J. Dermatol. 107 (Suppl. 22) , 53 (198
2)). It is also known that PGD ₂ is excessively produced in mastocytosis (Roberts, LJ et al. N. Engl. J.
Med. 303 , 1400-1404 (1980)), and the involvement of PG, which is an arachidonic acid metabolite, in the expression of the above-mentioned symptoms is also considered.
PG is increased in basal cell carcinoma or stab cell carcinoma among skin cancers, and it has been suggested that PG is involved in the growth of the tumor (Vanderveen, EE et al. Arch.Dermatol.
122 , 407-412 (1986)). As described above, it is considered that abnormalities of arachidonic acid metabolism are involved in these skin diseases, and drugs that suppress skin inflammation caused by arachidonic acid are considered to be effective therapeutic agents for these skin diseases.

[0004] Among arachidonic acid-induced skin diseases, in particular, psoriasis is known as a persistent skin disease. Also, although psoriasis is responsive to temporary treatments, there is still no definitive and ideal therapeutic agent, and more effective drugs have side effects. Under such circumstances, since treatment is prolonged, it can be said that the principle of psoriasis treatment is to properly combine various treatments and obtain the maximum effect with minimum side effects.
In that sense, etretinate (vitamin A
Derivatives, pharmacological agents such as active vitamin D3 and cyclosporine have a different mechanism of action from conventional treatments, and can be said to be epoch-making agents that have greatly expanded the choices of dermatologists for psoriasis treatment. However, since etretinate has various side effects of vitamin A, the administration of a necessary and sufficient amount of medicinal effect is restricted. In addition, active vitamin D3
The effect is not always sufficient, and cyclosporin has nephrotoxicity and blood pressure increasing effects, and therefore requires various precautions when used. From the above, there is still a demand for a drug that can be treated or prevented with good and few side effects for treating psoriasis.
(Latest skin disease treatment '97 -'98, p4-7, 106
-107).

[0005]

The problem to be solved by the present invention is that 1H
A skin disease induced by arachidonic acid, comprising a compound R837 (imiquimod) having an imidazo [4,5-C] quinolin-4-amine structure as an active ingredient,
An object of the present invention is to provide a novel skin disease therapeutic agent that can treat or prevent a skin disease caused by increased production of PG and the like.

[0006]

Means for Solving the Problems The present inventors have intensively studied the drugs involved in inhibiting the production of arachidonic acid metabolites, and as a result, have found that 1H-imidazo [4,5-C] quinoline-4.
-It has been found that compounds having an amine structure, particularly imiquimod, have a remarkable inhibitory effect, and the present invention has been completed. In addition, the following is reported about the pharmacological effect of imiquimod conventionally known.

1) Antiviral activity Herpes simplex virus in guinea pigs
rus), it has been reported that imiquimod exhibits an antiviral effect in infectious systems (Harrison, CJ et al. An
timicrob.Agents Chemother. 38 , 2059-2064 (199
Four)). In addition, guinea pig cytomegalovirus (cyto
megalovirus) Infectious strain (Chen, M. et al. Antimicrob. Age
nts Chemother. 32 , 678-683 (1988)) and an arbovirus infection system in mice (Adv. Biosci. (1988)).
68 : 51-63) have also been shown to exhibit antiviral activity. In addition, it has been reported that the antiviral effect of imiquimod is not a direct effect on the virus, but rather through induction of interferon α (IFN-α) (Antiviral Res. (1988) 10 : 2
09-224). In fact, it has been reported that imiquimod induces IFN-α in vitro or in vivo in mouse experiments (Reiter, MJ et al. J. Leukoc.
Biol. 55 , 234-240 (1994)).

2) Antitumor activity Imiquimod has also been reported to exhibit antitumor activity in various experimental systems (Sidky, YA. Et al. Cancer).
Res. 52 , 3528-3533 (1992)). The imiquimod can also induce the production of interleukins (IL-1, IL-6, IL-8) and tumor necrosis factor α (TNF-α) in a mouse experimental system in vitro or in vivo. (Reiter, MJ et al. J. Leukoc. Biol.
55 , 234-240 (1994)), and in particular, because it induces the production of TNF-α, some
-Α has been suggested as a possible cause.

As described above, it has been reported that imiquimod has antiviral and antitumor activities, and that it induces IFN-α or TNF-α as a mechanism, but imiquimod is induced by arachidonic acid. These documents do not teach at all that it is possible to treat or prevent a skin disease caused by the increased production of PG or the like.

The present invention has been completed based on the above findings. That is, the gist of the present invention is as follows: (1) A therapeutic agent for arachidonic acid-induced skin disease containing R837 (imiquimod) as an active ingredient. (2) The arachidonic acid-induced skin disease is psoriasis.
(3) The arachidonic acid-induced skin disease is ultraviolet dermatitis,
The therapeutic agent for a skin disease according to the above (1) (4) The therapeutic agent for a skin disease according to the above (1), wherein the arachidonic acid-induced skin disease is mastocytosis; The therapeutic agent for a skin disease according to (1), wherein the arachidonic acid-induced skin disease is stab cell carcinoma.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, “therapeutic agent for arachidonic acid-induced skin disease” means a therapeutic agent for a skin disease induced by arachidonic acid, ie, a skin disease caused by enhanced production of arachidonic acid metabolite. I do. The therapeutic agent of the present invention contains imiquimod or an acid addition salt thereof as an active ingredient.

Imiquimod and its acid addition salt can be easily synthesized according to known methods. For example, it can be synthesized according to the method described in Japanese Patent Publication No. 5-86391. The acid of the imiquimod acid addition salt may be any pharmacologically acceptable acid, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, and ascorbic acid, and organic acids.

The agent for treating arachidonic acid-induced skin disease of the present invention may be a solvate such as imiquimod or an acid addition salt thereof, or a hydrate thereof. And the like can be produced by blending with imiquimod. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like which are generally acceptable can also be added.

As the administration method, both oral and parenteral administration can be used. For oral administration, it can be administered in the form of inhalants or capsules, tablets, granules, etc.For parenteral administration, subcutaneous or intravenous injections, drops, ointments, etc. with aqueous suspensions Can be used.

The dose can be used in an amount sufficient to effectively treat the target disease. In general, the dose varies depending on the condition, age, body weight, etc. of the patient.
For adults, the range of about 1 to about 1000 mg, preferably about 10 to about 500 mg per day can be administered once or in several divided doses. In the case of parenteral administration (injection), the range is about 0.1 to about 500 mg, preferably about 3 to 500 mg.
A range of about 100 mg can be administered once or in several divided doses.

[0016]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Inhibition of imiquimod against arachidonic acid-induced intradermal reaction
Use 1) the test animals BALB / c mice (female, 6 weeks old) Charles River Japan (Kanagawa, were purchased from Japan), was pre-breeding use up to 7 weeks of age. 2) Test drug: R837 (imiquimod)

3) Test Drug Administration Method R837 was weighed and suspended in acetone (Kanto Chemical, Tokyo, Japan) at a concentration of 20 mg / ml. Under anesthesia with diethyl ether, the R837 suspension was applied to the front and back of the left auricle of the mouse in 10 μl portions (R837 administration group). As a control group, mice to which 10 μl of acetone alone was applied to the front and back of the left auricle were prepared.

4) Application of arachidonic acid Two hours after application of R837 or acetone, 10% arachidonic acid (CAYMAN CHEMICAL. Co., Michigan, USA) was applied to the front and back of the left auricle of the R837-administered group and the control group.
Each μl was applied.

5) Measurement of intradermal reaction R837 or acetone before application (without antigen induction) and 10
One hour after the application of arachidonic acid (antigen-induced), dialthickness gage (Mitutoyo C
o., Tokyo, Japan).

The intradermal reaction was determined by (the thickness of the left ear pinna induced by the antigen)
-(Thickness of the right auricle without inducing antigen).

6) Results The results are as follows: Student's t-tes
t) A significant difference test was performed. When a significant difference was observed at a risk rate of 1% or less, it was indicated by p <0.01.
Table 1 shows the results.

[0023]

[Table 1] Inhibitory effect of R837 on arachidonic acid-induced intradermal reaction

As is clear from Table 1, R837 showed a significant inhibitory effect on arachidonic acid-induced intradermal reaction. This result indicates that R837 is effective as a therapeutic agent for arachidonic acid-induced skin diseases such as psoriasis.

[0025]

According to the present invention, it has been found for the first time that R837 inhibits a skin inflammatory response induced by skin irritation by arachidonic acid. This fact indicates that R837 is useful as a therapeutic agent for various skin diseases caused by arachidonic acid metabolism abnormality. Diseases that can be expected to have such therapeutic effects include psoriasis, ultraviolet dermatitis, mastocytosis, and skin diseases including skin cancers such as basal cell carcinoma and stab cell carcinoma.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Masako Uchida 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi, Japan Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Masazumi Terashima Kasuganaka, Konohana-ku, Osaka-shi, Osaka 3-chome No. 98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Ochi 3-11 Kanda Surugadai, Chiyoda-ku, Tokyo F-term (reference) 4C065 AA01 AA05 BB06 CC09 DD03 EE02 HH01 JJ01 KK01 LL07 PP01 4C086 AA01 AA02 CB05 MA01 MA52 MA55 NA14 ZA89 ZB26 ZB33

Claims (10)

[Claims] 1. An agent for preventing or treating arachidonic acid-induced skin disease, comprising imiquimod or an acid addition salt or solvate thereof as an active ingredient. 2. The method according to claim 1, wherein the arachidonic acid-induced skin disease is psoriasis. 3. The method according to claim 1, wherein the arachidonic acid-induced skin disease is ultraviolet dermatitis. 4. The method according to claim 1, wherein the arachidonic acid-induced skin disease is mastocytosis. 5. The method according to claim 1, wherein the arachidonic acid-induced skin disease is basal cell carcinoma. 6. The drug according to claim 1, wherein the arachidonic acid-induced skin disease is stab cell carcinoma. 7. The medicament according to claim 1, which is in a dosage form for oral administration. 8. The medicament of claim 7, comprising a dosage unit dose of imiquimod of about 1 to about 1000 mg / day. 9. The medicament according to claim 1, which is in a dosage form for parenteral administration. 10. The method of claim 9, wherein the agent comprises imiquimod in a dosage unit dose of about 0.1 to about 500 mg / day.