JP4500483B2 - Human-derived prostaglandin synthase inhibitors - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel prostaglandin synthase inhibitor. The present invention also relates to an allergy preventive or therapeutic agent, sleep regulator, body temperature regulator, sexual cycle regulator, analgesic or olfactory regulator using the inhibitory action of this prostaglandin synthase. Furthermore, this invention relates to the health thru | or functional food / beverage products which can carry out allergy suppression, sleep regulation, body temperature regulation, sexual cycle regulation, analgesia, or olfactory regulation.
[0002]
[Prior art]
In recent years, allergic diseases are increasing rapidly. For example, according to Miyamoto “Clinical and Research; February 20, 2002 (Vol. 925)” page 189, the incidence of bronchial asthma in Japan was said to be around 1% of the total population for both children and adults. Are said to be 4.5% for infants, 4-7% for children, and 3-4% for adults. In addition, hay fever, which was considered to be extremely rare even if there was none before the war, is significantly more than 10% of the population in some regions even with cedar pollinosis alone, and the incidence of allergic rhinitis including hay fever Are 7.5% of infants, 24.6% of children, and 22.0% of adults, and it is said that the age of onset tends to shift to younger age groups.
Genetic factors and environmental factors are involved in the development of these allergic diseases, and various specific factors are mentioned.
[0003]
Allergic reactions are classified into types I, II, III, and IV by Coombs and Gell. Among these, the onset of bronchial asthma, atopic dermatitis, allergic rhinitis, conjunctivitis and the like is considered to involve type I allergic reaction. Antiallergic agents are used for the purpose of preventing this type I allergic reaction and preventing or treating allergies. Such anti-allergic agents include antihistamines, chemical mediator release inhibitors, leukotriene receptor antagonists, TXA ₂ synthesis inhibitors and receptor antagonists, Th ₂ cytokine inhibitors, immunosuppressants, etc. ("Clinical and Research", Vol. 79, No. 2, pp. 30-33 (February 2002)).
However, these antiallergic agents are not effective enough or have many side effects, and further development of antiallergic agents with high medicinal properties and low side effects has been demanded.
[0004]
[Problems to be solved by the invention]
The present invention has been made under such circumstances, and provides a human-derived prostaglandin synthase inhibitor that inhibits human-derived prostaglandin D ₂ synthase at a low dose and has few side effects. Let it be an issue.
Prostaglandin D ₂ is known to induce sleep, lower body temperature, suppress progesterone secretion, and regulate pain and odor responses in the central nervous system (Urade Y. et al., Vitam Horm, 58, 89-120 (2000), Urade Y. et al., J. Biol. Chem., 260, 2140-2415 (1985), Urade Y. et al., Biochimica Biophysica Acta, 1482, 259-271 (2000)), prostaglandins substances which inhibit D ₂ synthase becomes physiopathology modifier from those surfaces.
The present invention also provides an antiallergic preventive or therapeutic agent containing such an inhibitor, a sexual cycle regulator, a sleep regulator, a body temperature regulator, an analgesic or an olfactory regulator, or a health food or drink for their use, It is intended to provide functional food and drink, enhanced food and drink, and the like.
The present invention provides an antiallergic preventive or therapeutic agent or a sexual cycle regulator, a sleep regulator, a body temperature regulator, an analgesic, an olfactory regulator, or the above-mentioned food and drink for those uses every day. It is intended to treat allergies, sexual cycle abnormalities, sleep abnormalities, body temperature abnormalities, pain, and olfactory abnormalities that prevent or develop sexual cycle abnormalities, sleep abnormalities, body temperature abnormalities, pain, and olfactory abnormalities.
[0005]
[Means for Solving the Problems]
That is, the present invention relates to a prostaglandin synthase inhibitor containing a compound represented by the following general formula (I) or (II) as an active ingredient.
[0006]
[Formula 4]
[Chemical formula 5]
However, in formula (I), A is —O— or —CO—, R ¹ is —SO ₂ (OH), —PO ₃ H or —COOH, or a salt thereof (Na ⁺ , K ⁺ , NH ₄ ⁺ ), R ² represents —SO ₂ NH ₂ , —SO ₂ N (R ⁴ ) ₂ , CON (R ⁴ ) ₂ , and R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Indicates. R ¹ may be present at the 2-position or 3-position, preferably at the 2-position, and R ² may be present at any position of ortho, meta, and para.
In addition, R ³ in the formula (II) is
And n in —NH— (CH ₂ ) n —NH— represents 0, 1 or 2, or may be opened to be —NH ₂ or NH ₂ —. R ⁵ and R ⁶ represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. X represents I ⁻ , Br ⁻ , Cl ⁻ , F ⁻ , HClO ₄ ⁻ , SO ₄ ²⁻ , or PO ₄ ²⁻ .
The present invention also relates to an allergy preventive or therapeutic agent, sexual cycle regulator, sleep regulator, body temperature regulator, analgesic agent, and olfactory regulator comprising the aforementioned compound. Furthermore, this invention relates to the health thru | or functional food / beverage products which have these effect | actions.
[0007]
Prostaglandin PGD ₂ is produced as a mediator of inflammation and allergy from mast cells in the peripheral nervous system. Its biosynthesis is carried out using PGH ₂ as a substrate, and a hematopoietic prostaglandin PGD synthase is responsible for isomerization to PGD ₂ . Recently, it has been reported that allergic reactions are promoted in mice overexpressing the PGD ₂ receptor (Fujitani, Y., et al. J. Immunol, 2002), and in contrast, PGD ₂ receptor knockout mice It has also been reported that there is no allergic reaction (Matsuoka, T. et al., Science, 2000). Therefore, human-derived prostaglandin D ₂ synthase (H • PGDS) is attracting attention as a target protein for developing “antiallergic agents” or “analgesics”, and 4-benz having the following chemical formula (III) It is known to inhibit the rat PGDS activity of hydryloxy-1- [3- (1H-tetrazol-5-yl) -propyl] piperidine (HQL-79), but it was not always sufficient.
[0008]
[Chemical 7]
[0009]
The present inventors paid attention to this, and measured the H · PGDS inhibitory activity of various compounds. As a result, they found a compound having a very high inhibition rate, and completed the present invention.
[0010]
That is, the present invention relates to a prostaglandin synthase inhibitor containing the compound represented by the general formula (I) or (II) as an active ingredient.
Of the compounds represented by the general formula, compounds represented by the following chemical formulas (IV) and (V), that is, 1-amino-4- (4-sulfamoylanilino) -anthraquinone-2-sulfonic acid (Compound formula (IV) (water-soluble red dye)), 2- (2'-benzothiazolyl-5-styryl-3- (4'-phthalhydrazidyl) tetrazolium chloride (compound formula (V) (insoluble) ) Is preferably used because it inhibits human-derived prostaglandin D ₂ synthase with a high inhibition rate.
[0011]
[Chemical 8]
[0012]
[Chemical 9]
[0013]
The compound used in the present invention is a known compound that has been conventionally known as a dye or the like.
In the present invention, these compounds have been found to have human prostaglandin D ₂ synthase inhibitory activity.
[0014]
【Example】
Next, examples of the present invention will be described. However, the present invention should not be construed as being limited to the examples.
[Example 1]
First, the PGDS activity of the compound used in the present invention was measured. The assay components shown in Table 1 are prepared for measuring PGDS activity.
[0015]
[Table 1]
[0016]
The measurement method is as follows.
Preincubate a solution containing other than [ ¹⁴ C] PGH ₂ at 25 ° C. for 5 minutes.
Add 1 μl [ ¹⁴ C] PGH ₂ and vortex to start the reaction.
React at 25 ° C. for 1 minute.
Add 250 μl Stop solution (ether: methanol: 1M citric acid = 30: 4: 1), vortex and leave on ice.
An appropriate amount of sodium sulfate is added with a spatula to hydrate the aqueous phase.
50 μl of the upper layer (organic solvent phase) is applied to a TLC plate and developed (developer: ethanol: methanol: acetic acid = 90: 2: 1).
After the plate is dried, the imaging plate is exposed.
1 hour to over night After exposure, quantify PGD ₂ . The quantitative results are shown in FIG.
Based on this figure, the percentage of the PGD ₂ band in one lane was calculated. The results are shown in Table 2.
[0017]
[Table 2]
──────────────────────────
Blank 9.43
Control 29.6
Compound formula (V) 15.62
Compound Formula (IV) 12.45
──────────────────────────
Thus, in the sample (drug concentration) 10 μM, compound formula (V) inhibits prostaglandin D ₂ synthase with an inhibition rate of 69% and compound formula (IV) with an inhibition rate of 85%.
When this result is compared with the PGD synthase inhibitory action of HQL-79 (Protein Nucleic Acid Enzyme 2000, vol.45, No.6 320p-324p), HQL-79 has no PGD synthase inhibitory activity at a drug concentration of 10 μM. Not shown, while an inhibition rate of 75% was shown at 100 μM, both compound formula (V) and compound formula (IV) showed high inhibitory activities of 69% and 85% inhibition rates at a drug concentration of 10 μM, respectively.
The eosinophil infiltration action can also be evaluated using an asthma model prepared by repeatedly inhaling an antigen in a guinea pig actively sensitized with ovalbumin.
[0018]
The dose when the compound of the present invention is used for the prevention or treatment of the development of allergy varies depending on symptoms, age, body weight, sex, etc., but is 1 μg / kg to 100 mg / kg, preferably 10 μg per adult day. / kg to 10 mg / kg, more preferably 50 μg / kg to 1 mg / kg may be administered orally or parenterally.
When administered in this manner, it exhibits human prostaglandin D ₂ synthase inhibitory action, and can prevent or reduce the symptoms of allergy. Furthermore, sleep regulation, body temperature regulation, sexual cycle regulation, analgesia or olfactory regulation can be performed. In addition, when added to food and drink, it may be administered so that the above amount can be taken per day per adult. As a result, it is possible to prevent the development of allergies, reduce allergies that have developed, and exhibit the physiological activities described above.
[0019]
The compound of the active ingredient in the present invention can be used in a form dissolved in water or the like, in a powdered form, or as it is, and may be used as a preparation, and can be appropriately blended in foods and drinks, medicines and the like. It is generally dissolved or dispersed in a suitable liquid carrier, or mixed with or adsorbed to a suitable powder carrier, and in some cases, further emulsifiers, dispersants, suspending agents, spreading Additives, penetrants, wetting agents, stabilizers, etc. are added and used as preparations such as emulsions, oils, wettable powders, powders, tablets, capsules (including soft capsules), and liquids. Compound formula (V) and compound formula (IV) have high hydrophilicity. In such a case, they are dispersed in a powder such as a medium-long chain fatty acid triglyceride or vegetable oil such as sesame oil in the form of ultrasonic waves. It may be taken in a state or dissolved in an organic solvent. When used as a preparation, the amount of the compound used varies depending on the form of the preparation, but is preferably 0.01% by weight or more and 50% by weight or less, and safely exhibits human-derived prostaglandin D ₂ synthase inhibitory activity in this range, Prevents the development of allergies and treats allergies that develop. Furthermore, sleep regulation, body temperature regulation, sexual cycle regulation, analgesia or olfactory regulation can be performed.
[0020]
When the active ingredient in the present invention is used as a prophylactic or therapeutic agent for allergy, it can contain a pharmaceutically acceptable carrier as described above. The dosage form is not particularly limited, and for example, oral preparations such as powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, or pills, or injections And parenteral preparations such as topical solutions, ointments, suppositories, topically applied creams, and eye drops.
Of these, oral preparations are excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, diluents, preservatives, colorants, fragrances, stabilizers, humectants, preservatives. Or it can manufacture in accordance with a conventional method using antioxidant. Similarly, parenteral preparations can be produced by conventional methods, and examples of the administration method include intramuscular injection, intravenous injection, transdermal administration, and rectal administration.
[0021]
[Example 2]
30 g of compound formula (IV) and 100 g of soybean hardened oil were charged into a jacketed high-speed fluid mixer, heated to 70 ° C. with stirring to melt the soybean hardened oil, and then stirred. This was cooled to 50 ° C. with stirring, solidified, and sized to give an agent for preventing (treating) allergy. This is taken 1 tablet 3 times a day to prevent hay fever.
[0022]
[Example 3]
A capsule was obtained by filling 2.5 mg of the compound (V) and 100 mg of dextrin powder into a gelatin capsule. This is taken 1 capsule 3 times a day to prevent hay fever.
[0023]
[Example 4]
Soft capsule making machine to uniformly disperse 50g of compound IV in 2kg of sesame oil with ultrasonic waves, bubble high purity argon gas into sesame oil suspension, remove dissolved oxygen, and contain 5mg of compound IV in one capsule A soft capsule was produced by using a conventional method.
Skin formulation (parts by weight in the final form)
Gelatin 10 parts by weight Glycerin 2
Preservative (Ethylparaben) 0.05
Titanium white 0.2
Water 0.2
[0024]
【The invention's effect】
According to the present invention, by inhibiting the human prostaglandin D ₂ synthase, it can inhibit allergic reactions occurring in humans to prevent and treat the development of allergy. Such allergies that can be prevented or treated include type I allergies such as bronchial asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, and hay fever. In addition, the compound in the present invention can be used as a lead compound for developing an antiallergic agent. Furthermore, sleep regulation, body temperature regulation, sexual cycle regulation, analgesia, olfactory regulation, etc. can be performed by ingestion of the compound in the present invention.
[Brief description of the drawings]
FIG. 1 shows a TLC of Example 1 of the present invention.

Claims (3)

Human prostaglandin D ₂ synthase inhibitor comprising as an active ingredient a compound represented by the following general formula (I).
In formula (I), A represents —O— or —CO—, R ¹ represents —SO ₂ (OH), —PO ₃ H or —COOH, or a salt thereof (Na ⁺ , K ⁺ , NH ₄ ⁺ ), R ² represents —SO ₂ NH ₂ , —SO ₂ N (R ⁴ ) ₂ , CON (R ⁴ ) ₂ , CONH (R ⁴ ), and R ⁴ represents a hydrogen atom or a carbon number of 1 to Up to 6 alkyl groups are shown.
R ¹ may be present at either the 2-position or the 3-position , and R ² may be present at any position of ortho, meta, and para. An allergy preventive or therapeutic agent, sexual cycle regulator, sleep regulator, body temperature regulator, analgesic or olfactory regulator comprising the compound according to claim 1. A health food / beverage product, functional food / beverage product or fortified food / beverage comprising the compound according to claim 1 and having allergy prevention or treatment, sexual cycle regulation, sleep regulation, body temperature regulation, analgesia or olfactory regulation. Goods.