JP2000080030A - Agent for preventing and treating granuloma - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine manifesting excellent preventive and remedy activities against granuloma, especially larynx granuloma by including a specific quinone derivative or the like. SOLUTION: This medicine contains about 0.1-80 wt.% quinone derivative of the formula [R1 and R2 are each methyl, methoxy or the like; R3 is a (substituted) phenyl, naphthyl or the like; R4 is carboxy or a group capable of being converted into the carboxyl in vivo; (n) is 3-15], or hydroquinone body thereof [preferably 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid], preferably in a proportion of about 0.1-80 wt.% based on the whole amount. For example, when the medicine is orally administered to an adult patient (having 60 kg body weight) to treat intubation-associated larynx granuloma, the dose is about 0.1-10 mg/kg body weight, and one to two doses are administered per day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for preventing or treating granuloma comprising a quinone or hydroquinone derivative.

[0002]

2. Description of the Related Art Granulomas are nodular inflammatory disorders.
It is usually a small, granular, hard, persistent lesion with a dense cluster of mononuclear phagocytes. For example, laryngeal granuloma is a non-specific granuloma that occurs in the internal part of the arytenoid vocal fold process. Depending on the cause, 1) contact granuloma, 2) intubation granuloma, 3) granuloma due to reflux of gastric juice. are categorized. However, at present, no effective therapeutic agent has been developed. JP-A-61-044840 discloses a compound represented by the general formula (I
a):

Embedded image Wherein R ¹ and R ² are either a methyl group or a methoxy group, attached R ¹ and R ² together with R ¹ and R ² -
R ³ represents an optionally substituted phenyl, naphthyl or thienyl group; R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo; Represents an integer of 3 to 15. The compound containing a quinone derivative or a hydroquinone derivative thereof is useful as an anti-asthmatic agent, anti-allergic agent or cerebral circulatory system improving agent. JP 6
No. 3,101,322 discloses that the compound (Ia) has a thromboxane A ₂ receptor antagonistic action, and is an antithrombotic agent, an anti-vasoconstrictor, an anti-vasoconstrictor, an anti-hypertensive, an anti-asthmatic, or an anti-artery It is described as being useful as sclerosis. JP-A-7-228526 describes that the compound (Ia) is useful as an antiallergic rhinitis agent. However, the compound (Ia)
There is no literature that describes or suggests that has therapeutic effects on granuloma such as laryngeal granuloma.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel pharmaceutical composition which exhibits an excellent preventive / therapeutic effect on granulomas, especially on laryngeal granulomas.

[0004]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the compound (Ia) used as an anti-asthmatic or anti-allergic rhinitis agent, etc. However, they have found that they have unexpectedly excellent therapeutic effects on granuloma such as laryngeal granuloma, and have completed the present invention.

That is, the present invention relates to (1) a compound represented by the general formula (I)
a):

Embedded image [Wherein, R ¹ and R ² each represent a methyl group or a methoxy group, or R ¹ and R ² may combine with each other to represent —CH ＝ CH—CH ＝ CH— with R ¹ and R ² , R ³ represents an optionally substituted phenyl, naphthyl or thienyl group, R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in a living body, and n represents an integer of 3 to 15. ]
A prophylactic / therapeutic agent for granuloma comprising a quinone derivative represented by the formula or a hydroquinone derivative thereof,

(2) The first (1) wherein the granuloma is a laryngeal granuloma
(3) The prophylactic / therapeutic agent according to (2), wherein the laryngeal granuloma is intubated laryngeal granuloma, (4) R
The prophylactic / therapeutic agent according to the above (1), wherein ¹ and R ² are each a methyl group, (5) R ³ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a halogen, a hydroxyl group , methylenedioxy or an agent for the prophylaxis or treatment of the above (1), wherein the phenyl group optionally substituted by trifluoromethyl, (6) R ³ is at least one substituent selected from lower alkyl groups and halogen The prophylaxis according to (1) above, which is a phenyl group which may be substituted with a group.
A therapeutic agent, (7) wherein R ³ is a phenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-thienyl group or
The prophylactic / therapeutic agent according to the above (1), which is a thienyl group,
(8) the prophylactic / therapeutic agent according to the above (1), wherein R ⁴ is a carboxyl group or a hydroxymethyl group;
The prophylactic / therapeutic agent according to the above (1), which is an integer of 9, and (10) a quinone derivative comprising 7- (3,5,6-trimethyl-
The prophylactic / therapeutic agent according to the above (1), which is 1,4-benzoquinon-2-yl) -7-phenylheptanoic acid.

[0007] Granuloma is a nodular inflammatory disease, usually a small, granular, hard, persistent lesion in which mononuclear phagocytes are densely clustered. As granulomas, for example, laryngeal granulomas, sunlight granulomas, amoebic granulomas, annular granulomas,
Beryllium granuloma, Bilharz resorption granuloma, dog sexually transmitted granuloma, coccidiotic granuloma, periodontal granuloma, endemic granuloma, eosinophilic granuloma, facial granuloma, foreign body granuloma, gangrene granuloma, Giant cell granulomas, gestational granulomas, infectious granulomas, inguinal granulomas, tropical inguinal granulomas, lipoid granulomas, granulomas, lipid phagocytotic granulomas, majocchi granulomas, malignant granulomas, pleomorphic granulomas Tumors, parasitic granulomas, perineal granulomas, schistosomiasis granulomas, sea urchin granulomas, silicon granulomas, pool granulomas, vasodilator granulomas, tropical granulomas, ulcerative vulvar granulomas, sexually pathogenic Granulomas, zirconium granulomas, allergic granulomatosis, central bronchial granulomatosis, lipoid granulomatosis,
Examples include lymphomatous granulomatosis, Meisher's granulomatosis, iron deposit granulomatosis, Wegener's granulomatosis, cutaneous granulomas, and among others, laryngeal granulomas are preferred. Laryngeal granulomas include contact granulomas, intubated granulomas, and granulomas due to reflux of gastric juice, with intubated granulomas being particularly preferred.

In the general formula (Ia), preferably, both R ¹ and R ² are methyl groups. As the naphthyl group represented by R ³ , 1- or 2-naphthyl bacteria are used, and as the thienyl group, 2- or 3-thienyl is used. R ³ is preferably an optionally substituted phenyl group or thienyl group, more preferably a phenyl group. Each of the phenyl, naphthyl, and thienyl groups represented by R ³ may have 1 to 3 substituents at any position on the ring. Such substituents include, for example, those having 1 carbon atom.
To 4 lower alkyl groups (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, etc.) and lower alkoxy groups having 1 to 4 carbon atoms (eg, methoxy, ethoxy, n-propoxy, i-propoxy) And the like, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, etc.), a hydroxyl group, a methylenedioxy group, a trifluoromethyl group, and the like. As the substituent, particularly a lower alkyl group,
A halogen atom is preferable, and a fluorine atom and a methyl group are more preferable. R ³ is particularly preferably a phenyl group, a 3- or 4-methylphenyl group, a 3- or 4-fluorophenyl group, a 2-thienyl group or a 3-thienyl group.

Examples of the group which can be converted into a carboxyl group in the living body represented by R ⁴ include a methyl group, an optionally substituted hydroxymethyl group, and a carboxyl group which may be esterified or amidated. Can be Examples of the optionally substituted hydroxymethyl group include, in addition to an unsubstituted hydroxymethyl group, for example, a methoxymethyloxy group, an acetoxymethyl group, a nitroxymethyl group,
An aminocarbonyloxymethyl group and the like are used. As the esterified carboxyl group, for example, a lower alkoxycarbonyl group having 2 to 8 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, pivaloyloxymethoxycarbonyl, etc.) is used. Examples of the carboxyl group which may be amidated include, for example, an aminocarbonyl group, a hydroxyaminocarbonyl group, a monoalkylaminocarbonyl group having 2 to 4 carbon atoms (eg, methylaminocarbonyl, ethylaminocarbonyl, etc.), a carbon atom having 3 carbon atoms. To 5 dialkylaminocarbonyl groups (eg, dimethylaminocarbonyl), cyclic aminocarbonyl groups (eg, morpholinocarbonyl, thiomorpholinocarbonyl). R ⁴ is preferably a carboxyl group or a hydroxymethyl group.

The hydroquinone compound of the compound represented by the general formula (Ia) is represented by the general formula (Ib):

Embedded image Wherein each symbol is as defined above. ] Is shown. Of the above compounds (Ia) and (Ib),
R ³ is phenyl, 3- or 4-methylphenyl, 3-
Alternatively, 4-fluorophenyl, 2-thienyl or 3-thienyl, a compound in which R ⁴ is a carboxyl group or hydroxymethyl and the number (n) of methylene groups is an integer of 5 to 9 is used as an active ingredient in the present invention. More preferred as a compound. In particular, 7- (3,5,6-trimethyl-1,
4-Benzoquinon-2-yl) -7-phenylheptanoic acid is preferred. The compound represented by the general formula (Ia) or (Ib) has an R-form and an S-form, and the present invention includes both isomers. When R ³ is an aryl group such as phenyl and naphthyl, the R-form is preferable from the viewpoint of efficacy.

The compounds (Ia) and (Ib) used as the active ingredients of the present invention are described in JP-A-61-04484 or JP-A-63-101322, and are described by the methods described therein. Can be manufactured. For example, compound (Ib) is obtained by reacting a corresponding hydroquinone compound having no asymmetric side chain with a compound represented by the formula: CH (OH) R ₃ — (CH ₂ ) n—R ⁴ in the presence of an acid catalyst. It can be manufactured by doing. Compound (Ia) can be produced by oxidizing compound (Ib). The quinone derivative represented by the above formula (Ia) can be biochemically interconverted with the hydroquinone derivative represented by the formula (Ib) in vivo, and these compounds have physiological and pharmacological properties. They can be considered equivalent in terms of their significance. The compounds (Ia) and (Ib) used as the active ingredient in the present invention have a bulky group at the carbon at the alpha (α) position of the side chain of the quinone nucleus or hydroquinone nucleus and have an asymmetric center.
In this action, one of the optical isomers due to the asymmetric center exhibits a specific strong activity, but a racemic compound does not cause any particular problem in the efficacy. The compound used as an active ingredient in the present invention is less susceptible to an inactivation reaction due to metabolism in vivo due to a structure having a bulky group at the carbon at the α-position of the side chain, and can increase the effective drug concentration in blood for a long time. It can be maintained and shows excellent efficacy at low dosages.

The compound used as an active ingredient in the present invention has low toxicity, for example, (±) -7- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -7-phenylheptane The acid was administered to 5 groups of 5 week-old ICR male mice per group.
After oral administration of 000 mg / kg, no deaths were observed for 7 days. The compound used as an active ingredient in the present invention may be a pharmaceutical composition as it is or mixed with a non-active ingredient such as a pharmacologically acceptable carrier known per se [eg, tablets (including sugar-coated tablets, film-coated tablets), powders] ,
Granules, capsules (including soft capsules and microcapsules), syrups, emulsions, suspensions, solutions, injections (eg, subcutaneous injections, intradermal injections, intramuscular injections, etc.), suppositories, sustained release Agent etc.] for the treatment and prevention of laryngeal granuloma. For example, an injection is used in a manner known per se, that is, the compound (Ia) or (Ib) is used as it is or together with another drug. As the aqueous solution for injection, for example, physiological saline, isotonic solution and the like are used,
If necessary, they may be used in combination with the following suspending agents. As the oily liquid, for example, sesame oil, soybean oil, and the like are used, and a dissolution aid shown below may be used in combination. The prepared injection solution is usually filled into a suitable ampoule.
As the pharmacologically acceptable carrier that may be used in the production of the pharmaceutical composition of the present invention, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Solvents, binders, disintegrants; solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers, soothing agents and the like are used. Also, if necessary,
Additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can also be used.

As the excipient, for example, lactose, sucrose, D
-Mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like are used. As the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like are used. Examples of the binder include crystalline cellulose, sucrose,
D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, corn starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like are used. As the disintegrant, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose and the like are used. As the solvent, for example, water for injection, alcohol, propylene glycol,
Macrogol, sesame oil, corn oil and the like are used. Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
Sodium citrate or the like is used. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate;
Polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,
Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose are used. As the tonicity agent, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like are used. As the buffer, for example, buffers such as phosphate, acetate, carbonate, citrate and the like are used. As the soothing agent, for example, benzyl alcohol and the like are used. As the preservative, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like are used. As the antioxidant, for example, sulfite, ascorbic acid and the like are used.

The compound (I) in the pharmaceutical composition of the present invention
The content of a) or (Ib) is usually about 0.1 to 100% by weight, preferably about 0.1 to 80% by weight based on the whole preparation.
% By weight. The content of a non-active ingredient such as a carrier in the pharmaceutical composition of the present invention is usually about 0.5 to the whole preparation.
1 to 99.9% by weight, preferably about 0.1 to 90% by weight
It is. When the pharmaceutical composition of the present invention is used as a prophylactic / therapeutic agent for laryngeal granuloma, compound (Ia) or (Ib)
In addition, a drug having a prophylactic or therapeutic effect on laryngeal granuloma (eg, beclomethasone, beclomethasone propionate (trade name: aldesin), etc.) may be added. In addition, at or before and after administration of the pharmaceutical composition of the present invention, drugs having a preventive / therapeutic effect on laryngeal granuloma (eg, beclomethasone, beclomethasone propionate (trade name:
Aldesine) may be used in combination as an inhalant. The pharmaceutical composition of the present invention can be used not only for humans but also for other mammals (eg, mice, rats, guinea pigs, rabbits,
Dogs, cats, sheep, horses, cows, pigs, monkeys, etc.). Further, the pharmaceutical composition of the present invention has low toxicity and few side effects. The administration route of the pharmaceutical composition of the present invention may be oral or parenteral (eg, topical, rectal, intravenous administration, etc.). The dosage varies somewhat depending on the administration subject, administration route, symptoms, and the like. For example, in the case of oral administration to an adult patient (as 60 kg) for the treatment of intubated laryngeal granuloma, the dose is usually about 0.1 mg. It is convenient to administer about 1 mg / kg to 20 mg / kg body weight, preferably about 0.1 mg / kg to 10 mg / kg body weight about once or twice a day.

[0015]

Next, the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples.

EXAMPLES Example 1 Production of tablets Tablets containing 40 mg of the active ingredient were produced by a conventional method. The composition of the composition of the 40 mg tablet is shown below. (±) -7- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -7-phenylheptanoic acid 40.0 mg hydroxypropylcellulose 3.6 magnesium stearate 0.4 corn starch 18. 0 Lactose 58.0 Total 120.0mg

Example 2 Preparation of tablets Tablets containing 80 mg of the active ingredient were prepared by a conventional method. The composition of the 80 mg tablet is shown below. (±) -7- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -7-phenylheptanoic acid 80.0 mg hydroxypropylcellulose 5.0 magnesium stearate 0.5 corn starch 24. 5 Lactose 50.0 Total 160.0mg

Example 3 Production of Granules Granules containing the active ingredient (10%) were produced by a conventional method. The composition of the 10% granules is shown below. (±) -7- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -7-phenylheptanoic acid 100.0 mg hydroxypropylcellulose 30.0 carmellose calcium 30.0 talc 10.0 Poloxamer 188 20.0 Microcrystalline cellulose 70.0 Maize starch 300.0 Lactose 440.0 Total 100.0mg

Test Example 1 Therapeutic effect of laryngeal granuloma Patient: 54-year-old male Test: A male (54-year-old) with intubated laryngeal granuloma was treated with 7- (3,5,6-trimethyl) on January 23, 1997. -1,4-benzoquinon-2-yl) -7-phenylheptanoic acid 8
Treatment with a 0 mg / day dose was started. February 20, 1997
On the day, the laryngeal granuloma shrank.

Test Example 2 Therapeutic effect of laryngeal granuloma (combined use with beclomethasone propionate inhalation) Test: After test example 1, beclomethasone propionate inhalation was added twice a day, 4 times a day, and it was March 5 The laryngeal granuloma almost disappeared.

Test Example 3 Therapeutic effect of intubated laryngeal granuloma (combination with inhalation of beclomethasone propionate) Patient: 51 years old Female chief complaint: laryngeal discomfort, hoarseness Medical history: operation on February 22, 1996 for subarachnoid hemorrhage Enforced. At this time, she underwent 42 hours of endotracheal intubation. After the operation, there was no occurrence, and on March 12, minimal granulation was observed in the posterior part of both vocal cords. On March 25, she underwent another 2.5 hours of endotracheal intubation for cranioplasty. From around May, laryngeal discomfort and hoarseness increased. A tumor was observed that obstructed the glottis with stems at the posterior sides of both vocal cords. Intubated laryngeal granulomas were treated with inhalation of beclomethasone and oral clarithromycin, but the granulation was large and the dyspnea was increased. On June 25, the tumor was removed and a steroid was locally injected into the base. . Pathological examination revealed a vascular-rich granulation tissue accompanied by infiltration of inflammatory cells, mainly lymphocytes. From early September, two and a half months after surgery, laryngeal discomfort and hoarseness reappeared and gradually increased. On September 19, granulation of bilateral vocal cords was observed, and oral administration of betamethasone / chlorpheniramine combination and inhalation of beclomethasone were started. On October 17, there was no improvement in symptoms and findings, but rather a tendency to hatred. Test: On October 17, the oral administration was changed to 80 mg of 7- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) -7-phenylheptanoic acid. After one month, the granulation disappeared on the left side and reduced on the right side on November 11, one month later, and the granulation disappeared completely on December 12, two months later.

Test Example 4 Therapeutic effect of skin granuloma SD male rats (5 weeks old, CLEA Japan) were used in groups of 10 rats. Cotton ball method, Winter, CA Risley, EA
and Nuss, GW (J. Pharmacol. Exp. Ther. 141, 369,
1963). Under anesthesia by intraperitoneal injection of pentobarbital, the back was shaved and the back skin was incised about 1 cm. 30 ± 1m autoclaved from the site
One g of cotton ball was implanted under the skin on the left and right ventral sides. 7- (3,
5,6-trimethyl-1,4-benzoquinon-2-yl)
-7-Phenylheptanoic acid (Compound 1) was orally administered once daily from the day of implantation of a cotton ball for 7 days (0.5 ml / 100
g, bw). On the 8th day, the animals were exsanguinated and killed, and the cotton balls wrapped with granulation were excised, weighed (wet weight), and then 65 ° C.
And dried for 12 hours, granulation weight (wet weight and dry weight)
Then, the inhibition rate (%) with respect to the control group was calculated. The experimental results are shown as a mean value ± standard error. For the significance test between the mean values, a one-way analysis of variance is performed, and when the F value is significant,
Dunnett's multiple comparison test was performed using BSAS. The results are shown in Table 1.

[0022]

[Table 1] As is evident from Table 1, 7- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) -7-phenylheptanoic acid was obtained at 30 and 100 mg / day, po, wet weight and dry weight. It showed a significant dose-dependent inhibitory effect on weight.

[0023]

The pharmaceutical composition containing the compound of the general formula (Ia) or (Ib) has excellent preventive and therapeutic effects on granuloma such as laryngeal granuloma.

Claims (10)

[Claims] 1. A compound of the general formula (Ia): Wherein R ¹ and R ² are either a methyl group or a methoxy group, attached R ¹ and R ² together with R ¹ and R ² -
R ³ represents an optionally substituted phenyl, naphthyl or thienyl group; R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo; Represents an integer of 3 to 15. And / or a hydroquinone derivative thereof. 2. The preventive / therapeutic agent according to claim 1, wherein the granuloma is a laryngeal granuloma. 3. The preventive / therapeutic agent according to claim 2, wherein the laryngeal granuloma is intubated laryngeal granuloma. 4. The prophylactic / therapeutic agent according to claim 1, wherein R ¹ and R ² are each a methyl group. 5. R ³ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a halogen, a hydroxyl group, a phenyl group which may be substituted by methylenedioxy or trifluoromethyl. The prophylactic / therapeutic agent according to claim 1. 6. The preventive / therapeutic agent according to claim 1, wherein R ³ is a phenyl group which may be substituted with at least one substituent selected from a lower alkyl group and a halogen. 7. R ³ is a phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3-methylphenyl group,
The prophylactic / therapeutic agent according to claim 1, which is a 4-methylphenyl group, a 2-thienyl group or a 3-thienyl group. 8. The method according to claim 1, wherein R ⁴ is a carboxyl group or a hydroxymethyl group. 9. The method according to claim 1, wherein n is an integer of 5 to 9. 10. The agent according to claim 1, wherein the quinone derivative is 7- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) -7-phenylheptanoic acid.