JP2008239540A - Prophylactic and/or therapeutic agent for endometriosis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic and/or therapeutic agent and the like for endometriosis, containing a dibenzo[b,e]oxepin derivative or a pharmacologically permissible salt thereof as an active ingredient. <P>SOLUTION: The prophylactic and/or therapeutic agent for endometriosis comprises a dibenzo[b,e]oxepin derivative represented by formula (I) (wherein, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>are the same or different and are each H or a lower alkyl; and m and n are the same or different and are each an integer of 1-4) or a pharmacologically permissible salt thereof as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a preventive and / or therapeutic agent for endometriosis, which contains a dibenzo [b, e] oxepin derivative or a pharmacologically acceptable salt thereof as an active ingredient.

  Endometriosis has been reported in Japan as a disease affecting approximately 10% (approximately 2.8 million) of women of reproductive age. In recent years, as women's self-medication awareness has increased, not only in the medical field but also in general women (Pipeline Insight: Endometriosis. Datamonitor; 2004.). Symptoms include menstrual pain, pelvic pain, intercourse pain, irregular menstruation, etc., and many reports point to a relationship with infertility. However, the etiology is unknown and treatment methods are limited.

Methods for treating endometriosis are mainly classified into drug therapy and surgical therapy.
Examples of drug therapy include symptomatic treatment by administration of analgesics, etc., and treatment of this disease such as hormone therapy by administration of oral contraceptives, etc. [Gynecological treatment, Vol. 78, No. 2, pp. 179-182 ( 1999)]. Pharmacotherapy is centered on hormone therapy, and high-priced gonadotropin-free hormone (GnRH) analogs occupy the majority of therapeutic drugs in Japan (Pipeline Insight: Endometriosis. Datamonitor; 2004.). GnRH analogs are highly effective and are effective in more than 80% of patients, but many women are reluctant to work on hormonal balance (Pipeline Insight: Endometriosis. Datamonitor; 2004.). Moreover, the medicine which cures endometriosis has not been developed so far. In addition, there are cases where surgical therapy is inadequate.

  In recent years, it has been pointed out that predisposition to allergy is involved in endometriosis (see Patent Documents 1 and 2), and clinical application of antiallergic drugs has been attempted [Konno R, Fujiwara H, Suzuki M. Effectiveness of leukotriene Fam Med. 2004; 36 (1): 8-9.] receptor antagonists for dysmenorrhea of endometriosis. However, at present, attempts to use antiallergic drugs for the treatment of this disease, which has been regarded as a hormone (estrogen) -dependent disease for many years, are not accepted by not only general clinicians but also specialists.

On the other hand, dibenzo [b, e] oxepin derivatives or pharmacologically acceptable salts thereof are compounds having, for example, antiallergic action, anti-inflammatory action, anti-asthma action, chronic sinusitis treatment action, sleep disorder treatment action, etc. (See Patent Documents 3 to 10 and Non-Patent Document 1).
Among them, (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid [compound (IA)] has histamine antagonistic activity (Non-patent Documents 2 and 3), chemical mediator release inhibitory action (see Non-Patent Document 4), inflammatory cytokine release inhibitory action (see Non-Patent Document 5), tachykinin release inhibitory action (see Non-Patent Document 6), allergic rhinitis therapeutic action (See Non-Patent Documents 7 and 8) and the like, and is clinically used as an antiallergic drug.
JP 2002-187855 A International Publication No. 02/49670 Pamphlet Japanese Patent Publication No. 5-86925 U.S. Patent No. 1282365 Japanese Unexamined Patent Publication No. 56-150082 JP 58-126883 A JP 59-227879 JP 60-28972 A International Publication No. 2005-102313 Pamphlet International Publication No. 2006-009093 Pamphlet "Journal of Medicinal Chemistry (J. Med. Chem.)", 1978, Vol. 21, pp. 633-639 "Pharmacology and Clinical Practice", 1995, Vol. 5, p. 1817-1824 “Pharmacology and Clinic”, 1995, Vol. 5, p.1825-1835 “International Archives of Allergy and Immunology”, 1996, 110, p.57-63 “Acta Ophthamol. Scand.”, 1999, 228, p.33-37 “Japanese Journal of Pharmacology (Jpn. J. Pharmacol.), 2001, Vol. 117, pp. 967-973 "Oto-nose", 1996, Vol. 42, p.633-658 "Allergy Clinical," 2003, Vol. 23, p.63-75

  An object of the present invention is to provide a prophylactic and / or therapeutic agent for endometriosis containing a benzo [b, e] oxepin derivative or a pharmacologically acceptable salt thereof as an active ingredient.

The present invention relates to the following (1) and (2).
(1) Formula (I)

（式中、R¹、R²およびR³は同一または異なって水素原子または低級アルキルを表し、mおよびnは同一または異なって1〜4の整数を表す）で表されるジベンゾ[b,e]オキセピン誘導体またはその薬理学的に許容される塩を有効成分として含有する子宮内膜症の予防および／または治療剤。
（2）式（IA）

(Wherein R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom or lower alkyl, and m and n are the same or different and each represents an integer of 1 to 4) A prophylactic and / or therapeutic agent for endometriosis comprising an oxepin derivative or a pharmacologically acceptable salt thereof as an active ingredient.
(2) Formula (IA)

で表される(Z)-11-(3-ジメチルアミノプロピリデン)-6,11-ジヒドロジベンゾ[b,e]オキセピン-2-酢酸またはその薬理学的に許容される塩を有効成分として含有する子宮内膜症の予防および／または治療剤。

Contains (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or a pharmacologically acceptable salt thereof as an active ingredient Preventive and / or therapeutic agent for endometriosis.

  The present invention provides a preventive and / or therapeutic agent for endometriosis, which contains a dibenzo [b, e] oxepin derivative or a pharmacologically acceptable salt thereof as an active ingredient.

In the present specification, the compounds represented by formula (I) and formula (IA) are referred to as compound (I) and compound (IA).
Examples of the lower alkyl in the definition of each group of formula (I) include linear or branched alkyl having 1 to 8 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like.

Examples of the pharmacologically acceptable salt of compound (I) or compound (IA) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. It is done.
Examples of the pharmacologically acceptable acid addition salt of compound (I) or compound (IA) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, Examples include organic acid salts such as tartrate, citrate and methanesulfonate, and pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, magnesium salt and calcium salt Alkaline earth metal salts, aluminum salts, zinc salts, and the like, and pharmacologically acceptable ammonium salts include, for example, salts such as ammonium and tetramethylammonium, and pharmacologically acceptable organic salts. Examples of amine addition salts include addition salts such as morpholine and piperidine. Examples of pharmacologically acceptable amino acid addition salts include lysine, glycine, and phenylaramid. Down, aspartic acid, addition salts of glutamic acid and the like. Of these, monohydrochloride is more preferable.

The production method of compound (I) and compound (IA) is not particularly limited, but compound (I) and compound (IA) can be obtained by, for example, the method described in JP-B-5-86925 or the like or a method analogous thereto. Can do. The intermediate can be subjected to the next reaction without any particular purification.
The target compound in the above production method can be isolated and purified by subjecting it to purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography.

When it is desired to obtain a salt of Compound (I) or Compound (IA), if Compound (I) or Compound (IA) is obtained in the form of a salt, it can be purified as it is, or it can be obtained in a free form. In this case, compound (I) or compound (IA) may be dissolved or suspended in a suitable solvent, and an acid or base may be added to form a salt.
In addition, compound (I), compound (IA) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also present in the uterus of the present invention. It can be used as a preventive and / or therapeutic agent for endometriosis.

Compound (I), compound (IA) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
The pharmaceutical preparation according to the present invention can contain Compound (I), Compound (IA) or a pharmacologically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient. . In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.

The administration route of the agent for preventing and / or treating endometriosis of the present invention is desirably the most effective in the treatment, and can include oral administration or parenteral administration such as intravenous administration. Oral administration is preferred.
Examples of preparations suitable for oral administration include capsules and tablets. Capsules, tablets and the like include, for example, excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropylcellulose, gelatin Etc., a surfactant such as a fatty acid ester, a plasticizer such as glycerin, and the like can be used as additives.

Examples of preparations suitable for parenteral administration include injections. The injection is prepared using, for example, a carrier composed of a salt solution, a glucose solution, or a mixture of both. In these parenteral preparations, the components exemplified as additives for oral preparations can also be added.
The dose or frequency of administration of the preventive and / or therapeutic agent for endometriosis of the present invention varies depending on the intended therapeutic effect, administration method, treatment period, age, weight, etc., but usually 10 μg / kg per adult day ~ 100 mg / kg.

Next, the effect of compound (I) on endometriosis will be specifically described with reference to test examples.
Test example: Effect of olopatadine hydrochloride [monohydrochloride of compound (IA)] on endometriosis This test was performed by a known method [Human Reproduction, Vol. 14, 2944-2950 (1999) )] Was modified.

  Balb / c female mice (Charles River Japan, Inc.) over 8 weeks of age that are considered to be sexually matured in mice were subjected to the experiment. After an acclimation period of 1 week after purchase, all individuals (25 donor mice, 33 recipient mice; 9 recipient mice, 9 mice in the 1 mg / kg group) Seven animals in the 10 mg / kg administration group, 9 in the positive control group, and 8 in the negative control group) were subjected to right and left ovariectomy, and then estrogen was administered exogenously. That is, pentobarbital [Somnopentyl (registered trademark), Takeda Schering-Plull Animal Health Co., Ltd.] 50 mg / kg was intraperitoneally administered to the back skin of a mouse anesthetized by about 1 cm along the midline. An incision (about 2 mm) was made in the peritoneum at the location of the left and right ovaries. The bilateral ovaries were removed from the cuts, and the back skin was quickly sutured and returned to the cage. Thereafter, 100 μg / kg of estrogen [Proginone (registered trademark) Depot 10 mg, Nippon Schering, estradiol valerate injection solution] was injected into the left hind limb muscle.

  Then, one week after the ovariectomy, the endometrial piece prepared by removing the uterus of the donor mouse was seeded in the abdominal cavity of the recipient mouse. That is, the peripheral adipose tissue and cervix were removed from the left and right uterus extracted from a donor mouse that had been exsanguinated, and the uterine body including the intima was cut into small pieces with a small surgical scissors. Endometrial strips in sterile HBSS solution (Hank's Balanced Salt Solution, Sigma) containing antibiotics [penicillin (50 units / mL) / streptomycin (100 μg / mL) (Lot. No. 1220027, Invitrogen)] Suspended and combined all donor mice into one. This recipient endometrial suspension 0.8 mL (equivalent to about 50 mg as an endometrial fragment) was intraperitoneally injected into a recipient mouse that had been anesthetized with pentobarbital 40 mg / kg using a syringe with a 20G needle (Terumo). Administered and seeded. The filling and administration of the endometrial fragment suspension into the syringe were performed so that the suspension was well agitated and not uneven. Thereafter, 100 μg / kg of estrogen was administered to the positive control group and the drug administration group, and sesame oil as an estrogen solvent was intramuscularly administered to the negative control group once a week.

The dosage of olopatadine hydrochloride [Kyowa Hakko Kogyo Co., Ltd., commercially available: available as Alleloc (registered trademark)] is set to a dose (1, 10 mg / kg, po) that exhibits sufficient antihistamine action when administered to mice did. In the case of 10 mg / kg po, 1 mg / mL olopatadine hydrochloride aqueous solution is orally administered at a rate of 10 mL / kg, and in the case of 1 mg / kg po, 0.1 mg / mL olopatadine hydrochloride aqueous solution is 10 mL / kg. Orally administered at a ratio [administration solvent: distilled water for injection (Otsuka Pharmaceutical)]. Olopatadine hydrochloride was orally administered 1 hour before uterine section seeding, and then administered at approximately the same time (9:00 to 11:00) every day until the day before evaluation. In the positive control group, distilled water was orally administered in the same volume as the administration of olopatadine hydrochloride. No solvent was administered to the negative control group. The body weight was measured every week from the date of seeding of the uterine section, and the dose was calculated based on the latest body weight data.
Evaluation of pathological condition Three weeks after uterine section seeding, the mice were exsanguinated and then laparotomized, and macroscopic evaluation of serous endometriosis-like lesions (measurement of formed lesion size) was performed. The maximum diameter of each lesion was measured using a vernier caliper (minimum scale 0.5 mm), and the lesion size was calculated by multiplying the longitudinal diameter and the lateral diameter. When multiple lesions were formed, the total area was taken as the total area.

The lesion formed in this model is a serous cyst, but rarely an abscess occurs. Since the occurrence of abscesses is likely due to infection, data analysis was performed excluding individuals with abscesses. The lesion size results are shown as individual values and average values.
The results for lesion formation are shown in FIG. In mice seeded with uterine sections and administered with estrogen, the lesion area increased significantly and the formation of endometriosis-like lesions was observed. For this lesion formation, administration of olopatadine hydrochloride showed a significant inhibitory effect by decreasing the lesion area with increasing dose.

From the above results, it can be seen that olopatadine hydrochloride has a therapeutic effect on endometriosis, and that compound (I) and compound (IA) are effective as a preventive and / or therapeutic agent for endometriosis. It was.
Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Tablets Tablets having the following composition are prepared by a conventional method.
Formulation Compound (IA) monohydrochloride 5 mg
Lactose 61 mg
Potato starch 30 mg
Polyvinyl alcohol 3 mg
Magnesium stearate 1 mg
100 mg

Powder A powder having the following composition is prepared by a conventional method.
Formulation Compound (IA) 10 mg
Lactose 190 mg
200 mg

Injectable Injectable with the following composition is prepared by a conventional method.
Formulation Compound (IA) 2 mg
Refined soybean oil 200 mg
Purified egg yolk lecithin 24 mg
Glycerin for injection 50 mg
Distilled water for injection 1.72 mL
2.00 mL

Syrup preparation A syrup preparation having the following composition is prepared by a conventional method.
Formulation Compound (IA) 300 mg
Purified white sugar 40 g
Methyl paraoxybenzoate 40 mg
Ethyl paraoxybenzoate 10 mg
Strawberry flavor 1 mL
Appropriate amount of distilled water
100.00mL

It is a figure showing the lesion formation inhibitory effect of the endometriosis of olopatadine hydrochloride in a test example. From the left, the horizontal axis represents the negative control group, the positive control group, the olopatadine hydrochloride 1 mg / kg oral administration group, and the olopatadine hydrochloride 10 mg / kg oral administration group. The vertical axis represents the lesion area (mm ² ). ***: P <0.001 [Aspin-Welch test compared to positive control group] ##: P <0.01 [Dunnett test compared to positive control group] ###: P <0.001 [Dunnett test compared to positive control group]

Claims (2)

Formula (I)

(Wherein R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom or lower alkyl, and m and n are the same or different and each represents an integer of 1 to 4) A prophylactic and / or therapeutic agent for endometriosis comprising an oxepin derivative or a pharmacologically acceptable salt thereof as an active ingredient. Formula (IA)

Contains (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or a pharmacologically acceptable salt thereof as an active ingredient Preventive and / or therapeutic agent for endometriosis.

Images