JP2020114805A - THERAPEUTIC AGENT USING ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITING EFFECT, FOR PAIN FROM GYNECOLOGICAL DISORDER SUCH AS ENDOMETRIOSIS AND UTERUS ADENOMYOSIS AND/OR STRUCTURAL LESION - Google Patents

Abstract

To provide a pharmaceutical agent for treatment of pain associated with a gynecological disorder and/or treatment of an organic lesion caused by a gynecological disorder.SOLUTION: A therapeutic agent for pain associated with a gynecological disorder and/or an organic lesion caused by the gynecological disorder, the therapeutic agent containing an estrogen receptor α inhibiting β partial agonist represented by structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an effective component.SELECTED DRAWING: Figure 1

Description

The present invention relates to a therapeutic agent for pain and/or organic lesions in gynecological diseases such as endometriosis and adenomyosis using an estrogen receptor β partial agonist having an estrogen receptor α inhibitory action.

Gynecological diseases include diseases caused by abnormalities such as estrogen and progesterone. For example, endometriosis, uterine adenomyosis, uterine fibroids and the like can be mentioned.

Surgical treatment such as surgical resection is still the first choice for the treatment of such diseases. As a drug therapy, administration of leuprin or Spurecure which is used as a gonadotropin agonist (GnRH agonist) is known. Their mechanism of action is to reduce the amount of estrogen by suppressing the secretion of gonadotropin consisting of luteinizing hormone (LH)/follicle stimulating hormone (FSH). However, since these drugs have side effects such as a decrease in bone mineral content (bone mass) and symptoms of ovarian function deficiency, their use period is limited and long-term use is difficult.

Therefore, there is a demand for a drug that can be used in the long term as a therapeutic drug for pain and organic lesions caused by gynecological diseases such as endometriosis and adenomyosis.

Conventionally, tamoxifen (registered trademark: Nolvadex) has been used as a selective estrogen receptor modulator (hereinafter, abbreviated as "SERM") domestically in Japan since 1980 with an indication of breast cancer. This drug is said to have an antagonistic effect on the mammary gland by competitively inhibiting the binding of estrogen to the receptor. However, this drug has been reported to cause endometrial cancer, uterine sarcoma, or endometriosis, and is not used for the treatment of estrogen-dependent diseases including endometriosis. The mechanism of the proliferative action of this drug on the endometrium is believed to be due to its intrinsic partial agonistic action on the estrogen receptor.

Subsequently, fulvestrant (registered trademark: Fesodex) was approved as an estrogen receptor antagonist as a therapeutic agent for postmenopausal breast cancer. Unlike tamoxifen, this drug does not show an endogenous partial agonist action on the estrogen receptor, but is said to show a pure antagonist action. However, since this drug has a low digestive tract absorption rate, it must be administered intramuscularly, and its dosage form is an intramuscular preparation. Therefore, it is not used as an oral drug for the treatment of estrogen-dependent diseases.

As another SERM, raloxifene (registered trademark: Evista) is approved as an indication for treatment of osteoporosis. However, this drug is a therapeutic drug for osteoporosis whose mechanism of action is an increase in bone mass due to the action of partial agonist of estrogen receptor existing in bone, and exacerbates the recurrence of endometriosis which is an estrogen-dependent disease. Since it has been reported that it is not used for the treatment of gynecological diseases such as uterine fibroids, adenomyosis uteri, and endometriosis.

Furthermore, as another SERM, (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3, which was developed as a therapeutic agent for breast cancer, was used. 5(10)-Trien-3-ol or a pharmaceutically acceptable salt thereof is known (see Patent Documents 1 and 2).

Furthermore, as a progesterone receptor agonist, Dinagest (registered trademark) is used for the treatment of endometriosis. However, it is said that this drug causes frequent bleeding frequently, which is a big problem for patients.

Non-Patent Documents 1 to 7 are further cited as documents relating to these.

International Publication No. 2001/058919 International Publication No. 1999/033859

Clinical Cancer Research, vol. 11, 315-322, 2005 Metabolism and Disposition, vol. 34 (2), 331-338, 2006 BBRC, vol. 312, 656-662, 2003 Journal of Clinical Pharmacology and Therapeutics, vol. 30, 456-470, 2005 Clinical Cancer Research, vol. 10, 5425-5431, 2004 Basic & Clinical Pharmacology & Toxicology, vol. 104, 352-359, 2009 Annals of Oncology, vol. 714, 1-6, 2009

An object of the present invention is to provide a drug for treating pain associated with a gynecological disease and/or treating an organic lesion caused by a gynecological disease.

The present inventor has carried out clinical research on patients with endometriosis or adenomyosis as a result of the above-mentioned problems. As a result, surprisingly, the following structural formula (a) was synthesized and clinically researched for the purpose of treating breast cancer. The compound represented by: functions as an estrogen receptor α inhibition β partial agonist, and is excellent in the therapeutic effect of pain in patients with estrogen-dependent gynecological diseases consisting of endometriosis and adenomyosis, and has an organic structure. It was found that the effect of improving the change was exhibited, and the present invention was completed.

The present invention provides the following specific embodiments (1) to (5).
(1) Accompanied by a gynecological disease containing an estrogen receptor α-inhibiting β-partial agonist represented by the following structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient A therapeutic agent for pain and/or an organic lesion caused by the gynecological disease.

(2) The therapeutic agent according to (1) above, wherein the gynecological disease is estrogen-dependent gynecological disease.
(3) The therapeutic agent according to (1) or (2) above, wherein the gynecological disease is endometriosis and/or adenomyosis uteri.
(4) The therapeutic agent according to any one of (1) to (3) above, wherein the pain is menstrual pain and/or pelvic pain associated with the gynecological disease.
(5) The therapeutic agent according to any one of (1) to (4) above, wherein the organic lesion is ovarian chocolate cyst, induration of Douglas fossa, and/or limitation of uterine mobility.

Further, the present invention provides the following specific aspects (6) to (10).
(6) An estrogen receptor α inhibitor β partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for treating pain associated with a premenopausal gynecological disease and/or an organic lesion due to the premenopausal gynecological disease.
(7) An estrogen receptor α inhibitor β partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for reducing pain associated with a premenopausal gynecological disease, and/or improving an organic lesion caused by the premenopausal gynecological disease.
(8) For treating pain associated with premenopausal gynecological diseases and/or organic lesions due to the premenopausal gynecological diseases; estrogen receptor α inhibition β represented by the structural formula (a) above Use of a partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(9) For producing a drug for treating pain associated with premenopausal gynecological diseases and/or organic lesions due to the premenopausal gynecological diseases; estrogen receptor represented by the above structural formula (a) Use of body α inhibitory β partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(10) The therapeutic agent according to (1) above is preferably used orally.

According to the present invention, a drug for treating pain associated with a gynecological disease and/or an organic lesion due to a gynecological disease can be provided.

It is a graph which shows the evaluation result by VAS of the pelvic pain of Test Example 1. 9 is a graph showing the evaluation results of pelvic pain scores based on the total value of Test Example 2. 9 is a graph showing evaluation results of pelvic pain scores according to the degree of pelvic pain in Test Example 3. 9 is a graph showing the evaluation results of pelvic pain scores by using the analgesic of Test Example 4. 9 is a graph showing the evaluation results of menstrual pain scores based on the total value of Test Example 5. 7 is a graph showing the evaluation results of menstrual pain scores according to the degree of menstrual pain in Test Example 6. 9 is a graph showing the evaluation results of menstrual pain scores by using the analgesic of Test Example 7. It is a graph which shows the evaluation result of the ovarian chocolate cyst of Test Example 8. 9 is a graph showing the evaluation results of induration of Douglas fovea in Test Example 9. 9 is a graph showing the evaluation results of uterine mobility limitation in Test Example 10.

Hereinafter, embodiments of the present invention will be described in detail, but the following embodiments are examples for describing the present invention, and the present invention is not limited to these and does not depart from the gist thereof. It can be implemented by arbitrarily changing it within the range. In the present specification, for example, the notation of a numerical range of "1 to 100" includes both the upper limit value "1" and the lower limit value "100". The same applies to other numerical ranges.

[Estrogen receptor α inhibition, estrogen receptor β partial agonist]
The compound represented by the following structural formula (a) used in the present invention is orally active and has an estrogen receptor α inhibitory action and an estrogen receptor β partial agonistic action.

The compound represented by the structural formula (a) used in the present invention can be used as a free form, a pharmaceutically acceptable salt, or a hydrate thereof. The pharmaceutically acceptable salt is not particularly limited, but inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide and phosphate; acetate, trifluoroacetate, lactate, propion Acid salt, tartrate salt, glycolate salt, pyruvate salt, oxalate salt, malate salt, malonate salt, succinate salt, maleate salt, fumarate salt, tartrate salt, citrate salt, benzoate salt, silicate salt Examples thereof include organic acid salts such as cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate and the like. Among these, organic acid salts are preferable, and more preferable. Citrate, fumarate, succinate, benzoate, malonate, and more preferably citrate (hereinafter, the citrate of the compound may be abbreviated as "SR16234"). ..

The compound represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof used in the present invention may be produced, for example, according to the methods described in Patent Documents 1 and 2. it can.

The compound represented by the structural formula (a), a pharmaceutically acceptable salt thereof, and a hydrate thereof are different from each other such as chocolate cyst of ovary as shown in Examples described later. It has an action of suppressing the proliferation of resident endometrial tissue, and the growth suppressing action is stable for a long period of time. Moreover, it can be administered orally, does not cause drug-related adverse events, and can be safely used even by premenopausal patients.

That is, the drug of the present invention is particularly useful as a therapeutic agent for pain associated with a gynecological disease and/or an organic lesion due to a gynecological disease. Among gynecological diseases, it is useful as a therapeutic agent for estrogen-dependent gynecological diseases. Examples of estrogen-dependent diseases include endometriosis, adenomyosis uteri, deep endometriosis, endometrial hyperplasia, and mastopathy (endometriosis). mastopathy) and the like. Among these, it is particularly useful as a therapeutic agent for endometriosis, pain associated with adenomyosis uteri, and/or organic lesions caused by endometriosis and adenomyosis uteri.

Pain includes menstrual pain, dysmenorrhea, and/or pelvic pain.
Gynecological diseases and organic lesions include cysts and cysts caused by ectopic endometrial hyperplasia; Douglas fossa induration due to ectopic endometrial hyperplasia, and limited uterine mobility And the like. Specific examples of cysts caused by ectopic endometrial proliferation include, for example, ovarian chocolate cysts occurring in the ovary. Then, the drug of the present invention exerts a reducing effect, a eliminating effect, and an improving effect on the above-mentioned gynecological diseases and organic lesions. In the present specification, the growth of ectopic endometrial tissue means that the tissue of the endometrium proliferates other than the endometrium, for example, the muscle and ligament of the uterus and surrounding tissues, and ovary. , Douglas fossa, rectum, peritoneum, oviduct, vagina, cervix, bladder, ureter, lung, umbilicus, groin and the like.

[Pain associated with gynecological diseases, and/or therapeutic agent for organic lesions due to gynecological diseases]
The therapeutic agent for pain associated with a gynecological disease and/or the organic lesion due to a gynecological disease of the present invention (hereinafter referred to as “the present therapeutic agent”) is represented by the above structural formula (a) as an active ingredient. It contains at least a compound. The present therapeutic agent may contain other components as necessary. Other components are not particularly limited, but include stabilizers, surfactants, plasticizers, lubricants, solubilizers, buffers, sweeteners, base materials, adsorbents, corrigents, binders, and suspending agents. Agents, antioxidants, brighteners, coating agents, fragrances, fragrances, wetting agents, moisturizing agents, defoamers, chewing agents, cooling agents, coloring agents, sugar coating agents, isotonic agents, pH adjustment Agents, softeners, emulsifiers, adhesives, adhesion enhancers, thickeners, thickeners, foaming agents, excipients, dispersants, propellants, disintegrants, disintegration aids, fragrances, moisture barriers, preservatives Pharmaceutical additives such as agents, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents and the like can be mentioned.

The administration form of the present therapeutic agent may be appropriately selected depending on the age, weight, disease, symptom and the degree of the patient, and is not particularly limited. For example, oral preparations such as tablets (including sublingual tablets and orally disintegrating tablets), granules, powders, solutions, syrups (including dry syrups), jellies, capsules (including soft capsules and microcapsules), etc. Administration; injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), suppositories (including rectal suppositories, vaginal suppositories), inhalants, transdermal absorption agents, eye drops And parenteral administration such as nasal drops. These may be controlled-release preparations such as immediate-release preparations and sustained-release preparations. Among these, the oral preparations by oral administration are preferable from the viewpoints of easy administration, easy compliance with medication compliance, and easy cost reduction. As the oral preparation, tablets, solutions and syrups are preferable, and tablets are more preferable.

The dose of the present therapeutic agent is appropriately determined according to the age, sex, body weight, disease, symptom and degree of the patient. It is not particularly limited as long as it is a pharmaceutically effective amount, but in the range of 1 to 200 mg (0.25 to 50 mg/kg body weight) per day in oral administration in terms of free form of the compound represented by the structural formula (a). Is more preferable, more preferably 4 to 120 mg (1 to 30 mg/kg body weight) per day, further preferably 8 to 60 mg (2 to 15 mg/kg body weight), and particularly preferably 10 to 40 mg (2.5 to The range is 10 mg/kg body weight). On the other hand, in parenteral administration, the range of 0.001 to 10 mg/kg body weight per day is preferable, more preferably 0.01 to 5 mg/kg body weight per day, and further preferably 0.5 to 2 mg/kg per day. The range of weight.

The therapeutic agent can be administered once or in multiple doses. In this case, the total dose is usually 0.1 to 5000 mg, and it is desirable to administer it in a single dose or in divided doses.

In formulating the present therapeutic agent, additives known in the art can be blended, and methods known in the art, such as the method described in the 16th revised Japanese Pharmacopoeia, can be applied. .. For example, when preparing a solid preparation for oral use, after adding an excipient, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. to the active ingredient, molding and granulating according to a conventional method. By encapsulating, etc., coated tablets, granules, powders, capsules and the like can be produced. When preparing a liquid preparation for oral use, the active ingredient is a solvent such as purified water or ethanol, a solubilizing agent, a suspending agent, a tonicity agent, a flavoring agent, a buffering agent, a stabilizing agent, a flavoring agent. After the addition of etc., an internal solution, a syrup, etc. can be produced by, for example, preparing a packaged solution according to a conventional method. Further, when preparing an injection, after adding a pH adjuster, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. to the active ingredient, aseptically encapsulating in a container according to a conventional method. As a result, subcutaneous, intramuscular, intravenous injections and the like can be produced. When a rectal suppository is prepared, it can be prepared by adding an excipient, a surfactant and the like to the active ingredient, and then mixing and molding according to a conventional method. Ointments, for example, when prepared in the form of paste, cream and gel, the active ingredient is mixed with a base such as white petrolatum or paraffin, a stabilizer, a wetting agent, a preservative such as methyl paraoxybenzoate, and the like, Mixing and the like may be performed according to a conventional method. When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a support such as a woven fabric, a non-woven fabric or a plastic film by a conventional method.

The therapeutic agent is intended for treating pain associated with gynecological diseases and/or organic lesions due to gynecological diseases. As described above, it is preferable to target endometriosis and adenomyosis because it has an action of suppressing the growth of estrogen-dependent tumors, especially ectopic endometrial tissue. More preferably, the disease is targeted. Furthermore, since side effects such as bone loss are weak, it can be safely used even by premenopausal patients. Further, symptoms such as hypermenorrhea, irregular genital bleeding, dysmenorrhea, and pressure symptoms caused by these diseases can be alleviated or treated.

Hereinafter, the present invention will be described in more detail based on various test results, but the present invention is not limited thereto.

[Test Example: Confirmation of inhibitory effect on pain and organic lesions in patients with endometriosis/adenomyosis]
<Clinical trial protocol in patients with endometriosis and adenomyosis>
[1] Evaluation items (1) Main evaluation items: Pelvic pain measured by Visual Analogue Scale (VAS) (2) Secondary evaluation items: Pelvic pain score, Menstrual pain score, Objective findings (size of ovarian chocolate cyst) , Induration of Douglas fossa, limitation of uterine mobility), and physical findings

[2] Selection criteria for clinical trial subjects Ten patients with endometriosis and adenomyosis satisfying the following conditions were designated as clinical trial subjects.
・Outpatients over 20 years old ・Patients with menstrual cycle ・Patients clinically diagnosed with endometriosis or adenomyosis ・Pelvic pain with endometriosis

[3] Exclusion criteria for clinical trial subjects However, patients who meet any of the following conditions will not be included in clinical trial subjects.
・Estrogen-dependent tumors (eg breast cancer, endometrial cancer), cervical cancer or patients suspected of that ・Patients diagnosed with uterine fibroids with a major axis of 3 cm or more Patients with a history of osteoporosis, bone loss or other metabolic bone disorders

[4] Study design and study outline This study is an uncontrolled, open-label study.
The study consists of a screening period and a 12-week treatment period. During the screening period, a screening test was conducted within 6 weeks before the start of administration of the study drug, and it was confirmed that the above selection criteria were satisfied and that the above exclusion criteria were not violated. Then, in the treatment period, the test drug was administered for 12 weeks, and the above evaluation items were evaluated.

[5] Usage, Dose, and Duration of Administration of Study Drug In this study, 40 mg of the study drug (SR16234) was orally administered once a day for 12 weeks after breakfast.

[6] Evaluation method of pelvic pain by Visual Analogue Scale (VAS) VAS of pelvic pain was measured by the following method.
(1) VAS is a 100 mm straight scale with no scale, "No pain" is displayed at the left end of the straight line, and "The most intense pain I have ever experienced" is displayed at the right end. "The most intense pain I have ever experienced" was 100 mm, and "no pain" was 0 mm. According to this scale, the subject himself/herself evaluated the VAS of pelvic pain for each evaluation period.
(2) As the VAS of pelvic pain before administration, which is a criterion for evaluation, the strongest pelvic pain was evaluated in the period from immediately before the start of menstruation immediately before to the day before the start of the next menstruation.
(3) VAS of pelvic pain after the start of administration evaluated the strongest pelvic pain in each period every 4 weeks after the start of administration.

[7] Evaluation Method Using Pelvic Pain Score (1) The subject himself/herself evaluated in accordance with the evaluation criteria for the pelvic pain score shown in Table 1 below. The pelvic pain score can be evaluated by a pelvic pain score based on the sum of the degree of pelvic pain and the use of analgesics, a pelvic pain score based on the degree of pelvic pain alone, and a pelvic pain score based on the use of analgesics alone, respectively. ..
(2) The pelvic pain score before administration, which serves as a criterion for evaluation, was the score of the degree of pelvic pain and/or the use of an analgesic during the period from immediately before the start of the last menstruation to the day before the start of the next menstruation.
(3) The pelvic pain score after the start of administration was the score of the degree of pelvic pain and/or the use of an analgesic during each period every 4 weeks after the start of administration.

[8] Evaluation Method Based on Menstrual Pain Score (1) The subject himself/herself evaluated in accordance with the evaluation criteria for the menstrual pain score shown in Table 2 below. The menstrual pain score can be evaluated by a menstrual pain score based on the sum of the degree of menstrual pain and the use of analgesics, a menstrual pain score based on the degree of menstrual pain alone, and a menstrual pain score based on the use of only analgesics. ..
(2) The pre-administration menstrual pain score, which serves as a criterion for evaluation, was the score of the degree of menstrual pain during the period from the most recent start of menstruation to the next day before the start of menstruation and/or the use of an analgesic.
(3) The menstrual pain score after the start of administration was a score according to the degree of menstrual pain and/or the use of an analgesic during each period every 4 weeks after the start of administration.

[9] Ultrasound examination The presence or absence of ovarian chocolate cysts was observed by transvaginal ultrasound examination. The observation was performed 4 times before the start of administration and every 4 weeks after the start of administration. When the ovarian chocolate cyst was “present”, the diameter (mm) in three directions (D1, D2, D3) or two directions (D1, D2) was measured. The volume of the ovarian chocolate cyst was calculated from the obtained diameter.

[10] Internal examination (Induration of Douglas fossa)
According to the evaluation criteria shown in Table 3 below, the induration was evaluated for induration of the Douglas fossa.

[11] Internal examination (limitation of uterine mobility)
According to the evaluation criteria shown in Table 4 below, uterine mobility limitation was evaluated by pelvic examination.

[12] Physical findings Interviews and consultations were conducted after administration of the study drug, and the results were evaluated as clinically significant events as adverse events as compared with before administration of the study drug.

<Clinical test results in patients with endometriosis and adenomyosis>
[1] Test Example 1: Evaluation results of pelvic pain by VAS With respect to VAS, values before administration (Baseline) and results of change amount from Baseline at each time point are shown in Table 5, and the results are shown in a graph. As shown in FIG. In this example, unless otherwise specified, the evaluation result is the average value of the results of 10 subjects.

[2] Test Example 2: Evaluation result of pelvic pain score based on total value of degree of pelvic pain and use of analgesic The pelvic pain score based on the total value of pre-administration value and change amount from Baseline at each time point The results are shown in Table 6, and a graph showing the results is shown in FIG.

[3] Test Example 3: Evaluation result of pelvic pain score according to degree of pelvic pain With respect to the pelvic pain score depending on the degree of pelvic pain, the value before administration and the result of the amount of change from the Baseline at each time point are shown in Table 7. A graph showing the results is shown in FIG.

[4] Test Example 4: Evaluation results of pelvic pain score due to use of analgesics Table 8 shows the results of the pelvic pain score due to use of analgesics, the values before administration, and the amount of change from the Baseline at each time point. The results are shown in a graph in FIG.

[5] Test Example 5: Evaluation result of menstrual pain score based on total value of degree of menstrual pain and use of analgesic The menstrual pain score based on the total value of pre-administration value and change amount from Baseline at each time point The results are shown in Table 9, and a graph showing the results is shown in FIG.

[6] Test Example 6: Evaluation result of menstrual pain score according to the degree of menstrual pain With respect to the menstrual pain score according to the degree of menstrual pain, the results before administration and the amount of change from Baseline at each time point are shown in Table 10. A graph showing the results is shown in FIG.

[7] Test Example 7: Results of evaluation of menstrual pain score by use of analgesic Table 11 shows the results of the pre-administration value of the menstrual pain score by use of analgesic and the change amount from the Baseline at each time point. A graph showing the results is shown in FIG.

[8] Test Example 8: Evaluation results of ovarian chocolate cysts Table 12 shows the values before administration and the measurement results at each time point for the volume (mm ³ ) of ovarian chocolate cysts, and a graph showing the results. 8 shows. This measurement result shows the result of one subject.

[9] Test Example 9: Evaluation result of induration of Douglas fossa Regarding the score of severity of induration of Douglas fossa, the value before administration and the evaluation result at 12 weeks are shown in Table 13, and this result is shown in a graph. Is shown in FIG. This measurement result shows the result of 9 subjects.

[10] Test Example 10: Evaluation Results of Restriction of Uterine Mobility The values of the severity of restriction of uterine mobility before administration and the evaluation results at 12 weeks are shown in Table 14, and the results are shown in a graph. What was done is shown in FIG. This measurement result shows the result of 9 subjects.

[11] Test Example 11: Adverse Event Evaluation Results Table 15 shows the results of the adverse events observed during the clinical study. All of these adverse events were judged by the investigator to be unrelated to study drug administration.

[12] Discussion As shown in Table 5 and FIG. 1, pelvic pain measured by VAS was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared to Baseline (Test Example). 1).
In addition, as shown in Table 6 and FIG. 2, Table 7 and FIG. 3, and Table 8 and FIG. 4, respectively, the total value, the degree of pelvic pain, and the pelvic pain score due to the use of analgesics were 40 mg per day. Oral administration of SR16234 resulted in a statistically significant improvement compared with Baseline (Test Examples 2 to 4).
In addition, as shown in Table 9 and FIG. 5, Table 10 and FIG. 6, and Table 11 and FIG. 7, respectively, the total value, the degree of menstrual pain, and the menstrual pain score due to the use of analgesics were 40 mg per day. Oral administration of SR16234 resulted in a statistically significant improvement compared to Baseline (Test Examples 5 to 7).

Such pelvic pain/menstrual pain reducing effect in patients with endometriosis/uterine adenomyosis has not been clinically proved by SERM and estrogen receptor antagonist until now, and was first confirmed by administration of SR16234. It is an effect. Thus, by suppressing pain, it became possible to significantly improve the quality of life (QOL) of a patient.

Furthermore, as shown in Table 12 and FIG. 8, the volume of ovarian chocolate cysts was significantly improved compared to Baseline by oral administration of 40 mg of SR16234 per day, and decreased with time, and after 12 weeks. Completely disappeared (Test Example 8).

The improvement effect of the ovarian chocolate cyst, which is an organic lesion in patients with such endometriosis and adenomyosis, has not been clinically proven by SERMs and estrogen receptor antagonists, and SR16234 administration This is the first effect confirmed by. Thus, it has become possible to significantly improve the quality of life of patients by treating the organic lesions of endometriosis.

Furthermore, as shown in Table 13 and FIG. 9, induration of Douglas fossa was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared with Baseline (Test Example 9).

The effect of improving the induration of Douglas's fossa, which is an organic lesion in patients with endometriosis/uterine adenomyosis, has not been clinically proven by SERMs and estrogen receptor antagonists, and SR16234's This is the first effect confirmed by administration. Thus, it has become possible to significantly improve the quality of life of patients by treating the organic lesions of endometriosis.

Furthermore, as shown in Table 14 and FIG. 10, the restriction of uterine mobility was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared with Baseline (Test Example 10).

The effect of improving the limitation of uterine motility, which is an organic lesion in patients with endometriosis and adenomyosis, has not been clinically proven by SERMs and estrogen receptor antagonists, and SR16234 This is the first effect confirmed by administration. Thus, it has become possible to significantly improve the quality of life of patients by treating the organic lesions of endometriosis.

Furthermore, as shown in Table 15, the adverse events observed during the clinical study were extremely mild symptoms even after oral administration of 40 mg of SR16234 per day, and adverse events considered to be related to the administration of SR16234 were not observed. It was not confirmed (Test Example 11).

This is different from the fact that GnRH agonists and progesterone receptor agonists have been reported to have adverse events related to drug administration clinically, such as bone loss and irregular hemorrhage, for the first time after administration of SR16234. It has been confirmed. Moreover, since there is no effect on bone mass, it can be said that add-back therapy for supplementing estrogen is unnecessary. In this way, it became possible to suppress pain and significantly improve organic lesions without compromising the safety of endometriosis patients.

The estrogen receptor α inhibitor β partial agonist of the present invention is orally administrable, has low toxicity, and is excellent in safety, and therefore, for estrogen-dependent gynecological diseases such as endometriosis and uterine adenomyosis. It can be widely and effectively used as a drug to be used.

Claims (5)

The following structural formula (a);

The pain associated with gynecological diseases, and/or the gynecological diseases, which comprises, as an active ingredient, an estrogen receptor α inhibition β partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof. For the treatment of organic lesions. The gynecological disease is estrogen-dependent gynecological disease,
The therapeutic agent according to claim 1. The gynecological disease is endometriosis and/or adenomyosis uteri,
The therapeutic agent according to claim 1 or 2. The pain is menstrual pain and/or pelvic pain associated with the gynecological disorder,
The therapeutic agent according to any one of claims 1 to 3. The organic lesion is a chocolate cyst of the ovary, induration of the Douglas fossa, and/or limitation of uterine mobility,
The therapeutic agent according to any one of claims 1 to 4.

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